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Sample records for nonlinear pde formulation

  1. Nonlinear Control of Delay and PDE Systems

    NASA Astrophysics Data System (ADS)

    Bekiaris-Liberis, Nikolaos

    In this dissertation we develop systematic procedures for the control and analysis of general nonlinear systems with delays and of nonlinear PDE systems. We design predictor feedback laws (i.e., feedback laws that use the future, rather than the current state of the system) for the compensation of delays (i.e., after the control signal reaches the system for the first time, the system behaves as there were no delay at all) that can be time-varying or state-dependent, on the input and on the state of nonlinear systems. We also provide designs of predic- tor feedback laws for linear systems with constant distributed delays and known or unknown plant parameters, and for linear systems with simultaneous known or unknown constant delays on the input and the state. Moreover, we intro- duce infinite-dimensional backstepping transformations for each particular prob-lem, which enables us to construct Lyapunov-Krasovskii functionals. With the available Lyapunov-Krasovskii functionals we study stability, as well as, robust- ness of our control laws to plant uncertainties. We deal with coupled PDE-ODE systems. We consider nonlinear systems with wave actuator dynamics, for which we design a predictor inspired feedback law. We study stability of the closed-loop system either by constructing Lyapunov functionals, or using arguments of explicit solutions. We also consider linear sys- tems with distributed actuator and sensor dynamics governed by diffusion or wave PDEs, for which we design stabilizing feedback laws. We study stability of the closed-loop systems using Lyapunov functionals that we construct with the intro- duction of infinite-dimensional transformations of forwarding type. Finally, we develop a control design methodology for coupled nonlinear first-order hyperbolic PDEs through an application to automotive catalysts.

  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. PMID:22588610

  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.

  4. Large Scale Non-Linear Programming for PDE Constrained Optimization

    SciTech Connect

    VAN BLOEMEN WAANDERS, BART G.; BARTLETT, ROSCOE A.; LONG, KEVIN R.; BOGGS, PAUL T.; SALINGER, ANDREW G.

    2002-10-01

    Three years of large-scale PDE-constrained optimization research and development are summarized in this report. We have developed an optimization framework for 3 levels of SAND optimization and developed a powerful PDE prototyping tool. The optimization algorithms have been interfaced and tested on CVD problems using a chemically reacting fluid flow simulator resulting in an order of magnitude reduction in compute time over a black box method. Sandia's simulation environment is reviewed by characterizing each discipline and identifying a possible target level of optimization. Because SAND algorithms are difficult to test on actual production codes, a symbolic simulator (Sundance) was developed and interfaced with a reduced-space sequential quadratic programming framework (rSQP++) to provide a PDE prototyping environment. The power of Sundance/rSQP++ is demonstrated by applying optimization to a series of different PDE-based problems. In addition, we show the merits of SAND methods by comparing seven levels of optimization for a source-inversion problem using Sundance and rSQP++. Algorithmic results are discussed for hierarchical control methods. The design of an interior point quadratic programming solver is presented.

  5. 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.

  6. A perception- and PDE-based nonlinear transformation for processing spoken words

    NASA Astrophysics Data System (ADS)

    Qi, Yingyong; Xin, Jack

    2001-02-01

    Speech signals are often produced or received in the presence of noise, which is known to degrade the performance of a speech recognition system. In this paper, a perception- and PDE-based nonlinear transformation was developed to process spoken words in noisy environment. Our goal is to distinguish essential speech features and suppress noise so that the processed words are better recognized by a computer software. The nonlinear transformation was made on the spectrogram (short-term Fourier spectra) of speech signals, which reveals the signal energy distribution in time and frequency. The transformation reduces noise through time adaptation (reducing temporally slowly varying portions of spectra) and enhances spectral peaks (formants) by evolving a focusing quadratic fourth-order PDE. Short-term spectra of speech signals were initially divided into three (low, mid and high) frequency bands based on the critical bandwidth of human audition. An algorithm was developed to trace the upper and lower intensity envelopes of signal in each band. The difference between the upper and lower envelopes reflects the signal-to-noise (SNR) ratio of each band. Constant, low SNR signals in each band were adaptively decreased to reduce noise. Then evolution of the focusing PDE was used to enhance the spectral peaks, and further reduce noise interference. Numerical results on noisy spoken words indicated that the transformed spectral pattern of the spoken words was insensitive to noise for SNR ranging from 0 to 20 dB (decibel). The spectral distances between noisy words and original words decreased after the transformation. A numerical experiment was performed on 11 spoken words at SNR=5 dB. A noisy word is recognized numerically by computing the closest L2 spectral distance from the clean template. The experiment reached a recognition rate as high as 100%. Analyses on the properties of the transformation are provided.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. He's Frequency Formulation for Nonlinear Oscillators

    ERIC Educational Resources Information Center

    Geng, Lei; Cai, Xu-Chu

    2007-01-01

    Based on an ancient Chinese algorithm, J H He suggested a simple but effective method to find the frequency of a nonlinear oscillator. In this paper, a modified version is suggested to improve the accuracy of the frequency; two examples are given, revealing that the obtained solutions are of remarkable accuracy and are valid for the whole solution…

  12. Geometric nonlinear formulation for thermal-rigid-flexible coupling system

    NASA Astrophysics Data System (ADS)

    Fan, Wei; Liu, Jin-Yang

    2013-10-01

    This paper develops geometric nonlinear hybrid formulation for flexible multibody system with large deformation considering thermal effect. Different from the conventional formulation, the heat flux is the function of the rotational angle and the elastic deformation, therefore, the coupling among the temperature, the large overall motion and the elastic deformation should be taken into account. Firstly, based on nonlinear strain-displacement relationship, variational dynamic equations and heat conduction equations for a flexible beam are derived by using virtual work approach, and then, Lagrange dynamics equations and heat conduction equations of the first kind of the flexible multibody system are obtained by leading into the vectors of Lagrange multiplier associated with kinematic and temperature constraint equations. This formulation is used to simulate the thermal included hub-beam system. Comparison of the response between the coupled system and the uncoupled system has revealed the thermal chattering phenomenon. Then, the key parameters for stability, including the moment of inertia of the central body, the incident angle, the damping ratio and the response time ratio, are analyzed. This formulation is also used to simulate a three-link system applied with heat flux. Comparison of the results obtained by the proposed formulation with those obtained by the approximate nonlinear model and the linear model shows the significance of considering all the nonlinear terms in the strain in case of large deformation. At last, applicability of the approximate nonlinear model and the linear model are clarified in detail.

  13. Analysis of a non-linear structure by considering two non-linear formulations

    NASA Astrophysics Data System (ADS)

    Majed, R.; Raynaud, J. L.

    2003-03-01

    In recent years, modal synthesis methods have been extended for solving non-linear dynamic problems subjected to harmonic excitation. These methods are based on the notion of non-linear or linearized modes and exploited in the case of structures affected by localized non-linearity. Actually, the experimental tests executed on non-linear structures are time consuming, particularly when repeated experimental tests are needed. It is often preferable to consider new non-linear methods with a view to decrease significantly the number of attempts during prototype tests and improving the accuracy of the dynamic behaviour. This article describes two fundamental non-linear formulations based on two different strategies. The first formulation exploits the eigensolutions of the associated linear system and the dynamics characteristics of each localized non-linearity. The second formulation is based on the exploitation of the linearized eigensolutions obtained using an iterative process. This article contains a numerical and an experimental study which examines the non-linear behaviour of the structure affected by localized non-linearities. The study is intended to validate the numerical algorithm and to evaluate the problems arising from the introduction of non-linearities. The complex responses are evaluated using the iterative Newton-Raphson method and for a series of discrete frequencies. The theory has been applied to a bi-dimensional structure and consists of evaluating the harmonic responses obtained using the proposed formulations by comparing measured and calculated transfer functions.

  14. 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.

  15. Nonlinear formulation for flexible multibody system with large deformation

    NASA Astrophysics Data System (ADS)

    Liu, Jinyang; Hong, Jiazhen

    2007-02-01

    In this paper, nonlinear modeling for flexible multibody system with large deformation is investigated. Absolute nodal coordinates are employed to describe the displacement, and variational motion equations of a flexible body are derived on the basis of the geometric nonlinear theory, in which both the shear strain and the transverse normal strain are taken into account. By separating the inner and the boundary nodal coordinates, the motion equations of a flexible multibody system are assembled. The advantage of such formulation is that the constraint equations and the forward recursive equations become linear because the absolute nodal coordinates are used. A spatial double pendulum connected to the ground with a spherical joint is simulated to investigate the dynamic performance of flexible beams with large deformation. Finally, the resultant constant total energy validates the present formulation.

  16. 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.

  17. Nonlinear stability of a heterogeneous state in a PDE-ODE model for acid-mediated tumor invasion.

    PubMed

    Tao, Youshan; Tello, J Ignacio

    2016-02-01

    This work studies a general reaction-diffusion model for acid-mediated tumor invasion, where tumor cells produce excess acid that primarily kills healthy cells, and thereby invade the microenvironment. The acid diffuses and could be cleared by vasculature, and the healthy and tumor cells are viewed as two species following logistic growth with mutual competition. A key feature of this model is the density-limited diffusion for tumor cells, reflecting that a healthy tissue will spatially constrain a tumor unless shrunk. Under appropriate assumptions on model parameters and on initial data, it is shown that the unique heterogeneous state is nonlinearly stable, which implies a long-term coexistence of the healthy and tumor cells in certain parameter space. Our theoretical result suggests that acidity may play a significant role in heterogeneous tumor progression. PMID:26776259

  18. Nonlinear stability of a heterogeneous state in a PDE-ODE model for acid-mediated tumor invasion.

    PubMed

    Tao, Youshan; Tello, J Ignacio

    2016-02-01

    This work studies a general reaction-diffusion model for acid-mediated tumor invasion, where tumor cells produce excess acid that primarily kills healthy cells, and thereby invade the microenvironment. The acid diffuses and could be cleared by vasculature, and the healthy and tumor cells are viewed as two species following logistic growth with mutual competition. A key feature of this model is the density-limited diffusion for tumor cells, reflecting that a healthy tissue will spatially constrain a tumor unless shrunk. Under appropriate assumptions on model parameters and on initial data, it is shown that the unique heterogeneous state is nonlinearly stable, which implies a long-term coexistence of the healthy and tumor cells in certain parameter space. Our theoretical result suggests that acidity may play a significant role in heterogeneous tumor progression.

  19. He's iteration formulation for solving nonlinear algebraic equations

    NASA Astrophysics Data System (ADS)

    Qian, W.-X.; Ye, Y.-H.; Chen, J.; Mo, L.-F.

    2008-02-01

    Newton iteration method is sensitive to initial guess and its slope. To overcome the shortcoming, He's iteration method is used to solve nonlinear algebraic equations where Newton iteration method becomes invalid. Some examples are given, showing that the method is effective.

  20. 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

  1. Unified kinetic formulation of incoherent waves propagating in nonlinear media with noninstantaneous response

    SciTech Connect

    Garnier, Josselin; Picozzi, Antonio

    2010-03-15

    This article presents a unified kinetic formulation of partially coherent nonlinear optical waves propagating in a noninstantaneous response Kerr medium. We derive a kinetic equation that combines the weak Langmuir turbulence kinetic equation and a Vlasov-like equation within a general framework: It describes the evolution of the spectrum of a random field that exhibits a quasistationary statistics in the presence of a noninstantaneous nonlinear response. The kinetic equation sheds new light on the dynamics of partially coherent nonlinear waves and allows for a qualitative interpretation of the interplay between the noninstantaneous nonlinearity and the nonstationary statistics of the incoherent field. It is shown that the incoherent modulational instability of a random nonlinear wave can be suppressed by the noninstantaneous nonlinear response. Moreover, incoherent modulational instability can prevent the generation of spectral incoherent solitons.

  2. A Riccati type PDE for light-front higher helicity vertices

    NASA Astrophysics Data System (ADS)

    Bengtsson, Anders K. H.

    2014-09-01

    This paper is based on a curious observation about an equation related to the tracelessness constraints of higher spin gauge fields. A similar equation also occurs in the theory of continuous spin representations of the Poincaré group. Expressed in an oscillator basis for the higher spin fields, the equation becomes a non-linear partial differential operator of the Riccati type acting on the vertex functions. The consequences of the equation for the cubic vertex is investigated in the light-front formulation of higher spin theory. The vertex is fixed by the PDE up to a set of terms that can be considered as boundary data for the PDE. These terms can serve as off-shell quantum corrections.

  3. 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.

  4. ODE/PDE analysis of corneal curvature.

    PubMed

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

    2014-10-01

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

  5. A Linear PDE Approach to the Bellman Equation of Ergodic Control with Periodic Structure

    SciTech Connect

    Fujita, Y.

    2003-03-12

    In this paper we give a new proof of the existence result of Bensoussan [1, Theorem II-6.1] for the Bellman equation of ergodic control with periodic structure. This Bellman equation is a nonlinear PDE, and he constructed its solution by using the solution of a nonlinear PDE. On the contrary, our key idea is to solve two linear PDEs. Hence, we propose a linear PDE approach to this Bellman equation.

  6. 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.

  7. An affine formulation for the prediction of the effective properties of nonlinear composites and polycrystals

    NASA Astrophysics Data System (ADS)

    Masson, R.; Bornert, M.; Suquet, P.; Zaoui, A.

    2000-06-01

    Variational approaches for nonlinear elasticity show that Hill's incremental formulation for the prediction of the overall behaviour of heterogeneous materials yields estimates which are too stiff and may even violate rigorous bounds. This paper aims at proposing an alternative 'affine' formulation, based on a linear thermoelastic comparison medium, which could yield softer estimates. It is first described for nonlinear elasticity and specified by making use of Hashin-Shtrikman estimates for the linear comparison composite; the associated affine self-consistent predictions are satisfactorily compared with incremental and tangent ones for power-law creeping polycrystals. Comparison is then made with the second-order procedure (Ponte Castañeda, P., 1996. Exact second-order estimates for the effective mechanical properties of nonlinear composite materials. J. Mech. Phys. Solids, 44 (6), 827-862) and some limitations of the affine method are pointed out; explicit comparisons between different procedures are performed for isotropic, two-phase materials. Finally, the affine formulation is extended to history-dependent behaviours; application to the self-consistent modelling of the elastoplastic behaviour of polycrystals shows that it offers an improved alternative to Hill's incremental formulation.

  8. 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.

  9. 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.

  10. Nonlinear dynamic analysis of multi-base seismically isolated structures with uplift potential I: formulation

    NASA Astrophysics Data System (ADS)

    Tsopelas, Panos C.; Roussis, Panayiotis C.; Constantinou, Michael C.

    2009-09-01

    The complexity of modern seismically isolated structures requires the analysis of the structural system and the isolation system in its entirety and the ability to capture potential discontinuous phenomena such as isolator uplift and their effects on the superstructures and the isolation hardware. In this paper, an analytical model is developed and a computational algorithm is formulated to analyze complex seismically isolated superstructures even when undergoing highly-nonlinear phenomena such as uplift. The computational model has the capability of modeling various types of isolation devices with strong nonlinearities, analyzing multiple superstructures (up to five separate superstructures) on multiple bases (up to five bases), and capturing the effects of lateral loads on bearing axial forces, including bearing uplift. The model developed herein has been utilized to form the software platform 3D-BASIS-ME-MB, which provides the practicing engineering community with a versatile tool for analysis and design of complex structures with modern isolation systems.

  11. Nonlinear aspects of high heat flux nucleate boiling heat transfer. Part 1, Formulation

    SciTech Connect

    Sadasivan, P.; Unal, C.; Nelson, R.

    1994-04-01

    This paper outlines the essential details of the formulation and numerical implementation of a model used to study nonlinear aspects of the macrolayer-controlled heat transfer process associated with high heat flux nucleate boiling and the critical heat flux. The model addresses the three-dimensional transient conduction heat transfer process within the problem domain comprised of the macrolayer and heater. Heat dissipation from the heater is modeled as the sum of transient transport into the macrolayer, and the heat loss resulting from evaporation of menisci associated with vapor stems.

  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. Aeroelastic coupling of geometrically nonlinear structures and linear unsteady aerodynamics: Two formulations

    NASA Astrophysics Data System (ADS)

    Demasi, L.; Livne, E.

    2009-07-01

    Two different time domain formulations of integrating commonly used frequency-domain unsteady aerodynamic models based on a modal approach with full order finite element models for structures with geometric nonlinearities are presented. Both approaches are tailored to flight vehicle configurations where geometric stiffness effects are important but where deformations are moderate, flow is attached, and linear unsteady aerodynamic modeling is adequate, such as low aspect ratio wings or joined-wing and strut-braced wings at small to moderate angles of attack. Results obtained using the two approaches are compared using both planar and non-planar wing configurations. Sub-critical and post-flutter speeds are considered. It is demonstrated that the two methods lead to the same steady solution for the sub-critical case after the transients subside. It is also shown that the two methods predict the amplitude and frequency of limit cycle oscillation (when present) with the same accuracy.

  15. 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.

  16. 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.

  17. A nonlinear solid shell element formulation for analysis of composite panels under blast wave pressure loading

    NASA Astrophysics Data System (ADS)

    Park, Hun

    A comprehensive methodology to accurately predict the dynamic response of composite panels under blast wave pressure loading has been successfully developed for the first time. It includes the modeling of geometrically nonlinear dynamic effect, progressive failure and strain-rate effect on constitutive equation and strength. For dynamic analysis, a nonlinear solid shell element formulation is combined with the trapezoidal rule for numerical integration in time. The progressive damage incorporates the effect of the material failure, such as fiber failure, matrix cracking and fiber-matrix shearing failure on the stiffness and strength. Material degradation models based on the rule of mixtures are proposed for each failure mode. To implement the strain-rate effect on the constitutive equation of the material, a viscoplastic model is adopted. In this model, three material parameters are determined by conducting uniaxial tension tests on off-axis specimen. The effect of strain rates on material strength is implemented via the linear least square fit of the test data. A key ingredient of the analysis is a geometrically nonlinear solid shell element based on the assumed strain formulation to alleviate element locking. In this approach, the composite shell is treated as a three-dimensional solid. Accordingly, the change of shell thickness is allowed and the kinematics of deformation is described by six vector components at a point on the shell midsurface. The mass matrix always remains constant during the analysis. Example problems under static and dynamic loadings are solved to investigate the behavior of composite panels undergoing large deformation while experiencing material damage. The analysis results are compared with the test data available. Results of the numerical analysis show that the effect of the progressive failure and strain-rates on structural responses are considerable. For a composite plate under static pressure loadings, maximum displacement and

  18. 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.

  19. From stiffness to strength in site response predictions: Formulation and validation of a hybrid hyperbolic nonlinear soil model

    NASA Astrophysics Data System (ADS)

    Asimaki, D.; Shi, J.

    2015-12-01

    Nonlinear site response analyses are becoming an increasingly important component of simulated ground motions intended for engineering applications. For regional-scale problems where geotechnical data are sparse, the challenge lies in computing nonlinear ground deformation to very strong ground shaking using a very small number of input parameters. We have developed a nonlinear model that addresses these issues: it simultaneously captures the soil's low-strain stiffness and large-strain strength of soil, and yields reliable predictions of soil response to weak and strong shaking using as sole input the shear wave velocity profile. We here present the formulation of the model and an extensive validation study based on downhole array recordings, with peak ground acceleration ranging from 0.01-0.9g. We also show that our model, referred to as hybrid hyperbolic, outperforms existing nonlinear formulations and simplified site response analyses widely used in practice for ground motions that induce more than 0.02% of soil strain (roughly equivalent to PGA higher than 0.02g). In addition to site-specific response predictions at sites with limited site characterization, the hybrid-hyperbolic model can help improve site amplification factors of ground motion prediction equations (GMPEs) by complementing the empirical data with simulated site response analyses for very strong ground shaking; as well as physics-based ground motion simulations, particularly for deeper sedimentary sites with low resonant frequencies.

  20. Mathematical formulation and analysis of the nonlinear system reconstruction of the online image-guided adaptive control of hyperthermia

    PubMed Central

    Cheng, Kung-Shan; Dewhirst, Mark W.; Stauffer, Paul F.; Das, Shiva

    2010-01-01

    Purpose: A nonlinear system reconstruction can theoretically provide timely system reconstruction when designing a real-time image-guided adaptive control for multisource heating for hyperthermia. This clinical need motivates an analysis of the essential mathematical characteristics and constraints of such an approach. Methods: The implicit function theorem (IFT), the Karush–Kuhn–Tucker (KKT) necessary condition of optimality, and the Tikhonov–Phillips regularization (TPR) were used to analyze and determine the requirements of the optimal system reconstruction. Two mutually exclusive generic approaches were analyzed to reconstruct the physical system: The traditional full reconstruction and the recently suggested partial reconstruction. Rigorous mathematical analysis based on IFT, KKT, and TPR was provided for all four possible nonlinear reconstructions: (1) Nonlinear noiseless full reconstruction, (2) nonlinear noisy full reconstruction, (3) nonlinear noiseless partial reconstruction, and (4) nonlinear noisy partial reconstruction, when a class of nonlinear formulations of system reconstruction is employed. Results: Effective numerical algorithms for solving each of the aforementioned four nonlinear reconstructions were introduced and formal derivations and analyses were provided. The analyses revealed the necessity of adding regularization when partial reconstruction is used. Regularization provides the theoretical support for one to uniquely reconstruct the optimal system. It also helps alleviate the negative influences of unavoidable measurement noise. Both theoretical analysis and numerical examples showed the importance of having a good initial guess for accomplishing nonlinear system reconstruction. Conclusions: Regularization is mandatory for partial reconstruction to make it well posed. The Tikhonov–Phillips regularized Gauss–Newton algorithm has nice theoretical performance for partial reconstruction of systems with and without noise. The

  1. 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.

  2. 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.

  3. 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.

  4. 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. PMID:26611112

  5. Finite-element formulation for the analysis of interfaces, nonlinear and large displacement problems in geotechnical engineering

    NASA Astrophysics Data System (ADS)

    Zeevaert, A. E.

    1980-03-01

    A mathematical formulation to model the behavior under load of a reinforced soil system, where a fabric is placed over a soft soil and covered with stone for use as a temporary haul road is discussed. This approach is used to improve the behavior of temporary roadways, particularly where very soft soils are encountered. The stress distribution and the load-deformation characteristics of the soil-fabric system for varying geometries and material properties are defined. Included in the mathematical formulation are such features as: nonlinear behavior of the soil and fabric materials, friction parameters of the interface, tension characteristics of the fabric materials, large displacements in finite deformation, "no tension" conditions of the cohesionless materials, and yielding of plastic materials. The mathematical model is a more complete approximation of the actual fabric-soil system than is presently available.

  6. 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.

  7. 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.

  8. 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.

  9. A Yeast-Based Chemical Screen Identifies a PDE Inhibitor That Elevates Steroidogenesis in Mouse Leydig Cells via PDE8 and PDE4 Inhibition

    PubMed Central

    Demirbas, Didem; Wyman, Arlene R.; Shimizu-Albergine, Masami; Cakici, Ozgur; Beavo, Joseph A.; Hoffman, Charles S.

    2013-01-01

    A cell-based high-throughput screen (HTS) was developed to detect phosphodiesterase 8 (PDE8) and PDE4/8 combination inhibitors. By replacing the Schizosaccharomyces pombe PDE gene with the murine PDE8A1 gene in strains lacking adenylyl cyclase, we generated strains whose protein kinase A (PKA)-stimulated growth in 5-fluoro orotic acid (5FOA) medium reflects PDE8 activity. From our previously-identified PDE4 and PDE7 inhibitors, we identified a PDE4/8 inhibitor that allowed us to optimize screening conditions. Of 222,711 compounds screened, ∼0.2% displayed composite Z scores of >20. Additional yeast-based assays using the most effective 367 compounds identified 30 candidates for further characterization. Among these, compound BC8-15 displayed the lowest IC50 value for both PDE4 and PDE8 inhibition in in vitro enzyme assays. This compound also displays significant activity against PDE10A and PDE11A. BC8-15 elevates steroidogenesis in mouse Leydig cells as a single pharmacological agent. Assays using BC8-15 and two structural derivatives support a model in which PDE8 is a primary regulator of testosterone production by Leydig cells, with an additional role for PDE4 in this process. BC8-15, BC8-15A, and BC8-15C, which are commercially available compounds, display distinct patterns of activity against PDE4, PDE8, PDE10A, and PDE11A, representing a chemical toolkit that could be used to examine the biological roles of these enzymes in cell culture systems. PMID:23967182

  10. 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.

  11. 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.

  12. 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

  13. Application of nonlinear regression in the development of a wide range formulation for HCFC-22

    NASA Astrophysics Data System (ADS)

    Kamei, A.; Beyerlein, S. W.; Jacobsen, R. T.

    1995-09-01

    An equation of state has been developed for HCFC-22 for temperatures from the triple point (115.73 K) to 550 K, at pressures up to 60 MPa. Based on comparisons between experimental data and calculated properties, the accuracy of the wide-range equation of state is ±0.1% in density, ±0.3% in speed of sound, and ±1.0% in isobaric heat capacity, except in the critical region. Nonlinear fitting techniques were used to fit a liquid equation of state based on P-ρ-T, speed of sound, and isobaric heat capacity data. Properties calculated from the liquid equation of state were then used to expand the range of validity of the wide range equation of state for HCFC-22.

  14. Emerging biology of PDE10A.

    PubMed

    Wilson, Lindsay S; Brandon, Nicholas J

    2015-01-01

    Cyclic AMP and cyclic GMP are essential second messengers that regulate multiple signaling pathways in virtually all cell types. Their accumulation in cells is finely regulated by cyclic nucleotide phosphodiesterases (PDEs), the only enzymes that can degrade these signaling molecules and thus provide exquisite control over intracellular signaling processes. One PDE family, PDE10A, is highly enriched in the brain and its unique expression profile in specific brain regions of interest, in particular to antipsychotic treatment, has made it an attractive therapeutic target for the treatment of schizophrenia. However, after a Phase II trial failure of a selective PDE10A inhibitor for the treatment of schizophrenia, it has encouraged the field to reexamine the role of this enzyme in the brain, and the possible CNS disorders in which PDE10A inhibition could be therapeutic. We will review the localization of PDE10A, both within the brain and the neuron and discuss how its role in regulating cAMP and cGMP accumulation modulates intracellular signaling pathways. Since this cellular signaling has best been documented in the striatum, we will focus our discussion of PDE10A in the context of disorders that affect the basal ganglia, including psychiatric disorders such as bipolar disorder and autism spectrum disorders and the movement disorders, including Parkinson's disease and Huntington's disease.

  15. 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

  16. 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.

  17. Nonlinear finite element formulation for the large displacement analysis in multibody system dynamics

    NASA Technical Reports Server (NTRS)

    Rismantab-Sany, J.; Chang, B.; Shabana, A. A.

    1989-01-01

    A total Lagrangian finite element formulation for the deformable bodies in multibody mechanical systems that undergo finite relative rotations is developed. The deformable bodies are discretized using finite element methods. The shape functions that are used to describe the displacement field are required to include the rigid body modes that describe only large translational displacements. This does not impose any limitations on the technique because most commonly used shape functions satisfy this requirement. The configuration of an element is defined using four sets of coordinate systems: Body, Element, Intermediate element, Global. The body coordinate system serves as a unique standard for the assembly of the elements forming the deformable body. The element coordinate system is rigidly attached to the element and therefore it translates and rotates with the element. The intermediate element coordinate system, whose axes are initially parallel to the element axes, has an origin which is rigidly attached to the origin of the body coordinate system and is used to conveniently describe the configuration of the element in undeformed state with respect to the body coordinate system.

  18. Characterization of the cellular activity of PDE 4 inhibitors using two novel PDE 4 reporter cell lines.

    PubMed

    Wunder, Frank; Quednau, Ramona; Geerts, Andreas; Barg, Martina; Tersteegen, Adrian

    2013-10-01

    We report here the generation and pharmacological characterization of two novel PDE 4B1 and PDE 4D3 reporter cell lines. Intracellular cAMP levels are monitored in these cells by a cAMP-sensitive biosensor. We used the recombinant PDE 4B1 and PDE 4D3 reporter cell lines to characterize the cellular effects of various competitive and allosteric PDE 4 inhibitors. In addition, we compared the cellular activity of these PDE 4 inhibitors with the in vitro inhibition of full-length PDE 4D3 and a truncated enzyme comprising the PDE 4D3 catalytic domain. Two different groups of PDE 4 inhibitors could be identified. The first group, including competitive inhibitors like roflumilast, cilomilast and piclamilast, shows similar in vitro activity on full-length and truncated PDE 4D3 and comparably low cellular activity. The second group, including the allosteric inhibitors PMNPQ, D159153, and D159404, shows much better inhibition of full-length versus truncated PDE 4D3. In addition, these compounds show high cellular activity. Our data obtained with the prototype PDE 4 inhibitor rolipram show that rolipram has properties intermediate between the two groups. The results imply that these novel PDE 4 reporter cell lines are well-suited for the characterization of the cellular activity of PDE 4 inhibitors and may also support a better understanding of the complex PDE 4 pharmacology.

  19. PDE-10A inhibitors as insulin secretagogues.

    PubMed

    Cantin, Louis-David; Magnuson, Steven; Gunn, David; Barucci, Nicole; Breuhaus, Marina; Bullock, William H; Burke, Jennifer; Claus, Thomas H; Daly, Michelle; Decarr, Lynn; Gore-Willse, Ann; Hoover-Litty, Helana; Kumarasinghe, Ellalahewage S; Li, Yaxin; Liang, Sidney X; Livingston, James N; Lowinger, Timothy; Macdougall, Margit; Ogutu, Herbert O; Olague, Alan; Ott-Morgan, Ronda; Schoenleber, Robert W; Tersteegen, Adrian; Wickens, Philip; Zhang, Zhonghua; Zhu, Jian; Zhu, Lei; Sweet, Laurel J

    2007-05-15

    Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured. PMID:17400452

  20. A high-order, purely frequency based harmonic balance formulation for continuation of periodic solutions: The case of non-polynomial nonlinearities

    NASA Astrophysics Data System (ADS)

    Karkar, Sami; Cochelin, Bruno; Vergez, Christophe

    2013-02-01

    In this paper, we extend the method proposed by Cochelin and Vergez [A high order purely frequency-based harmonic balance formulation for continuation of periodic solutions, Journal of Sound and Vibration, 324 (2009) 243-262] to the case of non-polynomial nonlinearities. This extension allows for the computation of branches of periodic solutions of a broader class of nonlinear dynamical systems. The principle remains to transform the original ODE system into an extended polynomial quadratic system for an easy application of the harmonic balance method (HBM). The transformation of non-polynomial terms is based on the differentiation of state variables with respect to the time variable, shifting the nonlinear non-polynomial nonlinearity to a time-independent initial condition equation, not concerned with the HBM. The continuation of the resulting algebraic system is here performed by the asymptotic numerical method (high order Taylor series representation of the solution branch) using a further differentiation of the non-polynomial algebraic equation with respect to the path parameter. A one dof vibro-impact system is used to illustrate how an exponential nonlinearity is handled, showing that the method works at very high order, 1000 in that case. Various kinds of nonlinear functions are also treated, and finally the nonlinear free pendulum is addressed, showing that very accurate periodic solutions can be computed with the proposed method.

  1. Nonlinear composites: a linearization procedure, exact to second-order in contrast and for which the strain-energy and affine formulations coincide

    NASA Astrophysics Data System (ADS)

    Lahellec, Noël; Suquet, Pierre

    2004-09-01

    This Note presents a new approximate scheme for nonlinear composites. The approximation which is made preserves certain features of the original second-order scheme of Ponte Castañeda, exactness to second-order in the contrast and existence of an effective energy, but improves on one drawback, which is the gap between the strain-energy formulation and the affine formulation. A numerical example shows the accuracy of the present method. To cite this article: N. Lahellec, P. Suquet, C. R. Mecanique 332 (2004).

  2. 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

  3. 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.

  4. 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.

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

    PubMed Central

    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 cell

  6. 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

  7. 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

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

    PubMed Central

    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 cell

  9. Generalized hamilton-jacobi-bellman formulation -based neural network control of affine nonlinear discrete-time systems.

    PubMed

    Chen, Zheng; Jagannathan, Sarangapani

    2008-01-01

    In this paper, we consider the use of nonlinear networks towards obtaining nearly optimal solutions to the control of nonlinear discrete-time (DT) systems. The method is based on least squares successive approximation solution of the generalized Hamilton-Jacobi-Bellman (GHJB) equation which appears in optimization problems. Successive approximation using the GHJB has not been applied for nonlinear DT systems. The proposed recursive method solves the GHJB equation in DT on a well-defined region of attraction. The definition of GHJB, pre-Hamiltonian function, HJB equation, and method of updating the control function for the affine nonlinear DT systems under small perturbation assumption are proposed. A neural network (NN) is used to approximate the GHJB solution. It is shown that the result is a closed-loop control based on an NN that has been tuned a priori in offline mode. Numerical examples show that, for the linear DT system, the updated control laws will converge to the optimal control, and for nonlinear DT systems, the updated control laws will converge to the suboptimal control. PMID:18269941

  10. Zero-sum two-player game theoretic formulation of affine nonlinear discrete-time systems using neural networks.

    PubMed

    Mehraeen, Shahab; Dierks, Travis; Jagannathan, S; Crow, Mariesa L

    2013-12-01

    In this paper, the nearly optimal solution for discrete-time (DT) affine nonlinear control systems in the presence of partially unknown internal system dynamics and disturbances is considered. The approach is based on successive approximate solution of the Hamilton-Jacobi-Isaacs (HJI) equation, which appears in optimal control. Successive approximation approach for updating control and disturbance inputs for DT nonlinear affine systems are proposed. Moreover, sufficient conditions for the convergence of the approximate HJI solution to the saddle point are derived, and an iterative approach to approximate the HJI equation using a neural network (NN) is presented. Then, the requirement of full knowledge of the internal dynamics of the nonlinear DT system is relaxed by using a second NN online approximator. The result is a closed-loop optimal NN controller via offline learning. A numerical example is provided illustrating the effectiveness of the approach. PMID:24273142

  11. PDE4B as a microglia target to reduce neuroinflammation.

    PubMed

    Pearse, Damien D; Hughes, Zoë A

    2016-10-01

    The importance of microglia in immune homeostasis within the brain is undisputed. Their role in a diversity of neurological and psychiatric diseases as well as CNS injury is the subject of much investigation. Cyclic adenosine monophosphate (AMP) is a critical regulator of microglia homeostasis; as the predominant negative modulator of cyclic AMP signaling within microglia, phosphodiesterase 4 (PDE4) represents a promising target for modulating immune function. PDE4 expression is regulated by inflammation, and in turn, PDE4 inhibition can alter microglia reactivity. As the prototypic PDE4 inhibitor, rolipram, was tested clinically in the 1980s, drug discovery and clinical development of PDE4 inhibitors have been severely hampered by tolerability issues involving nausea and emesis. The two PDE4 inhibitors approved for peripheral inflammatory disorders (roflumilast and apremilast) lack brain penetration and are dose-limited by side effects making them unsuitable for modulating microglial function. Subtype selective inhibitors targeting PDE4B are of high interest given the critical role PDE4B plays in immune function versus the association of PDE4D with nausea and emesis. The challenges and requirements for successful development of a novel brain-penetrant PDE4B inhibitor are discussed in the context of early clinical development strategies. Furthermore, the challenges of monitoring the state of microglia in vivo are highlighted, including a description of the currently available tools and their limitations. Continued drug discovery efforts to identify safe and well-tolerated, brain-penetrant PDE4 inhibitors are a reflection of the confidence in the rationale for modulation of this target to produce meaningful therapeutic benefit in a wide range of neurological conditions and injury. GLIA 2016;64:1698-1709. PMID:27038323

  12. 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.

  13. The numerical simulation of non-linear non-radial stellar pulsations: a conservative formulation of gravity

    NASA Astrophysics Data System (ADS)

    Glatzel, W.; Chernigovski, S.

    2016-04-01

    The simulation of finite amplitude stellar pulsations and the theoretical determination of the final fate of violently unstable stellar models require the complete consideration of the mechanics and thermodynamics of a star. In particular, non-linear effects need to be taken into account. Numerical methods for the study of non-linear pulsations are available so far only for spherically symmetric radial pulsations. This paper is meant as a first step towards a numerical scheme which allows for the representation of non-radial non-linear stellar pulsations. A characteristic of stellar pulsations are dominant gravitational and thermal energies exceeding the kinetic energy by several orders of magnitude. As a consequence, numerical simulations of stellar pulsations require an extremely high accuracy, which can be met only by sophisticated intrinsically strictly conservative numerical schemes. Whether gravity can be represented numerically in a fully conservative way is the subject of this study. A fully conservative discrete form of gravity is derived explicitly and proven to satisfy all common conservation laws intrinsically.

  14. 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.

  15. 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.

  16. 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. PMID:25837309

  17. 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.

  18. PDE and cognitive processing: beyond the memory domain.

    PubMed

    Heckman, P R A; Blokland, A; Ramaekers, J; Prickaerts, J

    2015-03-01

    Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Both cAMP and cGMP signaling are essential for a variety of cellular functions and exert their effects both pre- and post-synaptically. Either of these second messengers relays and amplifies incoming signals at receptors on the cell surface making them important elements in signal transduction cascades and essential in cellular signaling in a variety of cell functions including neurotransmitter release and neuroprotection. Consequently, these processes can be influenced by PDE-Is as they increase cAMP and/or cGMP concentrations. PDE-Is have been considered as possible therapeutic agents to treat impaired memory function linked to several brain disorders, including depression, schizophrenia and Alzheimer's disease (AD). This review will, however, focus on the possible role of phosphodiesterases (PDEs) in cognitive decline beyond the memory domain. Here we will discuss the involvement of PDEs on three related domains: attention, information filtering (sensory- and sensorimotor gating) and response inhibition (drug-induced hyperlocomotion). Currently, these are emerging cognitive domains in the field of PDE research. Here we discuss experimental studies and the potential beneficial effects of PDE-I drugs on these cognitive domains, as effects of PDE-Is on these domains could potentially influence effects on memory performance. Overall, PDE4 seems to be the most promising target for all domains discussed in this review.

  19. Novel mutations in PDE6B causing human retinitis pigmentosa

    PubMed Central

    Cheng, Lu-Lu; Han, Ru-Yi; Yang, Fa-Yu; Yu, Xin-Ping; Xu, Jin-Ling; Min, Qing-Jie; Tian, Jie; Ge, Xiang-Lian; Zheng, Si-Si; Lin, Ye-Wen; Zheng, Yi-Han; Qu, Jia; Gu, Feng

    2016-01-01

    AIM To identify the genetic defects of a Chinese patient with sporadic retinitis pigmentosa (RP). METHODS Ophthalmologic examinations were performed on the sporadic RP patient, 144 genes associated with retinal diseases were scanned with capture next generation sequencing (CNGS) approach. Two heterozygous mutations in PDE6B were confirmed in the pedigree by Sanger sequencing subsequently. The carrier frequency of PDE6B mutations of reported PDE6B mutations based on the available two public exome databases (1000 Genomes Project and ESP6500 Genomes Project) and one in-house exome database was investigated. RESULTS We identified compound heterozygosity of two novel nonsense mutations c.1133G>A (p.W378X) and c.2395C>T (p.R799X) in PDE6B, one reported causative gene for RP. Neither of the two mutations in our study was presented in three exome databases. Two mutations (p.R74C and p.T604I) in PDE6B have relatively high frequencies in the ESP6500 and in-house databases, respectively, while no common dominant mutation in each of the database or across all databases. CONCLUSION We demonstrates that compound heterozygosity of two novel nonsense mutations in PDE6B could lead to RP. These results collectively point to enormous potential of next-generation sequencing in determining the genetic etiology of RP and how various mutations in PDE6B contribute to the genetic heterogeneity of RP. PMID:27588261

  20. Accurate investigation of lateral vibrations of a quintic nonlinear beam on an elastic foundation: Using an exact formulation of the beam curvature

    NASA Astrophysics Data System (ADS)

    Sedighi, H. M.; Shirazi, K. H.

    2014-11-01

    This article attains a new formulation of beam vibrations on an elastic foundation with quintic nonlinearity, including exact expressions for the beam curvature. To achieve a proper design of the beam structures, it is essential to realize how the beam vibrates in its transverse mode, which, in turn, yields the natural frequency of the system. In this direction, a powerful analytical method called the parameter expansion method is employed to obtain the exact solution of the frequency-amplitude relationship. It is clearly shown that the first term in series expansions is sufficient to produce a highly accurate approximation of the above-mentioned system. Finally, the accuracy of the present analytic procedure is evaluated through comparisons with numerical calculations.

  1. A multi-target antisense approach against PDE4 and PDE7 reduces smoke-induced lung inflammation in mice

    PubMed Central

    Fortin, Marylène; D'Anjou, Hélène; Higgins, Marie-Ève; Gougeon, Jasmine; Aubé, Paméla; Moktefi, Kamel; Mouissi, Sonia; Séguin, Serge; Séguin, Rosanne; Renzi, Paolo M; Paquet, Luc; Ferrari, Nicolay

    2009-01-01

    Background Recent development in the field of COPD has focused on strategies aimed at reducing the underlying inflammation through selective inhibition of the phosphodiesterase type IV (PDE4) isoform. Although the anti-inflammatory and bronchodilator activity of selective PDE4 inhibitors has been well documented, their low therapeutic ratio and dose-dependent systemic side effects have limited their clinical utility. This study examined the effect of 2'-deoxy-2'-Fluoro-β-D-Arabinonucleic Acid (FANA)-containing antisense oligonucleotides (AON) targeting the mRNA for the PDE4B/4D and 7A subtypes on lung inflammatory markers, both in vitro and in vivo. Methods Normal human bronchial epithelial (NHBE) cells were transfected with FANA AON against PDE4B/4D and 7A alone or in combination. mRNA levels for target PDE subtypes, as well as secretion of pro-inflammatory chemokines were then measured following cell stimulation. Mice were treated with combined PDE4B/4D and 7A AON via endo-tracheal delivery, or with roflumilast via oral delivery, and exposed to cigarette smoke for one week. Target mRNA inhibition, as well as influx of inflammatory cells and mediators were measured in lung lavages. A two-week smoke exposure protocol was also used to test the longer term potency of PDE4B/4D and 7A AONs. Results In NHBE cells, PDE4B/4D and 7A AONs dose-dependently and specifically inhibited expression of their respective target mRNA. When used in combination, PDE4B/4D and 7A AONs significantly abrogated the cytokine-induced secretion of IL-8 and MCP-1 to near baseline levels. In mice treated with combined PDE4B/4D and 7A AONs and exposed to cigarette smoke, significant protection against the smoke-induced recruitment of neutrophils and production of KC and pro-MMP-9 was obtained, which was correlated with inhibition of target mRNA in cells from lung lavages. In this model, PDE AONs exerted more potent and broader anti-inflammatory effects against smoke-induced lung inflammation

  2. 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.

  3. 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.

  4. Scissors implementation within length-gauge formulations of the frequency-dependent nonlinear optical response of semiconductors

    NASA Astrophysics Data System (ADS)

    Nastos, F.; Olejnik, B.; Schwarz, K.; Sipe, J. E.

    2005-07-01

    We show that previous calculations of the nonlinear optical response of semiconductors using the “length-gauge” approach of Aversa and Sipe[Phys. Rev. B 52, 14636 (1995)] have incorrectly implemented the scissors correction. Previous calculations have first modified the expressions such that the crystal momentum position operator interband matrix elements rnma(k) and their generalized k -derivatives rnm;ba(k) are written in terms of the local density approximation (LDA) momentum matrix elements and energy eigenvalues, which are then adjusted to account for the scissors correction. This method is incorrect as it violates specific sum rules. We give a consistent implementation that respects the sum rules: rnma(k) and rnm;ba(k) , when written in terms of momentum matrix elements and energy eigenvalues, should be evaluated within Kohn-Sham LDA and not with the scissored one. Calculated spectra via full potential augmented plane wave plus local orbital band structures for the second-harmonic generation tensor χ2xyz(-2ω;ω,ω) show that the errors in previous calculations are approximately 39% and 28% for GaAs and GaP, respectively.

  5. 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.

  6. Novel Roflumilast analogs as soft PDE4 inhibitors.

    PubMed

    Boland, Sandro; Alen, Jo; Bourin, Arnaud; Castermans, Karolien; Boumans, Nicki; Panitti, Laura; Vanormelingen, Jessica; Leysen, Dirk; Defert, Olivier

    2014-09-15

    PDE4 inhibitors are of high interest for treatment of a wide range of inflammatory or autoimmune diseases. Their potential however has not yet been realized due to target-associated side effects, resulting in a low therapeutic window. We herein report the design, synthesis and evaluation of novel PDE4 inhibitors containing a γ-lactone structure. Such molecules are designed to undergo metabolic inactivation when entering circulation, thereby limiting systemic exposure and reducing the risk for side effects. The resulting inhibitors were highly active on both PDE4B1 and PDE4D2 and underwent rapid degradation in human plasma by paraoxonase 1. In contrast, their metabolites displayed markedly reduced permeability and/or on-target activity.

  7. 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.

  8. Intramolecular signaling in tandem-GAF domains from PDE5 and PDE10 studied with a cyanobacterial adenylyl cyclase reporter.

    PubMed

    Banjac, Ana; Zimmermann, Markus O; Boeckler, Frank M; Kurz, Ursula; Schultz, Anita; Schultz, Joachim E

    2012-03-01

    The dimeric mammalian phosphodiesterases (PDEs) are regulated by N-terminal domains. In PDE5, the GAF-A subdomain of a GAF-tandem (GAF-A and -B) binds the activator cGMP and in PDE10 GAF-B binds cAMP. GAF-tandem chimeras of PDE5 and 10 in which the 36 aa linker helix between GAF-A and -B was swapped lost allosteric regulation of a reporter adenylyl cyclase. In 16 consecutive constructs we substituted the PDE10 linker with that from PDE5. An initial stretch of 10 amino acids coded for isoform specificity. A C240Y substitution uncoupled cyclase activity from regulation, whereas C240F, L or G did not. The C240Y substitution increased basal activity to stimulated levels. Notably, over the next 12 substitutions basal cyclase activity decreased linearly. Further targeted substitutions were based on homology modeling using the PDE2 structure. No combination of substitutions within the initial 10 linker residues caused loss of regulation. The full 10 aa stretch was required. Modeling indicated a potential interaction of the linker with a loop from GAF-A. To interrupt H-bonding a glycine substitution of the loop segment was generated. Despite reduction of basal activity, loss of regulation was maintained. Possibly, the orientation of the linker helix is determined by formation of the dimer at the initial linker segment. Downstream deflections of the linker helix may have caused loss of regulation.

