Reconfigurable Analog PDE computation for Baseband and RFComputation

DTIC Science & Technology

2017-03-01

waveguiding PDEs. One-dimensional ladder topologies enable linear delays, linear-phase analog filters , as well as analog beamforming, potentially at RF...performance. This discussion focuses on ODE / PDE analog computation available in SoC FPAA structures. One such computation is a ladder filter (Fig...Implementation of a one-dimensional ladder filter for computing inductor (L) and capacitor (C) lines. These components can be implemented in CABs or as

Output Tracking for Systems with Non-Hyperbolic and Near Non-Hyperbolic Internal Dynamics: Helicopter Hover Control

NASA Technical Reports Server (NTRS)

Devasia, Santosh

1996-01-01

A technique to achieve output tracking for nonminimum phase linear systems with non-hyperbolic and near non-hyperbolic internal dynamics is presented. This approach integrates stable inversion techniques, that achieve exact-tracking, with approximation techniques, that modify the internal dynamics to achieve desirable performance. Such modification of the internal dynamics is used (1) to remove non-hyperbolicity which an obstruction to applying stable inversion techniques and (2) to reduce large pre-actuation time needed to apply stable inversion for near non-hyperbolic cases. The method is applied to an example helicopter hover control problem with near non-hyperbolic internal dynamic for illustrating the trade-off between exact tracking and reduction of pre-actuation time.

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.

The algebraic-hyperbolic approach to the linearized gravitational constraints on a Minkowski background

NASA Astrophysics Data System (ADS)

Winicour, Jeffrey

2017-08-01

An algebraic-hyperbolic method for solving the Hamiltonian and momentum constraints has recently been shown to be well posed for general nonlinear perturbations of the initial data for a Schwarzschild black hole. This is a new approach to solving the constraints of Einstein’s equations which does not involve elliptic equations and has potential importance for the construction of binary black hole data. In order to shed light on the underpinnings of this approach, we consider its application to obtain solutions of the constraints for linearized perturbations of Minkowski space. In that case, we find the surprising result that there are no suitable Cauchy hypersurfaces in Minkowski space for which the linearized algebraic-hyperbolic constraint problem is well posed.

Congruence Approximations for Entrophy Endowed Hyperbolic Systems

NASA Technical Reports Server (NTRS)

Barth, Timothy J.; Saini, Subhash (Technical Monitor)

1998-01-01

Building upon the standard symmetrization theory for hyperbolic systems of conservation laws, congruence properties of the symmetrized system are explored. These congruence properties suggest variants of several stabilized numerical discretization procedures for hyperbolic equations (upwind finite-volume, Galerkin least-squares, discontinuous Galerkin) that benefit computationally from congruence approximation. Specifically, it becomes straightforward to construct the spatial discretization and Jacobian linearization for these schemes (given a small amount of derivative information) for possible use in Newton's method, discrete optimization, homotopy algorithms, etc. Some examples will be given for the compressible Euler equations and the nonrelativistic MHD equations using linear and quadratic spatial approximation.

Linear guided waves in a hyperbolic planar waveguide. Dispersion relations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lyashko, E I; Maimistov, A I

2015-11-30

We have theoretically investigated waveguide modes propagating in a planar waveguide formed by a layer of an isotropic dielectric surrounded by hyperbolic media. The case, when the optical axis of hyperbolic media is perpendicular to the interface, is considered. Dispersion relations are derived for the cases of TE and TM waves. The differences in the characteristics of a hyperbolic and a conventional dielectric waveguide are found. In particular, it is shown that in hyperbolic waveguides for each TM mode there are two cut-off frequencies and the number of propagating modes is always limited. (metamaterials)

Fast wavelet based algorithms for linear evolution equations

NASA Technical Reports Server (NTRS)

Engquist, Bjorn; Osher, Stanley; Zhong, Sifen

1992-01-01

A class was devised of fast wavelet based algorithms for linear evolution equations whose coefficients are time independent. The method draws on the work of Beylkin, Coifman, and Rokhlin which they applied to general Calderon-Zygmund type integral operators. A modification of their idea is applied to linear hyperbolic and parabolic equations, with spatially varying coefficients. A significant speedup over standard methods is obtained when applied to hyperbolic equations in one space dimension and parabolic equations in multidimensions.

Backstepping-based boundary control design for a fractional reaction diffusion system with a space-dependent diffusion coefficient.

PubMed

Chen, Juan; Cui, Baotong; Chen, YangQuan

2018-06-11

This paper presents a boundary feedback control design for a fractional reaction diffusion (FRD) system with a space-dependent (non-constant) diffusion coefficient via the backstepping method. The contribution of this paper is to generalize the results of backstepping-based boundary feedback control for a FRD system with a space-independent (constant) diffusion coefficient to the case of space-dependent diffusivity. For the boundary stabilization problem of this case, a designed integral transformation treats it as a problem of solving a hyperbolic partial differential equation (PDE) of transformation's kernel, then the well posedness of the kernel PDE is solved for the plant with non-constant diffusivity. Furthermore, by the fractional Lyapunov stability (Mittag-Leffler stability) theory and the backstepping-based boundary feedback controller, the Mittag-Leffler stability of the closed-loop FRD system with non-constant diffusivity is proved. Finally, an extensive numerical example for this closed-loop FRD system with non-constant diffusivity is presented to verify the effectiveness of our proposed controller. Copyright © 2018 ISA. Published by Elsevier Ltd. All rights reserved.

Modified hyperbolic sine model for titanium dioxide-based memristive thin films

NASA Astrophysics Data System (ADS)

Abu Bakar, Raudah; Syahirah Kamarozaman, Nur; Fazlida Hanim Abdullah, Wan; Herman, Sukreen Hana

2018-03-01

Since the emergence of memristor as the newest fundamental circuit elements, studies on memristor modeling have been evolved. To date, the developed models were based on the linear model, linear ionic drift model using different window functions, tunnelling barrier model and hyperbolic-sine function based model. Although using hyperbolic-sine function model could predict the memristor electrical properties, the model was not well fitted to the experimental data. In order to improve the performance of the hyperbolic-sine function model, the state variable equation was modified. On the one hand, the addition of window function cannot provide an improved fitting. By multiplying the Yakopcic’s state variable model to Chang’s model on the other hand resulted in the closer agreement with the TiO2 thin film experimental data. The percentage error was approximately 2.15%.

Domain decomposition in time for PDE-constrained optimization

DOE PAGES

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.

A new method of imposing boundary conditions for hyperbolic equations

NASA Technical Reports Server (NTRS)

Funaro, D.; ative.

1987-01-01

A new method to impose boundary conditions for pseudospectral approximations to hyperbolic equations is suggested. This method involves the collocation of the equation at the boundary nodes as well as satisfying boundary conditions. Stability and convergence results are proven for the Chebyshev approximation of linear scalar hyperbolic equations. The eigenvalues of this method applied to parabolic equations are shown to be real and negative.

Luminescent hyperbolic metasurfaces

NASA Astrophysics Data System (ADS)

Smalley, J. S. T.; Vallini, F.; Montoya, S. A.; Ferrari, L.; Shahin, S.; Riley, C. T.; Kanté, B.; Fullerton, E. E.; Liu, Z.; Fainman, Y.

2017-01-01

When engineered on scales much smaller than the operating wavelength, metal-semiconductor nanostructures exhibit properties unobtainable in nature. Namely, a uniaxial optical metamaterial described by a hyperbolic dispersion relation can simultaneously behave as a reflective metal and an absorptive or emissive semiconductor for electromagnetic waves with orthogonal linear polarization states. Using an unconventional multilayer architecture, we demonstrate luminescent hyperbolic metasurfaces, wherein distributed semiconducting quantum wells display extreme absorption and emission polarization anisotropy. Through normally incident micro-photoluminescence measurements, we observe absorption anisotropies greater than a factor of 10 and degree-of-linear polarization of emission >0.9. We observe the modification of emission spectra and, by incorporating wavelength-scale gratings, show a controlled reduction of polarization anisotropy. We verify hyperbolic dispersion with numerical simulations that model the metasurface as a composite nanoscale structure and according to the effective medium approximation. Finally, we experimentally demonstrate >350% emission intensity enhancement relative to the bare semiconducting quantum wells.

A Theoretical Framework for Lagrangian Descriptors

NASA Astrophysics Data System (ADS)

Lopesino, C.; Balibrea-Iniesta, F.; García-Garrido, V. J.; Wiggins, S.; Mancho, A. M.

This paper provides a theoretical background for Lagrangian Descriptors (LDs). The goal of achieving rigorous proofs that justify the ability of LDs to detect invariant manifolds is simplified by introducing an alternative definition for LDs. The definition is stated for n-dimensional systems with general time dependence, however we rigorously prove that this method reveals the stable and unstable manifolds of hyperbolic points in four particular 2D cases: a hyperbolic saddle point for linear autonomous systems, a hyperbolic saddle point for nonlinear autonomous systems, a hyperbolic saddle point for linear nonautonomous systems and a hyperbolic saddle point for nonlinear nonautonomous systems. We also discuss further rigorous results which show the ability of LDs to highlight additional invariants sets, such as n-tori. These results are just a simple extension of the ergodic partition theory which we illustrate by applying this methodology to well-known examples, such as the planar field of the harmonic oscillator and the 3D ABC flow. Finally, we provide a thorough discussion on the requirement of the objectivity (frame-invariance) property for tools designed to reveal phase space structures and their implications for Lagrangian descriptors.

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

PubMed

Talaei, Behzad; Jagannathan, Sarangapani; Singler, John

2018-04-01

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

Hyperbolic-symmetry vector fields.

PubMed

Gao, Xu-Zhen; Pan, Yue; Cai, Meng-Qiang; Li, Yongnan; Tu, Chenghou; Wang, Hui-Tian

2015-12-14

We present and construct a new kind of orthogonal coordinate system, hyperbolic coordinate system. We present and design a new kind of local linearly polarized vector fields, which is defined as the hyperbolic-symmetry vector fields because the points with the same polarization form a series of hyperbolae. We experimentally demonstrate the generation of such a kind of hyperbolic-symmetry vector optical fields. In particular, we also study the modified hyperbolic-symmetry vector optical fields with the twofold and fourfold symmetric states of polarization when introducing the mirror symmetry. The tight focusing behaviors of these vector fields are also investigated. In addition, we also fabricate micro-structures on the K9 glass surfaces by several tightly focused (modified) hyperbolic-symmetry vector fields patterns, which demonstrate that the simulated tightly focused fields are in good agreement with the fabricated micro-structures.

Computational Methods for Design, Estimation and Real-Time Control of PDE Systems with Applications to Mobile Sensor Networks

DTIC Science & Technology

2013-08-14

TIME CONTROL OF PDE SYSTEMS WITH APPLICATIONS TO MOBILE SENSOR NETWORKS Finall Report: AFOSR Grant...linear time invariant (LTI) control problem. If the control is a linear function of the states, then the closed loop system then takes the form[ żr u̇...Ar2 A r 3 0T 0 ] − [ Br 1 ] K ) ︸ ︷︷ ︸ Ac [ zr u ] . (3) As the purpose of the control law is to stabilize the system , it is desired to have

First-Order Hyperbolic System Method for Time-Dependent Advection-Diffusion Problems

DTIC Science & Technology

2014-03-01

accuracy, with rapid convergence over each physical time step, typically less than five Newton iter - ations. 1 Contents 1 Introduction 3 2 Hyperbolic...however, we employ the Gauss - Seidel (GS) relaxation, which is also an O(N) method for the discretization arising from hyperbolic advection-diffusion system...advection-diffusion scheme. The linear dependency of the iterations on Table 1: Boundary layer problem ( Convergence criteria: Residuals < 10−8.) log10Re

Lyapunov-based control of limit cycle oscillations in uncertain aircraft systems

NASA Astrophysics Data System (ADS)

Bialy, Brendan

Store-induced limit cycle oscillations (LCO) affect several fighter aircraft and is expected to remain an issue for next generation fighters. LCO arises from the interaction of aerodynamic and structural forces, however the primary contributor to the phenomenon is still unclear. The practical concerns regarding this phenomenon include whether or not ordnance can be safely released and the ability of the aircrew to perform mission-related tasks while in an LCO condition. The focus of this dissertation is the development of control strategies to suppress LCO in aircraft systems. The first contribution of this work (Chapter 2) is the development of a controller consisting of a continuous Robust Integral of the Sign of the Error (RISE) feedback term with a neural network (NN) feedforward term to suppress LCO behavior in an uncertain airfoil system. The second contribution of this work (Chapter 3) is the extension of the development in Chapter 2 to include actuator saturation. Suppression of LCO behavior is achieved through the implementation of an auxiliary error system that features hyperbolic functions and a saturated RISE feedback control structure. Due to the lack of clarity regarding the driving mechanism behind LCO, common practice in literature and in Chapters 2 and 3 is to replicate the symptoms of LCO by including nonlinearities in the wing structure, typically a nonlinear torsional stiffness. To improve the accuracy of the system model a partial differential equation (PDE) model of a flexible wing is derived (see Appendix F) using Hamilton's principle. Chapters 4 and 5 are focused on developing boundary control strategies for regulating the bending and twisting deformations of the derived model. The contribution of Chapter 4 is the construction of a backstepping-based boundary control strategy for a linear PDE model of an aircraft wing. The backstepping-based strategy transforms the original system to a exponentially stable system. A Lyapunov-based stability analysis is then used to show boundedness of the wing bending dynamics. A Lyapunov-based boundary control strategy for an uncertain nonlinear PDE model of an aircraft wing is developed in Chapter 5. In this chapter, a proportional feedback term is coupled with an gradient-based adaptive update law to ensure asymptotic regulation of the flexible states.

Cotton-type and joint invariants for linear elliptic systems.

PubMed

Aslam, A; Mahomed, F M

2013-01-01

Cotton-type invariants for a subclass of a system of two linear elliptic equations, obtainable from a complex base linear elliptic equation, are derived both by spliting of the corresponding complex Cotton invariants of the base complex equation and from the Laplace-type invariants of the system of linear hyperbolic equations equivalent to the system of linear elliptic equations via linear complex transformations of the independent variables. It is shown that Cotton-type invariants derived from these two approaches are identical. Furthermore, Cotton-type and joint invariants for a general system of two linear elliptic equations are also obtained from the Laplace-type and joint invariants for a system of two linear hyperbolic equations equivalent to the system of linear elliptic equations by complex changes of the independent variables. Examples are presented to illustrate the results.

Cotton-Type and Joint Invariants for Linear Elliptic Systems

PubMed Central

Aslam, A.; Mahomed, F. M.

2013-01-01

Cotton-type invariants for a subclass of a system of two linear elliptic equations, obtainable from a complex base linear elliptic equation, are derived both by spliting of the corresponding complex Cotton invariants of the base complex equation and from the Laplace-type invariants of the system of linear hyperbolic equations equivalent to the system of linear elliptic equations via linear complex transformations of the independent variables. It is shown that Cotton-type invariants derived from these two approaches are identical. Furthermore, Cotton-type and joint invariants for a general system of two linear elliptic equations are also obtained from the Laplace-type and joint invariants for a system of two linear hyperbolic equations equivalent to the system of linear elliptic equations by complex changes of the independent variables. Examples are presented to illustrate the results. PMID:24453871

Ergodicity-breaking bifurcations and tunneling in hyperbolic transport models

NASA Astrophysics Data System (ADS)

Giona, M.; Brasiello, A.; Crescitelli, S.

2015-11-01

One of the main differences between parabolic transport, associated with Langevin equations driven by Wiener processes, and hyperbolic models related to generalized Kac equations driven by Poisson processes, is the occurrence in the latter of multiple stable invariant densities (Frobenius multiplicity) in certain regions of the parameter space. This phenomenon is associated with the occurrence in linear hyperbolic balance equations of a typical bifurcation, referred to as the ergodicity-breaking bifurcation, the properties of which are thoroughly analyzed.

Fluid displacement between two parallel plates: a non-empirical model displaying change of type from hyperbolic to elliptic equations

NASA Astrophysics Data System (ADS)

Shariati, M.; Talon, L.; Martin, J.; Rakotomalala, N.; Salin, D.; Yortsos, Y. C.

2004-11-01

We consider miscible displacement between parallel plates in the absence of diffusion, with a concentration-dependent viscosity. By selecting a piecewise viscosity function, this can also be considered as ‘three-fluid’ flow in the same geometry. Assuming symmetry across the gap and based on the lubrication (‘equilibrium’) approximation, a description in terms of two quasi-linear hyperbolic equations is obtained. We find that the system is hyperbolic and can be solved analytically, when the mobility profile is monotonic, or when the mobility of the middle phase is smaller than its neighbours. When the mobility of the middle phase is larger, a change of type is displayed, an elliptic region developing in the composition space. Numerical solutions of Riemann problems of the hyperbolic system spanning the elliptic region, with small diffusion added, show good agreement with the analytical outside, but an unstable behaviour inside the elliptic region. In these problems, the elliptic region arises precisely at the displacement front. Crossing the elliptic region requires the solution of essentially an eigenvalue problem of the full higher-dimensional model, obtained here using lattice BGK simulations. The hyperbolic-to-elliptic change-of-type reflects the failing of the lubrication approximation, underlying the quasi-linear hyperbolic formalism, to describe the problem uniformly. The obtained solution is analogous to non-classical shocks recently suggested in problems with change of type.

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

NASA Astrophysics Data System (ADS)

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

2015-12-01

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

A New Discretization Method of Order Four for the Numerical Solution of One-Space Dimensional Second-Order Quasi-Linear Hyperbolic Equation

ERIC Educational Resources Information Center

Mohanty, R. K.; Arora, Urvashi

2002-01-01

Three level-implicit finite difference methods of order four are discussed for the numerical solution of the mildly quasi-linear second-order hyperbolic equation A(x, t, u)u[subscript xx] + 2B(x, t, u)u[subscript xt] + C(x, t, u)u[subscript tt] = f(x, t, u, u[subscript x], u[subscript t]), 0 less than x less than 1, t greater than 0 subject to…

Effects of the approximations of light propagation on quantitative photoacoustic tomography using two-dimensional photon diffusion equation and linearization

NASA Astrophysics Data System (ADS)

Okawa, Shinpei; Hirasawa, Takeshi; Kushibiki, Toshihiro; Ishihara, Miya

2017-12-01

Quantitative photoacoustic tomography (QPAT) employing a light propagation model will play an important role in medical diagnoses by quantifying the concentration of hemoglobin or a contrast agent. However, QPAT by the light propagation model with the three-dimensional (3D) radiative transfer equation (RTE) requires a huge computational load in the iterative forward calculations involved in the updating process to reconstruct the absorption coefficient. The approximations of the light propagation improve the efficiency of the image reconstruction for the QPAT. In this study, we compared the 3D/two-dimensional (2D) photon diffusion equation (PDE) approximating 3D RTE with the Monte Carlo simulation based on 3D RTE. Then, the errors in a 2D PDE-based linearized image reconstruction caused by the approximations were quantitatively demonstrated and discussed in the numerical simulations. It was clearly observed that the approximations affected the reconstructed absorption coefficient. The 2D PDE-based linearized algorithm succeeded in the image reconstruction of the region with a large absorption coefficient in the 3D phantom. The value reconstructed in the phantom experiment agreed with that in the numerical simulation, so that it was validated that the numerical simulation of the image reconstruction predicted the relationship between the true absorption coefficient of the target in the 3D medium and the reconstructed value with the 2D PDE-based linearized algorithm. Moreover, the the true absorption coefficient in 3D medium was estimated from the 2D reconstructed image on the basis of the prediction by the numerical simulation. The estimation was successful in the phantom experiment, although some limitations were revealed.

Guidance of Nonlinear Nonminimum-Phase Dynamic Systems

NASA Technical Reports Server (NTRS)

Devasia, Santosh

1996-01-01

The research work has advanced the inversion-based guidance theory for: systems with non-hyperbolic internal dynamics; systems with parameter jumps; and systems where a redesign of the output trajectory is desired. A technique to achieve output tracking for nonminimum phase linear systems with non-hyperbolic and near non-hyperbolic internal dynamics was developed. This approach integrated stable inversion techniques, that achieve exact-tracking, with approximation techniques, that modify the internal dynamics to achieve desirable performance. Such modification of the internal dynamics was used (a) to remove non-hyperbolicity which is an obstruction to applying stable inversion techniques and (b) to reduce large preactuation times needed to apply stable inversion for near non-hyperbolic cases. The method was applied to an example helicopter hover control problem with near non-hyperbolic internal dynamics for illustrating the trade-off between exact tracking and reduction of preactuation time. Future work will extend these results to guidance of nonlinear non-hyperbolic systems. The exact output tracking problem for systems with parameter jumps was considered. Necessary and sufficient conditions were derived for the elimination of switching-introduced output transient. While previous works had studied this problem by developing a regulator that maintains exact tracking through parameter jumps (switches), such techniques are, however, only applicable to minimum-phase systems. In contrast, our approach is also applicable to nonminimum-phase systems and leads to bounded but possibly non-causal solutions. In addition, for the case when the reference trajectories are generated by an exosystem, we developed an exact-tracking controller which could be written in a feedback form. As in standard regulator theory, we also obtained a linear map from the states of the exosystem to the desired system state, which was defined via a matrix differential equation.

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

NASA Technical Reports Server (NTRS)

Cai, Wei; Wang, Jian-Zhong

1993-01-01

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

Construction of energy-stable projection-based reduced order models

DOE PAGES

Kalashnikova, Irina; Barone, Matthew F.; Arunajatesan, Srinivasan; ...

2014-12-15

Our paper aims to unify and extend several approaches for building stable projection-based reduced order models (ROMs) using the energy method and the concept of “energy-stability”. Attention is focused on linear time-invariant (LTI) systems. First, an approach for building energy stable Galerkin ROMs for linear hyperbolic or incompletely parabolic systems of partial differential equations (PDEs) using continuous projection is proposed. The key idea is to apply to the system a transformation induced by the Lyapunov function for the system, and to build the ROM in the transformed variables. The result of this procedure will be a ROM that is energy-stablemore » for any choice of reduced basis. It is shown that, for many PDE systems, the desired transformation is induced by a special inner product, termed the “symmetry inner product”. Next, attention is turned to building energy-stable ROMs via discrete projection. A discrete counterpart of the continuous symmetry inner product, termed the “Lyapunov inner product”, is derived. Moreover, it is shown that the Lyapunov inner product can be computed in a black-box fashion for a stable LTI system ari sing from the discretization of a system of PDEs in space. Projection in this inner product guarantees a ROM that is energy-stable, again for any choice of reduced basis. Connections between the Lyapunov inner product and the inner product induced by the balanced truncation algorithm are made. We also made comparisons between the symmetry inner product and the Lyapunov inner product. Performance of ROMs constructed using these inner products is evaluated on several benchmark test cases.« less

3D quantitative photoacoustic image reconstruction using Monte Carlo method and linearization

NASA Astrophysics Data System (ADS)

Okawa, Shinpei; Hirasawa, Takeshi; Tsujita, Kazuhiro; Kushibiki, Toshihiro; Ishihara, Miya

2018-02-01

To quantify the functional and structural information of peripheral blood vessels for diagnoses of diseases which affects peripheral blood vessels such as diabetes and peripheral vascular disease, a 3D quantitative photoacoustic tomography (QPAT) reconstructing the optical properties such as the absorption coefficient reflecting microvascular structures and hemoglobin concentration and oxygenation saturation is studied. QPAT image reconstruction algorithms based on radiative transfer equation (RTE) and photon diffusion equation (PDE) have been proposed. However, it is not easy to use RTE in the clinical practice because of the huge computational load and long calculation time. On the other hand, it is always considered problematic to use PDE, because it does not approximate RTE well near the illuminating position. In this study, we developed the 3D QPAT image reconstruction using Monte Carlo (MC) method which approximates RTE better than PDE to reconstruct the optical properties in the region near the illuminating surface. To reduce the calculation time, we applied linearization. The QPAT image reconstruction algorithm with MC method and linearization was examined in numerical simulations and phantom experiment by use of a scanning system with a single probe consisting of P(VDF-TrFE) piezo electric film and optical fiber.

MUSTA fluxes for systems of conservation laws

NASA Astrophysics Data System (ADS)

Toro, E. F.; Titarev, V. A.

2006-08-01

This paper is about numerical fluxes for hyperbolic systems and we first present a numerical flux, called GFORCE, that is a weighted average of the Lax-Friedrichs and Lax-Wendroff fluxes. For the linear advection equation with constant coefficient, the new flux reduces identically to that of the Godunov first-order upwind method. Then we incorporate GFORCE in the framework of the MUSTA approach [E.F. Toro, Multi-Stage Predictor-Corrector Fluxes for Hyperbolic Equations. Technical Report NI03037-NPA, Isaac Newton Institute for Mathematical Sciences, University of Cambridge, UK, 17th June, 2003], resulting in a version that we call GMUSTA. For non-linear systems this gives results that are comparable to those of the Godunov method in conjunction with the exact Riemann solver or complete approximate Riemann solvers, noting however that in our approach, the solution of the Riemann problem in the conventional sense is avoided. Both the GFORCE and GMUSTA fluxes are extended to multi-dimensional non-linear systems in a straightforward unsplit manner, resulting in linearly stable schemes that have the same stability regions as the straightforward multi-dimensional extension of Godunov's method. The methods are applicable to general meshes. The schemes of this paper share with the family of centred methods the common properties of being simple and applicable to a large class of hyperbolic systems, but the schemes of this paper are distinctly more accurate. Finally, we proceed to the practical implementation of our numerical fluxes in the framework of high-order finite volume WENO methods for multi-dimensional non-linear hyperbolic systems. Numerical results are presented for the Euler equations and for the equations of magnetohydrodynamics.

Planckian Information (Ip): A New Measure of Order in Atoms, Enzymes, Cells, Brains, Human Societies, and the Cosmos

NASA Astrophysics Data System (ADS)

Ji, Sungchul

A new mathematical formula referred to as the Planckian distribution equation (PDE) has been found to fit long-tailed histograms generated in various fields of studies, ranging from atomic physics to single-molecule enzymology, cell biology, brain neurobiology, glottometrics, econophysics, and to cosmology. PDE can be derived from a Gaussian-like equation (GLE) by non-linearly transforming its variable, x, while keeping the y coordinate constant. Assuming that GLE represents a random distribution (due to its symmetry), it is possible to define a binary logarithm of the ratio between the areas under the curves of PDE and GLE as a measure of the non-randomness (or order) underlying the biophysicochemical processes generating long-tailed histograms that fit PDE. This new function has been named the Planckian information, IP, which (i) may be a new measure of order that can be applied widely to both natural and human sciences and (ii) can serve as the opposite of the Boltzmann-Gibbs entropy, S, which is a measure of disorder. The possible rationales for the universality of PDE may include (i) the universality of the wave-particle duality embedded in PDE, (ii) the selection of subsets of random processes (thereby breaking the symmetry of GLE) as the basic mechanism of generating order, organization, and function, and (iii) the quantity-quality complementarity as the connection between PDE and Peircean semiotics.

Incorporating inductances in tissue-scale models of cardiac electrophysiology

NASA Astrophysics Data System (ADS)

Rossi, Simone; Griffith, Boyce E.

2017-09-01

In standard models of cardiac electrophysiology, including the bidomain and monodomain models, local perturbations can propagate at infinite speed. We address this unrealistic property by developing a hyperbolic bidomain model that is based on a generalization of Ohm's law with a Cattaneo-type model for the fluxes. Further, we obtain a hyperbolic monodomain model in the case that the intracellular and extracellular conductivity tensors have the same anisotropy ratio. In one spatial dimension, the hyperbolic monodomain model is equivalent to a cable model that includes axial inductances, and the relaxation times of the Cattaneo fluxes are strictly related to these inductances. A purely linear analysis shows that the inductances are negligible, but models of cardiac electrophysiology are highly nonlinear, and linear predictions may not capture the fully nonlinear dynamics. In fact, contrary to the linear analysis, we show that for simple nonlinear ionic models, an increase in conduction velocity is obtained for small and moderate values of the relaxation time. A similar behavior is also demonstrated with biophysically detailed ionic models. Using the Fenton-Karma model along with a low-order finite element spatial discretization, we numerically analyze differences between the standard monodomain model and the hyperbolic monodomain model. In a simple benchmark test, we show that the propagation of the action potential is strongly influenced by the alignment of the fibers with respect to the mesh in both the parabolic and hyperbolic models when using relatively coarse spatial discretizations. Accurate predictions of the conduction velocity require computational mesh spacings on the order of a single cardiac cell. We also compare the two formulations in the case of spiral break up and atrial fibrillation in an anatomically detailed model of the left atrium, and we examine the effect of intracellular and extracellular inductances on the virtual electrode phenomenon.

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.

Triangle based TVD schemes for hyperbolic conservation laws

NASA Technical Reports Server (NTRS)

Durlofsky, Louis J.; Osher, Stanley; Engquist, Bjorn

1990-01-01

A triangle based total variation diminishing (TVD) scheme for the numerical approximation of hyperbolic conservation laws in two space dimensions is constructed. The novelty of the scheme lies in the nature of the preprocessing of the cell averaged data, which is accomplished via a nearest neighbor linear interpolation followed by a slope limiting procedures. Two such limiting procedures are suggested. The resulting method is considerably more simple than other triangle based non-oscillatory approximations which, like this scheme, approximate the flux up to second order accuracy. Numerical results for linear advection and Burgers' equation are presented.

Well-posedness of characteristic symmetric hyperbolic systems

NASA Astrophysics Data System (ADS)

Secchi, Paolo

1996-06-01

We consider the initial-boundary-value problem for quasi-linear symmetric hyperbolic systems with characteristic boundary of constant multiplicity. We show the well-posedness in Hadamard's sense (i.e., existence, uniqueness and continuous dependence of solutions on the data) of regular solutions in suitable functions spaces which take into account the loss of regularity in the normal direction to the characteristic boundary.

Hyperbolic conservation laws and numerical methods

NASA Technical Reports Server (NTRS)

Leveque, Randall J.

1990-01-01

The mathematical structure of hyperbolic systems and the scalar equation case of conservation laws are discussed. Linear, nonlinear systems and the Riemann problem for the Euler equations are also studied. The numerical methods for conservation laws are presented in a nonstandard manner which leads to large time steps generalizations and computations on irregular grids. The solution of conservation laws with stiff source terms is examined.

On solvability of boundary value problems for hyperbolic fourth-order equations with nonlocal boundary conditions of integral type

NASA Astrophysics Data System (ADS)

Popov, Nikolay S.

2017-11-01

Solvability of some initial-boundary value problems for linear hyperbolic equations of the fourth order is studied. A condition on the lateral boundary in these problems relates the values of a solution or the conormal derivative of a solution to the values of some integral operator applied to a solution. Nonlocal boundary-value problems for one-dimensional hyperbolic second-order equations with integral conditions on the lateral boundary were considered in the articles by A.I. Kozhanov. Higher-dimensional hyperbolic equations of higher order with integral conditions on the lateral boundary were not studied earlier. The existence and uniqueness theorems of regular solutions are proven. The method of regularization and the method of continuation in a parameter are employed to establish solvability.

Stability Analysis of Finite Difference Schemes for Hyperbolic Systems, and Problems in Applied and Computational Linear Algebra.

DTIC Science & Technology

FINITE DIFFERENCE THEORY, * LINEAR ALGEBRA , APPLIED MATHEMATICS, APPROXIMATION(MATHEMATICS), BOUNDARY VALUE PROBLEMS, COMPUTATIONS, HYPERBOLAS, MATHEMATICAL MODELS, NUMERICAL ANALYSIS, PARTIAL DIFFERENTIAL EQUATIONS, STABILITY.

High-Order Accurate Solutions to the Helmholtz Equation in the Presence of Boundary Singularities

DTIC Science & Technology

2015-03-31

FD scheme is only consistent for classical solutions of the PDE . For this reason, we implement the method of singularity subtraction as a means for...regularity due to the boundary conditions. This is because the FD scheme is only consistent for classical solutions of the PDE . For this reason, we...Introduction In the present work, we develop a high-order numerical method for solving linear elliptic PDEs with well-behaved variable coefficients on

Computer-Aided Transformation of PDE Models: Languages, Representations, and a Calculus of Operations

DTIC Science & Technology

2016-01-05

discretizations . We maintain that what is clear at the mathematical level should be equally clear in computation. In this small STIR project, we separate the...concerns of describing and discretizing such models by defining an input language representing PDE, including steady-state and tran- sient, linear and...solvers, such as [8, 9], focused on the solvers themselves and particular families of discretizations (e. g. finite elements), and now it is natural to

Hyperbolic phonon polaritons in hexagonal boron nitride (Conference Presentation)

NASA Astrophysics Data System (ADS)

Dai, Siyuan; Ma, Qiong; Fei, Zhe; Liu, Mengkun; Goldflam, Michael D.; Andersen, Trond; Garnett, William; Regan, Will; Wagner, Martin; McLeod, Alexander S.; Rodin, Alexandr; Zhu, Shou-En; Watanabe, Kenji; Taniguchi, T.; Dominguez, Gerado; Thiemens, Mark; Castro Neto, Antonio H.; Janssen, Guido C. A. M.; Zettl, Alex; Keilmann, Fritz; Jarillo-Herrero, Pablo; Fogler, Michael M.; Basov, Dmitri N.

2016-09-01

Uniaxial materials whose axial and tangential permittivities have opposite signs are referred to as indefinite or hyperbolic media. While hyperbolic responses are normally achieved with metamaterials, hexagonal boron nitride (hBN) naturally possesses this property due to the anisotropic phonons in the mid-infrared. Using scattering-type scanning near-field optical microscopy, we studied polaritonic phenomena in hBN. We performed infrared nano-imaging of highly confined and low-loss hyperbolic phonon polaritons in hBN. The polariton wavelength was shown to be governed by the hBN thickness according to a linear law persisting down to few atomic layers [1]. Additionally, we carried out the modification of hyperbolic response in meta-structures comprised of a mononlayer graphene deposited on hBN [2]. Electrostatic gating of the top graphene layer allows for the modification of wavelength and intensity of hyperbolic phonon polaritons in bulk hBN. The physics of the modification originates from the plasmon-phonon coupling in the hyperbolic medium. Furthermore, we demonstrated the "hyperlens" for subdiffractional focusing and imaging using a slab of hBN [3]. References [1] S. Dai et al., Science, 343, 1125 (2014). [2] S. Dai et al., Nature Nanotechnology, 10, 682 (2015). [3] S. Dai et al., Nature Communications, 6, 6963 (2015).

A simple finite element method for linear hyperbolic problems

DOE PAGES

Mu, Lin; Ye, Xiu

2017-09-14

Here, we introduce a simple finite element method for solving first order hyperbolic equations with easy implementation and analysis. Our new method, with a symmetric, positive definite system, is designed to use discontinuous approximations on finite element partitions consisting of arbitrary shape of polygons/polyhedra. Error estimate is established. Extensive numerical examples are tested that demonstrate the robustness and flexibility of the method.

A simple finite element method for linear hyperbolic problems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mu, Lin; Ye, Xiu

Here, we introduce a simple finite element method for solving first order hyperbolic equations with easy implementation and analysis. Our new method, with a symmetric, positive definite system, is designed to use discontinuous approximations on finite element partitions consisting of arbitrary shape of polygons/polyhedra. Error estimate is established. Extensive numerical examples are tested that demonstrate the robustness and flexibility of the method.

Effect of Operating Frequency on PDE Driven Ejector Thrust Performance

NASA Technical Reports Server (NTRS)

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

2005-01-01

Results of an on-going study of pulse detonation engine driven ejectors are presented and discussed. The experiments were conducted using a pulse detonation engine (PDE) designed to operate at frequencies up to 50 Hz. The PDE used in these experiments utilizes an equi-molar mixture of oxygen and nitrogen as the oxidizer, and ethylene (C2H4) as the fuel, with the propellant mixture having an equivalence ratio of one. A line of sight laser absorption technique was used to determine the time needed for proper filling of the tube. Thrust measurements were made using an integrated spring damper system coupled with a linear variable displacement transducer. The baseline thrust of the PDE was first measured at each desired frequency and agrees with experimental and modeling results found in the literature. Thrust augmentation measurements were then made for constant diameter ejectors. The ejectors had varying lengths, and two different inlet geometries were tested for each ejector configuration. The parameter space for the study included PDE operation frequency, ejector length, overlap distance and the radius of curvature for the ejector inlets. For the studied experimental matrix, the results showed a maximum thrust augmentation of 106% at an operational frequency of 30 Hz.

First-Order Hyperbolic System Method for Time-Dependent Advection-Diffusion Problems

NASA Technical Reports Server (NTRS)

Mazaheri, Alireza; Nishikawa, Hiroaki

2014-01-01

A time-dependent extension of the first-order hyperbolic system method for advection-diffusion problems is introduced. Diffusive/viscous terms are written and discretized as a hyperbolic system, which recovers the original equation in the steady state. The resulting scheme offers advantages over traditional schemes: a dramatic simplification in the discretization, high-order accuracy in the solution gradients, and orders-of-magnitude convergence acceleration. The hyperbolic advection-diffusion system is discretized by the second-order upwind residual-distribution scheme in a unified manner, and the system of implicit-residual-equations is solved by Newton's method over every physical time step. The numerical results are presented for linear and nonlinear advection-diffusion problems, demonstrating solutions and gradients produced to the same order of accuracy, with rapid convergence over each physical time step, typically less than five Newton iterations.

Mixed Integer PDE Constrained Optimization for the Control of a Wildfire Hazard

DTIC Science & Technology

2017-01-01

are nodes suitable for extinguishing the fire. We introduce a discretization of the time horizon [0, T] by the set of time T := {0, At,..., ntZ\\t = T...of the constraints and objective with a discrete counterpart. The PDE is replaced by a linear system obtained from a convergent finite difference...method [5] and the integral is replaced by a quadrature formula. The domain is discretized by replacing 17 with an equidistant grid of length Ax

Weighted graph based ordering techniques for preconditioned conjugate gradient methods

NASA Technical Reports Server (NTRS)

Clift, Simon S.; Tang, Wei-Pai

1994-01-01

We describe the basis of a matrix ordering heuristic for improving the incomplete factorization used in preconditioned conjugate gradient techniques applied to anisotropic PDE's. Several new matrix ordering techniques, derived from well-known algorithms in combinatorial graph theory, which attempt to implement this heuristic, are described. These ordering techniques are tested against a number of matrices arising from linear anisotropic PDE's, and compared with other matrix ordering techniques. A variation of RCM is shown to generally improve the quality of incomplete factorization preconditioners.

Evolution of finite-amplitude localized vortices in planar homogeneous shear flows

NASA Astrophysics Data System (ADS)

Karp, Michael; Shukhman, Ilia G.; Cohen, Jacob

2017-02-01

An analytical-based method is utilized to follow the evolution of localized initially Gaussian disturbances in flows with homogeneous shear, in which the base velocity components are at most linear functions of the coordinates, including hyperbolic, elliptic, and simple shear. Coherent structures, including counterrotating vortex pairs (CVPs) and hairpin vortices, are formed for the cases where the streamlines of the base flow are open (hyperbolic and simple shear). For hyperbolic base flows, the dominance of shear over rotation leads to elongation of the localized disturbance along the outlet asymptote and formation of CVPs. For simple shear CVPs are formed from linear and nonlinear disturbances, whereas hairpins are observed only for highly nonlinear disturbances. For elliptic base flows CVPs, hairpins and vortex loops form initially, however they do not last and break into various vortical structures that spread in the spanwise direction. The effect of the disturbance's initial amplitude and orientation is examined and the optimal orientation achieving maximal growth is identified.

Chaotic Oscillations of Second Order Linear Hyperbolic Equations with Nonlinear Boundary Conditions: A Factorizable but Noncommutative Case

NASA Astrophysics Data System (ADS)

Li, Liangliang; Huang, Yu; Chen, Goong; Huang, Tingwen

If a second order linear hyperbolic partial differential equation in one-space dimension can be factorized as a product of two first order operators and if the two first order operators commute, with one boundary condition being the van der Pol type and the other being linear, one can establish the occurrence of chaos when the parameters enter a certain regime [Chen et al., 2014]. However, if the commutativity of the two first order operators fails to hold, then the treatment in [Chen et al., 2014] no longer works and significant new challenges arise in determining nonlinear boundary conditions that engenders chaos. In this paper, we show that by incorporating a linear memory effect, a nonlinear van der Pol boundary condition can cause chaotic oscillations when the parameter enters a certain regime. Numerical simulations illustrating chaotic oscillations are also presented.

High-Order Hyperbolic Residual-Distribution Schemes on Arbitrary Triangular Grids

NASA Technical Reports Server (NTRS)

Mazaheri, Alireza; Nishikawa, Hiroaki

2015-01-01

In this paper, we construct high-order hyperbolic residual-distribution schemes for general advection-diffusion problems on arbitrary triangular grids. We demonstrate that the second-order accuracy of the hyperbolic schemes can be greatly improved by requiring the scheme to preserve exact quadratic solutions. We also show that the improved second-order scheme can be easily extended to third-order by further requiring the exactness for cubic solutions. We construct these schemes based on the LDA and the SUPG methodology formulated in the framework of the residual-distribution method. For both second- and third-order-schemes, we construct a fully implicit solver by the exact residual Jacobian of the second-order scheme, and demonstrate rapid convergence of 10-15 iterations to reduce the residuals by 10 orders of magnitude. We demonstrate also that these schemes can be constructed based on a separate treatment of the advective and diffusive terms, which paves the way for the construction of hyperbolic residual-distribution schemes for the compressible Navier-Stokes equations. Numerical results show that these schemes produce exceptionally accurate and smooth solution gradients on highly skewed and anisotropic triangular grids, including curved boundary problems, using linear elements. We also present Fourier analysis performed on the constructed linear system and show that an under-relaxation parameter is needed for stabilization of Gauss-Seidel relaxation.

A simple robust and accurate a posteriori sub-cell finite volume limiter for the discontinuous Galerkin method on unstructured meshes

NASA Astrophysics Data System (ADS)

Dumbser, Michael; Loubère, Raphaël

2016-08-01

In this paper we propose a simple, robust and accurate nonlinear a posteriori stabilization of the Discontinuous Galerkin (DG) finite element method for the solution of nonlinear hyperbolic PDE systems on unstructured triangular and tetrahedral meshes in two and three space dimensions. This novel a posteriori limiter, which has been recently proposed for the simple Cartesian grid case in [62], is able to resolve discontinuities at a sub-grid scale and is substantially extended here to general unstructured simplex meshes in 2D and 3D. It can be summarized as follows: At the beginning of each time step, an approximation of the local minimum and maximum of the discrete solution is computed for each cell, taking into account also the vertex neighbors of an element. Then, an unlimited discontinuous Galerkin scheme of approximation degree N is run for one time step to produce a so-called candidate solution. Subsequently, an a posteriori detection step checks the unlimited candidate solution at time t n + 1 for positivity, absence of floating point errors and whether the discrete solution has remained within or at least very close to the bounds given by the local minimum and maximum computed in the first step. Elements that do not satisfy all the previously mentioned detection criteria are flagged as troubled cells. For these troubled cells, the candidate solution is discarded as inappropriate and consequently needs to be recomputed. Within these troubled cells the old discrete solution at the previous time tn is scattered onto small sub-cells (Ns = 2 N + 1 sub-cells per element edge), in order to obtain a set of sub-cell averages at time tn. Then, a more robust second order TVD finite volume scheme is applied to update the sub-cell averages within the troubled DG cells from time tn to time t n + 1. The new sub-grid data at time t n + 1 are finally gathered back into a valid cell-centered DG polynomial of degree N by using a classical conservative and higher order accurate finite volume reconstruction technique. Consequently, if the number Ns is sufficiently large (Ns ≥ N + 1), the subscale resolution capability of the DG scheme is fully maintained, while preserving at the same time an essentially non-oscillatory behavior of the solution at discontinuities. Many standard DG limiters only adjust the discrete solution in troubled cells, based on the limiting of higher order moments or by applying a nonlinear WENO/HWENO reconstruction on the data at the new time t n + 1. Instead, our new DG limiter entirely recomputes the troubled cells by solving the governing PDE system again starting from valid data at the old time level tn, but using this time a more robust scheme on the sub-grid level. In other words, the piecewise polynomials produced by the new limiter are the result of a more robust solution of the PDE system itself, while most standard DG limiters are simply based on a mere nonlinear data post-processing of the discrete solution. Technically speaking, the new method corresponds to an element-wise checkpointing and restarting of the solver, using a lower order scheme on the sub-grid. As a result, the present DG limiter is even able to cure floating point errors like NaN values that have occurred after divisions by zero or after the computation of roots from negative numbers. This is a unique feature of our new algorithm among existing DG limiters. The new a posteriori sub-cell stabilization approach is developed within a high order accurate one-step ADER-DG framework on multidimensional unstructured meshes for hyperbolic systems of conservation laws as well as for hyperbolic PDE with non-conservative products. The method is applied to the Euler equations of compressible gas dynamics, to the ideal magneto-hydrodynamics equations (MHD) as well as to the seven-equation Baer-Nunziato model of compressible multi-phase flows. A large set of standard test problems is solved in order to assess the accuracy and robustness of the new limiter.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dumbser, Michael, E-mail: michael.dumbser@unitn.it; Balsara, Dinshaw S., E-mail: dbalsara@nd.edu

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

Discounting of reward sequences: a test of competing formal models of hyperbolic discounting

PubMed Central

Zarr, Noah; Alexander, William H.; Brown, Joshua W.

2014-01-01

Humans are known to discount future rewards hyperbolically in time. Nevertheless, a formal recursive model of hyperbolic discounting has been elusive until recently, with the introduction of the hyperbolically discounted temporal difference (HDTD) model. Prior to that, models of learning (especially reinforcement learning) have relied on exponential discounting, which generally provides poorer fits to behavioral data. Recently, it has been shown that hyperbolic discounting can also be approximated by a summed distribution of exponentially discounted values, instantiated in the μAgents model. The HDTD model and the μAgents model differ in one key respect, namely how they treat sequences of rewards. The μAgents model is a particular implementation of a Parallel discounting model, which values sequences based on the summed value of the individual rewards whereas the HDTD model contains a non-linear interaction. To discriminate among these models, we observed how subjects discounted a sequence of three rewards, and then we tested how well each candidate model fit the subject data. The results show that the Parallel model generally provides a better fit to the human data. PMID:24639662

Automatic Control via Thermostats of a Hyperbolic Stefan Problem with Memory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colli, P.; Grasselli, M.; Sprekels, J.

1999-03-15

A hyperbolic Stefan problem based on the linearized Gurtin-Pipkin heat conduction law is considered. The temperature and free boundary are controlled by a thermostat acting on the boundary. This feedback control is based on temperature measurements performed by real thermal sensors located within the domain containing the two-phase system and/or at its boundary. Three different types of thermostats are analyzed: simple switch, relay switch, and a Preisach hysteresis operator. The resulting models lead to integrodifferential hyperbolic Stefan problems with nonlinear and nonlocal boundary conditions. Existence results are proved in all the cases. Uniqueness is also shown, except in the situationmore » corresponding to the ideal switch.« less

Linear and nonlinear stability criteria for compressible MHD flows in a gravitational field

NASA Astrophysics Data System (ADS)

Moawad, S. M.; Moawad

2013-10-01

The equilibrium and stability properties of ideal magnetohydrodynamics (MHD) of compressible flow in a gravitational field with a translational symmetry are investigated. Variational principles for the steady-state equations are formulated. The MHD equilibrium equations are obtained as critical points of a conserved Lyapunov functional. This functional consists of the sum of the total energy, the mass, the circulation along field lines (cross helicity), the momentum, and the magnetic helicity. In the unperturbed case, the equilibrium states satisfy a nonlinear second-order partial differential equation (PDE) associated with hydrodynamic Bernoulli law. The PDE can be an elliptic or a parabolic equation depending on increasing the poloidal flow speed. Linear and nonlinear Lyapunov stability conditions under translational symmetric perturbations are established for the equilibrium states.

Mathematical Methods in Wave Propagation: Part 2--Non-Linear Wave Front Analysis

ERIC Educational Resources Information Center

Jeffrey, Alan

1971-01-01

The paper presents applications and methods of analysis for non-linear hyperbolic partial differential equations. The paper is concluded by an account of wave front analysis as applied to the piston problem of gas dynamics. (JG)

An approach to the development of numerical algorithms for first order linear hyperbolic systems in multiple space dimensions: The constant coefficient case

NASA Technical Reports Server (NTRS)

Goodrich, John W.

1995-01-01

Two methods for developing high order single step explicit algorithms on symmetric stencils with data on only one time level are presented. Examples are given for the convection and linearized Euler equations with up to the eighth order accuracy in both space and time in one space dimension, and up to the sixth in two space dimensions. The method of characteristics is generalized to nondiagonalizable hyperbolic systems by using exact local polynominal solutions of the system, and the resulting exact propagator methods automatically incorporate the correct multidimensional wave propagation dynamics. Multivariate Taylor or Cauchy-Kowaleskaya expansions are also used to develop algorithms. Both of these methods can be applied to obtain algorithms of arbitrarily high order for hyperbolic systems in multiple space dimensions. Cross derivatives are included in the local approximations used to develop the algorithms in this paper in order to obtain high order accuracy, and improved isotropy and stability. Efficiency in meeting global error bounds is an important criterion for evaluating algorithms, and the higher order algorithms are shown to be up to several orders of magnitude more efficient even though they are more complex. Stable high order boundary conditions for the linearized Euler equations are developed in one space dimension, and demonstrated in two space dimensions.

An instability of hyperbolic space under the Yang-Mills flow

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gegenberg, Jack; Day, Andrew C.; Liu, Haitao

2014-04-15

We consider the Yang-Mills flow on hyperbolic 3-space. The gauge connection is constructed from the frame-field and (not necessarily compatible) spin connection components. The fixed points of this flow include zero Yang-Mills curvature configurations, for which the spin connection has zero torsion and the associated Riemannian geometry is one of constant curvature. We analytically solve the linearized flow equations for a large class of perturbations to the fixed point corresponding to hyperbolic 3-space. These can be expressed as a linear superposition of distinct modes, some of which are exponentially growing along the flow. The growing modes imply the divergence ofmore » the (gauge invariant) perturbative torsion for a wide class of initial data, indicating an instability of the background geometry that we confirm with numeric simulations in the partially compactified case. There are stable modes with zero torsion, but all the unstable modes are torsion-full. This leads us to speculate that the instability is induced by the torsion degrees of freedom present in the Yang-Mills flow.« less

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

PubMed

Bardhan, Jaydeep P; Altman, Michael D; Tidor, B; White, Jacob K

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.

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

A one-dimensional nonlinear problem of thermoelasticity in extended thermodynamics

NASA Astrophysics Data System (ADS)

Rawy, E. K.

2018-06-01

We solve a nonlinear, one-dimensional initial boundary-value problem of thermoelasticity in generalized thermodynamics. A Cattaneo-type evolution equation for the heat flux is used, which differs from the one used extensively in the literature. The hyperbolic nature of the associated linear system is clarified through a study of the characteristic curves. Progressive wave solutions with two finite speeds are noted. A numerical treatment is presented for the nonlinear system using a three-step, quasi-linearization, iterative finite-difference scheme for which the linear system of equations is the initial step in the iteration. The obtained results are discussed in detail. They clearly show the hyperbolic nature of the system, and may be of interest in investigating thermoelastic materials, not only at low temperatures, but also during high temperature processes involving rapid changes in temperature as in laser treatment of surfaces.

Asymptotic of the Solutions of Hyperbolic Equations with a Skew-Symmetric Perturbation

NASA Astrophysics Data System (ADS)

Gallagher, Isabelle

1998-12-01

Using methods introduced by S. Schochet inJ. Differential Equations114(1994), 476-512, we compute the first term of an asymptotic expansion of the solutions of hyperbolic equations perturbated by a skew-symmetric linear operator. That result is first applied to two systems describing the motion of geophysic fluids: the rotating Euler equations and the primitive system of the quasigeostrophic equations. Finally in the last part, we study the slightly compressible Euler equations by application of that same result.

A priori error estimates for an hp-version of the discontinuous Galerkin method for hyperbolic conservation laws

NASA Technical Reports Server (NTRS)

Bey, Kim S.; Oden, J. Tinsley

1993-01-01

A priori error estimates are derived for hp-versions of the finite element method for discontinuous Galerkin approximations of a model class of linear, scalar, first-order hyperbolic conservation laws. These estimates are derived in a mesh dependent norm in which the coefficients depend upon both the local mesh size h(sub K) and a number p(sub k) which can be identified with the spectral order of the local approximations over each element.

Conformational statistics of stiff macromolecules as solutions to partial differential equations on the rotation and motion groups

PubMed

Chirikjian; Wang

2000-07-01

Partial differential equations (PDE's) for the probability density function (PDF) of the position and orientation of the distal end of a stiff macromolecule relative to its proximal end are derived and solved. The Kratky-Porod wormlike chain, the Yamakawa helical wormlike chain, and the original and revised Marko-Siggia models are examples of stiffness models to which the present formulation is applied. The solution technique uses harmonic analysis on the rotation and motion groups to convert PDE's governing the PDF's of interest into linear algebraic equations which have mathematically elegant solutions.

Quadratic constrained mixed discrete optimization with an adiabatic quantum optimizer

NASA Astrophysics Data System (ADS)

Chandra, Rishabh; Jacobson, N. Tobias; Moussa, Jonathan E.; Frankel, Steven H.; Kais, Sabre

2014-07-01

We extend the family of problems that may be implemented on an adiabatic quantum optimizer (AQO). When a quadratic optimization problem has at least one set of discrete controls and the constraints are linear, we call this a quadratic constrained mixed discrete optimization (QCMDO) problem. QCMDO problems are NP-hard, and no efficient classical algorithm for their solution is known. Included in the class of QCMDO problems are combinatorial optimization problems constrained by a linear partial differential equation (PDE) or system of linear PDEs. An essential complication commonly encountered in solving this type of problem is that the linear constraint may introduce many intermediate continuous variables into the optimization while the computational cost grows exponentially with problem size. We resolve this difficulty by developing a constructive mapping from QCMDO to quadratic unconstrained binary optimization (QUBO) such that the size of the QUBO problem depends only on the number of discrete control variables. With a suitable embedding, taking into account the physical constraints of the realizable coupling graph, the resulting QUBO problem can be implemented on an existing AQO. The mapping itself is efficient, scaling cubically with the number of continuous variables in the general case and linearly in the PDE case if an efficient preconditioner is available.

Parallel High Order Accuracy Methods Applied to Non-Linear Hyperbolic Equations and to Problems in Materials Sciences

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jan Hesthaven

2012-02-06

Final report for DOE Contract DE-FG02-98ER25346 entitled Parallel High Order Accuracy Methods Applied to Non-Linear Hyperbolic Equations and to Problems in Materials Sciences. Principal Investigator Jan S. Hesthaven Division of Applied Mathematics Brown University, Box F Providence, RI 02912 Jan.Hesthaven@Brown.edu February 6, 2012 Note: This grant was originally awarded to Professor David Gottlieb and the majority of the work envisioned reflects his original ideas. However, when Prof Gottlieb passed away in December 2008, Professor Hesthaven took over as PI to ensure proper mentoring of students and postdoctoral researchers already involved in the project. This unusual circumstance has naturally impacted themore » project and its timeline. However, as the report reflects, the planned work has been accomplished and some activities beyond the original scope have been pursued with success. Project overview and main results The effort in this project focuses on the development of high order accurate computational methods for the solution of hyperbolic equations with application to problems with strong shocks. While the methods are general, emphasis is on applications to gas dynamics with strong shocks.« less

Coupled variational formulations of linear elasticity and the DPG methodology

NASA Astrophysics Data System (ADS)

Fuentes, Federico; Keith, Brendan; Demkowicz, Leszek; Le Tallec, Patrick

2017-11-01

This article presents a general approach akin to domain-decomposition methods to solve a single linear PDE, but where each subdomain of a partitioned domain is associated to a distinct variational formulation coming from a mutually well-posed family of broken variational formulations of the original PDE. It can be exploited to solve challenging problems in a variety of physical scenarios where stability or a particular mode of convergence is desired in a part of the domain. The linear elasticity equations are solved in this work, but the approach can be applied to other equations as well. The broken variational formulations, which are essentially extensions of more standard formulations, are characterized by the presence of mesh-dependent broken test spaces and interface trial variables at the boundaries of the elements of the mesh. This allows necessary information to be naturally transmitted between adjacent subdomains, resulting in coupled variational formulations which are then proved to be globally well-posed. They are solved numerically using the DPG methodology, which is especially crafted to produce stable discretizations of broken formulations. Finally, expected convergence rates are verified in two different and illustrative examples.