  9. 2d PDE Linear Symmetric Matrix Solver

    1983-10-01

    ICCG2 (Incomplete Cholesky factorized Conjugate Gradient algorithm for 2d symmetric problems) was developed to solve a linear symmetric matrix system arising from a 9-point discretization of two-dimensional elliptic and parabolic partial differential equations found in plasma physics applications, such as resistive MHD, spatial diffusive transport, and phase space transport (Fokker-Planck equation) problems. These problems share the common feature of being stiff and requiring implicit solution techniques. When these parabolic or elliptic PDE''s are discretized withmore » finite-difference or finite-element methods,the resulting matrix system is frequently of block-tridiagonal form. To use ICCG2, the discretization of the two-dimensional partial differential equation and its boundary conditions must result in a block-tridiagonal supermatrix composed of elementary tridiagonal matrices. The incomplete Cholesky conjugate gradient algorithm is used to solve the linear symmetric matrix equation. Loops are arranged to vectorize on the Cray1 with the CFT compiler, wherever possible. Recursive loops, which cannot be vectorized, are written for optimum scalar speed. For matrices lacking symmetry, ILUCG2 should be used. Similar methods in three dimensions are available in ICCG3 and ILUCG3. A general source containing extensions and macros, which must be processed by a pre-compiler to obtain the standard FORTRAN source, is provided along with the standard FORTRAN source because it is believed to be more readable. The pre-compiler is not included, but pre-compilation may be performed by a text editor as described in the UCRL-88746 Preprint.« less

  10. 2d PDE Linear Asymmetric Matrix Solver

    1983-10-01

    ILUCG2 (Incomplete LU factorized Conjugate Gradient algorithm for 2d problems) was developed to solve a linear asymmetric matrix system arising from a 9-point discretization of two-dimensional elliptic and parabolic partial differential equations found in plasma physics applications, such as plasma diffusion, equilibria, and phase space transport (Fokker-Planck equation) problems. These equations share the common feature of being stiff and requiring implicit solution techniques. When these parabolic or elliptic PDE''s are discretized with finite-difference or finite-elementmore » methods, the resulting matrix system is frequently of block-tridiagonal form. To use ILUCG2, the discretization of the two-dimensional partial differential equation and its boundary conditions must result in a block-tridiagonal supermatrix composed of elementary tridiagonal matrices. A generalization of the incomplete Cholesky conjugate gradient algorithm is used to solve the matrix equation. Loops are arranged to vectorize on the Cray1 with the CFT compiler, wherever possible. Recursive loops, which cannot be vectorized, are written for optimum scalar speed. For problems having a symmetric matrix ICCG2 should be used since it runs up to four times faster and uses approximately 30% less storage. Similar methods in three dimensions are available in ICCG3 and ILUCG3. A general source, containing extensions and macros, which must be processed by a pre-compiler to obtain the standard FORTRAN source, is provided along with the standard FORTRAN source because it is believed to be more readable. The pre-compiler is not included, but pre-compilation may be performed by a text editor as described in the UCRL-88746 Preprint.« less

  11. PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease

    PubMed Central

    Teich, Andrew F.; Sakurai, Mikako; Patel, Mitesh; Holman, Cameron; Saeed, Faisal; Fiorito, Jole; Arancio, Ottavio

    2016-01-01

    Phosphodiesterase 5 (PDE5) is a critical component of the cGMP-PKG axis of cellular signaling in neurons, and inhibition of PDE5 has been shown to be therapeutic in a wide range of neurologic conditions in animal models. However, enthusiasm for PDE5 inhibitors in humans is limited by data suggesting that PDE5 may not exist in human neurons. Here, we first show that past attempts to quantify PDE5 mRNA were flawed due to the use of incorrect primers, and that when correct primers are used, PDE5 mRNA is detectable in human brain tissue. We then show that PDE5 protein exists in human brain by western blot and ELISA. Most importantly, we performed immunohistochemistry and demonstrate that PDE5 is present in human neurons. We hope that this work will trigger a renewed interest in the development of PDE5 inhibitors for neurologic disease. PMID:26967220

  12. PDE-5 Inhibitors for BPH-Associated LUTS.

    PubMed

    Brousil, Philip; Shabbir, Majid; Zacharakis, E; Sahai, Arun

    2015-01-01

    Lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH-LUTS) are a highly prevalent problem, and with considerable burden to quality of life. Evidence has emerged that a strong correlation exists in men suffering both BPH-LUTS and erectile dysfunction (ED). Phosphodiesterase type 5 inhibitors (PDE5i) have been shown to be highly effective in treating ED and more recently there is evidence that men with LUTS also benefit. In this review article we discuss the common pathogenic pathways of ED and LUTS, the scientific basis of PDE5i use, the efficacy of PDE5i in LUTS either as monotherapy or in combination with other established medications used in LUTS. PMID:26470799

  13. Novel PDE4 Inhibitors Derived from Chinese Medicine Forsythia

    PubMed Central

    Coon, Tiffany A.; McKelvey, Alison C.; Weathington, Nate M.; Birru, Rahel L.; Lear, Travis; Leikauf, George D.; Chen, Bill B.

    2014-01-01

    Cyclic adenosine monophosphate (cAMP) is a crucial intracellular second messenger molecule that converts extracellular molecules to intracellular signal transduction pathways generating cell- and stimulus-specific effects. Importantly, specific phosphodiesterase (PDE) subtypes control the amplitude and duration of cAMP-induced physiological processes and are therefore a prominent pharmacological target currently used in a variety of fields. Here we tested the extracts from traditional Chinese medicine, Forsythia suspense seeds, which have been used for more than 2000 years to relieve respiratory symptoms. Using structural-functional analysis we found its major lignin, Forsynthin, acted as an immunosuppressant by inhibiting PDE4 in inflammatory and immune cell. Moreover, several novel, selective small molecule derivatives of Forsythin were tested in vitro and in murine models of viral and bacterial pneumonia, sepsis and cytokine-driven systemic inflammation. Thus, pharmacological targeting of PDE4 may be a promising strategy for immune-related disorders characterized by amplified host inflammatory response. PMID:25549252

  14. 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.

  15. 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

  16. 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…

  17. PDE5 inhibitors enhance celecoxib killing in multiple tumor types.

    PubMed

    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

    2015-05-01

    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

  18. 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

  19. 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.

  20. Characterisation of Lu AF33241: A novel, brain-penetrant, dual inhibitor of phosphodiesterase (PDE) 2A and PDE10A.

    PubMed

    Redrobe, John P; Rasmussen, Lars K; Christoffersen, Claus T; Bundgaard, Christoffer; Jørgensen, Morten

    2015-08-15

    Here, we present a preliminary pharmacological characterisation of Lu AF33241, a novel, brain penetrant phosphodiesterase inhibitor of (PDE) 2A and 10A tool compound, in in vitro/in vivo assays indicative of PDE2A and/or PDE10A inhibition, and in vivo models/assays relevant to cognitive processing and antipsychotic-like activity. An assay was also included to investigate potential effects on motor activity. The in vitro selectivity of Lu AF33241 was determined against a panel of PDE enzymes. Lu AF33241 potently inhibited both full-length recombinant hPDE2A (Ki=4.2nM) and hPDE10A (Ki=42nM). The compound moderately inhibited both hPDE1C (Ki=1200nM), hPDE7B (Ki=890nM), and hPDE11A (Ki=1800nM). Lu AF33241 displayed a Ki above 5000nM against all other tested members of the PDE family. Albeit within a narrow dose range, Lu AF33241 attenuated sub-chronic phencyclidine-induced deficits in novel object recognition (3 and 10mg/kg), displayed antipsychotic-like activity in the conditioned avoidance response paradigm (10mg/kg), and did not induce catalepsy within a dose-range of 2-6mg/kg. Further catalepsy studies are needed to investigate a predictive safety window. Lu AF33241 represents a novel PDE2A/PDE10A inhibitor tool compound that may serve to further the understanding of the roles played by these enzymes in various CNS disorders.

  1. Phosphodiesterase4D (PDE4D)--A risk factor for atrial fibrillation and stroke?

    PubMed

    Jørgensen, Carina; Yasmeen, Saiqa; Iversen, Helle K; Kruuse, Christina

    2015-12-15

    Mutations in the gene encoding phosphodiesterase 4D (PDE4D) enzyme are associated with ischemic stroke; however the functional implications of such mutations are not well understood. PDE4D is part of a complex protein family modulating intracellular signalling by cyclic nucleotides. The PDE4 family includes subtypes A-D, all of which show unique intracellular, cellular and tissue distribution. PDE4D is the major subtype expressed in human atrial myocytes and involved in the pathophysiology of arrhythmias, such as atrial fibrillation. The PDE4D enzyme hydrolyses cyclic adenosine monophosphate (cAMP). Though diverging results are reported, several population based studies describe association of various PDE4D single nucleotide polymorphisms (SNP) with cardio-embolic stroke in particular. Functionally, a down regulation of PDE4D variants has been reported in stroke patients. The anti-inflammatory and vasodilator properties of PDE4 inhibitors make them suitable for treatment of stroke and cardiovascular disease. PDE4D has recently been suggested as factor in atrial fibrillation. This review summarizes the possible function of PDE4D in the brain, heart, and vasculature. Further, association of the described SNPs, in particular, with cardioembolic stroke, is reviewed. Current findings on the PDE4D mutations suggest functionality involves an increased cardiac risk factor as well as augmented risk of atrial fibrillation. PMID:26671126

  2. 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.

  3. 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.

  4. Estimating the magnitude of near-membrane PDE4 activity in living cells.

    PubMed

    Xin, Wenkuan; Feinstein, Wei P; Britain, Andrea L; Ochoa, Cristhiaan D; Zhu, Bing; Richter, Wito; Leavesley, Silas J; Rich, Thomas C

    2015-09-15

    Recent studies have demonstrated that functionally discrete pools of phosphodiesterase (PDE) activity regulate distinct cellular functions. While the importance of localized pools of enzyme activity has become apparent, few studies have estimated enzyme activity within discrete subcellular compartments. Here we present an approach to estimate near-membrane PDE activity. First, total PDE activity is measured using traditional PDE activity assays. Second, known cAMP concentrations are dialyzed into single cells and the spatial spread of cAMP is monitored using cyclic nucleotide-gated channels. Third, mathematical models are used to estimate the spatial distribution of PDE activity within cells. Using this three-tiered approach, we observed two pharmacologically distinct pools of PDE activity, a rolipram-sensitive pool and an 8-methoxymethyl IBMX (8MM-IBMX)-sensitive pool. We observed that the rolipram-sensitive PDE (PDE4) was primarily responsible for cAMP hydrolysis near the plasma membrane. Finally, we observed that PDE4 was capable of blunting cAMP levels near the plasma membrane even when 100 μM cAMP were introduced into the cell via a patch pipette. Two compartment models predict that PDE activity near the plasma membrane, near cyclic nucleotide-gated channels, was significantly lower than total cellular PDE activity and that a slow spatial spread of cAMP allowed PDE activity to effectively hydrolyze near-membrane cAMP. These results imply that cAMP levels near the plasma membrane are distinct from those in other subcellular compartments; PDE activity is not uniform within cells; and localized pools of AC and PDE activities are responsible for controlling cAMP levels within distinct subcellular compartments.

  5. PDE Based Algorithms for Smooth Watersheds.

    PubMed

    Hodneland, Erlend; Tai, Xue-Cheng; Kalisch, Henrik

    2016-04-01

    Watershed segmentation is useful for a number of image segmentation problems with a wide range of practical applications. Traditionally, the tracking of the immersion front is done by applying a fast sorting algorithm. In this work, we explore a continuous approach based on a geometric description of the immersion front which gives rise to a partial differential equation. The main advantage of using a partial differential equation to track the immersion front is that the method becomes versatile and may easily be stabilized by introducing regularization terms. Coupling the geometric approach with a proper "merging strategy" creates a robust algorithm which minimizes over- and under-segmentation even without predefined markers. Since reliable markers defined prior to segmentation can be difficult to construct automatically for various reasons, being able to treat marker-free situations is a major advantage of the proposed method over earlier watershed formulations. The motivation for the methods developed in this paper is taken from high-throughput screening of cells. A fully automated segmentation of single cells enables the extraction of cell properties from large data sets, which can provide substantial insight into a biological model system. Applying smoothing to the boundaries can improve the accuracy in many image analysis tasks requiring a precise delineation of the plasma membrane of the cell. The proposed segmentation method is applied to real images containing fluorescently labeled cells, and the experimental results show that our implementation is robust and reliable for a variety of challenging segmentation tasks.

  6. 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

  7. β1-adrenergic receptor antagonists signal via PDE4 translocation.

    PubMed

    Richter, Wito; Mika, Delphine; Blanchard, Elise; Day, Peter; Conti, Marco

    2013-03-01

    It is generally assumed that antagonists of Gs-coupled receptors do not activate cAMP signalling, because they do not stimulate cAMP production via Gs-protein/adenylyl cyclase activation. Here, we report a new signalling pathway whereby antagonists of β1-adrenergic receptors (β1ARs) increase cAMP levels locally without stimulating cAMP production directly. Binding of antagonists causes dissociation of a preformed complex between β1ARs and Type-4 cyclic nucleotide phosphodiesterases (PDE4s). This reduces the local concentration of cAMP-hydrolytic activity, thereby increasing submembrane cAMP and PKA activity. Our study identifies receptor/PDE4 complex dissociation as a novel mechanism of antagonist action that contributes to the pharmacological properties of β1AR antagonists and might be shared by other receptor subtypes.

  8. Universal structure and universal equations (PDE) for unitary ensembles

    NASA Astrophysics Data System (ADS)

    Rumanov, Igor

    2010-08-01

    Random matrix ensembles with unitary invariance of measure (UE) are described in a unified way using a combination of Tracy-Widom (TW) and Adler-Shiota-van Moerbeke approaches to the derivation of partial differential equations (PDEs) for spectral gap probabilities. First, general three-term recurrence relations for UE restricted to subsets of real line, or, in other words, for functions in the resolvent kernel, are obtained. Using them, simple universal relations between all TW dependent variables and one-dimensional Toda lattice τ-functions are found. A universal system of PDE for UE is derived from previous relations, which leads also to a single independent PDE for spectral gap probability of various UE. Thus, orthogonal function bases and Toda lattice are seen at the core of correspondence of different approaches. Moreover, Toda-AKNS system provides a common structure of PDE for unitary ensembles. Interestingly, this structure can be seen in two very different forms: one arises from orthogonal function-Toda lattice considerations, while the other comes from Schlesinger equations for isomonodromic deformations and their relation to TW equations. The simple example of Gaussian matrices most neatly exposes this structure.

  9. 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

    2016-04-01

    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

  10. 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

  11. PDE4D phosphorylation: A coincidence detector integrating multiple signaling pathways.

    PubMed

    Mika, Delphine; Conti, Marco

    2016-07-01

    In Eukaryotes, more than 100 different phosphodiesterase (PDE) proteins serve to fine-tune cyclic nucleotide (cAMP and cGMP) signals and contribute to specificity of signaling. In mammals, PDEs are divided into 11 families, of which PDE4 represents the largest family. Four genes (pde4a, pde4b, pde4c and pde4d) encode for this class of enzymes in mammals and give rise to more than 20 variants. Within this family of genes, PDE4D was discovered on the basis of its regulatory properties and its induction by hormones and cAMP. PDE4D has often been used as the prototype PDE4 and large body of work has been generated on the biochemical, pharmacological, and physiological properties of this enzyme. This review covers the regulation of PDE4D by phosphorylation, the impact of this regulation in the context of the structure of this protein, and the functional consequences of this complex pattern of posttranslational modifications. PMID:26562185

  12. Domain Organization and Conformational Plasticity of the G Protein Effector, PDE6*

    PubMed Central

    Zhang, Zhixian; He, Feng; Constantine, Ryan; Baker, Matthew L.; Baehr, Wolfgang; Schmid, Michael F.; Wensel, Theodore G.; Agosto, Melina A.

    2015-01-01

    The cGMP phosphodiesterase of rod photoreceptor cells, PDE6, is the key effector enzyme in phototransduction. Two large catalytic subunits, PDE6α and -β, each contain one catalytic domain and two non-catalytic GAF domains, whereas two small inhibitory PDE6γ subunits allow tight regulation by the G protein transducin. The structure of holo-PDE6 in complex with the ROS-1 antibody Fab fragment was determined by cryo-electron microscopy. The ∼11 Å map revealed previously unseen features of PDE6, and each domain was readily fit with high resolution structures. A structure of PDE6 in complex with prenyl-binding protein (PrBP/δ) indicated the location of the PDE6 C-terminal prenylations. Reconstructions of complexes with Fab fragments bound to N or C termini of PDE6γ revealed that PDE6γ stretches from the catalytic domain at one end of the holoenzyme to the GAF-A domain at the other. Removal of PDE6γ caused dramatic structural rearrangements, which were reversed upon its restoration. PMID:25809480

  13. Does phosphodiesterase 11A (PDE11A) hold promise as a future therapeutic target?

    PubMed

    Kelly, Michy P

    2015-01-01

    Phosphodiesterase 11A (PDE11A) is the most recently discovered 3', 5'-cyclic nucleotide phosphodiesterase. By breaking down both cAMP and cGMP, PDE11A is a critical regulator of intracellular signaling. To date, PDE11A has been implicated to play a role in tumorigenesis, brain function, and inflammation. Here, we consolidate and, where necessary, reconcile the PDE11A literature to evaluate this enzyme as a potential therapeutic target. We compare the results and methodologies of numerous studies that report conflicting tissue expression profiles for PDE11A. We conclude that PDE11A expression is relatively restricted in the body, with reliable expression reported in tissues such as the brain (particularly the hippocampus), the prostate, and the adrenal gland. Each of the four PDE11A splice variants (PDE11A1-4) appears to exhibit a distinct tissue expression profile and has a unique N-terminal regulatory region, suggesting that each isoform could be individually targeted with a small molecule or biologic. Progress has been made in identifying a tool PDE11A inhibitor as well as an activator; however, the functional effects of these pharmacological tools remain to be determined. Importantly, PDE11A knockout mice do exist and appear healthy into late age, suggesting a potential safety window for targeting this enzyme. Considering the implication of PDE11A in disease-relevant biology, the potential to selectively target specific PDE11A variants, and the possibility of either activating or inhibiting the enzyme, we believe PDE11A holds promise as a potential future therapeutic target.

  14. Identification and characterization of DdPDE3, a cGMP-selective phosphodiesterase from Dictyostelium.

    PubMed Central

    Kuwayama, H; Snippe, H; Derks, M; Roelofs, J; Van Haastert, P J

    2001-01-01

    In Dictyostelium cAMP and cGMP have important functions as first and second messengers in chemotaxis and development. Two cyclic-nucleotide phosphodiesterases (DdPDE 1 and 2) have been identified previously, an extracellular dual-specificity enzyme and an intracellular cAMP-specific enzyme (encoded by the psdA and regA genes respectively). Biochemical data suggest the presence of at least one cGMP-specific phosphodiesterase (PDE) that is activated by cGMP. Using bioinformatics we identified a partial sequence in the Dictyostelium expressed sequence tag database that shows a high degree of amino acid sequence identity with mammalian PDE catalytic domains (DdPDE3). The deduced amino acid sequence of a full-length DdPDE3 cDNA isolated in this study predicts a 60 kDa protein with a 300-residue C-terminal PDE catalytic domain, which is preceded by approx. 200 residues rich in asparagine and glutamine residues. Expression of the DdPDE3 catalytic domain in Escherichia coli shows that the enzyme has Michaelis-Menten kinetics and a higher affinity for cGMP (K(m)=0.22 microM) than for cAMP (K(m)=145 microM); cGMP does not stimulate enzyme activity. The enzyme requires bivalent cations for activity; Mn(2+) is preferred to Mg(2+), whereas Ca(2+) yields no activity. DdPDE3 is inhibited by 3-isobutyl-1-methylxanthine with an IC(50) of approx. 60 microM. Overexpression of the DdPDE3 catalytic domain in Dictyostelium confirms these kinetic properties without indications of its activation by cGMP. The properties of DdPDE3 resemble those of mammalian PDE9, which also shows the highest sequence similarity within the catalytic domains. DdPDE3 is the first cGMP-selective PDE identified in lower eukaryotes. PMID:11171061

  15. Identification and tissue-specific expression of PDE7 phosphodiesterase splice variants

    PubMed Central

    Bloom, Timothy J.; Beavo, Joseph A.

    1996-01-01

    Type 7 cyclic nucleotide phosphodiesterases (PDE7s) are a newly described family of enzymes having high affinity and specificity for cAMP. However, little is known about their structure, function, or regulation. We have isolated a mouse skeletal muscle cDNA representing a new alternative splice variant (PDE7A2) of the PDE7 gene. The ORF encodes a 456-amino acid protein having a predicted molecular weight of 52.4 kDa. The 5′ end of the mouse PDE7A2 is divergent from the 5′ end of the human PDE7A1 sequence and is more hydrophobic. A comparison of the 5′ ends of the two cDNA clones with human genomic sequence indicates that they represent alternate splice products rather than species variation. RNase protection analysis of several mouse tissues indicates that PDE7 is expressed widely with highest levels in skeletal muscle. HPLC fractionation and Western blot analysis of two human lymphocyte T-cell lines shows that an unknown PDE activity described by Ichimura and Kase [Ichimura, M. & Kase, H. (1993) Biochem. Biophys. Res. Commun. 193, 985–990] is most likely to be PDE7A1. A single immunoreactive band of ≈55 kDa, which comigrates with PDE7A1, is seen in fractions of the HPLC profile containing this activity suggesting that the original human PDE7A1 clone contains a full-length ORF, and is not truncated at the 5′ end as was originally postulated. In a human lymphocyte B-cell line and also in mouse skeletal muscle, a large amount of PDE7 mRNA but little PDE7 protein or activity is expressed suggesting that the translation or stability of PDE7 protein may be highly regulated in these tissues. PMID:8943082

  16. 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.

  17. Rapid regulation of PDE-2 and PDE-4 cyclic AMP phosphodiesterase activity following ligation of the T cell antigen receptor on thymocytes: analysis using the selective inhibitors erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) and rolipram.

    PubMed

    Michie, A M; Lobban, M; Müller, T; Harnett, M M; Houslay, M D

    1996-02-01

    The PDE2, cyclic GMP-stimulated, and the PDE4, cyclic AMP-specific enzymes provide the major, detectable cyclic AMP phosphodiesterase activities in murine thymocytes. In the absence of the cyclic GMP, PDE4 activity predominated (approximately 80% total) but in the presence of low (10 microM) cyclic GMP concentrations, PDE2 activity constituted the major PDE activity in thymocytes (approximately 80% total). The PDE4 selective inhibitor rolipram dose-dependently inhibited thymocyte PDE4 activity (IC50 approximately 65 nM). PDE2 was dose-dependently activated (EC50 approximately 1 microM) by cyclic GMP and inhibited by erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) (IC50 approximately 4 microM). EHNA was shown to serve as a selective inhibitor of PDE-2 activity as assessed from studies using separated PDE1, PDE2, PDE3 and PDE4 species from hepatocytes as well as human PDE2 and PDE4 enzymes. EHNA completely ablated the ability of cyclic GMP to activate PDE2 activity, whilst having a much smaller inhibitory effect on the unstimulated PDE2 activity. EHNA exhibited normal Michaelian kinetics of inhibition for the cyclic GMP-stimulated PDE2 activity with Hill plots near unity. Apparent negative co-operative effect were seen in the absence of cyclic GMP with Hill coefficients of approximately 0.3 for inhibition of PDE2 activity. Within 5 min of challenge of thymocytes with the lectin phytohaemagglutinin (PHA) there was a transient decrease (approximately 83%) in PDE-4 activity and in PDE2 activity (approximately 40%). Both anti-TCR antibodies also caused an initial reduction in the PDE4 activity which was followed by a sustained and profound increase in activity. In contrast to that observed with PHA, anti-TCR/CD3 antisera had little effect on PDE2 activity. It is suggested that, dependent upon the intracellular concentrations of cyclic GMP, thymocyte cyclic AMP metabolism can be expected to switch from being under the predominant control of PDE4 activity to that determined

  18. Global attractors for a third order in time nonlinear dynamics

    NASA Astrophysics Data System (ADS)

    Caixeta, Arthur H.; Lasiecka, Irena; Cavalcanti, Valéria N. D.

    2016-07-01

    Long time behavior of a third order (in time) nonlinear PDE equation is considered. This type of equations arises in the context of nonlinear acoustics [12,20,22,24] where modeling accounts for a finite speed of propagation paradox, the latter results in hyperbolic nature of the dynamics. It will be proved that the underlying PDE generates a well-posed dynamical system which admits a global and finite dimensional attractor. The main difficulty associated with the problem studied is the lack of Lyapunov function along with the lack of compactness of trajectories, which fact prevents applicability of standard tools in the area of dynamical systems.

  19. William Harvey Research Conference on PDE inhibitors: drugs with an expanding range of therapeutic uses.

    PubMed

    O'Donnell

    2000-03-01

    Presentations at the William Harvey Research Conference on PDE Inhibitors described the molecular biology, biochemical regulation. pharmacology, and therapeutic utility of inhibitors of cyclic nucleotide phosphodiesterases (PDEs). Most of the talks focused on PDE4 and PDE5. two members of the 11-member PDE family that have attracted much interest over the last several years. These enzymes have been shown to be targets for drugs with wide-ranging clinical utility, including treatment of inflammation, depression, and male erectile dysfunction. The continued investigation of PDEs and the development of potent and selective inhibitors should provide even more therapeutic agents in years to come.

  20. "One-shot" analysis of PDE-5 inhibitors and analogues in counterfeit herbal natural products using an LC-DAD-QTOF system.

    PubMed

    Bortolini, Claudio; Pivato, Antonio; Bogialli, Sara; Pastore, Paolo

    2015-08-01

    A highly selective and robust method for simultaneous screening and confirmation of target and non-target phosphodiesterase type 5 (PDE-5) inhibitor analogues within a single chromatographic run in counterfeit herbal products was developed. The protocol, based on an easy and rapid extraction with a water/acetonitrile 1 % formic acid solution, followed by sonication and centrifugation, exploits an LC-diode array detector-quadrupole-time-of-flight (DAD-QTOF) system. The extraction method was optimized both at high concentrations and at trace levels. These two situations are typically encountered in pharmaceutical formulations and herbal food supplements. Carryover effects, never reported before and occurring mainly for vardenafil, were overcome using a polymer-based column. An in-house validation was carried out using five blanks of different bulk matrices spiked with seven standard analytes, namely yohimbine, sildenafil, vardenafil, tadalafil, homosildenafil, pseudovardenafil and hydroxyhomovardenafil. Reliable quantitation was possible using a conventional standard solution for all the pharmaceutical and herbal samples considered, as matrix effects were eliminated. Accuracy ranged from 80.9 to 108.1 % with overall relative standard deviation (RSD) <11 % (N = 15), measured at 1.0, 5.0 and 10.0 μg/g. Limits of detection (LODs) obtained ensured the determination of cross contaminations at nanogram per gram levels. A database with 82 PDE-5 inhibitor analogues was implemented for automatic non-target analysis. Among the 26 samples of dietary supplements and herbal remedies bulk marketed for erectile dysfunctions, three samples were found to be contaminated with both registered and unregistered synthetic PDE-5 inhibitors, i.e. yohimbine, sildenafil, dimethylsildenafil and thiodimethylsildenafil or thiomethisosildenafil. The occurrence of such contaminations, both at trace levels and at pharmaceutical dosage, indicates the illicit use of synthetic PDE-5 analogues

  1. "One-shot" analysis of PDE-5 inhibitors and analogues in counterfeit herbal natural products using an LC-DAD-QTOF system.

    PubMed

    Bortolini, Claudio; Pivato, Antonio; Bogialli, Sara; Pastore, Paolo

    2015-08-01

    A highly selective and robust method for simultaneous screening and confirmation of target and non-target phosphodiesterase type 5 (PDE-5) inhibitor analogues within a single chromatographic run in counterfeit herbal products was developed. The protocol, based on an easy and rapid extraction with a water/acetonitrile 1 % formic acid solution, followed by sonication and centrifugation, exploits an LC-diode array detector-quadrupole-time-of-flight (DAD-QTOF) system. The extraction method was optimized both at high concentrations and at trace levels. These two situations are typically encountered in pharmaceutical formulations and herbal food supplements. Carryover effects, never reported before and occurring mainly for vardenafil, were overcome using a polymer-based column. An in-house validation was carried out using five blanks of different bulk matrices spiked with seven standard analytes, namely yohimbine, sildenafil, vardenafil, tadalafil, homosildenafil, pseudovardenafil and hydroxyhomovardenafil. Reliable quantitation was possible using a conventional standard solution for all the pharmaceutical and herbal samples considered, as matrix effects were eliminated. Accuracy ranged from 80.9 to 108.1 % with overall relative standard deviation (RSD) <11 % (N = 15), measured at 1.0, 5.0 and 10.0 μg/g. Limits of detection (LODs) obtained ensured the determination of cross contaminations at nanogram per gram levels. A database with 82 PDE-5 inhibitor analogues was implemented for automatic non-target analysis. Among the 26 samples of dietary supplements and herbal remedies bulk marketed for erectile dysfunctions, three samples were found to be contaminated with both registered and unregistered synthetic PDE-5 inhibitors, i.e. yohimbine, sildenafil, dimethylsildenafil and thiodimethylsildenafil or thiomethisosildenafil. The occurrence of such contaminations, both at trace levels and at pharmaceutical dosage, indicates the illicit use of synthetic PDE-5 analogues

  2. A PDE Formulation of Non-Equilibrium Statistical Mechanics for Ionic Permeation

    NASA Astrophysics Data System (ADS)

    Schuss, Zeev; Nadler, Boaz; Singer, Amit; Eisenberg, Robert S.

    2003-05-01

    When there is a steady net flux in a system of interacting particles, the microscopic structure of the system can no longer be determined from the Boltzmann equilibrium distribution (partition function). Nonetheless, the microscopic structure of a finite system of diffusing interacting particles can be described by Poisson-Nernst-Planck-type partial differential equations. These equations, defined in a finite domain, are the non-equilibrium generalization of the BBGKY hierarchy of equilibrium statistical mechanics. Indeed, when no-flux conditions are imposed on the domain boundaries, equilibrium results are recovered. When non-homogeneous boundary conditions are given for these equations, the solutions describe densities and electrostatic potentials of particle systems not in equilibrium. The construction of a pair correlation function under these conditions will be a new result in statistical physics. As in the equilibrium case, a closure relation between a higher and a lower order correlation function has to be assumed. However, since we are considering a finite system, boundary conditions for the higher order correlation functions must also be derived. In applications to the permeation of ions through protein channels of biological membranes the computation of the pair correlation function will lead to a prediction of current through an open channel, given the spatial structure and fixed charge distribution. The pair correlation function contains finite size effects that lead to blocking in a narrow channel and possibly to selectivity.

  3. 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. PMID:26066272

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Tau approximation techniques for identification of coefficients in parabolic PDE

    NASA Technical Reports Server (NTRS)

    Banks, H. T.; Wade, J. G.

    1989-01-01

    A variant of the Tau method, called the weak Tau method, is developed on the basis of the weak form of the PDE for use in least-squares parameter estimation; also presented is a suitable abstract convergence framework. The emphasis is on the theoretical framework that allows treatment of the weak Tau method when it is applied to a wide class of inverse problems, including those for diffusion-advection equations, the Fokker-Planck model for population dynamics, and damped beam equations. Extensive numerical testing of the weak Tau method has demonstrated that it compares quite favorably with existing methods.

  9. 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.

  10. Characterization of Conformational Changes and Protein-Protein Interactions of Rod Photoreceptor Phosphodiesterase (PDE6)*

    PubMed Central

    Matte, Suzanne L.; Laue, Thomas M.; Cote, Rick H.

    2012-01-01

    As the central effector of visual transduction, the regulation of photoreceptor phosphodiesterase (PDE6) is controlled by both allosteric mechanisms and extrinsic binding partners. However, the conformational changes and interactions of PDE6 with known interacting proteins are poorly understood. Using a fluorescence detection system for the analytical ultracentrifuge, we examined allosteric changes in PDE6 structure and protein-protein interactions with its inhibitory γ-subunit, the prenyl-binding protein (PrBP/δ), and activated transducin. In solution, the PDE6 catalytic dimer (Pαβ) exhibits a more asymmetric shape (axial ratio of 6.6) than reported previously. The inhibitory Pγ subunit behaves as an intrinsically disordered protein in solution but binds with high affinity to the catalytic dimer to reconstitute the holoenzyme without a detectable change in shape. Whereas the closely related PDE5 homodimer undergoes a significant change in its sedimentation properties upon cGMP binding to its regulatory cGMP binding site, no such change was detected upon ligand binding to the PDE6 catalytic dimer. However, when Pαβ was reconstituted with Pγ truncation mutants lacking the C-terminal inhibitory region, cGMP-dependent allosteric changes were observed. PrBP/δ bound to the PDE6 holoenzyme with high affinity (KD = 6.2 nm) and induced elongation of the protein complex. Binding of activated transducin to PDE6 holoenzyme resulted in a concentration-dependent increase in the sedimentation coefficient, reflecting a dynamic equilibrium between transducin and PDE6. We conclude that allosteric regulation of PDE6 is more complex than for PDE5 and is dependent on interactions of regions of Pγ with the catalytic dimer. PMID:22514270

  11. Molecular cloning and subcellular distribution of the novel PDE4B4 cAMP-specific phosphodiesterase isoform.

    PubMed Central

    Shepherd, Malcolm; McSorley, Theresa; Olsen, Aileen E; Johnston, Lee Ann; Thomson, Neil C; Baillie, George S; Houslay, Miles D; Bolger, Graeme B

    2003-01-01

    We have isolated cDNAs encoding PDE4B4, a new cAMP-specific phosphodiesterase (PDE4) isoform with novel properties. The amino acid sequence of PDE4B4 demonstrates that it is encoded by the PDE4B gene, but that it differs from the previously isolated PDE4B1, PDE4B2 and PDE4B3 isoforms by the presence of a novel N-terminal region of 17 amino acids. PDE4B4 contains both of the upstream conserved region 1 (UCR1) and UCR2 regulatory units that are characteristic of 'long' PDE4 isoforms. RNase protection demonstrated that PDE4B4 mRNA is expressed preferentially in liver, skeletal muscle and various regions of the brain, which differs from the pattern of tissue distribution of the other known PDE4B long forms, PDE4B1 and PDE4B3. Expression of PDE4B4 cDNA in COS7 cells produced a protein of 85 kDa under denaturing conditions. Subcellular fractionation of recombinant, COS7-cell expressed PDE4B4 showed that the protein was localized within the cytosol, which was confirmed by confocal microscopic analysis of living COS7 cells transfected with a green fluorescent protein-PDE4B4 chimaera. PDE4B4 exhibited a K(m) for cAMP of 5.4 microM and a V(max), relative to that of the long PDE4B1 isoform, of 2.1. PDE4B4 was inhibited by the prototypical PDE4 inhibitor rolipram [4-[3-(cyclopentoxyl)-4-methoxyphenyl]-2-pyrrolidinone] with an IC(50) of 83 nM. Treatment of COS7 cells with forskolin, to elevate cAMP levels, produced activation of PDE4B4, which was associated with the phosphorylation of PDE4B4 on Ser-56 within UCR1. The unique tissue distribution and intracellular targeting of PDE4B4 suggests that this isoform may have a distinct functional role in regulating cAMP levels in specific cell types. PMID:12441002

  12. 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.

  13. 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

  14. PDE5 inhibitors protect against post-infarction heart failure.

    PubMed

    Li, Na; Yuan, Yuan; Li, Shuang; Zeng, Cao; Yu, Wenjun; Shen, Mingzhi; Zhang, Rongqing; Li, Congye; Zhang, Yingmei; Wang, Haichang

    2016-01-01

    Heart failure (HF) is one of the main causes for cardiovascular morbidity and mortality. This study was designed to examine the effect of PDE-5 inhibition on cardiac geometry, function and apoptosis in post-infarct HF. Our data revealed that treatment of the PDE-5 inhibitor sildenafil, beginning 3 days after left anterior descending coronary artery ligation, attenuated LV remodeling, cardiac dysfunction, cardiomyocyte apoptosis and mitochondrial anomalies including ATP production, mitochondrial respiratory defects, decline of mitochondrial membrane potential (MMP) and compromised mitochondrial ultrastructure. Sildenafil partially ameliorated the downregulation of Sirt3 protein and acetylation of PGC-1alpha in peri-infarct myocardial regions. In cultured neonatal mouse ventricular myocytes subjected to hypoxia for 24 hrs, sildenafil suppressed apoptosis, promoted ATP production and elevated MMP, along with the increased Sirt3 protein expression and decreased PGC-1alpha acetylation. Interestingly, knock down of Sirt3 attenuated or nullified sildenafil-offered beneficial effects. Our findings demonstrated that sildenafil exerts its cardioprotective effect against post-infarction injury by improving mitochondrial ultrastructure and function via the Sirt3/PGC-1alpha pathway. This observation should shed some lights towards application of sildenafil in energy-related cardiovascular diseases. PMID:27100500

  15. A novel thermoregulatory role for PDE10A in mouse and human adipocytes.

    PubMed

    Hankir, Mohammed K; Kranz, Mathias; Gnad, Thorsten; Weiner, Juliane; Wagner, Sally; Deuther-Conrad, Winnie; Bronisch, Felix; Steinhoff, Karen; Luthardt, Julia; Klöting, Nora; Hesse, Swen; Seibyl, John P; Sabri, Osama; Heiker, John T; Blüher, Matthias; Pfeifer, Alexander; Brust, Peter; Fenske, Wiebke K

    2016-01-01

    Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small-animal PET/MRI and the novel radioligand [(18)F]-AQ28A, we found marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice. Pharmacological inactivation of PDE10A with the highly selective inhibitor MP-10 recruited BAT and potentiated thermogenesis in vivo In diet-induced obese mice, chronic administration of MP-10 caused weight loss associated with increased energy expenditure, browning of white adipose tissue, and improved insulin sensitivity. Analysis of human PET data further revealed marked levels of PDE10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Finally, the inhibition of PDE10A with MP-10 stimulated thermogenic gene expression in human brown adipocytes and induced browning of human white adipocytes. Collectively, our findings highlight a novel thermoregulatory role for PDE10A in mouse and human adipocytes and promote PDE10A inhibitors as promising candidates for the treatment of obesity and diabetes. PMID:27247380

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

    PubMed

    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.

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

    PubMed

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

    2014-06-01

    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

  18. 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

  19. 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…

  20. 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.

  1. 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. PMID:24998992

  2. Analytical solutions to the backward Kolmogorov PDE via an adiabatic approximation to the Schrödinger PDE

    NASA Astrophysics Data System (ADS)

    Haven, Emmanuel

    2005-11-01

    Analytical solutions to the backward Kolmogorov PDE are very dependent on the functional form of b(y,t) and a(y,t). We suggest one solution technique for obtaining analytical solutions via the use of an adiabatic approximation to the Schrödinger PDE. This approximation takes the specific form of a so-called WKB (W D Wentzel [G. Wentzel, Eine Verallgemeinerung der Quantenbedingungen für die Zwecke der Wellenmechanik, Z. Phys. 38 (1926) 518-529], K D Kramers [H. Kramers, Wellenmechanik und halbzahlige Quantisierung, Z. Phys. 39 (1926) 828-840], B D Brillouin [L. Brillouin, La mécanique ondulatoire de Schrödinger: une méthode générale de résolution par approximations successives, C. R. Acad. Sci. 183 (1926) 24-26]) approximation. We provide for two examples, in financial option pricing, where we show how the proposed approximation could be of use.

  3. 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

  4. The upstream conserved regions (UCRs) mediate homo- and hetero-oligomerization of type 4 cyclic nucleotide phosphodiesterases (PDE4s).

    PubMed

    Xie, Moses; Blackman, Brigitte; Scheitrum, Colleen; Mika, Delphine; Blanchard, Elise; Lei, Tao; Conti, Marco; Richter, Wito

    2014-05-01

    PDE4s (type 4 cyclic nucleotide phosphodiesterases) are divided into long and short forms by the presence or absence of conserved N-terminal domains termed UCRs (upstream conserved regions). We have shown previously that PDE4D2, a short variant, is a monomer, whereas PDE4D3, a long variant, is a dimer. In the present study, we have determined the apparent molecular masses of various long and short PDE4 variants by size-exclusion chromatography and sucrose density-gradient centrifugation. Our results indicate that dimerization is a conserved property of all long PDE4 forms, whereas short forms are monomers. Dimerization is mediated by the UCR domains. Given their high sequence conservation, the UCR domains mediate not only homo-oligomerization, but also hetero-oligomerization of distinct PDE4 long forms as detected by co-immunoprecipitation assays and FRET microscopy. Endogenous PDE4 hetero-oligomers are, however, low in abundance compared with homo-dimers, revealing the presence of mechanisms that predispose PDE4s towards homo-oligomerization. Oligomerization is a prerequisite for the regulatory properties of the PDE4 long forms, such as their PKA (protein kinase A)-dependent activation, but is not necessary for PDE4 protein-protein interactions. As a result, individual PDE4 protomers may independently mediate protein-protein interactions, providing a mechanism whereby PDE4s contribute to the assembly of macromolecular signalling complexes.

  5. 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

  6. Exome sequencing identifies PDE4D mutations in acrodysostosis.

    PubMed

    Lee, Hane; Graham, John M; Rimoin, David L; Lachman, Ralph S; Krejci, Pavel; Tompson, Stuart W; Nelson, Stanley F; Krakow, Deborah; Cohn, Daniel H

    2012-04-01

    Acrodysostosis is a dominantly-inherited, multisystem disorder characterized by skeletal, endocrine, and neurological abnormalities. To identify the molecular basis of acrodysostosis, we performed exome sequencing on five genetically independent cases. Three different missense mutations in PDE4D, which encodes cyclic AMP (cAMP)-specific phosphodiesterase 4D, were found to be heterozygous in three of the cases. Two of the mutations were demonstrated to have occurred de novo, providing strong genetic evidence of causation. Two additional cases were heterozygous for de novo missense mutations in PRKAR1A, which encodes the cAMP-dependent regulatory subunit of protein kinase A and which has been recently reported to be the cause of a form of acrodysostosis resistant to multiple hormones. These findings demonstrate that acrodysostosis is genetically heterogeneous and underscore the exquisite sensitivity of many tissues to alterations in cAMP homeostasis. PMID:22464252

  7. On PDE solution in transient optimization of gas networks

    NASA Astrophysics Data System (ADS)

    Steinbach, Marc C.

    2007-06-01

    Operative planning in gas distribution networks leads to large-scale mixed-integer optimization problems involving a hyperbolic PDE defined on a graph. We consider the NLP obtained under prescribed combinatorial decisions--or as relaxation in a branch-and-bound framework, addressing in particular the KKT systems arising in primal-dual interior methods. We propose a custom solution algorithm using sparse projections locally in time, based on the KKT systems' structural properties in space as induced by the discretized gas flow equations in combination with the underlying network topology. The numerical efficiency and accuracy of the algorithm are investigated, and detailed computational comparisons with a previously developed control space method and with the multifrontal solver MA27 are provided.

  8. The Study of the Tether Motion with Time-Varying Length Using the Absolute Nodal Coordinate Formulation with Multiple Nonlinear Time Scales

    NASA Astrophysics Data System (ADS)

    Kawaguti, Keisuke; Terumichi, Yoshiaki; Takehara, Shoichiro; Kaczmarczyk, Stefan; Sogabe, Kiyoshi

    In this study, the modeling and formulation for tether motion with time-varying length, large rotation, large displacement and large deformation are proposed. A tether or cable is an important element in lift systems, construction machines for transportation and often is used with a time-varying length. In some cases, these systems are large and the tether has a long length, large deformation and large displacement. The dynamic behavior of a tether in extension and retraction using the proposed method is discussed in this paper. In the passage through resonance, significant tether motions with large rotation and large deformation result. In the analysis of this phenomenon, the transient fluctuations of the motion amplitudes are examined and compared with the corresponding steady state motions. The accuracy and the cost of the calculations are also verified by comparison with the experimental results.

  9. 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

  10. 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.

  11. New classes of PDE7 inhibitors identified by a fission yeast-based HTS

    PubMed Central

    Alaamery, Manal A.; Wyman, Arlene R.; Ivey, F. Douglas; Allain, Christina; Demirbas, Didem; Wang, Lili; Ceyhan, Ozge; Hoffman, Charles S.

    2010-01-01

    Studies of the phosphodiesterase PDE7 family are impeded by there being only one commercially-available PDE7 inhibitor, BRL50481. We have employed a high throughput screen of commercial chemical libraries, using a fission yeast-based assay, to identify PDE7 inhibitors that include steroids, podocarpanes, and an unusual heterocyclic compound, BC30. In vitro enzyme assays measuring the potency of BC30 and two podocarpanes, in comparison with BRL50481, produce data consistent with those from yeast-based assays. In other enzyme assays, BC30 stimulates the PDE4D catalytic domain, but not full-length PDE4D2, suggesting an allosteric site of action. BC30 significantly enhances the anti-inflammatory effect of the PDE4 inhibitor rolipram as measured by release of TNFα from activated monocytes. These studies introduce several new PDE7 inhibitors that may be excellent candidates for medicinal chemistry due to the requirements for drug-like characteristics placed on them by the nature of the yeast-based screen. PMID:20228279

  12. 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

  13. Rare inactivating PDE11A variants associated with testicular germ cell tumors.

    PubMed

    Pathak, Anand; Stewart, Douglas R; Faucz, Fabio R; Xekouki, Paraskevi; Bass, Sara; Vogt, Aurelie; Zhang, Xijun; Boland, Joseph; Yeager, Meredith; Loud, Jennifer T; Nathanson, Katherine L; McGlynn, Katherine A; Stratakis, Constantine A; Greene, Mark H; Mirabello, Lisa

    2015-12-01

    Germline inactivating mutations of isoform 4 of phosphodiesterase (PDE) 11A (coded by the PDE11A gene) have been associated with familial adrenocortical tumors and familial testicular cancer. Testicular tissue is unique in expressing all four isoforms of PDE11A. In a prior candidate gene study of 94 familial testicular germ cell tumor (TGCT) subjects, we identified a significant association between the presence of functionally abnormal variants in PDE11A and familial TGCT risk. To validate this novel observation, we sequenced the PDE11A coding region in 259 additional TGCT patients (both familial and sporadic) and 363 controls. We identified 55 PDE11A variants: 20 missense, four splice-site, two nonsense, seven synonymous, and 22 intronic. Ten missense variants were novel; nine occurred in transcript variant 4 and one in transcript variant 3. Five rare mutations (p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R) were present only in cases and were significantly more common in cases vs controls (P=0.0037). The latter two novel variants were functionally characterized and shown to be functionally inactivating, resulting in reduced PDE activity and increased cAMP levels. In further analysis of this cohort, we focused on white participants only to minimize confounding due to population stratification. This study builds upon our prior reports implicating PDE11A variants in familial TGCT, provides the first independent validation of those findings, extends that work to sporadic testicular cancer, demonstrates that these variants are uncommonly but reproducibly associated with TGCT, and refines our understanding regarding which specific inactivating PDE11A variants are most likely to be associated with TGCT risk. PMID:26459559

  14. Decentralized optimal control of a class of interconnected nonlinear discrete-time systems by using online Hamilton-Jacobi-Bellman formulation.

    PubMed

    Mehraeen, Shahab; Jagannathan, Sarangapani

    2011-11-01

    In this paper, the direct neural dynamic programming technique is utilized to solve the Hamilton-Jacobi-Bellman equation forward-in-time for the decentralized near optimal regulation of a class of nonlinear interconnected discrete-time systems with unknown internal subsystem and interconnection dynamics, while the input gain matrix is considered known. Even though the unknown interconnection terms are considered weak and functions of the entire state vector, the decentralized control is attempted under the assumption that only the local state vector is measurable. The decentralized nearly optimal controller design for each subsystem consists of two neural networks (NNs), an action NN that is aimed to provide a nearly optimal control signal, and a critic NN which evaluates the performance of the overall system. All NN parameters are tuned online for both the NNs. By using Lyapunov techniques it is shown that all subsystems signals are uniformly ultimately bounded and that the synthesized subsystems inputs approach their corresponding nearly optimal control inputs with bounded error. Simulation results are included to show the effectiveness of the approach. PMID:21965197

  15. Luteinizing Hormone Causes Phosphorylation and Activation of the cGMP Phosphodiesterase PDE5 in Rat Ovarian Follicles, Contributing, Together with PDE1 Activity, to the Resumption of Meiosis.

    PubMed

    Egbert, Jeremy R; Uliasz, Tracy F; Shuhaibar, Leia C; Geerts, Andreas; Wunder, Frank; Kleiman, Robin J; Humphrey, John M; Lampe, Paul D; Artemyev, Nikolai O; Rybalkin, Sergei D; Beavo, Joseph A; Movsesian, Matthew A; Jaffe, Laurinda A

    2016-05-01

    The meiotic cell cycle of mammalian oocytes in preovulatory follicles is held in prophase arrest by diffusion of cGMP from the surrounding granulosa cells into the oocyte. Luteinizing hormone (LH) then releases meiotic arrest by lowering cGMP in the granulosa cells. The LH-induced reduction of cGMP is caused in part by a decrease in guanylyl cyclase activity, but the observation that the cGMP phosphodiesterase PDE5 is phosphorylated during LH signaling suggests that an increase in PDE5 activity could also contribute. To investigate this idea, we measured cGMP-hydrolytic activity in rat ovarian follicles. Basal activity was due primarily to PDE1A and PDE5, and LH increased PDE5 activity. The increase in PDE5 activity was accompanied by phosphorylation of PDE5 at serine 92, a protein kinase A/G consensus site. Both the phosphorylation and the increase in activity were promoted by elevating cAMP and opposed by inhibiting protein kinase A, supporting the hypothesis that LH activates PDE5 by stimulating its phosphorylation by protein kinase A. Inhibition of PDE5 activity partially suppressed LH-induced meiotic resumption as indicated by nuclear envelope breakdown, but inhibition of both PDE5 and PDE1 activities was needed to completely inhibit this response. These results show that activities of both PDE5 and PDE1 contribute to the LH-induced resumption of meiosis in rat oocytes, and that phosphorylation and activation of PDE5 is a regulatory mechanism.

  16. 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.

  17. Expression, intracellular distribution and basis for lack of catalytic activity of the PDE4A7 isoform encoded by the human PDE4A cAMP-specific phosphodiesterase gene.

    PubMed Central

    Johnston, Lee Ann; Erdogan, Suat; Cheung, York Fong; Sullivan, Michael; Barber, Rachael; Lynch, Martin J; Baillie, George S; Van Heeke, Gino; Adams, David R; Huston, Elaine; Houslay, Miles D

    2004-01-01

    PDE4A7 is an isoform encoded by the human PDE4A cAMP-specific phosphodiesterase gene that fails to hydrolyse cAMP and whose transcripts are widely expressed. Removal of either the N- or C-terminal unique portions of PDE4A7 did not reconstitute catalytic activity, showing that they did not exert a chronic inhibitory effect. A chimera (Hyb2), formed by swapping the unique N-terminal portion of PDE4A7 with that of the active PDE4A4C form, was not catalytically active. However, one formed (Hyb1) by swapping the unique C-terminal portion of PDE4A7 with that common to all active PDE4 isoforms was catalytically active. Compared with the active PDE4A4B isoform, Hyb1 exhibited a similar K(m) value for cAMP and IC50 value for rolipram inhibition, but was less sensitive to inhibition by Ro-20-1724 and denbufylline, and considerably more sensitive to thermal denaturation. The unique C-terminal region of PDE4A7 was unable to support an active catalytic unit, whereas its unique N-terminal region can. The N-terminal portion of the PDE4 catalytic unit is essential for catalytic activity and can be supplied by either highly conserved sequence found in active PDE4 isoforms from all four PDE4 subfamilies or the unique N-terminal portion of PDE4A7. A discrete portion of the conserved C-terminal region in active PDE4A isoforms underpins their aberrant migration on SDS/PAGE. Unlike active PDE4A isoforms, PDE4A7 is exclusively localized to the P1 particulate fraction in cells. A region located within the C-terminal portion of active PDE4 isoforms prevents such exclusive targeting. Three functional regions in PDE4A isoforms are identified, which influence catalytic activity, subcellular targeting and conformational status. PMID:15025561

  18. 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.

  19. Identification of two splice variant forms of type-IVB cyclic AMP phosphodiesterase, DPD (rPDE-IVB1) and PDE-4 (rPDE-IVB2) in brain: selective localization in membrane and cytosolic compartments and differential expression in various brain regions.

    PubMed

    Lobban, M; Shakur, Y; Beattie, J; Houslay, M D

    1994-12-01

    In order to detect the two splice variant forms of type-IVB cyclic AMP phosphodiesterase (PDE) activity, DPD (type-IVB1) and PDE-4 (type-IVB2), anti-peptide antisera were generated. One set ('DPD/PDE-4-common'), generated against a peptide sequence found at the common C-terminus of these two PDEs, detected both PDEs. A second set was PDE-4 specific, being directed against a peptide sequence found within the unique N-terminal region of PDE-4. In brain, DPD was found exclusively in the cytosol and PDE-4 exclusively associated with membranes. Both brain DPD and PDE-4 activities, isolated by immunoprecipitation, were cyclic AMP-specific (KmcyclicAMP: approximately 5 microM for DPD; approximately 4 microM for PDE-4) and were inhibited by low rolipram concentrations (K1rolipram approximately 1 microM for both). Transient expression of DPD in COS-1 cells allowed identification of an approx. 64 kDa species which co-migrated on SDS/PAGE with the immunoreactive species identified in both brain cytosol and membrane fractions using the DPD/PDE-4-common antisera. The subunit size observed for PDE-4 (approx. 64 kDa) in brain membranes was similar to that predicted from the cDNA sequence, but that observed for DPD was approx. 4 kDa greater. Type-IV, rolipram-inhibited PDE activity was found in all brain regions except the pituitary, where it formed between 30 and 70% of the PDE activity in membrane and cytosolic fractions when assayed with 1 microM cyclic AMP, PDE-4 formed 40-50% of the membrane type-IV activity in all brain regions save the midbrain (approx. 20%). DPD distribution was highly restricted to certain regions, providing approx. 35% of the type-IV cytosolic activity in hippocampus and 13-21% in cortex, hypothalamus and striatum with no presence in brain stem, cerebellum, midbrain and pituitary. The combined type-IVB PDE activities of DPD and PDE-4 contributed approx. 10% of the total PDE activity in most brain regions except for the pituitary (zero) and the mid

  20. 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

  1. 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. PMID:26188004

  2. 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. PMID:25281278

  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. Data on the utilization of treatment modalities for ED in Taiwan in the era of PDE5 inhibitors.

    PubMed

    Tsai, W-K; Jiann, B-P

    2014-01-01

    Oral PDE5 inhibitors, intracavernosal injection and penile implants are mainstay treatments for ED. Data on their utilization reflect economic aspects of ED, but are underreported. We report utilization data and user characteristics for these modalities in Taiwan between 1999 and 2011. Sales data on PDE5 inhibitors-sildenafil citrate, tadalafil and vardenafil and on alprostadil were retrieved from International Market Services Health, and on penile implants from the local importing company for them. Users' clinical characteristics were derived from one institution. Between 1999 and 2011, sales of PDE5 inhibitors increased 5.9-fold, whereas those of alprostadil and penile implants remained stable. Over 90% of PDE5 inhibitors were purchased in pharmacies without a prescription. Between 1999 and 2011, the number of patients who received PDE5 inhibitors (n=4715) exceeded those who underwent penile injection (n=333) and penile implantation (n=108). The mean age of patients with ED who first received PDE5 inhibitors tended to decrease over consecutive years. Discontinuation of treatment with PDE5 inhibitors or intracavernosal injection reached 90% within 3 years of treatment initiation. Our data on the increasing market for PDE5 inhibitors and the trend for first use of PDE5 inhibitors at younger ages highlight the growing burden of ED and the acceptance of PDE5 inhibitors as the primary treatment for ED. PMID:24451166

  5. Discovery of a novel orally active PDE-4 inhibitor effective in an ovalbumin-induced asthma murine model.

    PubMed

    Kwak, Hyun Jeong; Nam, Ji Yeon; Song, Jin Sook; No, Zaesung; Yang, Sung Don; Cheon, Hyae Gyeong

    2012-06-15

    Phosphodiesterase-4 (PDE-4) is responsible for metabolizing adenosine 3',5'-cyclic monophosphate that reduces the activation of a wide range of inflammatory cells including eosinophils. PDE-4 inhibitors are under development for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Herein, we report a novel PDE-4 inhibitor, PDE-423 (3-[1-(3-cyclopropylmethoxy-4-difluoromethoxybenzyl)-1H-pyrazol-3-yl]-benzoic acid), which shows good in vitro and in vivo oral activities. PDE-423 exhibited in vitro IC(50)s of 140 nM and 550 nM in enzyme assay and cell-based assay, respectively. In vivo study using ovalbumin-induced asthmatic mice revealed that PDE-423 reduced methacholine-stimulated airway hyperreactivity in a dose-dependent manner by once daily oral administration (ED(50)=18.3 mg/kg), in parallel with decreased eosinophil peroxidase activity and improved lung histology. In addition, PDE-423 was effective in diminishing lipopolysaccharide-induced neutrophilia in vivo as well as in vitro. Oral administration of PDE-423 (100 mg/kg) had no effect on the duration of xylazine/ketamine-induced anesthesia and did not induce vomiting incidence in ferrets up to the dose of 1000 mg/kg. The present study indicates that a novel PDE-4 inhibitor, PDE-423, has good pharmacological profiles implicating this as a potential candidate for the development of a new anti-asthmatic drug. PMID:22554769

  6. 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. PMID:27544407

  7. 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.

  8. Nonlinear optics at interfaces

    SciTech Connect

    Chen, C.K.

    1980-12-01

    Two aspects of surface nonlinear optics are explored in this thesis. The first part is a theoretical and experimental study of nonlinear intraction of surface plasmons and bulk photons at metal-dielectric interfaces. The second part is a demonstration and study of surface enhanced second harmonic generation at rough metal surfaces. A general formulation for nonlinear interaction of surface plasmons at metal-dielectric interfaces is presented and applied to both second and third order nonlinear processes. Experimental results for coherent second and third harmonic generation by surface plasmons and surface coherent antiStokes Raman spectroscopy (CARS) are shown to be in good agreement with the theory.

  9. 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.

  10. 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.

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

    PubMed

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

    2015-03-01

    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 of 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 anti-cancer benefits. Despite mixed results of these clinical trials, there is a 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

  12. 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. PMID:25891816

  13. 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

  14. 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

  15. 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.

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

    DOE PAGES

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

    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

  17. Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis.

    PubMed

    Lynch, Danielle C; Dyment, David A; Huang, Lijia; Nikkel, Sarah M; Lacombe, Didier; Campeau, Philippe M; Lee, Brendan; Bacino, Carlos A; Michaud, Jacques L; Bernier, Francois P; Parboosingh, Jillian S; Innes, A Micheil

    2013-01-01

    Acrodysostosis is characterized by nasal hypoplasia, peripheral dysostosis, variable short stature, and intellectual impairment. Recently, mutations in PRKAR1A were reported in patients with acrodysostosis and hormone resistance. Subsequently, mutations in a phosphodiesterase gene (PDE4D) were identified in seven sporadic cases. We sequenced PDE4D in seven acrodysostosis patients from five families. Missense mutations were identified in all cases. Families showed de novo inheritance except one family with three affected children whose father was subsequently found to have subtle features of acrodysostosis. There were no recurrent mutations. Short stature and endocrine resistance are rare in this series; however, cognitive involvement and obesity were frequent. This last finding is relevant given PDE4D is insulin responsive and potentially involved in lipolysis. PDE4D encodes a cyclic AMP regulator and places PDE4D-related acrodysostosis within the same family of diseases as pseudohypoparathyroidism, pseudopseudohypoparathyroidism, PRKAR1A-related acrodysostosis and brachydactyly-mental retardation syndrome; all characterized by cognitive impairment and short distal extremities. PMID:23033274

  18. Rutin inhibits B[a]PDE-induced cyclooxygenase-2 expression by targeting EGFR kinase activity.

    PubMed

    Choi, Seunghwan; Lim, Tae-Gyu; Hwang, Mun Kyung; Kim, Yoon-A; Kim, Jiyoung; Kang, Nam Joo; Jang, Tae Su; Park, Jun-Seong; Yeom, Myeong Hun; Lee, Ki Won

    2013-11-15

    Rutin is a well-known flavonoid that exists in various natural sources. Accumulative studies have represented the biological effects of rutin, such as anti-oxidative and anti-inflammatory effects. However, the underlying mechanisms of rutin and its direct targets are not understood. We investigated whether rutin reduced B[a]PDE-induced-COX-2 expression. The transactivation of AP-1 and NF-κB were inhibited by rutin. Rutin also attenuated B[a]PDE-induced Raf/MEK/ERK and Akt activation, but had no effect on the phosphorylation of EGFR. An in vitro kinase assay revealed rutin suppressed EGFR kinase activity. We also confirmed direct binding between rutin and EGFR, and found that the binding was regressed by ATP. The EGFR inhibitor also inhibited the B[a]PDE-induced MEK/ERK and Akt signaling pathways and subsequently, suppressed COX-2 expression and promoter activity, in addition to suppressing the transactivation of AP-1 and NF-κB. In EGFR(-/-)mouse embryonic fibroblast cells, B[a]PDE-induced COX-2 expression was also diminished. Collectively, rutin inhibits B[a]PDE-induced COX-2 expression by suppressing the Raf/MEK/ERK and Akt signaling pathways. EGFR appeared to be the direct target of rutin.

  19. Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis.

    PubMed

    Lynch, Danielle C; Dyment, David A; Huang, Lijia; Nikkel, Sarah M; Lacombe, Didier; Campeau, Philippe M; Lee, Brendan; Bacino, Carlos A; Michaud, Jacques L; Bernier, Francois P; Parboosingh, Jillian S; Innes, A Micheil

    2013-01-01

    Acrodysostosis is characterized by nasal hypoplasia, peripheral dysostosis, variable short stature, and intellectual impairment. Recently, mutations in PRKAR1A were reported in patients with acrodysostosis and hormone resistance. Subsequently, mutations in a phosphodiesterase gene (PDE4D) were identified in seven sporadic cases. We sequenced PDE4D in seven acrodysostosis patients from five families. Missense mutations were identified in all cases. Families showed de novo inheritance except one family with three affected children whose father was subsequently found to have subtle features of acrodysostosis. There were no recurrent mutations. Short stature and endocrine resistance are rare in this series; however, cognitive involvement and obesity were frequent. This last finding is relevant given PDE4D is insulin responsive and potentially involved in lipolysis. PDE4D encodes a cyclic AMP regulator and places PDE4D-related acrodysostosis within the same family of diseases as pseudohypoparathyroidism, pseudopseudohypoparathyroidism, PRKAR1A-related acrodysostosis and brachydactyly-mental retardation syndrome; all characterized by cognitive impairment and short distal extremities.

  20. 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.

  1. Refolding and purification of recombinant human PDE7A expressed in Escherichia coli as inclusion bodies.

    PubMed

    Richter, Wito; Hermsdorf, Thomas; Kronbach, Thomas; Dettmer, Dietrich

    2002-06-01

    We have investigated the refolding and purification of the catalytic domain of human 3',5'-cyclic nucleotide phosphodiesterase 7A1 (PDE7A1) expressed in Escherichia coli. A cDNA encoding an N-terminal-truncated PDE7A1(147-482-His) was amplified by RT-PCR from human peripheral blood cells and inserted into the vector pET21-C for bacterial expression of the enzyme fused to a C-terminal His-tag. The PDE was found to be expressed in the form of inclusion bodies which could be refolded to an active enzyme in buffer containing high concentrations of arginine hydrochloride, ethylene glycol, and magnesium chloride at pH 8.5. The PDE7A1(147-482-His) construct could be purified after dialysis and concentration steps by either Zn2+-IDA-Sepharose chromatography or ResourceQ ion-exchange chromatography to homogeneity. In comparison to the metal-chelate column, the ResourceQ purification resulted in a distinctly better yield and enrichment of the protein. Both the Vmax (0.46 micromol. min(-1). mg(-1) ) and the K(m) (0.1 microM) of the purified enzyme were found to be comparable with published data for native or recombinant catalytically active expressed PDE7A1. Using SDS/PAGE, a molecular mass of 39 kDa was determined (theoretical value 38.783 kDa). As known from several other mammalian PDEs, size-exclusion chromatography using refolded PDE7A1(147-482-His) indicated the formation of dimers. The purified enzyme was soluble at concentrations up to 100 microg/ml. A further increase of protein concentration resulted, however, in precipitation of the enzyme.

  2. Functional Analysis of a c-di-AMP-specific Phosphodiesterase MsPDE from Mycobacterium smegmatis

    PubMed Central

    Tang, Qing; Luo, Yunchao; Zheng, Cao; Yin, Kang; Ali, Maria Kanwal; Li, Xinfeng; He, Jin

    2015-01-01

    Cyclic di‑AMP (c-di-AMP) is a second signaling molecule involved in the regulation of bacterial physiological processes and interaction between pathogen and host. However, the regulatory network mediated by c-di-AMP in Mycobacterium remains obscure. In M. smegmatis, a diadenylate cyclase (DAC) was reported recently, but there is still no investigation on c-di-AMP phosphodiesterase (PDE). Here, we provide a systematic study on signaling mechanism of c-di-AMP PDE in M. smegmatis. Based on our enzymatic analysis, MsPDE (MSMEG_2630), which contained a DHH-DHHA1 domain, displayed a 200-fold higher hydrolytic efficiency (kcat/Km) to c-di-AMP than to c-di-GMP. MsPDE was capable of converting c-di-AMP to pApA and AMP, and hydrolyzing pApA to AMP. Site-directed mutations in DHH and DHHA1 revealed that DHH domain was critical for the phosphodiesterase activity. To explore the regulatory role of c-di-AMP in vivo, we constructed the mspde mutant (Δmspde) and found that deficiency of MsPDE significantly enhanced intracellular C12-C20 fatty acid accumulation. Deficiency of DAC in many bacteria results in cell death. However, we acquired the M. smegmatis strain with DAC gene disrupted (ΔmsdisA) by homologous recombination approach. Deletion of msdisA reduced bacterial C12-C20 fatty acids production but scarcely affected bacterial survival. We also provided evidences that superfluous c-di-AMP in M. smegmatis could lead to abnormal colonial morphology. Collectively, our results indicate that MsPDE is a functional c-di-AMP-specific phosphodiesterase both in vitro and in vivo. Our study also expands the regulatory network mediated by c-di-AMP in M. smegmatis. PMID:26078723

  3. Coupling vs decoupling approaches for PDE/ODE systems modeling intercellular signaling

    NASA Astrophysics Data System (ADS)

    Carraro, Thomas; Friedmann, Elfriede; Gerecht, Daniel

    2016-06-01

    We consider PDE/ODE systems for the simulation of intercellular signaling in multicellular environments. The intracellular processes for each cell described here by ODEs determine the long-time dynamics, but the PDE part dominates the solving effort. Thus, it is not clear if commonly used decoupling methods can outperform a coupling approach. Based on a sensitivity analysis, we present a systematic comparison between coupling and decoupling approaches for this class of problems and show numerical results. For biologically relevant configurations of the model, our quantitative study shows that a coupling approach performs much better than a decoupling one.

  4. FRS 1000, an extract of red onion peel, strongly inhibits phosphodiesterase 5A (PDE 5A).

    PubMed

    Lines, T C; Ono, M

    2006-03-01

    As part of our ongoing search for flavonoids that are bioactive in humans, it was determined that FRS 1000, a beverage containing flavonoids extracted from onion peel, showed unexpected improvement of male sexual function. An in vitro enzyme assay clearly showed that FRS 1000 has a strong phosphodiesterase 5A (PDE 5A) inhibitory activity, which is considered to be important for treatment of erectile dysfunction. Detailed assays of each major ingredient indicated that the antioxidative flavonoid quercetin was responsible for the activity. Results also suggested that PDE 5A inhibition is not directly related to the free radical scavenging activity of flavonoids. PMID:16492525

  5. 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…

  6. Use of Particular Analytical Solutions for Calculations of Nonlinear PDEs

    SciTech Connect

    Porubov, A.; Bouche, D.; Bonnaud, G.

    2008-10-30

    It is shown, how analytical solutions of non-linear partial differential equations (PDE) may be applied for a design of their numerical solutions are considered. First, explicit particular exact and asymptotic solutions predict important features of the waves behavior even outside their formal applicability realized in numerics. Thus a prediction may be done whether an arbitrary initial condition splits into the train of localized waves, and each of these waves in numerical solution is described by the analytical travelling wave solution. This happens both for the bell-shaped and kink-shaped localized waves. Second application concerns the study of numerical dispersion and dissipation using the method of differential approximation. This method allows us to study defects of a discrete scheme by an analysis of a non-linear PDE obtained from the scheme. In particular, exact solutions of this equation help us to improve the scheme diminishing unwanted effects.

  7. 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

  8. 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. PMID:25739440

  9. 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.

  10. 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.

  11. 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

    2015-01-01

    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.

  12. Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors.

    PubMed

    Meegalla, Sanath K; Huang, Hui; Illig, Carl R; Parks, Daniel J; Chen, Jinsheng; Lee, Yu-Kai; Wilson, Kenneth J; Patel, Sharmila K; Cheung, Wing S; Lu, Tianbao; Kirchner, Thomas; Askari, Hossein B; Geisler, John; Patch, Raymond J; Gibbs, Alan C; Rady, Brian; Connelly, Margery; Player, Mark R

    2016-09-01

    Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo. PMID:27491708

  13. A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia.

    PubMed

    Kohl, Susanne; Coppieters, Frauke; Meire, Françoise; Schaich, Simone; Roosing, Susanne; Brennenstuhl, Christina; Bolz, Sylvia; van Genderen, Maria M; Riemslag, Frans C C; Lukowski, Robert; den Hollander, Anneke I; Cremers, Frans P M; De Baere, Elfride; Hoyng, Carel B; Wissinger, Bernd

    2012-09-01

    Achromatopsia (ACHM) is an autosomal-recessive retinal dystrophy characterized by color blindness, photophobia, nystagmus, and severely reduced visual acuity. Its prevalence has been estimated to about 1 in 30,000 individuals. Four genes, GNAT2, PDE6C, CNGA3, and CNGB3, have been implicated in ACHM, and all encode functional components of the phototransduction cascade in cone photoreceptors. Applying a functional-candidate-gene approach that focused on screening additional genes involved in this process in a cohort of 611 index cases with ACHM or other cone photoreceptor disorders, we detected a homozygous single base change (c.35C>G) resulting in a nonsense mutation (p.Ser12(∗)) in PDE6H, encoding the inhibitory γ subunit of the cone photoreceptor cyclic guanosine monophosphate phosphodiesterase. The c.35C>G mutation was present in three individuals from two independent families with a clinical diagnosis of incomplete ACHM and preserved short-wavelength-sensitive cone function. Moreover, we show through immunohistochemical colocalization studies in mouse retina that Pde6h is evenly present in all retinal cone photoreceptors, a fact that had been under debate in the past. These findings add PDE6H to the set of genes involved in autosomal-recessive cone disorders and demonstrate the importance of the inhibitory γ subunit in cone phototransduction. PMID:22901948

  14. Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies.

    PubMed

    Hu, Essa; Chen, Ning; Kunz, Roxanne K; Hwang, Dah-Ren; Michelsen, Klaus; Davis, Carl; Ma, Ji; Shi, Jianxia; Lester-Zeiner, Dianna; Hungate, Randall; Treanor, James; Chen, Hang; Allen, Jennifer R

    2016-07-14

    We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding potential (BPND) in NHP than our previously reported tracer 1, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washout rate in vivo. Five candidates (2-6) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines (2, 3) and one keto-benzimidazole (5) exhibited PDE10A target specificity and brain uptake comparable to or better than 1 in the in vivo LC-MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [(18)F]-5 produced a significantly improved BPND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies. PMID:27437084

  15. 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

  16. 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

    2016-04-01

    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. PMID:27058447

  17. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis.

    PubMed

    Michot, Caroline; Le Goff, Carine; Goldenberg, Alice; Abhyankar, Avinash; Klein, Céline; Kinning, Esther; Guerrot, Anne-Marie; Flahaut, Philippe; Duncombe, Alice; Baujat, Genevieve; Lyonnet, Stanislas; Thalassinos, Caroline; Nitschke, Patrick; Casanova, Jean-Laurent; Le Merrer, Martine; Munnich, Arnold; Cormier-Daire, Valérie

    2012-04-01

    Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368*]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368(∗)] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis. PMID:22464250

  18. 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.

  19. 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.

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

    PubMed Central

    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. PMID:24305610

  1. 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. PMID:24261938

  2. 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. PMID:24305610

  3. 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.

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

    NASA Astrophysics Data System (ADS)

    Bilgin, Bilgesu; Kalantarov, Varga; Zelik, Sergey

    2016-06-01

    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.

  5. Rolipram attenuates bile duct ligation-induced liver injury in rats: a potential pathogenic role of PDE4.

    PubMed

    Gobejishvili, Leila; Barve, Shirish; Breitkopf-Heinlein, Katja; Li, Yan; Zhang, JingWen; Avila, Diana V; Dooley, Steven; McClain, Craig J

    2013-10-01

    Anti-inflammatory and antifibrotic effects of the broad spectrum phosphodiesterase (PDE) inhibitor pentoxifylline have suggested an important role for cyclic nucleotides in the pathogenesis of hepatic fibrosis; however, studies examining the role of specific PDEs are lacking. Endotoxemia and Toll-like receptor 4 (TLR4)-mediated inflammatory and profibrotic signaling play a major role in the development of hepatic fibrosis. Because cAMP-specific PDE4 critically regulates lipopolysaccharide (LPS)-TLR4-induced inflammatory cytokine expression, its pathogenic role in bile duct ligation-induced hepatic injury and fibrogenesis in Sprague-Dawley rats was examined. Initiation of cholestatic liver injury and fibrosis was accompanied by a significant induction of PDE4A, B, and D expression and activity. Treatment with the PDE4-specific inhibitor rolipram significantly decreased liver PDE4 activity, hepatic inflammatory and profibrotic cytokine expression, injury, and fibrosis. At the cellular level, in relevance to endotoxemia and inflammatory cytokine production, PDE4B was observed to play a major regulatory role in the LPS-inducible tumor necrosis factor (TNF) production by isolated Kupffer cells. Moreover, PDE4 expression was also involved in the in vitro activation and transdifferentiation of isolated hepatic stellate cells (HSCs). Particularly, PDE4A, B, and D upregulation preceded induction of the HSC activation marker α-smooth muscle actin (α-SMA). In vitro treatment of HSCs with rolipram effectively attenuated α-SMA, collagen expression, and accompanying morphologic changes. Overall, these data strongly suggest that upregulation of PDE4 expression during cholestatic liver injury plays a potential pathogenic role in the development of inflammation, injury, and fibrosis. PMID:23887098

  6. PDE2 activity differs in right and left rat ventricular myocardium and differentially regulates β2 adrenoceptor-mediated effects

    PubMed Central

    Soler, Fernando; Fernández-Belda, Francisco; Pérez-Schindler, Joaquín; Handschin, Christoph; Fuente, Teodomiro

    2015-01-01

    The important regulator of cardiac function, cAMP, is hydrolyzed by different cyclic nucleotide phosphodiesterases (PDEs), whose expression and activity are not uniform throughout the heart. Of these enzymes, PDE2 shapes β1 adrenoceptor-dependent cardiac cAMP signaling, both in the right and left ventricular myocardium, but its role in regulating β2 adrenoceptor-mediated responses is less well known. Our aim was to investigate possible differences in PDE2 transcription and activity between right (RV) and left (LV) rat ventricular myocardium, as well as its role in regulating β2 adrenoceptor effects. The free walls of the RV and the LV were obtained from Sprague–Dawley rat hearts. Relative mRNA for PDE2 (quantified by qPCR) and PDE2 activity (evaluated by a colorimetric procedure and using the PDE2 inhibitor EHNA) were determined in RV and LV. Also, β2 adrenoceptor-mediated effects (β2-adrenoceptor agonist salbutamol + β1 adrenoceptor antagonist CGP-20712A) on contractility and cAMP concentrations, in the absence or presence of EHNA, were studied in the RV and LV. PDE2 transcript levels were less abundant in RV than in LV and the contribution of PDE2 to the total PDE activity was around 25% lower in the microsomal fraction of the RV compared with the LV. β2 adrenoceptor activation increased inotropy and cAMP levels in the LV when measured in the presence of EHNA, but no such effects were observed in the RV, either in the presence or absence of EHNA. These results indicate interventricular differences in PDE2 transcript and activity levels, which may distinctly regulate β2 adrenoceptor-mediated contractility and cAMP concentrations in the RV and in the LV of the rat heart. PMID:25432985

  7. Protein kinase C-mediated phosphorylation and activation of PDE3A regulate cAMP levels in human platelets.

    PubMed

    Hunter, Roger W; Mackintosh, Carol; Hers, Ingeborg

    2009-05-01

    The elevation of [cAMP](i) is an important mechanism of platelet inhibition and is regulated by the opposing activity of adenylyl cyclase and phosphodiesterase (PDE). In this study, we demonstrate that a variety of platelet agonists, including thrombin, significantly enhance the activity of PDE3A in a phosphorylation-dependent manner. Stimulation of platelets with the PAR-1 agonist SFLLRN resulted in rapid and transient phosphorylation of PDE3A on Ser(312), Ser(428), Ser(438), Ser(465), and Ser(492), in parallel with the PKC (protein kinase C) substrate, pleckstrin. Furthermore, phosphorylation and activation of PDE3A required the activation of PKC, but not of PI3K/PKB, mTOR/p70S6K, or ERK/RSK. Activation of PKC by phorbol esters also resulted in phosphorylation of the same PDE3A sites in a PKC-dependent, PKB-independent manner. This was further supported by the finding that IGF-1, which strongly activates PI3K/PKB, but not PKC, did not regulate PDE3A. Platelet activation also led to a PKC-dependent association between PDE3A and 14-3-3 proteins. In contrast, cAMP-elevating agents such as PGE(1) and forskolin-induced phosphorylation of Ser(312) and increased PDE3A activity, but did not stimulate 14-3-3 binding. Finally, complete antagonism of PGE(1)-evoked cAMP accumulation by thrombin required both G(i) and PKC activation. Together, these results demonstrate that platelet activation stimulates PKC-dependent phosphorylation of PDE3A on Ser(312), Ser(428), Ser(438), Ser(465), and Ser(492) leading to a subsequent increase in cAMP hydrolysis and 14-3-3 binding. PMID:19261611

  8. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization.

    PubMed Central

    Houslay, Miles D; Adams, David R

    2003-01-01

    cAMP is a second messenger that controls many key cellular functions. The only way to inactivate cAMP is to degrade it through the action of cAMP phosphodiesterases (PDEs). PDEs are thus poised to play a key regulatory role. PDE4 cAMP-specific phosphodiesterases appear to have specific functions with selective inhibitors serving as potent anti-inflammatory agents. The recent elucidation of the structure of the PDE4 catalytic unit allows for molecular insight into the mode of catalysis as well as substrate and inhibitor selectivity. The four PDE4 genes encode over 16 isoforms, each of which is characterized by a unique N-terminal region. PDE4 isoforms play a pivotal role in controlling functionally and spatially distinct pools of cAMP by virtue of their unique intracellular targeting. Targeting occurs by association with proteins, such as arrestins, SRC family tyrosyl kinases, A-kinase anchoring proteins ('AKAPs') and receptor for activated C kinase 1 ('RACK1'), and, in the case of isoform PDE4A1, by a specific interaction (TAPAS-1) with phosphatidic acid. PDE4 isoforms are 'designed' to be regulated by extracellular-signal-related protein kinase (ERK), which binds to anchor sites on the PDE4 catalytic domain that it phosphorylates. The upstream conserved region 1 (UCR1) and 2 (UCR2) modules that abut the PDE4 catalytic unit confer regulatory functions by orchestrating the functional outcome of phosphorylation by cAMP-dependent protein kinase ('PKA') and ERK. PDE4 enzymes stand at a crossroads that allows them to integrate various signalling pathways with that of cAMP in spatially distinct compartments. PMID:12444918

  9. Global methods for nonlinear complementarity problems

    SciTech Connect

    More, J.J.

    1994-04-01

    Global methods for nonlinear complementarity problems formulate the problem as a system of nonsmooth nonlinear equations approach, or use continuation to trace a path defined by a smooth system of nonlinear equations. We formulate the nonlinear complementarity problem as a bound-constrained nonlinear least squares problem. Algorithms based on this formulation are applicable to general nonlinear complementarity problems, can be started from any nonnegative starting point, and each iteration only requires the solution of systems of linear equations. Convergence to a solution of the nonlinear complementarity problem is guaranteed under reasonable regularity assumptions. The converge rate is Q-linear, Q-superlinear, or Q-quadratic, depending on the tolerances used to solve the subproblems.

  10. 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.

  11. 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

  12. AB020. Penile rehabilitation with PDE5 inhibitors in men following radical prostatectomy

    PubMed Central

    Jiann, Bang-Ping

    2015-01-01

    Post-radical prostatectomy (RP) erectile dysfunction (ED) remains a challenge for the urologist. Despite the improvements in surgical technique, ED occurs between 20% and 90% in patients treated with bilateral nerve-sparing RP. Patient factors, cancer selection, type of surgery, surgical techniques, and surgeon factors represent the key significant contributors to erectile function recovery. The aim of a penile rehabilitation program is to preserve the functional smooth-muscle content of the corpus cavernosum during the neuropraxia period. Phosphodiesterase type 5 (PDE5) inhibitors are commonly used in rehabilitation programs. In animal models, such an approach could promote erectile function recovery, improve smooth muscle-to-collagen penile ration, reduce penile apoptotic index, preserve penile endothelial function and promote neuroprotection during nerve damage. Despite the strong basic science support from animal studies, discordant results have been reached in humans. The previous randomized trials comparing chronic versus on-demand PDE-5 inhibitors use after RP may be affected by improper patient selection in that only men at low risk of postoperative ED were included. These patients would recover erectile function regardless of the type of PDE5 inhibitor administration because of their excellent baseline profile. Prospective, randomized trials have shown a significant benefit of daily PDE5-I administration as compared with placebo in terms of postoperative EF recovery. Patients with intermediate risk of ED after surgery are the best candidates for daily treatment with PDE5 inhibitor after bilateral nerve-sparing RP. The maximal effect of penile rehabilitation may be found in those men with a certain (but not high) degree of systemic and erectile impairment preoperatively. In conclusion, penile rehabilitation could achieve faster and better natural erectile function after RP and should be started as early as possible. Chronic use of PDE5-I may confer the

  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. 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

  15. PDE-based Morphology for Matrix Fields: Numerical Solution Schemes

    NASA Astrophysics Data System (ADS)

    Burgeth, Bernhard; Breuß, Michael; Didas, Stephan; Weickert, Joachim

    Tensor fields are important in digital imaging and computer vision. Hence there is a demand for morphological operations to perform e.g. shape analysis, segmentation or enhancement procedures. Recently, fundamental morphological concepts have been transferred to the setting of fields of symmetric positive definite matrices, which are symmetric rank two tensors. This has been achieved by a matrix-valued extension of the nonlinear morphological partial differential equations (PDEs) for dilation and erosion known for grey scale images. Having these two basic operations at our disposal, more advanced morphological operators such as top hats or morphological derivatives for matrix fields with symmetric, positive semidefinite matrices can be constructed. The approach realises a proper coupling of the matrix channels rather than treating them independently. However, from the algorithmic side the usual scalar morphological PDEs are transport equations that require special upwind-schemes or novel high-accuracy predictor-corrector approaches for their adequate numerical treatment. In this chapter we propose the non-trivial extension of these schemes to the matrix-valued setting by exploiting the special algebraic structure available for symmetric matrices. Furthermore we compare the performance and juxtapose the results of these novel matrix-valued high-resolution-type (HRT) numerical schemes by considering top hats and morphological derivatives applied to artificial and real world data sets.

  16. 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. PMID:27301679

  17. 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

  18. Microvascular dysfunction and efficacy of PDE5 inhibitors in BPH-LUTS.

    PubMed

    Cellek, Selim; Cameron, Norman E; Cotter, Mary A; Fry, Christopher H; Ilo, Dapo

    2014-04-01

    Benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS) and erectile dysfunction commonly coexist, and both respond to phosphodiesterase (PDE) 5 inhibitors, suggesting a shared pathophysiological mechanism. We propose that both BPH-LUTS and erectile dysfunction are caused by microvascular dysfunction within the pelvic organs, and we present an overview of preclinical and clinical studies supporting the hypothesis that, within both the penis and the lower urinary tract, a combination of endothelial and neural dysfunction leads to a vicious cycle of hypoxia, vasoconstriction, altered smooth muscle contractility, and degeneration of autonomic neurons and ganglia. This hypothesis explains much of the preclinical and clinical research relating to these two conditions, and provides a rationale for further investigation into the effects of PDE5 inhibitors on the pathophysiology and symptoms of BPH-LUTS.

  19. 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.

  20. 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.

  1. Microvascular dysfunction and efficacy of PDE5 inhibitors in BPH-LUTS.

    PubMed

    Cellek, Selim; Cameron, Norman E; Cotter, Mary A; Fry, Christopher H; Ilo, Dapo

    2014-04-01

    Benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS) and erectile dysfunction commonly coexist, and both respond to phosphodiesterase (PDE) 5 inhibitors, suggesting a shared pathophysiological mechanism. We propose that both BPH-LUTS and erectile dysfunction are caused by microvascular dysfunction within the pelvic organs, and we present an overview of preclinical and clinical studies supporting the hypothesis that, within both the penis and the lower urinary tract, a combination of endothelial and neural dysfunction leads to a vicious cycle of hypoxia, vasoconstriction, altered smooth muscle contractility, and degeneration of autonomic neurons and ganglia. This hypothesis explains much of the preclinical and clinical research relating to these two conditions, and provides a rationale for further investigation into the effects of PDE5 inhibitors on the pathophysiology and symptoms of BPH-LUTS. PMID:24619381

  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. 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

  4. 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.

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

    PubMed

    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.

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

    PubMed

    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. 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.

  8. 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.

  9. 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

  10. RPGR, a prenylated retinal ciliopathy protein, is targeted to cilia in a prenylation- and PDE6D-dependent manner

    PubMed Central

    Dutta, Nirmal

    2016-01-01

    ABSTRACT RPGR (retinitis pigmentosa GTPase regulator) is a ciliary protein associated with several forms of inherited retinal degenerative diseases. PDE6D is a ubiquitously expressed prenyl-binding protein and involved in ciliary targeting of prenylated proteins. The current working model for the RPGR function depicts that RPGR acts as a scaffold protein to recruit cargo-loaded PDE6D to primary cilia. Here, we present evidence demonstrating an alternative relationship between RPGR and PDE6D, in which RPGR is a cargo of PDE6D for ciliary targeting. We found that the constitutive isoform of RPGR, which is prenylated, requires prenylation for its ciliary localization. We also found that there are at least two independent ciliary targeting signals in RPGR: one within the N-terminal region that contains the RCC1-like domain and the other near the prenylation site at the C-terminus. Ablation of PDE6D blocked ciliary targeting of RPGR. Our study indicates that prenylated RPGR is one of the cargos of PDE6D for ciliary trafficking and provides insight into the mechanisms by which RPGR is targeted to cilia. PMID:27493202

  11. RPGR, a prenylated retinal ciliopathy protein, is targeted to cilia in a prenylation- and PDE6D-dependent manner.

    PubMed

    Dutta, Nirmal; Seo, Seongjin

    2016-09-15

    RPGR (retinitis pigmentosa GTPase regulator) is a ciliary protein associated with several forms of inherited retinal degenerative diseases. PDE6D is a ubiquitously expressed prenyl-binding protein and involved in ciliary targeting of prenylated proteins. The current working model for the RPGR function depicts that RPGR acts as a scaffold protein to recruit cargo-loaded PDE6D to primary cilia. Here, we present evidence demonstrating an alternative relationship between RPGR and PDE6D, in which RPGR is a cargo of PDE6D for ciliary targeting. We found that the constitutive isoform of RPGR, which is prenylated, requires prenylation for its ciliary localization. We also found that there are at least two independent ciliary targeting signals in RPGR: one within the N-terminal region that contains the RCC1-like domain and the other near the prenylation site at the C-terminus. Ablation of PDE6D blocked ciliary targeting of RPGR. Our study indicates that prenylated RPGR is one of the cargos of PDE6D for ciliary trafficking and provides insight into the mechanisms by which RPGR is targeted to cilia.

  12. RPGR, a prenylated retinal ciliopathy protein, is targeted to cilia in a prenylation- and PDE6D-dependent manner.

    PubMed

    Dutta, Nirmal; Seo, Seongjin

    2016-01-01

    RPGR (retinitis pigmentosa GTPase regulator) is a ciliary protein associated with several forms of inherited retinal degenerative diseases. PDE6D is a ubiquitously expressed prenyl-binding protein and involved in ciliary targeting of prenylated proteins. The current working model for the RPGR function depicts that RPGR acts as a scaffold protein to recruit cargo-loaded PDE6D to primary cilia. Here, we present evidence demonstrating an alternative relationship between RPGR and PDE6D, in which RPGR is a cargo of PDE6D for ciliary targeting. We found that the constitutive isoform of RPGR, which is prenylated, requires prenylation for its ciliary localization. We also found that there are at least two independent ciliary targeting signals in RPGR: one within the N-terminal region that contains the RCC1-like domain and the other near the prenylation site at the C-terminus. Ablation of PDE6D blocked ciliary targeting of RPGR. Our study indicates that prenylated RPGR is one of the cargos of PDE6D for ciliary trafficking and provides insight into the mechanisms by which RPGR is targeted to cilia. PMID:27493202

  13. Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4.

    PubMed

    Richter, Wito; Day, Peter; Agrawal, Rani; Bruss, Matthew D; Granier, Sébastien; Wang, Yvonne L; Rasmussen, Søren G F; Horner, Kathleen; Wang, Ping; Lei, Tao; Patterson, Andrew J; Kobilka, Brian; Conti, Marco

    2008-01-23

    Beta1- and beta2-adrenergic receptors (betaARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by beta1AR but not beta2AR signaling, and chronic stimulation of the two receptors has opposing effects on myocyte apoptosis and cell survival. Differences in the assembly of macromolecular signaling complexes may explain the distinct biological outcomes. Here, we demonstrate that beta1AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a beta2AR/beta-arrestin/PDE complex reported previously. The beta1AR binds a PDE variant, PDE4D8, in a direct manner, and occupancy of the receptor by an agonist causes dissociation of this complex. Conversely, agonist binding to the beta2AR is a prerequisite for the recruitment of a complex consisting of beta-arrestin and the PDE4D variant, PDE4D5, to the receptor. We propose that the distinct modes of interaction with PDEs result in divergent cAMP signals in the vicinity of the two receptors, thus, providing an additional layer of complexity to enforce the specificity of beta1- and beta2-adrenoceptor signaling.

  14. 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

  15. Identification and in vivo evaluation of a fluorine-18 rolipram analogue, [(18) F]MNI-617, as a radioligand for PDE4 imaging in mammalian brain.