Fast solution of elliptic partial differential equations using linear combinations of plane waves.

PubMed

Pérez-Jordá, José M

2016-02-01

Given an arbitrary elliptic partial differential equation (PDE), a procedure for obtaining its solution is proposed based on the method of Ritz: the solution is written as a linear combination of plane waves and the coefficients are obtained by variational minimization. The PDE to be solved is cast as a system of linear equations Ax=b, where the matrix A is not sparse, which prevents the straightforward application of standard iterative methods in order to solve it. This sparseness problem can be circumvented by means of a recursive bisection approach based on the fast Fourier transform, which makes it possible to implement fast versions of some stationary iterative methods (such as Gauss-Seidel) consuming O(NlogN) memory and executing an iteration in O(Nlog(2)N) time, N being the number of plane waves used. In a similar way, fast versions of Krylov subspace methods and multigrid methods can also be implemented. These procedures are tested on Poisson's equation expressed in adaptive coordinates. It is found that the best results are obtained with the GMRES method using a multigrid preconditioner with Gauss-Seidel relaxation steps.

Doubly stratified MHD tangent hyperbolic nanofluid flow due to permeable stretched cylinder

NASA Astrophysics Data System (ADS)

Nagendramma, V.; Leelarathnam, A.; Raju, C. S. K.; Shehzad, S. A.; Hussain, T.

2018-06-01

An investigation is exhibited to analyze the presence of heat source and sink in doubly stratified MHD incompressible tangent hyperbolic fluid due to stretching of cylinder embedded in porous space under nanoparticles. To develop the mathematical model of tangent hyperbolic nanofluid, movement of Brownian and thermophoretic are accounted. The established equations of continuity, momentum, thermal and solutal boundary layers are reassembled into sets of non-linear expressions. These assembled expressions are executed with the help of Runge-Kutta scheme with MATLAB. The impacts of sundry parameters are illustrated graphically and the engineering interest physical quantities like skin friction, Nusselt and Sherwood number are examined by computing numerical values. It is clear that the power-law index parameter and curvature parameter shows favorable effect on momentum boundary layer thickness whereas Weissennberg number reveals inimical influence.

On hyperbolicity and Gevrey well-posedness. Part two: Scalar or degenerate transitions

NASA Astrophysics Data System (ADS)

Morisse, Baptiste

2018-04-01

For first-order quasi-linear systems of partial differential equations, we formulate an assumption of a transition from initial hyperbolicity to ellipticity. This assumption bears on the principal symbol of the first-order operator. Under such an assumption, we prove a strong Hadamard instability for the associated Cauchy problem, namely an instantaneous defect of Hölder continuity of the flow from Gσ to L2, with 0 < σ <σ0, the limiting Gevrey index σ0 depending on the nature of the transition. We restrict here to scalar transitions, and non-scalar transitions in which the boundary of the hyperbolic zone satisfies a flatness condition. As in our previous work for initially elliptic Cauchy problems [B. Morisse, On hyperbolicity and Gevrey well-posedness. Part one: the elliptic case, arxiv:arXiv:1611.07225], the instability follows from a long-time Cauchy-Kovalevskaya construction for highly oscillating solutions. This extends recent work of N. Lerner, T. Nguyen, and B. Texier [The onset of instability in first-order systems, to appear in J. Eur. Math. Soc.].

A high-order relaxation method with projective integration for solving nonlinear systems of hyperbolic conservation laws

NASA Astrophysics Data System (ADS)

Lafitte, Pauline; Melis, Ward; Samaey, Giovanni

2017-07-01

We present a general, high-order, fully explicit relaxation scheme which can be applied to any system of nonlinear hyperbolic conservation laws in multiple dimensions. The scheme consists of two steps. In a first (relaxation) step, the nonlinear hyperbolic conservation law is approximated by a kinetic equation with stiff BGK source term. Then, this kinetic equation is integrated in time using a projective integration method. After taking a few small (inner) steps with a simple, explicit method (such as direct forward Euler) to damp out the stiff components of the solution, the time derivative is estimated and used in an (outer) Runge-Kutta method of arbitrary order. We show that, with an appropriate choice of inner step size, the time step restriction on the outer time step is similar to the CFL condition for the hyperbolic conservation law. Moreover, the number of inner time steps is also independent of the stiffness of the BGK source term. We discuss stability and consistency, and illustrate with numerical results (linear advection, Burgers' equation and the shallow water and Euler equations) in one and two spatial dimensions.

Control of Distributed Parameter Systems

DTIC Science & Technology

1990-08-01

vari- ant of the general Lotka - Volterra model for interspecific competition. The variant described the emergence of one subpopulation from another as a...distribut ion unlimited. I&. ARSTRACT (MAUMUnw2O1 A unified arioroximation framework for Parameter estimation In general linear POE models has been completed...unified approximation framework for parameter estimation in general linear PDE models. This framework has provided the theoretical basis for a number of

Summation by parts, projections, and stability

NASA Technical Reports Server (NTRS)

Olsson, Pelle

1993-01-01

We have derived stability results for high-order finite difference approximations of mixed hyperbolic-parabolic initial-boundary value problems (IBVP). The results are obtained using summation by parts and a new way of representing general linear boundary conditions as an orthogonal projection. By slightly rearranging the analytic equations, we can prove strict stability for hyperbolic-parabolic IBVP. Furthermore, we generalize our technique so as to yield strict stability on curvilinear non-smooth domains in two space dimensions. Finally, we show how to incorporate inhomogeneous boundary data while retaining strict stability. Using the same procedure one can prove strict stability in higher dimensions as well.

Cell-centered high-order hyperbolic finite volume method for diffusion equation on unstructured grids

NASA Astrophysics Data System (ADS)

Lee, Euntaek; Ahn, Hyung Taek; Luo, Hong

2018-02-01

We apply a hyperbolic cell-centered finite volume method to solve a steady diffusion equation on unstructured meshes. This method, originally proposed by Nishikawa using a node-centered finite volume method, reformulates the elliptic nature of viscous fluxes into a set of augmented equations that makes the entire system hyperbolic. We introduce an efficient and accurate solution strategy for the cell-centered finite volume method. To obtain high-order accuracy for both solution and gradient variables, we use a successive order solution reconstruction: constant, linear, and quadratic (k-exact) reconstruction with an efficient reconstruction stencil, a so-called wrapping stencil. By the virtue of the cell-centered scheme, the source term evaluation was greatly simplified regardless of the solution order. For uniform schemes, we obtain the same order of accuracy, i.e., first, second, and third orders, for both the solution and its gradient variables. For hybrid schemes, recycling the gradient variable information for solution variable reconstruction makes one order of additional accuracy, i.e., second, third, and fourth orders, possible for the solution variable with less computational work than needed for uniform schemes. In general, the hyperbolic method can be an effective solution technique for diffusion problems, but instability is also observed for the discontinuous diffusion coefficient cases, which brings necessity for further investigation about the monotonicity preserving hyperbolic diffusion method.

A Textbook for a First Course in Computational Fluid Dynamics

NASA Technical Reports Server (NTRS)

Zingg, D. W.; Pulliam, T. H.; Nixon, David (Technical Monitor)

1999-01-01

This paper describes and discusses the textbook, Fundamentals of Computational Fluid Dynamics by Lomax, Pulliam, and Zingg, which is intended for a graduate level first course in computational fluid dynamics. This textbook emphasizes fundamental concepts in developing, analyzing, and understanding numerical methods for the partial differential equations governing the physics of fluid flow. Its underlying philosophy is that the theory of linear algebra and the attendant eigenanalysis of linear systems provides a mathematical framework to describe and unify most numerical methods in common use in the field of fluid dynamics. Two linear model equations, the linear convection and diffusion equations, are used to illustrate concepts throughout. Emphasis is on the semi-discrete approach, in which the governing partial differential equations (PDE's) are reduced to systems of ordinary differential equations (ODE's) through a discretization of the spatial derivatives. The ordinary differential equations are then reduced to ordinary difference equations (O(Delta)E's) using a time-marching method. This methodology, using the progression from PDE through ODE's to O(Delta)E's, together with the use of the eigensystems of tridiagonal matrices and the theory of O(Delta)E's, gives the book its distinctiveness and provides a sound basis for a deep understanding of fundamental concepts in computational fluid dynamics.

ADER schemes for scalar non-linear hyperbolic conservation laws with source terms in three-space dimensions

NASA Astrophysics Data System (ADS)

Toro, E. F.; Titarev, V. A.

2005-01-01

In this paper we develop non-linear ADER schemes for time-dependent scalar linear and non-linear conservation laws in one-, two- and three-space dimensions. Numerical results of schemes of up to fifth order of accuracy in both time and space illustrate that the designed order of accuracy is achieved in all space dimensions for a fixed Courant number and essentially non-oscillatory results are obtained for solutions with discontinuities. We also present preliminary results for two-dimensional non-linear systems.

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.

Hyperbolic/parabolic development for the GIM-STAR code. [flow fields in supersonic inlets

NASA Technical Reports Server (NTRS)

Spradley, L. W.; Stalnaker, J. F.; Ratliff, A. W.

1980-01-01

Flow fields in supersonic inlet configurations were computed using the eliptic GIM code on the STAR computer. Spillage flow under the lower cowl was calculated to be 33% of the incoming stream. The shock/boundary layer interaction on the upper propulsive surface was computed including separation. All shocks produced by the flow system were captured. Linearized block implicit (LBI) schemes were examined to determine their application to the GIM code. Pure explicit methods have stability limitations and fully implicit schemes are inherently inefficient; however, LBI schemes show promise as an effective compromise. A quasiparabolic version of the GIM code was developed using elastical parabolized Navier-Stokes methods combined with quasitime relaxation. This scheme is referred to as quasiparabolic although it applies equally well to hyperbolic supersonic inviscid flows. Second order windward differences are used in the marching coordinate and either explicit or linear block implicit time relaxation can be incorporated.

Internal friction between fluid particles of MHD tangent hyperbolic fluid with heat generation: Using coefficients improved by Cash and Karp

NASA Astrophysics Data System (ADS)

Salahuddin, T.; Khan, Imad; Malik, M. Y.; Khan, Mair; Hussain, Arif; Awais, Muhammad

2017-05-01

The present work examines the internal resistance between fluid particles of tangent hyperbolic fluid flow due to a non-linear stretching sheet with heat generation. Using similarity transformations, the governing system of partial differential equations is transformed into a coupled non-linear ordinary differential system with variable coefficients. Unlike the current analytical works on the flow problems in the literature, the main concern here is to numerically work out and find the solution by using Runge-Kutta-Fehlberg coefficients improved by Cash and Karp (Naseer et al., Alexandria Eng. J. 53, 747 (2014)). To determine the relevant physical features of numerous mechanisms acting on the deliberated problem, it is sufficient to have the velocity profile and temperature field and also the drag force and heat transfer rate all as given in the current paper.

A finite difference method for the solution of the transonic flow around harmonically oscillating wings

NASA Technical Reports Server (NTRS)

Ehlers, E. F.

1974-01-01

A finite difference method for the solution of the transonic flow about a harmonically oscillating wing is presented. The partial differential equation for the unsteady transonic flow was linearized by dividing the flow into separate steady and unsteady perturbation velocity potentials and by assuming small amplitudes of harmonic oscillation. The resulting linear differential equation is of mixed type, being elliptic or hyperbolic whereever the steady flow equation is elliptic or hyperbolic. Central differences were used for all derivatives except at supersonic points where backward differencing was used for the streamwise direction. Detailed formulas and procedures are described in sufficient detail for programming on high speed computers. To test the method, the problem of the oscillating flap on a NACA 64A006 airfoil was programmed. The numerical procedure was found to be stable and convergent even in regions of local supersonic flow with shocks.

A dimensionally split Cartesian cut cell method for hyperbolic conservation laws

NASA Astrophysics Data System (ADS)

Gokhale, Nandan; Nikiforakis, Nikos; Klein, Rupert

2018-07-01

We present a dimensionally split method for solving hyperbolic conservation laws on Cartesian cut cell meshes. The approach combines local geometric and wave speed information to determine a novel stabilised cut cell flux, and we provide a full description of its three-dimensional implementation in the dimensionally split framework of Klein et al. [1]. The convergence and stability of the method are proved for the one-dimensional linear advection equation, while its multi-dimensional numerical performance is investigated through the computation of solutions to a number of test problems for the linear advection and Euler equations. When compared to the cut cell flux of Klein et al., it was found that the new flux alleviates the problem of oscillatory boundary solutions produced by the former at higher Courant numbers, and also enables the computation of more accurate solutions near stagnation points. Being dimensionally split, the method is simple to implement and extends readily to multiple dimensions.

Exact Solutions of Linear Reaction-Diffusion Processes on a Uniformly Growing Domain: Criteria for Successful Colonization

PubMed Central

Simpson, Matthew J

2015-01-01

Many processes during embryonic development involve transport and reaction of molecules, or transport and proliferation of cells, within growing tissues. Mathematical models of such processes usually take the form of a reaction-diffusion partial differential equation (PDE) on a growing domain. Previous analyses of such models have mainly involved solving the PDEs numerically. Here, we present a framework for calculating the exact solution of a linear reaction-diffusion PDE on a growing domain. We derive an exact solution for a general class of one-dimensional linear reaction—diffusion process on 0

Exact solutions of linear reaction-diffusion processes on a uniformly growing domain: criteria for successful colonization.

PubMed

Simpson, Matthew J

2015-01-01

Many processes during embryonic development involve transport and reaction of molecules, or transport and proliferation of cells, within growing tissues. Mathematical models of such processes usually take the form of a reaction-diffusion partial differential equation (PDE) on a growing domain. Previous analyses of such models have mainly involved solving the PDEs numerically. Here, we present a framework for calculating the exact solution of a linear reaction-diffusion PDE on a growing domain. We derive an exact solution for a general class of one-dimensional linear reaction-diffusion process on 0

High-Order Residual-Distribution Hyperbolic Advection-Diffusion Schemes: 3rd-, 4th-, and 6th-Order

NASA Technical Reports Server (NTRS)

Mazaheri, Alireza R.; Nishikawa, Hiroaki

2014-01-01

In this paper, spatially high-order Residual-Distribution (RD) schemes using the first-order hyperbolic system method are proposed for general time-dependent advection-diffusion problems. The corresponding second-order time-dependent hyperbolic advection- diffusion scheme was first introduced in [NASA/TM-2014-218175, 2014], where rapid convergences over each physical time step, with typically less than five Newton iterations, were shown. In that method, the time-dependent hyperbolic advection-diffusion system (linear and nonlinear) was discretized by the second-order upwind RD scheme in a unified manner, and the system of implicit-residual-equations was solved efficiently by Newton's method over every physical time step. In this paper, two techniques for the source term discretization are proposed; 1) reformulation of the source terms with their divergence forms, and 2) correction to the trapezoidal rule for the source term discretization. Third-, fourth, and sixth-order RD schemes are then proposed with the above techniques that, relative to the second-order RD scheme, only cost the evaluation of either the first derivative or both the first and the second derivatives of the source terms. A special fourth-order RD scheme is also proposed that is even less computationally expensive than the third-order RD schemes. The second-order Jacobian formulation was used for all the proposed high-order schemes. The numerical results are then presented for both steady and time-dependent linear and nonlinear advection-diffusion problems. It is shown that these newly developed high-order RD schemes are remarkably efficient and capable of producing the solutions and the gradients to the same order of accuracy of the proposed RD schemes with rapid convergence over each physical time step, typically less than ten Newton iterations.

AZTEC: A parallel iterative package for the solving linear systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hutchinson, S.A.; Shadid, J.N.; Tuminaro, R.S.

1996-12-31

We describe a parallel linear system package, AZTEC. The package incorporates a number of parallel iterative methods (e.g. GMRES, biCGSTAB, CGS, TFQMR) and preconditioners (e.g. Jacobi, Gauss-Seidel, polynomial, domain decomposition with LU or ILU within subdomains). Additionally, AZTEC allows for the reuse of previous preconditioning factorizations within Newton schemes for nonlinear methods. Currently, a number of different users are using this package to solve a variety of PDE applications.

Compatible diagonal-norm staggered and upwind SBP operators

NASA Astrophysics Data System (ADS)

Mattsson, Ken; O'Reilly, Ossian

2018-01-01

The main motivation with the present study is to achieve a provably stable high-order accurate finite difference discretisation of linear first-order hyperbolic problems on a staggered grid. The use of a staggered grid makes it non-trivial to discretise advective terms. To overcome this difficulty we discretise the advective terms using upwind Summation-By-Parts (SBP) operators, while the remaining terms are discretised using staggered SBP operators. The upwind and staggered SBP operators (for each order of accuracy) are compatible, here meaning that they are based on the same diagonal norms, allowing for energy estimates to be formulated. The boundary conditions are imposed using a penalty (SAT) technique, to guarantee linear stability. The resulting SBP-SAT approximations lead to fully explicit ODE systems. The accuracy and stability properties are demonstrated for linear hyperbolic problems in 1D, and for the 2D linearised Euler equations with constant background flow. The newly derived upwind and staggered SBP operators lead to significantly more accurate numerical approximations, compared with the exclusive usage of (previously derived) central-difference first derivative SBP operators.

A study to establish reasonable action limits for patient-specific quality assurance in intensity-modulated radiation therapy.

PubMed

Both, Stefan; Alecu, Ionut M; Stan, Andrada R; Alecu, Marius; Ciura, Andrei; Hansen, Jeremy M; Alecu, Rodica

2007-03-07

An effective patient quality assurance (QA) program for intensity-modulated radiation therapy (IMRT) requires accurate and realistic plan acceptance criteria--that is, action limits. Based on dose measurements performed with a commercially available two-dimensional (2D) diode array, we analyzed 747 fluence maps resulting from a routine patient QA program for IMRT plans. The fluence maps were calculated by three different commercially available (ADAC, CMS, Eclipse) treatment planning systems (TPSs) and were delivered using 6-MV X-ray beams produced by linear accelerators. To establish reasonably achievable and clinically acceptable limits for the dose deviations, the agreement between the measured and calculated fluence maps was evaluated in terms of percent dose error (PDE) for a few points and percent of passing points (PPP) for the isodose distribution. The analysis was conducted for each TPS used in the study (365 ADAC, 162 CMS,220 Eclipse), for multiple treatment sites (prostate, pelvis, head and neck, spine, rectum, anus, lung, brain), at the normalization point for 3% percentage difference (%Diff) and 3-mm distance to agreement (DTA) criteria. We investigated the treatment-site dependency of PPP and PDE. The results show that, at 3% and 3-mm criteria, a 95% PPP and 3% PDE can be achieved for prostate treatments and a 90% PPP and 5% PDE are attainable for any treatment site.

Identification of the gamma subunit-interacting residues on photoreceptor cGMP phosphodiesterase, PDE6alpha '.

PubMed

Granovsky, A E; Artemyev, N O

2000-12-29

Photoreceptor cGMP phosphodiesterase (PDE6) is the effector enzyme in the G protein-mediated visual transduction cascade. In the dark, the activity of PDE6 is shut off by the inhibitory gamma subunit (Pgamma). Chimeric proteins between cone PDE6alpha' and cGMP-binding and cGMP-specific PDE (PDE5) have been constructed and expressed in Sf9 cells to study the mechanism of inhibition of PDE6 catalytic activity by Pgamma. Substitution of the segment PDE5-(773-820) by the corresponding PDE6alpha'-(737-784) sequence in the wild-type PDE5 or in a PDE5/PDE6alpha' chimera containing the catalytic domain of PDE5 results in chimeric enzymes capable of inhibitory interaction with Pgamma. The catalytic properties of the chimeric PDEs remained similar to those of PDE5. Ala-scanning mutational analysis of the Pgamma-binding region, PDE6alpha'-(750-760), revealed PDE6alpha' residues essential for the interaction. The M758A mutation markedly impaired and the Q752A mutation moderately impaired the inhibition of chimeric PDE by Pgamma. The analysis of the catalytic properties of mutant PDEs and a model of the PDE6 catalytic domain suggest that residues Met(758) and Gln(752) directly bind Pgamma. A model of the PDE6 catalytic site shows that PDE6alpha'-(750-760) forms a loop at the entrance to the cGMP-binding pocket. Binding of Pgamma to Met(758) would effectively block access of cGMP to the catalytic cavity, providing a structural basis for the mechanism of PDE6 inhibition.

Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs.

PubMed

Zhang, Han-Ting

2009-01-01

Phosphodiesterase-4 (PDE4), one of eleven PDE enzyme families, specifically catalyzes hydrolysis of cyclic AMP (cAMP); it has four subtypes (PDE4A-D) with at least 25 splice variants. PDE4 plays a critical role in the control of intracellular cAMP concentrations. PDE4 inhibitors produce antidepressant actions in both animals and humans via enhancement of cAMP signaling in the brain. However, their clinical utility has been hampered by side effects, in particular nausea and emesis. While there is still a long way to go before PDE4 inhibitors with high therapeutic indices are available for treatment of depressive disorders, important advances have been made in the development of PDE4 inhibitors as antidepressants. First, limited, but significant studies point to PDE4D as the major PDE4 subtype responsible for antidepressant-like effects of PDE4 inhibitors, although the role of PDE4A cannot be excluded. Second, PDE4D may contribute to emesis, the major side effect of PDE4 inhibitors. For this reason, identification of roles of PDE4D splice variants in mediating antidepressant activity is particularly important. Recent studies using small interfering RNAs (siRNAs) have demonstrated the feasibility to identify cellular functions of individual PDE4 variants. Third, mixed inhibitors of PDE4 and PDE7 or PDE4 and serotonin reuptake have been developed and may be potential antidepressants with minimized side effects. Finally, relatively selective inhibitors of one or two PDE4 subtypes have been synthesized using structure- and scaffold-based design. This review also discusses the relationship between PDE4 and antidepressant activity based on structures, brain distributions, and pharmacological properties of PDE4 and its isoforms.

Tooth wear and feeding ecology in mountain gorillas from Volcanoes National Park, Rwanda.

PubMed

Galbany, Jordi; Imanizabayo, Olive; Romero, Alejandro; Vecellio, Veronica; Glowacka, Halszka; Cranfield, Michael R; Bromage, Timothy G; Mudakikwa, Antoine; Stoinski, Tara S; McFarlin, Shannon C

2016-03-01

Ecological factors have a dramatic effect on tooth wear in primates, although it remains unclear how individual age contributes to functional crown morphology. The aim of this study is to determine how age and individual diet are related to tooth wear in wild mountain gorillas (Gorilla beringei beringei) from Volcanoes National Park, Rwanda. We calculated the percent of dentine exposure (PDE) for all permanent molars (M1-M3) of known-age mountain gorillas (N = 23), to test whether PDE varied with age using regression analysis. For each molar position, we also performed stepwise multiple linear regression to test the effects of age and percentage of time spent feeding on different food categories on PDE, for individuals subject to long-term observational studies by the Dian Fossey Gorilla Fund International's Karisoke Research Center. PDE increased significantly with age for both sexes in all molars. Moreover, a significant effect of gritty plant root consumption on PDE was found among individuals. Our results support prior reports indicating reduced tooth wear in mountain gorillas compared to western gorillas, and compared to other known-aged samples of primate taxa from forest and savanna habitats. Our findings corroborate that mountain gorillas present very low molar wear, and support the hypothesis that age and the consumption of particular food types, namely roots, are significant determinants of tooth wear variation in mountain gorillas. Future research should characterize the mineral composition of the soil in the Virunga habitat, to test the hypothesis that the physical and abrasive properties of gritty foods such as roots influence intra- and interspecific patterns of tooth wear. © 2015 Wiley Periodicals, Inc.

Nitric oxide-induced changes in endothelial expression of phosphodiesterases 2, 3, and 5.

PubMed

Schankin, Christoph J; Kruse, Lars S; Reinisch, Veronika M; Jungmann, Steffen; Kristensen, Julie C; Grau, Stefan; Ferrari, Uta; Sinicina, Inga; Goldbrunner, Roland; Straube, Andreas; Kruuse, Christina

2010-03-01

To investigate nitric oxide (NO)-mediated changes in expression of cyclic nucleotide degrading phosphodiesterases 2A (PDE2A), PDE3B, and PDE5A in human endothelial cells. Nitric oxide induces production of cyclic guanosine monophosphate (cGMP), which along with cyclic adenosine monophosphate (cAMP) is degraded by PDEs. NO donors and selective inhibitors of PDE3 and PDE5 induce migraine-like headache and play a role in endothelial dysfunction during stroke. The current study investigates possible NO modulation of cGMP-related PDEs relevant to headache induction in a cell line containing such PDEs. Real time polymerase chain reaction and Western blots were used to show expression of PDE2A, PDE3B, and PDE5A in a stable cell line of human brain microvascular endothelial cells. Effects of NO on PDE expression were analyzed at specific time intervals after continued DETA NONOate administration. This study shows the expression of PDE2A, PDE3B, and PDE5A mRNA and PDE3B and PDE5A protein in human cerebral endothelial cells. Long-term DETA NONOate administration induced an immediate mRNA up-regulation of PDE5A (1.9-fold, 0.5 hour), an early peak of PDE2A (1.4-fold, 1 and 2 hours) and later up-regulation of both PDE3B (1.6-fold, 4 hours) and PDE2A (1.7-fold, 8 hours and 1.2-fold after 24 hours). Such changes were, however, not translated into significant changes in protein expression indicating few, if any, functional effects. Long-term NO stimulation modulated PDE3 and PDE5 mRNA expression in endothelial cells. However, PDE3 and PDE5 protein levels were unaffected by NO. The presence of PDE3 or PDE5 in endothelial cells indicates that selective inhibitors may have functional effects in such cells. A complex interaction of cGMP and cAMP in response to NO administration may take place if the mRNA translates into active protein. Whether or not this plays a role in the headache mechanisms remains to be investigated.

A boundary-value problem for a first-order hyperbolic system in a two-dimensional domain

NASA Astrophysics Data System (ADS)

Zhura, N. A.; Soldatov, A. P.

2017-06-01

We consider a strictly hyperbolic first-order system of three equations with constant coefficients in a bounded piecewise-smooth domain. The boundary of the domain is assumed to consist of six smooth non-characteristic arcs. A boundary-value problem in this domain is posed by alternately prescribing one or two linear combinations of the components of the solution on these arcs. We show that this problem has a unique solution under certain additional conditions on the coefficients of these combinations, the boundary of the domain and the behaviour of the solution near the characteristics passing through the corner points of the domain.

Quantum error correcting codes and 4-dimensional arithmetic hyperbolic manifolds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guth, Larry, E-mail: lguth@math.mit.edu; Lubotzky, Alexander, E-mail: alex.lubotzky@mail.huji.ac.il

2014-08-15

Using 4-dimensional arithmetic hyperbolic manifolds, we construct some new homological quantum error correcting codes. They are low density parity check codes with linear rate and distance n{sup ε}. Their rate is evaluated via Euler characteristic arguments and their distance using Z{sub 2}-systolic geometry. This construction answers a question of Zémor [“On Cayley graphs, surface codes, and the limits of homological coding for quantum error correction,” in Proceedings of Second International Workshop on Coding and Cryptology (IWCC), Lecture Notes in Computer Science Vol. 5557 (2009), pp. 259–273], who asked whether homological codes with such parameters could exist at all.

Determinants of anti-benzo[a]pyrene diol epoxide-DNA adduct formation in lymphomonocytes of the general population.

PubMed

Pavanello, Sofia; Pulliero, Alessandra; Saia, Bruno Onofrio; Clonfero, Erminio

2006-12-10

We evaluated determinants of anti-benzo[a]pyrenediolepoxide-(B[a]PDE)-DNA adduct formation (adduct induced by the ultimate carcinogenic metabolite of B[a]P) in lymphomonocytes of subjects environmentally exposed to low doses of polycyclic aromatic hydrocarbons (PAHs) (B[a]P). Our study population consisted of 585 Caucasian subjects, all municipal workers living in North-East Italy and recruited during their periodic check-ups after informed consent. PAH (B[a]P) exposure was assessed by questionnaire. Anti-B[a]PDE-DNA levels were measured by HPLC fluorescence analysis. We found that cigarette smoking (smokers (22%) versus non-smokers, p<0.0001), dietary intake of PAH-rich meals (> or =52 (38%) versus <52 times/year, p<0.0001), and outdoor exposure (> or =4 (19%) versus <4h/day; p=0.0115) significantly influenced adduct levels. Indoor exposure significantly increased the frequency of positive subjects (> or =0.5 adducts/10(8) nucleotides; chi(2) for linear trend, p=0.051). In linear multiple regression analysis the major determinants of increased DNA adduct levels (ln values) were smoking (t=6.362, p<0.0001) and diet (t=4.035, p<0.0001). In this statistical analysis, indoor and outdoor exposure like other factors of PAH exposure had no influence. In non-smokers, the influence of diet (p<0.0001) and high indoor exposure (p=0.016) on anti-B[a]PDE-DNA adduct formation became more evident, but not that of outdoor exposure, as was confirmed by linear multiple regression analysis (diet, t=3.997, p<0.0001 and high indoor exposure, t=2.522, p=0.012). This study indicates that anti-B[a]PDE-DNA adducts can be detected in the general population and are modulated by PAH (B[a]P) exposure not only with smoking - information already known from studies with limited number of subjects - but also with dietary habits and high indoor exposure. In non-smokers, these two factors are the principal determinants of DNA adduct formation. The information provided here seems to be important, since DNA adduct formation in surrogate tissue is an index of genotoxic exposure also in target organs (e.g., lung) and their increase may also be predictive of higher risk for PAH-related cancers.

Composite scheme using localized relaxation with non-standard finite difference method for hyperbolic conservation laws

NASA Astrophysics Data System (ADS)

Kumar, Vivek; Raghurama Rao, S. V.

2008-04-01

Non-standard finite difference methods (NSFDM) introduced by Mickens [ Non-standard Finite Difference Models of Differential Equations, World Scientific, Singapore, 1994] are interesting alternatives to the traditional finite difference and finite volume methods. When applied to linear hyperbolic conservation laws, these methods reproduce exact solutions. In this paper, the NSFDM is first extended to hyperbolic systems of conservation laws, by a novel utilization of the decoupled equations using characteristic variables. In the second part of this paper, the NSFDM is studied for its efficacy in application to nonlinear scalar hyperbolic conservation laws. The original NSFDMs introduced by Mickens (1994) were not in conservation form, which is an important feature in capturing discontinuities at the right locations. Mickens [Construction and analysis of a non-standard finite difference scheme for the Burgers-Fisher equations, Journal of Sound and Vibration 257 (4) (2002) 791-797] recently introduced a NSFDM in conservative form. This method captures the shock waves exactly, without any numerical dissipation. In this paper, this algorithm is tested for the case of expansion waves with sonic points and is found to generate unphysical expansion shocks. As a remedy to this defect, we use the strategy of composite schemes [R. Liska, B. Wendroff, Composite schemes for conservation laws, SIAM Journal of Numerical Analysis 35 (6) (1998) 2250-2271] in which the accurate NSFDM is used as the basic scheme and localized relaxation NSFDM is used as the supporting scheme which acts like a filter. Relaxation schemes introduced by Jin and Xin [The relaxation schemes for systems of conservation laws in arbitrary space dimensions, Communications in Pure and Applied Mathematics 48 (1995) 235-276] are based on relaxation systems which replace the nonlinear hyperbolic conservation laws by a semi-linear system with a stiff relaxation term. The relaxation parameter ( λ) is chosen locally on the three point stencil of grid which makes the proposed method more efficient. This composite scheme overcomes the problem of unphysical expansion shocks and captures the shock waves with an accuracy better than the upwind relaxation scheme, as demonstrated by the test cases, together with comparisons with popular numerical methods like Roe scheme and ENO schemes.

Influence of the light propagation models on a linearized photoacoustic image reconstruction of the light absorption coefficient

NASA Astrophysics Data System (ADS)

Okawa, Shinpei; Hirasawa, Takeshi; Kushibiki, Toshihiro; Ishihara, Miya

2015-03-01

Quantification of the optical properties of the tissues and blood by noninvasive photoacoustic (PA) imaging may provide useful information for screening and early diagnosis of diseases. Linearized 2D image reconstruction algorithm based on PA wave equation and the photon diffusion equation (PDE) can reconstruct the image with computational cost smaller than a method based on 3D radiative transfer equation. However, the reconstructed image is affected by the differences between the actual and assumed light propagations. A quantitative capability of a linearized 2D image reconstruction was investigated and discussed by the numerical simulations and the phantom experiment in this study. The numerical simulations with the 3D Monte Carlo (MC) simulation and the 2D finite element calculation of the PDE were carried out. The phantom experiment was also conducted. In the phantom experiment, the PA pressures were acquired by a probe which had an optical fiber for illumination and the ring shaped P(VDF-TrFE) ultrasound transducer. The measured object was made of Intralipid and Indocyanine green. In the numerical simulations, it was shown that the linearized image reconstruction method recovered the absorption coefficients with alleviating the dependency of the PA amplitude on the depth of the photon absorber. The linearized image reconstruction method worked effectively under the light propagation calculated by 3D MC simulation, although some errors occurred. The phantom experiments validated the result of the numerical simulations.

Regularization of Grad’s 13 -Moment-Equations in Kinetic Gas Theory

DTIC Science & Technology

2011-01-01

variant of the moment method has been proposed by Eu (1980) and is used, e.g., in Myong (2001). Recently, a maximum- entropy 10-moment system has been used...small amplitude linear waves, the R13 system is linearly stable in time for all modes and wave lengths. The instability of the Burnett system indicates...Boltzmann equation. Related to the problem of global hyperbolicity is the questions of the existence of an entropy law for the R13 system . In the linear

The high-affinity phosphodiesterase PdeH regulates development and aflatoxin biosynthesis in Aspergillus flavus.

PubMed

Yang, Kunlong; Liu, Yinghang; Liang, Linlin; Li, Zhenguo; Qin, Qiuping; Nie, Xinyi; Wang, Shihua

2017-04-01

Cyclic AMP signaling controls a range of physiological processes in response to extracellular stimuli in organisms. Among the signaling cascades, cAMP, as a second messenger, is orchestrated by adenylate cyclase (biosynthesis) and cAMP phosphodiesterases (PDEs) (hydrolysis). In this study, we investigated the function of the high-affinity (PdeH) and low-affinity (PdeL) cAMP phosphodiesterase from the carcinogenic aflatoxin producing fungus Aspergillus flavus, and found that instead of PdeL, inactivation of PdeH exhibited a reduction in conidiation and sclerotia formation. However, the ΔpdeL/ΔpdeH mutant exhibited an enhanced phenotype defects, a similar phenotype defects to wild-type strain treated with exogenous cAMP. The activation of PKA activity was inhibited in the ΔpdeH or ΔpdeL/ΔpdeH mutant, both of whom exhibited increasing AF production. Further analysis by qRT-PCR revealed that pdeH had a high transcriptional level compared to pdeL in wild-type strain, and affected pdeL transcription. Green fluorescent protein tagging at the C-terminus of PDEs showed that PdeH-GFP is broadly compartmentalized in the cytosol, while PdeL-GFP localized mainly to the nucleus. Overall, our results indicated that PdeH plays a major role, but has overlapping function with PdeL, in vegetative growth, development and AF biosynthesis in A. flavus. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

A Model for Displacements Between Parallel Plates That Shows Change of Type from Hyperbolic to Elliptic

NASA Astrophysics Data System (ADS)

Shariati, Maryam; Yortsos, Yannis; Talon, Laurent; Martin, Jerome; Rakotomalala, Nicole; Salin, Dominique

2003-11-01

We consider miscible displacement between parallel plates, where the viscosity is a function of the concentration. By selecting a piece-wise representation, the problem can be considered as ``three-phase'' flow. Assuming a lubrication-type approximation, the mathematical description is in terms of two quasi-linear hyperbolic equations. When the mobility of the middle phase is smaller than its neighbors, the system is genuinely hyperbolic and can be solved analytically. However, when it is larger, an elliptic region develops. This change-of-type behavior is for the first time proved here based on sound physical principles. Numerical solutions with a small diffusion are presented. Good agreement is obtained outside the elliptic region, but not inside, where the numerical results show unstable behavior. We conjecture that for the solution of the real problem in the mixed-type case, the full higher-dimensionality problem must be considered inside the elliptic region, in which the lubrication (parallel-flow) approximation is no longer appropriate. This is discussed in a companion presentation.

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

PubMed Central

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

2016-01-01

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

The Shock and Vibration Digest. Volume 16, Number 11

DTIC Science & Technology

1984-11-01

wave [19], a secular equation for Rayleigh waves on ing, seismic risk, and related problems are discussed. the surface of an anisotropic half-space...waves in an !so- tive equation of an elastic-plastic rack medium was....... tropic linear elastic half-space with plane material used; the coefficient...pair of semi-linear hyperbolic partial differential -- " Conditions under which the equations of motion equations governing slow variations in amplitude

Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei

PubMed Central

Rascón, Ana; Soderling, Scott H.; Schaefer, Jonathan B.; Beavo, Joseph A.

2002-01-01

Here we report the cloning, expression, and characterization of a cAMP-specific phosphodiesterase (PDE) from Trypanosoma brucei (TbPDE2B). Using a bioinformatic approach, two different expressed sequence tag clones were identified and used to isolate the complete sequence of two identical PDE genes arranged in tandem. Each gene consists of 2,793 bases that predict a protein of 930 aa with a molecular mass of 103.2 kDa. Two GAF (for cGMP binding and stimulated PDEs, Anabaena adenylyl cyclases, and Escherichia coli FhlA) domains, similar to those contained in many signaling molecules including mammalian PDE2, PDE5, PDE6, PDE10, and PDE11, were located N-terminal to a consensus PDE catalytic domain. The catalytic domain is homologous to the catalytic domain of all 11 mammalian PDEs, the Dictyostelium discoideum RegA, and a probable PDE from Caenorhabditis elegans. It is most similar to the T. brucei PDE2A (89% identity). TbPDE2B has substrate specificity for cAMP with a Km of 2.4 μM. cGMP is not hydrolyzed by TbPDE2B nor does this cyclic nucleotide modulate cAMP PDE activity. The nonselective PDE inhibitors 3-isobutyl-1-methylxanthine, papaverine and pentoxifyline are poor inhibitors of TbPDE2B. Similarly, PDE inhibitors selective for the mammalian PDE families 2, 3, 5, and 6 (erythro-9-[3-(2-hydroxynonyl)]-adenine, enoximone, zaprinast, and sildenafil) were also unable to inhibit this enzyme. However, dipyridamole was a reasonably good inhibitor of this enzyme with an IC50 of 27 μM. cAMP plays key roles in cell growth and differentiation in this parasite, and PDEs are responsible for the hydrolysis of this important second messenger. Therefore, parasite PDEs, including this one, have the potential to be attractive targets for selective drug design. PMID:11930017

A spatial domain decomposition approach to distributed H ∞ observer design of a linear unstable parabolic distributed parameter system with spatially discrete sensors

NASA Astrophysics Data System (ADS)

Wang, Jun-Wei; Liu, Ya-Qiang; Hu, Yan-Yan; Sun, Chang-Yin

2017-12-01

This paper discusses the design problem of distributed H∞ Luenberger-type partial differential equation (PDE) observer for state estimation of a linear unstable parabolic distributed parameter system (DPS) with external disturbance and measurement disturbance. Both pointwise measurement in space and local piecewise uniform measurement in space are considered; that is, sensors are only active at some specified points or applied at part thereof of the spatial domain. The spatial domain is decomposed into multiple subdomains according to the location of the sensors such that only one sensor is located at each subdomain. By using Lyapunov technique, Wirtinger's inequality at each subdomain, and integration by parts, a Lyapunov-based design of Luenberger-type PDE observer is developed such that the resulting estimation error system is exponentially stable with an H∞ performance constraint, and presented in terms of standard linear matrix inequalities (LMIs). For the case of local piecewise uniform measurement in space, the first mean value theorem for integrals is utilised in the observer design development. Moreover, the problem of optimal H∞ observer design is also addressed in the sense of minimising the attenuation level. Numerical simulation results are presented to show the satisfactory performance of the proposed design method.

A study to establish reasonable action limits for patient‐specific quality assurance in intensity‐modulated radiation therapy

PubMed Central

Alecu, Ionut M.; Stan, Andrada R.; Alecu, Marius; Ciura, Andrei; Hansen, Jeremy M.; Alecu, Rodica

2007-01-01

An effective patient quality assurance (QA) program for intensity‐modulated radiation therapy (IMRT) requires accurate and realistic plan acceptance criteria—that is, action limits. Based on dose measurements performed with a commercially available two‐dimensional (2D) diode array, we analyzed 747 fluence maps resulting from a routine patient QA program for IMRT plans. The fluence maps were calculated by three different commercially available (ADAC, CMS, Eclipse) treatment planning systems (TPSs) and were delivered using 6‐MV X‐ray beams produced by linear accelerators. To establish reasonably achievable and clinically acceptable limits for the dose deviations, the agreement between the measured and calculated fluence maps was evaluated in terms of percent dose error (PDE) for a few points and percent of passing points (PPP) for the isodose distribution. The analysis was conducted for each TPS used in the study (365 ADAC, 162 CMS, 220 Eclipse), for multiple treatment sites (prostate, pelvis, head and neck, spine, rectum, anus, lung, brain), at the normalization point for 3% percentage difference (%Diff) and 3‐mm distance to agreement (DTA) criteria. We investigated the treatment‐site dependency of PPP and PDE. The results show that, at 3% and 3‐mm criteria, a 95% PPP and 3% PDE can be achieved for prostate treatments and a 90% PPP and 5% PDE are attainable for any treatment site. PACS Numbers: 87.53Dq, 87.53Tf, 87.53Xd, 87.56Fc PMID:17592459

Boundary Korn Inequality and Neumann Problems in Homogenization of Systems of Elasticity

NASA Astrophysics Data System (ADS)

Geng, Jun; Shen, Zhongwei; Song, Liang

2017-06-01

This paper is concerned with a family of elliptic systems of linear elasticity with rapidly oscillating periodic coefficients, arising in the theory of homogenization. We establish uniform optimal regularity estimates for solutions of Neumann problems in a bounded Lipschitz domain with L 2 boundary data. The proof relies on a boundary Korn inequality for solutions of systems of linear elasticity and uses a large-scale Rellich estimate obtained in Shen (Anal PDE, arXiv:1505.00694v2).

An HP Adaptive Discontinuous Galerkin Method for Hyperbolic Conservation Laws. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Bey, Kim S.

1994-01-01

This dissertation addresses various issues for model classes of hyperbolic conservation laws. The basic approach developed in this work employs a new family of adaptive, hp-version, finite element methods based on a special discontinuous Galerkin formulation for hyperbolic problems. The discontinuous Galerkin formulation admits high-order local approximations on domains of quite general geometry, while providing a natural framework for finite element approximations and for theoretical developments. The use of hp-versions of the finite element method makes possible exponentially convergent schemes with very high accuracies in certain cases; the use of adaptive hp-schemes allows h-refinement in regions of low regularity and p-enrichment to deliver high accuracy, while keeping problem sizes manageable and dramatically smaller than many conventional approaches. The use of discontinuous Galerkin methods is uncommon in applications, but the methods rest on a reasonable mathematical basis for low-order cases and has local approximation features that can be exploited to produce very efficient schemes, especially in a parallel, multiprocessor environment. The place of this work is to first and primarily focus on a model class of linear hyperbolic conservation laws for which concrete mathematical results, methodologies, error estimates, convergence criteria, and parallel adaptive strategies can be developed, and to then briefly explore some extensions to more general cases. Next, we provide preliminaries to the study and a review of some aspects of the theory of hyperbolic conservation laws. We also provide a review of relevant literature on this subject and on the numerical analysis of these types of problems.

Displacement Models for THUNDER Actuators having General Loads and Boundary Conditions

NASA Technical Reports Server (NTRS)

Wieman, Robert; Smith, Ralph C.; Kackley, Tyson; Ounaies, Zoubeida; Bernd, Jeff; Bushnell, Dennis M. (Technical Monitor)

2001-01-01

This paper summarizes techniques for quantifying the displacements generated in THUNDER actuators in response to applied voltages for a variety of boundary conditions and exogenous loads. The PDE (partial differential equations) models for the actuators are constructed in two steps. In the first, previously developed theory quantifying thermal and electrostatic strains is employed to model the actuator shapes which result from the manufacturing process and subsequent repoling. Newtonian principles are then employed to develop PDE models which quantify displacements in the actuator due to voltage inputs to the piezoceramic patch. For this analysis, drive levels are assumed to be moderate so that linear piezoelectric relations can be employed. Finite element methods for discretizing the models are developed and the performance of the discretized models are illustrated through comparison with experimental data.

Pharmacophore Based Virtual Screening Approach to Identify Selective PDE4B Inhibitors

PubMed Central

Gaurav, Anand; Gautam, Vertika

2017-01-01

Phosphodiesterase 4 (PDE4) has been established as a promising target in asthma and chronic obstructive pulmonary disease. PDE4B subtype selective inhibitors are known to reduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. To achieve this goal, ligand based pharmacophore modeling approach is employed. Separate pharmacophore hypotheses for PDE4B and PDE4D inhibitors were generated using HypoGen algorithm and 106 PDE4 inhibitors from literature having thiopyrano [3,2-d] Pyrimidines, 2-arylpyrimidines, and triazines skeleton. Suitable training and test sets were created using the molecules as per the guidelines available for HypoGen program. Training set was used for hypothesis development while test set was used for validation purpose. Fisher validation was also used to test the significance of the developed hypothesis. The validated pharmacophore hypotheses for PDE4B and PDE4D inhibitors were used in sequential virtual screening of zinc database of drug like molecules to identify selective PDE4B inhibitors. The hits were screened for their estimated activity and fit value. The top hit was subjected to docking into the active sites of PDE4B and PDE4D to confirm its selectivity for PDE4B. The hits are proposed to be evaluated further using in-vitro assays. PMID:29201082

Partial reconstitution of photoreceptor cGMP phosphodiesterase characteristics in cGMP phosphodiesterase-5.

PubMed

Granovsky, A E; Artemyev, N O

2001-06-15

Photoreceptor cGMP phosphodiesterases (PDE6) are uniquely qualified to serve as effector enzymes in the vertebrate visual transduction cascade. In the dark-adapted photoreceptors, the activity of PDE6 is blocked via tight association with the inhibitory gamma-subunits (Pgamma). The Pgamma block is removed in the light-activated PDE6 by the visual G protein, transducin. Transducin-activated PDE6 exhibits an exceptionally high catalytic rate of cGMP hydrolysis ensuring high signal amplification. To identify the structural determinants for the inhibitory interaction with Pgamma and the remarkable cGMP hydrolytic ability, we sought to reproduce the PDE6 characteristics by mutagenesis of PDE5, a related cyclic GMP-specific, cGMP-binding PDE. PDE5 is insensitive to Pgamma and has a more than 100-fold lower k(cat) for cGMP hydrolysis. Our mutational analysis of chimeric PDE5/PDE6alpha' enzymes revealed that the inhibitory interaction of cone PDE6 catalytic subunits (PDE6alpha') with Pgamma is mediated primarily by three hydrophobic residues at the entry to the catalytic pocket, Met(758), Phe(777), and Phe(781). The maximal catalytic rate of PDE5 was enhanced by at least 10-fold with substitutions of PDE6alpha'-specific glycine residues for the corresponding PDE5 alanine residues, Ala(608) and Ala(612). The Gly residues are adjacent to the highly conserved metal binding motif His-Asn-X-X-His, which is essential for cGMP hydrolysis. Our results suggest that the unique Gly residues allow the PDE6 metal binding site to adopt a more favorable conformation for cGMP hydrolysis.

Phosphodiesterase 4 regulates the migration of B16-F10 melanoma cells.

PubMed

Watanabe, Yoshihiro; Murata, Taku; Shimizu, Kasumi; Morita, Hiroshi; Inui, Madoka; Tagawa, Toshiro

2012-08-01

Phosphodiesterases (PDEs) are important regulators of signal transduction processes. Eleven PDE gene families (PDE1-11) have been identified and several PDE isoforms are selectively expressed in various cell types. PDE4 family members specifically hydrolyze cyclic AMP (cAMP). Four genes (PDE4A-D) are known to encode PDE4 enzymes, with additional diversity generated by the use of alternative mRNA splicing and the use of different promoters. While PDE4 selective inhibitors show therapeutic potential for treating major diseases such as asthma and chronic obstructive pulmonary disease, little is known concerning the role of PDE4 in malignant melanoma. In this study, we examined the role of PDE4 in mouse B16-F10 melanoma cells. In these cells, PDE4 activity was found to be ∼60% of total PDE activity. RT-PCR detected only PDE4B and PDE4D mRNA. Cell growth was inhibited by the cAMP analog, 8-bromo-cAMP, but not by the specific PDE4 inhibitors, rolipram and denbufylline, which increased intracellular cAMP concentrations. Finally, migration of the B16-F10 cells was inhibited by the PDE4 inhibitors and 8-bromo-cAMP, while migration was increased by a protein kinase A (PKA) inhibitor, PKI(14-22), and was not affected by 8-pCPT-2'-O-Me-cAMP, which is an analog of exchange protein activated by cAMP (Epac). The inhibitory effect of rolipram on migration was reversed by PKI(14-22). Based on these results, PDE4 appears to play an important role in the migration of B16-F10 cells, and therefore may be a novel target for the treatment of malignant melanoma.

[Hyperbolic growth of marine and continental biodiversity through the phanerozoic and community evolution].

PubMed

Markov, A V; Korotaev, A V

2008-01-01

Among diverse models that are used to describe and interpret the changes in global biodiversity through the Phanerozoic, the exponential and logistic models (traditionally used in population biology) are the most popular. As we have recently demonstrated (Markov, Korotayev, 2007), the growth of the Phanerozoic marine biodiversity at genus level correlates better with the hyperbolic model (widely used in demography and macrosociology). Here we show that the hyperbolic model is also applicable to the Phanerozoic continental biota at genus and family levels, and to the marine biota at species, genus, and family levels. There are many common features in the evolutionary dynamics of the marine and continental biotas that imply similarity and common nature of the factors and mechanisms underlying the hyperbolic growth. Both marine and continental biotas are characterized by continuous growth of the mean longevity of taxa, by decreasing extinction and origination rates, by similar pattern of replacement of dominant groups, by stepwise accumulation of evolutionary stable, adaptable and "physiologically buffered" taxa with effective mechanisms of parental care, protection of early developmental stages, etc. At the beginning of the development of continental biota, the observed taxonomic diversity was substantially lower than that predicted by the hyperbolic model. We suggest that this is due, firstly, to the fact that, during the earliest stages of the continental biota evolution, the groups that are not preserved in the fossil record (such as soil bacteria, unicellular algae, lichens, etc.) played a fundamental role, and secondly, to the fact that the continental biota initially formed as a marginal portion of the marine biota, rather than a separate system. The hyperbolic dynamics is most prominent when both marine and continental biotas are considered together. This fact can be interpreted as a proof of the integrated nature of the biosphere. In the macrosociological models, the hyperbolic pattern of the world population growth arises from a non-linear second-order positive feedback between the demographic growth and technological development (more people - more potential inventors - faster technological growth - the carrying capacity of the Earth grows faster - faster population growth - more people - more potential inventors, and so on). Based on the analogy with macrosociological models and diverse paleontological data, we suggest that the hyperbolic character of biodiversity growth can be similarly accounted for by a non-linear second-order positive feedback between the diversity growth and community structure complexity. The feedback can work via two parallel mechanisms: 1) decreasing extinction rate (more taxa- higher alpha diversity, or mean number of taxa in a community - communities become more complex and stable - extinction rate decreases - more taxa, and so on) and 2) increasing origination rate (new taxa facilitate niche construction; newly formed niches can be occupied by the next "generation" of taxa). The latter possibility makes the mechanisms underlying the hyperbolic growth of biodiversity and human population even more similar, because the total ecospace of the biota is analogous to the "carrying capacity of the Earth" in demography. As far as new species can increase ecospace and facilitate opportunities for additional species entering the community, they are analogous to the "inventors" of the demographic models whose inventions increase the carrying capacity of the Earth. The hyperbolic growth of the Phanerozoic biodiverstiy suggests that "cooperative" interactions between taxa can play an important role in evolution, along with generally accepted competitive interactions. Due to this "cooperation", the evolution of biodiversity acquires some features of a self-accelerating process. Macroevolutionary "cooperation" reveals itself in: 1) increasing stability of communities that arises from alpha diversity growth; 2) ability of species to facilitate opportunities for additional species entering the community.

Direct interaction of the inhibitory gamma-subunit of Rod cGMP phosphodiesterase (PDE6) with the PDE6 GAFa domains.

PubMed

Muradov, Khakim G; Granovsky, Alexey E; Schey, Kevin L; Artemyev, Nikolai O

2002-03-26

Retinal rod and cone cGMP phosphodiesterases (PDE6 family) function as the effector enzyme in the vertebrate visual transduction cascade. The activity of PDE6 catalytic subunits is controlled by the Pgamma-subunits. In addition to the inhibition of cGMP hydrolysis at the catalytic sites, Pgamma is known to stimulate a noncatalytic binding of cGMP to the regulatory GAFa-GAFb domains of PDE6. The latter role of Pgamma has been attributed to its polycationic region. To elucidate the structural basis for the regulation of cGMP binding to the GAF domains of PDE6, a photoexcitable peptide probe corresponding to the polycationic region of Pgamma, Pgamma-21-45, was specifically cross-linked to rod PDE6alphabeta. The site of Pgamma-21-45 cross-linking was localized to Met138Gly139 within the PDE6alpha GAFa domain using mass spectrometric analysis. Chimeras between PDE5 and cone PDE6alpha', containing GAFa and/or GAFb domains of PDE6alpha' have been generated to probe a potential role of the GAFb domains in binding to Pgamma. Analysis of the inhibition of the PDE5/PDE6alpha' chimeras by Pgamma supported the role of PDE6 GAFa but not GAFb domains in the interaction with Pgamma. Our results suggest that a direct binding of the polycationic region of Pgamma to the GAFa domains of PDE6 may lead to a stabilization of the noncatalytic cGMP-binding sites.

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

Effects of PDE4 Pathway Inhibition in Rat Experimental Stroke

PubMed Central

Yang, Fan; Sumbria, Rachita K.; Xue, Dong; Yu, Chuanhui; He, Dan; Liu, Shuo; Paganini-Hill, Annlia; Fisher, Mark J.