    PubMed

    Thomae, David; Morley, Thomas J; Lee, Hsiaoju S; Barret, Olivier; Constantinescu, Cristian; Papin, Caroline; Baldwin, Ronald M; Tamagnan, Gilles D; Alagille, David

    2016-05-15

    Phosphodiesterase (PDE) 4 is the most prevalent PDE in the central nervous system (CNS) and catalyzes hydrolysis of intracellular cAMP, a secondary messenger. By therapeutic inhibition of PDE4, intracellular cAMP levels can be stabilized, and the symptoms of psychiatric and neurodegenerative disorders including depression, memory loss and Parkinson's disease can be ameliorated. Radiotracers targeting PDE4 can be used to study PDE4 density and function, and evaluate new PDE4 therapeutics, in vivo in a non-invasive way, as has been shown using the carbon-11 labeled PDE4 inhibitor R-(-)-rolipram. Herein we describe a small series of rolipram analogs that contain fluoro- or iodo-substituents that could be used as fluorine-18 PET or iodine-123 SPECT PDE4 radiotracers. This series was evaluated with an in vitro binding assay and a 4-(fluoromethyl) derivative of rolipram, MNI-617, was identified, with a five-fold increase in affinity for PDE4 (Kd  = 0.26 nM) over R-(-)-rolipram (Kd  = 1.6 nM). A deutero-analogue d2 -[(18) F]MNI-617 was radiolabeled and produced in 23% yield with high (>5 Ci/µmol) specific activity and evaluated in non-human primate, where it rapidly entered the brain, with SUVs between 4 and 5, and with a distribution pattern consistent with that of PDE4. PMID:27006107

  16. Light-dependent phosphorylation of the gamma subunit of cGMP-Phophodiesterase (PDE6γ) at residue threonine 22 in intact photoreceptor neurons

    PubMed Central

    Janisch, Kerstin M; Kasanuki, J. Mie; Naumann, Matthew C; Davis, Richard J; Lin, Chyuan-Sheng; Semple-Rowland, Susan; Tsang, Stephen H

    2009-01-01

    The γ subunit of rod-specific cGMP phosphodiesterase 6 (PDE6γ), an effector of the G-protein GNAT1, is a key regulator of phototransduction. The results of several in vitro biochemical reconstitution experiments conducted to examine the effects of phosphorylation of PDE6γ on its ability to regulate the PDE6 catalytic core have been inconsistent, showing that phosphorylation of PDE6γ may increase or decrease the ability of PDE6γ to deactivate phototransduction. To resolve role of phosphorylation of PDE6γ in living photoreceptors, we generated transgenic mice in which either one or both Threonine (T) sites in PDE6γ (T22 and T35), which are candidates for putative regulatory phosphorylation, were substituted with alanine (A). Phosphorylation of these sites was examined as a function of light exposure. We found that phosphorylation of T22 increases with light exposure in intact mouse rods while constitutive phosphorylation of T35 is unaffected by light in intact mouse rods and cones. Phosphorylation of the cone isoform of PDE6γ, PDE6H, is constitutively phosphorylated at the T20 residue. Light-induced T22 phosphorylation was lost in T35A transgenic rods, and T35 phosphorylation was extinguished in T22A transgenic rods. The interdependency of phosphorylation of T22 and T35 suggests that light-induced, post-translational modification of PDE6γ is essential for the regulation of G-protein signaling. PMID:19878658

  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. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

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

    PubMed

    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.

  4. 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

  5. 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.

  6. A CaMKII/PDE4D negative feedback regulates cAMP signaling

    PubMed Central

    Mika, Delphine; Richter, Wito; Conti, Marco

    2015-01-01

    cAMP production and protein kinase A (PKA) are the most widely studied steps in β-adrenergic receptor (βAR) signaling in the heart; however, the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is also activated in response to βAR stimulation and is involved in the regulation of cardiac excitation-contraction coupling. Its activity and expression are increased during cardiac hypertrophy, in heart failure, and under conditions that promote arrhythmias both in animal models and in the human heart, underscoring the clinical relevance of CaMKII in cardiac pathophysiology. Both CaMKII and PKA phosphorylate a number of protein targets critical for Ca2+ handling and contraction with similar, but not always identical, functional consequences. How these two pathways communicate with each other remains incompletely understood, however. To maintain homeostasis, cyclic nucleotide levels are regulated by phosphodiesterases (PDEs), with PDE4s predominantly responsible for cAMP degradation in the rodent heart. Here we have reassessed the interaction between cAMP/PKA and Ca2+/CaMKII signaling. We demonstrate that CaMKII activity constrains basal and βAR-activated cAMP levels. Moreover, we show that these effects are mediated, at least in part, by CaMKII regulation of PDE4D. This regulation establishes a negative feedback loop necessary to maintain cAMP/CaMKII homeostasis, revealing a previously unidentified function for PDE4D as a critical integrator of cAMP/PKA and Ca2+/CaMKII signaling. PMID:25646485

  7. 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.

  8. 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

  9. 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. PMID:23721687

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

    PubMed

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

    2015-01-01

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

  11. Validation of PDE9A Gene Identified in GWAS Showing Strong Association with Milk Production Traits in Chinese Holstein

    PubMed Central

    Yang, Shao-Hua; Bi, Xiao-Jun; Xie, Yan; Li, Cong; Zhang, Sheng-Li; Zhang, Qin; Sun, Dong-Xiao

    2015-01-01

    Phosphodiesterase9A (PDE9A) is a cyclic guanosine monophosphate (cGMP)-specific enzyme widely expressed among the tissues, which is important in activating cGMP-dependent signaling pathways. In our previous genome-wide association study, a single nucleotide polymorphism (SNP) (BTA-55340-no-rsb) located in the intron 14 of PDE9A, was found to be significantly associated with protein yield. In addition, we found that PDE9A was highly expressed in mammary gland by analyzing its mRNA expression in different tissues. The objectives of this study were to identify genetic polymorphisms of PDE9A and to determine the effects of these variants on milk production traits in dairy cattle. DNA sequencing identified 11 single nucleotide polymorphisms (SNPs) and six SNPs in 5′ regulatory region were genotyped to test for the subsequent association analyses. After Bonferroni correction for multiple testing, all these identified SNPs were statistically significant for one or more milk production traits (p < 0.0001~0.0077). Interestingly, haplotype-based association analysis revealed similar effects on milk production traits (p < 0.01). In follow-up RNA expression analyses, two SNPs (c.-1376 G>A, c.-724 A>G) were involved in the regulation of gene expression. Consequently, our findings provide confirmatory evidences for associations of PDE9A variants with milk production traits and these identified SNPs may serve as genetic markers to accelerate Chinese Holstein breeding program. PMID:26556348

  12. 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

  13. 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.

  14. 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.

  15. Carnosic acid slows photoreceptor degeneration in the Pde6brd10 mouse model of retinitis pigmentosa

    PubMed Central

    Kang, Kai; Tarchick, Matthew J.; Yu, Xiaoshan; Beight, Craig; Bu, Ping; Yu, Minzhong

    2016-01-01

    The photoreceptor cell death associated with the various genetic forms of retinitis pigmentosa (RP) is currently untreatable and leads to partial or complete vision loss. Carnosic acid (CA) upregulates endogenous antioxidant enzymes and has proven neuroprotective in studies of neurodegenerative models affecting the brain. In this study, we examined the potential effect of CA on photoreceptor death in the Pde6brd10 mouse model of RP. Our data shows that CA provided morphological and functional preservation of photoreceptors. CA appears to exert its neuroprotective effects through inhibition of oxidative stress and endoplasmic reticulum stress. PMID:26961159

  16. 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.

  17. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity.

    PubMed

    Schafer, P H; Parton, A; Capone, L; Cedzik, D; Brady, H; Evans, J F; Man, H-W; Muller, G W; Stirling, D I; Chopra, R

    2014-09-01

    Apremilast, an oral small molecule inhibitor of phosphodiesterase 4 (PDE4), is in development for chronic inflammatory disorders, and has shown efficacy in psoriasis, psoriatic arthropathies, and Behçet's syndrome. In March 2014, the US Food and Drug Administration approved apremilast for the treatment of adult patients with active psoriatic arthritis. The properties of apremilast were evaluated to determine its specificity, effects on intracellular signaling, gene and protein expression, and in vivo pharmacology using models of innate and adaptive immunity. Apremilast inhibited PDE4 isoforms from all four sub-families (A1A, B1, B2, C1, and D2), with IC50 values in the range of 10 to 100 nM. Apremilast did not significantly inhibit other PDEs, kinases, enzymes, or receptors. While both apremilast and thalidomide share a phthalimide ring structure, apremilast lacks the glutarimide ring and thus fails to bind to cereblon, the target of thalidomide action. In monocytes and T cells, apremilast elevated intracellular cAMP and induced phosphorylation of the protein kinase A substrates CREB and activating transcription factor-1 while inhibiting NF-κB transcriptional activity, resulting in both up- and down-regulation of several genes induced via TLR4. Apremilast reduced interferon-α production by plasmacytoid dendritic cells and inhibited T-cell cytokine production, but had little effect on B-cell immunoglobulin secretion. In a transgenic T-cell and B-cell transfer murine model, apremilast (5mg/kg/day p.o.) did not affect clonal expansion of either T or B cells and had little or no effect on their expression of activation markers. The effect of apremilast on innate immunity was tested in the ferret lung neutrophilia model, which allows monitoring of the known PDE4 inhibitor gastrointestinal side effects (nausea and vomiting). Apremilast significantly inhibited lung neutrophilia at 1mg/kg, but did not induce significant emetic reflexes at doses <30 mg/kg. Overall, the

  18. Dysregulation of hepatic cAMP levels via altered Pde4b expression plays a critical role in alcohol-induced steatosis.

    PubMed

    Avila, Diana V; Barker, David F; Zhang, JingWen; McClain, Craig J; Barve, Shirish; Gobejishvili, Leila

    2016-09-01

    Alcohol-induced hepatic steatosis is a significant risk factor for progressive liver disease. Cyclic adenosine monophosphate (cAMP) signalling has been shown to significantly regulate lipid metabolism; however, the role of altered cAMP homeostasis in alcohol-mediated hepatic steatosis has never been studied. Our previous work demonstrated that increased expression of hepatic phosphodiesterase 4 (Pde4), which specifically hydrolyses and decreases cAMP levels, plays a pathogenic role in the development of liver inflammation/injury. The aim of this study was to examine the role of PDE4 in alcohol-induced hepatic steatosis. C57BL/6 wild-type and Pde4b knockout (Pde4b(-/-) ) mice were pair-fed control or ethanol liquid diets. One group of wild-type mice received rolipram, a PDE4-specific inhibitor, during alcohol feeding. We demonstrate for the first time that an early increase in PDE4 enzyme expression and a resultant decrease in hepatic cAMP levels are associated with the significant reduction in carnitine palmitoyltransferase 1A (Cpt1a) expression. Notably, alcohol-fed (AF) Pde4b(-/-) mice and AF wild-type mice treated with rolipram had significantly lower hepatic free fatty acid content compared with AF wild-type mice. Importantly, PDE4 inhibition in alcohol-fed mice prevented the decrease in hepatic Cpt1a expression via the Pparα/Sirt1/Pgc1α pathway. These results demonstrate that the alcohol- induced increase in hepatic Pde4, specifically Pde4b expression, and compromised cAMP signalling predispose the liver to impaired fatty acid oxidation and the development of steatosis. Moreover, these data also suggest that hepatic PDE4 may be a clinically relevant therapeutic target for the treatment of alcohol-induced hepatic steatosis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27287961

  19. 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

  20. Effects of PDE type 5 inhibitors on left ventricular diastolic dysfunction in resistant hypertension.

    PubMed

    Faria, Ana Paula Cabral de; Modolo, Rodrigo; Moreno, Beatriz Vaz Domingues; Moreno, Heitor

    2015-01-01

    Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.

  1. 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.

  2. PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model.

    PubMed

    Black, Keith L; Yin, Dali; Ong, John M; Hu, Jinwei; Konda, Bindu M; Wang, Xiao; Ko, MinHee K; Bayan, Jennifer-Ann; Sacapano, Manuel R; Espinoza, Andreas; Irvin, Dwain K; Shu, Yan

    2008-09-16

    The blood-brain tumor barrier (BTB) significantly limits delivery of therapeutic concentrations of chemotherapy to brain tumors. A novel approach to selectively increase drug delivery is pharmacologic modulation of signaling molecules that regulate BTB permeability, such as those in cGMP signaling. Here we show that oral administration of sildenafil (Viagra) and vardenafil (Levitra), inhibitors of cGMP-specific PDE5, selectively increased tumor capillary permeability in 9L gliosarcoma-bearing rats with no significant increase in normal brain capillaries. Tumor-bearing rats treated with the chemotherapy agent, adriamycin, in combination with vardenafil survived significantly longer than rats treated with adriamycin alone. The selective increase in tumor capillary permeability appears to be mediated by a selective increase in tumor cGMP levels and increased vesicular transport through tumor capillaries, and could be attenuated by iberiotoxin, a selective inhibitor for calcium-dependent potassium (K(Ca)) channels, that are effectors in cGMP signaling. The effect by sildenafil could be further increased by simultaneously using another BTB "opener", bradykinin. Collectively, this data demonstrates that oral administration of PDE5 inhibitors selectively increases BTB permeability and enhances anti-tumor efficacy for a chemotherapeutic agent. These findings have significant implications for improving delivery of anti-tumor agents to brain tumors. PMID:18674521

  3. 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

  4. Inhibition of PDE5 Restores Depressed Baroreflex Sensitivity in Renovascular Hypertensive Rats

    PubMed Central

    Cavalcanti, Clênia de Oliveira; Alves, Rafael R.; de Oliveira, Alessandro L.; Cruz, Josiane de Campos; de França-Silva, Maria do Socorro; Braga, Valdir de Andrade; Balarini, Camille de Moura

    2016-01-01

    Renal artery stenosis is frequently associated with resistant hypertension, which is defined as failure to normalize blood pressure (BP) even when combined drugs are used. Inhibition of PDE5 by sildenafil has been shown to increase endothelial function and decrease blood pressure in experimental models. However, no available study evaluated the baroreflex sensitivity nor autonomic balance in renovascular hypertensive rats treated with sildenafil. In a translational medicine perspective, our hypothesis is that sildenafil could improve autonomic imbalance and baroreflex sensitivity, contributing to lower blood pressure. Renovascular hypertensive 2-kidney-1-clip (2K1C) and sham rats were treated with sildenafil (45 mg/Kg/day) during 7 days. At the end of treatment, BP and heart rate (HR) were recorded in conscious rats after a 24-h-recovery period. Spontaneous and drug-induced baroreflex sensitivity and autonomic tone were evaluated; in addition, lipid peroxidation was measured in plasma samples. Treatment was efficient in increasing both spontaneous and induced baroreflex sensitivity in treated hypertensive animals. Inhibition of PDE5 was also capable of ameliorating autonomic imbalance in 2K1C rats and decreasing systemic oxidative stress. Taken together, these beneficial effects resulted in significant reductions in BP without affecting HR. We suggest that sildenafil could be considered as a promising alternative to treat resistant hypertension. PMID:26858657

  5. Effects of PDE type 5 inhibitors on left ventricular diastolic dysfunction in resistant hypertension.

    PubMed

    Faria, Ana Paula Cabral de; Modolo, Rodrigo; Moreno, Beatriz Vaz Domingues; Moreno, Heitor

    2015-01-01

    Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients. PMID:25352458

  6. [Patient with testosterone deficit syndrome and erectile dysfunction non-responder to PDE-5 inhibitors].

    PubMed

    Rodríguez-Izquierdo, Marta; Martínez-Salamanca, Juan I; Moncada, Ignacio; Linares Espinós, Estefanía; del Portillo, Luis; Areche, Jennifer; Carballido, Joaquín

    2013-09-01

    Androgens play an essential role in the corporo-venous occlusive mechanism that provokes erection. Accordingly to various studies based on animal models,testosterone deficit syndrome causes an endothelial disorder in the corpora cavernosa with diminished secretion of NO, alteration of penile smooth muscle and tunica albuginea structure, and increase of the number of adipocytes within the erectile tissue, which favors fibrosis and impairs erection. All these alterations are reversible with the exogenous administration of androgens. There are not enough studies to get definitive conclusions about androgen supply improving erectile dysfunction in patients with hypogonadism. Studies have been published in which seems that exogenous testosterone could be useful in the treatment of this type of patients. Nevertheless,in most published randomized double blind studies comparing with placebo, testosterone supply does not provide greater benefit on erectile dysfunction than PDE-5 Inhibitors exclusively. All studies coincide in the need to optimize the treatment with PDE-5 Inhibitors since they do have proven to be effective for the treatment of erectile dysfunction in patients with testosterone deficit syndrome. PMID:24047632

  7. PDE4B mediates local feedback regulation of β₁-adrenergic cAMP signaling in a sarcolemmal compartment of cardiac myocytes.

    PubMed

    Mika, Delphine; Richter, Wito; Westenbroek, Ruth E; Catterall, William A; Conti, Marco

    2014-03-01

    Multiple cAMP phosphodiesterase (PDE) isoforms play divergent roles in cardiac homeostasis but the molecular basis for their non-redundant function remains poorly understood. Here, we report a novel role for the PDE4B isoform in β-adrenergic (βAR) signaling in the heart. Genetic ablation of PDE4B disrupted βAR-induced cAMP transients, as measured by FRET sensors, at the sarcolemma but not in the bulk cytosol of cardiomyocytes. This effect was further restricted to a subsarcolemmal compartment because PDE4B regulates β1AR-, but not β2AR- or PGE2-induced responses. The spatially restricted function of PDE4B was confirmed by its selective effects on PKA-mediated phosphorylation patterns. PDE4B limited the PKA-mediated phosphorylation of key players in excitation-contraction coupling that reside in the sarcolemmal compartment, including L-type Ca(2+) channels and ryanodine receptors, but not phosphorylation of distal cytosolic proteins. β1AR- but not β2AR-ligation induced PKA-dependent activation of PDE4B and interruption of this negative feedback with PKA inhibitors increased sarcolemmal cAMP. Thus, PDE4B mediates a crucial PKA-dependent feedback that controls β1AR-dependent cAMP signals in a restricted subsarcolemmal domain. Disruption of this feedback augments local cAMP/PKA signals, leading to an increased intracellular Ca(2+) level and contraction rate.

  8. 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.

  9. 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. PMID:25794375

  10. Nonlinear evolution-type equations and their exact solutions using inverse variational methods

    NASA Astrophysics Data System (ADS)

    Kara, A. H.; Khalique, C. M.

    2005-05-01

    We present the role of invariants in obtaining exact solutions of differential equations. Firstly, conserved vectors of a partial differential equation (p.d.e.) allow us to obtain reduced forms of the p.d.e. for which some of the Lie point symmetries (in vector field form) are easily concluded and, therefore, provide a mechanism for further reduction. Secondly, invariants of reduced forms of a p.d.e. are obtainable from a variational principle even though the p.d.e. itself does not admit a Lagrangian. In this latter case, the reductions carry all the usual advantages regarding Noether symmetries and double reductions. The examples we consider are nonlinear evolution-type equations such as the Korteweg-deVries equation, but a detailed analysis is made on the Fisher equation (which describes reaction-diffusion waves in biology, inter alia). Other diffusion-type equations lend themselves well to the method we describe (e.g., the Fitzhugh Nagumo equation, which is briefly discussed). Some aspects of Painlevé properties are also suggested.

  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. 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

    2016-01-01

    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. PMID:27063844

  14. 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

  15. 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

  16. 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.

  17. Solid state of a new PDE-5 inhibitor DA-8159: characterization, dissolution, transformation.

    PubMed

    Ryu, Ji Yoon; Sohn, Young-Taek

    2012-05-01

    The polymorphic forms of a new PDE-5 inhibitor DA-8159 were prepared and characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and thermogravimetric analysis (TG). Two crystal forms and one amorphous form of DA-8159 have been isolated by recrystallization and characterized by DSC, TG and PXRD. From the TG data it was confirmed that two crystal forms are neither solvates nor hydrates. The PXRD patterns of the two crystal forms were different. In the dissolution studies in simulated intestinal fluid at 37 ± 0.5°C, the solubility decreased in the order of amorphous form > Form 1 > Form 2. After storage of 60 days, Form 1 was transformed to Form 2. Form 2 was not transformed. The amorphous form was transformed to Form 2 at 52% R.H. and 95% R.H., but it did not transform at 0% R.H. PMID:22644853

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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. PMID:27565496

  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. 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.

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

    NASA Technical Reports Server (NTRS)

    Smith, Ralph C.

    1998-01-01

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

  6. 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

  7. 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

  8. 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

  9. Identification of PDE9 as a cGMP-specific phosphodiesterase in germinal vesicle oocytes: A proposed role in the resumption of meiosis

    PubMed Central

    Hanna, Carol B.; Yao, Shan; Wu, Xuemei; Jensen, Jeffrey T.

    2012-01-01

    Objective To identify a cGMP-specific phosphodiesterase (PDE) in non-human primate germinal vesicle (GV) oocytes and establish a proposed effect on oocyte maturation through preliminary experiments in mouse GV oocytes. Design Controlled non-human primate and rodent experiments. Setting Academic research institution. Animals Rhesus macaques and B6/129F1 mice. Interventions Rhesus macaques were stimulated with FSH to collect GV oocytes and cumulus for gene expression analysis. Female mice were stimulated with PMSG to collect GV oocytes. Main Outcome Measures PDE transcript expression in primate GV oocytes and cumulus cells. Fluorescence polarization (FP) measurements of PDE3A activity. Spontaneous resumption of meiosis in mouse GV oocytes. Results Five PDE transcripts were detected in Rhesus GV oocytes, only PDE9A was cGMP-specific. FP assays indicated cGMP has an inhibitory effect on PDE3A while the PDE9 inhibitor, BAY73-6691, did not. Similarly, BAY73-6691, had little effect on preventing spontaneous maturation in oocytes, but did augment the inhibitory effects of cGMP. Inclusion of 0µM (control), 10µM, 100µM, and 1 mM BAY73-6691 significantly increased the proportion of mouse oocytes maintaining GV arrest in the presence of the cGMP analog 8-Br-cGMP at: 100µM (8.8%, 11.4%, 18.8%, and 28%), 500µM (21.1%, 38.1%, 74.5%,and 66.5%), and 1 mM (57.8%, 74.5%, 93.9%, and 94.0%) respectively, when P<0.05. Conclusions PDE9 is a cGMP-specific hydrolyzing enzyme present in primate oocytes, and PDE9 antagonists augment the inhibitory effect of cGMP during spontaneous in vitro maturation of GV mouse oocytes. PMID:22704629

  10. PDE inhibitors--Second William Harvey Research Conference. Drugs with an expanding range of therapeutic uses. 1-3 December 1999, Nice, France.

    PubMed

    Torphy, T J

    2000-02-01

    This meeting underscored advances in the exploitation of cyclic nucleotide phosphodiesterases (PDEs) as drug targets. One highlight of the meeting was the disclosure of a new PDE isozyme, bringing to 11 the total number of genetically distinct isozyme families thus far identified. Also reported was the phenotypic characterization of a PDE4D murine genetic knockout. With respect to drug discovery and development, the most encouraging information presented centered on advances in targeting PDE4 with therapeutically useful inhibitors. Historically, the therapeutic utility of isozyme-selective PDE4 inhibitors has been limited by class-associated side effects, namely nausea and dyspepsia. New PDE4 inhibitors are being designed with the specific intent of improving upon the therapeutic ratio of first-generation agents. The profiles of two second-generation PDE4 inhibitors, SB-207499 (Ariflo; Smithkline Beecham plc) and PD-189659, were presented. SB-207499 demonstrated marked efficacy in phase II clinical trials in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD), a disease of very high unmet medical need. PD-189659 has yet to enter clinical trials, but its preclinical profile indicates that this agent can produce substantial anti-inflammatory effects without producing class-associated side effects in animal models. A number of presentations were also given on the utility of PDE5 inhibitors in the treatment of male erectile dysfunction (MED). The widespread use of Viagra (sildenafil; Pfizer Inc) over the last year has reinforced the perception that PDE5 inhibitors are safe and effective agents for the treatment of MED. The overall tenor of the meeting was distinctly upbeat, with most participants believing that PDE isozymes are becoming ever more accessible as targets for drug discovery in a variety of therapeutic areas.

  11. Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis.

    PubMed

    Kaname, Tadashi; Ki, Chang-Seok; Niikawa, Norio; Baillie, George S; Day, Jonathan P; Yamamura, Ken-Ichi; Ohta, Tohru; Nishimura, Gen; Mastuura, Nobuo; Kim, Ok-Hwa; Sohn, Young Bae; Kim, Hyun Woo; Cho, Sung Yoon; Ko, Ah-Ra; Lee, Jin Young; Kim, Hyun Wook; Ryu, Sung Ho; Rhee, Hwanseok; Yang, Kap-Seok; Joo, Keehyoung; Lee, Jooyoung; Kim, Chi Hwa; Cho, Kwang-Hyun; Kim, Dongsan; Yanagi, Kumiko; Naritomi, Kenji; Yoshiura, Ko-Ichiro; Kondoh, Tatsuro; Nii, Eiji; Tonoki, Hidefumi; Houslay, Miles D; Jin, Dong-Kyu

    2014-11-01

    Acrodysostosis without hormone resistance is a rare skeletal disorder characterized by brachydactyly, nasal hypoplasia, mental retardation and occasionally developmental delay. Recently, loss-of-function mutations in the gene encoding cAMP-hydrolyzing phosphodiesterase-4D (PDE4D) have been reported to cause this rare condition but the pathomechanism has not been fully elucidated. To understand the pathogenetic mechanism of PDE4D mutations, we conducted 3D modeling studies to predict changes in the binding efficacy of cAMP to the catalytic pocket in PDE4D mutants. Our results indicated diminished enzyme activity in the two mutants we analyzed (Gly673Asp and Ile678Thr; based on PDE4D4 residue numbering). Ectopic expression of PDE4D mutants in HEK293 cells demonstrated this reduction in activity, which was identified by increased cAMP levels. However, the cells from an acrodysostosis patient showed low cAMP accumulation, which resulted in a decrease in the phosphorylated cAMP Response Element-Binding Protein (pCREB)/CREB ratio. The reason for this discrepancy was due to a compensatory increase in expression levels of PDE4A and PDE4B isoforms, which accounted for the paradoxical decrease in cAMP levels in the patient cells expressing mutant isoforms with a lowered PDE4D activity. Skeletal radiographs of 10-week-old knockout (KO) rats showed that the distal part of the forelimb was shorter than in wild-type (WT) rats and that all the metacarpals and phalanges were also shorter in KO, as the name acrodysostosis implies. Like the G-protein α-stimulatory subunit and PRKAR1A, PDE4D critically regulates the cAMP signal transduction pathway and influences bone formation in a way that activity-compromising PDE4D mutations can result in skeletal dysplasia. We propose that specific inhibitory PDE4D mutations can lead to the molecular pathology of acrodysostosis without hormone resistance but that the pathological phenotype may well be dependent on an over-compensatory induction

  12. Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

    PubMed Central

    2015-01-01

    A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12. PMID:25815146

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

    NASA Astrophysics Data System (ADS)

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

    2016-07-01

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

  14. Nonlinear optics and nonlinear dynamics

    NASA Astrophysics Data System (ADS)

    Chen, C. H.

    1990-08-01

    The author was invited by the Institute of Atomic and Molecular Sciences, Academia Sinica, in Taiwan to give six lectures on nonlinear optics. The participants included graduate students, postdoctoral fellows, research staff, and professors from several research organizations and universities. Extensive discussion followed each lecture. Since both the Photophysics Group at Oak Ridge National Laboratory (ORNL) and Institute of Atomic and Molecular Sciences in Taiwan have been actively participating in nonlinear optics research, the discussions are very beneficial to ORNL programs. The author also visited several laboratories at IAMS to exchange research ideas on nonlinear optics.

  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. 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.

  17. Functional mapping of interacting regions of the photoreceptor phosphodiesterase (PDE6) γ-subunit with PDE6 catalytic dimer, transducin, and regulator of G-protein signaling9-1 (RGS9-1).

    PubMed

    Zhang, Xiu-Jun; Gao, Xiong-Zhuo; Yao, Wei; Cote, Rick H

    2012-07-27

    The cGMP phosphodiesterase (PDE6) involved in visual transduction in photoreceptor cells contains two inhibitory γ-subunits (Pγ) which bind to the catalytic core (Pαβ) to inhibit catalysis and stimulate cGMP binding to the GAF domains of Pαβ. During visual excitation, interaction of activated transducin with Pγ relieves inhibition. Pγ also participates in a complex with RGS9-1 and other proteins to accelerate the GTPase activity of activated transducin. We studied the structural determinants for these important functions of Pγ. First, we identified two important sites in the middle region of Pγ (amino acids 27-38 and 52-54) that significantly stabilize the overall binding affinity of Pγ with Pαβ. The ability of Pγ to stimulate noncatalytic cGMP binding to the GAF domains of PDE6 has been localized to amino acids 27-30 of Pγ. Transducin activation of PDE6 catalysis critically depends on the presence of Ile54 in the glycine-rich region of Pγ in order to relieve inhibition of catalysis. The central glycine-rich region of Pγ is also required for transducin to increase cGMP exchange at the GAF domains. Finally, Thr-65 and/or Val-66 of Pγ are critical residues for Pγ to stimulate GTPase activity of transducin in a complex with RGS9-1. We propose that the glycine-rich region of Pγ is a primary docking site for PDE6-interacting proteins involved in the activation/inactivation pathways of visual transduction. This functional mapping of Pγ with its binding partners demonstrates the remarkable versatility of this multifunctional protein and its central role in regulating the activation and lifetime of visual transduction.

  18. Formulation of natural shampoos.

    PubMed

    Mainkar, A R; Jolly, C I

    2001-02-01

    Formulating cosmetics using completely natural raw materials is a difficult task. The challenge lies in selecting materials that can be rationally justified as 'natural' and formulating them into cosmetics whose functionality is comparable with their synthetic counterparts. The present paper focuses on the formulation of completely natural shampoos, their evaluation and comparison with commercial herbal shampoos. Attention is drawn to the fact that, due to the ambiguous definition of the word 'natural', several so-called natural cosmetics are available in the Indian market. It is up to the cosmetic chemists themselves to promote and encourage the development and use of truly natural cosmetics.

  19. 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.

  20. The use of PDE-5 inhibitors in the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.

    PubMed

    Lythgoe, Casey; McVary, Kevin T

    2013-12-01

    The relationship between lower urinary tract symptoms secondary to BPH and ED has recently been the subject of significant research due to the prevalence of both conditions concomitantly existing in older men. Many large-scale studies have demonstrated an association between erectile dysfunction and lower urinary tract symptoms. Although the mechanisms underlying the relationship between LUTS and ED are not fully elucidated, several theories are currently proposed in literature: the nitric oxide/cGMP pathway, RhoA/Rho-kinase signaling, pelvic atherosclerosis associated with chronic hypoxia, and autonomic adrenergic hyperactivity. The mechanisms by which these pathways affect the bladder, prostate, pelvic vasculature and spinal cord are also the subject of current research. In this chapter, we examine the randomized, placebo-controlled trials that have evaluated the use of PDE-5Is in LUTS, as well as randomized, controlled trials (RCTs) researching combination PDE-5Is and alpha blockers. PMID:24136683

  1. 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.

  2. Reducing alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4)

    PubMed Central

    Franklin, Kelle M.; Hauser, Sheketha R.; Lasek, Amy W.; McClintick, Jeanette; Ding, Zheng-Ming; McBride, William J.; Bell, Richard L.

    2015-01-01

    Rationale Phosphodiesterase-4 (PDE4) and neuroimmune signaling have been posited to regulate alcohol drinking. Objectives This study evaluated the involvement of PDE4 and Il22ra2 on ethanol (EtOH) intake by alcohol-preferring (P) and high-alcohol drinking (HAD1) rats. Methods Exp 1 determined the dose-response effects of PDE4 inhibitors, rolipram and Ro 20-1724, on 2h/day free-choice EtOH intake by adult P and HAD1 rats. Exps 2–3 examined the effects of repeated administration with the PDE4 inhibitors on EtOH or sucrose intake, and locomotor behavior. Exp 4 determined Pde4-associated gene expression differences in subregions of the extended amygdala, between high- and low-alcohol-consuming rat lines. Exp 5 evaluated the effects of infusing short hairpin RNA to knock down Il22ra2 in the nucleus accumbens (NAc) shell on 24h free-choice EtOH drinking by P rats. Results Administration of rolipram or Ro 20-1724 reduced EtOH intake by P rats; Ro 20-1724 reduced EtOH intake by HAD1 rats. Repeated rolipram or Ro 20-1724 exposure reduced EtOH intake by P and HAD1 rats. PDE4 inhibition induced motor impairment during the first hour of EtOH intake by P rats. Higher gene expression levels for PDE4A were found in the NAc shell of P vs. NP rats. ShRNAs targeting Il22ra2 in the NAc shell significantly reduced chronic EtOH intake. Conclusions PDE4 and neuroinflammatory/immune signaling pathways could represent molecular targets for the treatment of alcohol use disorders, in genetically predisposed subjects. This study underscores the importance of testing compounds over multiple days and rat lines when determining efficacy to disrupt excessive alcohol intake. PMID:25585681

  3. In vitro and in vivo characterisation of Lu AF64280, a novel, brain penetrant phosphodiesterase (PDE) 2A inhibitor: potential relevance to cognitive deficits in schizophrenia.

    PubMed

    Redrobe, John P; Jørgensen, Morten; Christoffersen, Claus T; Montezinho, Liliana P; Bastlund, Jesper F; Carnerup, Martin; Bundgaard, Christoffer; Lerdrup, Linda; Plath, Niels

    2014-08-01

    Here, we present the pharmacological characterisation of Lu AF64280, a novel, selective, brain penetrant phosphodiesterase (PDE) 2A inhibitor, in in vitro/in vivo assays indicative of PDE2A inhibition, and in vivo models/assays relevant to cognitive processing or antipsychotic-like activity. The in vitro selectivity of Lu AF64280 was determined against a panel of PDE enzymes and 3',5'-cyclic guanosine monophosphate (cGMP) levels in the hippocampus were determined using in vivo microdialysis. Lu AF64280 potently inhibited hPDE2A (Ki = 20 nM), 50-fold above moderate inhibition of both hPDE9A (Ki = 1,000 nM) and hPDE10A (Ki = 1,800 nM), and displayed a >250-fold selectivity over all other full-length human recombinant PDE family members (Ki above 5,000 nM). Lu AF64280 (20 mg/kg) significantly increased cGMP levels in the hippocampus (p < 0.01 versus vehicle-treated mice), attenuated sub-chronic phencyclidine-induced deficits in novel object exploration in rats (10 mg/kg, p < 0.001 versus vehicle-treated), blocked early postnatal phencyclidine-induced deficits in the intradimensional/extradimensional shift task in rats (1 and 10 mg/kg, p < 0.001 versus vehicle-treated) and attenuated spontaneous P20-N40 auditory gating deficits in DBA/2 mice (20 mg/kg, p < 0.05 versus vehicle-treated). In contrast, Lu AF64280 failed to attenuate phencyclidine-induced hyperactivity in mice, and was devoid of antipsychotic-like activity in the conditioned avoidance response paradigm in rats, at any dose tested. Lu AF64280 represents a novel tool compound for selective PDE2A inhibition that substantiates a critical role of this enzyme in cognitive processes under normal and pathological conditions.

  4. DISC1–ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1

    PubMed Central

    Soda, T; Frank, C; Ishizuka, K; Baccarella, A; Park, Y-U; Flood, Z; Park, S K; Sawa, A; Tsai, L-H

    2013-01-01

    Disrupted-In-Schizophrenia 1 (DISC1), a risk factor for major mental illnesses, has been studied extensively in the context of neurodevelopment. However, the role of DISC1 in neuronal signaling, particularly in conjunction with intracellular cascades that occur in response to dopamine, a neurotransmitter implicated in numerous psychiatric disorders, remains elusive. Previous data suggest that DISC1 interacts with numerous proteins that impact neuronal function, including activating transcription factor 4 (ATF4). In this study, we identify a novel DISC1 and ATF4 binding region in the genomic locus of phosphodiesterase 4D (PDE4D), a gene implicated in psychiatric disorders. We found that the loss of function of either DISC1 or ATF4 increases PDE4D9 transcription, and that the association of DISC1 with the PDE4D9 locus requires ATF4. We also show that PDE4D9 is increased by D1-type dopamine receptor dopaminergic stimulation. We demonstrate that the mechanism for this increase is due to DISC1 dissociation from the PDE4D locus in mouse brain. We further characterize the interaction of DISC1 with ATF4 to show that it is regulated via protein kinase A-mediated phosphorylation of DISC1 serine-58. Our results suggest that the release of DISC1-mediated transcriptional repression of PDE4D9 acts as feedback inhibition to regulate dopaminergic signaling. Furthermore, as DISC1 loss-of-function leads to a specific increase in PDE4D9, PDE4D9 itself may represent an attractive target for therapeutic approaches in psychiatric disorders. PMID:23587879

  5. 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

  6. 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

  7. 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

  8. Polymorphisms in PDE4D are associated with a risk of COPD in non-emphysematous Koreans.

    PubMed

    Yoon, Hyoung-Kyu; Hu, Hae-Jin; Rhee, Chin-Kook; Shin, Seung-Hoon; Oh, Yeon-Mok; Lee, Sang-Do; Jung, Seung-Hyun; Yim, Seon-Hee; Kim, Tae-Min; Chung, Yeun-Jun

    2014-12-01

    Despite extensive effort, only a few chronic obstructive pulmonary disease (COPD)-associated genes have been suggested, indicating that there must be additional risk-associated loci. Here we aimed to identify additional COPD-associated SNPs and to explore the potential relationship between COPD subgroups and the SNPs in the Korean population. We performed a genome-wide association study (GWAS) with 990 Korean individuals; 102 COPD cases and 544 controls for GWAS using Affymetrix SNP array 5.0, and 173 COPD cases and 171 controls for replication. After validating the candidate single nucleotide polymorphisms (SNP), we performed subgroup analysis by disease phenotype. Through GWAS, we identified a novel SNP in the phosphodiesterase-4D (PDE4D) gene [rs16878037 (C>T), p = 1.66 ◊ 10(-6)] that was significantly associated with COPD. This signal in PDE4D was successfully replicated in the independent set (p = 0.041). When we combined the discovery and replication data, the association signal became more significant (p = 5.69 ◊ 10(-7)). In the COPD subgroup analysis, the T allele of rs16878037 was significantly more frequent in COPD patients without severe diffusion capacity impairment (mild mixed and obstruction-dominant group) than in patients with severe impairment (severe mixed and emphysema-dominant groups). This result supports that PDE4D polymorphisms might be involved in the susceptibility to COPD especially in non-emphysematous individuals and that they could also affect the responsiveness of the PDE4 inhibitor treatment. PMID:24926854

  9. 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

  10. Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model

    PubMed Central

    Boomkamp, S D; McGrath, M A; Houslay, M D; Barnett, S C

    2014-01-01

    Background and Purpose cAMP and pharmacological inhibition of PDE4, which degrades it, are promising therapeutic targets for the treatment of spinal cord injury (SCI). Using our previously described in vitro SCI model, we studied the mechanisms by which cAMP modulators promote neurite outgrowth and myelination using enantiomers of the PDE4-specific inhibitor rolipram and other modulators of downstream signalling effectors. Experimental Approach Rat mixed neural cell myelinating cultures were cut with a scalpel and treated with enantiomers of the PDE4-specific inhibitor rolipram, Epac agonists and PKA antagonists. Neurite outgrowth, density and myelination were assessed by immunocytochemistry and cytokine levels analysed by qPCR. Key Results Inhibition of the high-affinity rolipram-binding state (HARBS), rather than the low-affinity rolipram binding state (LARBS) PDE4 conformer promoted neurite outgrowth and myelination. These effects were mediated through the activation of Epac and not through PKA. Expression of the chemokine CXCL10, known to inhibit myelination, was markedly elevated in astrocytes after Rho inhibition and this was blocked by inhibition of Rho kinase or PDE4. Conclusions and Implications PDE4 inhibitors targeted at the HARBS conformer or Epac agonists may provide promising novel targets for the treatment of SCI. Our study demonstrates the differential mechanisms of action of these compounds, as well as the benefit of a combined pharmacological approach and highlighting potential promising targets for the treatment of SCI. These findings need to be confirmed in vivo. PMID:24467222

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

    NASA Technical Reports Server (NTRS)

    Taasan, Shlomo

    1995-01-01

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

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

    PubMed

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

    2016-02-01

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

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

    PubMed

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

    2016-05-01

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

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

    PubMed

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

    2013-11-21

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

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

    NASA Technical Reports Server (NTRS)

    1980-01-01

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

  16. Upregulation of cAMP-specific PDE-4 activity following ligation of the TCR complex on thymocytes is blocked by selective inhibitors of protein kinase C and tyrosyl kinases.

    PubMed

    Michie, A M; Rena, G; Harnett, M M; Houslay, M D

    1998-01-01

    We have previously shown that the major cAMP phosphodiesterase (PDE) isoforms present in murine thymocytes are the cGMP-stimulated PDE activity (PDE-2) and the cAMP-specific PDE activity (PDE-4), and that these isoforms are differentially regulated following ligation of the TCR (Michie, A.M., Lobban, M. D., Mueller, T., Harnett, M. M., and Houslay, M.D. [1996] Cell. Signalling 8, 97-110). We show here that the anti-CD3-stimulated elevation in PDE-4 activity in murine thymocytes is dependent on protein tyrosine kinase and protein kinase C (PKC)-mediated signals as the TCR-coupled increase in PDE-4 activity can be abrogated by both the tyrosine kinase inhibitor, genistein, and the PKC selective inhibitors chelerythrine and staurosporine. Moreover, the PKC-activating phorbol ester, phorbol-12-myristate, 13-acetate (PMA) caused an increase in PDE-4 activity, similar to that observed in cells challenged with anti-CD3 monoclonal antibodies and which was not additive with cochallenge using anti-CD3 antibodies. Both the PMA- and the anti-CD3 antibody-mediated increases in PDE-4 activity were blocked by treatment with either cycloheximide or actinomycin D. Despite the upregulation of PDE-4 activity consequent to TCR ligation, intracellular cAMP levels increased on challenge of thymocytes with anti-CD3 antibody, indicating that adenylate cyclase activity was also increased by TCR ligation. It is suggested that the anti-CD3-mediated increase in PDE-4 activity was owing to a rapid PKC-dependent induction of PDE-4 activity following crosslinking of the TCR complex. This identifies "crosstalk" occurring between the PKA and PKC signaling pathways initiated by ligation of the antigen receptor in murine thymocytes. That both adenylate cyclase and PDE-4 activities were increased may indicate the presence of compartmentalized cAMP responses present in these cells. PMID:9515165

  17. 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.

  18. 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…

  19. Association of PDE4B Polymorphisms with Susceptibility to Schizophrenia: A Meta-Analysis of Case-Control Studies

    PubMed Central

    Feng, Yanguo; Cheng, Dejun; Zhang, Chaofeng; Li, Yuchun; Zhang, Zhiying; Wang, Juan; Shi, Yuzhong

    2016-01-01

    Background The PDE4B single nucleotide polymorphisms (SNPs) have been reported to be associated with schizophrenia risk. However, current findings are ambiguous or even conflicting. To better facilitate the understanding the genetic role played by PDE4B in susceptibility to schizophrenia, we collected currently available data and conducted this meta-analysis. Methods A comprehensive electronic literature searching of PubMed, Embase, Web of Science and Cochrane Library was performed. The association between PDE4B SNPs and schizophrenia was evaluated by odds ratios (ORs) and 95% confidence intervals (CIs) under allelic, dominant and recessive genetic models. The random effects model was utilized when high between-study heterogeneity (I2 > 50%) existed, otherwise the fixed effects model was used. Results Five studies comprising 2376 schizophrenia patients and 3093 controls were finally included for meta-analysis. The rs1040716 was statistically significantly associated with schizophrenia risk in Asian and Caucasian populations under dominant model (OR = 0.87, 95% CI: 0.76–0.99, P = 0.04). The rs2180335 was significantly related with schizophrenia risk in Asian populations under allelic (OR = 0.82, 95% CI: 0.72–0.93, P = 0.003) and dominant (OR = 0.75, 95% CI: 0.64–0.88, P < 0.001) models. A significant association was also observed between rs4320761 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.75–1.00, P = 0.048). In addition, a strong association tendency was found between rs6588190 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.76–1.00, P = 0.055). Conclusion This meta-analysis suggests that PDE4B SNPs are genetically associated with susceptibility to schizophrenia. However, due to limited sample size, more large-scale, multi-racial association studies are needed to further clarify the genetic association between various PDE4B variants and schizophrenia. PMID:26756575

  20. 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.

  1. 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.

  2. 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.

  3. Granulated decontamination formulations

    DOEpatents

    Tucker, Mark D.

    2007-10-02

    A decontamination formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a sorbent additive, and water. A highly adsorbent sorbent additive (e.g., amorphous silica, sorbitol, mannitol, etc.) is used to "dry out" one or more liquid ingredients into a dry, free-flowing powder that has an extended shelf life, and is more convenient to handle and mix in the field.

  4. Advanced protein formulations.

    PubMed

    Wang, Wei

    2015-07-01

    It is well recognized that protein product development is far more challenging than that for small-molecule drugs. The major challenges include inherent sensitivity to different types of stresses during the drug product manufacturing process, high rate of physical and chemical degradation during long-term storage, and enhanced aggregation and/or viscosity at high protein concentrations. In the past decade, many novel formulation concepts and technologies have been or are being developed to address these product development challenges for proteins. These concepts and technologies include use of uncommon/combination of formulation stabilizers, conjugation or fusion with potential stabilizers, site-specific mutagenesis, and preparation of nontraditional types of dosage forms-semiaqueous solutions, nonfreeze-dried solid formulations, suspensions, and other emerging concepts. No one technology appears to be mature, ideal, and/or adequate to address all the challenges. These gaps will likely remain in the foreseeable future and need significant efforts for ultimate resolution.