2015-01-01

PURPOSE The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS Rats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model. RESULTS Global inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (p<0.01) and 138% (p<0.05) of control in the ligation and embolic models, respectively. PDE4D knockout rats subjected to embolic stroke showed no change in infarct size compared to wild-type control. CONCLUSIONS Despite increase in infarct size after global inhibition of the PDE4 pathway with rolipram, specific inhibition of the PDE4D isoform had no effect on experimental stroke. These findings support a role for the PDE4 pathway, independent of the PDE4D isoform, in ischemic stroke pathogenesis. PMID:25224348

On the design of experiments for determining ternary mixture free energies from static light scattering data using a nonlinear partial differential equation

PubMed Central

Wahle, Chris W.; Ross, David S.; Thurston, George M.

2012-01-01

We mathematically design sets of static light scattering experiments to provide for model-independent measurements of ternary liquid mixing free energies to a desired level of accuracy. A parabolic partial differential equation (PDE), linearized from the full nonlinear PDE [D. Ross, G. Thurston, and C. Lutzer, J. Chem. Phys. 129, 064106 (2008)10.1063/1.2937902], describes how data noise affects the free energies to be inferred. The linearized PDE creates a net of spacelike characteristic curves and orthogonal, timelike curves in the composition triangle, and this net governs diffusion of information coming from light scattering measurements to the free energy. Free energy perturbations induced by a light scattering perturbation diffuse along the characteristic curves and towards their concave sides, with a diffusivity that is proportional to the local characteristic curvature radius. Consequently, static light scattering can determine mixing free energies in regions with convex characteristic curve boundaries, given suitable boundary data. The dielectric coefficient is a Lyapunov function for the dynamical system whose trajectories are PDE characteristics. Information diffusion is heterogeneous and system-dependent in the composition triangle, since the characteristics depend on molecular interactions and are tangent to liquid-liquid phase separation coexistence loci at critical points. We find scaling relations that link free energy accuracy, total measurement time, the number of samples, and the interpolation method, and identify the key quantitative tradeoffs between devoting time to measuring more samples, or fewer samples more accurately. For each total measurement time there are optimal sample numbers beyond which more will not improve free energy accuracy. We estimate the degree to which many-point interpolation and optimized measurement concentrations can improve accuracy and save time. For a modest light scattering setup, a sample calculation shows that less than two minutes of measurement time is, in principle, sufficient to determine the dimensionless mixing free energy of a non-associating ternary mixture to within an integrated error norm of 0.003. These findings establish a quantitative framework for designing light scattering experiments to determine the Gibbs free energy of ternary liquid mixtures. PMID:22830693

Mutation in rod PDE6 linked to congenital stationary night blindness impairs the enzyme inhibition by its gamma-subunit.

PubMed

Muradov, Khakim G; Granovsky, Alexey E; Artemyev, Nikolai O

2003-03-25

Photoreceptor cGMP phosphodiesterase (PDE6) is the effector enzyme in the vertebrate visual transduction cascade. The activity of rod PDE6 catalytic alpha- and beta-subunits is blocked in the dark by two inhibitory Pgamma-subunits. The inhibition is released upon light-stimulation of photoreceptor cells. Mutation H258N in PDE6beta has been linked to congenital stationary night blindness (CSNB) in a large Danish family (Rambusch pedigree) (Gal, A., Orth, U., Baehr, W., Schwinger, E., and Rosenberg, T. (1994) Nat. Genet. 7, 64-67.) We have analyzed the consequences of this mutation for PDE6 function using a Pgamma-sensitive PDE6alpha'/PDE5 chimera, Chi16. Biochemical analysis of the H257N mutant, an equivalent of PDE6betaH258N, demonstrates that this substitution does not alter the ability of chimeric PDE to dimerize or the enzyme's catalytic properties. The sensitivity of H257N to a competitive inhibitor zaprinast was also unaffected. However, the mutant displayed a significant impairment in the inhibitory interaction with Pgamma, which was apparent from a approximately 20-fold increase in the K(i) value (46 nM) and incomplete maximal inhibition. The inhibitory defect of H257N is not due to perturbation of noncatalytic cGMP binding to the PDE6alpha' GAF domains. The noncatalytic cGMP-binding characteristics of the H257N mutant were similar to those of the parent PDE6alpha'/PDE5 chimera. Since rod PDE6 in the Rambusch CSNB is a catalytic heterodimer of the wild-type PDE6alpha and mutant PDE6beta, Chi16 and H257N were coexpressed, and a heterodimeric PDE, Chi16/H257N, was isolated. It displayed two Pgamma inhibitory sites with the K(i) values of 5 and 57 nM. Our results support the hypothesis that mutation H258N in PDE6beta causes CSNB through incomplete inhibition of PDE6 activity by Pgamma, which leads to desensitization of rod photoreceptors.

AKAP3 Selectively Binds PDE4A Isoforms in Bovine Spermatozoa1

PubMed Central

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

2006-01-01

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

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. Copyright © 2015 the American Physiological Society.

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

Mice deficient in phosphodiesterase-4A display anxiogenic-like behavior.

PubMed

Hansen, Rolf T; Conti, Marco; Zhang, Han-Ting

2014-08-01

Phosphodiesterases (PDEs) are a super family of enzymes responsible for the halting of intracellular cyclic nucleotide signaling and may represent novel therapeutic targets for treatment of cognitive disorders. PDE4 is of considerable interest to cognitive research because it is highly expressed in the brain, particularly in the cognition-related brain regions. Recently, the functional role of PDE4B and PDE4D, two of the four PDE4 subtypes (PDE4A, B, C, and D), in behavior has begun to be identified; however, the role of PDE4A in the regulation of behavior is still unknown. The purpose of this study was to characterize the functional role of PDE4A in behavior. The role of PDE4A in behavior was evaluated through a battery of behavioral tests using PDE4A knockout (KO) mice; urine corticosterone levels were also measured. PDE4A KO mice exhibited improved memory in the step-through-passive-avoidance test. They also displayed anxiogenic-like behavior in elevated-plus maze, holeboard, light-dark transition, and novelty suppressed feeding tests. Consistent with the anxiety profile, PDE4A KO mice had elevated corticosterone levels compared with wild-type controls post-stress. Interestingly, PDE4A KO mice displayed no change in object recognition, Morris water maze, forced swim, tail suspension, and duration of anesthesia induced by co-administration of xylazine and ketamine (suggesting that PDE4A KO may not be emetic). These results suggest that PDE4A may be important in the regulation of emotional memory and anxiety-like behavior, but not emesis. PDE4A could possibly represent a novel therapeutic target in the future for anxiety or disorders affecting memory.

A conformational switch in the inhibitory gamma-subunit of PDE6 upon enzyme activation by transducin.

PubMed

Granovsky, A E; Artemyev, N O

2001-11-06

In response to light, a photoreceptor G protein, transducin, activates cGMP-phosphodiesterase (PDE6) by displacing the inhibitory gamma-subunits (Pgamma) from the enzyme's catalytic sites. Evidence suggests that the activation of PDE6 involves a conformational change of the key inhibitory C-terminal domain of Pgamma. In this study, the C-terminal region of Pgamma, Pgamma-73-85, has been targeted for Ala-scanning mutagenesis to identify the point-to-point interactions between Pgamma and the PDE6 catalytic subunits and to probe the nature of the conformational change. Pgamma mutants were tested for their ability to inhibit PDE6 and a chimeric PDE5-conePDE6 enzyme containing the Pgamma C-terminus-binding site of cone PDE. This analysis has revealed that in addition to previously characterized Ile86 and Ile87, important inhibitory contact residues of Pgamma include Asn74, His75, and Leu78. The patterns of mutant PDE5-conePDE6 enzyme inhibition suggest the interaction between the PgammaAsn74/His75 sequence and Met758 of the cone PDE6alpha' catalytic subunit. This interaction, and the interaction between the PgammaIle86/Ile87 and PDE6alpha'Phe777/Phe781 residues, is most consistent with an alpha-helical structure of the Pgamma C-terminus. The analysis of activation of PDE6 enzymes containing Pgamma mutants with Ala-substituted transducin-contact residues demonstrated the critical role of PgammaLeu76. Accordingly, we hypothesize that the initial step in PDE6 activation involves an interaction of transducin-alpha with PgammaLeu76. This interaction introduces a bend into the alpha-helical structure of the Pgamma C-terminus, allowing transducin-alpha to further twist the C-terminus thereby uncovering the catalytic pocket of PDE6.

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

PubMed Central

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

2015-01-01

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. PMID:26201952

cAMP-specific PDE4 Phosphodiesterases and AIP in the Pathogenesis of Pituitary Tumors

PubMed Central

Bolger, Graeme B.; Bizzi, Mariana Ferreira; Brant Pinheiro, Sergio Veloso; Trivellin, Giampaolo; Smoot, Lisa; Accavitti, Mary-Ann; Korbonits, Márta; Ribeiro-Oliveira, Antonio

2016-01-01

PDE4 cyclic nucleotide phosphodiesterases regulate cAMP abundance in cells and thereby regulate numerous processes, including cell growth and differentiation. The rat PDE4A5 isoform (human homologue PDE4A4) interacts with the AIP protein (also called XAP2 or ARA-9). Germline mutations in AIP occur in approximately 20% of patients with Familial Isolated Pituitary Adenoma (FIPA) and 20% of childhood-onset simplex somatotroph adenomas. We therefore examined the protein expression of PDE4A4 and the closely-related isoform PDE4A8 in normal human pituitary tissue and in pituitary adenomas. PDE4A4 had low expression in normal pituitary, but was significantly over-expressed in somatotroph, lactotroph, corticotroph and clinically non-functioning gonadotroph adenomas (P<0.0001 for all subtypes). Likewise, PDE4A8 was expressed in normal pituitary and was also significantly over-expressed in the adenoma subtypes (P<0.0001 for all). Among the different adenoma subtypes, corticotroph and lactotroph adenomas were the highest and lowest expressed for PDE4A4, respectively, whereas the opposite was observed for PDE4A8. Naturally occurring oncogenic variants in AIP were shown by a two-hybrid assay to disrupt the ability of AIP to interact with PDE4A5. A reverse-two-hybrid screen identified numerous additional variants in the TPR region of AIP that also disrupted its ability to interact with PDE4A5. The expression of PDE4A4 and PDE4A8 in normal pituitary, their increased expression in adenomatous pituitary cells where AIP is meant to participate, and the disruption of the PDE4A4-AIP interaction by AIP mutants may play a role in pituitary tumorigenesis. PMID:27267386

A Role for Phosphodiesterase 11A (PDE11A) in the Formation of Social Memories and the Stabilization of Mood

PubMed Central

Kelly, Michy P.

2017-01-01

The most recently discovered 3′,5′-cyclic nucleotide phosphodiesterase family is the Phosphodiesterase 11 (PDE11) family, which is encoded by a single gene PDE11A. PDE11A is a dual-specific PDE, breaking down both cAMP and cGMP. There are four PDE11A splice variants (PDE11A1–4) with distinct tissue expression profiles and unique N-terminal regulatory regions, suggesting that each isoform could be individually targeted with a small molecule or biologic. PDE11A4 is the PDE11A isoform expressed in brain and is found in the hippocampal formation of humans and rodents. Studies in rodents show that PDE11A4 mRNA expression in brain is, in fact, restricted to the hippocampal formation (CA1, possibly CA2, subiculum, and the adjacently connected amygdalohippocampal area). Within the hippocampal formation of rodents, PDE11A4 protein is expressed in neurons but not astrocytes, with a distribution across nuclear, cytoplasmic, and membrane compartments. This subcellular localization of PDE11A4 is altered in response to social experience in mouse, and in vitro studies show the compartmentalization of PDE11A4 is controlled, at least in part, by homodimerization and N-terminal phosphorylation. PDE11A4 expression dramatically increases in the hippocampus with age in the rodent hippocampus, from early postnatal life to late aging, suggesting PDE11A4 function may evolve across the lifespan. Interestingly, PDE11A4 protein shows a 3–10-fold enrichment in the rodent ventral hippocampal formation (VHIPP; a.k.a. anterior in primates) versus dorsal hippocampal formation (DHIPP). Consistent with this enrichment in VHIPP, studies in knockout mice show that PDE11A regulates the formation of social memories and the stabilization of mood and is a critical mechanism by which social experience feeds back to modify the brain and subsequent social behaviors. PDE11A4 likely controls behavior by regulating hippocampal glutamatergic, oxytocin, and cytokine signaling, as well as protein translation. Given its unique tissue distribution and relatively selective effects on behavior, PDE11A may represent a novel therapeutic target for neuropsychiatric, neurodevelopmental, or age-related disorders. Therapeutically targeting PDE11A4 may be a way to selectively restore aberrant cyclic nucleotide signaling in the hippocampal formation while leaving the rest of the brain and periphery untouched, thus, relieving deficits while avoiding unwanted side effects. PMID:28956334

Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships.

PubMed

Zhou, Zhong-Zhen; Ge, Bing-Chen; Chen, Yu-Fang; Shi, Xiu-Dong; Yang, Xue-Mei; Xu, Jiang-Ping

2015-11-15

In this study, a series of catechol-based amides (8a-n) with different amide linkers linking the catecholic moiety to the terminal phenyl ring was designed and synthesized as potent phosphodiesterase (PDE) 4D inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4B1 and PDE4D7 enzymes, and other PDE family members. The results indicated the majority of compounds 8a-n displayed moderate to good inhibitory activities against PDE4CAT. Among these compounds, compound 8 j with a short amide linker (-CONHCH2-) displayed comparable PDE4CAT inhibitory activity (IC50=410 nM) with rolipram. More interestingly, compound 8 g, a potent and selective PDE4D inhibitor (IC50=94 nM), exhibited a 10-fold selectivity over the PDE4B subtypes and an over 1000-fold selectivity against other PDE family members. Docking simulations suggested that 8 g forms three extra H-bonds with the N-H of residue Asn487 and two water molecules. Copyright © 2015 Elsevier Ltd. All rights reserved.

Myocardial Response to Milrinone in Single Right Ventricle Heart Disease.

PubMed

Nakano, Stephanie J; Nelson, Penny; Sucharov, Carmen C; Miyamoto, Shelley D

2016-07-01

Empiric treatment with milrinone, a phosphodiesterase (PDE) 3 inhibitor, has become increasingly common in patients with single ventricle heart disease of right ventricular (RV) morphology (SRV); our objective was to characterize the myocardial response to PDE3 inhibition (PDE3i) in the pediatric population with SRV. Cyclic adenosine monophosphate levels, PDE activity, and phosphorylated phospholamban (PLN) were determined in explanted human ventricular myocardium from nonfailing pediatric donors (n = 10) and pediatric patients transplanted secondary to SRV. Subjects with SRV were further classified by PDE3i treatment (n = 13 with PDE3i and n = 12 without PDE3i). In comparison with nonfailing RV myocardium (n = 8), cyclic adenosine monophosphate levels are lower in patients with SRV treated with PDE3i (n = 12, P = .021). Chronic PDE3i does not alter total PDE or PDE3 activity in SRV myocardium. Compared with nonfailing RV myocardium, SRV myocardium (both with and without PDE3i) demonstrates equivalent phosphorylated PLN at the protein kinase A phosphorylation site. As evidenced by preserved phosphorylated PLN, the molecular adaptation associated with SRV differs significantly from that demonstrated in pediatric heart failure because of dilated cardiomyopathy. These alterations support a pathophysiologically distinct mechanism of heart failure in pediatric patients with SRV, which has direct implications regarding the presumed response to PDE3i treatment in this population. Copyright © 2016 Elsevier Inc. All rights reserved.

Existence and Regularity Results for the Inviscid Primitive Equations with Lateral Periodicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamouda, Makram, E-mail: mahamoud@indiana.edu; Jung, Chang-Yeol, E-mail: changyeoljung@gmail.com; Temam, Roger, E-mail: temam@indiana.edu

2016-06-15

The article is devoted to prove the existence and regularity of the solutions of the 3D inviscid Linearized Primitive Equations (LPEs) in a channel with lateral periodicity. This was assumed in a previous work (Hamouda et al. in Discret Contin Dyn Syst Ser S 6(2):401–422, 2013) which is concerned with the boundary layers generated by the corresponding viscous problem. Although the equations under investigation here are of hyperbolic type, the standard methods do not apply because of the specificity of the hyperbolic system. A set of non-local boundary conditions for the inviscid LPEs has to be imposed at the lateralmore » boundary of the channel making thus the system well-posed.« less

A numerical method to solve the 1D and the 2D reaction diffusion equation based on Bessel functions and Jacobian free Newton-Krylov subspace methods

NASA Astrophysics Data System (ADS)

Parand, K.; Nikarya, M.

2017-11-01

In this paper a novel method will be introduced to solve a nonlinear partial differential equation (PDE). In the proposed method, we use the spectral collocation method based on Bessel functions of the first kind and the Jacobian free Newton-generalized minimum residual (JFNGMRes) method with adaptive preconditioner. In this work a nonlinear PDE has been converted to a nonlinear system of algebraic equations using the collocation method based on Bessel functions without any linearization, discretization or getting the help of any other methods. Finally, by using JFNGMRes, the solution of the nonlinear algebraic system is achieved. To illustrate the reliability and efficiency of the proposed method, we solve some examples of the famous Fisher equation. We compare our results with other methods.

Pseudo almost periodic solutions to some systems of nonlinear hyperbolic second-order partial differential equations

NASA Astrophysics Data System (ADS)

Al-Islam, Najja Shakir

In this Dissertation, the existence of pseudo almost periodic solutions to some systems of nonlinear hyperbolic second-order partial differential equations is established. For that, (Al-Islam [4]) is first studied and then obtained under some suitable assumptions. That is, the existence of pseudo almost periodic solutions to a hyperbolic second-order partial differential equation with delay. The second-order partial differential equation (1) represents a mathematical model for the dynamics of gas absorption, given by uxt+a x,tux=Cx,t,u x,t , u0,t=4 t, 1 where a : [0, L] x RR , C : [0, L] x R x RR , and ϕ : RR are (jointly) continuous functions ( t being the greatest integer function) and L > 0. The results in this Dissertation generalize those of Poorkarimi and Wiener [22]. Secondly, a generalization of the above-mentioned system consisting of the non-linear hyperbolic second-order partial differential equation uxt+a x,tux+bx,t ut+cx,tu=f x,t,u, x∈ 0,L,t∈ R, 2 equipped with the boundary conditions ux,0 =40x, u0,t=u 0t, uxx,0=y 0x, x∈0,L, t∈R, 3 where a, b, c : [0, L ] x RR and f : [0, L] x R x RR are (jointly) continuous functions is studied. Under some suitable assumptions, the existence and uniqueness of pseudo almost periodic solutions to particular cases, as well as the general case of the second-order hyperbolic partial differential equation (2) are studied. The results of all studies contained within this text extend those obtained by Aziz and Meyers [6] in the periodic setting.

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

PubMed

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

2014-01-01

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

Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy

PubMed Central

Miller, Clint L.; Oikawa, Masayoshi; Cai, Yujun; Wojtovich, Andrew P.; Nagel, David J.; Xu, Xiangbin; Xu, Haodong; Florio, Vince; Rybalkin, Sergei D.; Beavo, Joseph A.; Chen, Yiu-Fai; Li, Jian-Dong; Blaxall, Burns C.; Abe, Jun-ichi; Yan, Chen

2009-01-01

Rationale Cyclic nucleotide phosphodiesterases (PDE) through the degradation of second messenger cyclic guanosine monophosphate (cGMP) play critical roles in maintaining cardiomyocyte homeostasis. Ca2+/CaM-activated cGMP-hydrolyzing PDE1 family may play a pivotal role in balancing intracellular Ca2+/CaM and cGMP signaling, however its function in cardiomyocytes is unknown. Objective Herein we investigate the role of Ca2+/CaM-stimulated PDE1 in regulating pathological cardiomyocyte hypertrophy in neonatal and adult rat ventricular myocytes (NRVM and ARVM) and in the heart in vivo. Methods and Results Inhibition of PDE1 activity using a PDE1 selective inhibitor IC86340 or downregulation of PDE1A using siRNA prevented phenylephrine (PE) induced pathological myocyte hypertrophy and hypertrophic marker expression in neonatal (NRVM) and adult (ARVM) rat ventricular myocytes. Importantly, administration of the PDE1 inhibitor IC86340 attenuated cardiac hypertrophy induced by chronic ISO infusion in vivo. Both PDE1A and PDE1C mRNA and protein were detected in human hearts, however PDE1A expression was conserved in rodent hearts. Moreover, PDE1A expression was significantly upregulated in vivo in the heart and myocytes from various pathological hypertrophy animal models and in vitro in isolated NRVM and ARVM treated with neurohumoral stimuli such as angiotensin II (Ang II) and ISO. Further, PDE1A plays a critical role in PE-induced reduction of intracellular cGMP and PKG activity, and thereby cardiomyocyte hypertrophy in vitro. Conclusions These results elucidate a novel role for Ca2+/CaM-stimulated PDE1, particularly PDE1A, in regulating pathological cardiomyocyte hypertrophy via a cGMP/PKG-dependent mechanism, thereby demonstrating Ca2+ and cGMP signaling cross-talk during cardiac hypertrophy. PMID:19797176

MYOCARDIAL RESPONSE TO MILRINONE IN SINGLE RIGHT VENTRICLE HEART DISEASE

PubMed Central

Nakano, Stephanie J.; Nelson, Penny; Sucharov, Carmen C.; Miyamoto, Shelley D.

2016-01-01

Objectives Empiric treatment with milrinone, a phosphodiesterase 3 inhibitor (PDE3i), has become increasingly common in patients with single ventricle heart disease of right ventricular morphology (SRV); our objective was to characterize the myocardial response to PDE3i in the pediatric population with SRV. Study design Cyclic adenosine monophosphate (cAMP) levels, phosphodiesterase (PDE) activity, and phospholamban phosphorylation (pPLN) were determined in explanted human ventricular myocardium from nonfailing pediatric donors (n=10) and pediatric patients transplanted secondary to SRV. SRV subjects were further classified by PDE3i treatment (n=13 with PDE3i and n=12 without PDE3i). Results In comparison with nonfailing RV myocardium, cAMP levels are lower in patients with SRV treated with PDE3i (p=0.021). Chronic PDE3i does not alter total PDE or PDE3 activity in SRV myocardium. When compared with nonfailing RV myocardium, SRV myocardium (both with and without PDE3i) demonstrates equivalent pPLN at the protein kinase A phosphorylation site. Conclusions As evidenced by preserved pPLN, the molecular adaptation associated with SRV differs significantly from that demonstrated in pediatric heart failure due to dilated cardiomyopathy. These alterations support a pathophysiologically distinct mechanism of heart failure in pediatric patients with SRV, which has direct implications regarding the presumed response to PDE3i treatment in this population. PMID:27181939

A simple smoothness indicator for the WENO scheme with adaptive order

NASA Astrophysics Data System (ADS)

Huang, Cong; Chen, Li Li

2018-01-01

The fifth order WENO scheme with adaptive order is competent for solving hyperbolic conservation laws, its reconstruction is a convex combination of a fifth order linear reconstruction and three third order linear reconstructions. Note that, on uniform mesh, the computational cost of smoothness indicator for fifth order linear reconstruction is comparable with the sum of ones for three third order linear reconstructions, thus it is too heavy; on non-uniform mesh, the explicit form of smoothness indicator for fifth order linear reconstruction is difficult to be obtained, and its computational cost is much heavier than the one on uniform mesh. In order to overcome these problems, a simple smoothness indicator for fifth order linear reconstruction is proposed in this paper.

PDE4 as a target for cognition enhancement

PubMed Central

Richter, Wito; Menniti, Frank S.; Zhang, Han-Ting; Conti, Marco

2014-01-01

Introduction The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs. Areas covered PDE4 is the largest of the eleven mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation. Expert opinion PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors. PMID:23883342

Bounding the electrostatic free energies associated with linear continuum models of molecular solvation.

PubMed

Bardhan, Jaydeep P; Knepley, Matthew G; Anitescu, Mihai

2009-03-14

The importance of electrostatic interactions in molecular biology has driven extensive research toward the development of accurate and efficient theoretical and computational models. Linear continuum electrostatic theory has been surprisingly successful, but the computational costs associated with solving the associated partial differential equations (PDEs) preclude the theory's use in most dynamical simulations. Modern generalized-Born models for electrostatics can reproduce PDE-based calculations to within a few percent and are extremely computationally efficient but do not always faithfully reproduce interactions between chemical groups. Recent work has shown that a boundary-integral-equation formulation of the PDE problem leads naturally to a new approach called boundary-integral-based electrostatics estimation (BIBEE) to approximate electrostatic interactions. In the present paper, we prove that the BIBEE method can be used to rigorously bound the actual continuum-theory electrostatic free energy. The bounds are validated using a set of more than 600 proteins. Detailed numerical results are presented for structures of the peptide met-enkephalin taken from a molecular-dynamics simulation. These bounds, in combination with our demonstration that the BIBEE methods accurately reproduce pairwise interactions, suggest a new approach toward building a highly accurate yet computationally tractable electrostatic model.

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.

Bounding the electrostatic free energies associated with linear continuum models of molecular solvation

NASA Astrophysics Data System (ADS)

Bardhan, Jaydeep P.; Knepley, Matthew G.; Anitescu, Mihai

2009-03-01

The importance of electrostatic interactions in molecular biology has driven extensive research toward the development of accurate and efficient theoretical and computational models. Linear continuum electrostatic theory has been surprisingly successful, but the computational costs associated with solving the associated partial differential equations (PDEs) preclude the theory's use in most dynamical simulations. Modern generalized-Born models for electrostatics can reproduce PDE-based calculations to within a few percent and are extremely computationally efficient but do not always faithfully reproduce interactions between chemical groups. Recent work has shown that a boundary-integral-equation formulation of the PDE problem leads naturally to a new approach called boundary-integral-based electrostatics estimation (BIBEE) to approximate electrostatic interactions. In the present paper, we prove that the BIBEE method can be used to rigorously bound the actual continuum-theory electrostatic free energy. The bounds are validated using a set of more than 600 proteins. Detailed numerical results are presented for structures of the peptide met-enkephalin taken from a molecular-dynamics simulation. These bounds, in combination with our demonstration that the BIBEE methods accurately reproduce pairwise interactions, suggest a new approach toward building a highly accurate yet computationally tractable electrostatic model.

Long-wave model for strongly anisotropic growth of a crystal step.

PubMed

Khenner, Mikhail

2013-08-01

A continuum model for the dynamics of a single step with the strongly anisotropic line energy is formulated and analyzed. The step grows by attachment of adatoms from the lower terrace, onto which atoms adsorb from a vapor phase or from a molecular beam, and the desorption is nonnegligible (the "one-sided" model). Via a multiscale expansion, we derived a long-wave, strongly nonlinear, and strongly anisotropic evolution PDE for the step profile. Written in terms of the step slope, the PDE can be represented in a form similar to a convective Cahn-Hilliard equation. We performed the linear stability analysis and computed the nonlinear dynamics. Linear stability depends on whether the stiffness is minimum or maximum in the direction of the step growth. It also depends nontrivially on the combination of the anisotropy strength parameter and the atomic flux from the terrace to the step. Computations show formation and coarsening of a hill-and-valley structure superimposed onto a long-wavelength profile, which independently coarsens. Coarsening laws for the hill-and-valley structure are computed for two principal orientations of a maximum step stiffness, the increasing anisotropy strength, and the varying atomic flux.

Homology modeling, docking studies and molecular dynamic simulations using graphical processing unit architecture to probe the type-11 phosphodiesterase catalytic site: a computational approach for the rational design of selective inhibitors.

PubMed

Cichero, Elena; D'Ursi, Pasqualina; Moscatelli, Marco; Bruno, Olga; Orro, Alessandro; Rotolo, Chiara; Milanesi, Luciano; Fossa, Paola

2013-12-01

Phosphodiesterase 11 (PDE11) is the latest isoform of the PDEs family to be identified, acting on both cyclic adenosine monophosphate and cyclic guanosine monophosphate. The initial reports of PDE11 found evidence for PDE11 expression in skeletal muscle, prostate, testis, and salivary glands; however, the tissue distribution of PDE11 still remains a topic of active study and some controversy. Given the sequence similarity between PDE11 and PDE5, several PDE5 inhibitors have been shown to cross-react with PDE11. Accordingly, many non-selective inhibitors, such as IBMX, zaprinast, sildenafil, and dipyridamole, have been documented to inhibit PDE11. Only recently, a series of dihydrothieno[3,2-d]pyrimidin-4(3H)-one derivatives proved to be selective toward the PDE11 isoform. In the absence of experimental data about PDE11 X-ray structures, we found interesting to gain a better understanding of the enzyme-inhibitor interactions using in silico simulations. In this work, we describe a computational approach based on homology modeling, docking, and molecular dynamics simulation to derive a predictive 3D model of PDE11. Using a Graphical Processing Unit architecture, it is possible to perform long simulations, find stable interactions involved in the complex, and finally to suggest guideline for the identification and synthesis of potent and selective inhibitors. © 2013 John Wiley & Sons A/S.

Time domain convergence properties of Lyapunov stable penalty methods

NASA Technical Reports Server (NTRS)

Kurdila, A. J.; Sunkel, John

1991-01-01

Linear hyperbolic partial differential equations are analyzed using standard techniques to show that a sequence of solutions generated by the Liapunov stable penalty equations approaches the solution of the differential-algebraic equations governing the dynamics of multibody problems arising in linear vibrations. The analysis does not require that the system be conservative and does not impose any specific integration scheme. Variational statements are derived which bound the error in approximation by the norm of the constraint violation obtained in the approximate solutions.

Lateralization of the Huggins pitch

NASA Astrophysics Data System (ADS)

Zhang, Peter Xinya; Hartmann, William M.

2004-05-01

The lateralization of the Huggins pitch (HP) was measured using a direct estimation method. The background noise was initially N0 or Nπ, and then the laterality of the entire stimulus was varied with a frequency-independent interaural delay, ranging from -1 to +1 ms. Two versions of the HP boundary region were used, stepped phase and linear phase. When presented in isolation, without the broadband background, the stepped boundary can be lateralized on its own but the linear boundary cannot. Nevertheless, the lateralizations of both forms of HP were found to be almost identical functions both of the interaural delay and of the boundary frequency over a two-octave range. In a third experiment, the same listeners lateralized sine tones in quiet as a function of interaural delay. Good agreement was found between lateralizations of the HP and of the corresponding sine tones. The lateralization judgments depended on the boundary frequency according to the expected hyperbolic law except when the frequency-independent delay was zero. For the latter case, the dependence on boundary frequency was much slower than hyperbolic. [Work supported by the NIDCD grant DC 00181.

Spectrophotometric evaluation of stability constants of 1:1 weak complexes from continuous variation data.

PubMed

Sayago, Ana; Asuero, Agustin G

2006-09-14

A bilogarithmic hyperbolic cosine method for the spectrophotometric evaluation of stability constants of 1:1 weak complexes from continuous variation data has been devised and applied to literature data. A weighting scheme, however, is necessary in order to take into account the transformation for linearization. The method may be considered a useful alternative to methods in which one variable is involved on both sides of the basic equation (i.e. Heller and Schwarzenbach, Likussar and Adsul and Ramanathan). Classical least squares lead in those instances to biased and approximate stability constants and limiting absorbance values. The advantages of the proposed method are: the method gives a clear indication of the existence of only one complex in solution, it is flexible enough to allow for weighting of measurements and the computation procedure yield the best value of logbeta11 and its limit of error. The agreement between the values obtained by applying the weighted hyperbolic cosine method and the non-linear regression (NLR) method is good, being in both cases the mean quadratic error at a minimum.

Optimal trajectories based on linear equations

NASA Technical Reports Server (NTRS)

Carter, Thomas E.

1990-01-01

The Principal results of a recent theory of fuel optimal space trajectories for linear differential equations are presented. Both impulsive and bounded-thrust problems are treated. A new form of the Lawden Primer vector is found that is identical for both problems. For this reason, starting iteratives from the solution of the impulsive problem are highly effective in the solution of the two-point boundary-value problem associated with bounded thrust. These results were applied to the problem of fuel optimal maneuvers of a spacecraft near a satellite in circular orbit using the Clohessy-Wiltshire equations. For this case two-point boundary-value problems were solved using a microcomputer, and optimal trajectory shapes displayed. The results of this theory can also be applied if the satellite is in an arbitrary Keplerian orbit through the use of the Tschauner-Hempel equations. A new form of the solution of these equations has been found that is identical for elliptical, parabolic, and hyperbolic orbits except in the way that a certain integral is evaluated. For elliptical orbits this integral is evaluated through the use of the eccentric anomaly. An analogous evaluation is performed for hyperbolic orbits.

Time-stable overset grid method for hyperbolic problems using summation-by-parts operators

NASA Astrophysics Data System (ADS)

Sharan, Nek; Pantano, Carlos; Bodony, Daniel J.

2018-05-01

A provably time-stable method for solving hyperbolic partial differential equations arising in fluid dynamics on overset grids is presented in this paper. The method uses interface treatments based on the simultaneous approximation term (SAT) penalty method and derivative approximations that satisfy the summation-by-parts (SBP) property. Time-stability is proven using energy arguments in a norm that naturally relaxes to the standard diagonal norm when the overlap reduces to a traditional multiblock arrangement. The proposed overset interface closures are time-stable for arbitrary overlap arrangements. The information between grids is transferred using Lagrangian interpolation applied to the incoming characteristics, although other interpolation schemes could also be used. The conservation properties of the method are analyzed. Several one-, two-, and three-dimensional, linear and non-linear numerical examples are presented to confirm the stability and accuracy of the method. A performance comparison between the proposed SAT-based interface treatment and the commonly-used approach of injecting the interpolated data onto each grid is performed to highlight the efficacy of the SAT method.

Investigating the use of a rational Runge Kutta method for transport modelling

NASA Astrophysics Data System (ADS)

Dougherty, David E.

An unconditionally stable explicit time integrator has recently been developed for parabolic systems of equations. This rational Runge Kutta (RRK) method, proposed by Wambecq 1 and Hairer 2, has been applied by Liu et al.3 to linear heat conduction problems in a time-partitioned solution context. An important practical question is whether the method has application for the solution of (nearly) hyperbolic equations as well. In this paper the RRK method is applied to a nonlinear heat conduction problem, the advection-diffusion equation, and the hyperbolic Buckley-Leverett problem. The method is, indeed, found to be unconditionally stable for the linear heat conduction problem and performs satisfactorily for the nonlinear heat flow case. A heuristic limitation on the utility of RRK for the advection-diffusion equation arises in the Courant number; for the second-order accurate one-step two-stage RRK method, a limiting Courant number of 2 applies. First order upwinding is not as effective when used with RRK as with Euler one-step methods. The method is found to perform poorly for the Buckley-Leverett problem.

Evaluation of the effect of phosphodiesterase on equine platelet activation and the effect of antigen challenge on platelet phosphodiesterase activity in horses with recurrent airway obstruction.

PubMed

Dunkel, Bettina; Rickards, Karen J; Werling, Dirk; Page, Clive P; Cunningham, Fiona M

2010-05-01

To determine whether expression of equine platelet activation-dependent surface markers is influenced by phospodiesterase (PDE) isoenzyme activity and whether antigen challenge alters platelet PDE activity in horses with recurrent airway obstruction (RAO). 16 horses. 7 healthy horses were used for in vitro experiments, 6 horses with RAO were used for antigen challenge, and 6 healthy horses were used as control animals. Three of the healthy horses had also been used in the in vitro experiments. Effects of PDE inhibition and activation of adenylyl cyclase on CD41/61 and CD62P expression on platelets and platelet-neutrophil aggregate formation in vitro were investigated via flow cytometry. Platelet PDE activity and sensitivity to inhibition of PDE3 and PDE5 isoenzymes were examined in horses with RAO and control horses before and after antigen challenge. Inhibition of PDE or activation of adenylyl cyclase significantly inhibited stimulus-induced expression of CD41/61 and CD62P (by approx 94% and 40%, respectively) and percentage of CD62P positive cells (by approx 30%). Only the PDE3 inhibitor, trequinsin, caused a significant (53%) reduction in platelet-neutrophil aggregate formation. Platelet PDE activity decreased following antigen challenge in RAO-affected horses and control horses. In horses with RAO, a significant increase in sensitivity of platelet PDE to inhibition by the PDE5 inhibitor zaprinast was observed after 5 hours. Results provided further evidence that PDE3 is an important regulator of equine platelet activation and suggested that changes in regulation of platelet PDE5 may contribute to antigen-induced response in horses with RAO.

Defining the Phosphodiesterase Superfamily Members in Rat Brain Microvessels

PubMed Central

2011-01-01

Eleven phosphodiesterase (PDE) families are known, each having several different isoforms and splice variants. Recent evidence indicates that expression of individual PDE family members is tissue-specific. Little is known concerning detailed PDE component expression in brain microvessels where the blood-brain-barrier and the local cerebral blood flow are thought to be regulated by PDEs. The present study attempted to identify PDE family members that are expressed in brain microvessels. Adult male F344 rats were sacrificed and blocks of the cerebral cortex and infratentorial areas were dissected. Microvessels were isolated using a filtration method, and total RNA was extracted. RNA quality and quantity were determined using an Agilent bioanalyzer. The isolated cortical and infratentorial microvessel total RNA amounts were 2720 ± 750 ng (n = 2) and 250 ± 40 ng (n = 2), respectively. Microarrays with 22 000 transcripts demonstrated that there were 16 PDE transcripts in the PDE superfamily, exhibiting quantifiable density in the microvessels. An additional immunofluorescent study verified that PDE4D (cAMP-specific) and PDE5A (cGMP-specific) were colocalized with RECA-1 (an endothelial marker) in the cerebral cortex using both F344 rats and Sprague–Dawley rats (n = 3–6/strain). In addition, PDE4D and PDE5A were found to be colocalized with alpha-smooth muscle actin which delineates cerebral arteries and arterioles as well as pericytes. In conclusion, a filtration method followed by microarray analyses allows PDE components to be identified in brain microvessels, and confirmed that PDE4D and PDE5A are the primary forms expressed in rat brain microvessels. PMID:22860158

Causal implications of viscous damping in compressible fluid flows

PubMed

Jordan; Meyer; Puri

2000-12-01

Classically, a compressible, isothermal, viscous fluid is regarded as a mathematical continuum and its motion is governed by the linearized continuity, Navier-Stokes, and state equations. Unfortunately, solutions of this system are of a diffusive nature and hence do not satisfy causality. However, in the case of a half-space of fluid set to motion by a harmonically vibrating plate the classical equation of motion can, under suitable conditions, be approximated by the damped wave equation. Since this equation is hyperbolic, the resulting solutions satisfy causal requirements. In this work the Laplace transform and other analytical and numerical tools are used to investigate this apparent contradiction. To this end the exact solutions, as well as their special and limiting cases, are found and compared for the two models. The effects of the physical parameters on the solutions and associated quantities are also studied. It is shown that propagating wave fronts are only possible under the hyperbolic model and that the concept of phase speed has different meanings in the two formulations. In addition, discontinuities and shock waves are noted and a physical system is modeled under both formulations. Overall, it is shown that the hyperbolic form gives a more realistic description of the physical problem than does the classical theory. Lastly, a simple mechanical analog is given and connections to viscoelastic fluids are noted. In particular, the research presented here supports the notion that linear compressible, isothermal, viscous fluids can, at least in terms of causality, be better characterized as a type of viscoelastic fluid.

Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction.

PubMed

Li, Longhu; Haider, Husnain Kh; Wang, Linlin; Lu, Gang; Ashraf, Muhammad

2012-05-15

We previously showed that treatment with tadalafil, a long-acting phosphodiesterase-5a (PDE5a) inhibitor, effectively prevented adverse left ventricular (LV) remodeling of the infarcted heart. We hypothesized that short-hairpin RNA (shRNA) therapy targeting PDE5a would simulate the effects of pharmacological intervention for treatment of postinfarction LV remodeling and dysfunction. Experimental model of myocardial infarction was developed in female mice by permanent ligation of left coronary artery. Immediately after that, an adenoviral vector encoding for shRNA sequence targeting PDE5a (Ad-shPDE5a) was injected intramyocardially, which specifically inhibited PDE5a in the heart. Four weeks later, Ad-shPDE5a treated mice showed significant mitigation of the left ventricle (LV) dilatation and dysfunction as indicated by smaller LV cavity and more preserved ejection fraction and fractional shortening. Infarction size and fibrosis were significantly reduced in Ad-shPDE5a-treated mice. Additionally, more salvaged cardiomyocytes, significantly reduced collagen contents, and higher blood vessel density were observed in Ad-shPDE5a-treated mice. The cytoprotective effects of Ad-shPDE5a were demonstrated in vitro in Ad-shPDE5a transfected cardiomyocytes cultured under oxygen glucose deprivation. Among downstream mediators of PDE5a signaling, cyclic GMP (cGMP) and cGMP-dependent protein kinase G (PKG) were activated with concomitant reduction in caspase-3 activity. However, no significant change in PKA and cAMP activities were observed in Ad-shPDE5a-treated hearts. Inhibition with shRNA improved cardiac remodeling and dysfunction by reducing infarction size and cardiac fibrosis and increased cGMP and PKG activity. These findings suggest that PDE5 inhibition with Ad-shPDE5a is a novel approach for treatment of myocardial infarction.

Inhibition of calmodulin-dependent phosphodiesterase induces apoptosis in human leukemic cells.

PubMed Central

Jiang, X; Li, J; Paskind, M; Epstein, P M

1996-01-01

Cytosolic extracts from a human lymphoblastoid B-cell line, RPMI-8392, established from a patient with acute lymphocytic leukemia, contain two major forms of cyclic nucleotide phosphodiesterase (PDE): Ca2+-calmodulin dependent PDE (PDE1) and cAMP-specific PDE (PDE4). In contrast, normal quiescent human peripheral blood lymphocytes (HPBL) are devoid of PDE1 activity [Epstein, P. M., Moraski, S., Jr., and Hachisu, R. (1987) Biochem. J. 243, 533-539]. Using reverse transcription-polymerase chain reaction (RT-PCR), we show that the mRNA encoding the 63-kDa form of PDE1 (PDE1B1) is expressed in RPMI-8392 cells, but not in normal, resting HPBL. This mRNA is, however, induced in HPBL following mitogenic stimulation by phytohemagglutinin (PHA). Also using RT-PCR, the full open reading frame for human PDE1B1 cDNA was cloned from RPMI-8392 cells and it encodes a protein of 536 amino acids with 96% identity to bovine, rat, and mouse species. RT-PCR also identifies the presence of PDE1B1 in other human lymphoblastoid and leukemic cell lines of B- (RPMI-1788, Daudi) and T-(MOLT-4, NA, Jurkat) cell origin. Inhibition of PDE1 or PDE4 activity by selective inhibitors induced RPMI-8392 cells, as well as the other cell lines, to undergo apoptosis. Culture of RPMI-8392 cells with an 18-bp phosphorothioate antisense oligodeoxynucleotide, targeted against the translation initiation region of the RPMI-8392 mRNA, led to a specific reduction in the amount of PDE1B1 mRNA after 1 day, and its disappearance after 2 days, and induced apoptosis in these cells in a sequence specific manner. This suggests that PDEs, particularly PDE1B1, because its expression is selective, may be useful targets for inducing the death of leukemic cells. Images Fig. 1 Fig. 3 Fig. 5 Fig. 6 PMID:8855339

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 frequency selection is achieved either by diffusion coefficients or by propagation time. Finally, we explore a large number of practical applications to further demonstrate the utility of proposed PDE transform. PMID:22207904

Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction

PubMed Central

Li, Longhu; Haider, Husnain Kh.; Wang, Linlin; Lu, Gang

2012-01-01

We previously showed that treatment with tadalafil, a long-acting phosphodiesterase-5a (PDE5a) inhibitor, effectively prevented adverse left ventricular (LV) remodeling of the infarcted heart. We hypothesized that short-hairpin RNA (shRNA) therapy targeting PDE5a would simulate the effects of pharmacological intervention for treatment of postinfarction LV remodeling and dysfunction. Experimental model of myocardial infarction was developed in female mice by permanent ligation of left coronary artery. Immediately after that, an adenoviral vector encoding for shRNA sequence targeting PDE5a (Ad-shPDE5a) was injected intramyocardially, which specifically inhibited PDE5a in the heart. Four weeks later, Ad-shPDE5a treated mice showed significant mitigation of the left ventricle (LV) dilatation and dysfunction as indicated by smaller LV cavity and more preserved ejection fraction and fractional shortening. Infarction size and fibrosis were significantly reduced in Ad-shPDE5a-treated mice. Additionally, more salvaged cardiomyocytes, significantly reduced collagen contents, and higher blood vessel density were observed in Ad-shPDE5a-treated mice. The cytoprotective effects of Ad-shPDE5a were demonstrated in vitro in Ad-shPDE5a transfected cardiomyocytes cultured under oxygen glucose deprivation. Among downstream mediators of PDE5a signaling, cyclic GMP (cGMP) and cGMP-dependent protein kinase G (PKG) were activated with concomitant reduction in caspase-3 activity. However, no significant change in PKA and cAMP activities were observed in Ad-shPDE5a-treated hearts. Inhibition with shRNA improved cardiac remodeling and dysfunction by reducing infarction size and cardiac fibrosis and increased cGMP and PKG activity. These findings suggest that PDE5 inhibition with Ad-shPDE5a is a novel approach for treatment of myocardial infarction. PMID:22447941

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

PubMed Central

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

2016-01-01

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

A pathophysiological role of PDE3 in allergic airway inflammation

PubMed Central

Beute, Jan; Lukkes, Melanie; Koekoek, Ewout P.; Nastiti, Hedwika; Ganesh, Keerthana; de Bruijn, Marjolein J.W.; Hockman, Steve; van Nimwegen, Menno; Braunstahl, Gert-Jan; Boon, Louis; Lambrecht, Bart N.; Manganiello, Vince C.; Hendriks, Rudi W.

2018-01-01

Phosphodiesterase 3 (PDE3) and PDE4 regulate levels of cyclic AMP, which are critical in various cell types involved in allergic airway inflammation. Although PDE4 inhibition attenuates allergic airway inflammation, reported side effects preclude its application as an antiasthma drug in humans. Case reports showed that enoximone, which is a smooth muscle relaxant that inhibits PDE3, is beneficial and lifesaving in status asthmaticus and is well tolerated. However, clinical observations also showed antiinflammatory effects of PDE3 inhibition. In this study, we investigated the role of PDE3 in a house dust mite–driven (HDM-driven) allergic airway inflammation (AAI) model that is characterized by T helper 2 cell activation, eosinophilia, and reduced mucosal barrier function. Compared with wild-type (WT) littermates, mice with a targeted deletion of the PDE3A or PDE3B gene showed significantly reduced HDM-driven AAI. Therapeutic intervention in WT mice showed that all hallmarks of HDM-driven AAI were abrogated by the PDE3 inhibitors enoximone and milrinone. Importantly, we found that enoximone also reduced the upregulation of the CD11b integrin on mouse and human eosinophils in vitro, which is crucial for their recruitment during allergic inflammation. This study provides evidence for a hitherto unknown antiinflammatory role of PDE3 inhibition in allergic airway inflammation and offers a potentially novel treatment approach. PMID:29367458

Phosphodiesterase type 4 inhibition enhances nitric oxide- and hydrogen sulfide-mediated bladder neck inhibitory neurotransmission.

PubMed

Agis-Torres, Ángel; Recio, Paz; López-Oliva, María Elvira; Martínez, María Pilar; Barahona, María Victoria; Benedito, Sara; Bustamante, Salvador; Jiménez-Cidre, Miguel Ángel; García-Sacristán, Albino; Prieto, Dolores; Fernandes, Vítor S; Hernández, Medardo

2018-03-16

Nitric oxide (NO) and hydrogen sulfide (H 2 S) play a pivotal role in nerve-mediated relaxation of the bladder outflow region. In the bladder neck, a marked phosphodiesterase type 4 (PDE4) expression has also been described and PDE4 inhibitors, as rolipram, produce smooth muscle relaxation. This study investigates the role of PDE4 isoenzyme in bladder neck gaseous inhibitory neurotransmission. We used Western blot and double immunohistochemical staining for the detection of NPP4 (PDE4) and PDE4A and organ baths for isometric force recording to roflumilast and tadalafil, PDE4 and PDE5, respectively, inhibitors in pig and human samples. Endogenous H 2 S production measurement and electrical field stimulation (EFS) were also performed. A rich PDE4 and PDE4A expression was observed mainly limited to nerve fibers of the smooth muscle layer of both species. Moreover, roflumilast produced a much more potent smooth muscle relaxation than that induced by tadalafil. In porcine samples, H 2 S generation was diminished by H 2 S and NO synthase inhibition and augmented by roflumilast. Relaxations elicited by EFS were potentiated by roflumilast. These results suggest that PDE4, mainly PDE4A, is mostly located within nerve fibers of the pig and human bladder neck, where roflumilast produces a powerful smooth muscle relaxation. In pig, the fact that roflumilast increases endogenous H 2 S production and EFS-induced relaxations suggests a modulation of PDE4 on NO- and H 2 S-mediated inhibitory neurotransmission.

A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex

PubMed Central

Horvath, Anelia; Giatzakis, Christoforos; Tsang, Kitman; Greene, Elizabeth; Osorio, Paulo; Boikos, Sosipatros; Libè, Rossella; Patronas, Yianna; Robinson-White, Audrey; Remmers, Elaine; Bertherat, Jerôme; Nesterova, Maria; Stratakis, Constantine A.

2009-01-01

Bilateral adrenocortical hyperplasia (BAH) is the second most common cause of corticotropin-independent Cushing syndrome (CS). Genetic forms of BAH have been associated with complex syndromes such as Carney Complex and McCune Albright syndrome or may present as isolated micronodular adrenocortical disease (iMAD) usually in children and young adults with CS. A genome-wide association study identified inactivating phosphodiesterase (PDE) 11A (PDE11A) sequencing defects as low-penetrance predisposing factors for iMAD and related abnormalities; we also described a mutation (c.914A>C/H305P) in cAMP-specific PDE8B, in a patient with iMAD. In this study we further characterize this mutation; we also found a novel PDE8B isoform, highly expressed in the adrenal gland. This mutation is shown to significantly affect the ability of the protein to degrade cAMP in vitro. Tumor tissues from patients with iMAD and no mutations in the coding PDE8B sequence or any other related genes (PRKAR1A, PDE11A) showed down-regulated PDE8B expression (compared to normal adrenal cortex). Pde8b is detectable in the adrenal gland of newborn mice and is widely expressed in other mouse tissues. We conclude that PDE8B is another PDE gene linked to iMAD; it is a candidate causative gene for other adrenocortical lesions linked to the cAMP-signaling pathway, and possibly for tumors in other tissues. PMID:18431404

Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension induced immobility and show upregulation of Pde10a.

PubMed

Hufgard, Jillian R; Williams, Michael T; Skelton, Matthew R; Grubisha, Olivera; Ferreira, Filipa M; Sanger, Helen; Wright, Mary E; Reed-Kessler, Tracy M; Rasmussen, Kurt; Duman, Ronald S; Vorhees, Charles V

2017-06-01

Major depressive disorder is a leading cause of suicide and disability. Despite this, current antidepressants provide insufficient efficacy in more than 60% of patients. Most current antidepressants are presynaptic reuptake inhibitors; postsynaptic signal regulation has not received as much attention as potential treatment targets. We examined the effects of disruption of the postsynaptic cyclic nucleotide hydrolyzing enzyme, phosphodiesterase (PDE) 1b, on depressive-like behavior and the effects on PDE1B protein in wild-type (WT) mice following stress. Littermate knockout (KO) and WT mice were tested in locomotor activity, tail suspension (TST), and forced swim tests (FST). FST was also used to compare the effects of two antidepressants, fluoxetine and bupropion, in KO versus WT mice. Messenger RNA (mRNA) expression changes were also determined. WT mice underwent acute or chronic stress and markers of stress and PDE1B expression were examined. Pde1b KO mice exhibited decreased TST and FST immobility. When treated with antidepressants, both WT and KO mice showed decreased FST immobility and the effect was additive in KO mice. Mice lacking Pde1b had increased striatal Pde10a mRNA expression. In WT mice, acute and chronic stress upregulated PDE1B expression while PDE10A expression was downregulated after chronic but not acute stress. PDE1B is a potential therapeutic target for depression treatment because of the antidepressant-like phenotype seen in Pde1b KO mice.

Partial differential equations constrained combinatorial optimization on an adiabatic quantum computer

NASA Astrophysics Data System (ADS)

Chandra, Rishabh

Partial differential equation-constrained combinatorial optimization (PDECCO) problems are a mixture of continuous and discrete optimization problems. PDECCO problems have discrete controls, but since the partial differential equations (PDE) are continuous, the optimization space is continuous as well. Such problems have several applications, such as gas/water network optimization, traffic optimization, micro-chip cooling optimization, etc. Currently, no efficient classical algorithm which guarantees a global minimum for PDECCO problems exists. A new mapping has been developed that transforms PDECCO problem, which only have linear PDEs as constraints, into quadratic unconstrained binary optimization (QUBO) problems that can be solved using an adiabatic quantum optimizer (AQO). The mapping is efficient, it scales polynomially with the size of the PDECCO problem, requires only one PDE solve to form the QUBO problem, and if the QUBO problem is solved correctly and efficiently on an AQO, guarantees a global optimal solution for the original PDECCO problem.

An Eigenvalue Analysis of finite-difference approximations for hyperbolic IBVPs

NASA Technical Reports Server (NTRS)

Warming, Robert F.; Beam, Richard M.

1989-01-01

The eigenvalue spectrum associated with a linear finite-difference approximation plays a crucial role in the stability analysis and in the actual computational performance of the discrete approximation. The eigenvalue spectrum associated with the Lax-Wendroff scheme applied to a model hyperbolic equation was investigated. For an initial-boundary-value problem (IBVP) on a finite domain, the eigenvalue or normal mode analysis is analytically intractable. A study of auxiliary problems (Dirichlet and quarter-plane) leads to asymptotic estimates of the eigenvalue spectrum and to an identification of individual modes as either benign or unstable. The asymptotic analysis establishes an intuitive as well as quantitative connection between the algebraic tests in the theory of Gustafsson, Kreiss, and Sundstrom and Lax-Richtmyer L(sub 2) stability on a finite domain.

Chosen interval methods for solving linear interval systems with special type of matrix

NASA Astrophysics Data System (ADS)

Szyszka, Barbara

2013-10-01

The paper is devoted to chosen direct interval methods for solving linear interval systems with special type of matrix. This kind of matrix: band matrix with a parameter, from finite difference problem is obtained. Such linear systems occur while solving one dimensional wave equation (Partial Differential Equations of hyperbolic type) by using the central difference interval method of the second order. Interval methods are constructed so as the errors of method are enclosed in obtained results, therefore presented linear interval systems contain elements that determining the errors of difference method. The chosen direct algorithms have been applied for solving linear systems because they have no errors of method. All calculations were performed in floating-point interval arithmetic.

Investigation into the role of phosphodiesterase IV in bronchorelaxation, including studies with human bronchus.

PubMed Central

Cortijo, J.; Bou, J.; Beleta, J.; Cardelús, I.; Llenas, J.; Morcillo, E.; Gristwood, R. W.

1993-01-01

1. We have investigated the role of cyclic nucleotide phosphodiesterase IV (PDE IV) in the relaxation of human bronchus and guinea-pig trachea in vitro and in guinea-pigs in vivo. 2. Functional studies showed that the selective PDE IV inhibitors, rolipram and denbufylline, relaxed human and guinea-pig preparations in vitro. 3. Two clinically used xanthine non-selective PDE inhibitors, theophylline and pentoxifylline, were also effective in these preparations, but were much less potent than the selective agents used. 4. The rank order of potency for the four PDE inhibitors in both species was similar. 5. Biochemical studies indicated that PDE IV was the major PDE isoform present in the human bronchial tissue. PDEs I, II and V were also identified. 6. Theophylline and pentoxifylline were, as expected, non-selective inhibitors of the human enzymes, but there was a good correlation between PDE IV inhibitory and bronchorelaxation potencies, suggesting that PDE IV inhibition is important for the clinical bronchodilator activities of the two xanthine compounds. 7. We have confirmed the ability of selective PDE IV inhibitors to cause bronchodilatation in guinea-pigs in vivo. 8. We conclude that our study has provided further evidence that selective PDE IV inhibitors could act as bronchodilators in the clinic. PMID:8383567

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

PubMed Central

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

2012-01-01

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

The localization and concentration of the PDE2-encoded high-affinity cAMP phosphodiesterase is regulated by cAMP-dependent protein kinase A in the yeast Saccharomyces cerevisiae.

PubMed

Hu, Yun; Liu, Enkai; Bai, Xiaojia; Zhang, Aili

2010-03-01

The genome of the yeast Saccharomyces cerevisiae encodes two cyclic AMP (cAMP) phosphodiesterases, a low-affinity one, Pde1, and a high-affinity one, Pde2. Pde1 has been ascribed a function for downregulating agonist-induced cAMP accumulation in a protein kinase A (PKA)-governed negative feedback loop, whereas Pde2 controls the basal cAMP level in the cell. Here we show that PKA regulates the localization and protein concentration of Pde2. Pde2 is accumulated in the nucleus in wild-type cells growing on glucose, or in strains with hyperactive PKA. In contrast, in derepressed wild-type cells or cells with attenuated PKA activity, Pde2 is distributed over the nucleus and cytoplasm. We also show evidence indicating that the Pde2 protein level is positively correlated with PKA activity. The increase in the Pde2 protein level in high-PKA strains and in cells growing on glucose was due to its increased half-life. These results suggest that, like its low-affinity counterpart, the high-affinity phosphodiesterase may also play an important role in the PKA-controlled feedback inhibition of intracellular cAMP.

Micronuclei related to anti-B[a]PDE-DNA adduct in peripheral blood lymphocytes of heavily polycyclic aromatic hydrocarbon-exposed nonsmoking coke-oven workers and controls.

PubMed

Pavanello, Sofia; Kapka, Lucyna; Siwinska, Ewa; Mielzyñska, Danuta; Bolognesi, Claudia; Clonfero, Erminio

2008-10-01

Micronuclei (MN) frequency associated to biologically effective dose of polycyclic aromatic hydrocarbons [PAH; anti-benzo[a]pyrene diolepoxide (B[a]PDE)-DNA] within the same subjects' peripheral blood lymphocytes (PBL) was evaluated. Study subjects were nonsmoking male Polish coke-oven workers (n=49) and matched controls (n=45) verified for PAH exposure by urinary 1-pyrenol. We found that coke-oven workers, heavily exposed to PAHs (80% workers exceeded the urinary 1-pyrenol biological exposure index value), presented significantly higher MN frequency in PBLs than controls (P<0.01). Substantial difference was also found for adduct levels in PBLs (P<0.01). Increase in MN levels was significantly related to anti-B[a]PDE-DNA formation, key adduct of the ultimate carcinogenic metabolite of B[a]P (n=94; r=0.47; P<0.001). The dose-response relationship was improved when subjects with adduct levels above the 3rd tertile (>or=4.35 adducts/10(8) nucleotides) were excluded (n=61; r=0.69; P<0.001). Saturation of adduct/MN formation at high levels may disturb the underlying relationship. Linear multiple regression analysis, without subjects of 3rd tertile adduct level (n=61), revealed that adduct formation (t=4.61; P<0.001), but not 1-pyrenol, was the significant determinant in increasing MN. In conclusion, the increase in MN frequency is mainly related to the specific anti-B[a]PDE-DNA formation within PBLs of the same subject. Our results substantiate, with the use of an early indicator of biological effect as well, that workers are at higher cancer risk than controls.

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. Copyright © 2012 Elsevier B.V. All rights reserved.

Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.

PubMed

Dyck, Brian; Branstetter, Bryan; Gharbaoui, Tawfik; Hudson, Andrew R; Breitenbucher, J Guy; Gomez, Laurent; Botrous, Iriny; Marrone, Tami; Barido, Richard; Allerston, Charles K; Cedervall, E Peder; Xu, Rui; Sridhar, Vandana; Barker, Ryan; Aertgeerts, Kathleen; Schmelzer, Kara; Neul, David; Lee, Dong; Massari, Mark Eben; Andersen, Carsten B; Sebring, Kristen; Zhou, Xianbo; Petroski, Robert; Limberis, James; Augustin, Martin; Chun, Lawrence E; Edwards, Thomas E; Peters, Marco; Tabatabaei, Ali

2017-04-27

A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory.

Expression of phosphodiesterase 6 (PDE6) in human breast cancer cells.

PubMed

Dong, Hongli; Claffey, Kevin P; Brocke, Stefan; Epstein, Paul M

2013-01-01

Considerable epidemiological evidence demonstrates a positive association between artificial light at night (LAN) levels and incidence rates of breast cancer, suggesting that exposure to LAN is a risk factor for breast cancer. There is a 30-50% higher risk of breast cancer in the highest LAN exposed countries compared to the lowest LAN countries, and studies showing higher incidence of breast cancer among shift workers exposed to more LAN have led the International Agency for Research on Cancer to classify shift work as a probable human carcinogen. Nevertheless, the means by which light can affect breast cancer is still unknown. In this study we examined established human breast cancer cell lines and patients' primary breast cancer tissues for expression of genetic components of phosphodiesterase 6 (PDE6), a cGMP-specific PDE involved in transduction of the light signal, and previously thought to be selectively expressed in photoreceptors. By microarray analysis we find highly significant expression of mRNA for the PDE6B, PDE6C, and PDE6D genes in both the cell lines and patients' tissues, minimal expression of PDE6A and PDE6G and no expression of PDE6H. Using antibody specific for PDE6β, we find expression of PDE6B protein in a wide range of patients' tissues by immunohistochemistry, and in MCF-7 breast cancer cells by immunofluorescence and Western blot analysis. Considerable expression of key circadian genes, PERIOD 2, CLOCK, TIMELESS, CRYPTOCHROME 1, and CRYPTOCHROME 2 was also seen in all breast cancer cell lines and all patients' breast cancer tissues. These studies indicate that genes for PDE6 and control of circadian rhythm are expressed in human breast cancer cells and tissues and may play a role in transducing the effects of light on breast cancer.

Non-invasive Management Options for Erectile Dysfunction When a Phosphodiesterase Type 5 Inhibitor Fails.

PubMed

Lee, Mary; Sharifi, Roohollah

2018-03-01

Phosphodiesterase type 5 inhibitors (PDE5Is) are the drug of choice for medical management of erectile dysfunction (ED). On-demand PDE5Is have an overall efficacy of 60-70% for ED; 30-35% of patients fail to respond to a PDE5I, and 30-50% of non-responders can be salvaged with detailed counseling on proper use and physician follow-up to ensure that the patient has been prescribed an appropriate and full PDE5I clinical trial. True non-responders may be offered intracavernosal injections of erectogenic drugs, intraurethral alprostadil, or surgical insertion of a penile prosthesis. Such options are not discreet and are associated with more adverse effects than PDE5Is. Thus patients may request additional non-invasive medical management options. This review describes published literature on patients who failed to respond to an on-demand PDE5I regimen and were treated with a non-invasive PDEI-based regimen, including switching from one PDE5I to another; increasing the dose of PDE5I above the labeled dosage range; using two PDE5Is concurrently; using a daily PDE5I regimen; or combining a PDE5I with a testosterone supplement, α-adrenergic antagonist, intraurethral or intracavernosal alprostadil, vacuum erection device, or low-intensity shock wave therapy. The limitations of published clinical trials do not allow for sufficient evidence to recommend one option over another. Therefore, in PDE5I-refractory patients, the choice of a specific next step should be individualized based on the preference of the patient and his sexual partner, the advantages and disadvantages of the various options, the concurrent medical illnesses and medications of the patient, and the patient's response to treatment.

Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-1B (PDE1B) enzyme.

PubMed

Siuciak, J A; McCarthy, S A; Chapin, D S; Reed, T M; Vorhees, C V; Repaske, D R

2007-07-01

PDE1B is a calcium-dependent cyclic nucleotide phosphodiesterase that is highly expressed in the striatum. In order to investigate the physiological role of PDE1B in the central nervous system, PDE1B knockout mice (C57BL/6N background) were assessed in behavioral tests and their brains were assayed for monoamine content. In a variety of well-characterized behavioral tasks, including the elevated plus maze (anxiety-like behavior), forced swim test (depression-like behavior), hot plate (nociception) and two cognition models (passive avoidance and acquisition of conditioned avoidance responding), PDE1B knockout mice performed similarly to wild-type mice. PDE1B knockout mice showed increased baseline exploratory activity when compared to wild-type mice. When challenged with amphetamine (AMPH) and methamphetamine (METH), male and female PDE1B knockout mice showed an exaggerated locomotor response. Male PDE1B knockout mice also showed increased locomotor responses to higher doses of phencyclidine (PCP) and MK-801; however, this effect was not consistently observed in female knockout mice. In the striatum, increased dopamine turnover (DOPAC/DA and HVA/DA ratios) was found in both male and female PDE1B knockout mice. Striatal serotonin (5-HT) levels were also decreased in PDE1B knockout mice, although levels of the metabolite, 5HIAA, were unchanged. The present studies demonstrate increased striatal dopamine turnover in PDE1B knockout mice associated with increased baseline motor activity and an exaggerated locomotor response to dopaminergic stimulants such as methamphetamine and amphetamine. These data further support a role for PDE1B in striatal function.

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.

Applications of Random Differential Equations to Engineering Science. Wave Propagation in Turbulent Media and Random Linear Hyperbolic Systems.

DTIC Science & Technology

1981-11-10

1976), 745-754. 4. (with W. C. Tam) Periodic and traveling wave solutions to Volterra - Lotka equation with diffusion. Bull. Math. Biol. 38 (1976), 643...with applications [17,19,20). (5) A general method for reconstructing the mutual coherent function of a static or moving source from the random

Parallelized Three-Dimensional Resistivity Inversion Using Finite Elements And Adjoint State Methods

NASA Astrophysics Data System (ADS)

Schaa, Ralf; Gross, Lutz; Du Plessis, Jaco

2015-04-01

The resistivity method is one of the oldest geophysical exploration methods, which employs one pair of electrodes to inject current into the ground and one or more pairs of electrodes to measure the electrical potential difference. The potential difference is a non-linear function of the subsurface resistivity distribution described by an elliptic partial differential equation (PDE) of the Poisson type. Inversion of measured potentials solves for the subsurface resistivity represented by PDE coefficients. With increasing advances in multichannel resistivity acquisition systems (systems with more than 60 channels and full waveform recording are now emerging), inversion software require efficient storage and solver algorithms. We developed the finite element solver Escript, which provides a user-friendly programming environment in Python to solve large-scale PDE-based problems (see https://launchpad.net/escript-finley). Using finite elements, highly irregular shaped geology and topography can readily be taken into account. For the 3D resistivity problem, we have implemented the secondary potential approach, where the PDE is decomposed into a primary potential caused by the source current and the secondary potential caused by changes in subsurface resistivity. The primary potential is calculated analytically, and the boundary value problem for the secondary potential is solved using nodal finite elements. This approach removes the singularity caused by the source currents and provides more accurate 3D resistivity models. To solve the inversion problem we apply a 'first optimize then discretize' approach using the quasi-Newton scheme in form of the limited-memory Broyden-Fletcher-Goldfarb-Shanno (L-BFGS) method (see Gross & Kemp 2013). The evaluation of the cost function requires the solution of the secondary potential PDE for each source current and the solution of the corresponding adjoint-state PDE for the cost function gradients with respect to the subsurface resistivity. The Hessian of the regularization term is used as preconditioner which requires an additional PDE solution in each iteration step. As it turns out, the relevant PDEs are naturally formulated in the finite element framework. Using the domain decomposition method provided in Escript, the inversion scheme has been parallelized for distributed memory computers with multi-core shared memory nodes. We show numerical examples from simple layered models to complex 3D models and compare with the results from other methods. The inversion scheme is furthermore tested on a field data example to characterise localised freshwater discharge in a coastal environment.. References: L. Gross and C. Kemp (2013) Large Scale Joint Inversion of Geophysical Data using the Finite Element Method in escript. ASEG Extended Abstracts 2013, http://dx.doi.org/10.1071/ASEG2013ab306

Co-possession of phosphodiesterase type-5 inhibitors (PDE5-I) with nitrates.

PubMed

Chang, Li-Ling; Ma, Mark; Allmen, Heather von; Henderson, Scott C; Harper, Kristine; Hornbuckle, Kenneth

2010-06-01

Estimate the proportion of phosphodiesterase type-5 inhibitor (PDE5-I) patients who co-possess nitrates and compare the proportion of tadalafil patients dispensed nitrates to a matched control group. Secondarily, examine the percentage of co-possession of PDE5-Is and nitrates where the products were dispensed on the same day or written by the same prescriber. Male patients aged 18+ years filling PDE5-I prescriptions between December 2003 and March 2006 were identified using a U.S. longitudinal prescription database (IMS Health LRx). Similar patients not dispensed a PDE5-I during this period were matched to the tadalafil-dispensed cohort using a propensity score approach. Co-possession, as a proxy for concurrent use, was defined as an overlap in time on therapy for a PDE5-I and nitrate and was compared for the three PDE5-Is and for tadalafil to the matched control group. Among 601,063 tadalafil patients, 3.31% were dispensed a nitrate during the study period, compared to 6.18% in control patients (n = 601,063). When co-possessed prescriptions were defined by overlapping exposure periods, the proportion of PDE5-I patients with co-possessed nitrates ranged from 1.44% (tadalafil) to 1.72% (vardenafil) and 2.13% (sildenafil). Co-possession percentages of PDE5-I prescriptions were 0.83% for tadalafil and 1.07% for sildenafil and vardenafil. The majority (54.29%) of co-possessed PDE5-I and nitrate prescriptions had the nitrate dispensed prior to the PDE5-I prescription identified in the study cohort. Keeping in mind the limitations of observational studies, these results suggest that co-dispensing of nitrates and PDE5-Is is low. Compared to control patients, the proportion of nitrate co-possession was lowest for patients filling tadalafil. Tadalafil patients also had the lowest co-possessed proportion among the three PDE5-I cohorts. While the majority of co-possessed drug pairs were prescribed by different providers, the highest percentage of co-prescribing from the same physician was among cardiologists. These results suggest that physicians adhere to contraindications and are careful about co-prescribing of nitrates with PDE-5Is.

Optimal moving grids for time-dependent partial differential equations

NASA Technical Reports Server (NTRS)

Wathen, A. J.

1992-01-01

Various adaptive moving grid techniques for the numerical solution of time-dependent partial differential equations were proposed. The precise criterion for grid motion varies, but most techniques will attempt to give grids on which the solution of the partial differential equation can be well represented. Moving grids are investigated on which the solutions of the linear heat conduction and viscous Burgers' equation in one space dimension are optimally approximated. Precisely, the results of numerical calculations of optimal moving grids for piecewise linear finite element approximation of PDE solutions in the least-squares norm are reported.

Immunoprecipitation of PDE2 phosphorylated and inactivated by an associated protein kinase.

PubMed

Bentley, J Kelley

2005-01-01

A PDE2A2-associated protein kinase phosphorylates PDE2A2 in vivo and in vitro to inhibit its catalytic activity. Rat brain PDE2A2 may be solubilized using nona (ethylene glycol) mono dodecyl ether (Lubrol 12A9). PDE2A2 exists in a complex with a protein kinase regulating its activity in an adenosine triphosphate-dependent manner. When native or recombinant PDE2 is immunoprecipitated from PC12 cells using an antibody to the amino terminus in a buffer containing Lubrol 12A9, protease inhibitors, and phosphatase inhibitors, a coimmunoprecipitating nerve growth factor-stimulated protein kinase acts to phosphorylate it. PDE2A2 phosphoryla-tion occurs optimally at pH 6.5 in a sodium 2-(4-morpholino)-ethane sulfonate buffer with 5 mM MgCl2 and 1 mM Na3VO4. I describe protocols for producing an antibody to an amino-terminal bacterial fusion protein encoding amino acids 1-251 of PDE2A2 as well as the use of this antibody in immunoprecipitating a PDE2: tyrosine protein-kinase complex from rat brain or PC12 cells.

Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice

PubMed Central

Blednov, Yuri A.; Benavidez, Jillian M.; Black, Mendy; Harris, R. Adron

2014-01-01

Some anti-inflammatory medications reduce alcohol consumption in rodent models. Inhibition of phosphodiesterases (PDE) increases cAMP and reduces inflammatory signaling. Rolipram, an inhibitor of PDE4, markedly reduced ethanol intake and preference in mice and reduced ethanol seeking and consumption in alcohol-preferring fawn-hooded rats (Hu et al., 2011; Wen et al., 2012). To determine if these effects were specific for PDE4, we compared nine PDE inhibitors with different subtype selectivity: propentofylline (nonspecific), vinpocetine (PDE1), olprinone, milrinone (PDE3), zaprinast (PDE5), rolipram, mesopram, piclamilast, and CDP840 (PDE4). Alcohol intake was measured in C57BL/6J male mice using 24-h two-bottle choice and two-bottle choice with limited (3-h) access to alcohol. Only the selective PDE4 inhibitors reduced ethanol intake and preference in the 24-h two-bottle choice test. For rolipram, piclamilast, and CDP840, this effect was observed after the first 6 h but not after the next 18 h. Mesopram, however, produced a long-lasting reduction of ethanol intake and preference. In the limited access test, rolipram, piclamilast, and mesopram reduced ethanol consumption and total fluid intake and did not change preference for ethanol, whereas CDP840 reduced both consumption and preference without altering total fluid intake. Our results provide novel evidence for a selective role of PDE4 in regulating ethanol drinking in mice. We suggest that inhibition of PDE4 may be an unexplored target for medication development to reduce excessive alcohol consumption. PMID:24904269

Phosphodiesterase-10A Inverse Changes in Striatopallidal and Striatoentopeduncular Pathways of a Transgenic Mouse Model of DYT1 Dystonia.

PubMed

D'Angelo, Vincenza; Castelli, Valentina; Giorgi, Mauro; Cardarelli, Silvia; Saverioni, Ilaria; Palumbo, Francesca; Bonsi, Paola; Pisani, Antonio; Giampà, Carmela; Sorge, Roberto; Biagioni, Stefano; Fusco, Francesca R; Sancesario, Giuseppe

2017-02-22

We report that changes of phosphodiesterase-10A (PDE10A) can map widespread functional imbalance of basal ganglia circuits in a mouse model of DYT1 dystonia overexpressing mutant torsinA. PDE10A is a key enzyme in the catabolism of second messenger cAMP and cGMP, whose synthesis is stimulated by D1 receptors and inhibited by D2 receptors preferentially expressed in striatoentopeducuncular/substantia nigra or striatopallidal pathways, respectively. PDE10A was studied in control mice (NT) and in mice carrying human wild-type torsinA (hWT) or mutant torsinA (hMT). Quantitative analysis of PDE10A expression was assessed in different brain areas by rabbit anti-PDE10A antibody immunohistochemistry and Western blotting. PDE10A-dependent cAMP hydrolyzing activity and PDE10A mRNA were also assessed. Striatopallidal neurons were identified by rabbit anti-enkephalin antibody.In NT mice, PDE10A is equally expressed in medium spiny striatal neurons and in their projections to entopeduncular nucleus/substantia nigra and to external globus pallidus. In hMT mice, PDE10A content selectively increases in enkephalin-positive striatal neuronal bodies; moreover, PDE10A expression and activity in hMT mice, compared with NT mice, significantly increase in globus pallidus but decrease in entopeduncular nucleus/substantia nigra. Similar changes of PDE10A occur in hWT mice, but such changes are not always significant. However, PDE10A mRNA expression appears comparable among NT, hWT, and hMT mice.In DYT1 transgenic mice, the inverse changes of PDE10A in striatoentopeduncular and striatopallidal projections might result over time in an imbalance between direct and indirect pathways for properly focusing movement. The decrease of PDE10A in the striatoentopeduncular/nigral projections might lead to increased intensity and duration of D1-stimulated cAMP/cGMP signaling; conversely, the increase of PDE10A in the striatopallidal projections might lead to increased intensity and duration of D2-inhibited cAMP/cGMP signaling. SIGNIFICANCE STATEMENT In DYT1 transgenic mouse model of dystonia, PDE10A, a key enzyme in cAMP and cGMP catabolism, is downregulated in striatal projections to entopeduncular nucleus/substantia nigra, preferentially expressing D1 receptors that stimulate cAMP/cGMP synthesis. Conversely, in DYT1 mice, PDE10A is upregulated in striatal projections to globus pallidus, preferentially expressing D2 receptors that inhibit cAMP/cGMP synthesis. The inverse changes to PDE10A in striatoentopeduncular/substantia nigra and striatopallidal pathways might tightly interact downstream to dopamine receptors, likely resulting over time to increased intensity and duration respectively of D1-stimulated and D2-inhibited cAMP/cGMP signals. Therefore, PDE10A changes in the DYT1 model of dystonia can upset the functional balance of basal ganglia circuits, affecting direct and indirect pathways simultaneously. Copyright © 2017 the authors 0270-6474/17/372113-13$15.00/0.

New Insights into the Cyclic Di-adenosine Monophosphate (c-di-AMP) Degradation Pathway and the Requirement of the Cyclic Dinucleotide for Acid Stress Resistance in Staphylococcus aureus.

PubMed

Bowman, Lisa; Zeden, Merve S; Schuster, Christopher F; Kaever, Volkhard; Gründling, Angelika

2016-12-30

Nucleotide signaling networks are key to facilitate alterations in gene expression, protein function, and enzyme activity in response to diverse stimuli. Cyclic di-adenosine monophosphate (c-di-AMP) is an important secondary messenger molecule produced by the human pathogen Staphylococcus aureus and is involved in regulating a number of physiological processes including potassium transport. S. aureus must ensure tight control over its cellular levels as both high levels of the dinucleotide and its absence result in a number of detrimental phenotypes. Here we show that in addition to the membrane-bound Asp-His-His and Asp-His-His-associated (DHH/DHHA1) domain-containing phosphodiesterase (PDE) GdpP, S. aureus produces a second cytoplasmic DHH/DHHA1 PDE Pde2. Although capable of hydrolyzing c-di-AMP, Pde2 preferentially converts linear 5'-phosphadenylyl-adenosine (pApA) to AMP. Using a pde2 mutant strain, pApA was detected for the first time in S. aureus, leading us to speculate that this dinucleotide may have a regulatory role under certain conditions. Moreover, pApA is involved in a feedback inhibition loop that limits GdpP-dependent c-di-AMP hydrolysis. Another protein linked to the regulation of c-di-AMP levels in bacteria is the predicted regulator protein YbbR. Here, it is shown that a ybbR mutant S. aureus strain has increased acid sensitivity that can be bypassed by the acquisition of mutations in a number of genes, including the gene coding for the diadenylate cyclase DacA. We further show that c-di-AMP levels are slightly elevated in the ybbR suppressor strains tested as compared with the wild-type strain. With this, we not only identified a new role for YbbR in acid stress resistance in S. aureus but also provide further insight into how c-di-AMP levels impact acid tolerance in this organism. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

New Insights into the Cyclic Di-adenosine Monophosphate (c-di-AMP) Degradation Pathway and the Requirement of the Cyclic Dinucleotide for Acid Stress Resistance in Staphylococcus aureus*

PubMed Central

Bowman, Lisa; Zeden, Merve S.; Kaever, Volkhard

2016-01-01

Nucleotide signaling networks are key to facilitate alterations in gene expression, protein function, and enzyme activity in response to diverse stimuli. Cyclic di-adenosine monophosphate (c-di-AMP) is an important secondary messenger molecule produced by the human pathogen Staphylococcus aureus and is involved in regulating a number of physiological processes including potassium transport. S. aureus must ensure tight control over its cellular levels as both high levels of the dinucleotide and its absence result in a number of detrimental phenotypes. Here we show that in addition to the membrane-bound Asp-His-His and Asp-His-His-associated (DHH/DHHA1) domain-containing phosphodiesterase (PDE) GdpP, S. aureus produces a second cytoplasmic DHH/DHHA1 PDE Pde2. Although capable of hydrolyzing c-di-AMP, Pde2 preferentially converts linear 5′-phosphadenylyl-adenosine (pApA) to AMP. Using a pde2 mutant strain, pApA was detected for the first time in S. aureus, leading us to speculate that this dinucleotide may have a regulatory role under certain conditions. Moreover, pApA is involved in a feedback inhibition loop that limits GdpP-dependent c-di-AMP hydrolysis. Another protein linked to the regulation of c-di-AMP levels in bacteria is the predicted regulator protein YbbR. Here, it is shown that a ybbR mutant S. aureus strain has increased acid sensitivity that can be bypassed by the acquisition of mutations in a number of genes, including the gene coding for the diadenylate cyclase DacA. We further show that c-di-AMP levels are slightly elevated in the ybbR suppressor strains tested as compared with the wild-type strain. With this, we not only identified a new role for YbbR in acid stress resistance in S. aureus but also provide further insight into how c-di-AMP levels impact acid tolerance in this organism. PMID:27834680

Recent advances in high-order WENO finite volume methods for compressible multiphase flows

NASA Astrophysics Data System (ADS)

Dumbser, Michael

2013-10-01

We present two new families of better than second order accurate Godunov-type finite volume methods for the solution of nonlinear hyperbolic partial differential equations with nonconservative products. One family is based on a high order Arbitrary-Lagrangian-Eulerian (ALE) formulation on moving meshes, which allows to resolve the material contact wave in a very sharp way when the mesh is moved at the speed of the material interface. The other family of methods is based on a high order Adaptive Mesh Refinement (AMR) strategy, where the mesh can be strongly refined in the vicinity of the material interface. Both classes of schemes have several building blocks in common, in particular: a high order WENO reconstruction operator to obtain high order of accuracy in space; the use of an element-local space-time Galerkin predictor step which evolves the reconstruction polynomials in time and that allows to reach high order of accuracy in time in one single step; the use of a path-conservative approach to treat the nonconservative terms of the PDE. We show applications of both methods to the Baer-Nunziato model for compressible multiphase flows.

Comparison of Numerical Approaches to a Steady-State Landscape Equation

NASA Astrophysics Data System (ADS)

Bachman, S.; Peckham, S.

2008-12-01

A mathematical model of an idealized fluvial landscape has been developed, in which a land surface will evolve to preserve dendritic channel networks as the surface is lowered. The physical basis for this model stems from the equations for conservation of mass for water and sediment. These equations relate the divergence of the 2D vector fields showing the unit-width discharge of water and sediment to the excess rainrate and tectonic uplift on the land surface. The 2D flow direction is taken to be opposite to the water- surface gradient vector. These notions are combined with a generalized Manning-type flow resistance formula and a generalized sediment transport law to give a closed mathematical system that can, in principle, be solved for all variables of interest: discharge of water and sediment, land surface height, vertically- averaged flow velocity, water depth, and shear stress. The hydraulic geometry equations (Leopold et. al, 1964, 1995) are used to incorporate width, depth, velocity, and slope of river channels as powers of the mean-annual river discharge. Combined, they give the unit- width discharge of the stream as a power, γ, of the water surface slope. The simplified steady-state model takes into account three components among those listed above: conservation of mass for water, flow opposite the gradient, and a slope-discharge exponent γ = -1 to reflect mature drainage networks. The mathematical representation of this model appears as a second-order hyperbolic partial differential equation (PDE) where the diffusivity is inversely proportional to the square of the local surface slope. The highly nonlinear nature of this PDE has made it very difficult to solve both analytically and numerically. We present simplistic analytic solutions to this equation which are used to test the validity of the numerical algorithms. We also present three such numerical approaches which have been used in solving the differential equation. The first is based on a nonlinear diffusion filtering technique (Welk et. al, 2007) that has been applied successfully in the context of image processing. The second uses a Ritz finite element approach to the Euler-Lagrange formulation of the PDE in which an eighth degree polynomial is solved whose coefficients are locally dependent on slope and elevation. Lastly, we show a variant to the diffusion filtering approach in which a single-stage Runge-Kutta method is used to iterate a time-derivative to steady- state. The relative merits and drawbacks of these approaches are discussed, as well as stability and consistency requirements.

Development of an Integrated Modeling Framework for Simulations of Coastal Processes in Deltaic Environments Using High-Performance Computing

DTIC Science & Technology

2008-01-01

exceeds the local water depth. The approximation eliminates the vertical dimension of the elliptic equation that is normally required for the fully non...used for vertical resolution. The shallow water equations (SWE) are a set of non-linear hyperbolic equations. As the equations are derived under...linear standing wave with a wavelength of 10 m in a square 10 m by 10 m basin. The still water depth is 0.5 m. In order to compare with the analytical

Partner symmetries and non-invariant solutions of four-dimensional heavenly equations

NASA Astrophysics Data System (ADS)

Malykh, A. A.; Nutku, Y.; Sheftel, M. B.

2004-07-01

We extend our method of partner symmetries to the hyperbolic complex Monge-Ampère equation and the second heavenly equation of Plebañski. We show the existence of partner symmetries and derive the relations between them. For certain simple choices of partner symmetries the resulting differential constraints together with the original heavenly equations are transformed to systems of linear equations by an appropriate Legendre transformation. The solutions of these linear equations are generically non-invariant. As a consequence we obtain explicitly new classes of heavenly metrics without Killing vectors.

[Not Available].

PubMed

Bernard, A M; Burgot, J L

1981-12-01

The variation in heat capacity and the thermal shifts which accompany a thermometric determination make the thermogram, even in the case of a very rapid and irreversible reaction, hyperbolic instead of formed of straight segments. These departures from linearity, which are inconvenient in the interpretation and exploitation of the thermograms, can be calculated as a function of the degree of titration. The relation obtained introduces a parameter which the authors call the apparent change of capacity at the equivalence point, and which takes into account the two causes of deviation from linearity. This relationship is confirmed experimentally.

Saturation of the magnetorotational instability at large Elsasser number

NASA Astrophysics Data System (ADS)

Jamroz, B.; Julien, K.; Knobloch, E.

2008-09-01

The magnetorotational instability is investigated within the shearing box approximation in the large Elsasser number regime. In this regime, which is of fundamental importance to astrophysical accretion disk theory, shear is the dominant source of energy, but the instability itself requires the presence of a weaker vertical magnetic field. Dissipative effects are weaker still but not negligible. The regime explored retains the condition that (viscous and ohmic) dissipative forces do not play a role in the leading order linear instability mechanism. However, they are sufficiently large to permit a nonlinear feedback mechanism whereby the turbulent stresses generated by the MRI act on and modify the local background shear in the angular velocity profile. To date this response has been omitted in shearing box simulations and is captured by a reduced pde model derived here from the global MHD fluid equations using multiscale asymptotic perturbation theory. Results from numerical simulations of the reduced pde model indicate a linear phase of exponential growth followed by a nonlinear adjustment to algebraic growth and decay in the fluctuating quantities. Remarkably, the velocity and magnetic field correlations associated with these algebraic growth and decay laws conspire to achieve saturation of the angular momentum transport. The inclusion of subdominant ohmic dissipation arrests the algebraic growth of the fluctuations on a longer, dissipative time scale.

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

PubMed

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

2013-11-14

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

Conformal and covariant Z4 formulation of the Einstein equations: Strongly hyperbolic first-order reduction and solution with discontinuous Galerkin schemes

NASA Astrophysics Data System (ADS)

Dumbser, Michael; Guercilena, Federico; Köppel, Sven; Rezzolla, Luciano; Zanotti, Olindo

2018-04-01

We present a strongly hyperbolic first-order formulation of the Einstein equations based on the conformal and covariant Z4 system (CCZ4) with constraint-violation damping, which we refer to as FO-CCZ4. As CCZ4, this formulation combines the advantages of a conformal and traceless formulation, with the suppression of constraint violations given by the damping terms, but being first order in time and space, it is particularly suited for a discontinuous Galerkin (DG) implementation. The strongly hyperbolic first-order formulation has been obtained by making careful use of first and second-order ordering constraints. A proof of strong hyperbolicity is given for a selected choice of standard gauges via an analytical computation of the entire eigenstructure of the FO-CCZ4 system. The resulting governing partial differential equations system is written in nonconservative form and requires the evolution of 58 unknowns. A key feature of our formulation is that the first-order CCZ4 system decouples into a set of pure ordinary differential equations and a reduced hyperbolic system of partial differential equations that contains only linearly degenerate fields. We implement FO-CCZ4 in a high-order path-conservative arbitrary-high-order-method-using-derivatives (ADER)-DG scheme with adaptive mesh refinement and local time-stepping, supplemented with a third-order ADER-WENO subcell finite-volume limiter in order to deal with singularities arising with black holes. We validate the correctness of the formulation through a series of standard tests in vacuum, performed in one, two and three spatial dimensions, and also present preliminary results on the evolution of binary black-hole systems. To the best of our knowledge, these are the first successful three-dimensional simulations of moving punctures carried out with high-order DG schemes using a first-order formulation of the Einstein equations.

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

PubMed Central

Ahmad, Faiyaz; Murata, Taku; Simizu, Kasumi; Degerman, Eva; Maurice, Donald; Manganiello, Vincent

2014-01-01

By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. Since these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multi-molecular signaling/regulatory complexes called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners. PMID:25056711

Multidimensional Riemann problem with self-similar internal structure - part III - a multidimensional analogue of the HLLI Riemann solver for conservative hyperbolic systems

NASA Astrophysics Data System (ADS)

Balsara, Dinshaw S.; Nkonga, Boniface

2017-10-01

Just as the quality of a one-dimensional approximate Riemann solver is improved by the inclusion of internal sub-structure, the quality of a multidimensional Riemann solver is also similarly improved. Such multidimensional Riemann problems arise when multiple states come together at the vertex of a mesh. The interaction of the resulting one-dimensional Riemann problems gives rise to a strongly-interacting state. We wish to endow this strongly-interacting state with physically-motivated sub-structure. The fastest way of endowing such sub-structure consists of making a multidimensional extension of the HLLI Riemann solver for hyperbolic conservation laws. Presenting such a multidimensional analogue of the HLLI Riemann solver with linear sub-structure for use on structured meshes is the goal of this work. The multidimensional MuSIC Riemann solver documented here is universal in the sense that it can be applied to any hyperbolic conservation law. The multidimensional Riemann solver is made to be consistent with constraints that emerge naturally from the Galerkin projection of the self-similar states within the wave model. When the full eigenstructure in both directions is used in the present Riemann solver, it becomes a complete Riemann solver in a multidimensional sense. I.e., all the intermediate waves are represented in the multidimensional wave model. The work also presents, for the very first time, an important analysis of the dissipation characteristics of multidimensional Riemann solvers. The present Riemann solver results in the most efficient implementation of a multidimensional Riemann solver with sub-structure. Because it preserves stationary linearly degenerate waves, it might also help with well-balancing. Implementation-related details are presented in pointwise fashion for the one-dimensional HLLI Riemann solver as well as the multidimensional MuSIC Riemann solver.

Initial value formulation of dynamical Chern-Simons gravity

NASA Astrophysics Data System (ADS)

Delsate, Térence; Hilditch, David; Witek, Helvi

2015-01-01

We derive an initial value formulation for dynamical Chern-Simons gravity, a modification of general relativity involving parity-violating higher derivative terms. We investigate the structure of the resulting system of partial differential equations thinking about linearization around arbitrary backgrounds. This type of consideration is necessary if we are to establish well-posedness of the Cauchy problem. Treating the field equations as an effective field theory we find that weak necessary conditions for hyperbolicity are satisfied. For the full field equations we find that there are states from which subsequent evolution is not determined. Generically the evolution system closes, but is not hyperbolic in any sense that requires a first order pseudodifferential reduction. In a cursory mode analysis we find that the equations of motion contain terms that may cause ill-posedness of the initial value problem.

On a fourth order accurate implicit finite difference scheme for hyperbolic conservation laws. II - Five-point schemes

NASA Technical Reports Server (NTRS)

Harten, A.; Tal-Ezer, H.

1981-01-01

This paper presents a family of two-level five-point implicit schemes for the solution of one-dimensional systems of hyperbolic conservation laws, which generalized the Crank-Nicholson scheme to fourth order accuracy (4-4) in both time and space. These 4-4 schemes are nondissipative and unconditionally stable. Special attention is given to the system of linear equations associated with these 4-4 implicit schemes. The regularity of this system is analyzed and efficiency of solution-algorithms is examined. A two-datum representation of these 4-4 implicit schemes brings about a compactification of the stencil to three mesh points at each time-level. This compact two-datum representation is particularly useful in deriving boundary treatments. Numerical results are presented to illustrate some properties of the proposed scheme.

Evolution and expression of the phosphodiesterase 6 genes unveils vertebrate novelty to control photosensitivity.

PubMed

Lagman, David; Franzén, Ilkin E; Eggert, Joel; Larhammar, Dan; Abalo, Xesús M

2016-06-13

Phosphodiesterase 6 (PDE6) is a protein complex that hydrolyses cGMP and acts as the effector of the vertebrate phototransduction cascade. The PDE6 holoenzyme consists of catalytic and inhibitory subunits belonging to two unrelated gene families. Rods and cones express distinct genes from both families: PDE6A and PDE6B code for the catalytic and PDE6G the inhibitory subunits in rods while PDE6C codes for the catalytic and PDE6H the inhibitory subunits in cones. We performed phylogenetic and comparative synteny analyses for both gene families in genomes from a broad range of animals. Furthermore, gene expression was investigated in zebrafish. We found that both gene families expanded from one to three members in the two rounds of genome doubling (2R) that occurred at the base of vertebrate evolution. The PDE6 inhibitory subunit gene family appears to be unique to vertebrates and expanded further after the teleost-specific genome doubling (3R). We also describe a new family member that originated in 2R and has been lost in amniotes, which we have named pde6i. Zebrafish has retained two additional copies of the PDE6 inhibitory subunit genes after 3R that are highly conserved, have high amino acid sequence identity, are coexpressed in the same photoreceptor type as their amniote orthologs and, interestingly, show strikingly different daily oscillation in gene expression levels. Together, these data suggest specialisation related to the adaptation to different light intensities during the day-night cycle, most likely maintaining the regulatory function of the PDE inhibitory subunits in the phototransduction cascade.

Recreational Use of Phosphodiesterase 5 Inhibitors and Its Associated Factors among Undergraduate Male Students in an Ethiopian University: A Cross-Sectional Study.

PubMed

Gebreyohannes, Eyob Alemayehu; Bhagavathula, Akshaya Srikanth; Gebresillassie, Begashaw Melaku; Tefera, Yonas Getaye; Belachew, Sewunet Admasu; Erku, Daniel Asfaw

2016-12-01

To assess the prevalence of phosphodiesterase 5 (PDE5) inhibitor use and associated factors among University of Gondar undergraduate students. An institution-based, cross-sectional study, using a survey questionnaire, was conducted from October to December 2015 to assess PDE5 inhibitor use and associated factors among male students at the University of Gondar. A Self-Esteem and Relationship questionnaire (14 items), an International Index of Erectile Function questionnaire (15 items) and a questionnaire on PDE5 inhibitor use (14 items) were included in the survey. Across all respondents (age, 21.9±1.88 years), more than half (55.7%, n=233) had heard about PDE5 inhibitors, but only 23 men (5.5%) reported trying a PDE5 inhibitor drug at least once. Older students were more likely to use PDE5 inhibitors compared to younger students (adjusted odds ratio [AOR], 1.40; 95% confidence interval [CI], 1.109~1.768). Those students who were smokers were 5.15 times more likely to use PDE5 inhibitors as compared to their non-smoking counterparts (AOR, 5.15; 95% CI, 2.096~12.687). In addition, multivariate logistic regression showed that being in a relationship, alcohol use, greater number of cigarettes smoked per day, and more sexual partners were significantly associated with PDE5 inhibitor use. The prevalence of PDE5 inhibitor use among undergraduate students was 5.5%. Cigarette smoking and other substance use, older age, and greater number of sexual partners were significantly associated factors for PDE5 inhibitor use. These findings suggest that restricting access to PDE5 inhibitor drugs is essential to curtailing misuse among university students.

Recreational Use of Phosphodiesterase 5 Inhibitors and Its Associated Factors among Undergraduate Male Students in an Ethiopian University: A Cross-Sectional Study

PubMed Central

Bhagavathula, Akshaya Srikanth; Gebresillassie, Begashaw Melaku; Tefera, Yonas Getaye; Belachew, Sewunet Admasu; Erku, Daniel Asfaw

2016-01-01

Purpose To assess the prevalence of phosphodiesterase 5 (PDE5) inhibitor use and associated factors among University of Gondar undergraduate students. Materials and Methods An institution-based, cross-sectional study, using a survey questionnaire, was conducted from October to December 2015 to assess PDE5 inhibitor use and associated factors among male students at the University of Gondar. A Self-Esteem and Relationship questionnaire (14 items), an International Index of Erectile Function questionnaire (15 items) and a questionnaire on PDE5 inhibitor use (14 items) were included in the survey. Results Across all respondents (age, 21.9±1.88 years), more than half (55.7%, n=233) had heard about PDE5 inhibitors, but only 23 men (5.5%) reported trying a PDE5 inhibitor drug at least once. Older students were more likely to use PDE5 inhibitors compared to younger students (adjusted odds ratio [AOR], 1.40; 95% confidence interval [CI], 1.109~1.768). Those students who were smokers were 5.15 times more likely to use PDE5 inhibitors as compared to their non-smoking counterparts (AOR, 5.15; 95% CI, 2.096~12.687). In addition, multivariate logistic regression showed that being in a relationship, alcohol use, greater number of cigarettes smoked per day, and more sexual partners were significantly associated with PDE5 inhibitor use. Conclusions The prevalence of PDE5 inhibitor use among undergraduate students was 5.5%. Cigarette smoking and other substance use, older age, and greater number of sexual partners were significantly associated factors for PDE5 inhibitor use. These findings suggest that restricting access to PDE5 inhibitor drugs is essential to curtailing misuse among university students. PMID:28053948

The oligomerization state determines regulatory properties and inhibitor sensitivity of type 4 cAMP-specific phosphodiesterases.

PubMed

Richter, Wito; Conti, Marco

2004-07-16

PDE4 splice variants are classified into long and short forms depending on the presence or absence of two unique N-terminal domains termed upstream conserved regions 1 and 2 (UCR1 and -2). We have shown previously that the UCR module mediates dimerization of PDE4 long forms, whereas short forms, which lack UCR1, behave as monomers. In the present study, we demonstrate that dimerization is an essential structural element that determines the regulatory properties and inhibitor sensitivities of PDE4 enzymes. Comparing the properties of the dimeric wild type PDE4D3 with several monomeric mutant PDE4D3 constructs revealed that disruption of dimerization ablates the activation of PDE4 long forms by either protein kinase A phosphorylation or phosphatidic acid binding. Moreover, the analysis of heterodimers consisting of a catalytically active and a catalytically inactive PDE4D3 subunit indicates that protein kinase A phosphorylation of both subunits is essential to fully activate PDE4 enzymes. In addition to affecting enzyme regulation, disruption of dimerization reduces the sensitivity of the enzymes toward the prototypical PDE4 inhibitor rolipram. Parallel binding assays indicated that this shift in rolipram sensitivity is likely mediated by a decrease in the number of inhibitor binding sites in the high affinity rolipram binding state. Thus, although dimerization is not a requirement for high affinity rolipram binding, it functions to stabilize PDE4 long forms in their high affinity rolipram binding conformation. Taken together, our data indicate that dimerization defines the properties of PDE4 enzymes and suggest a common structural and functional organization for all PDEs.

Behavioral characterization of mice deficient in the phosphodiesterase-10A (PDE10A) enzyme on a C57/Bl6N congenic background.

PubMed

Siuciak, Judith A; McCarthy, Sheryl A; Chapin, Douglas S; Martin, Ashley N; Harms, John F; Schmidt, Christopher J

2008-02-01

The phenotype of genetically modified animals is strongly influenced by both the genetic background of the animal as well as environmental factors. We have previously reported the behavioral and neurochemical characterization of PDE10A knockout mice maintained on a DBA1LacJ (PDE10A(DBA)) genetic background. The aim of the present studies was to assess the behavioral and neurochemical phenotype of PDE10A knockout mice on an alternative congenic C57BL/6N (PDE10A(C57)) genetic background. Consistent with our previous results, PDE10A(C57) knockout mice showed a decrease in exploratory locomotor activity and a delay in the acquisition of conditioned avoidance responding. Also consistent with previous studies, the elimination of PDE10A did not alter basal levels of striatal cGMP or cAMP or affect behavior in several other well-characterized behavioral assays. PDE10A(C57) knockout mice showed a blunted response to MK-801, although to a lesser degree than previously observed in the PDE10A(DBA) knockout mice, and no differences were observed following a PCP challenge. PDE10A(C57) knockout mice showed a significant change in striatal dopamine turnover, which was accompanied by an enhanced locomotor response to AMPH, These studies demonstrate that while many of the behavioral effects of the PDE10A gene deletion appear to be independent of genetic background, the impact of the deletion on behavior can vary in magnitude. Furthermore, the effects on the dopaminergic system appear to be background-dependent, with significant effects observed only in knockout mice on the C57BL6N genetic background.

Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling

PubMed Central

Kim, Dongsoo; Aizawa, Toru; Wei, Heng; Pi, Xinchun; Rybalkin, Sergei D.; Berk, Bradford C.; Yan, Chen

2014-01-01

Angiotensin II (Ang II) and nitric oxide (NO)/natriuretic peptide (NP) signaling pathways mutually regulate each other. Imbalance of Ang II and NO/NP has been implicated in the pathophysiology of many vascular diseases. cGMP functions as a key mediator in the interaction between Ang II and NO/NP. Cyclic nucleotide phosphodiesterase 5A (PDE5A) is important in modulating cGMP signaling by hydrolyzing cGMP in vascular smooth muscle cells (VSMC). Therefore, we examined whether Ang II negatively modulates intracellular cGMP signaling in VSMC by regulating PDE5A. Ang II rapidly and transiently increased PDE5A mRNA levels in rat aortic VSMC. Upregulation of PDE5A mRNA was associated with a time-dependent increase of both PDE5 protein expression and activity. Increased PDE5A mRNA level was transcription-dependent and mediated by the Ang II type 1 receptor. Ang II-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was essential for Ang II-induced PDE5A upregulation. Pretreatment of VSMC with Ang II inhibited C-type NP (CNP) stimulated cGMP signaling, such as cGMP dependent protein kinase (PKG)-mediated phosphorylation of vasodilator-stimulated-phosphoprotein (VASP). Ang II-mediated inhibition of PKG was blocked when PDE5 activity was decreased by selective PDE5 inhibitors, suggesting that upregulation of PDE5A expression is an important mechanism for Ang II to attenuate cGMP signaling. PDE5A may also play a critical role in the growth promoting effects of Ang II because inhibition of PDE5A activity significantly decreased Ang II-stimulated VSMC growth. These observations establish a new mechanism by which Ang II antagonizes cGMP signaling and stimulates VSMC growth. PMID:15623434

Distinct phosphodiesterase 5A-containing compartments allow selective regulation of cGMP-dependent signalling in human arterial smooth muscle cells.

PubMed

Wilson, Lindsay S; Guo, Manhong; Umana, M Bibiana; Maurice, Donald H

2017-08-01

Cyclic GMP (cGMP) translates and integrates much of the information encoded by nitric oxide (NO · ) and several natriuretic peptides, including the atrial natriuretic peptide (ANP). Previously, we reported that integration of a cGMP-specific cyclic nucleotide phosphodiesterase, namely phosphodiesterase 5A (PDE5A), into a protein kinase G (PKG)- and inositol-1,4,5-trisphosphate receptor (IP 3 R)-containing endoplasmic reticulum (ER) signalosome allows localized control of PDE5A activity and of PKG-dependent inhibition of IP 3 -mediated release of ER Ca 2+ in human platelets. Herein, we report that PDE5A integrates into an analogous signalosome in human arterial smooth muscle cells (HASMC), wherein it regulates muscarinic agonist-dependent Ca 2+ release and is activated selectively by PKG-dependent phosphorylation. In addition, we report that PDE5A also regulates HASMC functions via events independent of PKG, but rather through actions coordinated by competitive cGMP-mediated inhibition of cAMP hydrolysis by the so-called cGMP-inhibited cAMP PDE, namely phosphodiesterase 3A (PDE3A). Indeed, we show that ANP increases both cGMP and cAMP levels in HASMC and promotes phosphorylation of vasodilator-stimulated phospho-protein (VASP) at each the PKG and PKA phospho-acceptor sites. Since selective inhibition of PDE5 decreased DNA synthesis and chemotaxis of HASMC, and that PDE3A knockdown obviated these effects, our findings are consistent with a role for a PDE5A-PDE3A-PKA axis in their regulation. Our findings provide insight into the existence of distinct "pools" of PDE5A in HASMC and support the idea that these discrete compartments regulate distinct cGMP-dependent events. As a corollary, we suggest that it may be possible to target these distinct PDE5A-regulated pools and in so-doing differentially impact selected cGMP-regulated functions in these cells. Copyright © 2017. Published by Elsevier Inc.

Synthesis, Pharmacological Profile and Docking Studies of New Sulfonamides Designed as Phosphodiesterase-4 Inhibitors

PubMed Central

Cardozo, Suzana Vanessa S.; Carvalho, Vinicius de Frias; Romeiro, Nelilma Correia; Silva, Patrícia Machado Rodrigues e; Martins, Marco Aurélio; Barreiro, Eliezer J.; Lima, Lídia Moreira

2016-01-01

Prior investigations showed that increased levels of cyclic AMP down-regulate lung inflammatory changes, stimulating the interest in phosphodiesterase (PDE)4 as therapeutic target. Here, we described the synthesis, pharmacological profile and docking properties of a novel sulfonamide series (5 and 6a-k) designed as PDE4 inhibitors. Compounds were screened for their selectivity against the four isoforms of human PDE4 using an IMAP fluorescence polarized protocol. The effect on allergen- or LPS-induced lung inflammation and airway hyper-reactivity (AHR) was studied in A/J mice, while the xylazine/ketamine-induced anesthesia test was employed as a behavioral correlate of emesis in rodents. As compared to rolipram, the most promising screened compound, 6a (LASSBio-448) presented a better inhibitory index concerning PDE4D/PDE4A or PDE4D/PDE4B. Accordingly, docking analyses of the putative interactions of LASSBio-448 revealed similar poses in the active site of PDE4A and PDE4C, but slight unlike orientations in PDE4B and PDE4D. LASSBio-448 (100 mg/kg, oral), 1 h before provocation, inhibited allergen-induced eosinophil accumulation in BAL fluid and lung tissue samples. Under an interventional approach, LASSBio-448 reversed ongoing lung eosinophilic infiltration, mucus exacerbation, peribronchiolar fibrosis and AHR by allergen provocation, in a mechanism clearly associated with blockade of pro-inflammatory mediators such as IL-4, IL-5, IL-13 and eotaxin-2. LASSBio-448 (2.5 and 10 mg/kg) also prevented inflammation and AHR induced by LPS. Finally, the sulfonamide derivative was shown to be less pro-emetic than rolipram and cilomilast in the assay employed. These findings suggest that LASSBio-448 is a new PDE4 inhibitor with marked potential to prevent and reverse pivotal pathological features of diseases characterized by lung inflammation, such as asthma. PMID:27695125

A new adaptively central-upwind sixth-order WENO scheme

NASA Astrophysics Data System (ADS)

Huang, Cong; Chen, Li Li

2018-03-01

In this paper, we propose a new sixth-order WENO scheme for solving one dimensional hyperbolic conservation laws. The new WENO reconstruction has three properties: (1) it is central in smooth region for low dissipation, and is upwind near discontinuities for numerical stability; (2) it is a convex combination of four linear reconstructions, in which one linear reconstruction is sixth order, and the others are third order; (3) its linear weights can be any positive numbers with requirement that their sum equals one. Furthermore, we propose a simple smoothness indicator for the sixth-order linear reconstruction, this smooth indicator not only can distinguish the smooth region and discontinuities exactly, but also can reduce the computational cost, thus it is more efficient than the classical one.

[Pulmonary artery pressure evaluation in adults by Doppler echocardiography].

PubMed

Campos Filho, O; Andrade, J L; Carvalho, A C; Luna Filho, B; Pfeferman, A; Arroyo, J B; Leão, L E; Martinez Filho, E E

1991-04-01

To assess the role of pulsed Doppler echocardiography (PDE) in the indirect assessment of pulmonary artery (PA) pressure (P), analysing the pulmonary velocity blood flow curves (PVBFC) profile. Sixty-one adults with several kinds of heart disease were submitted to heart catheterization to obtain PAP (systolic, diastolic, mean), and other hemodynamic variables. A PDE examination was performed in all to obtain the PVBFC at the level of the pulmonic annulus. Qualitative features of the curve were analysed (morphological pattern, presence of pulmonic regurgitation) as well as quantitative data (acceleration time = AT, right ventricle ejection time = RVET index, AT/RVET index AT corrected for heart rate = ATC), which were compared to the invasive measurements. An abnormal rapid acceleration of the PVBFC, with triangular configuration, was noted in patient with pulmonary hypertension (PH), in contrast to the dome-like shape of the PVBFC in normal PAP. Pulmonary regurgitation was more frequent (p less than 0.05) in patients with severe PH (mean PAP greater than or equal to 40 mmHg), comparing with patients with PAP less than 40 mmHg. Inverse linear correlations were observed between AT and mean PAP, particularly when sinus rhythm was present (r = 0.89; p less than 0.05) excluding patients with atrial fibrilation (19 cases). PDE is an useful and noninvasive method for indirect evaluation of PAP in adults, especially during stable sinus rhythm, in heart rate range from 60 to 115 bpm.

Corridengum: Linear and fractional response for the SRB measure of smooth hyperbolic attractors and discontinuous observables (2017 Nonlinearity 30 1204)

NASA Astrophysics Data System (ADS)

Baladi, Viviane; Kuna, Tobias; Lucarini, Valerio

2017-08-01

The first main result of Baladi et al (2017 Nonlinearity 30 1204-20) is modified as follows: For any θ in the Sobolev space H^r_p(M) , with 1 and 0, the map t\\mapsto \\int θ dρt is α-Hölder continuous for all \

Utilizing a Coupled Nonlinear Schrödinger Model to Solve the Linear Modal Problem for Stratified Flows

NASA Astrophysics Data System (ADS)

Liu, Tianyang; Chan, Hiu Ning; Grimshaw, Roger; Chow, Kwok Wing

2017-11-01

The spatial structure of small disturbances in stratified flows without background shear, usually named the `Taylor-Goldstein equation', is studied by employing the Boussinesq approximation (variation in density ignored except in the buoyancy). Analytical solutions are derived for special wavenumbers when the Brunt-Väisälä frequency is quadratic in hyperbolic secant, by comparison with coupled systems of nonlinear Schrödinger equations intensively studied in the literature. Cases of coupled Schrödinger equations with four, five and six components are utilized as concrete examples. Dispersion curves for arbitrary wavenumbers are obtained numerically. The computations of the group velocity, second harmonic, induced mean flow, and the second derivative of the angular frequency can all be facilitated by these exact linear eigenfunctions of the Taylor-Goldstein equation in terms of hyperbolic function, leading to a cubic Schrödinger equation for the evolution of a wavepacket. The occurrence of internal rogue waves can be predicted if the dispersion and cubic nonlinearity terms of the Schrödinger equations are of the same sign. Partial financial support has been provided by the Research Grants Council contract HKU 17200815.