  5. Advanced protein formulations

    PubMed Central

    Wang, Wei

    2015-01-01

    It is well recognized that protein product development is far more challenging than that for small-molecule drugs. The major challenges include inherent sensitivity to different types of stresses during the drug product manufacturing process, high rate of physical and chemical degradation during long-term storage, and enhanced aggregation and/or viscosity at high protein concentrations. In the past decade, many novel formulation concepts and technologies have been or are being developed to address these product development challenges for proteins. These concepts and technologies include use of uncommon/combination of formulation stabilizers, conjugation or fusion with potential stabilizers, site-specific mutagenesis, and preparation of nontraditional types of dosage forms—semiaqueous solutions, nonfreeze-dried solid formulations, suspensions, and other emerging concepts. No one technology appears to be mature, ideal, and/or adequate to address all the challenges. These gaps will likely remain in the foreseeable future and need significant efforts for ultimate resolution. PMID:25858529

  6. Formulation of Automotive Lubricants

    NASA Astrophysics Data System (ADS)

    Atkinson, D.; Brown, A. J.; Jilbert, D.; Lamb, G.

    The formulation of lubricants for current light- and heavy-duty vehicles (passenger cars and trucks) and also motorcycles/small engines is described in terms of engine types and meeting European, US and Japanese emission control requirements. Trends in the formulation of lubricants are discussed and the importance of high and low 'SAPS' for future developments emphasised. Specification and evaluation of lubricant performance for light-vehicle gasoline and diesel, and also heavy-duty diesel engines are described. Emphasis is given to diesel engine cleanliness by soot and deposit control and the effect of emission controls on lubricant formulation. The lubricant requirements for motorcycle and small engines, primarily two-stroke cycle, and their specifications are described.

  7. Surface effect on the nonlinear forced vibration of cantilevered nanobeams

    NASA Astrophysics Data System (ADS)

    Dai, H. L.; Zhao, D. M.; Zou, J. J.; Wang, L.

    2016-06-01

    The nonlinear forced vibration behavior of a cantilevered nanobeam is investigated in this paper, essentially considering the effect due to the surface elastic layer. The governing equation of motion for the nano-cantilever is derived, with consideration of the geometrical nonlinearity and the effects of additional flexural rigidity and residual stress of the surface layer. Then, the nonlinear partial differential equation (PDE) is discretized into a set of nonlinear ordinary differential equations (ODEs) by means of the Galerkin's technique. It is observed that surface effects on the natural frequency of the nanobeam is of significance, especially for the case when the aspect ratio of the nanobeam is large. The nonlinear resonant dynamics of the nanobeam system is evaluated by varying the excitation frequency around the fundamental resonance, showing that the nanobeam would display hardening-type behavior and hence the frequency-response curves bend to the right in the presence of positive residual surface stress. However, with the negative residual surface stress, this hardening-type behavior can be shifted to a softening-type one which becomes even more evident with increase of the aspect ratio parameter. It is also demonstrated that the combined effects of the residual stress and aspect ratio on the maximum amplitude of the nanobeam may be pronounced.

  8. PDE4 Inhibition by Rolipram Promotes Neuronal Differentiation in Human Bone Marrow Mesenchymal Stem Cells.

    PubMed

    Joe, I-Seul; Cho, Goang-Won

    2016-08-01

    Increased intracellular cyclic adenosine monophosphate (cAMP) can promote axonal elongation and facilitate neuronal repair, while decreased cAMP is associated with losses in neuronal regenerative capacity. Rolipram, which upregulates intracellular cAMP by blocking phosphodiesterase-4 (PDE4) enzyme activity, can mitigate diverse neurological disorders. In this study, we investigated whether rolipram induces neuronal differentiation of human bone marrow-mesenchymal stem cells (hBM-MSCs). Rolipram-treated MSCs (Roli-MSCs) had significantly increased expression of the neuroprogenitor proteins Nestin, Musashi, GFAP, and Sox-2. When Roli-MSCs were differentiated with neuronal induction media (Roli-dMSCs), they exhibited cell body and dendritic morphologies similar to those of neurons. The neurite number and length of Roli-dMSCs were significantly increased compared to those of differentiated MSCs (dMSCs). Compared with undifferentiated hBM-MSCs, the Roli-dMSCs and dMSCs showed significantly increased expression of the neuronal-specific marker genes Nestin, Musashi, CD133, GFAP, NF-M, MAP-2, KCNH1, KCNH5, SCN3A, and CACNA1A, and decreased expression of other lineage-specific markers Adiponectin, ALP, FABP4, and MMP13. The Roli-dMSCs also showed a higher expression of the neuronal markers Nestin, Musashi, Sox-2, NF-M, and Tuj-1 compared to those of the undifferentiated hBM-MSCs, measured by immunocytochemistry and immunoblotting assay. Thus, we have shown that rolipram ameliorates neuronal differentiation by the regulation of neuroprogenitor expression in hBM-MSCs, and rolipram treatment of MSCs may improve the therapeutic efficacy of stem cell therapy for neurodegenerative disorders. PMID:27459581

  9. Dynamical and Hamiltonian Formulation of General Relativity

    NASA Astrophysics Data System (ADS)

    Giulini, Domenico

    Einstein's theory of General Relativity describes spacetime as a solution of a set of non-linear partial differential equations. These equations are initially not in the form of evolution equations and it is hence not clear how to formulate and solve initial-value problems, as would be physically highly desirable. In this contribution it will be shown how to cast Einstein's equations into the form of a constrained Hamiltonian system. This will allow to formulate and solve initial-value problems, integrate Einstein's equations by numerical codes, characterize dynamical degrees of freedom, and characterize isolated systems and their conserved quantities, like energy, momentum, and angular momentum. Moreover, this reformulation of General Relativity is also the starting point for various attempts to subject the gravitational field to the program of canonical quantization. The exposition given here is, to some degree, self contained. It attempts to comprehensively account for all the relevant geometric constructions, including the relevant symplectic geometry of constrained Hamiltonian systems.

  10. Coherent states formulation of polymer field theory

    SciTech Connect

    Man, Xingkun; Villet, Michael C.; Delaney, Kris T.; Orland, Henri; Fredrickson, Glenn H.

    2014-01-14

    We introduce a stable and efficient complex Langevin (CL) scheme to enable the first direct numerical simulations of the coherent-states (CS) formulation of polymer field theory. In contrast with Edwards’ well-known auxiliary-field (AF) framework, the CS formulation does not contain an embedded nonlinear, non-local, implicit functional of the auxiliary fields, and the action of the field theory has a fully explicit, semi-local, and finite-order polynomial character. In the context of a polymer solution model, we demonstrate that the new CS-CL dynamical scheme for sampling fluctuations in the space of coherent states yields results in good agreement with now-standard AF-CL simulations. The formalism is potentially applicable to a broad range of polymer architectures and may facilitate systematic generation of trial actions for use in coarse-graining and numerical renormalization-group studies.

  11. Hamiltonian Formulation for Wave-Current Interactions in Stratified Rotational Flows

    NASA Astrophysics Data System (ADS)

    Constantin, A.; Ivanov, R. I.; Martin, C.-I.

    2016-09-01

    We show that the Hamiltonian framework permits an elegant formulation of the nonlinear governing equations for the coupling between internal and surface waves in stratified water flows with piecewise constant vorticity.

  12. PDE4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells

    PubMed Central

    Meyers, John A.; Taverna, Josephine; Chaves, Jorge; Makkinje, Anthony; Lerner, Adam

    2009-01-01

    Purpose Type 4 cAMP phosphodiesterase (PDE4) inhibitors, compounds that activate cAMP-mediated signaling by inhibiting cAMP catabolism, potentiate glucocorticoid-mediated apoptosis in chronic lymphocytic leukemia (CLL) cells but the mechanism by which this occurs is unknown. In this study, we sought to address whether PDE4 inhibitors alter expression of glucocorticoid receptor (GRα) in CLL cells. Experimental Design CLL cells or normal hematopoietic cells were treated with PDE4 inhibitors followed by analysis of GRα transcript and protein by real-time PCR and Western analysis. Results PDE4 inhibitors up-regulate glucocorticoid receptor transcript levels in CLL cells but not normal circulating T cells, B cells, monocytes or neutrophils. As GRα transcript half-life does not vary in CLL cells treated with the prototypic PDE4 inhibitor rolipram, the four-fold increase in GRα mRNA levels observed within four hours of rolipram treatment appears to result from an increase in transcription. Rolipram treatment increases levels of transcripts derived from the 1A3 promoter to a greater extent than the 1B promoter. Treatment of CLL cells with cilomilast and roflumilast, two PDE4 inhibitors previously studied in clinical trials also augments GRα transcript levels and glucocorticoid-mediated apoptosis. Washout studies demonstrate that simultaneous treatment with both drug classes irreversibly augments apoptosis over the same time frame that glucocorticoid receptor up-regulation occurs. While treatment of CLL cells with glucocorticoids reduces basal GRα transcript levels in a dose-related manner, co-treatment with rolipram maintained GRα transcript levels above baseline. Conclusion Our results suggest that PDE4 inhibitors may sensitize CLL cells to glucocorticoid-induced apoptosis by augmenting GRα expression. PMID:17699872

  13. Activated G-protein releases cGMP from high affinity binding sites on PDE from toad rod outer segments (ROS)

    SciTech Connect

    Yuen, P.S.T.; Walseth, T.F.; Panter, S.S.; Sundby, S.R.; Graeff, R.M.; Goldberg, N.D.

    1987-05-01

    cGMP binding proteins in toad ROS were identified by direct photoaffinity labeling (PAL) with /sup 32/P-cGMP and quantified by retention of complexes on nitrocellulose filters. By PAL, high affinity sites were present on the ..cap alpha.. and ..beta.. subunits of the cGMP-specific phosphodiesterase (PDE) which have MW/sub app/ of 94 and 90 kDa. A doublet was deduced from its photolabeling properties to represent PDE/sub ..gamma../ photocrosslinked with PDE/sub ..cap alpha../ or PDE/sub ..beta../, respectively. cGMP prebound to these high affinity sites was released by light-activated G-protein or its ..cap alpha.. subunit complexed with GTP..gamma..S; this inhibition of cGMP binding to PDE did not result from decreased cGMP availability due to enhanced hydrolysis. A low affinity cGMP binding component identified by PAL is tightly associated with ROS membranes. Apparent ATP/light-dependent stimulation of cGMP binding was shown to result from light activated cGMP hydrolysis in conjunction with ATP-promoted conversion of GMP to GDP/GTP and increased GDP/GTP binding. These findings coincide with a model for light-related regulation of cGMP binding and metabolism predicted from intact and cellfree kinetic measurements: in the dark state the cGMP hydrolic rate is constrained by the availability of cGMP because of its binding to high affinity sites on PDE. Light activated G-protein releases cGMP from these sites and allows for its redistribution to lower affinity sites represented by PDE catalytic site(s) and possible cGMP-dependent membrane cation channels.

  14. The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors*

    PubMed Central

    Wood, Edgar R.; Bledsoe, Randy; Chai, Jing; Daka, Philias; Deng, Hongfeng; Ding, Yun; Harris-Gurley, Sarah; Kryn, Luz Helena; Nartey, Eldridge; Nichols, James; Nolte, Robert T.; Prabhu, Ninad; Rise, Cecil; Sheahan, Timothy; Shotwell, J. Brad; Smith, Danielle; Tai, Vince; Taylor, J. David; Tomberlin, Ginger; Wang, Liping; Wisely, Bruce; You, Shihyun; Xia, Bing; Dickson, Hamilton

    2015-01-01

    2′,5′-Oligoadenylate synthetase (OAS) enzymes and RNase-L constitute a major effector arm of interferon (IFN)-mediated antiviral defense. OAS produces a unique oligonucleotide second messenger, 2′,5′-oligoadenylate (2–5A), that binds and activates RNase-L. This pathway is down-regulated by virus- and host-encoded enzymes that degrade 2–5A. Phosphodiesterase 12 (PDE12) was the first cellular 2–5A- degrading enzyme to be purified and described at a molecular level. Inhibition of PDE12 may up-regulate the OAS/RNase-L pathway in response to viral infection resulting in increased resistance to a variety of viral pathogens. We generated a PDE12-null cell line, HeLaΔPDE12, using transcription activator-like effector nuclease-mediated gene inactivation. This cell line has increased 2–5A levels in response to IFN and poly(I-C), a double-stranded RNA mimic compared with the parental cell line. Moreover, HeLaΔPDE12 cells were resistant to viral pathogens, including encephalomyocarditis virus, human rhinovirus, and respiratory syncytial virus. Based on these results, we used DNA-encoded chemical library screening to identify starting points for inhibitor lead optimization. Compounds derived from this effort raise 2–5A levels and exhibit antiviral activity comparable with the effects observed with PDE12 gene inactivation. The crystal structure of PDE12 complexed with an inhibitor was solved providing insights into the structure-activity relationships of inhibitor potency and selectivity. PMID:26055709

  15. Parallelized solvers for heat conduction formulations

    NASA Technical Reports Server (NTRS)

    Padovan, Joe; Kwang, Abel

    1991-01-01

    Based on multilevel partitioning, this paper develops a structural parallelizable solution methodology that enables a significant reduction in computational effort and memory requirements for very large scale linear and nonlinear steady and transient thermal (heat conduction) models. Due to the generality of the formulation of the scheme, both finite element and finite difference simulations can be treated. Diverse model topologies can thus be handled, including both simply and multiply connected (branched/perforated) geometries. To verify the methodology, analytical and numerical benchmark trends are verified in both sequential and parallel computer environments.

  16. Phosphodiesterase 11A (PDE11A) Gene Defects in Patients with ACTH-Independent Macronodular Adrenal Hyperplasia (AIMAH): Functional Variants May Contribute to Genetic Susceptibility of Bilateral Adrenal Tumors

    PubMed Central

    Vezzosi, Delphine; Libé, Rossella; Baudry, Camille; Rizk-Rabin, Marthe; Horvath, Anelia; Levy, Isaac; René-Corail, Fernande; Ragazzon, Bruno; Stratakis, Constantine A.; Vandecasteele, Grégoire

    2012-01-01

    Context: Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP levels. PDE11A function has been linked to predisposition to adrenocortical tumors. Objective: The aim of the study was to study the PDE11A gene in a large cohort of patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in control subjects. Design: The PDE11A entire coding region was sequenced in 46 patients with AIMAH and 192 controls. Two variants found in AIMAH patients were transiently expressed in HEK 293 and adrenocortical H295R cells for further functional studies. Results: The frequency of all PDE11A variants was significantly higher among patients with AIMAH (28%) compared to controls (7.2%) (P = 5 × 10−5). Transfection of the two PDE11A variants found in AIMAH patients only (D609N or M878V) showed that cAMP levels were higher, after forskolin stimulation, in cells transfected with the PDE11A mutants, compared to cells transfected with the wild-type PDE11A in HEK 293 cells (P < 0.05). Moreover, transfection with mutants PDE11A increased transcriptional activity of a cAMP-response element reporter construct compared to wild-type PDE11A in HEK 293 cells (P < 0.0004 for D609N and P < 0.003 for M878V) and in the adrenocortical H295R cells (P < 0.05 for D609N and M878V). In addition, analysis of cAMP levels in intact living culture cells by fluorescence resonance energy transfer probes showed increased cAMP in forskolin-treated cells transfected with PDE11A variants compared with wild-type PDE11A (P < 0.05). Conclusion: We conclude that PDE11A genetic variants may increase predisposition to AIMAH. PMID:22996146

  17. Development of solution techniques for nonlinear structural analysis

    NASA Technical Reports Server (NTRS)

    Vos, R. G.; Andrews, J. S.

    1974-01-01

    Nonlinear structural solution methods in the current research literature are classified according to order of the solution scheme, and it is shown that the analytical tools for these methods are uniformly derivable by perturbation techniques. A new perturbation formulation is developed for treating an arbitrary nonlinear material, in terms of a finite-difference generated stress-strain expansion. Nonlinear geometric effects are included in an explicit manner by appropriate definition of an applicable strain tensor. A new finite-element pilot computer program PANES (Program for Analysis of Nonlinear Equilibrium and Stability) is presented for treatment of problems involving material and geometric nonlinearities, as well as certain forms on nonconservative loading.

  18. Nonlinear radial oscillations of neutron stars

    SciTech Connect

    Gabler, Michael; Sperhake, Ulrich; Andersson, Nils

    2009-09-15

    The effects of nonlinear oscillations in compact stars are attracting considerable current interest. In order to study such phenomena in the framework of fully nonlinear general relativity, highly accurate numerical studies are required. A numerical scheme specifically tailored for such a study is based on formulating the time evolution in terms of deviations from a stationary equilibrium configuration. Using this technique, we investigate over a wide range of amplitudes nonlinear effects in the evolution of radial oscillations of neutron stars. In particular, we discuss mode coupling due to nonlinear interaction, the occurrence of resonance phenomena, shock formation near the stellar surface as well as the capacity of nonlinearities to stabilize perturbatively unstable neutron star models.

  19. A note on the generation of phase plane plots on a digital computer. [for solution of nonlinear differential equations

    NASA Technical Reports Server (NTRS)

    Simon, M. K.

    1980-01-01

    A technique is presented for generating phase plane plots on a digital computer which circumvents the difficulties associated with more traditional methods of numerical solving nonlinear differential equations. In particular, the nonlinear differential equation of operation is formulated.

  20. A “Reverse-Schur” Approach to Optimization With Linear PDE Constraints: Application to Biomolecule Analysis and Design

    PubMed Central

    Bardhan, Jaydeep P.; Altman, Michael D.

    2009-01-01

    We present a partial-differential-equation (PDE)-constrained approach for optimizing a molecule’s electrostatic interactions with a target molecule. The approach, which we call reverse-Schur co-optimization, can be more than two orders of magnitude faster than the traditional approach to electrostatic optimization. The efficiency of the co-optimization approach may enhance the value of electrostatic optimization for ligand-design efforts–in such projects, it is often desirable to screen many candidate ligands for their viability, and the optimization of electrostatic interactions can improve ligand binding affinity and specificity. The theoretical basis for electrostatic optimization derives from linear-response theory, most commonly continuum models, and simple assumptions about molecular binding processes. Although the theory has been used successfully to study a wide variety of molecular binding events, its implications have not yet been fully explored, in part due to the computational expense associated with the optimization. The co-optimization algorithm achieves improved performance by solving the optimization and electrostatic simulation problems simultaneously, and is applicable to both unconstrained and constrained optimization problems. Reverse-Schur co-optimization resembles other well-known techniques for solving optimization problems with PDE constraints. Model problems as well as realistic examples validate the reverse-Schur method, and demonstrate that our technique and alternative PDE-constrained methods scale very favorably compared to the standard approach. Regularization, which ordinarily requires an explicit representation of the objective function, can be included using an approximate Hessian calculated using the new BIBEE/P (boundary-integral-based electrostatics estimation by preconditioning) method. PMID:23055839

  1. Liposomal formulations for inhalation.

    PubMed

    Cipolla, David; Gonda, Igor; Chan, Hak-Kim

    2013-08-01

    No marketed inhaled products currently use sustained release formulations such as liposomes to enhance drug disposition in the lung, but that may soon change. This review focuses on the interaction between liposomal formulations and the inhalation technology used to deliver them as aerosols. There have been a number of dated reviews evaluating nebulization of liposomes. While the information they shared is still accurate, this paper incorporates data from more recent publications to review the factors that affect aerosol performance. Recent reviews have comprehensively covered the development of dry powder liposomes for aerosolization and only the key aspects of those technologies will be summarized. There are now at least two inhaled liposomal products in late-stage clinical development: ARIKACE(®) (Insmed, NJ, USA), a liposomal amikacin, and Pulmaquin™ (Aradigm Corp., CA, USA), a liposomal ciprofloxacin, both of which treat a variety of patient populations with lung infections. This review also highlights the safety of inhaled liposomes and summarizes the clinical experience with liposomal formulations for pulmonary application. PMID:23919478

  2. Micosoft Excel Sensitivity Analysis for Linear and Stochastic Program Feed Formulation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sensitivity analysis is a part of mathematical programming solutions and is used in making nutritional and economic decisions for a given feed formulation problem. The terms, shadow price and reduced cost, are familiar linear program (LP) terms to feed formulators. Because of the nonlinear nature of...

  3. Computation and analysis of a nonlinear nonlocal cochlear model with applications to multitone interactions in hearing

    NASA Astrophysics Data System (ADS)

    Xin, Jack; Qi, Yingyong; Deng, Li

    2002-11-01

    A nonlinear nonlocal cochlear model of the transmission line type is studied to capture the multitone interactions and tonal suppression effects. The model can serve as a module for voice signal processing. It is a one-dimensional (in space) damped dispersive nonlinear partial differential equation (PDE) based on mechanics and phenomenology of hearing. The elastic damping is a nonlinear and nonlocal functional of basilar-membrane displacement. The initial boundary value problem is solved with a semi-implicit second-order finite difference method. Numerical results are shown on two-tone suppression from both high-frequency and low-frequency sides, consistent with known behavior. Suppression effects among three tones are demonstrated by showing how the response magnitudes of the two fixed tones are reduced as the third tone is varied in frequency and amplitude. Qualitative agreement with existing cat auditory neural data is observed. The model is thus simple and efficient as a processing tool for voice signals. Mathematical analysis of global well-posedness of the model PDE and the existence of multitone solutions will also be shown via the method of a priori estimates and fixed point theory. [Work partially supported by ARO and NSF.

  4. A comparison of two formulations of the fin efficiency for straight fins

    NASA Astrophysics Data System (ADS)

    Momoniat, Ebrahim

    2012-04-01

    A formulation of the fin efficiency based on Newton's law of cooling is compared with a formulation based on a ratio of heat transferred from the fin surface to the surrounding fluid to the heat conducted through the base. The first formulation requires that the solution of the nonlinear fin equations for constant heat transfer coefficient and constant thermal conductivity is known, whilst the second formulation of the fin efficiency requires only that a first integral of the model equation is known. This paper shows the first formulation of the fin efficiency contains approximation errors as only power series and approximate solutions to the nonlinear fin equations have been determined. The second formulation of the fin efficiency is exact when the first integrals can be determined.

  5. On shallow water waves in a medium with time-dependent dispersion and nonlinearity coefficients.

    PubMed

    Abdel-Gawad, Hamdy I; Osman, Mohamed

    2015-07-01

    In this paper, we studied the progression of shallow water waves relevant to the variable coefficient Korteweg-de Vries (vcKdV) equation. We investigated two kinds of cases: when the dispersion and nonlinearity coefficients are proportional, and when they are not linearly dependent. In the first case, it was shown that the progressive waves have some geometric structures as in the case of KdV equation with constant coefficients but the waves travel with time dependent speed. In the second case, the wave structure is maintained when the nonlinearity balances the dispersion. Otherwise, water waves collapse. The objectives of the study are to find a wide class of exact solutions by using the extended unified method and to present a new algorithm for treating the coupled nonlinear PDE's.

  6. On shallow water waves in a medium with time-dependent dispersion and nonlinearity coefficients.

    PubMed

    Abdel-Gawad, Hamdy I; Osman, Mohamed

    2015-07-01

    In this paper, we studied the progression of shallow water waves relevant to the variable coefficient Korteweg-de Vries (vcKdV) equation. We investigated two kinds of cases: when the dispersion and nonlinearity coefficients are proportional, and when they are not linearly dependent. In the first case, it was shown that the progressive waves have some geometric structures as in the case of KdV equation with constant coefficients but the waves travel with time dependent speed. In the second case, the wave structure is maintained when the nonlinearity balances the dispersion. Otherwise, water waves collapse. The objectives of the study are to find a wide class of exact solutions by using the extended unified method and to present a new algorithm for treating the coupled nonlinear PDE's. PMID:26199750

  7. Extended Painlevé Expansion, Nonstandard Truncation and Special Reductions of Nonlinear Evolution Equations

    NASA Astrophysics Data System (ADS)

    Lou, Sen-yue

    1998-05-01

    To study a nonlinear partial differential equation (PDE), the Painleve expansion developed by Weiss, Tabor and Carnevale (WTC) is one of the most powerful methods. In this paper, using any singular manifold, the expansion series in the usual Painleve analysis is shown to be resummable in some different ways. A simple nonstandard truncated expansion with a quite universal reduction function is used for many nonlinear integrable and nonintegrable PDEs such as the Burgers, Korteweg de-Vries (KdV), Kadomtsev-Petviashvli (KP), Caudrey-Dodd-Gibbon-Sawada-Kortera (CDGSK), Nonlinear Schrödinger (NLS), Davey-Stewartson (DS), Broer-Kaup (BK), KdV-Burgers (KdVB), λf4 , sine-Gordon (sG) etc.

  8. How to characterize the nonlinear amplifier?

    NASA Technical Reports Server (NTRS)

    Kallistratova, Dmitri Kouznetsov; Cotera, Carlos Flores

    1994-01-01

    The conception of the amplification of the coherent field is formulated. The definition of the coefficient of the amplification as the relation between the mean value of the field at the output to the value at the input and the definition of the noise as the difference between the number of photons in the output mode and square of the modulus of the mean value of the output amplitude are considered. Using a simple example it is shown that by these definitions the noise of the nonlinear amplifier may be less than the noise of the ideal linear amplifier of the same amplification coefficient. Proposals to search another definition of basic parameters of the nonlinear amplifiers are discussed. This definition should enable us to formulate the universal fundamental lower limit of the noise which should be valid for linear quantum amplifiers as for nonlinear ones.

  9. Nonlinear mechanical behavior of thermoplastic matrix materials for advanced composites

    NASA Technical Reports Server (NTRS)

    Arenz, R. J.; Landel, R. F.

    1989-01-01

    Two recent theories of nonlinear mechanical response are quantitatively compared and related to experimental data. Computer techniques are formulated to handle the numerical integration and iterative procedures needed to solve the associated sets of coupled nonlinear differential equations. Problems encountered during these formulations are discussed and some open questions described. Bearing in mind these cautions, the consequences of changing parameters that appear in the formulations on the resulting engineering properties are discussed. Hence, engineering approaches to the analysis of thermoplastic matrix material can be suggested.

  10. Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease.

    PubMed

    Gobejishvili, Leila; Barve, Shirish; Joshi-Barve, Swati; McClain, Craig

    2008-10-01

    Increased plasma and hepatic TNF-alpha expression is well documented in patients with alcoholic hepatitis and is implicated in the pathogenesis of alcoholic liver disease. We have previously shown that monocytes from patients with alcoholic hepatitis show increased constitutive and LPS-induced NF-kappaB activation and TNF-alpha production. Our recent studies showed that chronic ethanol exposure significantly decreased cellular cAMP levels in both LPS-stimulated and unstimulated monocytes and Kupffer cells, leading to an increase in LPS-inducible TNF-alpha production by affecting NF-kappaB activation and induction of TNF mRNA expression. Accordingly, the mechanisms underlying this ethanol-induced decrease in cellular cAMP leading to an increase in TNF expression were examined in monocytes/macrophages. In this study, chronic ethanol exposure was observed to significantly increase LPS-inducible expression of cAMP-specific phosphodiesterase (PDE)4B that degrades cellular cAMP. Increased PDE4B expression was associated with enhanced NF-kappaB activation and transcriptional activity and subsequent priming of monocytes/macrophages leading to enhanced LPS-inducible TNF-alpha production. Selective inhibition of PDE4 by rolipram abrogated LPS-mediated TNF-alpha expression at both protein and mRNA levels in control and ethanol-treated cells. Notably, PDE4 inhibition did not affect LPS-inducible NF-kappaB activation but significantly decreased NF-kappaB transcriptional activity. These findings strongly support the pathogenic role of PDE4B in the ethanol-mediated priming of monocytes/macrophages and increased LPS-inducible TNF production and the subsequent development of alcoholic liver disease (ALD). Since enhanced TNF expression plays a significant role in the evolution of clinical and experimental ALD, its downregulation via selective PDE4B inhibitors could constitute a novel therapeutic approach in the treatment of ALD. PMID:18687753

  11. TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms.

    PubMed

    Suzuki, Kazunori; Harada, Akina; Suzuki, Hirobumi; Miyamoto, Maki; Kimura, Haruhide

    2016-08-01

    Phosphodiesterase 10A (PDE10A) inhibitors are expected to be novel drugs for schizophrenia through activation of both direct and indirect pathway medium spiny neurons. However, excess activation of the direct pathway by a dopamine D1 receptor agonist SKF82958 canceled antipsychotic-like effects of a dopamine D2 receptor antagonist haloperidol in methamphetamine (METH)-induced hyperactivity in rats. Thus, balanced activation of these pathways may be critical for PDE10A inhibitors. Current antipsychotics and the novel PDE10A inhibitor TAK-063, but not the selective PDE10A inhibitor MP-10, produced dose-dependent antipsychotic-like effects in METH-induced hyperactivity and prepulse inhibition in rodents. TAK-063 and MP-10 activated the indirect pathway to a similar extent; however, MP-10 caused greater activation of the direct pathway than did TAK-063. Interestingly, the off-rate of TAK-063 from PDE10A in rat brain sections was faster than that of MP-10, and a slower off-rate PDE10A inhibitor with TAK-063-like chemical structure showed an MP-10-like pharmacological profile. In general, faster off-rate enzyme inhibitors are more sensitive than slower off-rate inhibitors to binding inhibition by enzyme substrates. As expected, TAK-063 was more sensitive than MP-10 to binding inhibition by cyclic nucleotides. Moreover, an immunohistochemistry study suggested that cyclic adenosine monophosphate levels in the direct pathway were higher than those in the indirect pathway. These data can explain why TAK-063 showed partial activation of the direct pathway compared with MP-10. The findings presented here suggest that TAK-063's antipsychotic-like efficacy may be attributable to its unique pharmacological properties, resulting in balanced activation of the direct and indirect striatal pathways. PMID:26849714

  12. Effect of PDE5 inhibition on the modulation of sympathetic α-adrenergic vasoconstriction in contracting skeletal muscle of young and older recreationally active humans.

    PubMed

    Nyberg, Michael; Piil, Peter; Egelund, Jon; Sprague, Randy S; Mortensen, Stefan P; Hellsten, Ylva

    2015-12-01

    Aging is associated with an altered regulation of blood flow to contracting skeletal muscle; however, the precise mechanisms remain unclear. We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not young human subjects. Here we examined whether this effect of PDE5 inhibition was related to an improved ability to blunt α-adrenergic vasoconstriction (functional sympatholysis) and/or improved efficacy of local vasodilator pathways. A group of young (23 ± 1 yr) and a group of older (72 ± 1 yr) male subjects performed knee-extensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. During both conditions, exercise was performed without and with arterial tyramine infusion to evoke endogenous norepinephrine release and consequently stimulation of α1- and α2-adrenergic receptors. The level of the sympatholytic compound ATP was measured in venous plasma by use of the microdialysis technique. Sildenafil increased (P < 0.05) vascular conductance during exercise in the older group, but tyramine infusion reduced (P < 0.05) this effect by 38 ± 9%. Similarly, tyramine reduced (P < 0.05) the vasodilation induced by arterial infusion of a nitric oxide (NO) donor by 54 ± 9% in the older group, and this effect was not altered by sildenafil. Venous plasma [ATP] did not change with PDE5 inhibition in the older subjects during exercise. Collectively, PDE5 inhibition in older humans was not associated with an improved ability for functional sympatholysis. An improved efficacy of the NO system may be one mechanism underlying the effect of PDE5 inhibition on exercise hyperemia in aging.

  13. Efficacy and safety of phosphodiesterase type 5 (PDE5) inhibitors in treating erectile dysfunction after bilateral nerve-sparing radical prostatectomy.

    PubMed

    Cui, Y; Liu, X; Shi, L; Gao, Z

    2016-02-01

    We carried out a systematic review and meta-analysis to assess the efficacy and safety of phosphodiesterase type 5 (PDE5) inhibitors for treating erectile dysfunction (ED) after bilateral nerve-sparing radical prostatectomy (BNSRP). A literature review was performed to identify all published randomised double-blind, placebo-controlled trials of PDE5 inhibitors for the treatment of ED after BNSRP. The search included the following databases: MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. Six publications involving a total of 1678 patients were used in the analysis, including six RCTs that compared PDE5 inhibitors (tadalafil, sildenafil, avanafil and vardenafil) with placebo. Co-primary efficacy end points: International Index of Erectile Function-Erectile Function (IIEF-EF) domain score [the standardised mean difference (SMD) = 4.04, 95% confidence interval (CI) = 2.87-5.22, P < 0.00001]; successful vaginal penetration (SEP2) [the odds ratio (OR) = 14.87, 95%CI = 4.57-48.37, P < 0.00001]; and successful intercourse (SEP3) (OR = 47, 95%CI = 3-13.98, P < 0.00001) indicated that PDE5 inhibitors was more effective than the placebo. Specific adverse events with PDE5 inhibitors included headache (12.08%), dyspepsia (6.76%) and flushing (6.52%), which were significantly less likely to occur with placebo. This meta-analysis indicates that PDE5 inhibitors to be an effective and well-tolerated treatment for ED after BNSRP.

  14. A PDE-Based Regularization Algorithm Toward Reducing Speckle Tracking Noise: A Feasibility Study for Ultrasound Breast Elastography.

    PubMed

    Guo, Li; Xu, Yan; Xu, Zhengfu; Jiang, Jingfeng

    2015-10-01

    Obtaining accurate ultrasonically estimated displacements along both axial (parallel to the acoustic beam) and lateral (perpendicular to the beam) directions is an important task for various clinical elastography applications (e.g., modulus reconstruction and temperature imaging). In this study, a partial differential equation (PDE)-based regularization algorithm was proposed to enhance motion tracking accuracy. More specifically, the proposed PDE-based algorithm, utilizing two-dimensional (2D) displacement estimates from a conventional elastography system, attempted to iteratively reduce noise contained in the original displacement estimates by mathematical regularization. In this study, tissue incompressibility was the physical constraint used by the above-mentioned mathematical regularization. This proposed algorithm was tested using computer-simulated data, a tissue-mimicking phantom, and in vivo breast lesion data. Computer simulation results demonstrated that the method significantly improved the accuracy of lateral tracking (e.g., a factor of 17 at 0.5% compression). From in vivo breast lesion data investigated, we have found that, as compared with the conventional method, higher quality axial and lateral strain images (e.g., at least 78% improvements among the estimated contrast-to-noise ratios of lateral strain images) were obtained. Our initial results demonstrated that this conceptually and computationally simple method could be useful for improving the image quality of ultrasound elastography with current clinical equipment as a post-processing tool.

  15. Genomewide Association Study of African Children Identifies Association of SCHIP1 and PDE8A with Facial Size and Shape

    PubMed Central

    Manyama, Mange; Kimwaga, Emmanuel; Mathayo, Joshua; Larson, Jacinda R.; Liberton, Denise K.; Lukowiak, Ken; Riccardi, Sheri L.; Li, Mao; Williams, Trevor; Li, Hong; Jones, Kenneth L.; Klein, Ophir D.; Santorico, Stephanie A.; Hallgrimsson, Benedikt; Spritz, Richard A.

    2016-01-01

    The human face is a complex assemblage of highly variable yet clearly heritable anatomic structures that together make each of us unique, distinguishable, and recognizable. Relatively little is known about the genetic underpinnings of normal human facial variation. To address this, we carried out a large genomewide association study and two independent replication studies of Bantu African children and adolescents from Mwanza, Tanzania, a region that is both genetically and environmentally relatively homogeneous. We tested for genetic association of facial shape and size phenotypes derived from 3D imaging and automated landmarking of standard facial morphometric points. SNPs within genes SCHIP1 and PDE8A were associated with measures of facial size in both the GWAS and replication cohorts and passed a stringent genomewide significance threshold adjusted for multiple testing of 34 correlated traits. For both SCHIP1 and PDE8A, we demonstrated clear expression in the developing mouse face by both whole-mount in situ hybridization and RNA-seq, supporting their involvement in facial morphogenesis. Ten additional loci demonstrated suggestive association with various measures of facial shape. Our findings, which differ from those in previous studies of European-derived whites, augment understanding of the genetic basis of normal facial development, and provide insights relevant to both human disease and forensics. PMID:27560698

  16. GIS-based versus PDE-based modeling to help identify wetland and stream restoration opportunities at the landscape scale

    NASA Astrophysics Data System (ADS)

    Wise, W. R.; Loinaz, M. C.; James, A. L.; Shaw, D. T.

    2003-04-01

    For the eleven-hundred square kilometer Fisheating Creek watershed in south Florida, USA, two competing strategies are compared for predicting wetland and stream restoration opportunities. The first is based on geographical information systems (GIS), while the second is grounded in the solution of partial differential equations (PDE) that describe overland flow, infiltration, depression storage, and groundwater flow subject to meteorological drivers. The GIS approach is based upon the evaluation of data layers including those pertaining to topography, aerial photographs, soils, vegetation, wetland classification, land use, and ownership. The data layers are well resolved, perhaps with the exception of topography, which is not uncommon in large flat expanses of the state. Previously ditched non-riparian wetlands are classified through a series of Boolean filters for their potential to help restore the stream hydrology. The effects of such restoration efforts are simulated using an integrated surface-water/groundwater model that simulates the watershed on a relatively coarse grid. The utility of the PDE-based modeling is examined in light of the admitted difficulty in obtaining a sufficiently resolved data/parameter set. In addition, restoration objectives are based more upon the modes of hydrologic distributions, rather than their extremes as in flood and drought planning. How this philosophical shift affects the value of detailed modeling will be explored.

  17. Genomewide Association Study of African Children Identifies Association of SCHIP1 and PDE8A with Facial Size and Shape.

    PubMed

    Cole, Joanne B; Manyama, Mange; Kimwaga, Emmanuel; Mathayo, Joshua; Larson, Jacinda R; Liberton, Denise K; Lukowiak, Ken; Ferrara, Tracey M; Riccardi, Sheri L; Li, Mao; Mio, Washington; Prochazkova, Michaela; Williams, Trevor; Li, Hong; Jones, Kenneth L; Klein, Ophir D; Santorico, Stephanie A; Hallgrimsson, Benedikt; Spritz, Richard A

    2016-08-01

    The human face is a complex assemblage of highly variable yet clearly heritable anatomic structures that together make each of us unique, distinguishable, and recognizable. Relatively little is known about the genetic underpinnings of normal human facial variation. To address this, we carried out a large genomewide association study and two independent replication studies of Bantu African children and adolescents from Mwanza, Tanzania, a region that is both genetically and environmentally relatively homogeneous. We tested for genetic association of facial shape and size phenotypes derived from 3D imaging and automated landmarking of standard facial morphometric points. SNPs within genes SCHIP1 and PDE8A were associated with measures of facial size in both the GWAS and replication cohorts and passed a stringent genomewide significance threshold adjusted for multiple testing of 34 correlated traits. For both SCHIP1 and PDE8A, we demonstrated clear expression in the developing mouse face by both whole-mount in situ hybridization and RNA-seq, supporting their involvement in facial morphogenesis. Ten additional loci demonstrated suggestive association with various measures of facial shape. Our findings, which differ from those in previous studies of European-derived whites, augment understanding of the genetic basis of normal facial development, and provide insights relevant to both human disease and forensics. PMID:27560698

  18. Autonomous selection of PDE inpainting techniques vs. exemplar inpainting techniques for void fill of high resolution digital surface models

    NASA Astrophysics Data System (ADS)

    Rahmes, Mark; Yates, J. Harlan; Allen, Josef DeVaughn; Kelley, Patrick

    2007-04-01

    High resolution Digital Surface Models (DSMs) may contain voids (missing data) due to the data collection process used to obtain the DSM, inclement weather conditions, low returns, system errors/malfunctions for various collection platforms, and other factors. DSM voids are also created during bare earth processing where culture and vegetation features have been extracted. The Harris LiteSite TM Toolkit handles these void regions in DSMs via two novel techniques. We use both partial differential equations (PDEs) and exemplar based inpainting techniques to accurately fill voids. The PDE technique has its origin in fluid dynamics and heat equations (a particular subset of partial differential equations). The exemplar technique has its origin in texture analysis and image processing. Each technique is optimally suited for different input conditions. The PDE technique works better where the area to be void filled does not have disproportionately high frequency data in the neighborhood of the boundary of the void. Conversely, the exemplar based technique is better suited for high frequency areas. Both are autonomous with respect to detecting and repairing void regions. We describe a cohesive autonomous solution that dynamically selects the best technique as each void is being repaired.

  19. Decreased permeability surface area for glucose in obese women with postprandial hyperglycemia: no effect of phosphodiesterase-5 (PDE-5) inhibition.

    PubMed

    Sandqvist, M; Strindberg, L; Lönnroth, P; Jansson, P-A

    2013-08-01

    Insulin-mediated microvascular recruitment is recognized as a potential mechanism contributing to insulin resistance. In this study, we compared a marker of microvascular function, the permeability surface area for glucose (PS(glu)), and forearm glucose uptake after an OGTT in obese women with impaired glucose metabolism and healthy lean nondiabetic women, with the aim to characterize whether decreased permeability surface area for glucose or decreased glucose uptake may contribute to postprandial hyperglycemia in the obese group. In addition, we evaluated whether the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, in a randomized double blind placebo controlled design, might attenuate postprandial glucose levels in obese women. For these purposes, intramuscular microdialysis, blood sampling from arterial and venous blood of the forearm, and measurements of forearm blood flow were performed. The results showed an impaired permeability surface area for glucose (IAUC PS(glu) 31±13 vs. 124±31; p<0.05) in obese when compared with lean participants, but no differences in forearm glucose uptake appeared between the groups. Furthermore, a single dose of tadalafil 10 mg showed no improvement of the permeability surface area for glucose, glucose uptake, or circulating glucose levels in obese participants. In conclusion, the postprandial PS(glu) response was impaired in obese women showing postprandial hyperglycemia, indicating a compromised microcirculation. However, we were unable to demonstrate any acute effect on either vascular function or glucose uptake of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil. PMID:23613014

  20. A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability.

    PubMed

    Allerton, Charlotte M N; Barber, Christopher G; Beaumont, Kevin C; Brown, David G; Cole, Susan M; Ellis, David; Lane, Charlotte A L; Maw, Graham N; Mount, Natalie M; Rawson, David J; Robinson, Colin M; Street, Stephen D A; Summerhill, Nicholas W

    2006-06-15

    Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic. PMID:16759100

  1. Targeted disruption of the heat shock protein 20–phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy

    PubMed Central

    Martin, Tamara P.; Hortigon-Vinagre, Maria P.; Findlay, Jane E.; Elliott, Christina; Currie, Susan; Baillie, George S.

    2014-01-01

    Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20–phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20–PDE4D interaction leads to attenuation of pathological cardiac remodelling. PMID:25426411

  2. Nonlinear wave propagation in discrete and continuous systems

    NASA Astrophysics Data System (ADS)

    Rothos, V. M.

    2016-09-01

    In this review we try to capture some of the recent excitement induced by a large volume of theoretical and computational studies addressing nonlinear Schrödinger models (discrete and continuous) and the localized structures that they support. We focus on some prototypical structures, namely the breather solutions and solitary waves. In particular, we investigate the bifurcation of travelling wave solution in Discrete NLS system applying dynamical systems methods. Next, we examine the combined effects of cubic and quintic terms of the long range type in the dynamics of a double well potential. The relevant bifurcations, the stability of the branches and their dynamical implications are examined both in the reduced (ODE) and in the full (PDE) setting. We also offer an outlook on interesting possibilities for future work on this theme.

  3. Nonlinear drainage of some non-Newtonian free films

    NASA Astrophysics Data System (ADS)

    Tabakova, S.

    2015-10-01

    In the present work we apply the generalized lubrication approach (including inertial, viscous, capillary and van-der-Waals forces) to study the dynamics of a free thin film of a non-Newtonian fluid, whose viscosity is described by the Power law and Carreau models. For planar films with fully mobile surfaces, this approach leads to a system of two nonlinear PDE for the film thickness and lateral velocity. This system is solved numerically in the case of laterally bounded free films. The calculations of the film shape and velocity are presented using data of some real liquids: blood and aqueous solution of 0.5% hydroxyethylcellulose. It is shown that the Power law model predicts a very different viscosity to the Carreau model viscosity, although that the film profiles are not very different for all film wetting angles.

  4. Multilevel algorithms for nonlinear optimization

    NASA Technical Reports Server (NTRS)

    Alexandrov, Natalia; Dennis, J. E., Jr.

    1994-01-01

    Multidisciplinary design optimization (MDO) gives rise to nonlinear optimization problems characterized by a large number of constraints that naturally occur in blocks. We propose a class of multilevel optimization methods motivated by the structure and number of constraints and by the expense of the derivative computations for MDO. The algorithms are an extension to the nonlinear programming problem of the successful class of local Brown-Brent algorithms for nonlinear equations. Our extensions allow the user to partition constraints into arbitrary blocks to fit the application, and they separately process each block and the objective function, restricted to certain subspaces. The methods use trust regions as a globalization strategy, and they have been shown to be globally convergent under reasonable assumptions. The multilevel algorithms can be applied to all classes of MDO formulations. Multilevel algorithms for solving nonlinear systems of equations are a special case of the multilevel optimization methods. In this case, they can be viewed as a trust-region globalization of the Brown-Brent class.

  5. Identification, characterization and regional distribution in brain of RPDE-6 (RNPDE4A5), a novel splice variant of the PDE4A cyclic AMP phosphodiesterase family.

    PubMed

    McPhee, I; Pooley, L; Lobban, M; Bolger, G; Houslay, M D

    1995-09-15

    COS-7 cells were transfected with a plasmid encoding a putative splice variant of PDE4A cyclic AMP-specific phosphodiesterase, RPDE-6 (RNPDE4A5). This led to the expression of a novel, cyclic AMP-specific, rolipram-inhibited phosphodiesterase activity. In such transfected cells a novel approximately 109 kDa species was recognized by anti-peptide sera raised against a dodecapeptide whose sequence is found at the extreme C-terminus of both RPDE-6 and another PDE4A splice variant. RD1 (RNPDE4A1A). RPDE-6 activity and immunoreactivity was found distributed between both pellet (approximately 25%) and cytosol (approximately 75%) fractions of transfected COS-7 cells. Soluble and pellet RPDE-6 activities exhibited similar low Km values for cyclic AMP (approximately 2.4 microM) and were both inhibited by low concentrations of rolipram, with IC50 values for the soluble activity being lower (approximately 0.16 microM) than for the pellet activity (approximately 1.2 microM). Pellet RPDE-6 was resistant to release by either high NaCl concentrations or the detergent Triton X-100. Probing brain homogenates with the anti-(C-terminal peptide) sera identified two immunoreactive species, namely an approximately 79 kDa species reflecting RD1 and an approximately 109 kDa species that co-migrated with the immunoreactive species seen in COS cells transfected to express RPDE-6. The approximately 109 kDa species was found distributed between both the low-speed (P1) and high-speed (P2) pellet fractions as well as the cytosol fractions derived from both brain and RPDE-6-transfected COS cells. In contrast, RD1 was found exclusively in the P2 fraction. Phosphodiesterase (PDE) activity immuno-precipitated by these antisera from brain cytosol had the characteristics of COS cell-expressed RPDE-6 with KmcyclicAMP approximately 3.7 microM and IC50rolipram approximately 0.12 microM. The distribution of PDE activity immunoprecipitated from the cytosol of various brain regions paralleled that seen for

  6. The activity of cAMP-phosphodiesterase 4D7 (PDE4D7) is regulated by protein kinase A-dependent phosphorylation within its unique N-terminus

    PubMed Central

    Byrne, Ashleigh M.; Elliott, Christina; Hoffmann, Ralf; Baillie, George S.