The surface-induced spatial-temporal structures in confined binary alloys

NASA Astrophysics Data System (ADS)

Krasnyuk, Igor B.; Taranets, Roman M.; Chugunova, Marina

2014-12-01

This paper examines surface-induced ordering in confined binary alloys. The hyperbolic initial boundary value problem (IBVP) is used to describe a scenario of spatiotemporal ordering in a disordered phase for concentration of one component of binary alloy and order parameter with non-linear dynamic boundary conditions. This hyperbolic model consists of two coupled second order differential equations for order parameter and concentration. It also takes into account effects of the “memory” on the ordering of atoms and their densities in the alloy. The boundary conditions characterize surface velocities of order parameter and concentration changing which is due to surface (super)cooling on walls confining the binary alloy. It is shown that for large times there are three classes of dynamic non-linear boundary conditions which lead to three different types of attractor’s elements for the IBVP. Namely, the elements of attractor are the limit periodic simple shock waves with fronts of “discontinuities” Γ. If Γ is finite, then the attractor contains spatiotemporal functions of relaxation type. If Γ is infinite and countable then we observe the functions of pre-turbulent type. If Γ is infinite and uncountable then we obtain the functions of turbulent type.

Phosphodiesterase 4 Inhibitor Therapies for Atopic Dermatitis: Progress and Outlook.

PubMed

Ahluwalia, Jusleen; Udkoff, Jeremy; Waldman, Andrea; Borok, Jenna; Eichenfield, Lawrence F

2017-09-01

Phosphodiesterase 4 (PDE4) is a cyclic AMP degrading enzyme in leukocytes. Several decades ago, increased PDE activity was demonstrated in patients with atopic dermatitis (AD). Currently, several PDE4 inhibitors in both topical and oral formulation have been developed to target the inflammatory cascade of AD. This review shows the pathogenic rationale behind these inhibitors, and discusses multiple PDE4 inhibitors that are under evaluation or in the market. PDE4 inhibitors may be considered as favorable agents in the repertoire of current interventions for AD.

New findings on phosphodiesterases, MoPdeH and MoPdeL, in Magnaporthe oryzae revealed by structural analysis.

PubMed

Yang, Li-Na; Yin, Ziyi; Zhang, Xi; Feng, Wanzhen; Xiao, Yuhan; Zhang, Haifeng; Zheng, Xiaobo; Zhang, Zhengguang

2018-05-01

The cyclic adenosine monophosphate (cAMP) signalling pathway mediates signal communication and sensing during infection-related morphogenesis in eukaryotes. Many studies have implicated cAMP as a critical mediator of appressorium development in the rice blast fungus, Magnaporthe oryzae. The cAMP phosphodiesterases, MoPdeH and MoPdeL, as key regulators of intracellular cAMP levels, play pleiotropic roles in cell wall integrity, cellular morphology, appressorium formation and infectious growth in M. oryzae. Here, we analysed the roles of domains of MoPdeH and MoPdeL separately or in chimeras. The results indicated that the HD and EAL domains of MoPdeH are indispensable for its phosphodiesterase activity and function. Replacement of the MoPdeH HD domain with the L1 and L2 domains of MoPdeL, either singly or together, resulted in decreased cAMP hydrolysis activity of MoPdeH. All of the transformants exhibited phenotypes similar to that of the ΔMopdeH mutant, but also revealed that EAL and L1 play additional roles in conidiation, and that L1 is involved in infectious growth. We further found that the intracellular cAMP level is important for surface signal recognition and hyphal autolysis. The intracellular cAMP level negatively regulates Mps1-MAPK and positively regulates Pmk1-MAPK in the rice blast fungus. Our results provide new information to better understand the cAMP signalling pathway in the development, differentiation and plant infection of the fungus. © 2017 BSPP AND JOHN WILEY & SONS LTD.

Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivo.

PubMed

Kleiman, Robin J; Chapin, Douglas S; Christoffersen, Curt; Freeman, Jody; Fonseca, Kari R; Geoghegan, Kieran F; Grimwood, Sarah; Guanowsky, Victor; Hajós, Mihály; Harms, John F; Helal, Christopher J; Hoffmann, William E; Kocan, Geralyn P; Majchrzak, Mark J; McGinnis, Dina; McLean, Stafford; Menniti, Frank S; Nelson, Fredrick; Roof, Robin; Schmidt, Anne W; Seymour, Patricia A; Stephenson, Diane T; Tingley, Francis David; Vanase-Frawley, Michelle; Verhoest, Patrick R; Schmidt, Christopher J

2012-05-01

Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems.

The dangers of sexual enhancement supplements and counterfeit drugs to "treat" erectile dysfunction.

PubMed

Chiang, Jason; Yafi, Faysal A; Dorsey, Philip J; Hellstrom, Wayne J G

2017-02-01

Counterfeit phosphodiesterase-5 inhibitors (PDE-5i) are an increasing problem. Already in widespread use, the market for PDE-5i is steadily growing as the population ages. Counterfeiters are taking advantage of this growing market by developing illicit and counterfeit PDE-5i products. Many factors are contributing to the rapid growth of the illicit market, such as the low risk of prosecution, potentially high financial reward, and ease of distribution via Internet pharmacies. Consumers of illicit PDE-5i often do not realize they are using counterfeit products and placing themselves at an unnecessary health risk. Others seek to bypass the legitimate healthcare system due to either embarrassment of the underlying condition or desire for cheaper alternatives. However, taking illicit PDE-5i may harm consumers directly, as many illicit products contain detrimental contaminants and inaccurate amounts of the active ingredient without the appropriate warnings. Bypassing the legitimate healthcare system also endangers consumers indirectly, as erectile dysfunction (ED) is often associated with other medical comorbidities that patients should be screened for. Furthermore, PDE-5i can have potentially dangerous interactions with other pharmaceuticals that are rarely warned against with counterfeit PDE-5i. This communication reviews the literature regarding counterfeit PDE-5i, and summarizes both the scope and dangers of the illicit PDE-5i market.

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

2016-07-01

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. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

PDE7B is involved in nandrolone decanoate hydrolysis in liver cytosol and its transcription is up-regulated by androgens in HepG2.

PubMed

Strahm, Emmanuel; Rane, Anders; Ekström, Lena

2014-01-01

Most androgenic drugs are available as esters for a prolonged depot action. However, the enzymes involved in the hydrolysis of the esters have not been identified. There is one study indicating that PDE7B may be involved in the activation of testosterone enanthate. The aims are to identify the cellular compartments where the hydrolysis of testosterone enanthate and nandrolone decanoate occurs, and to investigate the involvement of PDE7B in the activation. We also determined if testosterone and nandrolone affect the expression of the PDE7B gene. The hydrolysis studies were performed in isolated human liver cytosolic and microsomal preparations with and without specific PDE7B inhibitor. The gene expression was studied in human hepatoma cells (HepG2) exposed to testosterone and nandrolone. We show that PDE7B serves as a catalyst of the hydrolysis of testosterone enanthate and nandrolone decanoate in liver cytosol. The gene expression of PDE7B was significantly induced 3- and 5- fold after 2 h exposure to 1 μM testosterone enanthate and nandrolone decanoate, respectively. These results show that PDE7B is involved in the activation of esterified nandrolone and testosterone and that the gene expression of PDE7B is induced by supra-physiological concentrations of androgenic drugs.

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

DISC1, PDE4B, and NDE1 at the centrosome and synapse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bradshaw, Nicholas J.; Ogawa, Fumiaki; Antolin-Fontes, Beatriz

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-dependantmore » 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.« less

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

PubMed Central

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

2013-01-01

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

Identification of a Phosphodiesterase-Inhibiting Fraction from Roasted Coffee (Coffea arabica) through Activity-Guided Fractionation.

PubMed

Röhrig, Teresa; Liesenfeld, David; Richling, Elke

2017-05-17

Recent reports that coffee can significantly inhibit cAMP phosphodiesterases (PDEs) in vitro, as well as in vivo, have described another beneficial effect of coffee consumption. However, the PDE-inhibiting substances remain mostly unknown. We chose activity-guided fractionation and an in vitro test system to identify the coffee components that are responsible for PDE inhibition. This approach indicated that a fraction of melanoidins reveals strong PDE-inhibiting potential (IC 50 = 130 ± 42 μg/mL). These melanoidins were characterized as water-soluble, low-molecular weight melanoidins (<3 kDa) with a nitrogen content of 4.2% and a carbohydrate content lower than those of other melanoidins. Fractions containing known PDE inhibitors such as chlorogenic acids, alkylpyrazines, or trigonelline as well as N-caffeoyl-tryptophan and N-p-coumaroyl-tryptophan did not exert PDE-inhibiting activity. We also observed that the known PDE inhibitor caffeine does not contribute to the PDE-inhibiting effects of coffee.

The Geometry of the Universe: Part 2

ERIC Educational Resources Information Center

Francis, Stephanie

2009-01-01

Hyperbolic geometry occurs on hyperbolic planes--the most commonly cited one being a saddle shape. In this article, the author explores negative hyperbolic curvature, and provides a detailed description of how she constructed two hyperbolic paraboloids. Hyperbolic geometry occurs on surfaces that have negative curvature. (Contains 11 figures and 4…

Effect of phosphodiesterase inhibitors in the bladder.

PubMed

Chughtai, Bilal; Ali, Aizaz; Dunphy, Claire; Kaplan, Steven A

2015-01-01

Many aging men will experience lower urinary tract symptoms (LUTS). Phosphodiesterase type 5 (PDE5) inhibitors have shown promise in treating LUTS in these patients. PDE5 inhibitors mediate their effects through several pathways including cAMP, NO/cGMP, K-channel modulated pathways, and the l -cysteine/H 2 S pathway. PDE5 inhibitors exert their effect in muscle cells, nerve fibers, and interstitial cells (ICs). The use of PDE5 inhibitors led to improvement in LUTS. This included urodynamic parameters. PDE5 inhibitors may play a significant role in LUTS due to their effect on the bladder rather than the prostate.

Observability of discretized partial differential equations

NASA Technical Reports Server (NTRS)

Cohn, Stephen E.; Dee, Dick P.

1988-01-01

It is shown that complete observability of the discrete model used to assimilate data from a linear partial differential equation (PDE) system is necessary and sufficient for asymptotic stability of the data assimilation process. The observability theory for discrete systems is reviewed and applied to obtain simple observability tests for discretized constant-coefficient PDEs. Examples are used to show how numerical dispersion can result in discrete dynamics with multiple eigenvalues, thereby detracting from observability.

Detonation Propagation Through Ducts in a Pulsed Detonation Engine

DTIC Science & Technology

2011-03-01

PDE head. This convention is used based on the fill and purge flow directions, not the detonation direction. Figure 21. Adapter used to rotate ...presented for the development of a continuously operating pulsed detonation engine ( PDE ). A PDE without a high energy ignition system or a... detonation wave. Propagation is left to right in the bottom tube. ..... 19  Figure 15. Research PDE head

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

PubMed

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

2011-01-01

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

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 surface capsid. Virus surface morphologies of different resolutions are attained by adjusting the propagation time. Therefore, the present PDE transform provides a multiresolution analysis in the surface visualization. Extensive numerical experiment and comparison with an established surface model indicate that the present PDE transform is a robust, stable and efficient approach for biomolecular surface generation in Cartesian meshes. PMID:22582140

Powerful relaxation of phosphodiesterase type 4 inhibitor rolipram in the pig and human bladder neck.

PubMed

Ribeiro, Ana S F; Fernandes, Vítor S; Martínez-Sáenz, Ana; Martínez, Pilar; Barahona, María Victoria; Orensanz, Luis M; Blaha, Igor; Serrano-Margüello, Daniel; Bustamante, Salvador; Carballido, Joaquín; García-Sacristán, Albino; Prieto, Dolores; Hernández, Medardo

2014-04-01

Phosphodiesterase type 5 (PDE5) inhibitors act as effective drugs for the treatment of lower urinary tract symptom (LUTS). There is a poor information, however, about the role of the PDE4 inhibitors on the bladder outflow region contractility. To investigate PDE4 expression and the relaxation induced by the PDE4 inhibitor rolipram versus that induced by the PDE5 blockers sildenafil and vardenafil, in the pig and human bladder neck. Immunohistochemistry for PDE4 expression, myographs for isometric force recordings and fura-2 fluorescence for simultaneous measurements of intracellular Ca2+ concentration ([Ca2+]i ) and tension for rolipram in bladder neck samples were used. PDE4 expression and relaxations to PDE4 and PDE5 inhibitors and simultaneous measurements of [Ca2+]i and tension. PDE4 expression was observed widely distributed in the smooth muscle layer of the pig and human bladder neck. On urothelium-denuded phenylephrine (PhE)-precontracted strips of pig and human, rolipram, sildenafil and vardenafil produced concentration-dependent relaxations with the following order of potency: rolipram> > sildenafil>vardenafil. In pig, the adenylyl cyclase activator forskolin potentiated rolipram-elicited relaxation, whereas protein kinase A (PKA) blockade reduced such effect. On potassium-enriched physiological saline solution (KPSS)-precontracted strips, rolipram evoked a lower relaxation than that obtained on PhE-stimulated preparations. Inhibition of large (BKCa ) and intermediate (IKCa ) conductance Ca2+ -activated K+ channels, neuronal voltage-gated Ca2+ channels, nitric oxide (NO) and hydrogen sulfide (H2 S) synthases reduced rolipram responses. Rolipram inhibited the contractions induced by PhE without reducing the PhE-evoked [Ca2+]i increase. PDE4 is present in the pig and human bladder neck smooth muscle, where rolipram exerts a much more potent relaxation than that elicited by PDE5 inhibitors. In pig, rolipram-induced response is produced through the PKA pathway involving BKCa and IKCa channel activation and [Ca2+]i desensitization-dependent mechanisms, this relaxation also being due to neuronal NO and H2S release. © 2014 International Society for Sexual Medicine.

Stability of semidiscrete approximations for hyperbolic initial-boundary-value problems: An eigenvalue analysis

NASA Technical Reports Server (NTRS)

Warming, Robert F.; Beam, Richard M.

1986-01-01

A hyperbolic initial-boundary-value problem can be approximated by a system of ordinary differential equations (ODEs) by replacing the spatial derivatives by finite-difference approximations. The resulting system of ODEs is called a semidiscrete approximation. A complication is the fact that more boundary conditions are required for the spatially discrete approximation than are specified for the partial differential equation. Consequently, additional numerical boundary conditions are required and improper treatment of these additional conditions can lead to instability. For a linear initial-boundary-value problem (IBVP) with homogeneous analytical boundary conditions, the semidiscrete approximation results in a system of ODEs of the form du/dt = Au whose solution can be written as u(t) = exp(At)u(O). Lax-Richtmyer stability requires that the matrix norm of exp(At) be uniformly bounded for O less than or = t less than or = T independent of the spatial mesh size. Although the classical Lax-Richtmyer stability definition involves a conventional vector norm, there is no known algebraic test for the uniform boundedness of the matrix norm of exp(At) for hyperbolic IBVPs. An alternative but more complicated stability definition is used in the theory developed by Gustafsson, Kreiss, and Sundstrom (GKS). The two methods are compared.

Diffusive instabilities in a hyperbolic activator-inhibitor system with superdiffusion

NASA Astrophysics Data System (ADS)

Mvogo, Alain; Macías-Díaz, Jorge E.; Kofané, Timoléon Crépin

2018-03-01

We investigate analytically and numerically the conditions for wave instabilities in a hyperbolic activator-inhibitor system with species undergoing anomalous superdiffusion. In the present work, anomalous superdiffusion is modeled using the two-dimensional Weyl fractional operator, with derivative orders α ∈ [1,2]. We perform a linear stability analysis and derive the conditions for diffusion-driven wave instabilities. Emphasis is placed on the effect of the superdiffusion exponent α , the diffusion ratio d , and the inertial time τ . As the superdiffusive exponent increases, so does the wave number of the Turing instability. Opposite to the requirement for Turing instability, the activator needs to diffuse sufficiently faster than the inhibitor in order for the wave instability to occur. The critical wave number for wave instability decreases with the superdiffusive exponent and increases with the inertial time. The maximum value of the inertial time for a wave instability to occur in the system is τmax=3.6 . As one of the main results of this work, we conclude that both anomalous diffusion and inertial time influence strongly the conditions for wave instabilities in hyperbolic fractional reaction-diffusion systems. Some numerical simulations are conducted as evidence of the analytical predictions derived in this work.

Nonlinear Conservation Laws and Finite Volume Methods

NASA Astrophysics Data System (ADS)

Leveque, Randall J.

Introduction Software Notation Classification of Differential Equations Derivation of Conservation Laws The Euler Equations of Gas Dynamics Dissipative Fluxes Source Terms Radiative Transfer and Isothermal Equations Multi-dimensional Conservation Laws The Shock Tube Problem Mathematical Theory of Hyperbolic Systems Scalar Equations Linear Hyperbolic Systems Nonlinear Systems The Riemann Problem for the Euler Equations Numerical Methods in One Dimension Finite Difference Theory Finite Volume Methods Importance of Conservation Form - Incorrect Shock Speeds Numerical Flux Functions Godunov's Method Approximate Riemann Solvers High-Resolution Methods Other Approaches Boundary Conditions Source Terms and Fractional Steps Unsplit Methods Fractional Step Methods General Formulation of Fractional Step Methods Stiff Source Terms Quasi-stationary Flow and Gravity Multi-dimensional Problems Dimensional Splitting Multi-dimensional Finite Volume Methods Grids and Adaptive Refinement Computational Difficulties Low-Density Flows Discrete Shocks and Viscous Profiles Start-Up Errors Wall Heating Slow-Moving Shocks Grid Orientation Effects Grid-Aligned Shocks Magnetohydrodynamics The MHD Equations One-Dimensional MHD Solving the Riemann Problem Nonstrict Hyperbolicity Stiffness The Divergence of B Riemann Problems in Multi-dimensional MHD Staggered Grids The 8-Wave Riemann Solver Relativistic Hydrodynamics Conservation Laws in Spacetime The Continuity Equation The 4-Momentum of a Particle The Stress-Energy Tensor Finite Volume Methods Multi-dimensional Relativistic Flow Gravitation and General Relativity References

Extended Thermodynamics: a Theory of Symmetric Hyperbolic Field Equations

NASA Astrophysics Data System (ADS)

Müller, Ingo

2008-12-01

Extended thermodynamics is based on a set of equations of balance which are supplemented by local and instantaneous constitutive equations so that the field equations are quasi-linear first order differential equations. If the constitutive functions are subject to the requirements of the entropy principle, one may write them in symmetric hyperbolic form by a suitable choice of fields. The kinetic theory of gases, or the moment theories based on the Boltzmann equation provide an explicit example for extended thermodynamics. The theory proves its usefulness and practicality in the successful treatment of light scattering in rarefied gases. This presentation is based upon the book [1] of which the author of this paper is a co-author. For more details about the motivation and exploitation of the basic principles the interested reader is referred to that reference. It would seem that extended thermodynamics is worthy of the attention of mathematicians. It may offer them a non-trivial field of study concerning hyperbolic equations, if ever they get tired of the Burgers equation. Physicists may prefer to appreciate the success of extended thermodynamics in light scattering and to work on the open problems concerning the modification of the Navier-Stokes-Fourier theory in rarefied gases as predicted by extended thermodynamics of 13, 14, and more moments.

A synthetic cGMP-sensitive gene switch providing Viagra(®)-controlled gene expression in mammalian cells and mice.

PubMed

Kim, Taeuk; Folcher, Marc; Charpin-El Hamri, Ghislaine; Fussenegger, Martin

2015-05-01

Cyclic guanosine monophosphate (cGMP) is a universal second messenger that is synthesized from guanosine triphosphate (GTP) by guanylyl cyclases (GCs) and hydrolyzed into guanosine monophosphate (GMP) by phosphodiesterases (PDEs). Small-molecule drugs that induce high cGMP levels in specialized tissues by boosting GC activity or inhibiting PDE activity have become the predominant treatment strategy for a wide range of medical conditions, including congestive heart failure, pulmonary hypertension, atherosclerosis-based claudication and erectile dysfunction. By fusing the cGMP receptor protein (CRP) of Rhodospirillum centenum to the Herpes simplex-derived transactivation domain VP16, we created a novel synthetic mammalian cGMP-sensing transcription factor (GTA) that activates synthetic promoters (PGTA) containing newly identified GTA-specific operator sites in a concentration-dependent manner. In cell lines expressing endogenous natriuretic peptide receptor A (NPR-A) (HeLa), GTA/PGTA-driven transgene expression was induced by B-type natriuretic peptide (BNP; Nesiritide(®)) in a concentration-dependent manner, which activated NPR-A׳s intracellular GC domain and triggered a corresponding cGMP surge. Ectopic expression of NPR-A in NPR-A-negative cell lines (HEK-293T) produced high cGMP levels and mediated maximum GTA/PGTA-driven transgene expression, which was suppressed by co-expression of PDEs (PDE-3A, PDE-5A and PDE-9A) and was re-triggered by the corresponding PDE inhibitor drugs (Pletal(®), Perfan(®), Primacor(®) (PDE-3A), Viagra(®), Levitra(®), Cialis(®) (PDE-5A) and BAY73-6691 (PDE-9A)). Mice implanted with microencapsulated designer cells co-expressing the GTA/PGTA device with NPR-A and PDE-5A showed control of blood SEAP levels through administration of sildenafil (Viagra(®)). Designer cells engineered for PDE inhibitor-modulated transgene expression may provide a cell-based PDE-targeting drug discovery platform and enable drug-adjusted gene- and cell-based therapies. Copyright © 2015 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Adaptive [theta]-methods for pricing American options

NASA Astrophysics Data System (ADS)

Khaliq, Abdul Q. M.; Voss, David A.; Kazmi, Kamran

2008-12-01

We develop adaptive [theta]-methods for solving the Black-Scholes PDE for American options. By adding a small, continuous term, the Black-Scholes PDE becomes an advection-diffusion-reaction equation on a fixed spatial domain. Standard implementation of [theta]-methods would require a Newton-type iterative procedure at each time step thereby increasing the computational complexity of the methods. Our linearly implicit approach avoids such complications. We establish a general framework under which [theta]-methods satisfy a discrete version of the positivity constraint characteristic of American options, and numerically demonstrate the sensitivity of the constraint. The positivity results are established for the single-asset and independent two-asset models. In addition, we have incorporated and analyzed an adaptive time-step control strategy to increase the computational efficiency. Numerical experiments are presented for one- and two-asset American options, using adaptive exponential splitting for two-asset problems. The approach is compared with an iterative solution of the two-asset problem in terms of computational efficiency.

Regularization techniques for backward--in--time evolutionary PDE problems

NASA Astrophysics Data System (ADS)

Gustafsson, Jonathan; Protas, Bartosz

2007-11-01

Backward--in--time evolutionary PDE problems have applications in the recently--proposed retrograde data assimilation. We consider the terminal value problem for the Kuramoto--Sivashinsky equation (KSE) in a 1D periodic domain as our model system. The KSE, proposed as a model for interfacial and combustion phenomena, is also often adopted as a toy model for hydrodynamic turbulence because of its multiscale and chaotic dynamics. Backward--in--time problems are typical examples of ill-posed problem, where disturbances are amplified exponentially during the backward march. Regularization is required to solve such problems efficiently and we consider approaches in which the original ill--posed problem is approximated with a less ill--posed problem obtained by adding a regularization term to the original equation. While such techniques are relatively well--understood for linear problems, they less understood in the present nonlinear setting. We consider regularization terms with fixed magnitudes and also explore a novel approach in which these magnitudes are adapted dynamically using simple concepts from the Control Theory.

Final Report: Subcontract B623868 Algebraic Multigrid solvers for coupled PDE systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brannick, J.

The Pennsylvania State University (“Subcontractor”) continued to work on the design of algebraic multigrid solvers for coupled systems of partial differential equations (PDEs) arising in numerical modeling of various applications, with a main focus on solving the Dirac equation arising in Quantum Chromodynamics (QCD). The goal of the proposed work was to develop combined geometric and algebraic multilevel solvers that are robust and lend themselves to efficient implementation on massively parallel heterogeneous computers for these QCD systems. The research in these areas built on previous works, focusing on the following three topics: (1) the development of parallel full-multigrid (PFMG) andmore » non-Galerkin coarsening techniques in this frame work for solving the Wilson Dirac system; (2) the use of these same Wilson MG solvers for preconditioning the Overlap and Domain Wall formulations of the Dirac equation; and (3) the design and analysis of algebraic coarsening algorithms for coupled PDE systems including Stokes equation, Maxwell equation and linear elasticity.« less

Phosphodiesterase 5a Inhibition with Adenoviral Short Hairpin RNA Benefits Infarcted Heart Partially through Activation of Akt Signaling Pathway and Reduction of Inflammatory Cytokines.

PubMed

Li, Longhu; Zhao, Dong; Jin, Zhe; Zhang, Jian; Paul, Christian; Wang, Yigang

2015-01-01

Treatment with short hairpin RNA (shRNA) interference therapy targeting phosphodiesterase 5a after myocardial infarction (MI) has been shown to mitigate post-MI heart failure. We investigated the mechanisms that underpin the beneficial effects of PDE5a inhibition through shRNA on post-MI heart failure. An adenoviral vector with an shRNA sequence inserted was adopted for the inhibition of phosphodiesterase 5a (Ad-shPDE5a) in vivo and in vitro. Myocardial infarction (MI) was induced in male C57BL/6J mice by left coronary artery ligation, and immediately after that, the Ad-shPDE5a was injected intramyocardially around the MI region and border areas. Four weeks post-MI, the Ad-shPDE5a-treated mice showed significant mitigation of the left ventricular (LV) dilatation and dysfunction compared to control mice. Infarction size and fibrosis were also significantly reduced in Ad-shPDE5a-treated mice. Additionally, Ad-shPDE5a treatment decreased the MI-induced inflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and transforming growth factor-β1, which was confirmed in vitro in Ad-shPDE5a transfected myofibroblasts cultured under oxygen glucose deprivation. Finally, Ad-shPDE5a treatment was found to activate the myocardial Akt signaling pathway in both in vivo and in vitro experiments. These findings indicate that PDE5a inhibition by Ad-shPDE5a via the Akt signal pathway could be of significant value in the design of future therapeutics for post-MI heart failure.

Erectile dysfunction and phosphodiesterase type 5 inhibitor use: associations with sexual activities, function and satisfaction in a population sample of older men.

PubMed

Lee, D M; Nazroo, J; Pendleton, N

2015-07-01

The objective of this study was to examine the association between sexual activities, problems and satisfaction, and ED and PDE5 inhibitor (PDE5i) use. A nationally representative sample of men (n=2612) aged 51-87 years from the English Longitudinal Study of Ageing completed an in-depth Sexual Relationships and Activities Questionnaire. Associations between ED and/or PDE5i use and sexual outcomes were explored using logistic regression models adjusted for age, health and lifestyle factors. PDE5i use in the preceding 3 months was reported by a total of 191 (7%) men, whereas 542 (21%) reported ED but no PDE5i use (untreated ED). Compared with men without ED, PDE5i users were more likely to be sexually active and report more frequent sexual intercourse. Men with untreated ED reported the lowest frequency of sexual activities. Compared with men without ED, both PDE5i users and those with untreated ED were more likely to report being concerned about their level of sexual desire, frequency of sexual activities, erectile function, waking erections and orgasmic experience. PDE5i users were also more concerned about and dissatisfied with their overall sex life than men without ED. This population-based study shows that while PDE5i use is associated with improved sexual functioning, this is not equally reflected in decreased levels of concern and dissatisfaction with their overall sexual health. Clinicians should be aware of this disparity between functional gains and continuing sexual concerns and dissatisfaction, and, where appropriate, offer psychosexual counselling as an adjunct to PDE5i medication.

Parabolic discounting of monetary rewards by physical effort.

PubMed

Hartmann, Matthias N; Hager, Oliver M; Tobler, Philippe N; Kaiser, Stefan

2013-11-01

When humans and other animals make decisions in their natural environments prospective rewards have to be weighed against costs. It is well established that increasing costs lead to devaluation or discounting of reward. While our knowledge about discount functions for time and probability costs is quite advanced, little is known about how physical effort discounts reward. In the present study we compared three different models in a binary choice task in which human participants had to squeeze a handgrip to earn monetary rewards: a linear, a hyperbolic, and a parabolic model. On the group as well as the individual level, the concave parabolic model explained most variance of the choice data, thus contrasting with the typical hyperbolic discounting of reward value by delay. Research on effort discounting is not only important to basic science but also holds the potential to quantify aberrant motivational states in neuropsychiatric disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

Absorbing boundary conditions for second-order hyperbolic equations

NASA Technical Reports Server (NTRS)

Jiang, Hong; Wong, Yau Shu

1989-01-01

A uniform approach to construct absorbing artificial boundary conditions for second-order linear hyperbolic equations is proposed. The nonlocal boundary condition is given by a pseudodifferential operator that annihilates travelling waves. It is obtained through the dispersion relation of the differential equation by requiring that the initial-boundary value problem admits the wave solutions travelling in one direction only. Local approximation of this global boundary condition yields an nth-order differential operator. It is shown that the best approximations must be in the canonical forms which can be factorized into first-order operators. These boundary conditions are perfectly absorbing for wave packets propagating at certain group velocities. A hierarchy of absorbing boundary conditions is derived for transonic small perturbation equations of unsteady flows. These examples illustrate that the absorbing boundary conditions are easy to derive, and the effectiveness is demonstrated by the numerical experiments.

Discretizing singular point sources in hyperbolic wave propagation problems

DOE PAGES

Petersson, N. Anders; O'Reilly, Ossian; Sjogreen, Bjorn; ...

2016-06-01

Here, we develop high order accurate source discretizations for hyperbolic wave propagation problems in first order formulation that are discretized by finite difference schemes. By studying the Fourier series expansions of the source discretization and the finite difference operator, we derive sufficient conditions for achieving design accuracy in the numerical solution. Only half of the conditions in Fourier space can be satisfied through moment conditions on the source discretization, and we develop smoothness conditions for satisfying the remaining accuracy conditions. The resulting source discretization has compact support in physical space, and is spread over as many grid points as themore » number of moment and smoothness conditions. In numerical experiments we demonstrate high order of accuracy in the numerical solution of the 1-D advection equation (both in the interior and near a boundary), the 3-D elastic wave equation, and the 3-D linearized Euler equations.« less

An hp-adaptivity and error estimation for hyperbolic conservation laws

NASA Technical Reports Server (NTRS)

Bey, Kim S.

1995-01-01

This paper presents an hp-adaptive discontinuous Galerkin method for linear hyperbolic conservation laws. A priori and a posteriori error estimates are derived in mesh-dependent norms which reflect the dependence of the approximate solution on the element size (h) and the degree (p) of the local polynomial approximation. The a posteriori error estimate, based on the element residual method, provides bounds on the actual global error in the approximate solution. The adaptive strategy is designed to deliver an approximate solution with the specified level of error in three steps. The a posteriori estimate is used to assess the accuracy of a given approximate solution and the a priori estimate is used to predict the mesh refinements and polynomial enrichment needed to deliver the desired solution. Numerical examples demonstrate the reliability of the a posteriori error estimates and the effectiveness of the hp-adaptive strategy.

The solution of non-linear hyperbolic equation systems by the finite element method

NASA Technical Reports Server (NTRS)

Loehner, R.; Morgan, K.; Zienkiewicz, O. C.

1984-01-01

A finite-element method for the solution of nonlinear hyperbolic systems of equations, such as those encountered in non-self-adjoint problems of transient phenomena in convection-diffusion or in the mixed representation of wave problems, is developed and demonstrated. The problem is rewritten in moving coordinates and reinterpolated to the original mesh by a Taylor expansion prior to a standard Galerkin spatial discretization, and it is shown that this procedure is equivalent to the time-discretization approach of Donea (1984). Numerical results for sample problems are presented graphically, including such shallow-water problems as the breaking of a dam, the shoaling of a wave, and the outflow of a river; compressible flows such as the isothermal flow in a nozzle and the Riemann shock-tube problem; and the two-dimensional scalar-advection, nonlinear-shallow-water, and Euler equations.

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.

Parameter Estimation of Partial Differential Equation Models.

PubMed

Xun, Xiaolei; Cao, Jiguo; Mallick, Bani; Carroll, Raymond J; Maity, Arnab

2013-01-01

Partial differential equation (PDE) models are commonly used to model complex dynamic systems in applied sciences such as biology and finance. The forms of these PDE models are usually proposed by experts based on their prior knowledge and understanding of the dynamic system. Parameters in PDE models often have interesting scientific interpretations, but their values are often unknown, and need to be estimated from the measurements of the dynamic system in the present of measurement errors. Most PDEs used in practice have no analytic solutions, and can only be solved with numerical methods. Currently, methods for estimating PDE parameters require repeatedly solving PDEs numerically under thousands of candidate parameter values, and thus the computational load is high. In this article, we propose two methods to estimate parameters in PDE models: a parameter cascading method and a Bayesian approach. In both methods, the underlying dynamic process modeled with the PDE model is represented via basis function expansion. For the parameter cascading method, we develop two nested levels of optimization to estimate the PDE parameters. For the Bayesian method, we develop a joint model for data and the PDE, and develop a novel hierarchical model allowing us to employ Markov chain Monte Carlo (MCMC) techniques to make posterior inference. Simulation studies show that the Bayesian method and parameter cascading method are comparable, and both outperform other available methods in terms of estimation accuracy. The two methods are demonstrated by estimating parameters in a PDE model from LIDAR data.

Prenatal Drug Exposure and Adolescent Cortisol Reactivity: Association with Behavioral Concerns.

PubMed

Buckingham-Howes, Stacy; Mazza, Dayna; Wang, Yan; Granger, Douglas A; Black, Maureen M

2016-09-01

To examine stress reactivity in a sample of adolescents with prenatal drug exposure (PDE) by examining the consequences of PDE on stress-related adrenocortical reactivity, behavioral problems, and drug experimentation during adolescence. Participants (76 PDE, 61 non-drug exposed [NE]; 99% African-American; 50% male; mean age = 14.17 yr, SD = 1.17) provided a urine sample, completed a drug use questionnaire, and provided saliva samples (later assayed for cortisol) before and after a mild laboratory stress task. Caregivers completed the Behavior Assessment System for Children, Second Edition (BASC II) and reported their relationship to the adolescent. The NE group was more likely to exhibit task-related cortisol reactivity compared to the PDE group. Overall behavior problems and drug experimentation were comparable across groups with no differences between PDE and NE groups. In unadjusted mediation analyses, cortisol reactivity mediated the association between PDE and BASC II aggression scores (95% bootstrap confidence interval [CI], 0.04-4.28), externalizing problems scores (95% bootstrap CI, 0.03-4.50), and drug experimentation (95% bootstrap CI, 0.001-0.54). The associations remain with the inclusion of gender as a covariate but not when age is included. Findings support and expand current research in cortisol reactivity and PDE by demonstrating that cortisol reactivity attenuates the association between PDE and behavioral problems (aggression) and drug experimentation. If replicated, PDE may have long-lasting effects on stress-sensitive physiological mechanisms associated with behavioral problems (aggression) and drug experimentation in adolescence.

Ion Trap Quantum Computing

DTIC Science & Technology

2011-12-01

quantum computer architecture schemes, but there are several problems that will be discussed later. 15 IV. ION TRAPS Wolfgang Paul was the first...famous physics experiment [62]. Wolfgang Paul demonstrated a similar apparatus during his Nobel Prize speech [63]. This device is hyperbolic-parabolic...Although it does not apply to linear traps, it is useful to understand the interaction between the Coulomb force and the repulsive quantum-mechanical Pauli

Scientific Activities Pursuant to the Provisions of AFOSR Grant 79-0018.

DTIC Science & Technology

1984-01-01

controllability implies stabilizability n the case of autono- mous finite dimensional linear systems , we are not surprised to find control ...Current Status of the Control Theory of Single Space Dim- ension Hyperbolicr Systems " was presented at the NASA JPL Symposium on Cbntrol and Stabilization ...theory of hyperbolic systems , including controllability , stabilization , control canonical form theory, etc. To allow a unified and not

Applications of Laser Diagnostics

DTIC Science & Technology

2005-03-01

Heat Transfer and Thermal Management of PDE . . . . 39 5.1.2 Application of Optical and Numerical Diagnostic Methods to PDE...in Reno, NV. The paper is included in the Appendix. 5.1.1.16 Heat Transfer and Thermal Management in PDE The unsteady nature of the PDE cycle...January 2003, Reno, NV. 57 “Heat Transfer and Thermal Management in a Pulsed Detonation Engine,” J. Hoke, R. Bradley, and F. Schauer, AIAA Paper No

PDE4 and PDE5 regulate cyclic nucleotide contents and relaxing effects on carbachol-induced contraction in the bovine abomasum.

PubMed

Kaneda, Takeharu; Kido, Yuuki; Tajima, Tsuyoshi; Urakawa, Norimoto; Shimizu, Kazumasa

2015-01-01

The effects of various selective phosphodiesterase (PDE) inhibitors on carbachol (CCh)-induced contraction in the bovine abomasum were investigated. Various selective PDE inhibitors, vinpocetine (type 1), erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, type 2), milrinone (type 3), Ro20-1724 (type 4), vardenafil (type 5), BRL-50481 (type 7) and BAY73-6691 (type 9), inhibited CCh-induced contractions in a concentration-dependent manner. Among the PDE inhibitors, Ro20-1724 and vardenafil induced more relaxation than the other inhibitors based on the data for the IC50 or maximum relaxation. In smooth muscle of the bovine abomasum, we showed the expression of PDE4B, 4C, 4D and 5 by RT-PCR analysis. In the presence of CCh, Ro20-1724 increased the cAMP content, but not the cGMP content. By contrast, vardenafil increased the cGMP content, but not the cAMP content. These results suggest that Ro20-1724-induced relaxation was correlated with cAMP and that vardenafil-induced relaxation was correlated with cGMP in the bovine abomasum. In conclusion, PDE4 and PDE5 are the enzymes involved in regulation of the relaxation associated with cAMP and cGMP, respectively, in the bovine abomasum.

Application of the Lienard-Wiechert solution to a lightning return stroke model

NASA Technical Reports Server (NTRS)

Meneghini, R.

1983-01-01

The electric and magnetic fields associated with the lightning return stroke are expressed as a convolution of the current waveform shape and the fields generated by a moving charge of amplitude one (i.e., the Lienard-Wiechert solution for a unit charge). The representation can be used to compute the fields produced by a current waveform of non-uniform velocity that propagates along a filament of arbitrary, but finite, curvature. To study numerically the effects of linear charge acceleration and channel curvature two simple channel models are used: the linear and the hyperbolic.

Application of the Lienard-Wiechert solution to a lightning return stroke model

NASA Technical Reports Server (NTRS)

Meneghini, R.

1984-01-01

The electric and magnetic fields associated with the lightning return stroke are expressed as a convolution of the current waveform shape and the fields generated by a moving charge of amplitude one (i.e., the Lienard-Wiechert solution for a unit charge). The representation can be used to compute the fields produced by a current waveform of non-uniform velocity that propagates along a filament of arbitrary, but finite, curvature. To study numerically the effects of linear charge acceleration and channel curvature two simple channel models are used: the linear and the hyperbolic.

Reaction-diffusion systems coupled at the boundary and the Morse-Smale property

NASA Astrophysics Data System (ADS)

Broche, Rita de Cássia D. S.; de Oliveira, Luiz Augusto F.

We study an one-dimensional nonlinear reaction-diffusion system coupled on the boundary. Such system comes from modeling problems of temperature distribution on two bars of same length, jointed together, with different diffusion coefficients. We prove the transversality property of unstable and stable manifolds assuming all equilibrium points are hyperbolic. To this end, we write the system as an equation with noncontinuous diffusion coefficient. We then study the nonincreasing property of the number of zeros of a linearized nonautonomous equation as well as the Sturm-Liouville properties of the solutions of a linear elliptic problem.

Multidimensional FEM-FCT schemes for arbitrary time stepping

NASA Astrophysics Data System (ADS)

Kuzmin, D.; Möller, M.; Turek, S.

2003-05-01

The flux-corrected-transport paradigm is generalized to finite-element schemes based on arbitrary time stepping. A conservative flux decomposition procedure is proposed for both convective and diffusive terms. Mathematical properties of positivity-preserving schemes are reviewed. A nonoscillatory low-order method is constructed by elimination of negative off-diagonal entries of the discrete transport operator. The linearization of source terms and extension to hyperbolic systems are discussed. Zalesak's multidimensional limiter is employed to switch between linear discretizations of high and low order. A rigorous proof of positivity is provided. The treatment of non-linearities and iterative solution of linear systems are addressed. The performance of the new algorithm is illustrated by numerical examples for the shock tube problem in one dimension and scalar transport equations in two dimensions.

Preclinical Characterization of the Phosphodiesterase 10A PET Tracer [(11)C]MK-8193.

PubMed

Hostetler, Eric D; Fan, Hong; Joshi, Aniket D; Zeng, Zhizhen; Eng, Waisi; Gantert, Liza; Holahan, Marie; Meng, Xianjun; Miller, Patricia; O'Malley, Stacey; Purcell, Mona; Riffel, Kerry; Salinas, Cristian; Williams, Mangay; Ma, Bennett; Buist, Nicole; Smith, Sean M; Coleman, Paul J; Cox, Christopher D; Flores, Brock A; Raheem, Izzat T; Cook, Jacquelynn J; Evelhoch, Jeffrey L

2016-08-01

A positron emission tomography (PET) tracer for the enzyme phosphodiesterase 10A (PDE10A) is desirable to guide the discovery and development of PDE10A inhibitors as potential therapeutics. The preclinical characterization of the PDE10A PET tracer [(11)C]MK-8193 is described. In vitro binding studies with [(3)H]MK-8193 were conducted in rat, monkey, and human brain tissue. PET studies with [(11)C]MK-8193 were conducted in rats and rhesus monkeys at baseline and following administration of a PDE10A inhibitor. [(3)H]MK-8193 is a high-affinity, selective PDE10A radioligand in rat, monkey, and human brain tissue. In vivo, [(11)C]MK-8193 displays rapid kinetics, low test-retest variability, and a large specific signal that is displaced by a structurally diverse PDE10A inhibitor, enabling the determination of pharmacokinetic/enzyme occupancy relationships. [(11)C]MK-8193 is a useful PET tracer for the preclinical characterization of PDE10A therapeutic candidates in rat and monkey. Further evaluation of [(11)C]MK-8193 in humans is warranted.

Quantum Field Theory on Spacetimes with a Compactly Generated Cauchy Horizon

NASA Astrophysics Data System (ADS)

Kay, Bernard S.; Radzikowski, Marek J.; Wald, Robert M.

1997-02-01

We prove two theorems which concern difficulties in the formulation of the quantum theory of a linear scalar field on a spacetime, (M,g_{ab}), with a compactly generated Cauchy horizon. These theorems demonstrate the breakdown of the theory at certain base points of the Cauchy horizon, which are defined as 'past terminal accumulation points' of the horizon generators. Thus, the theorems may be interpreted as giving support to Hawking's 'Chronology Protection Conjecture', according to which the laws of physics prevent one from manufacturing a 'time machine'. Specifically, we prove: Theorem 1. There is no extension to (M,g_{ab}) of the usual field algebra on the initial globally hyperbolic region which satisfies the condition of F-locality at any base point. In other words, any extension of the field algebra must, in any globally hyperbolic neighbourhood of any base point, differ from the algebra one would define on that neighbourhood according to the rules for globally hyperbolic spacetimes. Theorem 2. The two-point distribution for any Hadamard state defined on the initial globally hyperbolic region must (when extended to a distributional bisolution of the covariant Klein-Gordon equation on the full spacetime) be singular at every base point x in the sense that the difference between this two point distribution and a local Hadamard distribution cannot be given by a bounded function in any neighbourhood (in M 2 M) of (x,x). In consequence of Theorem 2, quantities such as the renormalized expectation value of J2 or of the stress-energy tensor are necessarily ill-defined or singular at any base point. The proof of these theorems relies on the 'Propagation of Singularities' theorems of Duistermaat and Hörmander.

Pharmacologic therapy for erectile dysfunction and its interaction with the cardiovascular system.

PubMed

Ioakeimidis, Nikolaos; Kostis, John B

2014-01-01

Phosphodiesterase (PDE) enzymes are widely distributed throughout the body, having numerous effects and functions. The PDE type 5 (PDE5) inhibitors are widely used to treat erectile dysfunction (ED). Recent, intense preclinical and clinical research with PDE5 inhibitors has shed light on new mechanisms and has revealed a number of pleiotropic effects on the cardiovascular (CV) system. To date, PDE5 inhibition has been shown to be effective for the treatment of idiopathic pulmonary arterial hypertension, and both sildenafil and tadalafil are approved for this indication. However, current or future PDE5 inhibitors have the potential of becoming clinically useful in a variety of CV conditions such as heart failure, coronary artery disease, and hypertension. The present review discusses recent findings regarding pharmacologic treatment of ED and its interaction with the CV system and highlights current and future clinical applications beyond ED.

Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design

NASA Astrophysics Data System (ADS)

Howard, Brittany L.; Thompson, Philip E.; Manallack, David T.

2011-08-01

The similarity between Plasmodium falciparum phosphodiesterase enzymes ( PfPDEs) and their human counterparts have been examined and human PDE9A was found to be a suitable template for the construction of homology models for each of the four PfPDE isoforms. In contrast, the architecture of the active sites of each model was most similar to human PDE1. Molecular docking was able to model cyclic guanosine monophosphate (cGMP) substrate binding in each case but a docking mode supporting cyclic adenosine monophosphate (cAMP) binding could not be found. Anticipating the potential of PfPDE inhibitors as anti-malarial drugs, a range of reported PDE inhibitors including zaprinast and sildenafil were docked into the model of PfPDEα. The results were consistent with their reported biological activities, and the potential of PDE1/9 inhibitor analogues was also supported by docking.

Expression of three mammalian cDNAs that interfere with RAS function in Saccharomyces cerevisiae.

PubMed Central

Colicelli, J; Nicolette, C; Birchmeier, C; Rodgers, L; Riggs, M; Wigler, M

1991-01-01

Saccharomyces cerevisiae strains expressing the activated RAS2Val19 gene or lacking both cAMP phosphodiesterase genes, PDE1 and PDE2, have impaired growth control and display an acute sensitivity to heat shock. We have isolated two classes of mammalian cDNAs from yeast expression libraries that suppress the heat shock-sensitive phenotype of RAS2Val19 strain. Members of the first class of cDNAs also suppress the heat shock-sensitive phenotype of pde1- pde2- strains and encode cAMP phosphodiesterases. Members of the second class fail to suppress the phenotype of pde1- pde2- strains and therefore are candidate cDNAs encoding proteins that interact with RAS proteins. We report the nucleotide sequence of three members of this class. Two of these cDNAs share considerable sequence similarity, but none are clearly similar to previously isolated genes. Images PMID:1849280

Phosphodiesterase Type 5 Inhibitors, Sport and Doping.

PubMed

Di Luigi, Luigi; Sansone, Massimiliano; Sansone, Andrea; Ceci, Roberta; Duranti, Guglielmo; Borrione, Paolo; Crescioli, Clara; Sgrò, Paolo; Sabatini, Stefania

Phosphodiesterase type 5 inhibitors (PDE5i) (e.g., sildenafil, tadalafil, vardenafil, and avanafil) are drugs commonly used to treat erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia. PDE5i are not prohibited by the World Anti-Doping Agency (WADA) but are alleged to be frequently misused by healthy athletes to improve sporting performance. In vitro and in vivo studies have reported various effects of PDE5i on cardiovascular, muscular, metabolic, and neuroendocrine systems and the potential, therefore, to enhance performance of healthy athletes during training and competition. This suggests well-controlled research studies to examine the ergogenic effects of PDE5i on performance during activities that simulate real sporting situations are warranted to determine if PDE5i should be included on the prohibited WADA list. In the meantime, there is concern that some otherwise healthy athletes will continue to misuse PDE5i to gain an unfair competitive advantage over their competitors.

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

PubMed

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

2016-08-24

Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular compartments. The phosphodiesterase 4 (PDE4) family coordinates the degradation of cAMP, leading to the local attenuation of cAMP-dependent signaling pathways. Sleep deprivation leads to increased hippocampal expression of the PDE4A5 isoform. Here, we explored whether PDE4A5 overexpression mimics behavioral and synaptic plasticity phenotypes associated with sleep deprivation. Viral expression of PDE4A5 in hippocampal neurons impairs long-term potentiation and attenuates the formation of hippocampus-dependent long-term memories. Our findings suggest that PDE4A5 is a molecular constraint on cognitive processes and may contribute to the development of novel therapeutic approaches to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. Copyright © 2016 Havekes et al.

cAMP Catalyzing Phosphodiesterases Control Cholinergic Muscular Activity But Their Inhibition Does Not Enhance 5-HT4 Receptor-Mediated Facilitation of Cholinergic Contractions in the Murine Gastrointestinal Tract

PubMed Central

Pauwelyn, Vicky; Lefebvre, Romain A.

2018-01-01

Background: As the signal transduction of 5-HT4 receptors on cholinergic neurons innervating smooth muscle is controlled by phosphodiesterase (PDE) 4 in porcine stomach and colon, and human large intestine, the in vivo gastroprokinetic effects of a 5-HT4 receptor agonist might be enhanced by combination with a selective PDE4 inhibitor. The presence of 5-HT4 receptors on cholinergic neurons towards murine gastrointestinal circular muscle was recently shown. If the control of this receptor pathway by PDE4 is also present in mice, this might be a good model for in vivo testing of the combination therapy. Therefore this study investigates the role of cAMP catalyzing PDEs in smooth muscle cell activity and in the intraneuronal signal transduction of the 5-HT4 receptors in the gastrointestinal tract of C57Bl/6J mice. Methods: In circular smooth muscle strips from murine fundus, jejunum, and colon, submaximal cholinergic contractions were induced by either electrical field stimulation (EFS) or by carbachol (muscarinic receptor agonist). The influence of the PDE inhibitors IBMX (non-selective), vinpocetine (PDE1), EHNA (PDE2), cilostamide (PDE3), and rolipram (PDE4) was tested on these contractions and on the facilitating effect of a submaximal concentration of prucalopride (5-HT4 receptor agonist) on EFS-induced contractions. Results: In the three gastrointestinal regions, IBMX and cilostamide concentration-dependently decreased carbachol- as well as EFS-induced contractions. Some inhibitory effect was also observed with rolipram. In the fundus a non-significant trend for an enhancement of the facilitating effect of prucalopride on EFS-induced contractions was observed with IBMX, but none of the selective PDE inhibitors enhanced the facilitating effect of prucalopride in fundus, jejunum or colon. Conclusion: In analogy with the porcine gastrointestinal tract, in murine fundus, jejunum, and colon circular smooth muscle PDE3 is the main regulator of the cAMP turnover, with some contribution of PDE4. In contrast to the porcine gastrointestinal tract, the in vitro facilitation of electrically induced cholinergic contractions by 5-HT4 receptor stimulation could not be enhanced by specific PDE inhibition. The C57Bl/6J murine model is thus not suitable for in vivo testing of a 5-HT4 receptor agonist combined with a selective PDE4 inhibitor. PMID:29568269

Economic analysis of use of counterfeit drugs: health impairment risk of counterfeit phosphodiesterase type 5 inhibitor taken as an example.

PubMed

Sugita, Minoru; Miyakawa, Michiko

2010-07-01

The size of the market for counterfeit drugs throughout the world is considerable. Many cases of health impairment due to counterfeits have been reported. The market share of counterfeits in drug markets in developed countries is smaller than that in developing countries. However, the size of the market for counterfeits of phosphodiesterase type 5 inhibitors (PDE5Is) used as anti-erectile-dysfunction drugs is not small. The purpose of the present study was to analyze the health impairment risk of taking the counterfeit PDE5Is and the convenience of obtaining the counterfeits in Japan, using an economic methodology in order to work out countermeasures for reducing the health impairment risk. Information was obtained by interviewing employees of pharmaceutical and chemical corporations in Japan. The size of the market for counterfeit PDE5Is in Japan was recently estimated to be about 2.5 times larger than that of genuine PDE5Is. The price of the counterfeits in their market is reported to be nearly equal to that of the genuine PDE5Is. An outbreak of severe hypoglycemia among users of counterfeit PDE5Is containing an antidiabetic drug in Singapore was reported in 2008, and seven patients remained comatose as a result of prolonged neuroglycopenia. Four of them subsequently died, so the health impairment risk due to counterfeit PDE5Is should not be ignored. In order to obtain a genuine PDE5I in Japan, a patient must be examined and have a prescription written at a medical institution, and buy it at a dispensing pharmacy. Focusing on the health impairment risk due to counterfeit PDE5Is and the convenience of obtaining the counterfeits in Japan, we analyzed the effects on the prices and quantities of PDE5Is in the market from demand and supply curves, using an economic methodology. From the analysis, it was shown that the health impairment risk due to the counterfeits is underestimated in the market in Japan. Physicians should warn their patients not to buy counterfeit PDE5Is, and when they write a prescription for purchasing genuine PDE5Is, should inform their patients of the severe health problems that occurred in Singapore. The present economic analysis indicates that the health impairment risk due to counterfeit PDE5Is is underestimated in the market in Japan. Clarification of the underestimation of the severe health impairment risk due to counterfeits is important.

In vivo effects of phosphodiesterase inhibition on basal cyclic guanosine monophosphate levels in the prefrontal cortex, hippocampus and cerebellum of freely moving rats.

PubMed

Marte, Antonella; Pepicelli, Olimpia; Cavallero, Anna; Raiteri, Maurizio; Fedele, Ernesto

2008-11-15

We have characterized the various phosphodiesterases (PDE) that degrade cyclic GMP in the prefrontal cortex, hippocampus, and cerebellum using the microdialysis technique to measure in vivo extracellular cyclic GMP in awake rats. The following PDE blockers were used (100 and 1,000 microM): 8-methoxymethyl-IBMX (8-MM-IBMX), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), milrinone, rolipram, and zaprinast. For solubility reasons, sildenafil was tested only at 100 microM. All drugs were administered locally in the brain regions through the dialysis probe. At 100 microM, 8-MM-IBMX enhanced the cyclic nucleotide extracellular levels in the prefrontal cortex and hippocampus but not in the cerebellum; EHNA and milrinone were active only in the hippocampus; rolipram was devoid of any effect; zaprinast and sildenafil were effective in all three brain areas. At 1 mM, 8-MM-IBMX, milrinone, and zaprinast increased extracellular cyclic GMP in all the brain regions examined, EHNA became active also in the prefrontal cortex and rolipram showed a significant effect only in the cerebellum. This is the first in vivo functional study showing that, in cortex, PDE1, -2, and -5/9 degrade cGMP, with PDE9 probably playing a major role; in hippocampus, PDE5/9 and PDE1 are mainly involved and seem almost equally active, but PDE2 and -3 also contribute; in cerebellum, PDE5/9 are the main cGMP hydrolyzing enzymes, but also PDE1 and -4 significantly operate.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 approachmore » 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.« less

Biomolecular surface construction by PDE transform.