    2015-01-01

    The cyclic AMP phosphodiesterases type 4 (PDE4s) are expressed in a cell specific manner, with intracellular targeting directed by unique N-terminal anchor domains. All long form PDE4s are phosphorylated and activated by PKA phosphorylation within their upstream conserved region 1 (UCR1). Here, we identify and characterise a novel PKA site (serine 42) within the N-terminal region of PDE4D7, an isoform whose activity is known to be important in prostate cancer progression and ischemic stroke. In contrast to the UCR1 site, PKA phosphorylation of the PDE4D7 N-terminus appears to occur constitutively and inhibits PDE4 activity to allow cAMP signalling under basal conditions. PMID:25680530

  7. New Nonlinear Multigrid Analysis

    NASA Technical Reports Server (NTRS)

    Xie, Dexuan

    1996-01-01

    The nonlinear multigrid is an efficient algorithm for solving the system of nonlinear equations arising from the numerical discretization of nonlinear elliptic boundary problems. In this paper, we present a new nonlinear multigrid analysis as an extension of the linear multigrid theory presented by Bramble. In particular, we prove the convergence of the nonlinear V-cycle method for a class of mildly nonlinear second order elliptic boundary value problems which do not have full elliptic regularity.

  8. α-Blockers, 5-α-Reductase Inhibitors, Acetylcholine, β3 Agonists, and Phosphodiesterase-5s in Medical Management of Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia: How Much Do the Different Formulations Actually Matter in the Classes?

    PubMed

    Chughtai, Bilal; Thomas, Dominique; Kaplan, Steven

    2016-08-01

    Many monotherapies are currently available to clinically treat and alleviate symptoms of lower urinary tract symptoms secondary to benign prostatic hyperplasia: α-blockers, 5ARIs, PDE5Is, β-3-andrenoceptor agonists, and anticholinergic agents. Current studies have evaluated the effective of these treatments in comparison to other groups or in combination therapies. The current review evaluates the effectiveness of class formulations. Based on the findings, α-blockers, specifically doxazosin and terazosin, were most effective in reducing IPSS scores and peak urinary flow rate, while being most cost-effective. However, further clinical investigations are required to evaluate the clinical implications of different formulations. PMID:27476127

  9. Nonlinear Dynamics of Structures with Material Degradation

    NASA Astrophysics Data System (ADS)

    Soltani, P.; Wagg, D. J.; Pinna, C.; Whear, R.; Briody, C.

    2016-09-01

    Structures usually experience deterioration during their working life. Oxidation, corrosion, UV exposure, and thermo-mechanical fatigue are some of the most well-known mechanisms that cause degradation. The phenomenon gradually changes structural properties and dynamic behaviour over their lifetime, and can be more problematic and challenging in the presence of nonlinearity. In this paper, we study how the dynamic behaviour of a nonlinear system changes as the thermal environment causes certain parameters to vary. To this end, a nonlinear lumped mass modal model is considered and defined under harmonic external force. Temperature dependent material functions, formulated from empirical test data, are added into the model. Using these functions, bifurcation parameters are defined and the corresponding nonlinear responses are observed by numerical continuation. A comparison between the results gives a preliminary insight into how temperature induced properties affects the dynamic response and highlights changes in stability conditions of the structure.

  10. Synthesis of higher order nonlinear circuit elements

    NASA Astrophysics Data System (ADS)

    Chua, L. O.; Szeto, E. W.

    1984-02-01

    Higher and mixed-order n-port circuit elements were introduced recently to provide a logically complete formulation for nonlinear circuit theory. In this paper, higher order mutators are defined and used to synthesize these elements. The class of all higher order mutators is shown to form a group under cascade interconnections. Each mutator is realized using only linear capacitors, linear inductors and linear controlled sources. An upper bound on each type of element needed to realize a mutator is also given. Each higher or mixed-order n-port element is realized by cascading approprimate mutators across each port of a nonlinear n-port resistor. The main theorem shows that any higher or mixed-order nonlinear n-port element with a constitutive relation defined on a compact set can be realized using linear capacitors, inductors, and controlled sources, and 2-terminal nonlinear resistors.

  11. Electromagnetic nonlinear gyrokinetics with polarization drift

    SciTech Connect

    Duthoit, F.-X.; Hahm, T. S.; Wang, Lu

    2014-08-15

    A set of new nonlinear electromagnetic gyrokinetic Vlasov equation with polarization drift and gyrokinetic Maxwell equations is systematically derived by using the Lie-transform perturbation method in toroidal geometry. For the first time, we recover the drift-kinetic expression for parallel acceleration [R. M. Kulsrud, in Basic Plasma Physics, edited by A. A. Galeev and R. N. Sudan (North-Holland, Amsterdam, 1983)] from the nonlinear gyrokinetic equations, thereby bridging a gap between the two formulations. This formalism should be useful in addressing nonlinear ion Compton scattering of intermediate-mode-number toroidal Alfvén eigenmodes for which the polarization current nonlinearity [T. S. Hahm and L. Chen, Phys. Rev. Lett. 74, 266 (1995)] and the usual finite Larmor radius effects should compete.

  12. Nonlinear modeling of MEMS piezoelectric energy harvesters

    NASA Astrophysics Data System (ADS)

    Wang, Y. C.; Huang, T. W.; Shu, Y. C.; Lin, S. C.; Wu, W. J.

    2016-04-01

    This article presents the modeling of nonlinear response of micro piezoelectric energy harvesters under amplified base excitation. The micro transducer is a composite cantilever beam made of the PZT thick film deposited on the stainless-steel substrate. The model is developed based on the Euler-Bernoulli beam theory considering geometric and inertia nonlinearities, and the reduced formulation is derived based on the Hamiltonian variational principle. The harmonic balance method is used to simulate the nonlinear frequency response under various magnitudes of excitation and electric loads. The hardening type of nonlinearity is predicted and is found to be in good agreement with experiment. However, the softening response is also observed in different samples fabricated under different conditions. Such disagreement is under investigation.

  13. Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG-positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression

    PubMed Central

    Böttcher, R; Henderson, D J P; Dulla, K; van Strijp, D; Waanders, L F; Tevz, G; Lehman, M L; Merkle, D; van Leenders, G J L H; Baillie, G S; Jenster, G; Houslay, M D; Hoffmann, R

    2015-01-01

    Background: There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples. Methods: About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold >3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample. Results: We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC). Conclusions: We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression. PMID:26575822

  14. Highly nonlinear stress-relaxation response of articular cartilage in indentation: Importance of collagen nonlinearity.

    PubMed

    Mäkelä, J T A; Korhonen, R K

    2016-06-14

    Modern fibril-reinforced computational models of articular cartilage can include inhomogeneous tissue composition and structure, and nonlinear mechanical behavior of collagen, proteoglycans and fluid. These models can capture well experimental single step creep and stress-relaxation tests or measurements under small strains in unconfined and confined compression. Yet, it is known that in indentation, especially at high strain velocities, cartilage can express highly nonlinear response. Different fibril reinforced poroelastic and poroviscoelastic models were used to assess measured highly nonlinear stress-relaxation response of rabbit articular cartilage in indentation. Experimentally measured depth-dependent volume fractions of different tissue constituents and their mechanical nonlinearities were taken into account in the models. In particular, the collagen fibril network was modeled using eight separate models that implemented five different constitutive equations to describe the nonlinearity. These consisted of linear elastic, nonlinear viscoelastic and multiple nonlinear elastic representations. The model incorporating the most nonlinearly increasing Young׳s modulus of collagen fibrils as a function of strain captured best the experimental data. Relative difference between the model and experiment was ~3%. Surprisingly, the difference in the peak forces between the experiment and the model with viscoelastic collagen fibrils was almost 20%. Implementation of the measured volume fractions did not improve the ability of the model to capture the measured mechanical data. These results suggest that a highly nonlinear formulation for collagen fibrils is needed to replicate multi-step stress-relaxation response of rabbit articular cartilage in indentation with high strain rates. PMID:27130474

  15. Highly nonlinear stress-relaxation response of articular cartilage in indentation: Importance of collagen nonlinearity.

    PubMed

    Mäkelä, J T A; Korhonen, R K

    2016-06-14

    Modern fibril-reinforced computational models of articular cartilage can include inhomogeneous tissue composition and structure, and nonlinear mechanical behavior of collagen, proteoglycans and fluid. These models can capture well experimental single step creep and stress-relaxation tests or measurements under small strains in unconfined and confined compression. Yet, it is known that in indentation, especially at high strain velocities, cartilage can express highly nonlinear response. Different fibril reinforced poroelastic and poroviscoelastic models were used to assess measured highly nonlinear stress-relaxation response of rabbit articular cartilage in indentation. Experimentally measured depth-dependent volume fractions of different tissue constituents and their mechanical nonlinearities were taken into account in the models. In particular, the collagen fibril network was modeled using eight separate models that implemented five different constitutive equations to describe the nonlinearity. These consisted of linear elastic, nonlinear viscoelastic and multiple nonlinear elastic representations. The model incorporating the most nonlinearly increasing Young׳s modulus of collagen fibrils as a function of strain captured best the experimental data. Relative difference between the model and experiment was ~3%. Surprisingly, the difference in the peak forces between the experiment and the model with viscoelastic collagen fibrils was almost 20%. Implementation of the measured volume fractions did not improve the ability of the model to capture the measured mechanical data. These results suggest that a highly nonlinear formulation for collagen fibrils is needed to replicate multi-step stress-relaxation response of rabbit articular cartilage in indentation with high strain rates.

  16. [Nonlinear magnetohydrodynamics

    SciTech Connect

    Not Available

    1994-01-01

    Resistive MHD equilibrium, even for small resistivity, differs greatly from ideal equilibrium, as do the dynamical consequences of its instabilities. The requirement, imposed by Faraday`s law, that time independent magnetic fields imply curl-free electric fields, greatly restricts the electric fields allowed inside a finite-resistivity plasma. If there is no flow and the implications of the Ohm`s law are taken into account (and they need not be, for ideal equilibria), the electric field must equal the resistivity times the current density. The vanishing of the divergence of the current density then provides a partial differential equation which, together with boundary conditions, uniquely determines the scalar potential, the electric field, and the current density, for any given resistivity profile. The situation parallels closely that of driven shear flows in hydrodynamics, in that while dissipative steady states are somewhat more complex than ideal ones, there are vastly fewer of them to consider. Seen in this light, the vast majority of ideal MHD equilibria are just irrelevant, incapable of being set up in the first place. The steady state whose stability thresholds and nonlinear behavior needs to be investigated ceases to be an arbitrary ad hoc exercise dependent upon the whim of the investigator, but is determined by boundary conditions and choice of resistivity profile.

  17. Segregation of Incomplete Achromatopsia and Alopecia Due to PDE6H and LPAR6 Variants in a Consanguineous Family from Pakistan.

    PubMed

    Pedurupillay, Christeen Ramane J; Landsend, Erlend Christoffer Sommer; Vigeland, Magnus Dehli; Ansar, Muhammad; Frengen, Eirik; Misceo, Doriana; Strømme, Petter

    2016-01-01

    We report on two brothers with visual impairment, and non-syndromic alopecia in the elder proband. The parents were first-degree Pakistani cousins. Whole exome sequencing of the elder brother and parents, followed by Sanger sequencing of all four family members, led to the identification of the variants responsible for the two phenotypes. One variant was a homozygous nonsense variant in the inhibitory subunit of the cone-specific cGMP phosphodiesterase gene, PDE6H:c.35C>G (p.Ser12*). PDE6H is expressed in the cones of the retina, which are involved in perception of color vision. This is the second report of a homozygous PDE6H:c.35C>G variant causing incomplete achromatopsia (OMIM 610024), thus strongly supporting the hypothesis that loss-of-function variants in PDE6H cause this visual deficiency phenotype. The second variant was a homozygous missense substitution in the lysophosphatidic acid receptor 6, LPAR6:c.188A>T (p.Asp63Val). LPAR6 acts as a G-protein-coupled receptor involved in hair growth. Biallelic loss-of-function variants in LPAR6 cause hypotrichosis type 8 (OMIM 278150), with or without woolly hair, a form of non-syndromic alopecia. Biallelic LPAR6:c.188A>T was previously described in five families from Pakistan. PMID:27472364

  18. PDE3A-SLCO1C1 locus is associated with response to anti-tumor necrosis factor therapy in psoriatic arthritis.

    PubMed

    Julià, Antonio; Rodríguez, Jesús; Fernández-Sueiro, José Luis; Gratacós, Jordi; Queiró, Rubén; Montilla, Carlos; Torre-Alonso, Juan Carlos; Pérez-Venegas, José Javier; Manrique-Arija, Sara; Muñoz-Fernández, Santiago; González, Carlos; Roig, Daniel; Zarco, Pedro; Erra, Alba; Castañeda, Santos; García, Alicia; Salvador, Georgina; Díaz-Torne, César; Blanco, Ricardo; Domínguez, Alfredo Willisch; Mosquera, José Antonio; Vela, Paloma; Tornero, Jesús; Sánchez-Fernández, Simón; Corominas, Héctor; Ramírez, Julio; Avila, Gabriela; Alonso, Arnald; Tortosa, Raül; López-Lasanta, María; Cañete, Juan D; Marsal, Sara

    2014-11-01

    Aim: Variation at PDE3A-SLCO1C1 locus has been recently associated with the response to anti-TNF therapy in rheumatoid arthritis. We undertook the present study to determine whether PDE3A-SLCO1C1 is also associated with the response to anti-TNF therapy in psoriatic arthritis. Patients & methods: Genomic DNA was obtained from 81 psoriatic arthritis patients that had been treated with anti-TNF therapy. PDE3A-SLCO1C1 SNP rs3794271 was genotyped using Taqman realt-time PCR. The clinical response to anti-TNF therapy was measured as the change from baseline in the level of disease activity according to the DAS28 score. Results: A significant association between rs3794271 and anti-TNF response in psoriatic arthritis was found (beta = -0.71; p = 0.0036). Conclusion: PDE3A-SLCO1C1 locus is also associated with response to anti-TNF therapy in psoriatic arthritis. Original submitted 12 May 2014; Revision submitted 18 August 2014.

  19. PDE5 inhibitors, sildenafil and vardenafil, reverse multidrug resistance by inhibiting the efflux function of multidrug resistance protein 7 (ATP-binding Cassette C10) transporter.

    PubMed

    Chen, Jun-Jiang; Sun, Yue-Li; Tiwari, Amit K; Xiao, Zhi-Jie; Sodani, Kamlesh; Yang, Dong-Hua; Vispute, Saraubh G; Jiang, Wen-Qi; Chen, Si-Dong; Chen, Zhe-Sheng

    2012-08-01

    Phosphodiesterase type 5 (PDE5) inhibitors are widely used in the treatment of male erectile dysfunction and pulmonary hypertension. Recently, several groups have evaluated the ability of PDE5 inhibitors for their anticancer activities. Previously, we had shown that sildenafil, vardenafil and tadalafil could reverse P-glycoprotein (ATP-binding cassette B1)-mediated MDR. In the present study, we determined whether these PDE5 inhibitors have the potential to reverse multidrug resistance protein 7 (MRP7; ATP-binding cassette C10)-mediated MDR. We found that sildenafil and vardenafil dose-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine, while tadalafil had only a minimal effect. Accumulation and efflux experiments demonstrated that sildenafil and vardenafil increased the intracellular accumulation of [(3)H]-paclitaxel by inhibiting the efflux of [(3 H]-paclitaxel in HEK/MRP7 cells. In addition, immunoblot and immunofluorescence analyses indicated that no significant alterations of MRP7 protein expression and localization in plasma membranes were found after treatment with sildenafil, vardenafil or tadalafil. These results demonstrate that sildenafil and vardenafil reverse MRP7-mediated a MDR through inhibition of the drug efflux function of MRP7. Our findings indicate a potentially novel use of PDE5 inhibitors as an adjuvant chemotherapeutic agent in clinical practice. PMID:22578167

  20. Segregation of Incomplete Achromatopsia and Alopecia Due to PDE6H and LPAR6 Variants in a Consanguineous Family from Pakistan

    PubMed Central

    Pedurupillay, Christeen Ramane J.; Landsend, Erlend Christoffer Sommer; Vigeland, Magnus Dehli; Ansar, Muhammad; Frengen, Eirik; Misceo, Doriana; Strømme, Petter

    2016-01-01

    We report on two brothers with visual impairment, and non-syndromic alopecia in the elder proband. The parents were first-degree Pakistani cousins. Whole exome sequencing of the elder brother and parents, followed by Sanger sequencing of all four family members, led to the identification of the variants responsible for the two phenotypes. One variant was a homozygous nonsense variant in the inhibitory subunit of the cone-specific cGMP phosphodiesterase gene, PDE6H:c.35C>G (p.Ser12*). PDE6H is expressed in the cones of the retina, which are involved in perception of color vision. This is the second report of a homozygous PDE6H:c.35C>G variant causing incomplete achromatopsia (OMIM 610024), thus strongly supporting the hypothesis that loss-of-function variants in PDE6H cause this visual deficiency phenotype. The second variant was a homozygous missense substitution in the lysophosphatidic acid receptor 6, LPAR6:c.188A>T (p.Asp63Val). LPAR6 acts as a G-protein-coupled receptor involved in hair growth. Biallelic loss-of-function variants in LPAR6 cause hypotrichosis type 8 (OMIM 278150), with or without woolly hair, a form of non-syndromic alopecia. Biallelic LPAR6:c.188A>T was previously described in five families from Pakistan. PMID:27472364

  1. Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease

    NASA Astrophysics Data System (ADS)

    Su, Tao; Zhang, Tianhua; Xie, Shishun; Yan, Jun; Wu, Yinuo; Li, Xingshu; Huang, Ling; Luo, Hai-Bin

    2016-02-01

    Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer’s disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ1-42 aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu2+-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.

  2. Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease

    PubMed Central

    Su, Tao; Zhang, Tianhua; Xie, Shishun; Yan, Jun; Wu, Yinuo; Li, Xingshu; Huang, Ling; Luo, Hai-Bin

    2016-01-01

    Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer’s disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ1-42 aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu2+-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD. PMID:26911795

  3. Nonrecursive formulations of multibody dynamics and concurrent multiprocessing

    NASA Technical Reports Server (NTRS)

    Kurdila, Andrew J.; Menon, Ramesh

    1993-01-01

    Since the late 1980's, research in recursive formulations of multibody dynamics has flourished. Historically, much of this research can be traced to applications of low dimensionality in mechanism and vehicle dynamics. Indeed, there is little doubt that recursive order N methods are the method of choice for this class of systems. This approach has the advantage that a minimal number of coordinates are utilized, parallelism can be induced for certain system topologies, and the method is of order N computational cost for systems of N rigid bodies. Despite the fact that many authors have dismissed redundant coordinate formulations as being of order N(exp 3), and hence less attractive than recursive formulations, we present recent research that demonstrates that at least three distinct classes of redundant, nonrecursive multibody formulations consistently achieve order N computational cost for systems of rigid and/or flexible bodies. These formulations are as follows: (1) the preconditioned range space formulation; (2) penalty methods; and (3) augmented Lagrangian methods for nonlinear multibody dynamics. The first method can be traced to its foundation in equality constrained quadratic optimization, while the last two methods have been studied extensively in the context of coercive variational boundary value problems in computational mechanics. Until recently, however, they have not been investigated in the context of multibody simulation, and present theoretical questions unique to nonlinear dynamics. All of these nonrecursive methods have additional advantages with respect to recursive order N methods: (1) the formalisms retain the highly desirable order N computational cost; (2) the techniques are amenable to concurrent simulation strategies; (3) the approaches do not depend upon system topology to induce concurrency; and (4) the methods can be derived to balance the computational load automatically on concurrent multiprocessors. In addition to the presentation of

  4. The dynamics of p53 in single cells: physiologically based ODE and reaction-diffusion PDE models

    NASA Astrophysics Data System (ADS)

    Eliaš, Ján; Dimitrio, Luna; Clairambault, Jean; Natalini, Roberto

    2014-08-01

    The intracellular signalling network of the p53 protein plays important roles in genome protection and the control of cell cycle phase transitions. Recently observed oscillatory behaviour in single cells under stress conditions has inspired several research groups to simulate and study the dynamics of the protein with the aim of gaining a proper understanding of the physiological meanings of the oscillations. We propose compartmental ODE and PDE models of p53 activation and regulation in single cells following DNA damage and we show that the p53 oscillations can be retrieved by plainly involving p53-Mdm2 and ATM-p53-Wip1 negative feedbacks, which are sufficient for oscillations experimentally, with no further need to introduce any delays into the protein responses and without considering additional positive feedback.

  5. A PDE-based methodology for modeling, parameter estimation and feedback control in structural and structural acoustic systems

    NASA Technical Reports Server (NTRS)

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

    1994-01-01

    A problem of continued interest concerns the control of vibrations in a flexible structure and the related problem of reducing structure-borne noise in structural acoustic systems. In both cases, piezoceramic patches bonded to the structures have been successfully used as control actuators. Through the application of a controlling voltage, the patches can be used to reduce structural vibrations which in turn lead to methods for reducing structure-borne noise. A PDE-based methodology for modeling, estimating physical parameters, and implementing a feedback control scheme for problems of this type is discussed. While the illustrating example is a circular plate, the methodology is sufficiently general so as to be applicable in a variety of structural and structural acoustic systems.

  6. Geometrically nonlinear behavior of piezoelectric laminated plates

    NASA Astrophysics Data System (ADS)

    Rabinovitch, Oded

    2005-08-01

    The geometrically nonlinear behavior of piezo-laminated plates actuated with isotropic or anisotropic piezoelectric layers is analytically investigated. The analytical model is derived using the variational principle of virtual work along with the lamination and plate theories, the von Karman large displacement and moderate rotation kinematic relations, and the anisotropic piezoelectric constitutive laws. A solution strategy that combines the approach of the method of lines, the advantages of the finite element concept, and the variational formulation is developed. This approach yields a set of nonlinear ordinary differential equations with nonlinear boundary conditions, which are solved using the multiple-shooting method. Convergence and verification of the model are examined through comparison with linear and nonlinear results of other approximation methods. The nonlinear response of two active plate structures is investigated numerically. The first plate is actuated in bending using monolithic piezoceramic layers and the second one is actuated in twist using macro-fiber composites. The results quantitatively reveal the complicated in-plane stress state associated with the piezoelectric actuation and the geometrically nonlinear coupling of the in-plane and out-of-plane responses of the plate. The influence of the nonlinear effects ranges from significant stiffening in certain combinations of electrical loads and boundary conditions to amplifications of the induced deflections in others. The paper closes with a summary and conclusions.

  7. Parallel Allostery by cAMP and PDE Coordinates Activation and Termination Phases in cAMP Signaling.

    PubMed

    Krishnamurthy, Srinath; Tulsian, Nikhil Kumar; Chandramohan, Arun; Anand, Ganesh S

    2015-09-15

    The second messenger molecule cAMP regulates the activation phase of the cAMP signaling pathway through high-affinity interactions with the cytosolic cAMP receptor, the protein kinase A regulatory subunit (PKAR). Phosphodiesterases (PDEs) are enzymes responsible for catalyzing hydrolysis of cAMP to 5' AMP. It was recently shown that PDEs interact with PKAR to initiate the termination phase of the cAMP signaling pathway. While the steps in the activation phase are well understood, steps in the termination pathway are unknown. Specifically, the binding and allosteric networks that regulate the dynamic interplay between PKAR, PDE, and cAMP are unclear. In this study, PKAR and PDE from Dictyostelium discoideum (RD and RegA, respectively) were used as a model system to monitor complex formation in the presence and absence of cAMP. Amide hydrogen/deuterium exchange mass spectrometry was used to monitor slow conformational transitions in RD, using disordered regions as conformational probes. Our results reveal that RD regulates its interactions with cAMP and RegA at distinct loci by undergoing slow conformational transitions between two metastable states. In the presence of cAMP, RD and RegA form a stable ternary complex, while in the absence of cAMP they maintain transient interactions. RegA and cAMP each bind at orthogonal sites on RD with resultant contrasting effects on its dynamics through parallel allosteric relays at multiple important loci. RD thus serves as an integrative node in cAMP termination by coordinating multiple allosteric relays and governing the output signal response.

  8. Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy

    PubMed Central

    Petit, Lolita; Lhériteau, Elsa; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Guihal, Caroline; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

    2012-01-01

    Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment. PMID:22828504

  9. Restoration of vision in the pde6β-deficient dog, a large animal model of rod-cone dystrophy.

    PubMed

    Petit, Lolita; Lhériteau, Elsa; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Guihal, Caroline; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

    2012-11-01

    Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment.

  10. Evaluation of a novel PDE10A PET radioligand, [(11) C]T-773, in nonhuman primates: brain and whole body PET and brain autoradiography.

    PubMed

    Takano, Akihiro; Stepanov, Vladimir; Gulyás, Balázs; Nakao, Ryuji; Amini, Nahid; Miura, Shotaro; Kimura, Haruhide; Taniguchi, Takahiko; Halldin, Christer

    2015-07-01

    Phosphodiesterase 10A (PDE10A) is considered to be a key target for the treatment of several neuropsychiatric diseases. The characteristics of [(11) C]T-773, a novel positron emission tomography (PET) radioligand with high binding affinity and selectivity for PDE10A, were evaluated in autoradiography and in nonhuman primate (NHP) PET. Brain PET measurements were performed under baseline conditions and after administration of a selective PDE10A inhibitor, MP-10. Total distribution volume (VT ) and binding potential (BPND ) were calculated using various kinetic models. Whole body PET measurements were performed to calculate the effective dose of [(11) C]T-773. Autoradiography studies in postmortem human and monkey brain sections showed high accumulation of [(11) C]T-773 in the striatum and substantia nigra which was blocked by MP-10. Brain PET showed high accumulation of [(11) C]T-773 in the striatum, and the data could be fitted using a two tissue compartment model. BPND was approximately 1.8 in the putamen when the cerebellum was used as the reference region. Approximately 70% of PDE10A binding was occupied by 1.8 mg/kg of MP-10. Whole body PET showed high accumulation of [(11) C]T-773 in the liver, kidney, heart, and brain in the initial phase. The radioligand was partly excreted via bile and the gastrointestinal tract, and partly excreted through the urinary tract. The calculated effective dose was 0.007 mSv/MBq. In conclusion, [(11) C]T-773 was demonstrated to be a promising PET radioligand for PDE10A with favorable brain kinetics. Dosimetry results support multiple PET measurements per person in human studies. Further research is required with [(11) C]T-773 in order to test the radioligand's potential clinical applications.

  11. Plutonium Immobilization Project Baseline Formulation

    SciTech Connect

    Ebbinghaus, B.

    1999-02-01

    A key milestone for the Immobilization Project (AOP Milestone 3.2a) in Fiscal Year 1998 (FY98) is the definition of the baseline composition or formulation for the plutonium ceramic form. The baseline formulation for the plutonium ceramic product must be finalized before the repository- and plant-related process specifications can be determined. The baseline formulation that is currently specified is given in Table 1.1. In addition to the baseline formulation specification, this report provides specifications for two alternative formulations, related compositional specifications (e.g., precursor compositions and mixing recipes), and other preliminary form and process specifications that are linked to the baseline formulation. The preliminary specifications, when finalized, are not expected to vary tremendously from the preliminary values given.

  12. Mathematical programming formulations for satellite synthesis

    NASA Technical Reports Server (NTRS)

    Bhasin, Puneet; Reilly, Charles H.

    1987-01-01

    The problem of satellite synthesis can be described as optimally allotting locations and sometimes frequencies and polarizations, to communication satellites so that interference from unwanted satellite signals does not exceed a specified threshold. In this report, mathematical programming models and optimization methods are used to solve satellite synthesis problems. A nonlinear programming formulation which is solved using Zoutendijk's method and a gradient search method is described. Nine mixed integer programming models are considered. Results of computer runs with these nine models and five geographically compatible scenarios are presented and evaluated. A heuristic solution procedure is also used to solve two of the models studied. Heuristic solutions to three large synthesis problems are presented. The results of our analysis show that the heuristic performs very well, both in terms of solution quality and solution time, on the two models to which it was applied. It is concluded that the heuristic procedure is the best of the methods considered for solving satellite synthesis problems.

  13. Explosive Formulation Code Naming SOP

    SciTech Connect

    Martz, H. E.

    2014-09-19

    The purpose of this SOP is to provide a procedure for giving individual HME formulations code names. A code name for an individual HME formulation consists of an explosive family code, given by the classified guide, followed by a dash, -, and a number. If the formulation requires preparation such as packing or aging, these add additional groups of symbols to the X-ray specimen name.

  14. Linear and nonlinear oscilations in Classical Mechanics

    NASA Astrophysics Data System (ADS)

    Cruz, Enrique; Martinez, Juan L.; Camacho, Edgar

    1997-04-01

    The theory of small oscilations is very important in many areas of physics and others sciences due to the simple form of the equations and the easy interpretetion of the results. In this work we show three examples of mechanical systems and using the Lagrangian formulation, we study the linear regime making approaches to the Lagrange's equations, and for the analysis of the nonlinear behavior of the systems we use the Hamiltonian formulation, we use the program MATHEMATICA for the whole analysis. MATHEMATICA is useful because many students can approach to the analysis and simulations using modern tools like the simbolic and numerical computacional packages.

  15. Baseline LAW Glass Formulation Testing

    SciTech Connect

    Kruger, Albert A.; Mooers, Cavin; Bazemore, Gina; Pegg, Ian L.; Hight, Kenneth; Lai, Shan Tao; Buechele, Andrew; Rielley, Elizabeth; Gan, Hao; Muller, Isabelle S.; Cecil, Richard

    2013-06-13

    The major objective of the baseline glass formulation work was to develop and select glass formulations that are compliant with contractual and processing requirements for each of the LAW waste streams. Other objectives of the work included preparation and characterization of glasses with respect to the properties of interest, optimization of sulfate loading in the glasses, evaluation of ability to achieve waste loading limits, testing to demonstrate compatibility of glass melts with melter materials of construction, development of glass formulations to support ILAW qualification activities, and identification of glass formulation issues with respect to contract specifications and processing requirements.

  16. Saltstone Clean Cap Formulation

    SciTech Connect

    Langton, C

    2005-04-22

    The current operation strategy for using Saltstone Vault 4 to receive 0.2 Ci/gallon salt solution waste involves pouring a clean grout layer over the radioactive grout prior to initiating pour into another cell. This will minimize the radiating surface area and reduce the dose rate at the vault and surrounding area. The Clean Cap will be used to shield about four feet of Saltstone poured into a Z-Area vault cell prior to moving to another cell. The minimum thickness of the Clean Cap layer will be determined by the cesium concentration and resulting dose levels and it is expected to be about one foot thick based on current calculations for 0.1 Ci Saltstone that is produced in the Saltstone process by stabilization of 0.2 Ci salt solution. This report documents experiments performed to identify a formulation for the Clean Cap. Thermal transient calculations, adiabatic temperature rise measurements, pour height, time between pour calculations and shielding calculations were beyond the scope and time limitations of this study. However, data required for shielding calculations (composition and specific gravity) are provided for shielding calculations. The approach used to design a Clean Cap formulation was to produce a slurry from the reference premix (10/45/45 weight percent cement/slag/fly ash) and domestic water that resembled as closely as possible the properties of the Saltstone slurry. In addition, options were investigated that may offer advantages such as less bleed water and less heat generation. The options with less bleed water required addition of dispersants. The options with lower heat contained more fly ash and less slag. A mix containing 10/45/45 weight percent cement/slag/fly ash with a water to premix ratio of 0.60 is recommended for the Clean Cap. Although this mix may generate more than 3 volume percent standing water (bleed water), it has rheological, mixing and flow properties that are similar to previously processed Saltstone. The recommended

  17. Operator Formulation of Classical Mechanics.

    ERIC Educational Resources Information Center

    Cohn, Jack

    1980-01-01

    Discusses the construction of an operator formulation of classical mechanics which is directly concerned with wave packets in configuration space and is more similar to that of convential quantum theory than other extant operator formulations of classical mechanics. (Author/HM)

  18. Nonlinear Acoustics in Fluids

    NASA Astrophysics Data System (ADS)

    Lauterborn, Werner; Kurz, Thomas; Akhatov, Iskander

    At high sound intensities or long propagation distances at in fluids sufficiently low damping acoustic phenomena become nonlinear. This chapter focuses on nonlinear acoustic wave properties in gases and liquids. The origin of nonlinearity, equations of state, simple nonlinear waves, nonlinear acoustic wave equations, shock-wave formation, and interaction of waves are presented and discussed. Tables are given for the nonlinearity parameter B/A for water and a range of organic liquids, liquid metals and gases. Acoustic cavitation with its nonlinear bubble oscillations, pattern formation and sonoluminescence (light from sound) are modern examples of nonlinear acoustics. The language of nonlinear dynamics needed for understanding chaotic dynamics and acoustic chaotic systems is introduced.

  19. Entropy-Based Approach To Nonlinear Stability

    NASA Technical Reports Server (NTRS)

    Merriam, Marshal L.

    1991-01-01

    NASA technical memorandum suggests schemes for numerical solution of differential equations of flow made more accurate and robust by invoking second law of thermodynamics. Proposes instead of using artificial viscosity to suppress such unphysical solutions as spurious numerical oscillations and nonlinear instabilities, one should formulate equations so that rate of production of entropy within each cell of computational grid be nonnegative, as required by second law.

  20. A Dependency-Driven Formulation of Parareal: Parallel-in-Time Solution of PDEs as a Many-Task Application

    SciTech Connect

    Elwasif, Wael R; Foley, Samantha S; Bernholdt, David E; Berry, Lee A; Samaddar, D.; Newman, David E; Sanchez, R.

    2011-01-01

    Parareal is a novel algorithm that allows the solution of time-dependent systems of differential or partial differential equations (PDE) to be parallelized in the temporal domain. Parareal-based implementations of PDE problems can take advantage of this parallelism to significantly reduce the time to solution for a simulation (though at an increased total cost) while making effective use of the much larger processor counts available on current high-end systems. In this paper, we present a dynamic, dependency-driven version of the parareal algorithm which breaks the final sequential bottleneck remaining in the original formulation, making it amenable to a "many-task" treatment. We further improve the cost and execution time of the algorithm by introducing a moving window for time slices, which avoids the execution of tasks which contribute little to the final global solution. We describe how this approach has been realized in the Integrated Plasma Simulator (IPS), a framework for coupled multiphysics simulations, and examine the trade-offs among time-to-solution, total cost, and resource utilization efficiency as a function of the compute resources applied to the problem.

  1. Nonlinear theory of a plasma Cherenkov maser

    SciTech Connect

    Choi, J.S.; Heo, E.G.; Choi, D.I.

    1995-12-31

    The nonlinear saturation state in a plasma Cherenkov maser (PCM) propagating the intense relativistic electron beam through a circular waveguide partially filled with a dense annular plasma, is analyzed from the nonlinear formulation based on the cold fluid-Maxwell equations. We obtain the nonlinear efficiency and the final operation frequency under consideration of the effects of the beam current, the beam energy and the slow wave structure. We show that the saturation mechanism of a PCM instablity is a close correspondence in that of the relativistic two stream instability by the coherent trapping of electrons in a single most-ustable wave. And the optimal conditions in PCM operation are also obtained from performing our nonliear analysis together with computer simulations.

  2. Nonlinear Control of Dynamical Systems from Time Series

    NASA Astrophysics Data System (ADS)

    Petrov, Valery; Showalter, Kenneth

    1996-04-01

    Feedback control of multidimensional, nonlinear single-input single-output systems is formulated in terms of an invariant hypersurface in the delayed state space of a system observable and a control parameter. The surface is created directly from the response of the system to random perturbations, providing a model-independent nonlinear control algorithm. The algorithm can be used to stabilize unstable states or to drive a system to any particular objective state in a minimum number of steps.

  3. Parallel computation of three-dimensional nonlinear magnetostatic problems.

    SciTech Connect

    Levine, D.; Gropp, W.; Forsman, K.; Kettunen, L.; Mathematics and Computer Science; Tampere Univ. of Tech.

    1999-02-01

    We describe a general-purpose parallel electromagnetic code for computing accurate solutions to large computationally demanding, 3D, nonlinear magnetostatic problems. The code, CORAL, is based on a volume integral equation formulation. Using an IBM SP parallel computer and iterative solution methods, we successfully solved the dense linear systems inherent in such formulations. A key component of our work was the use of the PETSc library, which provides parallel portability and access to the latest linear algebra solution technology.

  4. Nonlinear Hysteretic Torsional Waves

    NASA Astrophysics Data System (ADS)

    Cabaret, J.; Béquin, P.; Theocharis, G.; Andreev, V.; Gusev, V. E.; Tournat, V.

    2015-07-01

    We theoretically study and experimentally report the propagation of nonlinear hysteretic torsional pulses in a vertical granular chain made of cm-scale, self-hanged magnetic beads. As predicted by contact mechanics, the torsional coupling between two beads is found to be nonlinear hysteretic. This results in a nonlinear pulse distortion essentially different from the distortion predicted by classical nonlinearities and in a complex dynamic response depending on the history of the wave particle angular velocity. Both are consistent with the predictions of purely hysteretic nonlinear elasticity and the Preisach-Mayergoyz hysteresis model, providing the opportunity to study the phenomenon of nonlinear dynamic hysteresis in the absence of other types of material nonlinearities. The proposed configuration reveals a plethora of interesting phenomena including giant amplitude-dependent attenuation, short-term memory, as well as dispersive properties. Thus, it could find interesting applications in nonlinear wave control devices such as strong amplitude-dependent filters.

  5. A nonlinear oscillator

    SciTech Connect

    Tomlin, R.

    1990-01-27

    A nonlinear oscillator design was imported from Cornell modified, and built for the purpose of simulating the chaotic states of a forced pendulum. Similar circuits have been investigated in the recent nonlinear explosion.

  6. Novel Formulations for Antimicrobial Peptides

    PubMed Central

    Carmona-Ribeiro, Ana Maria; Carrasco, Letícia Dias de Melo

    2014-01-01

    Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. This review discusses how novel formulations may improve the therapeutic index of antimicrobial peptides by protecting their activity and improving their bioavailability. The diversity of novel formulations using lipids, liposomes, nanoparticles, polymers, micelles, etc., within the limits of nanotechnology may also provide novel applications going beyond antimicrobial chemotherapy. PMID:25302615

  7. Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment.

    PubMed

    Gallant, Michel; Aspiotis, Renee; Day, Stephen; Dias, Rebecca; Dubé, Daniel; Dubé, Laurence; Friesen, Richard W; Girard, Mario; Guay, Daniel; Hamel, Pierre; Huang, Zheng; Lacombe, Patrick; Laliberté, Sebastien; Lévesque, Jean-François; Liu, Susana; Macdonald, Dwight; Mancini, Joseph; Nicholson, Donald W; Styhler, Angela; Townson, Karen; Waters, Kerry; Young, Robert N; Girard, Yves

    2010-11-15

    The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.

  8. Differential effects of black raspberry and strawberry extracts on BaPDE-induced activation of transcription factors and their target genes.

    PubMed

    Li, Jingxia; Zhang, Dongyun; Stoner, Gary D; Huang, Chuanshu

    2008-04-01

    The chemopreventive properties of edible berries have been demonstrated both in vitro and in vivo, however, the specific molecular mechanisms underlying their anti-cancer effects are largely unknown. Our previous studies have shown that a methanol extract fraction of freeze-dried black raspberries inhibits benzoapyrene (BaP)-induced transformation of Syrian hamster embryo cells. This fraction also blocks activation of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB) induced by benzoapyrene diol-epoxide (BaPDE) in mouse epidermal JB6 Cl 41 cells. To determine if different berry types exhibit specific mechanisms for their anti-cancer effects, we compared the effects of extract fractions from both black raspberries and strawberries on BaPDE-induced activation of various signaling pathways in Cl 41 cells. Black raspberry fractions inhibited the activation of AP-1, NF-kappaB, and nuclear factor of activated T cells (NFAT) by BaPDE as well as their upstream PI-3K/Akt-p70(S6K) and mitogen-activated protein kinase pathways. In contrast, strawberry fractions inhibited NFAT activation, but did not inhibit the activation of AP-1, NF-kappaB or the PI-3K/Akt-p70(S6K) and mitogen-activated protein kinase pathways. Consistent with the effects on NFAT activation, tumor necrosis factor-alpha (TNF-alpha) induction by BaPDE was blocked by extract fractions of both black raspberries and strawberries, whereas vascular endothelial growth factor (VEGF) expression, which depends on AP-1 activation, was suppressed by black raspberry fractions but not strawberry fractions. These results suggest that black raspberry and strawberry components may target different signaling pathways in exerting their anti-carcinogenic effects.

  9. RNA interference-mediated knockdown of long-form phosphodiesterase-4D (PDE4D) enzyme reverses amyloid-β42-induced memory deficits in mice.

    PubMed

    Zhang, Cong; Cheng, Yufang; Wang, Haitao; Wang, Chuang; Wilson, Steven P; Xu, Jiangping; Zhang, Han-Ting

    2014-01-01

    Phosphodiesterase-4 (PDE4) inhibitors enhance memory, increase hippocampal neurogenesis, and reverse amyloid-β (Aβ)-induced memory deficits. Here, we examined whether long-form PDE4D knockdown by lentiviral RNA construct containing a specific microRNA/miRNA-mir hairpin structure (4DmiRNA) reversed memory impairment caused by amyloid-β1-42 (Aβ42) in mice using the Morris water maze (MWM) and novelty object recognition tests. Western blotting analysis was used to assess protein levels of cAMP response element-binding protein (CREB, unphosphorylated and phosphorylated [pCREB]), brain-derived neurotrophic factor (BDNF), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB) to explore the neurochemical mechanisms. Aggregated Aβ42 (0.5 μg/side) bilaterally infused in dentate gyrus decreased cAMP levels (p < 0.01) and produced memory deficits in the MWM (p < 0.01) and object recognition tests (p < 0.01). Microinfusions of lentiviruses resulted in downregulated expression of PDE4D4 and 4D5 proteins and reversed Aβ42-induced cAMP decline (p < 0.05) and memory deficits. Treatment also concomitantly increased pCREB (p < 0.05) and BDNF (p < 0.01) and reduced IL-1β (p < 0.05), TNF-α (p < 0.01), and NF-κB (p65) (p < 0.05) in the hippocampus of Aβ42-challenged mice. These results suggest that long-form PDE4D knockdown may offer a promising treatment for memory loss associated with Alzheimer's disease.

  10. Thermodynamic and structural characterization of halogen bonding in protein-ligand interactions: a case study of PDE5 and its inhibitors.

    PubMed

    Ren, Jing; He, Yang; Chen, Wuyan; Chen, Tiantian; Wang, Guan; Wang, Zhen; Xu, Zhijian; Luo, Xiaomin; Zhu, Weiliang; Jiang, Hualiang; Shen, Jingshan; Xu, Yechun

    2014-04-24

    The significance of halogen bonding in protein-ligand interactions has been recognized recently. We present here the first comprehensive thermodynamic and structural characterization of halogen bonding in PDE5-inhibitor interactions. ITC studies reveal that binding strength of the halogen bonding between chlorine, bromine, and iodine of inhibitor and the protein is -1.57, -3.09, and -5.59 kJ/mol, respectively. The halogens interact with the designed residue Y612 and an unexpected buried water molecule.

  11. Differential effects of black raspberry and strawberry extracts on BaPDE-induced activation of transcription factors and their target genes.

    PubMed

    Li, Jingxia; Zhang, Dongyun; Stoner, Gary D; Huang, Chuanshu

    2008-04-01

    The chemopreventive properties of edible berries have been demonstrated both in vitro and in vivo, however, the specific molecular mechanisms underlying their anti-cancer effects are largely unknown. Our previous studies have shown that a methanol extract fraction of freeze-dried black raspberries inhibits benzoapyrene (BaP)-induced transformation of Syrian hamster embryo cells. This fraction also blocks activation of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB) induced by benzoapyrene diol-epoxide (BaPDE) in mouse epidermal JB6 Cl 41 cells. To determine if different berry types exhibit specific mechanisms for their anti-cancer effects, we compared the effects of extract fractions from both black raspberries and strawberries on BaPDE-induced activation of various signaling pathways in Cl 41 cells. Black raspberry fractions inhibited the activation of AP-1, NF-kappaB, and nuclear factor of activated T cells (NFAT) by BaPDE as well as their upstream PI-3K/Akt-p70(S6K) and mitogen-activated protein kinase pathways. In contrast, strawberry fractions inhibited NFAT activation, but did not inhibit the activation of AP-1, NF-kappaB or the PI-3K/Akt-p70(S6K) and mitogen-activated protein kinase pathways. Consistent with the effects on NFAT activation, tumor necrosis factor-alpha (TNF-alpha) induction by BaPDE was blocked by extract fractions of both black raspberries and strawberries, whereas vascular endothelial growth factor (VEGF) expression, which depends on AP-1 activation, was suppressed by black raspberry fractions but not strawberry fractions. These results suggest that black raspberry and strawberry components may target different signaling pathways in exerting their anti-carcinogenic effects. PMID:18085529

  12. Characterization of CHO-K1 cells stably expressing PDE-IV enzymes. Whole-cell cAMP determinations vs broken-cell enzymatic assays.