PubMed

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

2012-03-01

This work proposes a new framework for the surface generation based on the partial differential equation (PDE) transform. The PDE transform has recently been introduced as a general approach for the mode decomposition of images, signals, and data. It relies on the use of arbitrarily high-order PDEs to achieve the time-frequency localization, control the spectral distribution, and regulate the spatial resolution. The present work provides a new variational derivation of high-order PDE transforms. The fast Fourier transform is utilized to accomplish the PDE transform so as to avoid stringent stability constraints in solving high-order PDEs. As a consequence, the time integration of high-order PDEs can be done efficiently with the fast Fourier transform. The present approach is validated with a variety of test examples in two-dimensional and three-dimensional settings. We explore the impact of the PDE transform parameters, such as the PDE order and propagation time, on the quality of resulting surfaces. Additionally, we utilize a set of 10 proteins to compare the computational efficiency of the present surface generation method and a standard approach in Cartesian meshes. Moreover, we analyze the present method by examining some benchmark indicators of biomolecular surface, that is, surface area, surface-enclosed volume, solvation free energy, and surface electrostatic potential. A test set of 13 protein molecules is used in the present investigation. The electrostatic analysis is carried out via the Poisson-Boltzmann equation model. To further demonstrate the utility of the present PDE transform-based surface method, we solve the Poisson-Nernst-Planck equations with a PDE transform surface of a protein. Second-order convergence is observed for the electrostatic potential and concentrations. Finally, to test the capability and efficiency of the present PDE transform-based surface generation method, we apply it to the construction of an excessively large biomolecule, a virus surface capsid. Virus surface morphologies of different resolutions are attained by adjusting the propagation time. Therefore, the present PDE transform provides a multiresolution analysis in the surface visualization. Extensive numerical experiment and comparison with an established surface model indicate that the present PDE transform is a robust, stable, and efficient approach for biomolecular surface generation in Cartesian meshes. Copyright © 2012 John Wiley & Sons, Ltd.

Schlieren Imaging of a Single-Ejector, Multi-Tube Pulsed Detonation Engine (Postprint)

DTIC Science & Technology

2009-01-01

studies have shown the potential of an ejector to almost double the thrust of a pulsed detonation engine ( PDE ) tube [1-3]. Axial misalignment of the... Detonation Research Facility in the Air Force Research Laboratory were used for this study. The PDE utilizes automotive valving to feed up to four... detonation tubes. The damped thrust stand was setup to measure PDE thrust alone for baseline tests or total thrust from ejector and PDE . This

Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human vascular smooth muscle cells: inhibition with iloprost and NONOate.

PubMed

Muzaffar, S; Shukla, N; Bond, M; Sala-Newby, G B; Newby, A C; Angelini, G D; Jeremy, J Y

2008-11-01

To determine whether there is an association between vascular NADPH oxidase (NOX), superoxide, the small GTPase Rac(1) and PDE type 5 (PDE5) in human vascular smooth muscle cell (hVSMCs). hVSMCs were incubated with xanthine-xanthine oxidase (X-XO; a superoxide generating system) or the thromboxane A(2) analogue, U46619 (+/-superoxide dismutase (SOD) or apocynin) for 16 h. The expression of PDE5 and NOX-1 was assessed using Western blotting and superoxide measured. The role of Rac(1) in superoxide generation was assessed by overexpressing either the dominant-negative or constitutively active Rac isoforms. The effects of iloprost, DETA-NONOate and the Rho-kinase inhibitor, Y27632, on PDE5 and NOX-1 expression were also studied. Following 16 h incubation, U46619 and X-XO promoted the expression of PDE5 and NOX-1, an effect blocked by SOD or apocynin when co-incubated over the same time course. X-XO and U46619 both promoted the formation of superoxide. Overexpression of dominant-negative Rac(1) or addition of iloprost, DETA-NONOate or Y27632 completely blocked both superoxide release and PDE5 protein expression and activity. These data demonstrate that superoxide derived from NOX upregulates the expression of PDE5 in human VSMCs. As PDE5 hydrolyses cyclic GMP, this effect may blunt the vasculoprotective actions of NO.

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

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

PubMed Central

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

2017-01-01

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

An approximation theory for nonlinear partial differential equations with applications to identification and control

NASA Technical Reports Server (NTRS)

Banks, H. T.; Kunisch, K.

1982-01-01

Approximation results from linear semigroup theory are used to develop a general framework for convergence of approximation schemes in parameter estimation and optimal control problems for nonlinear partial differential equations. These ideas are used to establish theoretical convergence results for parameter identification using modal (eigenfunction) approximation techniques. Results from numerical investigations of these schemes for both hyperbolic and parabolic systems are given.

Transforming wealth: using the inverse hyperbolic sine (IHS) and splines to predict youth's math achievement.

PubMed

Friedline, Terri; Masa, Rainier D; Chowa, Gina A N

2015-01-01

The natural log and categorical transformations commonly applied to wealth for meeting the statistical assumptions of research may not always be appropriate for adjusting for skewness given wealth's unique properties. Finding and applying appropriate transformations is becoming increasingly important as researchers consider wealth as a predictor of well-being. We present an alternative transformation-the inverse hyperbolic sine (IHS)-for simultaneously dealing with skewness and accounting for wealth's unique properties. Using the relationship between household wealth and youth's math achievement as an example, we apply the IHS transformation to wealth data from US and Ghanaian households. We also explore non-linearity and accumulation thresholds by combining IHS transformed wealth with splines. IHS transformed wealth relates to youth's math achievement similarly when compared to categorical and natural log transformations, indicating that it is a viable alternative to other transformations commonly used in research. Non-linear relationships and accumulation thresholds emerge that predict youth's math achievement when splines are incorporated. In US households, accumulating debt relates to decreases in math achievement whereas accumulating assets relates to increases in math achievement. In Ghanaian households, accumulating assets between the 25th and 50th percentiles relates to increases in youth's math achievement. Copyright © 2014 Elsevier Inc. All rights reserved.

The lifespan of 3D radial solutions to the non-isentropic relativistic Euler equations

NASA Astrophysics Data System (ADS)

Wei, Changhua

2017-10-01

This paper investigates the lower bound of the lifespan of three-dimensional spherically symmetric solutions to the non-isentropic relativistic Euler equations, when the initial data are prescribed as a small perturbation with compact support to a constant state. Based on the structure of the hyperbolic system, we show the almost global existence of the smooth solutions to Eulerian flows (polytropic gases and generalized Chaplygin gases) with genuinely nonlinear characteristics. While for the Eulerian flows (Chaplygin gas and stiff matter) with mild linearly degenerate characteristics, we show the global existence of the radial solutions, moreover, for the non-strictly hyperbolic system (pressureless perfect fluid) satisfying the mild linearly degenerate condition, we prove the blowup phenomenon of the radial solutions and show that the lifespan of the solutions is of order O(ɛ ^{-1}), where ɛ denotes the width of the perturbation. This work can be seen as a complement of our work (Lei and Wei in Math Ann 367:1363-1401, 2017) for relativistic Chaplygin gas and can also be seen as a generalization of the classical Eulerian fluids (Godin in Arch Ration Mech Anal 177:497-511, 2005, J Math Pures Appl 87:91-117, 2007) to the relativistic Eulerian fluids.

Development of intra-strain self-cloning procedure for breeding baker's yeast strains.

PubMed

Nakagawa, Youji; Ogihara, Hiroyuki; Mochizuki, Chisato; Yamamura, Hideki; Iimura, Yuzuru; Hayakawa, Masayuki

2017-03-01

Previously reported self-cloning procedures for breeding of industrial yeast strains require DNA from other strains, plasmid DNA, or mutagenesis. Therefore, we aimed to construct a self-cloning baker's yeast strain that exhibits freeze tolerance via an improved self-cloning procedure. We first disrupted the URA3 gene of a prototrophic baker's yeast strain without the use of any marker gene, resulting in a Δura3 homozygous disruptant. Then, the URA3 gene of the parental baker's yeast strain was used as a selection marker to introduce the constitutive TDH3 promoter upstream of the PDE2 gene encoding high-affinity cyclic AMP phosphodiesterase. This self-cloning procedure was performed without using DNA from other Saccharomyces cerevisiae strains, plasmid DNA, or mutagenesis and was therefore designated an intra-strain self-cloning procedure. Using this self-cloning procedure, we succeeded in producing self-cloning baker's yeast strains that harbor the TDH3p-PDE2 gene heterozygously and homozygously, designated TDH3p-PDE2 hetero and TDH3p-PDE2 homo strains, respectively. These self-cloning strains expressed much higher levels of PDE2 mRNA than the parental strain and exhibited higher viability after freeze stress, as well as higher fermentation ability in frozen dough, when compared with the parental strain. The TDH3p-PDE2 homo strain was genetically more stable than the TDH3p-PDE2 hetero strain. These results indicate that both heterozygous and homozygous strains of self-cloning PDE2-overexpressing freeze-tolerant strains of industrial baker's yeast can be prepared using the intra-strain self-cloning procedure, and, from a practical viewpoint, the TDH3p-PDE2 homo strain constructed in this study is preferable to the TDH3p-PDE2 hetero strain for frozen dough baking. Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

In permanent atrial fibrillation, PDE3 reduces force responses to 5‐HT, but PDE3 and PDE4 do not cause the blunting of atrial arrhythmias

PubMed Central

Schwarz, Simon; Ravens, Ursula; Knaut, Michael

2016-01-01

Abstract Background and Purpose 5‐HT increases force and L‐type Ca2 + current (ICa,L) and causes arrhythmias through 5‐HT4 receptors in human atrium. In permanent atrial fibrillation (peAF), atrial force responses to 5‐HT are blunted, arrhythmias abolished but ICa,L responses only moderately attenuated. We investigated whether, in peAF, this could be due to an increased function of PDE3 and/or PDE4, using the inhibitors cilostamide (300 nM) and rolipram (1 μM) respectively. Experimental Approach Contractile force, arrhythmic contractions and ICa,L were assessed in right atrial trabeculae and myocytes, obtained from patients with sinus rhythm (SR), paroxysmal atrial fibrillation (pAF) and peAF. Key Results Maximum force responses to 5‐HT were reduced to 15% in peAF, but not in pAF. Cilostamide, but not rolipram, increased both the blunted force responses to 5‐HT in peAF and the inotropic potency of 5‐HT fourfold to sevenfold in trabeculae of patients with SR, pAF and peAF. Lusitropic responses to 5‐HT were not decreased in peAF. Responses of ICa,L to 5‐HT did not differ and were unaffected by cilostamide or rolipram in myocytes from patients with SR or peAF. Concurrent cilostamide and rolipram increased 5‐HT's propensity to elicit arrhythmias in trabeculae from patients with SR, but not with peAF. Conclusions and Implications PDE3, but not PDE4, reduced inotropic responses to 5‐HT in peAF, independently of lusitropy and ICa,L, but PDE3 activity was the same as that in patients with SR and pAF. Atrial remodelling in peAF abolished the facilitation of 5‐HT to induce arrhythmias by inhibition of PDE3 plus PDE4. PMID:27238373

Use of the KlADH3 promoter for the quantitative production of the murine PDE5A isoforms in the yeast Kluyveromyces lactis.

PubMed

Cardarelli, Silvia; Giorgi, Mauro; Naro, Fabio; Malatesta, Francesco; Biagioni, Stefano; Saliola, Michele

2017-09-22

Phosphodiesterases (PDE) are a superfamily of enzymes that hydrolyse cyclic nucleotides (cAMP/cGMP), signal molecules in transduction pathways regulating crucial aspects of cell life. PDEs regulate the intensity and duration of the cyclic nucleotides signal modulating the downstream biological effect. Due to this critical role associated with the extensive distribution and multiplicity of isozymes, the 11 mammalian families (PDE1 to PDE11) constitute key therapeutic targets. PDE5, one of these cGMP-specific hydrolysing families, is the molecular target of several well known drugs used to treat erectile dysfunction and pulmonary hypertension. Kluyveromyces lactis, one of the few yeasts capable of utilizing lactose, is an attractive host alternative to Saccharomyces cerevisiae for heterologous protein production. Here we established K. lactis as a powerful host for the quantitative production of the murine PDE5 isoforms. Using the promoter of the highly expressed KlADH3 gene, multicopy plasmids were engineered to produce the native and recombinant Mus musculus PDE5 in K. lactis. Yeast cells produced large amounts of the purified A1, A2 and A3 isoforms displaying K m , V max and Sildenafil inhibition values similar to those of the native murine enzymes. PDE5 whose yield was nearly 1 mg/g wet weight biomass for all three isozymes (30 mg/L culture), is well tolerated by K. lactis cells without major growth deficiencies and interferences with the endogenous cAMP/cGMP signal transduction pathways. To our knowledge, this is the first time that the entire PDE5 isozymes family containing both regulatory and catalytic domains has been produced at high levels in a heterologous eukaryotic organism. K. lactis has been shown to be a very promising host platform for large scale production of mammalian PDEs for biochemical and structural studies and for the development of new specific PDE inhibitors for therapeutic applications in many pathologies.

In silico design of novel hERG-neutral sildenafil-like PDE5 inhibitors.

PubMed

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

2017-10-01

Cyclic nucleotide phosphodiesterase enzymes (PDEs) have functions in regulating the levels of intracellular second messengers, 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP), via hydrolysis and decomposing mechanisms in cells. They take essential roles in modulating various cellular activities such as memory and smooth muscle functions. PDE type 5 (PDE5) inhibitors enhance the vasodilatory effects of cGMP in the corpus cavernosum and they are used to treat erectile dysfunction. Patch clamp experiments showed that the IC 50 values of the human ether-à-go-go-related gene (hERG1) potassium (K) ion channel blocking affinity of PDE5 inhibitors sildenafil, vardenafil, and tadalafil as 33, 12, and 100 μM, respectively. hERG1 channel is responsible for the regulation of the action potential of human ventricular myocyte by contributing the rapid component of delayed rectifier K + current (I Kr ) component of the cardiac action potential. In this work, interaction patterns and binding affinity predictions of selected PDE5 inhibitors against the hERG1 channel are studied. It is attempted to develop PDE5 inhibitor analogs with lower binding affinity to hERG1 ion channel while keeping their pharmacological activity against their principal target PDE5 using in silico methods. Based on detailed analyses of docking poses and predicted interaction energies, novel analogs of PDE5 inhibitors with lower predicted binding affinity to hERG1 channels without loosing their principal target activity were proposed. Moreover, molecular dynamics (MD) simulations and post-processing MD analyses (i.e. Molecular Mechanics/Generalized Born Surface Area calculations) were performed. Detailed analysis of molecular simulations helped us to better understand the PDE5 inhibitor-target binding interactions in the atomic level. Results of this study can be useful for designing of novel and safe PDE5 inhibitors with enhanced activity and other tailored properties.

Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4

DOE PAGES

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

2015-03-09

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

An Obstruction to the Integrability of a Class of Non-linear Wave Equations by 1-Stable Cartan Characteristics

NASA Astrophysics Data System (ADS)

Fackerell, E. D.; Hartley, D.; Tucker, R. W.

We examine in detail the Cauchy problem for a class of non-linear hyperbolic equations in two independent variables. This class is motivated by the analysis of the dynamics of a line of non-linearly coupled particles by Fermi, Pasta, and Ulam and extends the recent investigation of this problem by Gardner and Kamran. We find conditions for the existence of a 1-stable Cartan characteristic of a Pfaffian exterior differential system whose integral curves provide a solution to the Cauchy problem. The same obstruction to involution is exposed in Darboux's method of integration and the two approaches are compared. A class of particular solutions to the obstruction is constructed.

First-generation phosphodiesterase type 5 inhibitors dropout: a comprehensive review and meta-analysis.

PubMed

Corona, G; Rastrelli, G; Burri, A; Serra, E; Gianfrilli, D; Mannucci, E; Jannini, E A; Maggi, M

2016-11-01

The discontinuation rate with phosphodiesterase type 5 inhibitors (PDE5i) remains very high. The aim of this study was to review and meta-analyze currently available data regarding dropout of the first-generation of PDE5i including sildenafil, vardenafil, and tadalafil. An extensive Medline Embase and Cochrane search was performed including the following words: 'PDE5i', 'discontinuation'. All observational studies reporting the dropout rate of PDE5i and its specific causes without any arbitrary restrictions were included. Out of 103 retrieved articles, 22 were included in the study. Retrieved trials included a total of 162,936 patients with a mean age of 58.8 ± 7.9 years. Prevalence of reported comorbid diabetes and hypertension were 27.7% and 36.9%, respectively. PDE5i were associated with a mean discontinuation rate of 4% per month (almost 50% after one year). This rate was higher in younger subjects and in those reporting a higher prevalence of associated morbidities. Six main reasons of PDE5i dropout were identified in the evaluated trials. Partner-related problems and lack of efficacy represented the most important reasons for PDE5i discontinuation, although no significant difference among factors was detected. In conclusion, despite their high efficacy and easy administration, the discontinuation rate and dissatisfaction with PDE5i are still very high. Our data showed that no single factor plays a major role in PDE5i dropout, suggesting that the discontinuation rate is usually because of a combination of both medical problems and psychosocial and relational factors. © 2016 American Society of Andrology and European Academy of Andrology.

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

PubMed Central

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

2014-01-01

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that impair its expression and/or chloride channel function. Here, we provide evidence that type 4 cyclic nucleotide phosphodiesterases (PDE4s) are critical regulators of the cAMP/PKA-dependent activation of CFTR in primary human bronchial epithelial cells. In non-CF cells, PDE4 inhibition increased CFTR activity under basal conditions (ΔISC 7.1 μA/cm2) and after isoproterenol stimulation (increased ΔISC from 13.9 to 21.0 μA/cm2) and slowed the return of stimulated CFTR activity to basal levels by >3-fold. In cells homozygous for ΔF508-CFTR, the most common mutation found in CF, PDE4 inhibition alone produced minimal channel activation. However, PDE4 inhibition strongly amplified the effects of CFTR correctors, drugs that increase expression and membrane localization of CFTR, and/or CFTR potentiators, drugs that increase channel gating, to reach ∼25% of the chloride conductance observed in non-CF cells. Biochemical studies indicate that PDE4s are anchored to CFTR and mediate a local regulation of channel function. Taken together, our results implicate PDE4 as an important determinant of CFTR activity in airway epithelia, and support the use of PDE4 inhibitors to potentiate the therapeutic benefits of CFTR correctors and potentiators.—Blanchard, E., Zlock, L., Lao, A., Mika, D., Namkung, W., Xie, M., Scheitrum, C., Gruenert, D.C., Verkman, A.S., Finkbeiner, W.E., Conti, M., Richter, W. Anchored PDE4 regulates chloride conductance in wild type and ΔF508-CFTR human airway epithelia. PMID:24200884

Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors

PubMed Central

Horvath, Anelia; Korde, Larissa; Greene, Mark H.; Libe, Rosella; Osorio, Paulo; Faucz, Fabio Rueda; Raffin-Sanson, Marie Laure; Tsang, Kit Man; Drori-Herishanu, Limor; Patronas, Yianna; Remmers, Elaine F; Nikita, Maria-Elena; Moran, Jason; Greene, Joseph; Nesterova, Maria; Merino, Maria; Bertherat, Jerome; Stratakis, Constantine A.

2009-01-01

Inactivating germline mutations in phosphodiesterase 11A (PDE11A) have been implicated in adrenal tumor susceptibility. PDE11A is highly-expressed in endocrine steroidogenic tissues, especially the testis, and mice with inactivated Pde11a exhibit male infertility, a known testicular germ cell tumor (TGCT) risk factor. We sequenced the PDE11A gene-coding region in 95 patients with TGCT from 64 unrelated kindreds. We identified 8 non-synonymous substitutions in 20 patients from 15 families: four (R52T; F258Y; G291R; V820M) were newly-recognized, three (R804H; R867G; M878V) were functional variants previously implicated in adrenal tumor predisposition, and one (Y727C) was a known polymorphism. We compared the frequency of these variants in our patients to unrelated controls that had been screened and found negative for any endocrine diseases: only the two previously-reported variants, R804H and R867G, known to be frequent in general population, were detected in these controls. The frequency of all PDE11A-gene variants (combined) was significantly higher among patients with TGCT (P=0.0002), present in 19% of the families of our cohort. Most variants were detected in the general population, but functional studies showed that all these mutations reduced PDE activity, and that PDE11A protein expression was decreased (or absent) in TGCT samples from carriers. This is the first demonstration of a PDE gene’s involvement in TGCT, although the cAMP signaling pathway has been investigated extensively in other reproductive organs and their diseases. In conclusion, we report that PDE11A-inactivating sequence variants may modify the risk of familial and bilateral TGCT. PMID:19549888

Effects of Alanyl-Glutamine Treatment on the Peritoneal Dialysis Effluent Proteome Reveal Pathomechanism-Associated Molecular Signatures*

PubMed Central

Herzog, Rebecca; Boehm, Michael; Unterwurzacher, Markus; Wagner, Anja; Parapatics, Katja; Májek, Peter; Mueller, André C.; Lichtenauer, Anton; Bennett, Keiryn L.; Alper, Seth L.; Vychytil, Andreas; Aufricht, Christoph; Kratochwill, Klaus

2018-01-01

Peritoneal dialysis (PD) is a modality of renal replacement therapy in which the high volumes of available PD effluent (PDE) represents a rich source of biomarkers for monitoring disease and therapy. Although this information could help guide the management of PD patients, little is known about the potential of PDE to define pathomechanism-associated molecular signatures in PD. We therefore subjected PDE to a high-performance multiplex proteomic analysis after depletion of highly-abundant plasma proteins and enrichment of low-abundance proteins. A combination of label-free and isobaric labeling strategies was applied to PDE samples from PD patients (n = 20) treated in an open-label, randomized, two-period, cross-over clinical trial with standard PD fluid or with a novel PD fluid supplemented with alanyl-glutamine (AlaGln). With this workflow we identified 2506 unique proteins in the PDE proteome, greatly increasing coverage beyond the 171 previously-reported proteins. The proteins identified range from high abundance plasma proteins to low abundance cellular proteins, and are linked to larger numbers of biological processes and pathways, some of which are novel for PDE. Interestingly, proteins linked to membrane remodeling and fibrosis are overrepresented in PDE compared with plasma, whereas the proteins underrepresented in PDE suggest decreases in host defense, immune-competence and response to stress. Treatment with AlaGln-supplemented PD fluid is associated with reduced activity of membrane injury-associated mechanisms and with restoration of biological processes involved in stress responses and host defense. Our study represents the first application of the PDE proteome in a randomized controlled prospective clinical trial of PD. This novel proteomic workflow allowed detection of low abundance biomarkers to define pathomechanism-associated molecular signatures in PD and their alterations by a novel therapeutic intervention. PMID:29208752

Discovery of a Phosphodiesterase 9A Inhibitor as a Potential Hypoglycemic Agent

PubMed Central

2015-01-01

Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer’s disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors. PMID:25432025

Multiscale Modeling of Angiogenesis and Predictive Capacity

NASA Astrophysics Data System (ADS)

Pillay, Samara; Byrne, Helen; Maini, Philip

Tumors induce the growth of new blood vessels from existing vasculature through angiogenesis. Using an agent-based approach, we model the behavior of individual endothelial cells during angiogenesis. We incorporate crowding effects through volume exclusion, motility of cells through biased random walks, and include birth and death-like processes. We use the transition probabilities associated with the discrete model and a discrete conservation equation for cell occupancy to determine collective cell behavior, in terms of partial differential equations (PDEs). We derive three PDE models incorporating single, multi-species and no volume exclusion. By fitting the parameters in our PDE models and other well-established continuum models to agent-based simulations during a specific time period, and then comparing the outputs from the PDE models and agent-based model at later times, we aim to determine how well the PDE models predict the future behavior of the agent-based model. We also determine whether predictions differ across PDE models and the significance of those differences. This may impact drug development strategies based on PDE models.

Phosphodiesterases regulate airway smooth muscle function in health and disease.

PubMed

Krymskaya, Vera P; Panettieri, Reynold A

2007-01-01

On the basis of structure, regulation, and kinetic properties, phosphodiesterases (PDEs) represent a superfamily of enzymes divided into 11 subfamilies that catalyze cytosolic levels of 3',5'-cyclic adenosine monophosphate (cAMP) or 3',5'-cyclic guanosine monophosphate (cGMP) to 5'-AMP or 5'-GMP, respectively. PDE4 represents the major PDE expressed in inflammatory cells as well as airway smooth muscle (ASM), and selective PDE4 inhibitors provide a broad spectrum of anti-inflammatory effects such as abrogating cytokine and chemokine release from inflammatory cells and inhibiting inflammatory cell trafficking. Due to cell- and tissue-specific gene expression and regulation, PDEs modulate unique organ-based functions. New tools or compounds that selectively inhibit PDE subfamilies and genetically engineered mice deficient in selective isoforms have greatly enhanced our understanding of PDE function in airway inflammation and resident cell function. This chapter will focus on recent advances in our understanding of the role of PDE in regulating ASM function.

A short review on structure and role of cyclic-3',5'-adenosine monophosphate-specific phosphodiesterase 4 as a treatment tool.

PubMed

Eskandari, Nahid; Mirmosayyeb, Omid; Bordbari, Gazaleh; Bastan, Reza; Yousefi, Zahra; Andalib, Alireza

2015-01-01

Cyclic nucleotide phosphodiesterases (PDEs) are known as a super-family of enzymes which catalyze the metabolism of the intracellular cyclic nucleotides, cyclic-3',5'-adenosine monophosphate (cAMP), and cyclic-3',5'-guanosine monophosphate that are expressed in a variety of cell types that can exert various functions based on their cells distribution. The PDE4 family has been the focus of vast research efforts over recent years because this family is considered as a prime target for therapeutic intervention in a number of inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and rheumatoid arthritis, and it should be used and researched by pharmacists. This is because the major isoform of PDE that regulates inflammatory cell activity is the cAMP-specific PDE, PDE4. This review discusses the relationship between PDE4 and its inhibitor drugs based on structures, cells distribution, and pharmacological properties of PDE4 which can be informative for all pharmacy specialists.

Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human vascular smooth muscle cells: inhibition with iloprost and NONOate

PubMed Central

Muzaffar, S; Shukla, N; Bond, M; Sala-Newby, G B; Newby, A C; Angelini, G D; Jeremy, J Y

2008-01-01

Background and purpose: To determine whether there is an association between vascular NADPH oxidase (NOX), superoxide, the small GTPase Rac1 and PDE type 5 (PDE5) in human vascular smooth muscle cell (hVSMCs). Experimental approach: hVSMCs were incubated with xanthine–xanthine oxidase (X-XO; a superoxide generating system) or the thromboxane A2 analogue, U46619 (±superoxide dismutase (SOD) or apocynin) for 16 h. The expression of PDE5 and NOX-1 was assessed using Western blotting and superoxide measured. The role of Rac1 in superoxide generation was assessed by overexpressing either the dominant-negative or constitutively active Rac isoforms. The effects of iloprost, DETA-NONOate and the Rho-kinase inhibitor, Y27632, on PDE5 and NOX-1 expression were also studied. Key results: Following 16 h incubation, U46619 and X-XO promoted the expression of PDE5 and NOX-1, an effect blocked by SOD or apocynin when co-incubated over the same time course. X-XO and U46619 both promoted the formation of superoxide. Overexpression of dominant-negative Rac1 or addition of iloprost, DETA-NONOate or Y27632 completely blocked both superoxide release and PDE5 protein expression and activity. Conclusions and implications: These data demonstrate that superoxide derived from NOX upregulates the expression of PDE5 in human VSMCs. As PDE5 hydrolyses cyclic GMP, this effect may blunt the vasculoprotective actions of NO. PMID:18660830

An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies

PubMed Central

Chen, Gong; Wang, Huanchen; Robinson, Howard; Cai, Jiwen; Wan, Yiqian; Ke, Hengming

2008-01-01

Selective inhibitors of cyclic nucleotide phosphodiesterase-5 (PDE5) have been used as drugs for treatment of male erectile dysfunction and pulmonary hypertension. An insight into the pharmacophores of PDE5 inhibitors is essential for development of second generation of PDE5 inhibitors, but has not been completely illustrated. Here we report the synthesis of a new class of the sildenafil derivatives and a crystal structure of the PDE5 catalytic domain in complex with 5-(2-ethoxy-5-(sulfamoyl)-3-thienyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one (12). Inhibitor 12 induces conformational change of the H-loop (residues 660–683), which is different from any of the known PDE5 structures. The pyrazolopyrimidinone groups of 12 and sildenafil are well superimposed, but their sulfonamide groups show a positional difference of as much as 1.5 Å. The structure-activity analysis suggests that a small hydrophobic pocket and the H-loop of PDE5 are important for the inhibitor affinity, in addition to two common elements for binding of almost all the PDE inhibitors: the stack against the phenylalanine and the hydrogen bond with the invariant glutamine. However, the PDE5-12 structure does not provide a full explanation to affinity changes of the inhibitors. Thus alternatives such as conformational change of the M-loop are open and further structural study is required. PMID:18346713

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. Copyright © 2014 Elsevier Inc. All rights reserved.

Dialysate bacterial endotoxin as a prognostic indicator of peritoneal dialysis related peritonitis.

PubMed

Szeto, Cheuk-Chun; Lai, Ka-Bik; Chow, Kai-Ming; Kwan, Bonnie Ching-Ha; Law, Man-Ching; Pang, Wing-Fai; Ma, Terry King-Wing; Leung, Chi-Bon; Li, Philip Kam-Tao

2016-12-01

Peritonitis is the major complication of peritoneal dialysis (PD). The aim of our present study is to explore the prognostic value of endotoxin level in PD effluent for the prediction of treatment failure in PD-related peritonitis. We studied 325 peritonitis episodes in 223 patients. PD effluent (PDE) was collected every 5 days for endotoxin level and leukocyte count. Patients were followed for relapsing or recurrent peritonitis. We found 20 episodes (6.2%) had primary treatment failure; 41 (12.6%) developed relapsing, 19 (5.8%) had recurrent, and 22 (6.8%) had repeat episodes. Endotoxin was detectable in the PDE of 19 episodes (24.4%) caused by Gram negative organisms, 4 episodes (6.8%) of mixed bacterial growth, and none of the culture negative episodes or those by Gram positive organisms. For episodes caused by Gram negative bacteria, a detectable endotoxin level in PDE on day 5 had a sensitivity and specificity of 66.7% and 83.3%, respectively, for predicting primary treatment failure. In contrast, PDE leukocyte count > 1000 per mm3 on day 5 had a sensitivity and specificity of 88.9% and 89.1%, respectively; the addition of PDE endotoxin assay did not improve the sensitivity or specificity. We conclude that detectable endotoxin in PDE 5 days after antibiotic therapy might predict primary treatment failure in peritonitis episodes caused by Gram negative organisms. However, the sensitivity and specificity of PDE endotoxin assay was inferior to PDE leukocyte count. © 2016 Asian Pacific Society of Nephrology.

Synchronization of relativistic particles in the hyperbolic Kuramoto model

NASA Astrophysics Data System (ADS)

Ritchie, Louis M.; Lohe, M. A.; Williams, Anthony G.

2018-05-01

We formulate a noncompact version of the Kuramoto model by replacing the invariance group SO(2) of the plane rotations by the noncompact group SO(1, 1). The N equations of the system are expressed in terms of hyperbolic angles αi and are similar to those of the Kuramoto model, except that the trigonometric functions are replaced by hyperbolic functions. Trajectories are generally unbounded, nevertheless synchronization occurs for any positive couplings κi, arbitrary positive multiplicative parameters λi and arbitrary exponents ωi. There are no critical values for the coupling constants. We measure the onset of synchronization by means of several order and disorder parameters. We show numerically and by means of exact solutions for N = 2 that solutions can develop singularities if the coupling constants are negative, or if the initial values are not suitably restricted. We describe a physical interpretation of the system as a cluster of interacting relativistic particles in 1 + 1 dimensions, subject to linear repulsive forces with space-time trajectories parametrized by the rapidity αi. The trajectories synchronize provided that the particle separations remain predominantly time-like, and the synchronized cluster can be viewed as a bound state of N relativistic particle constituents. We extend the defining equations of the system to higher dimensions by means of vector equations which are covariant with respect to SO(p, q).

New approach of a traditional analysis for predicting near-exit jet liquid instabilities

NASA Astrophysics Data System (ADS)

Jaramillo, Guillermo; Collicott, Steven

2015-11-01

Traditional linear instability theory for round liquid jets requires an exit-plane velocity profile be assumed so as to derive the characteristic growth rates and wavelengths of instabilities. This requires solving an eigenvalue problem for the Rayleigh Equation. In this new approach, a hyperbolic tangent velocity profile is assumed at the exit-plane of a round jet and a comparison is made with a hyperbolic secant profile. Temporal and Spatial Stability Analysis (TSA and SSA respectively) are the employed analytical tools to compare results of predicted most-unstable wavelengths from the given analytical velocity profiles and from previous experimental work. The local relevance of the velocity profile in the near-exit region of a liquid jet and the validity of an inviscid formulation through the Rayleigh equation are discussed as well. A comparison of numerical accuracy is made between two different mathematical approaches for the hyperbolic tangent profile with and without the Ricatti transformation. Reynolds number based on the momentum thickness of the boundary layer at the exit plane non-dimensionalizes the problem and, the Re range, based on measurements by Portillo in 2011, is 185 to 600. Wavelength measurements are taken from Portillo's experiment. School of Mechanical Engineering at Universidad del Valle, supported by a grant from Fulbright and Colciencias. Ph.D. student at the School of Aeronautics and Astronautics Purdue University.

Exploration of POD-Galerkin Techniques for Developing Reduced Order Models of the Euler Equations

DTIC Science & Technology

2015-07-01

modes [1]. Barone et al [15, 16] proposed to stabilize the reduced system by symmetrizing the higher-order PDE with a preconditioning matrix. Rowley et...advection scalar equation. The ROM is obtained by employing Galerkin’s method to reduce the high-order PDEs to a lower- order ODE system by means of POD...high-order PDEs to a lower-order ODE system by means of POD eigen-bases. For purposes of this study, a linearized version of the Euler equations is

Hyperbolic and semi-hyperbolic surface codes for quantum storage

NASA Astrophysics Data System (ADS)

Breuckmann, Nikolas P.; Vuillot, Christophe; Campbell, Earl; Krishna, Anirudh; Terhal, Barbara M.

2017-09-01

We show how a hyperbolic surface code could be used for overhead-efficient quantum storage. We give numerical evidence for a noise threshold of 1.3 % for the \\{4,5\\}-hyperbolic surface code in a phenomenological noise model (as compared with 2.9 % for the toric code). In this code family, parity checks are of weight 4 and 5, while each qubit participates in four different parity checks. We introduce a family of semi-hyperbolic codes that interpolate between the toric code and the \\{4,5\\}-hyperbolic surface code in terms of encoding rate and threshold. We show how these hyperbolic codes outperform the toric code in terms of qubit overhead for a target logical error probability. We show how Dehn twists and lattice code surgery can be used to read and write individual qubits to this quantum storage medium.

Representation of the contextual statistical model by hyperbolic amplitudes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khrennikov, Andrei

We continue the development of a so-called contextual statistical model (here context has the meaning of a complex of physical conditions). It is shown that, besides contexts producing the conventional trigonometric cos-interference, there exist contexts producing the hyperbolic cos-interference. Starting with the corresponding interference formula of total probability we represent such contexts by hyperbolic probabilistic amplitudes or in the abstract formalism by normalized vectors of a hyperbolic analogue of the Hilbert space. There is obtained a hyperbolic Born's rule. Incompatible observables are represented by noncommutative operators. This paper can be considered as the first step towards hyperbolic quantum probability. Wemore » also discuss possibilities of experimental verification of hyperbolic quantum mechanics: in physics of elementary particles, string theory as well as in experiments with nonphysical systems, e.g., in psychology, cognitive sciences, and economy.« less

Representation of the contextual statistical model by hyperbolic amplitudes

NASA Astrophysics Data System (ADS)

Khrennikov, Andrei

2005-06-01

We continue the development of a so-called contextual statistical model (here context has the meaning of a complex of physical conditions). It is shown that, besides contexts producing the conventional trigonometric cos-interference, there exist contexts producing the hyperbolic cos-interference. Starting with the corresponding interference formula of total probability we represent such contexts by hyperbolic probabilistic amplitudes or in the abstract formalism by normalized vectors of a hyperbolic analogue of the Hilbert space. There is obtained a hyperbolic Born's rule. Incompatible observables are represented by noncommutative operators. This paper can be considered as the first step towards hyperbolic quantum probability. We also discuss possibilities of experimental verification of hyperbolic quantum mechanics: in physics of elementary particles, string theory as well as in experiments with nonphysical systems, e.g., in psychology, cognitive sciences, and economy.

Photoaffinity labelling of cyclic GMP-inhibited phosphodiesterase (PDE III) in human and rat platelets and rat tissues: effects of phosphodiesterase inhibitors.

PubMed

Tang, K M; Jang, E K; Haslam, R J

1994-06-15

Ultraviolet irradiation of human platelet cytosol in the presence of 32P-labelled cyclic GMP (cGMP) can specifically label 110, 80, 55, 49 and 38 kDa proteins; the 110 kDa species is the subunit of cGMP-inhibited phosphodiesterase (PDE III) and the 80 kDa species that of cGMP-dependent protein kinase (Tang et al., 1993, Biochem. J. 294, 329). We have now shown that although photolabelling of platelet PDE III was inhibited by unlabelled cGMP, 8-bromo-cGMP and cyclic AMP (cAMP), it was not affected by phosphorothioate analogues of these cyclic nucleotides. Specific concentration-dependent inhibitions of the photolabelling of PDE III were observed with the following PDE inhibitors: trequinsin (IC50 = 13 +/- 2 nM), lixazinone (IC50 = 22 +/- 4 nM), milrinone (IC50 = 56 +/- 12 nM), cilostamide (IC50 = 70 +/- 9 nM), siguazodan (IC50 = 117 +/- 29 nM) and 3-isobutyl 1-methylxanthine (IBMX) (IC50 = 3950 +/- 22 nM). Thus, measurements of the inhibitory effects of compounds on the photolabelling of platelet PDE III provide a simple quantitative means of investigating their actions at a molecular level that avoids the need to purify the enzyme. Photolabelling of rat platelet lysate or rat heart homogenate by [32P]cGMP showed that the 110 kDa PDE III present in human material was replaced by a 115 kDa protein, labelling of which was also blocked by PDE III inhibitors. Heart and other rat tissues contained much less of this putative 115 kDa PDE III than rat platelets. In contrast, the 80 kDa protein was labelled much less in platelets than in many other rat tissue homogenates (e.g., heart, aorta, uterus and lung). Thus, comparison of the relative amounts of specific photolabelled proteins in different cells may provide an indication of different patterns of cyclic nucleotide action. We compared the abilities of phosphodiesterase inhibitors to block the photolabelling of PDE III in human platelet cytosol and to increase the iloprost-stimulated accumulation of cAMP in intact platelets. Whereas trequinsin (EC50 = 19 +/- 3 nM), lixazinone (EC50 = 122 +/- 8 nM), milrinone (EC50 = 5320 +/- 970 nM) and siguazodan (EC50 = 18880 +/- 3110 nM) all increased platelet cAMP to the same maximum extent, cilostamide and IBMX increased cAMP further, indicating that they inhibited a PDE isozyme in addition to PDE III.

Impact of hyperbolicity on chimera states in ensembles of nonlocally coupled chaotic oscillators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Semenova, N.; Anishchenko, V.; Zakharova, A.

2016-06-08

In this work we analyse nonlocally coupled networks of identical chaotic oscillators. We study both time-discrete and time-continuous systems (Henon map, Lozi map, Lorenz system). We hypothesize that chimera states, in which spatial domains of coherent (synchronous) and incoherent (desynchronized) dynamics coexist, can be obtained only in networks of chaotic non-hyperbolic systems and cannot be found in networks of hyperbolic systems. This hypothesis is supported by numerical simulations for hyperbolic and non-hyperbolic cases.

PDE1 Encodes a P-Type ATPase Involved in Appressorium-Mediated Plant Infection by the Rice Blast Fungus Magnaporthe grisea

PubMed Central

Balhadère, Pascale V.; Talbot, Nicholas J.

2001-01-01

Plant infection by the rice blast fungus Magnaporthe grisea is brought about by the action of specialized infection cells called appressoria. These infection cells generate enormous turgor pressure, which is translated into an invasive force that allows a narrow penetration hypha to breach the plant cuticle. The Magnaporthe pde1 mutant was identified previously by restriction enzyme–mediated DNA integration mutagenesis and is impaired in its ability to elaborate penetration hyphae. Here we report that the pde1 mutation is the result of an insertion into the promoter of a P-type ATPase-encoding gene. Targeted gene disruption confirmed the role of PDE1 in penetration hypha development and pathogenicity but highlighted potential differences in PDE1 regulation in different Magnaporthe strains. The predicted PDE1 gene product was most similar to members of the aminophospholipid translocase group of P-type ATPases and was shown to be a functional homolog of the yeast ATPase gene ATC8. Spatial expression studies showed that PDE1 is expressed in germinating conidia and developing appressoria. These findings implicate the action of aminophospholipid translocases in the development of penetration hyphae and the proliferation of the fungus beyond colonization of the first epidermal cell. PMID:11549759

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

PubMed

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

2015-05-01

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. Published by Elsevier Inc.

Tailoring High Order Time Discretizations for Use with Spatial Discretizations of Hyperbolic PDEs

DTIC Science & Technology

2015-05-19

Duration of Grant Sigal Gottlieb, Professor of Mathematics, UMass Dartmouth. Daniel Higgs , Graduate Student, UMass Dartmouth. Zachary Grant, Undergraduate...Grant, and D. Higgs , “Optimal Explicit Strong Stability Preserving Runge– Kutta Methods with High Linear Order and optimal Nonlinear Order.” Accepted...for publica- tion in Mathematics of Computation. Available on Arxiv at http://arxiv.org/abs/1403. 6519 4. C. Bresten, S. Gottlieb, Z. Grant, D. Higgs

PDE3, but not PDE4, reduces β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

PubMed Central

Molenaar, Peter; Christ, Torsten; Hussain, Rizwan I; Engel, Andreas; Berk, Emanuel; Gillette, Katherine T; Chen, Lu; Galindo-Tovar, Alejandro; Krobert, Kurt A; Ravens, Ursula; Levy, Finn Olav; Kaumann, Alberto J

2013-01-01

Background and Purpose PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3–1 μM) or PDE4 inhibitor rolipram (1–10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. Experimental Approach Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β1 adrenoceptors (β2 adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2 adrenoceptors (β1 adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from –logEC50s. Key Results Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. Conclusions and Implications Metoprolol induces a control by PDE3 of ventricular effects mediated through both β1 and β2 adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β2 adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle. Linked Article This article is commented on by Eschenhagen, pp 524–527 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12168 PMID:23489141

CHBPR: Decreased cGMP level contributes to increased contraction in arteries from hypertensive rats: role of PDE1

PubMed Central

Giachini, Fernanda R.; Lima, Victor V.; Carneiro, Fernando S.; Tostes, Rita C.; Webb, R. Clinton

2011-01-01

Recent evidence suggests that angiotensin II (Ang II) upregulates phosphodiesterase (PDE)-1A expression. We hypothesized that Ang II augmented PDE1 activation, decreasing the bioavailability of cyclic cyclic guanosine 3', 5'-monophosphate (cGMP), contributing to increased vascular contractility. Male Sprague-Dawley rats received mini-osmotic pumps with Ang II (60 ng.min−1) or saline for 14 days. PE-induced contractions were increased in aorta (Emax168±8 vs. 136±4%) and small-mesenteric arteries [(SMA), Emax170±6 vs. 143±3%] from Ang II infused rats compared to control. PDE1 inhibition with vinpocetine (10µM) reduced PE-induced contraction in aortas from Ang II rats (Emax94±12%) but not in control (154±7%). Vinpocetine decreased the sensitivity to PE in SMA from Ang II rats compared to vehicle (pD2 5.1±0.1 vs. 5.9±0.06), but not in control (6.0±0.03 vs. 6.1±0.04). Sildenafil (10µM), a PDE5 inhibitor reduced PE-induced maximal contraction similarly in Ang II and control rats. Arteries were contracted with PE (1µM) and concentration-dependent relaxation to vinpocetine and sildenafil was evaluated. Aortas from Ang II rats displayed increased relaxation to vinpocetine compared to control (Emax82±12 vs. 44±5%). SMA from Ang II rats showed greater sensitivity during vinpocetine-induced relaxation, compared to control (pD2 6.1±0.3 vs. 5.3±0.1). No differences in sildenafil-induced relaxation were observed. PDE1A and PDE1C expressions in aorta and PDE1A expression in SMA were increased in Ang II rats. cGMP production, which is decreased in arteries from Ang II rats, was restored after PDE1 blockade. We conclude that PDE1 activation reduces cGMP bioavailability in arteries from ANG II, contributing to increased contractile responsiveness. PMID:21282562

Cyanidin-3-glucoside suppresses B[a]PDE-induced cyclooxygenase-2 expression by directly inhibiting Fyn kinase activity.

PubMed

Lim, Tae-Gyu; Kwon, Jung Yeon; Kim, Jiyoung; Song, Nu Ry; Lee, Kyung Mi; Heo, Yong-Seok; Lee, Hyong Joo; Lee, Ki Won

2011-07-15

Benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE) is a well-known carcinogen that is associated with skin cancer. Abnormal expression of cyclooxygenase-2 (COX-2) is an important mediator in inflammation and tumor promotion. We investigated the inhibitory effect of cyanidin-3-glucoside (C3G), an anthocyanin present in fruits, on B[a]PDE-induced COX-2 expression in mouse epidermal JB6 P+ cells. Pretreatment with C3G resulted in the reduction of B[a]PDE-induced expression of COX-2 and COX-2 promoter activity. The activation of activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) induced by B[a]PDE was also attenuated by C3G. C3G attenuated the B[a]PDE-induced phosphorylation of MEK, MKK4, Akt, and mitogen-activated protein kinases (MAPKs), but no effect on the phosphorylation of the upstream MAPK regulator Fyn. However, kinase assays demonstrated that C3G suppressed Fyn kinase activity and C3G directly binds Fyn kinase noncompetitively with ATP. By using PP2, a pharmacological inhibitor for SFKs, we showed that Fyn kinase regulates B[a]PDE-induced COX-2 expression by activating MAPKs, AP-1 and NF-κB. These results suggest that C3G suppresses B[a]PDE-induced COX-2 expression mainly by blocking the activation of the Fyn signaling pathway, which may contribute to its chemopreventive potential. Copyright © 2011 Elsevier Inc. All rights reserved.

Regulation of Phosphodiesterase 3 in the Pulmonary Arteries During the Perinatal Period in Sheep

PubMed Central

Chen, Bernadette; Lakshminrusimha, Satyan; Czech, Lyubov; Groh, Beezly S.; Gugino, Sylvia F.; Russell, James A.; Farrow, Kathryn N.; Steinhorn, Robin H.

2009-01-01

The role of cAMP in the pulmonary vasculature during the transition from intrauterine to extrauterine life is poorly understood. We hypothesized that cAMP levels are regulated by alterations in phosphodiesterase 3 (PDE3), which hydrolyzes cAMP. PDE3 protein expression and hydrolytic activity were increased in resistance pulmonary arteries (PA) from spontaneously breathing one-day-old (1dSB) lambs relative to equivalent-gestation fetuses. This was accompanied by a decrease in steady-state cAMP. Ventilation with 21% O2 and 100% O2 for 24h disrupted the normal transition, whereas ventilation with 100% O2+inhaled NO (iNO) for 24h restored both PDE3 activity and cAMP to 1dSB levels. Consistent with these findings, relaxation to milrinone, a PDE3 inhibitor, was greater in PA isolated from 1dSB and 100% O2+iNO lambs, relative to fetal, 21% O2, and 100% O2 lambs. In conclusion, PDE3 expression and activity in PA dramatically increase after birth, with a concomitant decrease in steady-state cAMP. Ventilation with either 21% O2 or 100% O2 blunts this PDE3 increase, whereas iNO restores PDE3 activity to levels equivalent to 1dSB lambs. The vasodilatory effects of milrinone were most pronounced in vessels from lambs with the highest PDE3 activity, i.e. 1dSB and 100% O2+iNO lambs. Thus, milrinone may be most beneficial when used in conjunction with iNO. PMID:19707176

Inhibition of Cyclic Adenosine Monophosphate-Specific Phosphodiesterase by Various Food Plant-Derived Phytotherapeutic Agents

PubMed Central

Pacjuk, Olga; Hernández-Huguet, Silvia; Körner, Johanna; Scherer, Katharina; Richling, Elke

2017-01-01

Background: Phosphodiesterases (PDEs) play a major role in the regulation of cyclic adenosine monophosphate (cAMP)- and cyclic guanosine monophosphate (cGMP)-mediated pathways. Their inhibitors exhibit anti-inflammatory, vasodilatory and antithrombotic effects. Therefore, consumption of foods with PDE-inhibiting potential may possess beneficial influence on the risk of cardiovascular diseases. Methods: Four plant extracts (Arbutus unedo, Camellia sinensis, Cynara scolymus, Zingiber officinale) with promising ingredient profiles and physiological effects were tested for their ability to inhibit cAMP-specific PDE in vitro in a radioactive assay. Results: Strawberry tree fruit (Arbutus unedo) and tea (Camellia sinensis) extracts did not inhibit PDE markedly. Alternatively, artichoke (Cynara scolymus) extract had a significant inhibitory influence on PDE activity (IC50 = 0.9 ± 0.1 mg/mL) as well as its flavone luteolin (IC50 = 41 ± 10 μM) and 3,4-dicaffeoylquinic acid (IC50 > 1.0 mM). Additionally, the ginger (Zingiber officinale) extract and one of its constituents, [6]-gingerol, significantly inhibited PDE (IC50 = 1.7 ± 0.2 mg/mL and IC50 > 1.7 mM, respectively). Crude fractionation of ginger extract showed that substances responsible for PDE inhibition were in the lipoid fraction (IC50 = 455 ± 19 μg/mL). Conclusions: A PDE-inhibitory effect was shown for artichoke and ginger extract. Whether PDE inhibition in vivo can be achieved through ingestion of artichoke or ginger extracts leading to physiological effects concerning cardiovascular health should be addressed in future research. PMID:29113064

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. Copyright © 2014 Elsevier Inc. All rights reserved.

A Reduced Model for the Magnetorotational Instability

NASA Astrophysics Data System (ADS)

Jamroz, Ben; Julien, Keith; Knobloch, Edgar

2008-11-01

The magnetorotational instability is investigated within the shearing box approximation in the large Elsasser number regime. In this regime, which is of fundamental importance to astrophysical accretion disk theory, shear is the dominant source of energy, but the instability itself requires the presence of a weaker vertical magnetic field. Dissipative effects are weaker still. However, they are sufficiently large to permit a nonlinear feedback mechanism whereby the turbulent stresses generated by the MRI act on and modify the local background shear in the angular velocity profile. To date this response has been omitted in shearing box simulations and is captured by a reduced pde model derived here from the global MHD fluid equations using multiscale asymptotic perturbation theory. Results from numerical simulations of the reduced pde model indicate a linear phase of exponential growth followed by a nonlinear adjustment to algebraic growth and decay in the fluctuating quantities. Remarkably, the velocity and magnetic field correlations associated with these algebraic growth and decay laws conspire to achieve saturation of the angular momentum transport. The inclusion of subdominant ohmic dissipation arrests the algebraic growth of the fluctuations on a longer, dissipative time scale.

Airbreathing Pulse Detonation Engine Performance

NASA Technical Reports Server (NTRS)

Povinelli, Louis A.; Yungster, Shaye

2002-01-01

This paper presents performance results for pulse detonation engines (PDE) taking into account the effects of dissociation and recombination. The amount of sensible heat recovered through recombination in the PDE chamber and exhaust process was found to be significant. These results have an impact on the specific thrust, impulse and fuel consumption of the PDE.

The safety of phosphodiesterase type 5 inhibitors for erectile dysfunction.

PubMed

Ventimiglia, Eugenio; Capogrosso, Paolo; Montorsi, Francesco; Salonia, Andrea

2016-01-01

Phosphodiesterase type 5 inhibitors (PDE5Is) are the leading drugs for the treatment of erectile dysfunction (ED), being recommended as a first line treatment by both the European and US urological guidelines. PDE5Is are highly effective as compared to placebo, well tolerated and have a very low, though not negligible, rate of severe treatment-related adverse events. This paper reviews the safety profile of currently available PDE5Is, comparing them in a broad spectrum ED population and outlining a number of real-life aspects of importance in the real-life everyday clinical setting. Guidelines unanimously agree in considering PDE5Is as first line treatments for ED when well-tolerated and not contraindicated. Despite the fact that no high-grade evidence comparing the efficacy and the safety for PDE5Is is currently available, published data seem to suggest that there are no major differences in their safety profiles. Moreover, although oral PDE5Is were shown to cause more AEs than placebo, they were generally mild and well tolerated.

A substrate selectivity and inhibitor design lesson from the PDE10-cAMP crystal structure: a computational study.

PubMed

Lau, Justin Kai-Chi; Li, Xiao-Bo; Cheng, Yuen-Kit

2010-04-22

Phosphodiesterases (PDEs) catalyze the hydrolysis of second messengers cAMP and cGMP in regulating many important cellular signals and have been recognized as important drug targets. Experimentally, a range of specificity/selectivity toward cAMP and cGMP is well-known for the individual PDE families. The study reported here reveals that PDEs might also exhibit selectivity toward conformations of the endogenous substrates cAMP and cGMP. Molecular dynamics simulations and free energy study have been applied to study the binding of the cAMP torsional conformers about the glycosyl bond in PDE10A2. The computational results elucidated that PDE10A2 is energetically more favorable in complex with the syn cAMP conformer (as reported in the crystal structure) and the binding of anti cAMP to PDE10A2 would lead to either a nonreactive configuration or significant perturbation on the catalytic pocket of the enzyme. This experimentally inaccessible information provides important molecular insights for the development of effective PDE10 ligands.

East Indian Sandalwood Oil Is a Phosphodiesterase Inhibitor: A New Therapeutic Option in the Treatment of Inflammatory Skin Disease.

PubMed

Sharma, Manju; Levenson, Corey; Browning, John C; Becker, Emily M; Clements, Ian; Castella, Paul; Cox, Michael E

2018-01-01

Cyclic adenosine monophosphate phosphodiesterases (PDEs) regulate pro-inflammatory cytokine production. One isoform, PDE4, is overactive in chronic relapsing inflammatory skin diseases: psoriasis and eczema/atopic dermatitis, and in several cancers. East Indian sandalwood oil (EISO) has significant anti-inflammatory properties. Here, we report that 75% of pediatric eczema/atopic dermatitis patients treated with topical EISO formulations achieved a >50% reduction in their Eczema Area and Severity Index score. EISO treatment of a psoriasis model reduced PDE4 expression and reversed histopathology. EISO directly inhibited PDE enzymatic activity in vitro . In lipopolysaccharide-stimulated human dermal fibroblast, BEAS-2B, A549, and THP-1 cells, EISO suppressed total cellular PDE activity, PDE4, and 7 transcript levels, nuclear factor kappa B (NF-κB) activation, and pro-inflammatory cytokines/chemokine production. These results suggest that EISO anti-inflammatory activity is mediated through suppressing PDE activity, thus facilitating cAMP-regulated inhibition of NF-κB and indicate EISO as an attractive natural therapeutic for chronic and acute inflammatory disorders.

Inhibitors of cyclic nucleotide phosphodiesterase 3 and 5 as therapeutic agents in heart failure.

PubMed

Stehlik, Josef; Movsesian, Matthew A

2006-07-01

Cyclic nucleotide phosphodiesterases (PDE) 3 and 5 regulate cAMP and cGMP signalling in cardiac and smooth muscle myocytes. Important advances in the understanding of the roles of these enzymes have recently been made. PDE3 inhibitors have inotropic and vasodilatory properties, and although they acutely improve haemodynamics in patients with heart failure, they do not improve long-term morbidity and mortality. Although combination therapy with beta-adrenergic receptor antagonists or selective inhibition of specific PDE3 isoforms might result in a more favourable long-term outcome, more clinical data are needed to test this proposition. The role of PDE5 inhibitors in the treatment of cardiac disease is evolving. PDE5 inhibitors cause pulmonary and systemic vasodilation. How these drugs will compare with other vasodilators in terms of long-term outcomes in patients with heart failure is unknown. Recent studies also suggest that PDE5 inhibitors may have antihypertropic effects, exerted through increased myocardial cGMP signalling, that could be of additional benefit in patients with heart failure.