    PubMed

    Pon, D J; Plant, M; Tkach, J; Boulet, L; Muise, E; Allen, R A; Rodger, I W

    1998-01-01

    A CHO-K1 cell line stably expressing a recombinant full-length human PDE-IVa (HSPDE4A4B) enzyme was established under hygromycin B selection. Full-length expression of the protein was determined by Western blot analysis, which revealed the presence of a 125-kDa immunoreactive band using rabbit anti-PDE-IVa antibodies. The potency of inhibitor compounds was examined by their ability to increase cAMP in the whole-cell, and by their ability to inhibit cAMP hydrolysis in a 100,000 g supernatant (soluble enzyme preparation) obtained from the same cell line. Inhibition of the expressed PDE-IVa activity by selective PDE-IV inhibitors--(R) and (S)-rolipram, RS 14203, and CDP 840--at 100 nM substrate demonstrated that RS 14203 and CDP 840 were the most potent with IC50 = 9 nM, followed by (R)-rolipram (IC50 = 110 nM) and (S)-rolipram (IC50 = 420 nM). The rank order of potencies of the inhibitors in elevating cAMP in the whole-cell assay was quite different from that on the soluble enzyme. RS 14203 was still the most potent compound in elevating cAMP. Moreover, the relative rank order of potencies between CDP 840 and (R)-rolipram changed dramatically, such that (R)-rolipram was more potent than CDP 840 = (S)-rolipram. An apparent 30-fold stereoselectivity between (R)- and (S)-rolipram was also noted. The whole-cell rank order of potencies was also maintained when PKA activity ratios were measured in place of cAMP levels. The ability of the compounds to elevate cAMP in the stable CHO-K1 cells appeared to track better with the potency of the compounds against the high-affinity (Sr) conformer of the enzyme rather than the low-affinity catalytic state.

  13. Efficacy of PARP inhibition in Pde6a mutant mouse models for retinitis pigmentosa depends on the quality and composition of individual human mutations

    PubMed Central

    Jiao, K; Sahaboglu, A; Zrenner, E; Ueffing, M; Ekström, P A R; Paquet-Durand, F

    2016-01-01

    Retinitis pigmentosa (RP), an inherited blinding disease, is caused by a variety of different mutations that affect retinal photoreceptor function and survival. So far there is neither effective treatment nor cure. We have previously shown that poly(ADP-ribose)polymerase (PARP) acts as a common and critical denominator of cell death in photoreceptors, qualifying it as a potential target for future therapeutic intervention. A significant fraction of RP-causing mutations affect the genes for the rod photoreceptor phosphodiesterase 6A (PDE6A) subunit, but it is not known whether they all engage the same death pathway. Analysing three homozygous point mutations (Pde6a R562W, D670G, and V685M) and one compound heterozygous Pde6aV685M/R562W mutation in mouse models that match human RP patients, we demonstrate excessive activation of PARP, which correlated in time with the progression of photoreceptor degeneration. The causal involvement of PARP activity in the neurodegenerative process was confirmed in organotypic retinal explant cultures treated with the PARP-selective inhibitor PJ34, using different treatment time-points and durations. Remarkably, the neuroprotective efficacy of PARP inhibition correlated inversely with the strength of the genetically induced insult, with the D670G mutant showing the best treatment effects. Our results highlight PARP as a target for neuroprotective interventions in RP caused by PDE6A mutations and are a first attempt towards personalized, genotype-matched therapy development for RP. In addition, for each of the different mutant situations, our work identifies windows of opportunity for an optimal treatment regimen for further in vivo experimentation and possibly clinical studies. PMID:27551530

  14. Simple formulation of magnetoplasmadynamic acceleration

    SciTech Connect

    Sasoh, A. )

    1994-03-01

    A simple formulation of magnetoplasmadynamic acceleration has been made based on energy conservation relations and a generalized Ohm's law. An exhaust velocity is expressed using three characteristic parameters: (1) a dimensionless characteristic velocity [ital [tilde U

  15. The identification of a nitrosated prodrug of the PDE-5 inhibitor aildenafil in a dietary supplement: a Viagra with a pop.

    PubMed

    Venhuis, B J; Zomer, G; Hamzink, M; Meiring, H D; Aubin, Y; de Kaste, D

    2011-03-25

    A new unapproved analogue of sildenafil was detected in capsules of a herbal dietary supplement promoted as a libido enhancing product. Using LC-DAD-MS, MS-MS, HRMS, IR and NMR the analogue was shown to be a derivative of the PDE-5 inhibitor aildenafil with a nitrosamine moiety. A hydrolysis experiment showed that the new analogue was a prodrug of aildenafil and was therefore named nitroso-prodenafil. A capsule contained 108 mg of nitroso-prodenafil which is equivalent to 84 mg of aildenafil and 5.1 mg of nitrogen monoxide (NO). Although it is unknown how much NO can be usefully generated there is 3-fold more NO present than in a 10 mg isorbide nitrate tablet. Both PDE-5 inhibitors and nitrosamines cause vasodilatation by increasing levels of NO. To their coincidental use is warned against because it may cause a fatal drop in blood pressure. In addition, nitrosamines are known carcinogens. This is the first time a PDE-5 inhibitor and a potential NO donor were identified in one molecule. The findings indicate the dangerous level of advancement in medicinal chemistry by producers of unapproved drugs. PMID:21145686

  16. Curcumin inhibits B[a]PDE-induced procarcinogenic signals in lung cancer cells, and curbs B[a]P-induced mutagenesis and lung carcinogenesis.

    PubMed

    Puliyappadamba, Vineshkumar T; Thulasidasan, Arun Kumar T; Vijayakurup, Vinod; Antony, Jayesh; Bava, Smitha V; Anwar, Shabna; Sundaram, Sankar; Anto, Ruby John

    2015-01-01

    Benzo[a]pyrene is a procarcinogen present in environment and cigarette smoke, which could be bio-transformed in vivo to B[a]PDE, a potent carcinogen known to form DNA adducts and induce mutations. We observed that curcumin, a known chemopreventive, could significantly inhibit the survival of lung cancer cells exposed to B[a]PDE. It also downregulates B[a]PDE-induced nuclear translocation of NF-κB as assessed by Electrophoretic Mobility Shift Assay (EMSA) and NF-κB-dependent reporter gene assay. Ames assay demonstrated its ability to revert the mutagenic property of benzo[a]pyrene. These observations prompted us to evaluate the efficacy of curcumin in preventing B[a]P-induced lung carcinogenesis in vivo and to explore the molecular mechanism associated with it. The average number of tumor nodules present in the lungs of the Swiss albino mice, which received benzo[a]pyrene, was significantly high compared to that received curcumin as 2% diet along with B[a]P. Curcumin treatment significantly reverted histopathological deviations in the lung tissues due to benzo[a]pyrene ingestion. Moreover, curcumin diet reduced benzo[a]pyrene-induced activation of NF-κB and MAPK signaling and Cox-2 transcription in lung tissues of mice. Taken together, this study illustrates multifaceted efficacy of curcumin in preventing lung cancer.

  17. Effects of Selective Inhibition of PDE4 by YM976 on Airway Reactivity and Cough in Ovalbumin-Sensitized Guinea Pigs.

    PubMed

    Mokrý, J; Urbanová, A; Medvedová, I; Kertys, M; Mikolka, P; Kosutová, P; Mokrá, D

    2016-01-01

    Phosphodiesterases (PDEs) are enzymes involved in the degradation of cAMP and cGMP. Selective PDE4 inhibitors (e.g., roflumilast) are effective in therapy of chronic obstructive pulmonary disease associated with neutrophil inflammation. The aim of this study was to evaluate the effects of a selective PDE4 inhibitor, YM976, on citric acid-induced cough, in vivo and in vitro airway smooth muscle reactivity to histamine, and on inflammatory mediators in ovalbumin-sensitized guinea pigs, with experimentally induced eosinophil inflammation. The YM976 was administered intraperitoneally at a dose of 1.0 mg/kg once daily for 7 days. Sensitization with ovalbumin led to a significant increase in the number of coughs, and in vivo and in vitro airway reactivity. Also, increased plasma levels of IL-4, IL-5, and PAF were observed, with a significant increase in the differential count of eosinophils in both blood and bronchoalveolar lavage fluid. The YM976 suppressed the number of coughs, the airway reactivity in tracheal tissue strips, and the IL-4 level. The findings indicate that PDE4 inhibition by YM976 exerts antitussive and anti-inflammatory effects in guinea pigs with ovalbumin-induced eosinophilic inflammation. PMID:27130219

  18. Selective inhibition of PDE4 in Wistar rats can lead to dilatation in testis, efferent ducts, and epididymis and subsequent formation of sperm granulomas.

    PubMed

    Heuser, Anke; Mecklenburg, Lars; Ockert, Deborah; Kohler, Manfred; Kemkowski, Jörg

    2013-01-01

    Testicular tubular dilatation and degeneration and epididymal sperm granulomas were frequently seen in 4-week toxicity studies using different phosphodiesterase-4 (PDE4) inhibitors in Wistar rats, including the prototypic PDE4 inhibitor BYK169171. To investigate the pathogenesis of testicular and epididymal lesions, a time course study with BYK169171 was conducted with sequential necropsies after 7, 14, 21, and 28 days of treatment. After 7 days, a dilatation of efferent ducts and of the initial segment of the epididymis and a subacute interstitial inflammation were seen followed by a diffuse dilatation of seminiferous tubules in the testis. Dilatation and inflammation were most pronounced after 14 days. Single animals also exhibited vascular necrosis in the inflamed interstitium. Although dilatation decreased later in the study, the incidence and severity of tubular degeneration increased from 14 days onward. Sperm granulomas developed in efferent ducts and in the caput and cauda of the epididymis after 14 days. Our results demonstrate a clear time course of PDE4 inhibition-induced lesions, with dilatation preceding sperm granuloma formation. We conclude that the most likely mechanism of toxicity is a disturbance of fluid homeostasis in efferent and epididymal ducts resulting in abnormal luminal fluid and sperm contents, epithelial damage at specific sites of the excurrent duct system, sperm leakage, and granuloma formation.

  19. Formulation Optimization of Arecoline Patches

    PubMed Central

    Wu, Pao-Chu; Tsai, Pi-Ju; Lin, Shin-Chen; Huang, Yaw-Bin

    2014-01-01

    The response surface methodology (RSM) including polynomial equations has been used to design an optimal patch formulation with appropriate adhesion and flux. The patch formulations were composed of different polymers, including Eudragit RS 100 (ERS), Eudragit RL 100 (ERL) and polyvinylpyrrolidone K30 (PVP), plasticizers (PEG 400), and drug. In addition, using terpenes as enhancers could increase the flux of the drug. Menthol showed the highest enhancement effect on the flux of arecoline. PMID:24707220

  20. Attempted suicide: an operant formulation.

    PubMed

    Bostock, T; Williams, C L

    1975-06-01

    An alternative formulation of attempted suicide is offered, in which the phenomenon is considered within the context of social learning theory. The suicidal behaviour is viewed as an operant which is reinforced and maintained by the consequent interpersonal contingencies. The modification of the suicidal behaviour then involves alteration of the contingent consequences. This theoretical formulation is elaborated and the treatment principles and practice are outlined.

  1. Familial micronodular adrenocortical disease, Cushing syndrome, and mutations of the gene encoding phosphodiesterase 11A4 (PDE11A).

    PubMed

    Carney, J Aidan; Gaillard, Rolf C; Bertherat, Jérôme; Stratakis, Constantine A

    2010-04-01

    We present the pathologic findings in the adrenal glands of 4 patients, aged 10 to 38 years, with Cushing syndrome and germline inactivating mutations of the gene PDE11A4 that encodes phosphodiesterase11A4. The gene is expressed in the adrenal cortex and catalyses the hydrolysis of cyclic adenosine monophosphate and cyclic guanosine monophosphate. Two of the patients were mother and daughter; the third had no affected relative; the fourth patient inherited the mutation from her father. Three of the group, including the mother and daughter, had the same pathology, primary pigmented nodular adrenocortical disease, a disorder known to be caused by inactivating mutations of the PRKAR1A gene. In these cases, the adrenal glands were small and the pathologic change was deep in the cortex in which numerous pigmented micronodules developed. In the remaining patient, the glands were slightly enlarged primarily owing to a diffuse hyperplasia of the superficial cortex that extended into the epi-adrenal fat. PMID:20351491

  2. Development and calibration of a nitrification PDE model based on experimental data issued from biofilter treating drinking water.

    PubMed

    Queinnec, I; Ochoa, J C; Wouwer, A Vande; Paul, E

    2006-06-01

    To remove ammonia for production of drinking water, nitrification can be performed in a bio-filter. At least 1 month is necessary to capture from the groundwater and then grow a sufficient amount of nitrifying bacteria to reach the desired removal efficiency. Improving start-up of bio-filters at low substrate concentration is therefore a major challenge. In this connection, it is important to develop appropriate models for designing, monitoring or analysing biofilm systems during start-up or following disinfection events. This study discusses the development and calibration of a nitrification PDE model which reflects the compromise between the complexity associated with the description of the full physical and biochemical mechanisms and the search for a simplified model with identifiable parameters. This model takes only the relevant phenomena (considering the full operating range) into account. The validity of the calibrated model has been evaluated through experiments under very different operational conditions, at the laboratory and under real industrial conditions, involving the full upstream chain of water treatment (iron oxidation and sand filter).

  3. An adaptive nonlinear solution scheme for reservoir simulation

    SciTech Connect

    Lett, G.S.

    1996-12-31

    Numerical reservoir simulation involves solving large, nonlinear systems of PDE with strongly discontinuous coefficients. Because of the large demands on computer memory and CPU, most users must perform simulations on very coarse grids. The average properties of the fluids and rocks must be estimated on these grids. These coarse grid {open_quotes}effective{close_quotes} properties are costly to determine, and risky to use, since their optimal values depend on the fluid flow being simulated. Thus, they must be found by trial-and-error techniques, and the more coarse the grid, the poorer the results. This paper describes a numerical reservoir simulator which accepts fine scale properties and automatically generates multiple levels of coarse grid rock and fluid properties. The fine grid properties and the coarse grid simulation results are used to estimate discretization errors with multilevel error expansions. These expansions are local, and identify areas requiring local grid refinement. These refinements are added adoptively by the simulator, and the resulting composite grid equations are solved by a nonlinear Fast Adaptive Composite (FAC) Grid method, with a damped Newton algorithm being used on each local grid. The nonsymmetric linear system of equations resulting from Newton`s method are in turn solved by a preconditioned Conjugate Gradients-like algorithm. The scheme is demonstrated by performing fine and coarse grid simulations of several multiphase reservoirs from around the world.

  4. Nonlinear Transient Problems Using Structure Compatible Heat Transfer Code

    NASA Technical Reports Server (NTRS)

    Hou, Gene

    2000-01-01

    The report documents the recent effort to enhance a transient linear heat transfer code so as to solve nonlinear problems. The linear heat transfer code was originally developed by Dr. Kim Bey of NASA Largely and called the Structure-Compatible Heat Transfer (SCHT) code. The report includes four parts. The first part outlines the formulation of the heat transfer problem of concern. The second and the third parts give detailed procedures to construct the nonlinear finite element equations and the required Jacobian matrices for the nonlinear iterative method, Newton-Raphson method. The final part summarizes the results of the numerical experiments on the newly enhanced SCHT code.

  5. Linear and nonlinear dynamic analysis of redundant load path bearingless rotor systems

    NASA Technical Reports Server (NTRS)

    Murthy, V. R.; Shultz, Louis A.

    1994-01-01

    The goal of this research is to develop the transfer matrix method to treat nonlinear autonomous boundary value problems with multiple branches. The application is the complete nonlinear aeroelastic analysis of multiple-branched rotor blades. Once the development is complete, it can be incorporated into the existing transfer matrix analyses. There are several difficulties to be overcome in reaching this objective. The conventional transfer matrix method is limited in that it is applicable only to linear branch chain-like structures, but consideration of multiple branch modeling is important for bearingless rotors. Also, hingeless and bearingless rotor blade dynamic characteristics (particularly their aeroelasticity problems) are inherently nonlinear. The nonlinear equations of motion and the multiple-branched boundary value problem are treated together using a direct transfer matrix method. First, the formulation is applied to a nonlinear single-branch blade to validate the nonlinear portion of the formulation. The nonlinear system of equations is iteratively solved using a form of Newton-Raphson iteration scheme developed for differential equations of continuous systems. The formulation is then applied to determine the nonlinear steady state trim and aeroelastic stability of a rotor blade in hover with two branches at the root. A comprehensive computer program is developed and is used to obtain numerical results for the (1) free vibration, (2) nonlinearly deformed steady state, (3) free vibration about the nonlinearly deformed steady state, and (4) aeroelastic stability tasks. The numerical results obtained by the present method agree with results from other methods.

  6. Social Groupwork. A Model for Goal Formulation.

    ERIC Educational Resources Information Center

    Tompkins, Rosamond P.; Gallo, Frank T.

    1978-01-01

    A conceptual model for goal formulation in social groupwork, discussion of existing models and their limitations, and an attempt to formulate an encompassing groupwork model that facilitates goal formulation. (Author/PD)

  7. 40 CFR 152.43 - Alternate formulations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... PESTICIDE REGISTRATION AND CLASSIFICATION PROCEDURES Registration Procedures § 152.43 Alternate formulations... label text of the alternate formulation product must be identical to that of the basic formulation....

  8. 40 CFR 152.43 - Alternate formulations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... PESTICIDE REGISTRATION AND CLASSIFICATION PROCEDURES Registration Procedures § 152.43 Alternate formulations... label text of the alternate formulation product must be identical to that of the basic formulation....

  9. Optimization approaches to nonlinear model predictive control

    SciTech Connect

    Biegler, L.T. . Dept. of Chemical Engineering); Rawlings, J.B. . Dept. of Chemical Engineering)

    1991-01-01

    With the development of sophisticated methods for nonlinear programming and powerful computer hardware, it now becomes useful and efficient to formulate and solve nonlinear process control problems through on-line optimization methods. This paper explores and reviews control techniques based on repeated solution of nonlinear programming (NLP) problems. Here several advantages present themselves. These include minimization of readily quantifiable objectives, coordinated and accurate handling of process nonlinearities and interactions, and systematic ways of dealing with process constraints. We motivate this NLP-based approach with small nonlinear examples and present a basic algorithm for optimization-based process control. As can be seen this approach is a straightforward extension of popular model-predictive controllers (MPCs) that are used for linear systems. The statement of the basic algorithm raises a number of questions regarding stability and robustness of the method, efficiency of the control calculations, incorporation of feedback into the controller and reliable ways of handling process constraints. Each of these will be treated through analysis and/or modification of the basic algorithm. To highlight and support this discussion, several examples are presented and key results are examined and further developed. 74 refs., 11 figs.

  10. Formulation of the aeroelastic stability and response problem of coupled rotor/support systems

    NASA Technical Reports Server (NTRS)

    Warmbrodt, W.; Friedmann, P.

    1979-01-01

    The consistent formulation of the governing nonlinear equations of motion for a coupled rotor/support system is presented. Rotor/support coupling is clearly documented by enforcing dynamic equilibrium between the rotor and the moving flexible support. The nonlinear periodic coefficient equations of motion are applicable to both coupled rotor/fuselage aeroelastic problems of helicopters in hover or forward flight and coupled rotor/tower dynamics of a large horizontal axis wind turbine (HAWT). Finally, the equations of motion are used to study the influence of flexible supports and nonlinear terms on rotor aeroelastic stability and response of a large two-bladed HAWT.

  11. Multilayer perceptron for nonlinear programming.

    SciTech Connect

    Reifman, J.; Feldman, E. E.; Reactor Analysis

    2002-08-01

    A new method for solving nonlinear programming problems within the framework of a multilayer neural network perceptron is proposed. The method employs the Penalty Function method to transform a constrained optimization problem into a sequence of unconstrained optimization problems and then solves the sequence of unconstrained optimizations of the transformed problem by training a series of multilayer perceptrons. The neural network formulation is represented in such a way that the multilayer perceptron prediction error to be minimized mimics the objective function of the unconstrained problem, and therefore, the minimization of the objective function for each unconstrained optimization is attained by training a single perceptron. The multilayer perceptron allows for the transformation of problems with two-sided bounding constraints on the decision variables x, e.g., a{<=}x{sub n}{<=}b, into equivalent optimization problems in which these constraints do not explicitly appear. Hence, when these are the only constraints in the problem, the transformed problem is constraint free (i.e., the transformed objective function contains no penalty terms) and is solved by training a multilayer perceptron only once. In addition, we present a new Penalty Function method for solving nonlinear programming problems that is parameter free and guarantees that feasible solutions are obtained when the optimal solution is on the boundary of the feasible region. Simulation results, including an example from operations research, illustrate the proposed methods.

  12. cAMP-stimulated Protein Phosphatase 2A Activity Associated with Muscle A Kinase-anchoring Protein (mAKAP) Signaling Complexes Inhibits the Phosphorylation and Activity of the cAMP-specific Phosphodiesterase PDE4D3*

    PubMed Central

    Dodge-Kafka, Kimberly L.; Bauman, Andrea; Mayer, Nicole; Henson, Edward; Heredia, Lorena; Ahn, Jung; McAvoy, Thomas; Nairn, Angus C.; Kapiloff, Michael S.

    2010-01-01

    The concentration of the second messenger cAMP is tightly controlled in cells by the activity of phosphodiesterases. We have previously described how the protein kinase A-anchoring protein mAKAP serves as a scaffold for the cAMP-dependent protein kinase PKA and the cAMP-specific phosphodiesterase PDE4D3 in cardiac myocytes. PKA and PDE4D3 constitute a negative feedback loop whereby PKA-catalyzed phosphorylation and activation of PDE4D3 attenuate local cAMP levels. We now show that protein phosphatase 2A (PP2A) associated with mAKAP complexes is responsible for reversing the activation of PDE4D3 by catalyzing the dephosphorylation of PDE4D3 serine residue 54. Mapping studies reveal that a C-terminal mAKAP domain (residues 2085–2319) binds PP2A. Binding to mAKAP is required for PP2A function, such that deletion of the C-terminal domain enhances both base-line and forskolin-stimulated PDE4D3 activity. Interestingly, PP2A holoenzyme associated with mAKAP complexes in the heart contains the PP2A targeting subunit B56δ. Like PDE4D3, B56δ is a PKA substrate, and PKA phosphorylation of mAKAP-bound B56δ enhances phosphatase activity 2-fold in the complex. Accordingly, expression of a B56δ mutant that cannot be phosphorylated by PKA results in increased PDE4D3 phosphorylation. Taken together, our findings demonstrate that PP2A associated with mAKAP complexes promotes PDE4D3 dephosphorylation, serving both to inhibit PDE4D3 in unstimulated cells and also to mediate a cAMP-induced positive feedback loop following adenylyl cyclase activation and B56δ phosphorylation. In general, PKA·PP2A·mAKAP complexes exemplify how protein kinases and phosphatases may participate in molecular signaling complexes to dynamically regulate localized intracellular signaling. PMID:20106966

  13. cAMP-stimulated protein phosphatase 2A activity associated with muscle A kinase-anchoring protein (mAKAP) signaling complexes inhibits the phosphorylation and activity of the cAMP-specific phosphodiesterase PDE4D3.

    PubMed

    Dodge-Kafka, Kimberly L; Bauman, Andrea; Mayer, Nicole; Henson, Edward; Heredia, Lorena; Ahn, Jung; McAvoy, Thomas; Nairn, Angus C; Kapiloff, Michael S

    2010-04-01

    The concentration of the second messenger cAMP is tightly controlled in cells by the activity of phosphodiesterases. We have previously described how the protein kinase A-anchoring protein mAKAP serves as a scaffold for the cAMP-dependent protein kinase PKA and the cAMP-specific phosphodiesterase PDE4D3 in cardiac myocytes. PKA and PDE4D3 constitute a negative feedback loop whereby PKA-catalyzed phosphorylation and activation of PDE4D3 attenuate local cAMP levels. We now show that protein phosphatase 2A (PP2A) associated with mAKAP complexes is responsible for reversing the activation of PDE4D3 by catalyzing the dephosphorylation of PDE4D3 serine residue 54. Mapping studies reveal that a C-terminal mAKAP domain (residues 2085-2319) binds PP2A. Binding to mAKAP is required for PP2A function, such that deletion of the C-terminal domain enhances both base-line and forskolin-stimulated PDE4D3 activity. Interestingly, PP2A holoenzyme associated with mAKAP complexes in the heart contains the PP2A targeting subunit B56delta. Like PDE4D3, B56delta is a PKA substrate, and PKA phosphorylation of mAKAP-bound B56delta enhances phosphatase activity 2-fold in the complex. Accordingly, expression of a B56delta mutant that cannot be phosphorylated by PKA results in increased PDE4D3 phosphorylation. Taken together, our findings demonstrate that PP2A associated with mAKAP complexes promotes PDE4D3 dephosphorylation, serving both to inhibit PDE4D3 in unstimulated cells and also to mediate a cAMP-induced positive feedback loop following adenylyl cyclase activation and B56delta phosphorylation. In general, PKA.PP2A.mAKAP complexes exemplify how protein kinases and phosphatases may participate in molecular signaling complexes to dynamically regulate localized intracellular signaling. PMID:20106966

  14. Bayesian Analysis of Structural Equation Models with Nonlinear Covariates and Latent Variables

    ERIC Educational Resources Information Center

    Song, Xin-Yuan; Lee, Sik-Yum

    2006-01-01

    In this article, we formulate a nonlinear structural equation model (SEM) that can accommodate covariates in the measurement equation and nonlinear terms of covariates and exogenous latent variables in the structural equation. The covariates can come from continuous or discrete distributions. A Bayesian approach is developed to analyze the…

  15. Nonlinear analysis of helix traveling wave tubes

    SciTech Connect

    Freund, H.P.; Zaidman, E.G.; Vanderplaats, N.R.; Kodis, M.A.

    1994-12-31

    A nonlinear formulation of the interaction in a helix traveling wave tube (TWT) is presented. The formulation is intended to treat a wide class of helix TWTs including both emission-gated and multi-tone operation. The essential feature of each of these configurations is that multiple waves must be included in the formulation. As a result, a fully time-dependent analysis is required. The numerical procedure for this in a helix TWT is complicated by the fact that the radial profile of the field varies with frequency. This contrasts, for example, with the case of a smooth bore waveguide in which the radial profile for each TE{sub ln} or TM{sub ln} mode is invariant in frequency. Because of this, a complete self-consistent particle-in-cell (PIC) formulation must be three-dimensional. In order to circumvent the computational expense of a 3D PIC formulation, the authors adopt an approach in which the electromagnetic field is represented as a superposition of azimuthally symmetric modes in a vacuum sheath helix. The specific electron distributions are chosen to model either a continuous beam for the multi-tone TWT and a pulsed beam for the emission-gated TWT. Numerical results of the simulation for examples of interest to an emission-gated TWT experiment at NRL will be presented.

  16. A nonlinear strategy for sensor based vehicle path control

    NASA Technical Reports Server (NTRS)

    Mayr, R.

    1994-01-01

    A method of transverse control which makes use of nonlinear formulations is presented. The strategy is utilized to stabilize a vehicle. The vehicle is autonomously guided and takes its control inputs from an optical sensing system. Additionally, the velocity of the vehicle is dictated by a longitudinal controller, which is also discussed.

  17. Survey and development of finite elements for nonlinear structural analysis. Volume 2: Nonlinear shell finite elements

    NASA Technical Reports Server (NTRS)

    1976-01-01

    The development of two new shell finite elements for applications to large deflection problems is considered. The elements in question are doubly curved and of triangular and quadrilateral planform. They are restricted to small strains of elastic materials, and can accommodate large rotations. The elements described, which are based on relatively simple linear elements, make use of a new displacement function approach specifically designed for strongly nonlinear problems. The displacement function development for nonlinear applications is based on certain beam element formulations, and the strain-displacement equations are of a shallow shell type. Additional terms were included in these equations in an attempt to avoid the large errors characteristic of shallow shell elements in certain types of problems. An incremental nonlinear solution procedure specifically adopted to the element formulation was developed. The solution procedure is of combined incremental and total Lagrangian type, and uses a new updating scheme. A computer program was written to evaluate the developed formulations. This program can accommodate small element groups in arbitrary arrangements. Two simple programs were successfully solved. The results indicate that this new type of element has definite promise and should be a fruitful area for further research.

  18. Decontamination formulation with sorbent additive

    DOEpatents

    Tucker; Mark D. , Comstock; Robert H.

    2007-10-16

    A decontamination formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a bleaching activator, a sorbent additive, and water. The highly adsorbent, water-soluble sorbent additive (e.g., sorbitol or mannitol) is used to "dry out" one or more liquid ingredients, such as the liquid bleaching activator (e.g., propylene glycol diacetate or glycerol diacetate) and convert the activator into a dry, free-flowing powder that has an extended shelf life, and is more convenient to handle and mix in the field.

  19. Applying Differential Transforms and ADER to Multi-Dimensional Atmospheric Transport and Non-Linear Dynamics

    NASA Astrophysics Data System (ADS)

    Norman, M. R.

    2013-12-01

    Differential Transforms (DTs), a core component of so-called "automatic" or "algorithmic" differentiation, offer significant flexibility and efficiency to any numerical method. The i-th and j-th DT, U(i,j), of a function, u(x,y), is simply U(i,j)=1/(i!j!)*∂(i+j)u/∂xi∂yj. Being a term in the Taylor series of u(x,y) makes the reverse transform trivial. This relation also computes initial DTs from known spatial derivatives. What is novel about DTs is how they simplify a complex PDE system, transforming most arithmetic, trigonometric, and other operators into simple recurrence relations in derivative space. This allows one to simply and quickly compute analytical derivatives of highly complex and non-linear functions. Consider a pseudo-conservation law system, u(x)t+f(u,x)x=s(u,x), for instance. The fluxes and source terms could be (and often are) highly complex, non-linear functions of the state vector and independent variables. Regardless of the spatial discretization (variational / finite-element, weak / finite-volume, or strong / finite-difference), one nearly always must resort to tensored quadrature to evaluate face fluxes and body source terms, and this treatment is expensive. However, if one uses DTs to analytically compute spatial derivatives of the flux and source terms, given spatial derivatives of u, then the fluxes and source terms are directly expanded as polynomials, allowing for significantly cheaper, quadrature-free integration, sampling, and differentiation with a single dot product. Besides being simpler, this also allows flexibility for Galerkin methods in particular to analytically and cheaply compute body integrals, which are often approximated inexactly with quadrature. Computing Nth-order DTs in D dimensions is of O(D2*N) complexity, and whether for transport or non-linear compressible Euler equations, they are cheaper to compute and integrate analytically than quadrature. Further, because time-dependent PDE systems relate spatial

  20. Diamond nonlinear photonics

    NASA Astrophysics Data System (ADS)

    Hausmann, B. J. M.; Bulu, I.; Venkataraman, V.; Deotare, P.; Lončar, M.

    2014-05-01

    Despite progress towards integrated diamond photonics, studies of optical nonlinearities in diamond have been limited to Raman scattering in bulk samples. Diamond nonlinear photonics, however, could enable efficient, in situ frequency conversion of single photons emitted by diamond's colour centres, as well as stable and high-power frequency microcombs operating at new wavelengths. Both of these applications depend crucially on efficient four-wave mixing processes enabled by diamond's third-order nonlinearity. Here, we have realized a diamond nonlinear photonics platform by demonstrating optical parametric oscillation via four-wave mixing using single-crystal ultrahigh-quality-factor (1 × 106) diamond ring resonators operating at telecom wavelengths. Threshold powers as low as 20 mW are measured, and up to 20 new wavelengths are generated from a single-frequency pump laser. We also report the first measurement of the nonlinear refractive index due to the third-order nonlinearity in diamond at telecom wavelengths.

  1. Nonlinear rotordynamics analysis

    NASA Technical Reports Server (NTRS)

    Day, W. B.

    1985-01-01

    The special nonlinearities of the Jeffcott equations in rotordynamics are examined. The immediate application of this analysis is directed toward understanding the excessive vibrations recorded in the LOX pump of the SSME during hot firing ground testing. Deadband, side force and rubbing are three possible sources of inducing nonlinearity in the Jeffcott equations. The present analysis initially reduces these problems to the same mathematical description. A special frequency, named the nonlinear natural frequency is defined and used to develop the solutions of the nonlinear Jeffcott equations as asympotic expansions. This nonlinear natural frequency which is the ratio of the cross-stiffness and the damping, plays a major role in determining response frequencies. Numerical solutions are included for comparison with the analysis. Also, nonlinear frequency-response tables are made for a typical range of values.

  2. IQCB1 and PDE6B Mutations Cause Similar Early Onset Retinal Degenerations in Two Closely Related Terrier Dog Breeds

    PubMed Central

    Goldstein, Orly; Mezey, Jason G.; Schweitzer, Peter A.; Boyko, Adam R.; Gao, Chuan; Bustamante, Carlos D.; Jordan, Julie Ann; Aguirre, Gustavo D.; Acland, Gregory M.

    2013-01-01

    Purpose. To identify the causative mutations in two early-onset canine retinal degenerations, crd1 and crd2, segregating in the American Staffordshire terrier and the Pit Bull Terrier breeds, respectively. Methods. Retinal morphology of crd1- and crd2-affected dogs was evaluated by light microscopy. DNA was extracted from affected and related unaffected controls. Association analysis was undertaken using the Illumina Canine SNP array and PLINK (crd1 study), or the Affymetrix Version 2 Canine array, the “MAGIC” genotype algorithm, and Fisher's Exact test for association (crd2 study). Positional candidate genes were evaluated for each disease. Results. Structural photoreceptor abnormalities were observed in crd1-affected dogs as young as 11-weeks old. Rod and cone inner segment (IS) and outer segments (OS) were abnormal in size, shape, and number. In crd2-affected dogs, rod and cone IS and OS were abnormal as early as 3 weeks of age, progressing with age to severe loss of the OS, and thinning of the outer nuclear layer (ONL) by 12 weeks of age. Genome-wide association study (GWAS) identified association at the telomeric end of CFA3 in crd1-affected dogs and on CFA33 in crd2-affected dogs. Candidate gene evaluation identified a three bases deletion in exon 21 of PDE6B in crd1-affected dogs, and a cytosine insertion in exon 10 of IQCB1 in crd2-affected dogs. Conclusions. Identification of the mutations responsible for these two early-onset retinal degenerations provides new large animal models for comparative disease studies and evaluation of potential therapeutic approaches for the homologous human diseases. PMID:24045995

  3. Stationary nonlinear Airy beams

    SciTech Connect

    Lotti, A.; Faccio, D.; Couairon, A.; Papazoglou, D. G.; Panagiotopoulos, P.; Tzortzakis, S.; Abdollahpour, D.

    2011-08-15

    We demonstrate the existence of an additional class of stationary accelerating Airy wave forms that exist in the presence of third-order (Kerr) nonlinearity and nonlinear losses. Numerical simulations and experiments, in agreement with the analytical model, highlight how these stationary solutions sustain the nonlinear evolution of Airy beams. The generic nature of the Airy solution allows extension of these results to other settings, and a variety of applications are suggested.

  4. Boundary formulations for shape sensitivity of temperature dependent conductivity problems

    NASA Technical Reports Server (NTRS)

    Kane, James H.; Wang, Hua

    1992-01-01

    Used in concert with the Kirchhoff transformation, implicit differentiation of the discretized boundary integral equations governing the conduction of heat in solids with temperature dependent thermal conductivity is shown to generate an accurate and economical approach for computation of shape sensitivities. For problems with specified temperature and heat flux boundary conditions, a linear problem results for both the analysis and sensitivity analysis. In problems with either convection or radiation boundary conditions, a nonlinear problem is generated. Several iterative strategies are presented for the solution of the resulting sets of nonlinear equations and the computational performances examined in detail. Multizone analysis and zone condensation strategies are demonstrated to provide substantive computational economies in this process for models with either localized nonlinear boundary conditions or regions of geometric insensitivity to design variables. A series of nonlinear example problems is presented that have closed form solutions. Exact analytical expressions for the shape sensitivities associated with these problems are developed and these are compared with the sensitivities computed using the boundary element formulation.

  5. Organic nonlinear optical materials

    NASA Technical Reports Server (NTRS)

    Umegaki, S.

    1987-01-01

    Recently, it became clear that organic compounds with delocalized pi electrons show a great nonlinear optical response. Especially, secondary nonlinear optical constants of more than 2 digits were often seen in the molecular level compared to the existing inorganic crystals such as LiNbO3. The crystallization was continuously tried. Organic nonlinear optical crystals have a new future as materials for use in the applied physics such as photomodulation, optical frequency transformation, opto-bistabilization, and phase conjugation optics. Organic nonlinear optical materials, e.g., urea, O2NC6H4NH2, I, II, are reviewed with 50 references.

  6. Nonlinear modes of clarinet-like musical instruments

    NASA Astrophysics Data System (ADS)

    Noreland, Daniel; Bellizzi, Sergio; Vergez, Christophe; Bouc, Robert

    2009-07-01

    The concept of nonlinear modes is applied in order to analyze the behavior of a model of woodwind reed instruments. Using a modal expansion of the impedance of the instrument, and by projecting the equation for the acoustic pressure on the normal modes of the air column, a system of second-order ordinary differential equations is obtained. The equations are coupled through the nonlinear relation describing the volume flow of air through the reed channel in response to the pressure difference across the reed. The system is treated using an amplitude-phase formulation for nonlinear modes, where the frequency and damping functions, as well as the invariant manifolds in the phase space, are unknowns to be determined. The formulation gives, without explicit integration of the underlying ordinary differential equation, access to the transient, the limit cycle, its period and stability. The process is illustrated for a model reduced to three normal modes of the air column.

  7. Second-order cone programming formulations for robust multiclass classification.

    PubMed

    Zhong, Ping; Fukushima, Masao

    2007-01-01

    Multiclass classification is an important and ongoing research subject in machine learning. Current support vector methods for multiclass classification implicitly assume that the parameters in the optimization problems are known exactly. However, in practice, the parameters have perturbations since they are estimated from the training data, which are usually subject to measurement noise. In this article, we propose linear and nonlinear robust formulations for multiclass classification based on the M-SVM method. The preliminary numerical experiments confirm the robustness of the proposed method.

  8. Nonlinear predictive energy management of residential buildings with photovoltaics & batteries

    NASA Astrophysics Data System (ADS)

    Sun, Chao; Sun, Fengchun; Moura, Scott J.

    2016-09-01

    This paper studies a nonlinear predictive energy management strategy for a residential building with a rooftop photovoltaic (PV) system and second-life lithium-ion battery energy storage. A key novelty of this manuscript is closing the gap between building energy management formulations, advanced load forecasting techniques, and nonlinear battery/PV models. Additionally, we focus on the fundamental trade-off between lithium-ion battery aging and economic performance in energy management. The energy management problem is formulated as a model predictive controller (MPC). Simulation results demonstrate that the proposed control scheme achieves 96%-98% of the optimal performance given perfect forecasts over a long-term horizon. Moreover, the rate of battery capacity loss can be reduced by 25% with negligible losses in economic performance, through an appropriate cost function formulation.

  9. General formulation of transverse hydrodynamics

    SciTech Connect

    Ryblewski, Radoslaw; Florkowski, Wojciech

    2008-06-15

    General formulation of hydrodynamics describing transversally thermalized matter created at the early stages of ultrarelativistic heavy-ion collisions is presented. Similarities and differences with the standard three-dimensionally thermalized relativistic hydrodynamics are discussed. The role of the conservation laws as well as the thermodynamic consistency of two-dimensional thermodynamic variables characterizing transversally thermalized matter is emphasized.

  10. Covariant Formulation of Hooke's Law.

    ERIC Educational Resources Information Center

    Gron, O.

    1981-01-01

    Introducing a four-vector strain and a four-force stress, Hooke's law is written as a four-vector equation. This formulation is shown to clarify seemingly paradoxical results in connection with uniformly accelerated motion, and rotational motion with angular acceleration. (Author/JN)

  11. Case Formulation in TADS CBT

    ERIC Educational Resources Information Center

    Rogers, Gregory M.; Reinecke, Mark A.; Curry, John F.

    2005-01-01

    For the Treatment for Adolescents With Depression Study (TADS), a cognitive-behavioral therapy (CBT) manual was developed with the aim of balancing standardization and flexibility. In this article, we describe the manual's case formulation procedures, which served as one major mechanism of flexibility in TADS CBT. We first describe the essential…

  12. Nonlinear Propagation of Infrasound from Large Explosions

    NASA Astrophysics Data System (ADS)

    de Groot-Hedlin, Catherine

    2015-04-01

    Atmospheric explosions release immense quantities of infrasound energy that can be detected at receivers located from hundreds to thousands of kilometers from the origin. This has led to the deployment of a global 60-station network of micro-barometer arrays to aid in nuclear explosion monitoring. Current methods of estimating the radiated source energy from remote recordings of infrasound signals use simplified empirical source-yield relations that account for stratospheric winds along the source-receiver path. These formulations apply only to direct and stratospherically ducted arrivals. More recently, considerable progress has been made in applying numerical modeling techniques to develop more accurate source-yield formulations for realistic sound and wind speed profiles. However, these methods assume linear infrasound propagation along the travel path even though nonlinear effects - which arise when the amplitude of the acoustic pressure perturbation is a finite fraction of the ambient atmospheric pressure - are known to significantly alter infrasound frequencies, velocities and amplitudes, and thus can affect derived source yield estimates. For realistic atmospheric profiles, nonlinearity can be significant both in the vicinity of a large explosive source as well as at much greater distances. Within the stratosphere, nonlinearity may arise at caustics created by ducting; in the thermosphere, nonlinearity may arise due to very low ambient pressures at high altitudes. In this study, the effects of nonlinearity on infrasound signal amplitudes and frequencies are simulated using a nonlinear finite difference, time-domain (FDTD) method. The key features that allow for accurate and efficient nonlinear synthesis of infrasound propagation through realistic media are that 1) it includes for atmospheric viscosity, and 2) the environmental models are constrained to have axial symmetry, yielding solutions relevant to a point source in a fully 3D model with rotational

  13. Modulation of mGlu2 Receptors, but Not PDE10A Inhibition Normalizes Pharmacologically-Induced Deviance in Auditory Evoked Potentials and Oscillations in Conscious Rats

    PubMed Central

    Ahnaou, Abdallah; Biermans, Ria; Drinkenburg, Wilhelmus H.

    2016-01-01

    Improvement of cognitive impairments represents a high medical need in the development of new antipsychotics. Aberrant EEG gamma oscillations and reductions in the P1/N1 complex peak amplitude of the auditory evoked potential (AEP) are neurophysiological biomarkers for schizophrenia that indicate disruption in sensory information processing. Inhibition of phosphodiesterase (i.e. PDE10A) and activation of metabotropic glutamate receptor (mGluR2) signaling are believed to provide antipsychotic efficacy in schizophrenia, but it is unclear whether this occurs with cognition-enhancing potential. The present study used the auditory paired click paradigm in passive awake Sprague Dawley rats to 1) model disruption of AEP waveforms and oscillations as observed in schizophrenia by peripheral administration of amphetamine and the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP); 2) confirm the potential of the antipsychotics risperidone and olanzapine to attenuate these disruptions; 3) evaluate the potential of mGluR2 agonist LY404039 and PDE10 inhibitor PQ-10 to improve AEP deficits in both the amphetamine and PCP models. PCP and amphetamine disrupted auditory information processing to the first click, associated with suppression of the P1/N1 complex peak amplitude, and increased cortical gamma oscillations. Risperidone and olanzapine normalized PCP and amphetamine-induced abnormalities in AEP waveforms and aberrant gamma/alpha oscillations, respectively. LY404039 increased P1/N1 complex peak amplitudes and potently attenuated the disruptive effects of both PCP and amphetamine on AEPs amplitudes and oscillations. However, PQ-10 failed to show such effect in either models. These outcomes indicate that modulation of the mGluR2 results in effective restoration of abnormalities in AEP components in two widely used animal models of psychosis, whereas PDE10A inhibition does not. PMID:26808689

  14. Nonlinear Optics and Applications

    NASA Technical Reports Server (NTRS)

    Abdeldayem, Hossin A. (Editor); Frazier, Donald O. (Editor)

    2007-01-01

    Nonlinear optics is the result of laser beam interaction with materials and started with the advent of lasers in the early 1960s. The field is growing daily and plays a major role in emerging photonic technology. Nonlinear optics play a major role in many of the optical applications such as optical signal processing, optical computers, ultrafast switches, ultra-short pulsed lasers, sensors, laser amplifiers, and many others. This special review volume on Nonlinear Optics and Applications is intended for those who want to be aware of the most recent technology. This book presents a survey of the recent advances of nonlinear optical applications. Emphasis will be on novel devices and materials, switching technology, optical computing, and important experimental results. Recent developments in topics which are of historical interest to researchers, and in the same time of potential use in the fields of all-optical communication and computing technologies, are also included. Additionally, a few new related topics which might provoke discussion are presented. The book includes chapters on nonlinear optics and applications; the nonlinear Schrodinger and associated equations that model spatio-temporal propagation; the supercontinuum light source; wideband ultrashort pulse fiber laser sources; lattice fabrication as well as their linear and nonlinear light guiding properties; the second-order EO effect (Pockels), the third-order (Kerr) and thermo-optical effects in optical waveguides and their applications in optical communication; and, the effect of magnetic field and its role in nonlinear optics, among other chapters.

  15. Nonlinearly realized extended supergravity

    SciTech Connect

    Izawa, K.-I.; Nakai, Y.; Takahashi, Ryo

    2010-10-01

    We provide a nonlinear realization of supergravity with an arbitrary number of supersymmetries by means of coset construction. The number of gravitino degrees of freedom counts the number of supersymmetries, which will possibly be probed in future experiments. We also consider Goldstino embedding in the construction to discuss the relation to nonlinear realizations with rigid supersymmetries.

  16. Friction and nonlinear dynamics

    NASA Astrophysics Data System (ADS)

    Manini, N.; Braun, O. M.; Tosatti, E.; Guerra, R.; Vanossi, A.

    2016-07-01

    The nonlinear dynamics associated with sliding friction forms a broad interdisciplinary research field that involves complex dynamical processes and patterns covering a broad range of time and length scales. Progress in experimental techniques and computational resources has stimulated the development of more refined and accurate mathematical and numerical models, capable of capturing many of the essentially nonlinear phenomena involved in friction.

  17. Mathematical nonlinear optics

    NASA Astrophysics Data System (ADS)

    McLaughlin, David W.