East Indian Sandalwood Oil Is a Phosphodiesterase Inhibitor: A New Therapeutic Option in the Treatment of Inflammatory Skin Disease

PubMed Central

Sharma, Manju; Levenson, Corey; Browning, John C.; Becker, Emily M.; Clements, Ian; Castella, Paul; Cox, Michael E.

2018-01-01

Cyclic adenosine monophosphate phosphodiesterases (PDEs) regulate pro-inflammatory cytokine production. One isoform, PDE4, is overactive in chronic relapsing inflammatory skin diseases: psoriasis and eczema/atopic dermatitis, and in several cancers. East Indian sandalwood oil (EISO) has significant anti-inflammatory properties. Here, we report that 75% of pediatric eczema/atopic dermatitis patients treated with topical EISO formulations achieved a >50% reduction in their Eczema Area and Severity Index score. EISO treatment of a psoriasis model reduced PDE4 expression and reversed histopathology. EISO directly inhibited PDE enzymatic activity in vitro. In lipopolysaccharide-stimulated human dermal fibroblast, BEAS-2B, A549, and THP-1 cells, EISO suppressed total cellular PDE activity, PDE4, and 7 transcript levels, nuclear factor kappa B (NF-κB) activation, and pro-inflammatory cytokines/chemokine production. These results suggest that EISO anti-inflammatory activity is mediated through suppressing PDE activity, thus facilitating cAMP-regulated inhibition of NF-κB and indicate EISO as an attractive natural therapeutic for chronic and acute inflammatory disorders. PMID:29593534

A numerical spectral approach to solve the dislocation density transport equation

NASA Astrophysics Data System (ADS)

Djaka, K. S.; Taupin, V.; Berbenni, S.; Fressengeas, C.

2015-09-01

A numerical spectral approach is developed to solve in a fast, stable and accurate fashion, the quasi-linear hyperbolic transport equation governing the spatio-temporal evolution of the dislocation density tensor in the mechanics of dislocation fields. The approach relies on using the Fast Fourier Transform algorithm. Low-pass spectral filters are employed to control both the high frequency Gibbs oscillations inherent to the Fourier method and the fast-growing numerical instabilities resulting from the hyperbolic nature of the transport equation. The numerical scheme is validated by comparison with an exact solution in the 1D case corresponding to dislocation dipole annihilation. The expansion and annihilation of dislocation loops in 2D and 3D settings are also produced and compared with finite element approximations. The spectral solutions are shown to be stable, more accurate for low Courant numbers and much less computation time-consuming than the finite element technique based on an explicit Galerkin-least squares scheme.

Topical otic drugs in a multi-purpose manufacturing facility: a guide on determination and application of permitted daily exposure (PDE).

PubMed

Wiesner, Lisa; Prause, Maarten; Lovsin Barle, Ester

2018-03-01

Due to newly introduced EU GMP (Good Manufacturing Practice) guideline for Medicinal Products for Human and Veterinary use, product specific permitted daily exposure (PDE) for toxicological evaluation in multi-purpose facilities are required within a documented process for risk assessment. European Medicines Agency (EMA) guidance on setting PDE limits so far focused on systemic administration routes such as intravenous (IV), oral or inhalation. This article provides guidance on setting PDE values for risk management purposes in multi-purpose facilities for active pharmaceutical ingredients (APIs) applied as topical otic drugs to the outer ear canal. The therewith determined PDE otic, is used for the calculation of maximum safe carry-over (MSC) in manufacturing scenarios where a topical otic product is manufactured followed by another topical otic product.

Contracting singular horseshoe

NASA Astrophysics Data System (ADS)

Morales, C. A.; San Martín, B.

2017-11-01

We suggest a notion of hyperbolicity adapted to the geometric Rovella attractor (Robinson 2012 An Introduction to Dynamical Systems—Continuous and Discrete (Pure and Applied Undergraduate Texts vol 19) 2nd edn (Providence, RI: American Mathematical Society)) . More precisely, we call a partially hyperbolic set asymptotically sectional-hyperbolic if its singularities are hyperbolic and if its central subbundle is asymptotically sectional expanding outside the stable manifolds of the singularities. We prove that there are highly chaotic flows with Rovella-like singularities exhibiting this kind of hyperbolicity. We shall call them contracting singular horseshoes.

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish.

PubMed

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

2014-05-01

Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c(w59) mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c(w59) embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed. Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c(w59) mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

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

PubMed

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

2014-05-01

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

Characterization of particulate cyclic nucleotide phosphodiesterases from bovine brain: Purification of a distinct cGMP-stimulated isoenzyme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murashima, Seiko; Tanaka, Takayuki; Hockman, S.

1990-06-05

In the absence of detergent, {approx}80-85% of the total cGMP-stimulated phosphodiesterase (PDE) activity in bovine brain was associated with washed particulate fractions; {approx}85-90% of the calmodulin-sensitive PDE was soluble. Particulate cGMP-stimulated PDE was higher in cerebral cortical gray matter than in other regions. Homogenization of the brain particulate fraction in 1% Lubrol increased cGMP-stimulated activity {approx}100% and calmodulin-stimulated {approx}400-500%. Although 1% Lubrol readily solubilized these PDE activities, {approx}75% of the cAMP PDE activity (0.5 {mu}M ({sup 3}H)cAMP) that was not affected by cGMP was not solubilized. This cAMP PDE activity was very sensitive to inhibition by Rolipram but not cilostamide.more » Thus, three different PDE types, i.e., cGMP stimulated, calmodulin sensitive, and Rolipram inhibited, are associated in different ways with crude bovine brain particulate fractions. The brain enzyme exhibited a slightly greater subunit M{sub r} than did soluble forms from calf liver or bovine brain, as evidenced by protein staining or immunoblotting after polyacrylamide gel electrophoresis under denaturing conditions. Incubation of brain particulate and liver soluble cGMP-stimulated PDEs with V{sub 8} protease produced several peptides of similar size, as well as at least two distinct fragments of {approx}27 kDa from the brain and {approx}23 kDa from the liver enzyme. After photolabeling in the presence of ({sup 32}P)cGMP and digestion with V{sub 8} protease, ({sup 32}P)cGMP in each PDE was predominantly recovered with a peptide of {approx}14 kDa. All of these observations are consistent with the existence of at least two discrete forms (isoenzymes) of cGMP-stimulated PDE.« less

Does educational status affect a patient's behavior toward erectile dysfunction?

PubMed

Salonia, Andrea; Abdollah, Firas; Gallina, Andrea; Pellucchi, Federico; Castillejos Molina, Ricardo Alonso; Maccagnano, Carmen; Rocchini, Lorenzo; Zanni, Giuseppe; Rigatti, Patrizio; Montorsi, Francesco

2008-08-01

Educational status has been investigated rarely as a potential factor affecting the behavior of patients with new onset erectile dysfunction (ED) toward seeking first medical help and subsequent compliance with prescribed phosphodiesterase type 5 inhibitor (PDE5) therapy. To test whether the educational status of patients with new onset ED and naïve to PDE5 therapy may have a significant impact on the delay before seeking first medical help (DSH) and compliance with the suggested PDE5. Assessing DSH and compliance with PDE5 in new onset ED patients according to their educational status by means of detailed logistic regression analyses. Data from 302 consecutive patients with new onset ED and naïve to PDE5s were comprehensively analyzed. Patients were segregated according to their educational status into low (elementary and/or secondary school education) and high (high school and/or university degrees) educational levels. Complete data were available for 231 assessable patients. Univariate (UVA) and multivariate (MVA) logistic regression analyses addressed the association between educational status and DSH after adjusting for age, relationship status, and Sexual Health Inventory for Men score. Likewise, UVA and MVA were performed to test the association between educational status and patient compliance with PDE5 at the 9-month median follow-up. Median DSH was 24 months (range 1-350; mean 38.1 +/- 42.8). The lower the educational status, the shorter the DSH (P = 0.03). In contrast, a significantly (P < 0.0001) greater proportion of patients with a higher educational status showed compliance with the suggested PDE5 at the 9-month follow-up. Overall, educational status was not an independent predictor of either DSH or patient compliance with PDE5 therapy. After adjusting for other variables, our findings suggest that in new onset ED patients, educational status does not independently affect the DSH and patient compliance with PDE5 therapy.

A boundary PDE feedback control approach for the stabilization of mortgage price dynamics

NASA Astrophysics Data System (ADS)

Rigatos, G.; Siano, P.; Sarno, D.

2017-11-01

Several transactions taking place in financial markets are dependent on the pricing of mortgages (loans for the purchase of residences, land or farms). In this article, a method for stabilization of mortgage price dynamics is developed. It is considered that mortgage prices follow a PDE model which is equivalent to a multi-asset Black-Scholes PDE. Actually it is a diffusion process evolving in a 2D assets space, where the first asset is the house price and the second asset is the interest rate. By applying semi-discretization and a finite differences scheme this multi-asset PDE is transformed into a state-space model consisting of ordinary nonlinear differential equations. For the local subsystems, into which the mortgage PDE is decomposed, it becomes possible to apply boundary-based feedback control. The controller design proceeds by showing that the state-space model of the mortgage price PDE stands for a differentially flat system. Next, for each subsystem which is related to a nonlinear ODE, a virtual control input is computed, that can invert the subsystem's dynamics and can eliminate the subsystem's tracking error. From the last row of the state-space description, the control input (boundary condition) that is actually applied to the multi-factor mortgage price PDE system is found. This control input contains recursively all virtual control inputs which were computed for the individual ODE subsystems associated with the previous rows of the state-space equation. Thus, by tracing the rows of the state-space model backwards, at each iteration of the control algorithm, one can finally obtain the control input that should be applied to the mortgage price PDE system so as to assure that all its state variables will converge to the desirable setpoints. By showing the feasibility of such a control method it is also proven that through selected modification of the PDE boundary conditions the price of the mortgage can be made to converge and stabilize at specific reference values.

The novel functions of cGMP-specific phosphodiesterase 5 and its inhibitors in carcinoma cells and pulmonary/cardiovascular vessels.

PubMed

Zhu, Bing; Strada, Samuel J

2007-01-01

PDE5 is a key enzyme involved in the regulation of cGMP-specific signaling pathways in normal physiological processes such as smooth muscle contraction and relaxation. For this reason, inhibition of the enzyme can alter those pathophysiological conditions associated with a lowering cGMP level in tissues. For example, selective PDE5 inhibitors, such as sildenafil (Viagra, Pfizer), tadalafil (Cialis, Lilly-ICOS), and vardenafil (Levitra, Bayer), have been successfully used to treat the condition of human erectile dysfunction. More recently, the involvement of this enzyme has been proposed to influence antiproliferation and proapoptotic mechanism in multiple carcinomas. The data supporting this idea is based on increases in PDE5 activities in many carcinomas and the ability of PDE5 inhibitors such as exisulind and its analogs related to anticancer activities. Inhibition of PDE5 that results in sustained increases in [cGMP](i) are required to modify the process of apoptosis and mitotic arrest in those carcinoma cells with enhanced PDE5 expressions. Increases in PDE5 are also involved in contributing to the pathological changes in the pulmonary system resulting in hyper-proliferative remodeling of both smooth muscle and endothelium in models of pulmonary hypertension. For this reason, the use of PDE5 inhibitors in the treatment of human pulmonary hypertension has met with some success. The differences that we have previously noted in PDE isoenzymes in pulmonary arterial and microvascular endothelial cells may provide a more selective cellular strategy for use of such inhibitor. Additional studies on structure biology of these enzymes should lead to the development of agents with better cellular specificity than currently available drugs. Considering the enormous progress that has been made in the last few years, the future looks promising for agents affecting this enzyme and related systems.

[A study of PDE6B gene mutation and phenotype in Chinese cases with retinitis pigmentosa].

PubMed

Cui, Yun; Zhao, Kan-xing; Wang, Li; Wang, Qing; Zhang, Wei; Chen, Wei-ying; Wang, Li-ming

2003-01-01

To identify the mutation spectrum of phosphodiesterase beta subunit (PDE6B) gene, the incidence in Chinese patients with retinitis pigmentosa (RP) and their clinical phenotypic characteristics. Screening of mutations within PDE6B gene was performed using polymerase chain reaction-heteroduplex-single strand conformation polymorphism (PCR-SSCP) and DNA sequence in 35 autosomal recessive (AR) RP and 55 sporadic RP cases. The phenotypes of the patients with the gene mutation were examined and analyzed. Novel complex heterozygous variants of PDE6B gene in a sporadic case, a T to C transversion in codon 323 resulting in the substitution of Gly by Ser and 2 base pairs (bp: G and T) insert between the 27th-28th bp upstream of the 5'-end of exon 10 were both present in a same isolate RP. But they are not found in 100 unrelated healthy individuals. Ocular findings showed diffuse pigmentary retinal degeneration in the midperipheral and peripheral fundi, optic atrophy and vessel attenuation. Multi-focal ERG indicated that the rod function was more severely deteriorated. A mutation was found in a case with RP in a ARRP family, a G to A transversion at 19th base upstream 5'-end of exon 11 (within intron 10) of PDE6B gene. A sporadic RP carried a sequence variant of PDE6B gene, a G to C transition, at the 15th base adjacent to the 3'-end of exon l8. In another isolate case with RP was found 2 bp (GT) insert between 31st and 32nd base upstream 5'-end of exon 4 (in intron 3) of PDE6B gene. There are novel complex heterozygous mutations of PDE6B gene responsible for a sporadic RP patient in China. This gene mutation associated with rod deterioration and RP. Several DNA variants were found in introns of PDE6B gene in national population.

A direct Arbitrary-Lagrangian-Eulerian ADER-WENO finite volume scheme on unstructured tetrahedral meshes for conservative and non-conservative hyperbolic systems in 3D

NASA Astrophysics Data System (ADS)

Boscheri, Walter; Dumbser, Michael

2014-10-01

In this paper we present a new family of high order accurate Arbitrary-Lagrangian-Eulerian (ALE) one-step ADER-WENO finite volume schemes for the solution of nonlinear systems of conservative and non-conservative hyperbolic partial differential equations with stiff source terms on moving tetrahedral meshes in three space dimensions. A WENO reconstruction technique is used to achieve high order of accuracy in space, while an element-local space-time Discontinuous Galerkin finite element predictor on moving curved meshes is used to obtain a high order accurate one-step time discretization. Within the space-time predictor the physical element is mapped onto a reference element using a high order isoparametric approach, where the space-time basis and test functions are given by the Lagrange interpolation polynomials passing through a predefined set of space-time nodes. Since our algorithm is cell-centered, the final mesh motion is computed by using a suitable node solver algorithm. A rezoning step as well as a flattener strategy are used in some of the test problems to avoid mesh tangling or excessive element deformations that may occur when the computation involves strong shocks or shear waves. The ALE algorithm presented in this article belongs to the so-called direct ALE methods because the final Lagrangian finite volume scheme is based directly on a space-time conservation formulation of the governing PDE system, with the rezoned geometry taken already into account during the computation of the fluxes. We apply our new high order unstructured ALE schemes to the 3D Euler equations of compressible gas dynamics, for which a set of classical numerical test problems has been solved and for which convergence rates up to sixth order of accuracy in space and time have been obtained. We furthermore consider the equations of classical ideal magnetohydrodynamics (MHD) as well as the non-conservative seven-equation Baer-Nunziato model of compressible multi-phase flows with stiff relaxation source terms.

Development of a Scintillation Proximity Assay (SPA) Based, High Throughput Screening Feasible Method for the Identification of PDE12 Activity Modulators.

PubMed

Mang, Samuel; Bucher, Hannes; Nickolaus, Peter

2016-01-01

The scintillation proximity assay (SPA) technology has been widely used to establish high throughput screens (HTS) for a range of targets in the pharmaceutical industry. PDE12 (aka. 2'- phosphodiesterase) has been published to participate in the degradation of oligoadenylates that are involved in the establishment of an antiviral state via the activation of ribonuclease L (RNAse-L). Degradation of oligoadenylates by PDE12 terminates these antiviral activities, leading to decreased resistance of cells for a variety of viral pathogens. Therefore inhibitors of PDE12 are discussed as antiviral therapy. Here we describe the use of the yttrium silicate SPA bead technology to assess inhibitory activity of compounds against PDE12 in a homogeneous, robust HTS feasible assay using tritiated adenosine-P-adenylate ([3H]ApA) as substrate. We found that the used [3H]ApA educt, was not able to bind to SPA beads, whereas the product [3H]AMP, as known before, was able to bind to SPA beads. This enables the measurement of PDE12 activity on [3H]ApA as a substrate using a wallac microbeta counter. This method describes a robust and high throughput capable format in terms of specificity, commonly used compound solvents, ease of detection and assay matrices. The method could facilitate the search for PDE12 inhibitors as antiviral compounds.

Experimental Study of a Pulse Detonation Engine Driven Ejector

NASA Technical Reports Server (NTRS)

Santoro, Robert J.; Pal, Sibtosh; Shehadeh, R.; Saretto, S.; Lee, S.-Y.

2005-01-01

Results of an experimental effort on pulse detonation driven ejectors are presented and discussed. The experiments were conducted using a pulse detonation engine (PDE)/ejector setup that was specifically designed for the study. The results of various experiments designed to probe different aspects of the PDE/ejector setup are reported. The baseline PDE was operated using ethylene (C2H4) as the fuel and an oxygen/nitrogen (O2 + N2) mixture at an equivalence ratio of one. The PDE only experiments included propellant mixture characterization using a laser absorption technique, high fidelity thrust measurements using an integrated spring-damper system, and shadowgraph imaging of the detonation/shock wave structure emanating from the tube. The baseline PDE thrust measurement results are in excellent agreement with experimental and modeling results reported in the literature. These PDE setup results were then used as a basis for quantifying thrust augmentation for various PDE/ejector setups with constant diameter ejector tubes and various detonation tube/ejector tube overlap distances. The results show that for the geometries studied here, a maximum thrust augmentation of 24% is achieved. Further increases are possible by tailoring the ejector geometry based on CFD predictions conducted elsewhere. The thrust augmentation results are complemented by shadowgraph imaging of the flowfield in the ejector tube inlet area and high frequency pressure transducer measurements along the length of the ejector tube.

Identification of New Signaling Components in the Sensory Epithelium of Human Saccule

PubMed Central

Degerman, Eva; Rauch, Uwe; Göransson, Olga; Lindberg, Sven; Hultgårdh, Anna; Magnusson, Måns

2011-01-01

Objective: To locate components and target proteins of relevance for the cAMP and cGMP signaling networks including cAMP and cGMP phosphodiesterases (PDEs), salt-inducible kinases (SIKs), subunits of Na+, K+-ATPases, and aquaporins (AQPs) in the human saccule. Methods: The human saccule was dissected out during the removal of vestibular schwannoma via the translabyrinthine approach and immediately fixed. Immunohistochemistry was performed using PDE, SIK, Na+, K+-ATPase, and AQP antibodies. Results: PDEs selective for cAMP (PDE4A, PDE4D, and PDE8A) and cGMP (PDE9A) as well a dual specificity PDE (PDE10A) were detected in the sensory epithelium of the saccule. Furthermore, AQP2, 4, and 9, SIK1 and the α-1 subunit of the Na+, K+-ATPase were detected. Conclusion: cAMP and cGMP are important regulators of ion and water homeostasis in the inner ear. The identification of PDEs and SIK1 in the vestibular system offers new treatment targets for endolymphatic hydrops. Exactly how the PDEs are connected to SIK1 and the SIK1 substrate Na+, K+-ATPase and to AQPs 2, 4, 9 remains to be elucidated. The dissection of the signaling networks utilizing these components and evaluating their roles will add new basic knowledge regarding inner ear physiology. PMID:21886636

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

Genetic deletion and pharmacological inhibition of phosphodiesterase 10A protects mice from diet-induced obesity and insulin resistance.

PubMed

Nawrocki, Andrea R; Rodriguez, Carlos G; Toolan, Dawn M; Price, Olga; Henry, Melanie; Forrest, Gail; Szeto, Daphne; Keohane, Carol Ann; Pan, Yie; Smith, Karen M; Raheem, Izzat T; Cox, Christopher D; Hwa, Joyce; Renger, John J; Smith, Sean M

2014-01-01

Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report a novel role of PDE10A in the regulation of caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) and associated metabolic disturbances. Inhibition of weight gain is due to hypophagia after mice are fed a highly palatable diet rich in fats and sugar but not a standard diet. PDE10A deficiency produces a decrease in caloric intake without affecting meal frequency, daytime versus nighttime feeding behavior, or locomotor activity. We tested THPP-6, a small molecule PDE10A inhibitor, in DIO mice. THPP-6 treatment resulted in decreased food intake, body weight loss, and reduced adiposity at doses that produced antipsychotic efficacy in behavioral models. We show that PDE10A inhibition increased whole-body energy expenditure in DIO mice fed a Western-style diet, achieving weight loss and reducing adiposity beyond the extent seen with food restriction alone. Therefore, chronic THPP-6 treatment conferred improved insulin sensitivity and reversed hyperinsulinemia. These data demonstrate that PDE10A inhibition represents a novel antipsychotic target that may have additional metabolic benefits over current medications for schizophrenia by suppressing food intake, alleviating weight gain, and reducing the risk for the development of diabetes.

The rational search for PDE10A inhibitors from Sophora flavescens roots using pharmacophore‑ and docking‑based virtual screening.

PubMed

Fan, Han-Tian; Guo, Jun-Fang; Zhang, Yu-Xin; Gu, Yu-Xi; Ning, Zhong-Qi; Qiao, Yan-Jiang; Wang, Xing

2018-01-01

Phosphodiesterase 10A (PDE10A) has been confirmed to be an important target for the treatment of central nervous system (CNS) disorders. The purpose of the present study was to identify PDE10A inhibitors from herbs used in traditional Chinese medicine. Pharmacophore and molecular docking techniques were used to virtually screen the chemical molecule database of Sophora flavescens, a well‑known Chinese herb that has been used for improving mental health and regulating the CNS. The pharmacophore model generated recognized the common functional groups of known PDE10A inhibitors. In addition, molecular docking was used to calculate the binding affinity of ligand‑PDE10A interactions and to investigate the possible binding pattern. Virtual screening based on the pharmacophore model and molecular docking was performed to identify potential PDE10A inhibitors from S. flavescens. The results demonstrated that nine hits from S. flavescens were potential PDE10A inhibitors, and their biological activity was further validated using literature mining. A total of two compounds were reported to inhibit cyclic adenosine monophosphate phosphodiesterase, and one protected against glutamate‑induced oxidative stress in the CNS. The remaining six compounds require further bioactivity validation. The results of the present study demonstrated that this method was a time‑ and cost‑saving strategy for the identification of bioactive compounds from traditional Chinese medicine.

A phosphodiesterase 4B-dependent interplay between tumor cells and the microenvironment regulates angiogenesis in B-cell lymphoma

PubMed Central

Suhasini, Avvaru N.; Lin, An-Ping; Bhatnagar, Harshita; Kim, Sang-Woo; Moritz, August W.; Aguiar, Ricardo C. T.

2015-01-01

Angiogenesis associates with poor outcome in diffuse large B-cell lymphoma (DLBCL), but the contribution of the lymphoma cells to this process remains unclear. Addressing this knowledge gap may uncover unsuspecting proangiogenic signaling nodes and highlight alternative antiangiogenic therapies. Here we identify the second messenger cyclic-AMP (cAMP) and the enzyme that terminates its activity, phosphodiesterase 4B (PDE4B), as regulators of B-cell lymphoma angiogenesis. We first show that cAMP, in a PDE4B-dependent manner, suppresses PI3K/AKT signals to down-modulate VEGF secretion and vessel formation in vitro. Next, we create a novel mouse model that combines the lymphomagenic Myc transgene with germline deletion of Pde4b. We show that lymphomas developing in a Pde4b-null background display significantly lower microvessel density in association with lower VEGF levels and PI3K/AKT activity. We recapitulate these observations by treating lymphoma-bearing mice with the FDA-approved PDE4 inhibitor Roflumilast. Lastly, we show that primary human DLBCLs with high PDE4B expression display significantly higher microvessel density. Here, we defined an unsuspected signaling circuitry in which the cAMP generated in lymphoma cells downmodulates PI3K/AKT and VEGF secretion to negatively influence vessel development in the microenvironment. These data identify PDE4 as an actionable antiangiogenic target in DLBCL. PMID:26503641

New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment.

PubMed

Brullo, Chiara; Ricciarelli, Roberta; Prickaerts, Jos; Arancio, Ottavio; Massa, Matteo; Rotolo, Chiara; Romussi, Alessia; Rebosio, Claudia; Marengo, Barbara; Pronzato, Maria Adelaide; van Hagen, Britt T J; van Goethem, Nick P; D'Ursi, Pasqualina; Orro, Alessandro; Milanesi, Luciano; Guariento, Sara; Cichero, Elena; Fossa, Paola; Fedele, Ernesto; Bruno, Olga

2016-11-29

Phosphodiesterase type 4D (PDE4D) has been indicated as a promising target for treating neurodegenerative pathologies such as Alzheimer's Disease (AD). By preventing cAMP hydrolysis, PDE4 inhibitors (PDE4Is) increase the cAMP response element-binding protein (CREB) phosphorylation, synaptic plasticity and long-term memory formation. Pharmacological and behavioral studies on our hit GEBR-7b demonstrated that selective PDE4DIs could improve memory without causing emesis and sedation. The hit development led to new molecule series, herein reported, characterized by a catechol structure bonded to five member heterocycles. Molecular modeling studies highlighted the pivotal role of a polar alkyl chain in conferring selective enzyme interaction. Compound 8a showed PDE4D3 selective inhibition and was able to increase intracellular cAMP levels in neuronal cells, as well as in the hippocampus of freely moving rats. Furthermore, 8a was able to readily cross the blood-brain barrier and enhanced memory performance in mice without causing any emetic-like behavior. These data support the view that PDE4D is an adequate molecular target to restore memory deficits in different neuropathologies, including AD, and also indicate compound 8a as a promising candidate for further preclinical development. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

An approximation theory for the identification of linear thermoelastic systems

NASA Technical Reports Server (NTRS)

Rosen, I. G.; Su, Chien-Hua Frank

1990-01-01

An abstract approximation framework and convergence theory for the identification of thermoelastic systems is developed. Starting from an abstract operator formulation consisting of a coupled second order hyperbolic equation of elasticity and first order parabolic equation for heat conduction, well-posedness is established using linear semigroup theory in Hilbert space, and a class of parameter estimation problems is then defined involving mild solutions. The approximation framework is based upon generic Galerkin approximation of the mild solutions, and convergence of solutions of the resulting sequence of approximating finite dimensional parameter identification problems to a solution of the original infinite dimensional inverse problem is established using approximation results for operator semigroups. An example involving the basic equations of one dimensional linear thermoelasticity and a linear spline based scheme are discussed. Numerical results indicate how the approach might be used in a study of damping mechanisms in flexible structures.

The Programming Language Python In Earth System Simulations

NASA Astrophysics Data System (ADS)

Gross, L.; Imranullah, A.; Mora, P.; Saez, E.; Smillie, J.; Wang, C.

2004-12-01

Mathematical models in earth sciences base on the solution of systems of coupled, non-linear, time-dependent partial differential equations (PDEs). The spatial and time-scale vary from a planetary scale and million years for convection problems to 100km and 10 years for fault systems simulations. Various techniques are in use to deal with the time dependency (e.g. Crank-Nicholson), with the non-linearity (e.g. Newton-Raphson) and weakly coupled equations (e.g. non-linear Gauss-Seidel). Besides these high-level solution algorithms discretization methods (e.g. finite element method (FEM), boundary element method (BEM)) are used to deal with spatial derivatives. Typically, large-scale, three dimensional meshes are required to resolve geometrical complexity (e.g. in the case of fault systems) or features in the solution (e.g. in mantel convection simulations). The modelling environment escript allows the rapid implementation of new physics as required for the development of simulation codes in earth sciences. Its main object is to provide a programming language, where the user can define new models and rapidly develop high-level solution algorithms. The current implementation is linked with the finite element package finley as a PDE solver. However, the design is open and other discretization technologies such as finite differences and boundary element methods could be included. escript is implemented as an extension of the interactive programming environment python (see www.python.org). Key concepts introduced are Data objects, which are holding values on nodes or elements of the finite element mesh, and linearPDE objects, which are defining linear partial differential equations to be solved by the underlying discretization technology. In this paper we will show the basic concepts of escript and will show how escript is used to implement a simulation code for interacting fault systems. We will show some results of large-scale, parallel simulations on an SGI Altix system. Acknowledgements: Project work is supported by Australian Commonwealth Government through the Australian Computational Earth Systems Simulator Major National Research Facility, Queensland State Government Smart State Research Facility Fund, The University of Queensland and SGI.

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

ERIC Educational Resources Information Center

Mamon, Rogemar S.

2004-01-01

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

Arbitrary-Lagrangian-Eulerian Discontinuous Galerkin schemes with a posteriori subcell finite volume limiting on moving unstructured meshes

NASA Astrophysics Data System (ADS)

Boscheri, Walter; Dumbser, Michael

2017-10-01

We present a new family of high order accurate fully discrete one-step Discontinuous Galerkin (DG) finite element schemes on moving unstructured meshes for the solution of nonlinear hyperbolic PDE in multiple space dimensions, which may also include parabolic terms in order to model dissipative transport processes, like molecular viscosity or heat conduction. High order piecewise polynomials of degree N are adopted to represent the discrete solution at each time level and within each spatial control volume of the computational grid, while high order of accuracy in time is achieved by the ADER approach, making use of an element-local space-time Galerkin finite element predictor. A novel nodal solver algorithm based on the HLL flux is derived to compute the velocity for each nodal degree of freedom that describes the current mesh geometry. In our algorithm the spatial mesh configuration can be defined in two different ways: either by an isoparametric approach that generates curved control volumes, or by a piecewise linear decomposition of each spatial control volume into simplex sub-elements. Each technique generates a corresponding number of geometrical degrees of freedom needed to describe the current mesh configuration and which must be considered by the nodal solver for determining the grid velocity. The connection of the old mesh configuration at time tn with the new one at time t n + 1 provides the space-time control volumes on which the governing equations have to be integrated in order to obtain the time evolution of the discrete solution. Our numerical method belongs to the category of so-called direct Arbitrary-Lagrangian-Eulerian (ALE) schemes, where a space-time conservation formulation of the governing PDE system is considered and which already takes into account the new grid geometry (including a possible rezoning step) directly during the computation of the numerical fluxes. We emphasize that our method is a moving mesh method, as opposed to total Lagrangian formulations that are based on a fixed computational grid and which instead evolve the mapping of the reference configuration to the current one. Our new Lagrangian-type DG scheme adopts the novel a posteriori sub-cell finite volume limiter method recently developed in [62] for fixed unstructured grids. In this approach, the validity of the candidate solution produced in each cell by an unlimited ADER-DG scheme is verified against a set of physical and numerical detection criteria, such as the positivity of pressure and density, the absence of floating point errors (NaN) and the satisfaction of a relaxed discrete maximum principle (DMP) in the sense of polynomials. Those cells which do not satisfy all of the above criteria are flagged as troubled cells and are recomputed at the aid of a more robust second order TVD finite volume scheme. To preserve the subcell resolution capability of the original DG scheme, the FV limiter is run on a sub-grid that is 2 N + 1 times finer compared to the mesh of the original unlimited DG scheme. The new subcell averages are then gathered back into a high order DG polynomial by a usual conservative finite volume reconstruction operator. The numerical convergence rates of the new ALE ADER-DG schemes are studied up to fourth order in space and time and several test problems are simulated in order to check the accuracy and the robustness of the proposed numerical method in the context of the Euler and Navier-Stokes equations for compressible gas dynamics, considering both inviscid and viscous fluids. Finally, an application inspired by Inertial Confinement Fusion (ICF) type flows is considered by solving the Euler equations and the PDE of viscous and resistive magnetohydrodynamics (VRMHD).

PDE 5 inhibitor improves insulin sensitivity by enhancing mitochondrial function in adipocytes.

PubMed

Yu, Hea Min; Chung, Hyo Kyun; Kim, Koon Soon; Lee, Jae Min; Hong, Jun Hwa; Park, Kang Seo

2017-11-04

Adipocytes are involved in many metabolic disorders. It was recently reported that phosphodiesterase type 5 (PDE5) is expressed in human adipose tissue. In addition, PDE5 inhibitors have been shown to improve insulin sensitivity in humans. However, the mechanism underlying the role of PDE5 inhibitors as an insulin sensitizer remains largely unknown. The present study was undertaken to investigate the role of the PDE5 inhibitor udenafil in insulin signaling in adipocytes and whether this is mediated through the regulation of mitochondrial function. To study the mechanism underlying the insulin sensitizing action of PDE5 inhibitors, we evaluated quantitative changes in protein or mRNA levels of mitochondrial oxidative phosphorylation (OxPhos) complex, oxygen consumption rate (OCR), and fatty acid oxidation with varying udenafil concentrations in 3T3-L1 cells. Our cell study suggested that udenafil enhanced the insulin signaling pathway in 3T3-L1 cells. Following udenafil treatment, basal mitochondrial OCR, maximal OxPhos capacity, and OxPhos gene expression significantly increased. Finally, we examined whether udenafil can affect the fatty acid oxidation process. Treatment of 3T3-L1 cells with udenafil (10 and 20 μM) significantly increased fatty acid oxidation rate in a dose-dependent manner. In addition, the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) significantly increased. We demonstrated that the PDE5 inhibitor udenafil enhances insulin sensitivity by improving mitochondrial function in 3T3-L1 cells. This might be the mechanism underlying the PDE5 inhibitor-enhanced insulin signaling in adipocytes. This also suggests that udenafil may provide benefit in the treatment of type 2 diabetes and other related cardiovascular diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

The multinational Men's Attitudes to Life Events and Sexuality (MALES) Study Phase II: understanding PDE5 inhibitor treatment seeking patterns, among men with erectile dysfunction.

PubMed

Fisher, William A; Rosen, Raymond C; Eardley, Ian; Niederberger, Craig; Nadel, Andrea; Kaufman, Joel; Sand, Michael

2004-09-01

The aim of Phase II of the Men's Attitudes to Life Events and Sexuality (MALES) Study is to explore PDE5 inhibitor treatment seeking among men with erectile dysfunction (ED). Phase II of the MALES study involved 2,912 men, aged 20-75 years, from 8 countries (U.S., U.K., Germany, France, Italy, Spain, Mexico, and Brazil), who reported ED. Participants were recruited from the MALES Phase I sample [1] and via booster methods (e.g., physician referral, street interception), and completed self-report questionnaires concerning the characteristics of their ED, their efforts to seek PDE5 inhibitor treatment for their sexual dysfunction, and attitudinal and referent influences that potentially affect treatment-seeking. Statistical analyses focus on identification of correlates of PDE5 inhibitor treatment seeking. PDE5 inhibitor utilization is strongly associated with ED sufferers' assessment of the severity of their sexual dysfunction, with their belief that medication for ED is dangerous, and with their perceptions of whether physicians, other professionals, and spouses or family members are supportive of their seeking treatment. ED sufferers who evaluate their sexual dysfunction as severe, who believe that medication for ED is not dangerous, and who perceive support for treatment seeking from referent others, are more likely to utilize PDE5 inhibitor treatment. Findings indicate that perceived ED severity, beliefs about ED medication, and referent influences are strongly correlated with utilization of PDE5 inhibitor therapy. These findings aid our understanding of factors that may incline men with ED to seek-or to avoid-PDE5 inhibitor therapy for their sexual dysfunction, and provide a basis for clinical and educational interventions to assist men with ED to seek appropriate treatment.

Phosphodiesterase (PDE5) inhibition assay for rapid detection of erectile dysfunction drugs and analogs in sexual enhancement products.

PubMed

Santillo, Michael F; Mapa, Mapa S T

2018-02-28

Products marketed as dietary supplements for sexual enhancement are frequently adulterated with phosphodiesterase-5 (PDE5) inhibitors, which are erectile dysfunction drugs or their analogs that can cause adverse health effects. Due to widespread adulteration, a rapid screening assay was developed to detect PDE5 inhibitors in adulterated products. The assay employs fluorescence detection and is based on measuring inhibition of PDE5 activity, the pharmacological mechanism shared among the adulterants. Initially, the assay reaction scheme was established and characterized, followed by analysis of 9 representative PDE5 inhibitors (IC 50 , 0.4-4.0 ng mL -1 ), demonstrating sensitive detection in matrix-free solutions. Next, dietary supplements serving as matrix blanks (n = 25) were analyzed to determine matrix interference and establish a threshold value; there were no false positives. Finally, matrix blanks were spiked with 9 individual PDE5 inhibitors, along with several mixtures. All 9 adulterants were successfully detected (≤ 5 % false negative rate; n = 20) at a concentration of 1.00 mg g -1 , which is over 5 times lower than concentrations commonly encountered in adulterated products. A major distinction of the PDE5 inhibition assay is the ability to detect adulterants without prior knowledge of their chemical structures, demonstrating a broad-based detection capability that can address a continuously evolving threat of new adulterants. The PDE5 inhibition assay can analyze over 40 samples simultaneously within 15 minutes and involves a single incubation step and simple data analysis, all of which are advantageous for combating the widespread adulteration of sex-enhancement products. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

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

PubMed Central

Polito, Marina; Guiot, Elvire; Gangarossa, Giuseppe; Longueville, Sophie; Doulazmi, Mohamed; Valjent, Emmanuel; Hervé, Denis; Girault, Jean-Antoine

2015-01-01

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

Aging has the opposite effect on cAMP and cGMP circadian variations in rat Leydig cells.

PubMed

Baburski, Aleksandar Z; Sokanovic, Srdjan J; Andric, Silvana A; Kostic, Tatjana S

2017-05-01

The Leydig cell physiology displays a circadian rhythm driven by a complex interaction of the reproductive axis hormones and circadian system. The final output of this regulatory process is circadian pattern of steroidogenic genes expression and testosterone production. Aging gradually decreases robustness of rhythmic testosterone secretion without change in pattern of LH secretion. Here, we analyzed effect of aging on circadian variation of cAMP and cGMP signaling in Leydig cells. Results showed opposite effect of aging on cAMP and cGMP daily variation. Reduced amplitude of cAMP circadian oscillation was probably associated with changed expression of genes involved in cAMP production (increased circadian pattern of Adcy7, Adcy9, Adcy10 and decreased Adcy3); cAMP degradation (increased Pde4a, decreased Pde8b, canceled rhythm of Pde4d, completely reversed circadian pattern of Pde7b and Pde8a); and circadian expression of protein kinase A subunits (Prkac/PRKAC and Prkar2a). Aging stimulates expression of genes responsible for cGMP production (Nos2, Gucy1a3 and Gucy1b3/GUCYB3) and degradation (Pde5a, Pde6a and Pde6h) but the overall net effect is elevation of cGMP circadian oscillations in Leydig cells. In addition, the expression of cGMP-dependent kinase, Prkg1/PRKG1 is up-regulated. It seems that aging potentiate cGMP- and reduce cAMP-signaling in Leydig cells. Since both signaling pathways affect testosterone production and clockwork in the cells, further insights into these signaling pathways will help to unravel disorders linked to the circadian timing system, aging and reproduction.

Targeting the Dopamine 1 Receptor or its Downstream Signalling by Inhibiting Phosphodiesterase-1 Improves Cognitive Performance.

PubMed

Pekcec, Anton; Schülert, Niklas; Stierstorfer, Birgit; Deiana, Serena; Dorner-Ciossek, Cornelia; Rosenbrock, Holger

2018-05-03

Insufficient prefrontal dopamine 1 (D1) receptor signalling has been linked to cognitive dysfunction in several psychiatric conditions. Because the phosphodiesterase-1 (PDE1) isoform B (PDE1B) is postulated to regulate D1 receptor-dependent signal transduction, this study intended to elucidate the role of PDE1 for cognitive processes reliant on D1 receptor function. Cognitive performance of the D1 receptor agonist, SKF38393, was studied in the T-maze continuous alternation task and the 5-Choice Serial Reaction Time Task. D1 receptor/ PDE1B double-immunohistochemistry was performed using human and rat prefrontal brain sections. Pharmacological activity of the PDE1 inhibitor, ITI-214, was assessed by measuring the increase of cAMP/ cGMP in prefrontal brain tissue and its effect on working memory performance. Mechanistic studies on modulation of prefrontal neuronal transmission by SKF38393 and ITI-214 were performed using extracellular recordings in brain slices. SKF38393 improved working memory and attentional performance in rodents. D1 receptor/ PDE1B co-expression was verified in both, human and rat prefrontal brain sections. The pharmacological activity of ITI-214 on its target was demonstrated by increased prefrontal cAMP/ cGMP upon administration. In addition, ITI-214 improved working memory performance. SKF38393 and ITI-214 facilitated neuronal transmission in prefrontal brain slices. We hypothesise that PDE1 inhibition may improve working memory performance by increasing prefrontal synaptic transmission and/or postsynaptic D1 receptor signalling, by modulating prefrontal downstream second messenger levels. These data may therefore support the use of PDE1 inhibitors as a potential approach for the treatment of cognitive dysfunction. This article is protected by copyright. All rights reserved.

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

PubMed Central

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

2009-01-01

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

Pinus densiflora extract protects human skin fibroblasts against UVB-induced photoaging by inhibiting the expression of MMPs and increasing type I procollagen expression.

PubMed

Jung, Hoe-Yune; Shin, Jae-Cheon; Park, Seon-Min; Kim, Na-Ri; Kwak, Wonjung; Choi, Bo-Hwa

2014-01-01

Exposure to ultraviolet (UV) light can cause skin photoaging, which is associated with upregulation of matrix metalloproteinases (MMPs) and downregulation of collagen synthesis. It has been reported that MMPs, especially MMP-1, MMP-3 and MMP-9, decrease the elasticity of the dermis by degrading collagen. In this study, we assessed the effects of Pinus densiflora extract (PDE) on photoaging and investigated its mechanism of action in human skin fibroblast (Hs68) cells after UVB exposure using real-time polymerase chain reaction, Western blot analysis, and enzymatic activity assays. PDE exhibited an antioxidant activity and inhibited elastase activities in vitro. We also found that PDE inhibited UVB-induced cytotoxicity, MMP-1 production and expression of MMP-1, -3 and -9 mRNA in Hs68 cells. In addition, PDE decreased UVB-induced MMP-2 activity and MMP-2 mRNA expression. Moreover, PDE prevented the decrease of type I procollagen mediated by exposure to UVB irradiation, an effect that is linked to the upregulation and downregulation of Smad3 and Smad7, respectively. Another effect of UV irradiation is to stimulate activator protein 1 (AP-1) activity via overexpression of c-Jun/c-Fos, which, in turn, upregulates MMP-1, -3, and -9. In this study, we found that PDE suppressed UV-induced c-Jun and c-Fos mRNA expression. Taken together, these results demonstrate that PDE regulates UVB-induced expression of MMPs and type I procollagen synthesis by inhibiting AP-1 activity and restoring impaired Smad signaling, suggesting that PDE may be useful as an effective anti-photoaging agent.

β2-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D

PubMed Central

Trian, Thomas; Burgess, Janette K.; Niimi, Kyoko; Moir, Lyn M.; Ge, Qi; Berger, Patrick; Liggett, Stephen B.; Black, Judith L.; Oliver, Brian G.

2011-01-01

Background and Objective Asthma is associated with airway narrowing in response to bronchoconstricting stimuli and increased airway smooth muscle (ASM) mass. In addition, some studies have suggested impaired β-agonist induced ASM relaxation in asthmatics, but the mechanism is not known. Objective To characterize the potential defect in β-agonist induced cAMP in ASM derived from asthmatic in comparison to non-asthmatic subjects and to investigate its mechanism. Methods We examined β2-adrenergic (β2AR) receptor expression and basal β-agonist and forskolin (direct activator of adenylyl cyclase) stimulated cAMP production in asthmatic cultured ASM (n = 15) and non-asthmatic ASM (n = 22). Based on these results, PDE activity, PDE4D expression and cell proliferation were determined. Results In the presence of IBMX, a pan PDE inhibitor, asthmatic ASM had ∼50% lower cAMP production in response to isoproterenol, albuterol, formoterol, and forskolin compared to non-asthmatic ASM. However when PDE4 was specifically inhibited, cAMP production by the agonists and forskolin was normalized in asthmatic ASM. We then measured the amount and activity of PDE4, and found ∼2-fold greater expression and activity in asthmatic ASM compared to non-asthmatic ASM. Furthermore, inhibition of PDE4 reduced asthmatic ASM proliferation but not that of non-asthmatic ASM. Conclusion Decreased β-agonist induced cAMP in ASM from asthmatics results from enhanced degradation due to increased PDE4D expression. Clinical manifestations of this dysregulation would be suboptimal β-agonist-mediated bronchodilation and possibly reduced control over increasing ASM mass. These phenotypes appear to be “hard-wired” into ASM from asthmatics, as they do not require an inflammatory environment in culture to be observed. PMID:21611147

The art and science of hyperbolic tessellations.

PubMed

Van Dusen, B; Taylor, R P

2013-04-01

The visual impact of hyperbolic tessellations has captured artists' imaginations ever since M.C. Escher generated his Circle Limit series in the 1950s. The scaling properties generated by hyperbolic geometry are different to the fractal scaling properties found in nature's scenery. Consequently, prevalent interpretations of Escher's art emphasize the lack of connection with nature's patterns. However, a recent collaboration between the two authors proposed that Escher's motivation for using hyperbolic geometry was as a method to deliberately distort nature's rules. Inspired by this hypothesis, this year's cover artist, Ben Van Dusen, embeds natural fractals such as trees, clouds and lightning into a hyperbolic scaling grid. The resulting interplay of visual structure at multiple size scales suggests that hybridizations of fractal and hyperbolic geometries provide a rich compositional tool for artists.

Reduced nucleotide excision repair and GSTM1-null genotypes influence anti-B[a]PDE-DNA adduct levels in mononuclear white blood cells of highly PAH-exposed coke oven workers.

PubMed

Pavanello, Sofia; Pulliero, Alessandra; Siwinska, Ewa; Mielzynska, Danuta; Clonfero, Erminio

2005-01-01

It is important to identify the potential genetic-susceptible factors that are able to modulate individual responses to exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs). In the present study we evaluated the influence of four polymorphisms of nucleotide excision repair (NER) genes [xeroderma pigmentosum-C (XPC)-PAT +/-, xeroderma pigmentosum-A (XPA) 5' non-coding region-A23G, XPD-exon 23 A35931C Lys751Gln, xeroderma pigmentosum-D (XPD)-exon 10 G23591A Asp312Asn] and that of glutathione S-transferase mu1 (GSTM1-active or -null) on benzo[a]pyrene diol epoxide (B[a]PDE)-DNA adduct levels from the lympho-monocyte fraction (LMF) of highly PAH benzo[a]pyrene (B[a]P)-exposed Polish coke oven workers (n = 67, 67% current smokers) with individual urinary post-shift excretion of 1-pyrenol exceeding the proposed biological exposure index (BEI) (2.28 micromol/mol creatinine). The bulky (+/-)-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-B[a]PDE)-DNA adduct levels were detected by high-performance liquid chromatography (HPLC)/fluorescence analysis and genotypes by polymerase chain reaction. We found that workers with the low DNA repair capacity of XPC-PAT+/+ and XPA-A23A genotypes had significantly increased anti-B[a]PDE-DNA adduct levels (Mann-Whitney U-test, z = 2.24, P = 0.02 and z = 2.65, P = 0.01). Moreover, DNA adducts were also raised in workers without GSTM1 activity (GSTM1-null genotype) (Mann-Whitney U-test, z = 2.25, P = 0.0246). Workers with unfavourable XPC-PAT+/+ and XPA-A23A NER genotypes, alone (approximately 65% of workers) or combined with GSTM1-null genotype (approximately 75% of workers) were in the tertile with the highest adduct level, i.e. >4.11 adducts/10(8) nt (chi2 = 5.85, P = 0.0156 and chi2 = 5.40, P = 0.01). The increase in anti-B[a]PDE-DNA adduct levels (ln values) was significantly related in a multiple linear regression analysis to PAH exposure (i.e. urinary post-shift excretion of 1-pyrenol) (t = 2.61, P = 0.0115), lack of GSTM1 activity (t = 2.41, P = 0.0192) and to low DNA repair capacity of the XPC-PAT+/+ genotype (t = 2.34, P = 0.0226). The influence of the XPA-A23A genotype was not evident in this statistical analysis, and no associations with XPD polymorphisms, dietary habits or tobacco smoking were found. The modulation of anti-B[a]PDE-DNA adducts in the LMF by GSTM1-null and some low-activity NER genotypes may be considered as a potential genetic susceptibility factor capable of modulating individual responses to PAH (B[a]P) genotoxic exposure and the consequent risk of cancer in coke oven workers.

A Posteriori Error Estimation for Discontinuous Galerkin Approximations of Hyperbolic Systems

NASA Technical Reports Server (NTRS)

Larson, Mats G.; Barth, Timothy J.

1999-01-01

This article considers a posteriori error estimation of specified functionals for first-order systems of conservation laws discretized using the discontinuous Galerkin (DG) finite element method. Using duality techniques, we derive exact error representation formulas for both linear and nonlinear functionals given an associated bilinear or nonlinear variational form. Weighted residual approximations of the exact error representation formula are then proposed and numerically evaluated for Ringleb flow, an exact solution of the 2-D Euler equations.

Attractors in complex networks

NASA Astrophysics Data System (ADS)

Rodrigues, Alexandre A. P.

2017-10-01

In the framework of the generalized Lotka-Volterra model, solutions representing multispecies sequential competition can be predictable with high probability. In this paper, we show that it occurs because the corresponding "heteroclinic channel" forms part of an attractor. We prove that, generically, in an attracting heteroclinic network involving a finite number of hyperbolic and non-resonant saddle-equilibria whose linearization has only real eigenvalues, the connections corresponding to the most positive expanding eigenvalues form part of an attractor (observable in numerical simulations).

Attractors in complex networks.

PubMed

Rodrigues, Alexandre A P

2017-10-01

In the framework of the generalized Lotka-Volterra model, solutions representing multispecies sequential competition can be predictable with high probability. In this paper, we show that it occurs because the corresponding "heteroclinic channel" forms part of an attractor. We prove that, generically, in an attracting heteroclinic network involving a finite number of hyperbolic and non-resonant saddle-equilibria whose linearization has only real eigenvalues, the connections corresponding to the most positive expanding eigenvalues form part of an attractor (observable in numerical simulations).

Recent Developments and Open Problems in the Mathematical Theory of Viscoelasticity.

DTIC Science & Technology

1984-11-01

integral terms . At each step of the iteration, we have to solve a linear parabolic equation with time-dependent coefficients. In Sobolevskii’s... parabolic Volterra integro- differential equation, SIAN J. Math. Anal. 13 (1982), ’ ~81-105. :-- 12. Heard, M. L., A class of hyperbolic Volterra ...then puts an n + 1 on the highest derivatives (the "principal terms " in the equation) and an n on lower order derivatives. Two things must then be

Fourth order difference methods for hyperbolic IBVP's

NASA Technical Reports Server (NTRS)

Gustafsson, Bertil; Olsson, Pelle

1994-01-01

Fourth order difference approximations of initial-boundary value problems for hyperbolic partial differential equations are considered. We use the method of lines approach with both explicit and compact implicit difference operators in space. The explicit operator satisfies an energy estimate leading to strict stability. For the implicit operator we develop boundary conditions and give a complete proof of strong stability using the Laplace transform technique. We also present numerical experiments for the linear advection equation and Burgers' equation with discontinuities in the solution or in its derivative. The first equation is used for modeling contact discontinuities in fluid dynamics, the second one for modeling shocks and rarefaction waves. The time discretization is done with a third order Runge-Kutta TVD method. For solutions with discontinuities in the solution itself we add a filter based on second order viscosity. In case of the non-linear Burger's equation we use a flux splitting technique that results in an energy estimate for certain different approximations, in which case also an entropy condition is fulfilled. In particular we shall demonstrate that the unsplit conservative form produces a non-physical shock instead of the physically correct rarefaction wave. In the numerical experiments we compare our fourth order methods with a standard second order one and with a third order TVD-method. The results show that the fourth order methods are the only ones that give good results for all the considered test problems.

Focal surfaces of hyperbolic cylinders

NASA Astrophysics Data System (ADS)

Georgiev, Georgi Hristov; Pavlov, Milen Dimov

2017-12-01

Cylindrical surfaces have many applications in geometric modeling, architecture and other branches of engineering. In this paper, we describe two cylindrical surfaces associated to a given hyperbolic cylinder. The first one is a focal surface which is determined by reciprocal principle curvature of the hyperbolic cylinder. The second one is a generalized focal surface obtained by reciprocal mean curvature of the same hyperbolic cylinder. In particular, we show that each of these surfaces admits three different parametric representations. As consequence, it is proved that the focal and generalized focal surfaces of the hyperbolic cylinder are rational surfaces. An illustrative example is included.

Hyperbolic Rendezvous at Mars: Risk Assessments and Mitigation Strategies

NASA Technical Reports Server (NTRS)

Jedrey, Ricky; Landau, Damon; Whitley, Ryan

2015-01-01

Given the current interest in the use of flyby trajectories for human Mars exploration, a key requirement is the capability to execute hyperbolic rendezvous. Hyperbolic rendezvous is used to transport crew from a Mars centered orbit, to a transiting Earth bound habitat that does a flyby. Representative cases are taken from future potential missions of this type, and a thorough sensitivity analysis of the hyperbolic rendezvous phase is performed. This includes early engine cutoff, missed burn times, and burn misalignment. A finite burn engine model is applied that assumes the hyperbolic rendezvous phase is done with at least two burns.

Genetic Variants Associated with Serum Thyroid Stimulating Hormone (TSH) Levels in European Americans and African Americans from the eMERGE Network

PubMed Central

Malinowski, Jennifer R.; Denny, Joshua C.; Bielinski, Suzette J.; Basford, Melissa A.; Bradford, Yuki; Peissig, Peggy L.; Carrell, David; Crosslin, David R.; Pathak, Jyotishman; Rasmussen, Luke; Pacheco, Jennifer; Kho, Abel; Newton, Katherine M.; Li, Rongling; Kullo, Iftikhar J.; Chute, Christopher G.; Chisholm, Rex L.; Jarvik, Gail P.; Larson, Eric B.; McCarty, Catherine A.; Masys, Daniel R.; Roden, Dan M.; de Andrade, Mariza; Ritchie, Marylyn D.; Crawford, Dana C.

2014-01-01

Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10−17, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10−6, β = −0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = −0.09), VEGFA (rs11755845 p = 0.01, β = −0.13), and NFIA (rs334699 p = 1.50×10−3, β = −0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations. PMID:25436638

Genetic variants associated with serum thyroid stimulating hormone (TSH) levels in European Americans and African Americans from the eMERGE Network.

PubMed

Malinowski, Jennifer R; Denny, Joshua C; Bielinski, Suzette J; Basford, Melissa A; Bradford, Yuki; Peissig, Peggy L; Carrell, David; Crosslin, David R; Pathak, Jyotishman; Rasmussen, Luke; Pacheco, Jennifer; Kho, Abel; Newton, Katherine M; Li, Rongling; Kullo, Iftikhar J; Chute, Christopher G; Chisholm, Rex L; Jarvik, Gail P; Larson, Eric B; McCarty, Catherine A; Masys, Daniel R; Roden, Dan M; de Andrade, Mariza; Ritchie, Marylyn D; Crawford, Dana C

2014-01-01

Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10-17, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10-6, β = -0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = -0.09), VEGFA (rs11755845 p = 0.01, β = -0.13), and NFIA (rs334699 p = 1.50×10-3, β = -0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations.