    1994-01-01

    The principal investigator, together with two post-doctoral fellows, several graduate students, and colleagues, has applied the modern mathematical theory of nonlinear waves to problems in nonlinear optics. Projects included the interaction of laser light with nematic liquid crystals, propagation through random nonlinear media, cross polarization instabilities and optical shocks for propagation along nonlinear optical fibers, and the dynamics of bistable optical switches coupled through both diffusion and diffraction. In the first project the extremely strong nonlinear response of a CW laser beam in a nematic liquid crystal medium produced striking undulation and filamentation of the CW beam which was observed experimentally and explained theoretically. In the second project the interaction of randomness with nonlinearity was investigated, as well as an effective randomness due to the simultaneous presence of many nonlinear instabilities. In the polarization problems theoretical hyperbolic structure (instabilities and homoclinic orbits) in the coupled nonlinear Schroedinger (NLS) equations was identified and used to explain cross polarization instabilities in both the focusing and defocusing cases, as well as to describe optical shocking phenomena. For the coupled bistable optical switches, a numerical code was carefully developed in two spatial and one temporal dimensions. The code was used to study the decay of temporal transients to 'on-off' steady states in a geometry which includes forward and backward longitudinal propagation, together with one dimensional transverse coupling of both electromagnetic diffraction and carrier diffusion.

  18. Spacecraft nonlinear control

    NASA Technical Reports Server (NTRS)

    Sheen, Jyh-Jong; Bishop, Robert H.

    1992-01-01

    The feedback linearization technique is applied to the problem of spacecraft attitude control and momentum management with control moment gyros (CMGs). The feedback linearization consists of a coordinate transformation, which transforms the system to a companion form, and a nonlinear feedback control law to cancel the nonlinear dynamics resulting in a linear equivalent model. Pole placement techniques are then used to place the closed-loop poles. The coordinate transformation proposed here evolves from three output functions of relative degree four, three, and two, respectively. The nonlinear feedback control law is presented. Stability in a neighborhood of a controllable torque equilibrium attitude (TEA) is guaranteed and this fact is demonstrated by the simulation results. An investigation of the nonlinear control law shows that singularities exist in the state space outside the neighborhood of the controllable TEA. The nonlinear control law is simplified by a standard linearization technique and it is shown that the linearized nonlinear controller provides a natural way to select control gains for the multiple-input, multiple-output system. Simulation results using the linearized nonlinear controller show good performance relative to the nonlinear controller in the neighborhood of the TEA.

  19. Lasers for nonlinear microscopy.

    PubMed

    Wise, Frank

    2013-03-01

    Various versions of nonlinear microscopy are revolutionizing the life sciences, almost all of which are made possible because of the development of ultrafast lasers. In this article, the main properties and technical features of short-pulse lasers used in nonlinear microscopy are summarized. Recent research results on fiber lasers that will impact future instruments are also discussed.

  20. Nonlinear filter design

    NASA Technical Reports Server (NTRS)

    Hunt, L. R.; Whitney, Paul

    1987-01-01

    A technique for identifying nonlinear systems was introduced, beginning with a single input-single output system. Assuming the system is initially at rest, the first kernel (first convolution integral in the continuous case or first convolution sum in the discrete case) was calculated. A controllable and observable linear realization was then obtained in a particular canonical form. The actual nonlinear system was probed with an appropriate input (or inputs) and the output (or outputs) determined. For the linear system, the input was computed that produces the same output. In the difference between the inputs to the nonlinear and linear systems, basic information was found about the nonlinear system. There is an interesting class of nonlinear systems for which this type of identification scheme should prove to be accurate.

  1. Chronic vasodilation increases renal medullary PDE5A and α-ENaC through independent renin-angiotensin-aldosterone system pathways.

    PubMed

    West, Crystal A; Shaw, Stefan; Sasser, Jennifer M; Fekete, Andrea; Alexander, Tyler; Cunningham, Mark W; Masilamani, Shyama M E; Baylis, Chris

    2013-11-15

    We have previously observed that many of the renal and hemodynamic adaptations seen in normal pregnancy can be induced in virgin female rats by chronic systemic vasodilation. Fourteen-day vasodilation with sodium nitrite or nifedipine (NIF) produced plasma volume expansion (PVE), hemodilution, and increased renal medullary phosphodiesterase 5A (PDE5A) protein. The present study examined the role of the renin-angiotensin-aldosterone system (RAAS) in this mechanism. Virgin females were treated for 14 days with NIF (10 mg·kg(-1)·day(-1) via diet), NIF with spironolactone [SPR; mineralocorticoid receptor (MR) blocker, 200-300 mg·kg(-1)·day(-1) via diet], NIF with losartan [LOS; angiotensin type 1 (AT1) receptor blocker, 20 mg·kg(-1)·day(-1) via diet], enalapril (ENAL; angiotensin-converting enzyme inhibitor, 62.5 mg/l via water), or vehicle (CON). Mean arterial pressure (MAP) was reduced 7.4 ± 0.5% with NIF, 6.33 ± 0.5% with NIF + SPR, 13.3 ± 0.9% with NIF + LOS, and 12.0 ± 0.4% with ENAL vs. baseline MAP. Compared with CON (3.6 ± 0.3%), plasma volume factored for body weight was increased by NIF (5.2 ± 0.4%) treatment but not by NIF + SPR (4.3 ± 0.3%), NIF + LOS (3.6 ± 0.1%), or ENAL (4.0 ± 0.3%). NIF increased PDE5A protein abundance in the renal inner medulla, and SPR did not prevent this increase (188 ± 16 and 204 ± 22% of CON, respectively). NIF increased the α-subunit of the epithelial sodium channel (α-ENaC) protein in renal outer (365 ± 44%) and inner (526 ± 83%) medulla, and SPR prevented these changes. There was no change in either PDE5A or α-ENaC abundance vs. CON in rats treated with NIF + LOS or ENAL. These data indicate that the PVE and renal medullary adaptations in response to chronic vasodilation result from RAAS signaling, with increases in PDE5A mediated through AT1 receptor and α-ENaC through the MR.

  2. Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene.

    PubMed Central

    Bolger, G B; Erdogan, S; Jones, R E; Loughney, K; Scotland, G; Hoffmann, R; Wilkinson, I; Farrell, C; Houslay, M D

    1997-01-01

    We have isolated and characterized complete cDNAs for two isoforms (HSPDE4D4 and HSPDE4A5) encoded by the human PDE4D gene, one of four genes that encode cAMP-specific rolipram-inhibited 3',5'-cyclic nucleotide phosphodiesterases (type IVPDEs; PDE4 family). The HSPDE4D4 and HSPDE4D5 cDNAs encode proteins of 810 and 746 amino acids respectively. A comparison of the nucleotide sequences of these two cDNAs with those encoding the three other human PDE4D proteins (HSPDE4D1, HSPDE4D2 and HSPDE4D3) demonstrates that each corresponding mRNA transcript has a unique region of sequence at or near its 5'-end, consistent with alternative mRNA splicing. Transient expression of the five cDNAs in monkey COS-7 cells produced proteins of apparent molecular mass under denaturing conditions of 68, 68, 95, 119 and 105 kDa for isoforms HSPDE4D1-5 respectively. Immunoblotting of human cell lines and rat brain demonstrated the presence of species that co-migrated with the proteins produced in COS-7 cells. COS-cell-expressed and native HSPDE4D1 and HSPDE4D2 were found to exist only in the cytosol, whereas HSPDE4D3, HSPDE4D4 and HSPDE4D5 were found in both cytosolic and particulate fractions. The IC50 values for the selective PDE4 inhibitor rolipram for the cytosolic forms of the five enzymes were similar (0.05-0.14 microM), whereas they were 2-7-fold higher for the particulate forms of HSPDE4D3 and HSPDE4D5 (0.32 and 0.59 microM respectively), than for the corresponding cytosolic forms. Our data indicate that the N-terminal regions of the HSPDE4D3, HSPDE4D4 and HSPDE4D5 proteins, which are derived from alternatively spliced regions of their mRNAs, are important in determining their subcellular localization, activity and differential sensitivity to inhibitors. PMID:9371713

  3. The role of intracavernosal injection therapy and the reasons of withdrawal from therapy in patients with erectile dysfunction in the era of PDE5 inhibitors.

    PubMed

    Sung, H H; Ahn, J S; Kim, J J; Choo, S H; Han, D H; Lee, S W

    2014-01-01

    There has been little data regarding the role of intracavernosal injection (ICI) treatment, its discontinuation rate and the reasons of withdrawal in patients with erectile dysfunction (ED) in the era of phosphodiesterase type 5 (PDE5) inhibitors. The aim of this study was to investigate the rate of withdrawal and its associated reasons in patients undergoing ICI therapy. Patients who were prescribed with ICI treatment two times or more were included since the introduction of sildenafil in Korea in 1999. Telephone surveys were performed to evaluate intercourse rates, withdrawal rates and their associated reasons, adverse events and the patients' satisfaction with their sex lives after the ICI treatments. Two hundred and ninety-four men were contacted by telephone. The mean age was 61.8 ± 7.9 years with a follow-up duration of 25.6 ± 32.1 months. At the last follow-up, 79.9% had discontinued the treatment. Most patients had previously failed PDE5 inhibitor treatment prior to the ICI therapy, and more than half had two or more risk factors of ED. Adequate penile rigidity after ICI therapy was restored in 60.2% of patients. The reasons for discontinuation of ICI were poor response (43.1%), inconvenience of use (18.3%), switch to other treatments (10.7%), loss of libido (6.7%), adverse events (5.5%) and return of spontaneous erection (2.8%). Pain was the most common adverse event in the withdrawal group, whereas prolonged erection was most common in the continuing group. Following ICI treatment, PDE5 inhibitors were the most common therapeutic option (63.1%). The overall satisfaction rate regarding sex life was significantly high in the treatment-continuing group. In conclusion, patients on ICI treatment had severe ED and high withdrawal rates in the era of PDE5 inhibitors. The most common reason for treatment discontinuation was poor response. Before initiating ICI treatments, sufficient counselling is necessary.

  4. Taming the nonlinearity of the Einstein equation.

    PubMed

    Harte, Abraham I

    2014-12-31

    Many of the technical complications associated with the general theory of relativity ultimately stem from the nonlinearity of Einstein's equation. It is shown here that an appropriate choice of dynamical variables may be used to eliminate all such nonlinearities beyond a particular order: Both Landau-Lifshitz and tetrad formulations of Einstein's equation are obtained that involve only finite products of the unknowns and their derivatives. Considerable additional simplifications arise in physically interesting cases where metrics become approximately Kerr or, e.g., plane waves, suggesting that the variables described here can be used to efficiently reformulate perturbation theory in a variety of contexts. In all cases, these variables are shown to have simple geometrical interpretations that directly relate the local causal structure associated with the metric of interest to the causal structure associated with a prescribed background. A new method to search for exact solutions is outlined as well.

  5. Nonlinear Elasticity in a Deforming Ambient Space

    NASA Astrophysics Data System (ADS)

    Yavari, Arash; Ozakin, Arkadas; Sadik, Souhayl

    2016-07-01

    In this paper, we formulate a nonlinear elasticity theory in which the ambient space is evolving. For a continuum moving in an evolving ambient space, we model time dependency of the metric by a time-dependent embedding of the ambient space in a larger manifold with a fixed background metric. We derive both the tangential and the normal governing equations. We then reduce the standard energy balance written in the larger ambient space to that in the evolving ambient space. We consider quasi-static deformations of the ambient space and show that a quasi-static deformation of the ambient space results in stresses, in general. We linearize the nonlinear theory about a reference motion and show that variation of the spatial metric corresponds to an effective field of body forces.

  6. Taming the nonlinearity of the Einstein equation.

    PubMed

    Harte, Abraham I

    2014-12-31

    Many of the technical complications associated with the general theory of relativity ultimately stem from the nonlinearity of Einstein's equation. It is shown here that an appropriate choice of dynamical variables may be used to eliminate all such nonlinearities beyond a particular order: Both Landau-Lifshitz and tetrad formulations of Einstein's equation are obtained that involve only finite products of the unknowns and their derivatives. Considerable additional simplifications arise in physically interesting cases where metrics become approximately Kerr or, e.g., plane waves, suggesting that the variables described here can be used to efficiently reformulate perturbation theory in a variety of contexts. In all cases, these variables are shown to have simple geometrical interpretations that directly relate the local causal structure associated with the metric of interest to the causal structure associated with a prescribed background. A new method to search for exact solutions is outlined as well. PMID:25615299

  7. Taming the Nonlinearity of the Einstein Equation

    NASA Astrophysics Data System (ADS)

    Harte, Abraham I.

    2014-12-01

    Many of the technical complications associated with the general theory of relativity ultimately stem from the nonlinearity of Einstein's equation. It is shown here that an appropriate choice of dynamical variables may be used to eliminate all such nonlinearities beyond a particular order: Both Landau-Lifshitz and tetrad formulations of Einstein's equation are obtained that involve only finite products of the unknowns and their derivatives. Considerable additional simplifications arise in physically interesting cases where metrics become approximately Kerr or, e.g., plane waves, suggesting that the variables described here can be used to efficiently reformulate perturbation theory in a variety of contexts. In all cases, these variables are shown to have simple geometrical interpretations that directly relate the local causal structure associated with the metric of interest to the causal structure associated with a prescribed background. A new method to search for exact solutions is outlined as well.

  8. Longitudinal displacements of base pairs in DNA and effects on the dynamics of nonlinear excitations.

    PubMed

    Di Garbo, Angelo

    2013-09-01

    A model of the DNA is proposed and studied analytically and numerically. The model is an extension of a well known model and describes the double helix as two chains of pendula (each pendulum representing a base). Each base (or pendulum) can rotate and translate along the helix axis. In the continuum limit the system is described by the perturbed Sine-Gordon equation describing the twist of the bases and by a nonlinear partial differential equation (PDE) describing the longitudinal displacements of the bases. This coupled system of PDEs was studied analytically using different approaches and the corresponding results were tested through numerical simulations. It was found that if the coupling parameters satisfy a well defined relationship, then there exist bounded travelling wave solutions.

  9. Longitudinal displacements of base pairs in DNA and effects on the dynamics of nonlinear excitations.

    PubMed

    Di Garbo, Angelo

    2013-09-01

    A model of the DNA is proposed and studied analytically and numerically. The model is an extension of a well known model and describes the double helix as two chains of pendula (each pendulum representing a base). Each base (or pendulum) can rotate and translate along the helix axis. In the continuum limit the system is described by the perturbed Sine-Gordon equation describing the twist of the bases and by a nonlinear partial differential equation (PDE) describing the longitudinal displacements of the bases. This coupled system of PDEs was studied analytically using different approaches and the corresponding results were tested through numerical simulations. It was found that if the coupling parameters satisfy a well defined relationship, then there exist bounded travelling wave solutions. PMID:23567838

  10. Nonlinear robust control of integrated vehicle dynamics

    NASA Astrophysics Data System (ADS)

    He, Zhengyi; Ji, Xuewu

    2012-02-01

    A new methodology to design the vehicle GCC (global chassis control) nonlinear controller is developed in this paper. Firstly, to handle the nonlinear coupling between sprung and unsprung masses, the vehicle is treated as a mechanical system of two-rigid-bodies which has 6 DOF (degree of freedom), including longitudinal, lateral, yaw, vertical, roll and pitch dynamics. The system equation is built in the yaw frame based on Lagrange's method, and it has been proved that the derived system remains the important physical properties of the general mechanical system. Then the GCC design problem is formulated as the trajectory tracking problem for a cascade system, with a Lagrange's system interconnecting with a linear system. The nonlinear robust control design problem of this cascade interconnected system is divided into two H ∞ control problems with respect to the two sub-systems. The parameter uncertainties in the system are tackled by adaptive theory, while the external uncertainties and disturbances are dealt with the H ∞ control theory. And the passivity of the mechanical system is applied to construct the solution of nonlinear H ∞ control problem. Finally, the effectiveness of the proposed controller is validated by simulation results even during the emergency manoeuvre.

  11. Nonlinear large-scale optimization with WORHP

    NASA Astrophysics Data System (ADS)

    Nikolayzik, Tim; Büskens, Christof; Gerdts, Matthias

    Nonlinear optimization has grown to a key technology in many areas of aerospace industry, e.g. satellite control, shape-optimization, aerodynamamics, trajectory planning, reentry prob-lems, interplanetary flights. One of the most extensive areas is the optimization of trajectories for aerospace applications. These problems typically are discretized optimal control problems, which leads to large sparse nonlinear optimization problems. In the end all these different problems from different areas can be described in the general formulation as a nonlinear opti-mization problem. WORHP is designed to solve nonlinear optimization problems with more then one million variables and one million constraints. WORHP uses a lot of different advanced techniques, e.g. reverse communication, to organize the optimization process as efficient and controllable by the user as possible. The solver has nine different interfaces, e.g. to MAT-LAB/SIMULINK and AMPL. Tests of WORHP had shown that WORHP is a very robust and promising solver. Several examples from space applications will be presented.

  12. Linearization strategies for the Iterative Nonlinear Contrast Source method for full-wave simulation of nonlinear ultrasound fields

    NASA Astrophysics Data System (ADS)

    Verweij, Martin D.; Demi, Libertario; van Dongen, Koen W. A.

    2012-09-01

    The Iterative Nonlinear Contrast Source (INCS) method is a full-wave method for the accurate computation of wide-angle, pulsed, nonlinear ultrasound fields appearing in, e.g., medical echoscopy. The method is based on the Westervelt equation and considers the occurring nonlinear term as a distributed contrast source that operates in a linear background medium. This formulation leads to an integral equation, which is solved in an iterative way. The original INCS method uses a Neumann scheme to successively approximate the nonlinear wave field in homogeneous, lossless, nonlinear media. To cope with attenuative and/or inhomogeneous nonlinear media, additional contrast sources may be introduced. Since these deteriorate the convergence rate of the Neumann scheme, more advanced iterative solution schemes like Bi-CGSTAB are required. To overcome the difficulty that such schemes only apply to linear integral equations, the nonlinear contrast source is linearized, at the cost of a significant systematic error in the fourth and higher harmonics. In this paper, a strategy is proposed in which the relevant iterative solution scheme is restarted with an updated version of the linearized contrast source. Results demonstrate the effectiveness of this strategy in eliminating the systematic error. In addition, it is shown that the same approach also improves the convergence rate in case of nonlinear propagation in media with attenuation.

  13. Nonlinear Seismic Response Of Single Piles

    SciTech Connect

    Cairo, R.; Conte, E.; Dente, G.

    2008-07-08

    In this paper, a method is proposed to analyse the seismic response of single piles under nonlinear soil condition. It is based on the Winkler foundation model formulated in the time domain, which makes use of p-y curves described by the Ramberg-Osgood relationship. The analyses are performed referring to a pile embedded in two-layer soil profiles with different sharp stiffness contrast. Italian seismic records are used as input motion. The calculated bending moments in the pile are compared to those obtained using other theoretical solutions.

  14. Group velocity and nonlinear dispersive wave propagation.

    NASA Technical Reports Server (NTRS)

    Hayes, W. D.

    1973-01-01

    By the use of a Hamiltonian formulation, a basic group velocity is defined as the derivative of frequency with respect to wavenumber keeping action density constant, and is shown to represent an incremental action velocity in the general nonlinear case. The stability treatment of Whitham and Lighthill is extended to several dimensions. The water-wave analysis of Whitham (1967) is extended to two space dimensions, and is shown to predict oblique-mode instabilities for kh smaller than 1.36. A treatment of Lighthill's (1965) solution in the one-dimensional elliptic case resolves the problem of the energy distribution in the solution past the critical time.

  15. Geometrically nonlinear analysis of laminated elastic structures

    NASA Technical Reports Server (NTRS)

    Reddy, J. N.; Chandrashekhara, K.; Chao, W. C.

    1993-01-01

    This final technical report contains three parts: Part 1 deals with the 2-D shell theory and its element formulation and applications. Part 2 deals with the 3-D degenerated element. These two parts constitute the two major tasks that were completed under the grant. Another related topic that was initiated during the present investigation is the development of a nonlinear material model. This topic is briefly discussed in Part 3. To make each part self-contained, conclusions and references are included in each part. In the interest of brevity, the discussions presented are relatively brief. The details and additional topics are described in the references cited.

  16. Nicotine enhances murine airway contractile responses to kinin receptor agonists via activation of JNK- and PDE4-related intracellular pathways

    PubMed Central

    2010-01-01

    ), glucocorticoid (dexamethasone) or adenylcyclase activator (forskolin) suppressed the nicotine-enhanced airway contractile response to des-Arg9-bradykinin and bradykinin. Conclusions Nicotine induces airway hyperresponsiveness via transcriptional up-regulation of airway kinin B1 and B2 receptors, an effect mediated via neuronal nicotinic receptors. The underlying molecular mechanisms involve activation of JNK- and PDE4-mediated intracellular inflammatory signal pathways. Our results might be relevant to active and passive smokers suffering from airway hyperresponsiveness, and suggest new therapeutic targets for the treatment of smoke-associated airway disease. PMID:20113502

  17. Uncertainty formulations for multislit interferometry

    NASA Astrophysics Data System (ADS)

    Biniok, Johannes C. G.

    2014-12-01

    In the context of (far-field) multislit interferometry we investigate the utility of two formulations of uncertainty in accounting for the complementarity of spatial localization and fringe width. We begin with a characterization of the relevant observables and general considerations regarding the suitability of different types of measures. The detailed analysis shows that both of the discussed uncertainty formulations yield qualitatively similar results, confirming that they correctly capture the relevant tradeoff. One approach, based on an idea of Aharonov and co-workers, is intuitively appealing and relies on a modification of the Heisenberg uncertainty relation. The other approach, developed by Uffink and Hilgevoord for single- and double-slit experiments, is readily applied to multislits. However, it is found that one of the underlying concepts requires generalization and that the choice of the parameters requires more consideration than was known.

  18. Nonlinear saturation characteristics of a dielectric Cherenkov maser

    SciTech Connect

    Choi, J.S.; Heo, E.G.; Choi, D.I.

    1995-12-31

    The nonlinear saturation state in a dielectric Cherenkov maser (DCM) with the TM mode and the intense relativistic electron beam is analyzed from the nonlinear formulation based on the cold fluid-Maxwell equations. We obtain the nonlinear efficiency and the final operation frequency under consideration of the effects of the beam current, the beam energy and the dielectric materials and show that the characteristics of a DCM instablity has a strong resemblance to that of the relativistic two stream instability by the coherent trapping of electrons in a single most-ustable wave. Finally, the nonlinear analysis shows that the Cherenkov maser operation with a lower-energy beam can be more efficient in the higher frequency regime for the case of the high power DCM with a high current.

  19. Geometric and material nonlinear analysis of tensegrity structures

    NASA Astrophysics Data System (ADS)

    Tran, Hoang Chi; Lee, Jaehong

    2011-12-01

    A numerical method is presented for the large deflection in elastic analysis of tensegrity structures including both geometric and material nonlinearities. The geometric nonlinearity is considered based on both total Lagrangian and updated Lagrangian formulations, while the material nonlinearity is treated through elastoplastic stress-strain relationship. The nonlinear equilibrium equations are solved using an incremental-iterative scheme in conjunction with the modified Newton-Raphson method. A computer program is developed to predict the mechanical responses of tensegrity systems under tensile, compressive and flexural loadings. Numerical results obtained are compared with those reported in the literature to demonstrate the accuracy and efficiency of the proposed program. The flexural behavior of the double layer quadruplex tensegrity grid is sufficiently good for lightweight large-span structural applications. On the other hand, its bending strength capacity is not sensitive to the self-stress level.

  20. Numerical modelling of nonlinear full-wave acoustic propagation

    SciTech Connect

    Velasco-Segura, Roberto Rendón, Pablo L.

    2015-10-28

    The various model equations of nonlinear acoustics are arrived at by making assumptions which permit the observation of the interaction with propagation of either single or joint effects. We present here a form of the conservation equations of fluid dynamics which are deduced using slightly less restrictive hypothesis than those necessary to obtain the well known Westervelt equation. This formulation accounts for full wave diffraction, nonlinearity, and thermoviscous dissipative effects. A two-dimensional, finite-volume method using Roe’s linearisation has been implemented to obtain numerically the solution of the proposed equations. This code, which has been written for parallel execution on a GPU, can be used to describe moderate nonlinear phenomena, at low Mach numbers, in domains as large as 100 wave lengths. Applications range from models of diagnostic and therapeutic HIFU, to parametric acoustic arrays and nonlinear propagation in acoustic waveguides. Examples related to these applications are shown and discussed.

  1. Enhanced element-specific modal formulations for flexible multibody dynamics

    NASA Technical Reports Server (NTRS)

    Ryan, Robert R.

    1989-01-01

    The accuracy of current flexible multibody formalisms based on assumed modes is examined in the context of standard spacecraft motions involving structural components undergoing both slow and fast overall translational and rotational motions as well as small deformations. Limitations of current techniques in treating: (1) element-specific coupling behavior of large motion and small deformation, and (2) motion-induced structural stiffness variations, are noted. The roles of nonlinear and linear elastic structural theories in accurately predicting transient large-displacement dynamic behavior of flexible multibody systems are examined in detail. Coupling effects between deformation and overall motion are carefully scrutinized in the context of assumed-mode discretization techniques. Consistently linearized beam, plate, and shell formulations involving in-plane stretch variables are proposed and shown to yield very accurate simulation results and extremely fast modal convergence for most motions involving small strains. In some particular cases, however, in which membrane stiffness dominates bending stiffness, a nonlinear strain formulation is required in order to capture proper coupling between deformation and overall motion.

  2. Nonlinear cochlear mechanics.

    PubMed

    Zweig, George

    2016-05-01

    An earlier paper characterizing the linear mechanical response of the organ of Corti [J. Acoust. Soc. Am. 138, 1102-1121 (2015)] is extended to the nonlinear domain. Assuming the existence of nonlinear oscillators nonlocally coupled through the pressure they help create, the oscillator equations are derived and examined when the stimuli are modulated tones and clicks. The nonlinearities are constrained by the requirements of oscillator stability and the invariance of zero crossings in the click response to changes in click amplitude. The nonlinear oscillator equations for tones are solved in terms of the fluid pressure that drives them, and its time derivative, presumably a proxy for forces created by outer hair cells. The pressure equation is reduced to quadrature, the integrand depending on the oscillators' responses. The resulting nonlocally coupled nonlinear equations for the pressure, and oscillator amplitudes and phases, are solved numerically in terms of the fluid pressure at the stapes. Methods for determining the nonlinear damping directly from measurements are described. Once the oscillators have been characterized from their tone and click responses, the mechanical response of the cochlea to natural sounds may be computed numerically. Signal processing inspired by cochlear mechanics opens up a new area of nonlocal nonlinear time-frequency analysis.

  3. Nonlinear cochlear mechanics.

    PubMed

    Zweig, George

    2016-05-01

    An earlier paper characterizing the linear mechanical response of the organ of Corti [J. Acoust. Soc. Am. 138, 1102-1121 (2015)] is extended to the nonlinear domain. Assuming the existence of nonlinear oscillators nonlocally coupled through the pressure they help create, the oscillator equations are derived and examined when the stimuli are modulated tones and clicks. The nonlinearities are constrained by the requirements of oscillator stability and the invariance of zero crossings in the click response to changes in click amplitude. The nonlinear oscillator equations for tones are solved in terms of the fluid pressure that drives them, and its time derivative, presumably a proxy for forces created by outer hair cells. The pressure equation is reduced to quadrature, the integrand depending on the oscillators' responses. The resulting nonlocally coupled nonlinear equations for the pressure, and oscillator amplitudes and phases, are solved numerically in terms of the fluid pressure at the stapes. Methods for determining the nonlinear damping directly from measurements are described. Once the oscillators have been characterized from their tone and click responses, the mechanical response of the cochlea to natural sounds may be computed numerically. Signal processing inspired by cochlear mechanics opens up a new area of nonlocal nonlinear time-frequency analysis. PMID:27250151

  4. Determination of a novel phosphodiesterase4 inhibitor, 3-[1-(3cyclopropylmethoxy-4-difluoromethoxybenzyl)-1H-pyrazol-3-yl]-benzoic acid (PDE-423) in rat plasma using liquid chromatography-tandem mass spectrometry.

    PubMed

    Cho, Woon-Ki; Seo, Hyewon; Choi, Sung Heum; Kwak, Hyun Jeong; Cheon, Hyae Gyeong; Jeon, Dong Ju; Kim, Sang Kyum; Bae, Myung Ae; Song, Jin Sook

    2015-03-01

    A method for determining a novel phosphodiesterase-4 inhibitor, 3-[1-(3cyclopropylmethoxy-4-difluoromethoxybenzyl)-1H-pyrazol-3-yl]-benzoic acid (PDE-423), in rat plasma was developed and validated using liquid chromatography-tandem mass spectrometry for further pharmacokinetic study for development as a novel anti-asthmatic drug. PDE-423 in the concentration range of 0.02-10 µg/mL was linear with a correlation coefficient of >0.99, and the mean intra- and inter-assay precisions of the assay were 7.50 and 3.86%, respectively. The validated method was used successfully for a pharmacokinetic study of PDE-423 in rats.

  5. Hybrid proper orthogonal decomposition formulation for linear structural dynamics

    NASA Astrophysics Data System (ADS)

    Placzek, A.; Tran, D.-M.; Ohayon, R.

    2008-12-01

    Hybrid proper orthogonal decomposition (PODh) formulation is a POD-based reduced-order modeling method where the continuous equation of the physical system is projected on the POD modes obtained from a discrete model of the system. The aim of this paper is to evaluate the hybrid POD formulation and to compare it with other POD formulations on the simple case of a linear elastic rod subject to prescribed displacements in the perspective of building reduced-order models for coupled fluid-structure systems in the future. In the first part of the paper, the hybrid POD is compared to two other formulations for the response to an initial condition: an approach based on the discrete finite elements equation of the rod called the discrete POD (PODd), and an analytical approach using the exact solution of the problem and consequently called the analytical POD (PODa). This first step is useful to ensure that the PODh performs well with respect to the other formulations. The PODh is therefore used afterwards for the forced motion response where a displacement is imposed at the free end of the rod. The main contribution of this paper lies in the comparison of three techniques used to take into account the non-homogeneous Dirichlet boundary condition with the hybrid POD: the first method relies on control functions, the second on the penalty method and the third on Lagrange multipliers. Finally, the robustness of the hybrid POD is investigated on two examples involving firstly the introduction of structural damping and secondly a nonlinear force applied at the free end of the rod.

  6. Nonlinear ordinary difference equations

    NASA Technical Reports Server (NTRS)

    Caughey, T. K.

    1979-01-01

    Future space vehicles will be relatively large and flexible, and active control will be necessary to maintain geometrical configuration. While the stresses and strains in these space vehicles are not expected to be excessively large, their cumulative effects will cause significant geometrical nonlinearities to appear in the equations of motion, in addition to the nonlinearities caused by material properties. Since the only effective tool for the analysis of such large complex structures is the digital computer, it will be necessary to gain a better understanding of the nonlinear ordinary difference equations which result from the time discretization of the semidiscrete equations of motion for such structures.

  7. Nonlinear mill control.

    PubMed

    Martin, G; McGarel, S

    2001-01-01

    A mill is a mechanical device that grinds mined or processed material into small particles. The process is known to display significant deadtime, and, more notably, severe nonlinear behavior. Over the past 25 years attempts at continuous mill control have met varying degrees of failure, mainly due to model mismatch caused by changes in the mill process gains. This paper describes an on-line control application on a closed-circuit cement mill that uses nonlinear model predictive control technology. The nonlinear gains for the control model are calculated on-line from a neural network model of the process.

  8. Multipole nonlinearity of metamaterials

    SciTech Connect

    Petschulat, J.; Chipouline, A.; Tuennermann, A.; Pertsch, T.; Menzel, C.; Rockstuhl, C.; Lederer, F.

    2009-12-15

    We report on the linear and nonlinear optical response of metamaterials evoked by first- and second-order multipoles. The analytical ground on which our approach is based permits for new insights into the functionality of metamaterials. For the sake of clarity we focus here on a key geometry, namely, the split-ring resonator, although the introduced formalism can be applied to arbitrary structures. We derive the equations that describe linear and nonlinear light propagation where special emphasis is put on second-harmonic generation. This contribution basically aims at stretching versatile and existing concepts to describe light propagation in nonlinear media toward the realm of metamaterials.

  9. NLINEAR - NONLINEAR CURVE FITTING PROGRAM

    NASA Technical Reports Server (NTRS)

    Everhart, J. L.

    1994-01-01

    A common method for fitting data is a least-squares fit. In the least-squares method, a user-specified fitting function is utilized in such a way as to minimize the sum of the squares of distances between the data points and the fitting curve. The Nonlinear Curve Fitting Program, NLINEAR, is an interactive curve fitting routine based on a description of the quadratic expansion of the chi-squared statistic. NLINEAR utilizes a nonlinear optimization algorithm that calculates the best statistically weighted values of the parameters of the fitting function and the chi-square that is to be minimized. The inputs to the program are the mathematical form of the fitting function and the initial values of the parameters to be estimated. This approach provides the user with statistical information such as goodness of fit and estimated values of parameters that produce the highest degree of correlation between the experimental data and the mathematical model. In the mathematical formulation of the algorithm, the Taylor expansion of chi-square is first introduced, and justification for retaining only the first term are presented. From the expansion, a set of n simultaneous linear equations are derived, which are solved by matrix algebra. To achieve convergence, the algorithm requires meaningful initial estimates for the parameters of the fitting function. NLINEAR is written in Fortran 77 for execution on a CDC Cyber 750 under NOS 2.3. It has a central memory requirement of 5K 60 bit words. Optionally, graphical output of the fitting function can be plotted. Tektronix PLOT-10 routines are required for graphics. NLINEAR was developed in 1987.

  10. Nonlinear Statistical Modeling of Speech

    NASA Astrophysics Data System (ADS)

    Srinivasan, S.; Ma, T.; May, D.; Lazarou, G.; Picone, J.

    2009-12-01

    Contemporary approaches to speech and speaker recognition decompose the problem into four components: feature extraction, acoustic modeling, language modeling and search. Statistical signal processing is an integral part of each of these components, and Bayes Rule is used to merge these components into a single optimal choice. Acoustic models typically use hidden Markov models based on Gaussian mixture models for state output probabilities. This popular approach suffers from an inherent assumption of linearity in speech signal dynamics. Language models often employ a variety of maximum entropy techniques, but can employ many of the same statistical techniques used for acoustic models. In this paper, we focus on introducing nonlinear statistical models to the feature extraction and acoustic modeling problems as a first step towards speech and speaker recognition systems based on notions of chaos and strange attractors. Our goal in this work is to improve the generalization and robustness properties of a speech recognition system. Three nonlinear invariants are proposed for feature extraction: Lyapunov exponents, correlation fractal dimension, and correlation entropy. We demonstrate an 11% relative improvement on speech recorded under noise-free conditions, but show a comparable degradation occurs for mismatched training conditions on noisy speech. We conjecture that the degradation is due to difficulties in estimating invariants reliably from noisy data. To circumvent these problems, we introduce two dynamic models to the acoustic modeling problem: (1) a linear dynamic model (LDM) that uses a state space-like formulation to explicitly model the evolution of hidden states using an autoregressive process, and (2) a data-dependent mixture of autoregressive (MixAR) models. Results show that LDM and MixAR models can achieve comparable performance with HMM systems while using significantly fewer parameters. Currently we are developing Bayesian parameter estimation and

  11. Nonlinear simulation of tumor growth.

    PubMed

    Cristini, Vittorio; Lowengrub, John; Nie, Qing

    2003-03-01

    We study solid tumor ( carcinoma) growth in the nonlinear regime using boundary-integral simulations. The tumor core is nonnecrotic and no inhibitor chemical species are present. A new formulation of the classical models [18,24,8,3] is developed and it is demonstrated that tumor evolution is described by a reduced set of two dimensionless parameters and is qualitatively unaffected by the number of spatial dimensions. One parameter describes the relative rate of mitosis to the relaxation mechanisms (cell mobility and cell-to-cell adhesion). The other describes the balance between apoptosis (programmed cell-death) and mitosis. Both parameters also include the effect of vascularization. Our analysis and nonlinear simulations reveal that the two new dimensionless groups uniquely subdivide tumor growth into three regimes associated with increasing degrees of vascularization: low (diffusion dominated, e.g., in vitro), moderate and high vascularization, that correspond to the regimes observed in vivo. We demonstrate that critical conditions exist for which the tumor evolves to nontrivial dormant states or grows self-similarly (i.e., shape invariant) in the first two regimes. This leads to the possibility of shape control and of controlling the release of tumor angiogenic factors by restricting the tumor volume-to-surface-area ratio. Away from these critical conditions, evolution may be unstable leading to invasive fingering into the external tissues and to topological transitions such as tumor breakup and reconnection. Interestingly we find that for highly vascularized tumors, while they grow unbounded, their shape always stays compact and invasive fingering does not occur. This is in agreement with recent experimental observations [30] of in vivo tumor growth, and suggests that the invasive growth of highly-vascularized tumors is associated to vascular and elastic anisotropies, which are not included in the model studied here.

  12. Comparison of three development approaches for Stationary Phase Optimised Selectivity Liquid Chromatography based screening methods Part II: A group of structural analogues (PDE-5 inhibitors in food supplements).

    PubMed

    Deconinck, E; Ghijs, L; Kamugisha, A; Courselle, P

    2016-02-01

    Three approaches for the development of a screening method to detect adulterated dietary supplements, based on Stationary Phase Optimised Selectivity Liquid Chromatography were compared for their easiness/speed of development and the performance of the optimal method obtained. This comparison was performed for a heterogeneous group of molecules, i.e. slimming agents (Part I) and a group of structural analogues, i.e. PDE-5 inhibitors (Part II). The first approach makes use of primary runs at one isocratic level, the second of primary runs in gradient mode and the third of primary runs at three isocratic levels to calculate the optimal combination of segments of stationary phases. In each approach the selection of the stationary phase was followed by a gradient optimisation. For the PDE-5 inhibitors, the group of structural analogues, only the method obtained with the third approach was able to differentiate between all the molecules in the development set. Although not all molecules are baseline separated, the method allows the identification of the selected adulterants in dietary supplements using only diode array detection. Though, due to the mobile phases used, the method could also be coupled to mass spectrometry. The method was validated for its selectivity following the guidelines as described for the screening of pesticide residues and residues of veterinary medicines in food.

  13. A fluorescent HTS assay for phosphohydrolases based on nucleoside 5'-fluorophosphates: its application in screening for inhibitors of mRNA decapping scavenger and PDE-I.

    PubMed

    Baranowski, M R; Nowicka, A; Jemielity, J; Kowalska, J

    2016-05-18

    Several nucleotide-specific phosphohydrolases can cleave P-F bonds in substrate analogues containing a fluorophosphate moiety to release fluoride ions. In this work, by employing a fluoride-sensitive molecular sensor, we harnessed this cleavage reaction to develop a fluorescence assay to screen for phosphohydrolase inhibitors. The assay is rapid, sensitive, and based on simple and synthetically available reagents. The assay was adapted to the high-throughput screening (HTS) format and its utility was demonstrated by screening an 'in-house' library of small nucleotides against two enzymes: DcpS, a metal-independent mRNA decapping pyrophosphatase of the histidine triad (HIT) family; and PDE-I, a divalent cation-dependent nuclease. Our screening results agreed with the known specificities of DcpS and PDE-I, and led to the selection of several inhibitors featuring low-micromolar IC50 values. For DcpS, we also verified the results by using an alternative method with the natural substrate. Notably, the assay presented here is the first fluorescence-based HTS-adaptable assay for DcpS, an established therapeutic target for spinal muscular atrophy. The assay should be useful for phosphohydrolase specificity profiling and inhibitor discovery, particularly in the context of DcpS and other HIT-family enzymes, which play key roles in maintaining cellular functions and have been linked to disease development.

  14. AKAP79, PKC, PKA and PDE4 participate in a Gq-linked muscarinic receptor and adenylate cyclase 2 cAMP signalling complex

    PubMed Central

    Shen, Jia X.; Cooper, Dermot M. F.

    2014-01-01

    AC2 (adenylate cyclase 2) is stimulated by activation of Gq-coupled muscarinic receptors through PKC (protein kinase C) to generate localized cAMP in HEK (human embryonic kidney)-293 cells. In the present study, we utilized a sensitive live-cell imaging technique to unravel the proteins that play essential roles in a Gq-coupled muscarinic receptor-mediated cAMP signalling complex. We reveal that, upon agonist binding to the Gq-coupled muscarinic receptor, AKAP79 (A-kinase-anchoring protein 79) recruits PKC to activate AC2 to produce cAMP. The cAMP formed is degraded by PDE4 (phosphodiesterase 4) activated by an AKAP-anchored PKA (protein kinase A). Calcineurin, a phosphatase bound to AKAP79, is not involved in this regulation. Overall, a transient cAMP increase is generated from AC2 by Gq-coupled muscarinic receptor activation, subject to sophisticated regulation through AKAP79, PKC, PDE4 and PKA, which significantly enhances acetylcholine-mediated signalling. PMID:23889134

  15. A fluorescent HTS assay for phosphohydrolases based on nucleoside 5'-fluorophosphates: its application in screening for inhibitors of mRNA decapping scavenger and PDE-I.

    PubMed

    Baranowski, M R; Nowicka, A; Jemielity, J; Kowalska, J

    2016-05-18

    Several nucleotide-specific phosphohydrolases can cleave P-F bonds in substrate analogues containing a fluorophosphate moiety to release fluoride ions. In this work, by employing a fluoride-sensitive molecular sensor, we harnessed this cleavage reaction to develop a fluorescence assay to screen for phosphohydrolase inhibitors. The assay is rapid, sensitive, and based on simple and synthetically available reagents. The assay was adapted to the high-throughput screening (HTS) format and its utility was demonstrated by screening an 'in-house' library of small nucleotides against two enzymes: DcpS, a metal-independent mRNA decapping pyrophosphatase of the histidine triad (HIT) family; and PDE-I, a divalent cation-dependent nuclease. Our screening results agreed with the known specificities of DcpS and PDE-I, and led to the selection of several inhibitors featuring low-micromolar IC50 values. For DcpS, we also verified the results by using an alternative method with the natural substrate. Notably, the assay presented here is the first fluorescence-based HTS-adaptable assay for DcpS, an established therapeutic target for spinal muscular atrophy. The assay should be useful for phosphohydrolase specificity profiling and inhibitor discovery, particularly in the context of DcpS and other HIT-family enzymes, which play key roles in maintaining cellular functions and have been linked to disease development. PMID:27031609

  16. Comparison of three development approaches for Stationary Phase Optimised Selectivity Liquid Chromatography based screening methods Part II: A group of structural analogues (PDE-5 inhibitors in food supplements).

    PubMed

    Deconinck, E; Ghijs, L; Kamugisha, A; Courselle, P

    2016-02-01

    Three approaches for the development of a screening method to detect adulterated dietary supplements, based on Stationary Phase Optimised Selectivity Liquid Chromatography were compared for their easiness/speed of development and the performance of the optimal method obtained. This comparison was performed for a heterogeneous group of molecules, i.e. slimming agents (Part I) and a group of structural analogues, i.e. PDE-5 inhibitors (Part II). The first approach makes use of primary runs at one isocratic level, the second of primary runs in gradient mode and the third of primary runs at three isocratic levels to calculate the optimal combination of segments of stationary phases. In each approach the selection of the stationary phase was followed by a gradient optimisation. For the PDE-5 inhibitors, the group of structural analogues, only the method obtained with the third approach was able to differentiate between all the molecules in the development set. Although not all molecules are baseline separated, the method allows the identification of the selected adulterants in dietary supplements using only diode array detection. Though, due to the mobile phases used, the method could also be coupled to mass spectrometry. The method was validated for its selectivity following the guidelines as described for the screening of pesticide residues and residues of veterinary medicines in food. PMID:26653459

  17. Nonlinear optomechanical pressure

    NASA Astrophysics Data System (ADS)

    Conti, Claudio; Boyd, Robert

    2014-03-01

    A transparent material exhibits ultrafast optical nonlinearity and is subject to optical pressure if irradiated by a laser beam. However, the effect of nonlinearity on optical pressure is often overlooked, even if a nonlinear optical pressure may be potentially employed in many applications, such as optical manipulation, biophysics, cavity optomechanics, quantum optics, and optical tractors, and is relevant in fundamental problems such as the Abraham-Minkoswky dilemma or the Casimir effect. Here, we show that an ultrafast nonlinear polarization gives indeed a contribution to the optical pressure that also is negative in certain spectral ranges; the theoretical analysis is confirmed by first-principles simulations. An order-of-magnitude estimate shows that the effect can be observable by measuring the deflection of a membrane made by graphene.

  18. Nonlinear Structural Analysis

    NASA Technical Reports Server (NTRS)

    1984-01-01

    Nonlinear structural analysis techniques for engine structures and components are addressed. The finite element method and boundary element method are discussed in terms of stress and structural analyses of shells, plates, and laminates.

  19. Library for Nonlinear Optimization

    2001-10-09

    OPT++ is a C++ object-oriented library for nonlinear optimization. This incorporates an improved implementation of an existing capability and two new algorithmic capabilities based on existing journal articles and freely available software.

  20. Nonlinear Dynamics in Cardiology

    PubMed Central

    Krogh-Madsen, Trine; Christini, David J.

    2013-01-01

    The dynamics of many cardiac arrhythmias, as well as the nature of transitions between different heart rhythms, have long been considered evidence of nonlinear phenomena playing a direct role in cardiac arrhythmogenesis. In most types of cardiac disease, the pathology develops slowly and gradually, often over many years. In contrast, arrhythmias often occur suddenly. In nonlinear systems, sudden changes in qualitative dynamics can, counter-intuitively, result from a gradual change in a system parameter –this is known as a bifurcation. Here, we review how nonlinearities in cardiac electrophysiology influence normal and abnormal rhythms and how bifurcations change the dynamics. In particular, we focus on the many recent developments in computational modeling at the cellular level focused on intracellular calcium dynamics. We discuss two areas where recent experimental and modeling work have suggested the importance of nonlinearities in calcium dynamics: repolarization alternans and pacemaker cell automaticity. PMID:22524390