Performance Characterization of Swept Ramp Obstacle Fields in Pulse Detonation Applications

DTIC Science & Technology

2010-03-01

field of practical obstacle geometries. 15. NUMBER OF PAGES 97 14. SUBJECT TERMS Pulse Detonation , PDE , Transient Plasma Ignition, TPI, Swept... Detonation Transition NI - National Instruments NPS - Naval Postgraduate School PDC - Pulse Detonation Combustor PDE - Pulse Detonation Engine...with incredible grace. xvi THIS PAGE INTENTIONALLY LEFT BLANK 1 I. INTRODUCTION Pulse detonation engines ( PDE ) continue to be explored due to

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…

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…

Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility.

PubMed

Rzasa, Robert M; Frohn, Michael J; Andrews, Kristin L; Chmait, Samer; Chen, Ning; Clarine, Jeffrey G; Davis, Carl; Eastwood, Heather A; Horne, Daniel B; Hu, Essa; Jones, Adrie D; Kaller, Matthew R; Kunz, Roxanne K; Miller, Silke; Monenschein, Holger; Nguyen, Thomas; Pickrell, Alexander J; Porter, Amy; Reichelt, Andreas; Zhao, Xiaoning; Treanor, James J S; Allen, Jennifer R

2014-12-01

We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.

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

PubMed

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

2015-12-01

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

An odor interaction model of binary odorant mixtures by a partial differential equation method.

PubMed

Yan, Luchun; Liu, Jiemin; Wang, Guihua; Wu, Chuandong

2014-07-09

A novel odor interaction model was proposed for binary mixtures of benzene and substituted benzenes by a partial differential equation (PDE) method. Based on the measurement method (tangent-intercept method) of partial molar volume, original parameters of corresponding formulas were reasonably displaced by perceptual measures. By these substitutions, it was possible to relate a mixture's odor intensity to the individual odorant's relative odor activity value (OAV). Several binary mixtures of benzene and substituted benzenes were respectively tested to establish the PDE models. The obtained results showed that the PDE model provided an easily interpretable method relating individual components to their joint odor intensity. Besides, both predictive performance and feasibility of the PDE model were proved well through a series of odor intensity matching tests. If combining the PDE model with portable gas detectors or on-line monitoring systems, olfactory evaluation of odor intensity will be achieved by instruments instead of odor assessors. Many disadvantages (e.g., expense on a fixed number of odor assessors) also will be successfully avoided. Thus, the PDE model is predicted to be helpful to the monitoring and management of odor pollutions.

Phosphodiesterase 4 inhibitors.

PubMed

Zebda, Rema; Paller, Amy S

2018-03-01

Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration-approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety. Copyright © 2017. Published by Elsevier Inc.

Beneficial long term effect of a phosphodiesterase-5-inhibitor in cirrhotic portal hypertension: A case report with 8 years follow-up.

PubMed

Deibert, Peter; Lazaro, Adhara; Stankovic, Zoran; Schaffner, Denise; Rössle, Martin; Kreisel, Wolfgang

2018-01-21

Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5 (PDE-5-inhibitors) reduce portal pressure in the acute setting by > 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored. In the acute setting, the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%. The portal blood flow increased by 28% based on Doppler sonography and by 16% using MRI technique. As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow. There were no recurrence of bleeding and no formation of new varices. Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis.

Ca(2+)/calmodulin-activated phosphodiesterase 1A is highly expressed in rabbit cardiac sinoatrial nodal cells and regulates pacemaker function.

PubMed

Lukyanenko, Yevgeniya O; Younes, Antoine; Lyashkov, Alexey E; Tarasov, Kirill V; Riordon, Daniel R; Lee, Joonho; Sirenko, Syevda G; Kobrinsky, Evgeny; Ziman, Bruce; Tarasova, Yelena S; Juhaszova, Magdalena; Sollott, Steven J; Graham, David R; Lakatta, Edward G

2016-09-01

Constitutive Ca(2+)/calmodulin (CaM)-activation of adenylyl cyclases (ACs) types 1 and 8 in sinoatrial nodal cells (SANC) generates cAMP within lipid-raft-rich microdomains to initiate cAMP-protein kinase A (PKA) signaling, that regulates basal state rhythmic action potential firing of these cells. Mounting evidence in other cell types points to a balance between Ca(2+)-activated counteracting enzymes, ACs and phosphodiesterases (PDEs) within these cells. We hypothesized that the expression and activity of Ca(2+)/CaM-activated PDE Type 1A is higher in SANC than in other cardiac cell types. We found that PDE1A protein expression was 5-fold higher in sinoatrial nodal tissue than in left ventricle, and its mRNA expression was 12-fold greater in the corresponding isolated cells. PDE1 activity (nimodipine-sensitive) accounted for 39% of the total PDE activity in SANC lysates, compared to only 4% in left ventricular cardiomyocytes (LVC). Additionally, total PDE activity in SANC lysates was lowest (10%) in lipid-raft-rich and highest (76%) in lipid-raft-poor fractions (equilibrium sedimentation on a sucrose density gradient). In intact cells PDE1A immunolabeling was not localized to the cell surface membrane (structured illumination microscopy imaging), but located approximately within about 150nm inside of immunolabeling of hyperpolarization-activated cyclic nucleotide-gated potassium channels (HCN4), which reside within lipid-raft-rich microenvironments. In permeabilized SANC, in which surface membrane ion channels are not functional, nimodipine increased spontaneous SR Ca(2+) cycling. PDE1A mRNA silencing in HL-1 cells increased the spontaneous beating rate, reduced the cAMP, and increased cGMP levels in response to IBMX, a broad spectrum PDE inhibitor (detected via fluorescence resonance energy transfer microscopy). We conclude that signaling via cAMP generated by Ca(2+)/CaM-activated AC in SANC lipid raft domains is limited by cAMP degradation by Ca(2+)/CaM-activated PDE1A in non-lipid raft domains. This suggests that local gradients of [Ca(2+)]-CaM or different AC and PDE1A affinity regulate both cAMP production and its degradation, and this balance determines the intensity of Ca(2+)-AC-cAMP-PKA signaling that drives SANC pacemaker function. Copyright © 2016. Published by Elsevier Ltd.

Very Efficient High-order Hyperbolic Schemes for Time-dependent Advection Diffusion Problems: Third-, Fourth-, and Sixth-order

DTIC Science & Technology

2014-07-07

boundary condition (x ¼ 7p =2; j ¼ 2p; U ¼ 1; m ¼ 1) on N ¼ 10 uniform nodes (Dt ¼ 0:01.) Table 10 Unsteady linear advection–diffusion problem with periodic...500 3rd 55 2 4th 55 2 6th 55 2 1000 3rd 116 2 4th 116 2 6th 116 2 Table 11 Unsteady linear advection–diffusion problem with oscillatory BC (x ¼ 7p =2; a...dependent problem with oscillatory BC (x ¼ 7p =2; a ¼ 1.) using the third-order RD-GT scheme with the BDF3 time discretization. Number of nodes Dt (BDF3

Local bounds preserving stabilization for continuous Galerkin discretization of hyperbolic systems

NASA Astrophysics Data System (ADS)

Mabuza, Sibusiso; Shadid, John N.; Kuzmin, Dmitri

2018-05-01

The objective of this paper is to present a local bounds preserving stabilized finite element scheme for hyperbolic systems on unstructured meshes based on continuous Galerkin (CG) discretization in space. A CG semi-discrete scheme with low order artificial dissipation that satisfies the local extremum diminishing (LED) condition for systems is used to discretize a system of conservation equations in space. The low order artificial diffusion is based on approximate Riemann solvers for hyperbolic conservation laws. In this case we consider both Rusanov and Roe artificial diffusion operators. In the Rusanov case, two designs are considered, a nodal based diffusion operator and a local projection stabilization operator. The result is a discretization that is LED and has first order convergence behavior. To achieve high resolution, limited antidiffusion is added back to the semi-discrete form where the limiter is constructed from a linearity preserving local projection stabilization operator. The procedure follows the algebraic flux correction procedure usually used in flux corrected transport algorithms. To further deal with phase errors (or terracing) common in FCT type methods, high order background dissipation is added to the antidiffusive correction. The resulting stabilized semi-discrete scheme can be discretized in time using a wide variety of time integrators. Numerical examples involving nonlinear scalar Burgers equation, and several shock hydrodynamics simulations for the Euler system are considered to demonstrate the performance of the method. For time discretization, Crank-Nicolson scheme and backward Euler scheme are utilized.

Probability Weighting Functions Derived from Hyperbolic Time Discounting: Psychophysical Models and Their Individual Level Testing.

PubMed

Takemura, Kazuhisa; Murakami, Hajime

2016-01-01

A probability weighting function (w(p)) is considered to be a nonlinear function of probability (p) in behavioral decision theory. This study proposes a psychophysical model of probability weighting functions derived from a hyperbolic time discounting model and a geometric distribution. The aim of the study is to show probability weighting functions from the point of view of waiting time for a decision maker. Since the expected value of a geometrically distributed random variable X is 1/p, we formulized the probability weighting function of the expected value model for hyperbolic time discounting as w(p) = (1 - k log p)(-1). Moreover, the probability weighting function is derived from Loewenstein and Prelec's (1992) generalized hyperbolic time discounting model. The latter model is proved to be equivalent to the hyperbolic-logarithmic weighting function considered by Prelec (1998) and Luce (2001). In this study, we derive a model from the generalized hyperbolic time discounting model assuming Fechner's (1860) psychophysical law of time and a geometric distribution of trials. In addition, we develop median models of hyperbolic time discounting and generalized hyperbolic time discounting. To illustrate the fitness of each model, a psychological experiment was conducted to assess the probability weighting and value functions at the level of the individual participant. The participants were 50 university students. The results of individual analysis indicated that the expected value model of generalized hyperbolic discounting fitted better than previous probability weighting decision-making models. The theoretical implications of this finding are discussed.

Molecular modeling study of binding to the catalytic site of PDE4 enzymes by a novel class of inhibitors

NASA Astrophysics Data System (ADS)

Lawrenz, Morgan E.; Salter, E. A.; Wierzbicki, Andrzej; Thompson, W. J.

Cyclic nucleotide phosphodiesterases (PDEs) comprise a superfamily of enzymes that hydrolyze the second messengers adenosine and guanosine 3',5'-cyclic monophosphate (cAMP and cGMP) to their noncyclic nucleotides (5'-AMP and 5'-GMP). Selective inhibitors of all 11 gene families of PDEs are being sought based on the different biochemical properties of the different isoforms, including their substrate specificities. The PDE4 gene family consists of cAMP-specific isoforms; selective PDE4 inhibitors such as rolipram have been developed, and related agents are used clinically as anti-inflammatory agents for asthma and COPD. The known crystal structures of PDE4 bound with rolipram and IBMX have allowed us to define plausible binding orientations for a novel class of benzylpyridazinone-based PDE4 inhibitors represented by EMD 94360 and EMD 95832 that are structurally distinct from rolipram. Molecular mechanics modeling with autodocking is used to explore energetically favorable binding orientations within the PDE4 catalytic site. We present two putative orientations for EMD 94360/95832 inhibitor binding. Our estimated interaction energies for rolipram, IBMX, EMD 94360, and EMD 95832 are consistent with the experimental data for their IC50 values. Key binding residues and interactions in these orientations are identified and compared with known binding motifs proposed for rolipram. The experimentally observed improved strength of inhibition exhibited by this novel class of PDE4 inhibitors is explained by the molecular modeling reported here.

Thrust Augmentation Measurements Using a Pulse Detonation Engine Ejector

NASA Technical Reports Server (NTRS)

Santoro, Robert J.; Pal, Sibtosh

2005-01-01

Results of an experimental effort on pulse detonation driven ejectors are presented and discussed. The experiments were conducted using a pulse detonation engine (PDE)/ejector setup that was specifically designed for the study and operated at frequencies up to 50 Hz. The results of various experiments designed to probe different aspects of the PDE/ejector setup are reported. The baseline PDE was operated using ethylene (C2H4) as the fuel and an oxygen/nitrogen O2 + N2) mixture at an equivalence ratio of one. The PDE only experiments included propellant mixture characterization using a laser absorption technique, high fidelity thrust measurements using an integrated spring-damper system, and shadowgraph imaging of the detonation/shock wave structure emanating from the tube. The baseline PDE thrust measurement results at each desired frequency agree with experimental and modeling results reported in the literature. These PDE setup results were then used as a basis for quantifying thrust augmentation for various PDE/ejector setups with constant diameter ejector tubes and various ejector lengths, the radius of curvature for the ejector inlets and various detonation tube/ejector tube overlap distances. For the studied experimental matrix, the results showed a maximum thrust augmentation of 106% at an operational frequency of 30 Hz. The thrust augmentation results are complemented by shadowgraph imaging of the flowfield in the ejector tube inlet area and high frequency pressure transducer measurements along the length of the ejector tube.

Phosphodiesterase 4B plays a role in benzophenone-3-induced phototoxicity in normal human keratinocytes.

PubMed

Kim, Hyoung-June; Lee, Eunyoung; Lee, Moonyoung; Ahn, Sungjin; Kim, Jungmin; Liu, Jingjing; Jin, Sun Hee; Ha, Jaehyoun; Bae, Il Hong; Lee, Tae Ryong; Noh, Minsoo

2018-01-01

Benzophenone-3 (BP-3), which is extensively used in organic sunscreen, has phototoxic potential in human skin. Phosphodiesterase 4B (PDE4B) has a well-established role in inflammatory responses in immune cells. Currently, it is unknown if PDE4B is associated with BP-3-induced phototoxicity in normal human keratinocytes (NHKs). We found that BP-3 significantly increased PDE4B expression in ultraviolet B (UVB)-irradiated NHKs. Notably, BP-8, a sunscreen agent that shares the 2-hydroxy-4-methoxyphenyl methanone moiety with BP-3, also upregulated PDE4B expression in NHKs. Upon UVB irradiation, BP-3 upregulated the expression of pro-inflammatory factors, such as prostaglandin endoperoxide synthase 2, tumor necrosis factor α, interleukin 8, and S100A7, and downregulated the level of cornified envelope associated proteins, which are important in the development of the epidermal permeability barrier. The additive effects of UVB-activated BP-3 on the expression of both pro-inflammatory mediators and cornified envelope associated proteins were antagonized by treatment with the PDE4 inhibitor rolipram. The BP-3 and UVB co-stimulation-induced PDE4B upregulation and its association with the upregulation of pro-inflammatory mediators and the downregulation of epidermal differentiation markers were confirmed in a reconstituted three dimensional human epidermis model. Therefore, PDE4B has a role in the mechanism of BP-3-induced phototoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

Early Alcohol Exposure Disrupts Visual Cortex Plasticity in Mice

PubMed Central

Lantz, Crystal L.; Wang, Weili; Medina, Alexandre E.

2012-01-01

There is growing evidence that deficits in neuronal plasticity underlie the cognitive problems seen in fetal alcohol spectrum disorders (FASD). However, the mechanisms behind these deficits are not clear. Here we test the effects of early alcohol exposure on ocular dominance plasticity (ODP) in mice and the reversibility of these effects by phosphodiesterase (PDE) inhibitors. Mouse pups were exposed to 5 g/kg of 25% ethanol i.p. on postnatal days (P) 5, 7 and 9. This type of alcohol exposure mimics binge drinking during the third trimester equivalent of human gestation. To assess ocular dominance plasticity animals were monocularly deprived at P21 for 10 days, and tested using optical imaging of intrinsic signals. During the period of monocular deprivation animals were treated with vinpocetine (20mg/kg; PDE1 inhibitor), rolipram (1.25 mg/Kg; PDE4 inhibitor), vardenafil (3 mg/Kg; PDE5 inhibitor) or vehicle solution. Monocular deprivation resulted in the expected shift in ocular dominance of the binocular zone in saline controls but not in the ethanol group. While vinpocetine successfully restored ODP in the ethanol group, rolipram and vardenafil did not. However, when rolipram and vardenafil were given simultaneously ODP was restored. PDE4 and PDE5 are specific to cAMP and cGMP respectively, while PDE1 acts on both of these nucleotides. Our findings suggest that the combined activation of the cAMP and cGMP cascades may be a good approach to improve neuronal plasticity in FASD models. PMID:22617459

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

PubMed Central

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

2004-01-01

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

Gummel Symmetry Test on charge based drain current expression using modified first-order hyperbolic velocity-field expression

NASA Astrophysics Data System (ADS)

Singh, Kirmender; Bhattacharyya, A. B.

2017-03-01

Gummel Symmetry Test (GST) has been a benchmark industry standard for MOSFET models and is considered as one of important tests by the modeling community. BSIM4 MOSFET model fails to pass GST as the drain current equation is not symmetrical because drain and source potentials are not referenced to bulk. BSIM6 MOSFET model overcomes this limitation by taking all terminal biases with reference to bulk and using proper velocity saturation (v -E) model. The drain current equation in BSIM6 is charge based and continuous in all regions of operation. It, however, adopts a complicated method to compute source and drain charges. In this work we propose to use conventional charge based method formulated by Enz for obtaining simpler analytical drain current expression that passes GST. For this purpose we adopt two steps: (i) In the first step we use a modified first-order hyperbolic v -E model with adjustable coefficients which is integrable, simple and accurate, and (ii) In the second we use a multiplying factor in the modified first-order hyperbolic v -E expression to obtain correct monotonic asymptotic behavior around the origin of lateral electric field. This factor is of empirical form, which is a function of drain voltage (vd) and source voltage (vs) . After considering both the above steps we obtain drain current expression whose accuracy is similar to that obtained from second-order hyperbolic v -E model. In modified first-order hyperbolic v -E expression if vd and vs is replaced by smoothing functions for the effective drain voltage (vdeff) and effective source voltage (vseff), it will as well take care of discontinuity between linear to saturation regions of operation. The condition of symmetry is shown to be satisfied by drain current and its higher order derivatives, as both of them are odd functions and their even order derivatives smoothly pass through the origin. In strong inversion region and technology node of 22 nm the GST is shown to pass till sixth-order derivative and for weak inversion it is shown till fifth-order derivative. In the expression of drain current major short channel phenomena like vertical field mobility reduction, velocity saturation and velocity overshoot have been taken into consideration.

On the local well-posedness of Lovelock and Horndeski theories

NASA Astrophysics Data System (ADS)

Papallo, Giuseppe; Reall, Harvey S.

2017-08-01

We investigate local well-posedness of the initial value problem for Lovelock and Horndeski theories of gravity. A necessary condition for local well-posedness is strong hyperbolicity of the equations of motion. Even weak hyperbolicity can fail for strong fields so we restrict to weak fields. The Einstein equation is known to be strongly hyperbolic in harmonic gauge so we study Lovelock theories in harmonic gauge. We show that the equation of motion is always weakly hyperbolic for weak fields but, in a generic weak-field background, it is not strongly hyperbolic. For Horndeski theories, we prove that, for weak fields, the equation of motion is always weakly hyperbolic in any generalized harmonic gauge. For some Horndeski theories there exists a generalized harmonic gauge for which the equation of motion is strongly hyperbolic in a weak-field background. This includes "k-essence" like theories. However, for more general Horndeski theories, there is no generalized harmonic gauge for which the equation of motion is strongly hyperbolic in a generic weak-field background. Our results show that the standard method used to establish local well-posedness of the Einstein equation does not extend to Lovelock or general Horndeski theories. This raises the possibility that these theories may not admit a well-posed initial value problem even for weak fields.

Hyperbolic metamaterials: Novel physics and applications

NASA Astrophysics Data System (ADS)

Smolyaninov, Igor I.; Smolyaninova, Vera N.

2017-10-01

Hyperbolic metamaterials were originally introduced to overcome the diffraction limit of optical imaging. Soon thereafter it was realized that hyperbolic metamaterials demonstrate a number of novel phenomena resulting from the broadband singular behavior of their density of photonic states. These novel phenomena and applications include super resolution imaging, new stealth technologies, enhanced quantum-electrodynamic effects, thermal hyperconductivity, superconductivity, and interesting gravitation theory analogues. Here we briefly review typical material systems, which exhibit hyperbolic behavior and outline important novel applications of hyperbolic metamaterials. In particular, we will describe recent imaging experiments with plasmonic metamaterials and novel VCSEL geometries, in which the Bragg mirrors may be engineered in such a way that they exhibit hyperbolic metamaterial properties in the long wavelength infrared range, so that they may be used to efficiently remove excess heat from the laser cavity. We will also discuss potential applications of three-dimensional self-assembled photonic hypercrystals, which are based on cobalt ferrofluids in external magnetic field. This system bypasses 3D nanofabrication issues, which typically limit metamaterial applications. Photonic hypercrystals combine the most interesting features of hyperbolic metamaterials and photonic crystals.

Comparative Analysis of a High Bypass Turbofan Using a Pulsed Detonation Combustor

DTIC Science & Technology

2007-03-01

Thrust Specific Fuel Consumption . . . . . . . . . . . . . 67 xiii List of Abbreviations Abbreviation Page PDE Pulsed Detonation Engine...past ten years to develop pulsed det- onation engines ( PDE ) as a means of aircraft propulsion. Detonation combustion holds the promise of a more...aviation engine, and detonation creates more of it than previous aircraft engines. It is hoped that a marriage of the PDE with traditional

Transient Heat Transfer Properties in a Pulse Detonation Combustor

DTIC Science & Technology

2011-03-01

strategies for future systems. 15. NUMBER OF PAGES 89 14. SUBJECT TERMS Pulse Detonation Engines, PDE , Heat Transfer 16. PRICE CODE 17. SECURITY...GUI Graphical User Interface NPS Naval Postgraduate School PDC Pulse Detonation Combustion PDE Pulse Detonation Engine RPL Rocket...a tactical missile with a Pulse Detonation Engine ( PDE ) and provide greater range for the same amount of fuel as compared to other current

Role of selective cyclic GMP phosphodiesterase inhibition in the myorelaxant actions of M&B 22,948, MY-5445, vinpocetine and 1-methyl-3-isobutyl-8-(methylamino)xanthine.

PubMed Central

Souness, J. E.; Brazdil, R.; Diocee, B. K.; Jordan, R.

1989-01-01

1. The mechanism by which M&B 22,948, MY-5445, vinpocetine and 1-methyl-3-isobutyl-8-(methylamino)xanthine (MIMAX), which have been described as selective cyclic GMP phosphodiesterase (PDE) inhibitors, relax rat aorta was investigated. 2. Three cyclic nucleotide PDEs were identified in the soluble fraction of rat aorta; a Ca2+-insensitive form exhibiting substrate selectivity for cyclic GMP (cGMP PDE), a Ca2+/calmodulin-stimulated form which also preferentially hydrolyzed cyclic GMP (Ca2+ PDE), and a form demonstrating substrate selectivity for cyclic AMP (cAMP PDE). 3. M&B 22,948 and MIMAX inhibited cGMP PDE (Ki = 0.16 microM and 0.43 microM, respectively) and Ca2+ PDE (Ki = 9.9 microM and 0.55 microM, respectively), but exhibited weak activity against cAMP PDE (Ki = 249 microM and 42 microM, respectively). MY-5445 selectivity inhibited cGMP PDE (Ki = 1.3 microM) and vinpocetine selectively inhibited Ca2+ PDE (Ki = 14 microM). 4. M&B 22,948 and MIMAX induced dose-dependent increases in the accumulation of cyclic GMP, but not cyclic AMP, in rat aorta pieces. These effects were greatly reduced by endothelial denudation and by methylene blue (5 microM) which blocks the actions of endothelium-derived relaxant factor. MY-5445 and vinpocetine had no effect on rat aorta cyclic GMP or cyclic AMP accumulation. 5. All four compounds caused dose-related relaxation of 5-hydroxytryptamine (10 microM) contracted, endothelium-intact rat aorta, the effects of M&B 22,948 and MIMAX being greatly reduced by methylene blue (5 microM). Methylene blue also caused 10 fold and 100 fold rightward shifts in the dose-response curves of MY-5445 and vinpocetine, respectively. 6. The results are consistent with the smooth muscle relaxant actions of M&B 22,948 and MIMAX, but not vinpocetine and MY-5445, being mediated through a mechanism involving inhibition of cyclic GMP hydrolysis. PMID:2480168

Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24-month follow-up.

PubMed

Hooijmans, M T; Doorenweerd, N; Baligand, C; Verschuuren, J J G M; Ronen, I; Niks, E H; Webb, A G; Kan, H E

2017-01-01

To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5-15.4 years) and 12 age-matched healthy controls (range: 5-14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets. PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR. The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients.

Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24–month follow-up

PubMed Central

Doorenweerd, N.; Baligand, C.; Verschuuren, J. J. G. M.; Ronen, I.; Niks, E. H.; Webb, A. G.; Kan, H. E.

2017-01-01

Objectives To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. Methods Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5–15.4 years) and 12 age-matched healthy controls (range: 5–14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets. Results PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR. Discussion and conclusion The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients. PMID:28763477

The Association Between Phosphodiesterase Type 5 Inhibitor Use and Risk of Non-Arteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Meta-Analysis.

PubMed

Liu, Bing; Zhu, Linxin; Zhong, Jingxiang; Zeng, Guohua; Deng, Tuo

2018-06-05

Phosphodiesterase type 5 inhibitors (PDE5-Is) are first-line drugs for erectile dysfunction. Non-arteritic anterior ischemic optic neuropathy (NAION) has been linked with PDE5-I use. However, no meta-analysis or conclusive review has explored the association between NAION and PDE5-I use. To investigate the association between PDE5-I use and risk of NAION. A comprehensive literature search was conducted using online databases in October 2017 to obtain studies researching the association between PDE5-I application and occurrence of NAION. Summarized unadjusted risk ratios (RRs) with 95% CIs were calculated for the strength of this association. This study was conducted in accordance to Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and registered in PROSPERO under number CRD42017080865. The strength of association between PDE5-I use and risk of NAION was assessed through pooled unadjusted RRs and 95% CIs. 5 original articles with 6 clinical observations were included in the meta-analysis. No significant higher risk of NAION was observed after the use of PDE5-Is within a 1-month period (RR = 1.16, 95% CI = 0.98-1.39, P = .09). Subgroup analyses indicated 2 PDE5-Is were significantly related to NAION (tadalafil: RR = 2.14, 95% CI = 1.20-3.84, P = .01; sildenafil: RR = 2.25, 95% CI = 1.29-3.94, P = .004). Although we found no association between NAION and PDE5-I use, our results should be interpreted cautiously because we included only observational studies and could not control for potential confounders. Because NAION is a rare ocular disease and difficult to diagnose, this association should be confirmed in prospective comparative studies with larger samples and more rigorous designs. Liu B, Zhu L, Zhong J, et al. The Association Between Phosphodiesterase Type 5 Inhibitor Use and Risk of Non-Arteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Meta-Analysis. Sex Med 2018;X:XXX-XXX. Copyright © 2018. Published by Elsevier Inc.

13-Moment System with Global Hyperbolicity for Quantum Gas

NASA Astrophysics Data System (ADS)

Di, Yana; Fan, Yuwei; Li, Ruo

2017-06-01

We point out that the quantum Grad's 13-moment system (Yano in Physica A 416:231-241, 2014) is lack of global hyperbolicity, and even worse, the thermodynamic equilibrium is not an interior point of the hyperbolicity region of the system. To remedy this problem, by fully considering Grad's expansion, we split the expansion into the equilibrium part and the non-equilibrium part, and propose a regularization for the system with the help of the new hyperbolic regularization theory developed in Cai et al. (SIAM J Appl Math 75(5):2001-2023, 2015) and Fan et al. (J Stat Phys 162(2):457-486, 2016). This provides us a new model which is hyperbolic for all admissible thermodynamic states, and meanwhile preserves the approximate accuracy of the original system. It should be noted that this procedure is not a trivial application of the hyperbolic regularization theory.

Magnetic hyperbolic optical metamaterials

DOE PAGES

Kruk, Sergey S.; Wong, Zi Jing; Pshenay-Severin, Ekaterina; ...

2016-04-13

Strongly anisotropic media where the principal components of electric permittivity or magnetic permeability tensors have opposite signs are termed as hyperbolic media. Such media support propagating electromagnetic waves with extremely large wave vectors exhibiting unique optical properties. However, in all artificial and natural optical materials studied to date, the hyperbolic dispersion originates solely from the electric response. This then restricts material functionality to one polarization of light and inhibits free-space impedance matching. Such restrictions can be overcome in media having components of opposite signs for both electric and magnetic tensors. Here we present the experimental demonstration of the magnetic hyperbolicmore » dispersion in three-dimensional metamaterials. We also measure metamaterial isofrequency contours and reveal the topological phase transition between the elliptic and hyperbolic dispersion. In the hyperbolic regime, we demonstrate the strong enhancement of thermal emission, which becomes directional, coherent and polarized. These findings show the possibilities for realizing efficient impedance-matched hyperbolic media for unpolarized light.« less

Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors.

PubMed

Chino, Ayaka; Seo, Ryushi; Amano, Yasushi; Namatame, Ichiji; Hamaguchi, Wataru; Honbou, Kazuya; Mihara, Takuma; Yamazaki, Mayako; Tomishima, Masaki; Masuda, Naoyuki

2018-01-01

In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

Second-order oriented partial-differential equations for denoising in electronic-speckle-pattern interferometry fringes.

PubMed

Tang, Chen; Han, Lin; Ren, Hongwei; Zhou, Dongjian; Chang, Yiming; Wang, Xiaohang; Cui, Xiaolong

2008-10-01

We derive the second-order oriented partial-differential equations (PDEs) for denoising in electronic-speckle-pattern interferometry fringe patterns from two points of view. The first is based on variational methods, and the second is based on controlling diffusion direction. Our oriented PDE models make the diffusion along only the fringe orientation. The main advantage of our filtering method, based on oriented PDE models, is that it is very easy to implement compared with the published filtering methods along the fringe orientation. We demonstrate the performance of our oriented PDE models via application to two computer-simulated and experimentally obtained speckle fringes and compare with related PDE models.

On the boundary treatment in spectral methods for hyperbolic systems

NASA Technical Reports Server (NTRS)

Canuto, C.; Quarteroni, A.

1986-01-01

Spectral methods were successfully applied to the simulation of slow transients in gas transportation networks. Implicit time advancing techniques are naturally suggested by the nature of the problem. The correct treatment of the boundary conditions are clarified in order to avoid any stability restriction originated by the boundaries. The Beam and Warming and the Lerat schemes are unconditionally linearly stable when used with a Chebyshev pseudospectral method. Engineering accuracy for a gas transportation problem is achieved at Courant numbers up to 100.

On the boundary treatment in spectral methods for hyperbolic systems

NASA Technical Reports Server (NTRS)

Canuto, Claudio; Quarteroni, Alfio

1987-01-01

Spectral methods were successfully applied to the simulation of slow transients in gas transportation networks. Implicit time advancing techniques are naturally suggested by the nature of the problem. The correct treatment of the boundary conditions is clarified in order to avoid any stability restriction originated by the boundaries. The Beam and Warming and the Lerat schemes are unconditionally linearly stable when used with a Chebyshev pseudospectral method. Engineering accuracy for a gas transportation problem is achieved at Courant numbers up to 100.

Stability Analysis of Finite Difference Approximations to Hyperbolic Systems,and Problems in Applied and Computational Matrix and Operator Theory

DTIC Science & Technology

1990-12-07

Fundaqao Calouste Gulbenkian, Instituto Gulbenkian de Ci~ncia, Centro de C6lculo Cientifico , Coimbra, 1973. 28, Dirac, P. A. M., Spinors in Hilbert Space...Office of Scientific Research grants 1965 Mathematical Association of America Editorial Prize for the article entitled: "Linear Transformations on...matrices" 1966 L.R. Ford Memorial Prize awarded by the Mathematical Association of America for the article , "Permanents" 1989 Outstanding Computer

The growth rate of vertex-transitive planar graphs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Babai, L.

1997-06-01

A graph is vertex-transitive if all of its vertices axe equivalent under automorphisms. Confirming a conjecture of Jon Kleinberg and Eva Tardos, we prove the following trichotomy theorem concerning locally finite vertex-transitive planar graphs: the rate of growth of a graph with these properties is either linear or quadratic or exponential. The same result holds more generally for locally finite, almost vertex-transitive planar graphs (the automorphism group has a finite number of orbits). The proof uses the elements of hyperbolic plane geometry.

Optimal strategies for the control of autonomous vehicles in data assimilation

NASA Astrophysics Data System (ADS)

McDougall, D.; Moore, R. O.

2017-08-01

We propose a method to compute optimal control paths for autonomous vehicles deployed for the purpose of inferring a velocity field. In addition to being advected by the flow, the vehicles are able to effect a fixed relative speed with arbitrary control over direction. It is this direction that is used as the basis for the locally optimal control algorithm presented here, with objective formed from the variance trace of the expected posterior distribution. We present results for linear flows near hyperbolic fixed points.

Rational rates of uniform decay for strong solutions to a fluid-structure PDE system

NASA Astrophysics Data System (ADS)

Avalos, George; Bucci, Francesca

2015-06-01

In this work we investigate the uniform stability properties of solutions to a well-established partial differential equation (PDE) model for a fluid-structure interaction. The PDE system under consideration comprises a Stokes flow which evolves within a three-dimensional cavity; moreover, a Kirchhoff plate equation is invoked to describe the displacements along a (fixed) portion - say, Ω - of the cavity wall. Contact between the respective fluid and structure dynamics occurs on the boundary interface Ω. The main result in the paper is as follows: the solutions to the composite PDE system, corresponding to smooth initial data, decay at the rate of O (1 / t). Our method of proof hinges upon the appropriate invocation of a relatively recent resolvent criterion for polynomial decays of C0-semigroups. While the characterization provided by said criterion originates in the context of operator theory and functional analysis, the work entailed here is wholly within the realm of PDE.

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.

Phosphodiesterase inhibitors in clinical urology.

PubMed

Ückert, Stefan; Kuczyk, Markus A; Oelke, Matthias

2013-05-01

To date, benign diseases of the male and female lower urinary and genital tract, such as erectile dysfunction, bladder overactivity, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and symptoms of female sexual dysfunction (including arousal and orgasmic disorders), can be therapeutically approached by influencing the function of the smooth musculature of the respective tissues. The use of isoenzyme-selective phosphodiesterase (PDE) inhibitors is considered a great opportunity to treat various diseases of the human urogenital tract. PDE inhibitors, in particular the PDE5 (cyclic GMP PDE) inhibitors avanafil, lodenafil, sildenafil, tadalafil, udenafil and vardenafil, are regarded as efficacious, having a fast onset of drug action and an improved effect-to-adverse event ratio, combining a high response rate with the advantage of an on-demand intake. The purpose of this review is to summarize recent as well as potential future indications, namely, erectile dysfunction, Peyronie's disease, overactive bladder, urinary stone disease, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and premature ejaculation, for the use of PDE inhibitors in clinical urology.

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

NASA Technical Reports Server (NTRS)

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

2005-01-01

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

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

PubMed

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

2016-02-25

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 Aβ(1-42) aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu(2+)-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.

Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors with Antioxidant Activities

NASA Astrophysics Data System (ADS)

Li, Jinxuan; Chen, Jing-Yi; Deng, Ya-Lin; Zhou, Qian; Wu, Yinuo; Wu, Deyan; Luo, Hai-Bin

2018-05-01

Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of thirteen designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds.

PubMed

Prosdocimi, Tommaso; Mollica, Luca; Donini, Stefano; Semrau, Marta S; Lucarelli, Anna Paola; Aiolfi, Egidio; Cavalli, Andrea; Storici, Paola; Alfei, Silvana; Brullo, Chiara; Bruno, Olga; Parisini, Emilio

2018-05-01

Selected members of the large rolipram-related GEBR family of type 4 phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term potentiation and to improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, few if any structure-activity relationship studies have been performed to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone. Furthermore, we assessed the stability of the observed ligand conformations in the context of the intact enzyme using molecular dynamics simulations. The longer and more flexible ligands appear to be capable of forming contacts with the regulatory portion of the enzyme, thus possibly allowing some degree of selectivity between the different PDE4 isoforms.

Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma.

PubMed

Ge, Xuecai; Milenkovic, Ljiljana; Suyama, Kaye; Hartl, Tom; Purzner, Teresa; Winans, Amy; Meyer, Tobias; Scott, Matthew P

2015-09-15

Alterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic targets. Here we show that phosphodiesterase 4D (PDE4D) acts downstream of Neuropilins to control Hh transduction and medulloblastoma growth. PDE4D interacts directly with Neuropilins, positive regulators of Hh pathway. The Neuropilin ligand Semaphorin3 enhances this interaction, promoting PDE4D translocation to the plasma membrane and cAMP degradation. The consequent inhibition of protein kinase A (PKA) enhances Hh transduction. In the developing cerebellum, genetic removal of Neuropilins reduces Hh signaling activity and suppresses proliferation of granule neuron precursors. In mouse medulloblastoma allografts, PDE4D inhibitors suppress Hh transduction and inhibit tumor growth. Our findings reveal a new regulatory mechanism of Hh transduction, and highlight PDE4D as a promising target to treat Hh-related tumors.

Prenatal drug exposure and peer victimization in early adolescence: testing childhood anxiety/depression and aggression as possible mediators.

PubMed

Buckingham-Howes, Stacy; Oberlander, Sarah E; Kim, Elizabeth M; Black, Maureen M

2012-06-01

Children who are prenatally exposed to drugs may be at risk for emotion dysregulation, including childhood anxiety/depression and aggression, potentially increasing their risk for peer victimization. The objectives of this study were to investigate how prenatal drug exposure relates to adolescent peer victimization and the mediating effects of childhood anxiety/depression and aggression. Seventy-six prenatally drug exposed (PDE) and 38 nonexposed (NE) adolescent-caregiver dyads followed since birth and middle childhood, respectively, participated in an evaluation during adolescence. In middle childhood, caregivers reported on their child's anxiety/depression and aggression, and children reported on violence exposure. In adolescence, caregivers and adolescents responded to a parallel single-item measure of peer victimization. Analyses were conducted using multivariate linear and logistic regression models, adjusting for covariates, including violence exposure. One-third (33.3%, n = 35) of the sample endorsed peer victimization: 40.8% PDE and 17.6% NE, p = .01. In middle childhood, PDE youth had more aggressive behaviors (11.92 vs 7.45, p < .01) and anxiety/depression symptoms (3.43 vs 1.76, p < .01) than NE youth. Anxious/depressed behavior during childhood mediated the association between prenatal drug exposure and adolescent peer victimization. Aggression was not a significant mediator. The consequences of prenatal drug exposure extend into adolescence. Prenatal drug exposure may interfere with emotion regulation, resulting in anxious/depressed behavior during childhood and significantly increasing the risk for peer victimization during adolescence, even in the presence of violence exposure. Strategies to reduce anxious/depressed behavior among children with a history of prenatal drug exposure may reduce adolescent peer victimization.

The Hype over Hyperbolic Browsers.

ERIC Educational Resources Information Center

Allen, Maryellen Mott

2002-01-01

Considers complaints about the usability in the human-computer interaction aspect of information retrieval and discusses information visualization, the Online Library of Information Visualization Environments, hyperbolic information structure, subject searching, real-world applications, relational databases and hyperbolic trees, and the future of…

Point coordinates extraction from localized hyperbolic reflections in GPR data

NASA Astrophysics Data System (ADS)

Ristić, Aleksandar; Bugarinović, Željko; Vrtunski, Milan; Govedarica, Miro

2017-09-01

In this paper, we propose an automated detection algorithm for the localization of apexes and points on the prongs of hyperbolic reflection incurred as a result of GPR scanning technology. The objects of interest encompass cylindrical underground utilities that have a distinctive form of hyperbolic reflection in radargram. Algorithm involves application of trained neural network to analyze radargram in the form of raster image, resulting with extracted segments of interest that contain hyperbolic reflections. This significantly reduces the amount of data for further analysis. Extracted segments represent the zone for localization of apices. This is followed by extraction of points on prongs of hyperbolic reflections which is carried out until stopping criterion is satisfied, regardless the borders of segment of interest. In final step a classification of false hyperbolic reflections caused by the constructive interference and their removal is done. The algorithm is implemented in MATLAB environment. There are several advantages of the proposed algorithm. It can successfully recognize true hyperbolic reflections in radargram images and extracts coordinates, with very low rate of false detections and without prior knowledge about the number of hyperbolic reflections or buried utilities. It can be applied to radargrams containing single and multiple hyperbolic reflections, intersected, distorted, as well as incomplete (asymmetric) hyperbolic reflections, all in the presence of higher level of noise. Special feature of algorithm is developed procedure for analysis and removal of false hyperbolic reflections generated by the constructive interference from reflectors associated with the utilities. Algorithm was tested on a number of synthetic and radargram acquired in the field survey. To illustrate the performances of the proposed algorithm, we present the characteristics of the algorithm through five representative radargrams obtained in real conditions. In these examples we present different acquisition scenarios by varying the number of buried objects, their disposition, size, and level of noise. Example with highest complexity was tested also as a synthetic radargram generated by gprMax. Processing time in examples with one or two hyperbolic reflections is from 0.1 to 0.3 s, while for the most complex examples it is from 2.2 to 4.9 s. In general, the obtained experimental results show that the proposed algorithm exhibits promising performances both in terms of utility detection and processing speed of the algorithm.

Branch Detonation of a Pulse Detonation Engine With Flash Vaporized JP-8

DTIC Science & Technology

2006-12-01

Mark F. Reeder (Member) date iii Abstract Pulse Detonation Engines ( PDE ) operating on liquid hydrocarbon fuels are... Detonation Transition FF – Fill Fraction FN – Flow Number NPT – National Pipe Thread OH – Hydroxyl PDE – Pulse Detonation Engine PF – Purge...Introduction Motivation Research on Pulsed Detonation Engines ( PDE ) has increased over the past ten years due to the potential for increased

Initiation Mechanisms of Low-loss Swept-ramp Obstacles for Deflagration to Detonation Transition in Pulse Detonation Combustors

DTIC Science & Technology

2009-12-01

minimal pressure losses. 15. NUMBER OF PAGES 113 14. SUBJECT TERMS Pulse Detonation Combustors, PDC, Pulse Detonation Engines, PDE , PDE ...Postgraduate School PDC Pulse Detonation Combustor PDE Pulse Detonation Engine RAM Random Access Memory RDT Research, Design and Test RPL...inhibiting the implementation of this advanced propulsion system. The primary advantage offered by pulse detonation engines ( PDEs ) is the high efficiency

Treatment of psoriasis with crisaborole.

PubMed

Lee, Erica B; Lebwohl, Mark G; Wu, Jashin J

2018-06-08

Crisaborole, a topical phosphodiesterase-4 (PDE4) inhibitor, is effective in patients with atopic dermatitis. As systemic PDE4 inhibition has also been used with success in psoriasis, clinical trials are underway to determine the utility of topical PDE4 inhibitors in these patients. However, there is no current literature documenting use of crisaborole for psoriasis. Here, we present two cases in which patients with psoriasis were treated successfully with crisaborole.

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. Copyright © 2013 Elsevier Inc. All rights reserved.

Thrust Augmentation Measurements Using a Pulse Detonation Engine Ejector

NASA Technical Reports Server (NTRS)

Santoro, Robert J.; Pal, Sibtosh

2003-01-01

The present NASA GRC-funded three-year research project is focused on studying PDE driven ejectors applicable to a hybrid Pulse Detonation/Turbofan Engine. The objective of the study is to characterize the PDE-ejector thrust augmentation. A PDE-ejector system has been designed to provide critical experimental data for assessing the performance enhancements possible with this technology. Completed tasks include demonstration of a thrust stand for measuring average thrust for detonation tube multi-cycle operation, and design of a 72-in.-long, 2.25-in.-diameter (ID) detonation tube and modular ejector assembly. This assembly will allow testing of both straight and contoured ejector geometries. Initial ejectors that have been fabricated are 72-in.-long-constant-diameter tubes (4-, 5-, and 6-in.-diameter) instrumented with high-frequency pressure transducers. The assembly has been designed such that the detonation tube exit can be positioned at various locations within the ejector tube. PDE-ejector system experiments with gaseous ethylene/ nitrogen/oxygen propellants will commence in the very near future. The program benefits from collaborations with Prof. Merkle of University of Tennessee whose PDE-ejector analysis helps guide the experiments. The present research effort will increase the TRL of PDE-ejectors from its current level of 2 to a level of 3.

Central serous chorioretinopathy and phosphodiesterase-5 inhibitors: a case-control postmarketing surveillance study.

PubMed

French, Dustin D; Margo, Curtis E

2010-02-01

The purpose of this study was to determine if there is an increased risk of central serous chorioretinopathy (CSC) associated with prescription exposure to phosphodiesterase-5 (PDE-5) inhibitors. A case-control study linking 2 National Veterans Health Administration databases (clinical and pharmacy) for fiscal years 2004 to 2005. The likelihood of past exposure to PDE-5 inhibitors among newly diagnosed patients with CSC, identified through International Classification of Diseases, 9th Edition, Clinical Modification codes, was compared with 2 age-matched control groups after excluding subjects with risk factors for CSC. Among 577 men, aged 59 years and younger with newly diagnosed CSC during the study year, 111 were prescribed a PDE-5 inhibitor (19.2%). The proportions of age-matched controls prescribed a PDE-5 inhibitor in the 2 groups were 18.5% and 21.5%. The odds ratio of exposure was 1.05 (95% confidence limit: 0.74-1.22) and 0.87 (95% confidence limit: 0.68-1.12). Patients with CSC had no increase in prescription exposure to PDE-5 inhibitors than did age-matched control subjects. Although the findings in this study do not support an association between CSC and PDE-5 inhibitors, postmarketing surveillance methods for drug-related side effects have acknowledged limitations.

New Therapeutic Applications of Phosphodiesterase 5 Inhibitors (PDE5-Is).

PubMed

Ribaudo, Giovanni; Pagano, Mario Angelo; Bova, Sergio; Zagotto, Giuseppe

2016-01-01

Phosphodiesterase 5 inhibitors (PDE5-Is) sildenafil, vardenafil, tadalafil and the recently approved avanafil represent the first-line choice for both on-demand and chronic treatment of erectile dysfunction (ED). In addition to this, sildenafil and tadalafil, have also been approved for the treatment of pulmonary arterial hypertension. Due to its expression and localization in many tissues, PDE5 and its regulation has been reported to be involved in several other diseases. We aim to provide an updated overview of the emerging therapeutic applications of PDE5-Is besides ED, taking into account the latest ongoing research reports. We searched online databases (Pubmed, Reaxys, Scopus) to lay the bases for an accurate, quality criteria-based literature update. We focused our attention on most recent research reports, in particular when supported by pre-clinical and clinical data. The regulation of PDE5 may influence pathological conditions such as, among the others, heart failure, cystic fibrosis, cancer, CNS-related diseases, diabetes and dysfunctions affecting male urinary/reproductive system. Sildenafil, vardenafil, tadalafil and the other chemical entities considered PDE5-Is showed overall positive results and significant improvements in the studied disease, thus some discordant results, in particular when comparing pre-clinical and clinical data, have to be pointed out, suggesting that further insights are needed especially to assess the exact molecular pathway underlying.

Sildenafil Can Affect Innate and Adaptive Immune System in Both Experimental Animals and Patients

PubMed Central

Boguska, Agnieszka

2017-01-01

Sildenafil, a type 5 phosphodiesterase inhibitor (PDE5-I), is primarily used for treating erectile dysfunction. Sildenafil inhibits the degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5. cGMP is a secondary messenger activating protein kinases and a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. PDE5 inhibitors (PDE-Is) found application in cardiology, nephrology, urology, dermatology, oncology, and gynecology. Positive result of sildenafil treatment is closely connected with its immunomodulatory effects. Sildenafil influences angiogenesis, platelet activation, proliferation of regulatory T cells, and production of proinflammatory cytokines and autoantibodies. Sildenafil action in humans and animals appears to be different. Surprisingly, it also acts differently in males and females organisms. Although the immunomodulatory effects of PDE5 inhibitors appear to be promising, none of them reached the point of being tested in clinical trials. Data on the influence of selective PDE5-Is on the human immune system are limited. The main objective of this review is to discuss the immunomodulatory effects of sildenafil in both patients and experimental animals. This is the first review of the current state of knowledge about the effects of sildenafil on the immune system. PMID:28316997

Wavelets and Affine Distributions: A Time-Frequency Perspective

DTIC Science & Technology

2005-01-07

Ville Distribution ( WVD ) • Prominent member of the AC: the WVD • Properties of the WVD : – Covariant to TF scaling and time shift (of course) – Covariant...QTFRs • Wigner - Ville distribution and affine smoothing • Doppler tolerance and hyperbolic impulses • Hyperbolic TF localization and Bertrand P0...satisfy hyperbolic TF localization property: • Not satisfied by WVD ! 25 – 49 –WAMA-04 Cargèse, France The Bertrand P0 distribution • The hyperbolic

Thermal emitter comprising near-zero permittivity materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luk, Ting S.; Campione, Salvatore; Sinclair, Michael B.

A novel thermal source comprising a semiconductor hyperbolic metamaterial provides control of the emission spectrum and the angular emission pattern. These properties arise because of epsilon-near-zero conditions in the semiconductor hyperbolic metamaterial. In particular, the thermal emission is dominated by the epsilon-near-zero effect in the doped quantum wells composing the semiconductor hyperbolic metamaterial. Furthermore, different properties are observed for s and p polarizations, following the characteristics of the strong anisotropy of hyperbolic metamaterials.

Effect of phoshpodiesterase 4 (PDE4) inhibibtors on eotaxin expression in humen bronchial epithelial cells.

PubMed

Paplinska, M; Chazan, R; Grubek-Jaworska, H

2011-06-01

The increasing number of eosinophils into bronchoaelvolar space is observed during noninfectious inflammatory lung diseases. Eotaxins (eotaxin-1/CCL11, eotaxin-2/CCL24, eotaxin-3/CCL26) are the strongest chemotactic agents for eosinophils. Inhibitors of phosphodiesterase 4 (PDE4), the enzyme decomposing cAMP, are anti-inflammatory agents which act through cAMP elevation and inhibit numerous steps of allergic inflammation. The effect of PDE4 inhibitors on eotaxin expression is not known in details. The aim of our study was to evaluate the influence of PDE4 inhibitors: rolipram and RO-20-1724 on expression of eotaxins in bronchial epithelial cell line BEAS-2B. Cells were preincubated with PDE4 inhibitors or dexamethasone for 1 hour and then stimulated with IL-4 or IL-13 alone or in combination with TNF-α. After 48 hours eotaxin protein level was measured by ELISA and mRNA level by real time PCR. PDE4 inhibitors decreased CCL11 and CCL26 expression only in cultures co-stimulated with TNF-α. In cultures stimulated with IL-4 and TNF-α rolipram and RO-20-1724 diminished CCL11 mRNA expression by 34 and 37%, respectively, and CCL26 by 43 and 47%. In cultures stimulated with IL-13 and TNF-α rolipram and RO-20-1724 decreased expression of both eotaxins by about 50%. These results were confirmed at the protein level. The effect of PDE4 inhibitors on eotaxin expression in BEAS-2B cells, in our experimental conditions, depends on TNF-α contribution.

Ab Initio QM/MM Study Shows a Highly Dissociated SN2 Hydrolysis Mechanism for the cGMP-Specific Phosphodiesterase-5.

PubMed

Li, Zhe; Wu, Yinuo; Feng, Ling-Jun; Wu, Ruibo; Luo, Hai-Bin

2014-12-09

Phosphodiesterases (PDEs) are the sole enzymes hydrolyzing the important second messengers cGMP and cAMP and have been identified as therapeutic targets for several diseases. The most successful examples are PDE5 inhibitors (i.e., sildenafil and tadalafil), which have been approved for the treatment of male erectile dysfunction and pulmonary hypertension. However, the side effects mostly due to nonselective inhibition toward other PDE isoforms, set back the clinical usage of PDE5 inhibitors. Until now, the exact catalytic mechanism of the substrate cGMP by PDE5 is still unclear. Herein, the first computational study on the catalytic hydrolysis mechanism of cGMP for PDE5 (catalytic domain) is performed by employing the state-of-the-art ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. Our simulations show a SN2 type reaction procedure via a highly dissociated transition state with a reaction barrier of 8.88 kcal/mol, which is quite different from the previously suggested hydrolysis mechanism of cAMP for PDE4. Furthermore, the subsequent ligand exchange and the release of the product GMP have also been investigated by binding energy analysis and MD simulations. It is deduced that ligand exchange would be the rate-determining step of the whole reaction, which is consistent with many previous experimental results. The obtained mechanistic insights should be valuable for not only the rational design of more specific inhibitors toward PDE5 but also understanding the general hydrolysis mechanism of cGMP-specific PDEs.

The limit of photoreceptor sensitivity: molecular mechanisms of dark noise in retinal cones.

PubMed

Holcman, David; Korenbrot, Juan I

2005-06-01

Detection threshold in cone photoreceptors requires the simultaneous absorption of several photons because single photon photocurrent is small in amplitude and does not exceed intrinsic fluctuations in the outer segment dark current (dark noise). To understand the mechanisms that limit light sensitivity, we characterized the molecular origin of dark noise in intact, isolated bass single cones. Dark noise is caused by continuous fluctuations in the cytoplasmic concentrations of both cGMP and Ca(2+) that arise from the activity in darkness of both guanylate cyclase (GC), the enzyme that synthesizes cGMP, and phosphodiesterase (PDE), the enzyme that hydrolyzes it. In cones loaded with high concentration Ca(2+) buffering agents, we demonstrate that variation in cGMP levels arise from fluctuations in the mean PDE enzymatic activity. The rates of PDE activation and inactivation determine the quantitative characteristics of the dark noise power density spectrum. We developed a mathematical model based on the dynamics of PDE activity that accurately predicts this power spectrum. Analysis of the experimental data with the theoretical model allows us to determine the rates of PDE activation and deactivation in the intact photoreceptor. In fish cones, the mean lifetime of active PDE at room temperature is approximately 55 ms. In nonmammalian rods, in contrast, active PDE lifetime is approximately 555 ms. This remarkable difference helps explain why cones are noisier than rods and why cone photocurrents are smaller in peak amplitude and faster in time course than those in rods. Both these features make cones less light sensitive than rods.

Preservation of nitric oxide-induced relaxation of porcine coronary artery: roles of the dimers of soluble guanylyl cyclase, phosphodiesterase type 5, and cGMP-dependent protein kinase.

PubMed

Liu, Juan; Chen, Zhengju; Ye, Liping; Liu, Huixia; Dou, Dou; Liu, Limei; Yu, Xiaoxing; Gao, Yuansheng

2014-10-01

Soluble guanylyl cyclase (sGC), phosphodiesterase type 5 (PDE5), and guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (PKG) are all dimeric. The present study was to determine the role of their dimeric status in nitric oxide-induced vasodilatation. In isolated porcine coronary arteries, after 20 h incubation with serum-free medium, serum-containing medium, or phosphate-buffered saline solution, the protein levels of the dimers of sGC, PDE5, and PKG were diminished while the monomer levels remained unchanged, associated with reduced cGMP elevation in response to DETA NONOate and decreased PDE5 activity; the activity of PKG was not significantly altered. DETA NONOate caused a greater relaxation in arteries incubated for 20 vs. 2 h. The relaxant response was largely abolished by 1H-[1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one, an sGC inhibitor. Zaprinast, a PDE5 inhibitor, had no effect on relaxation caused by DETA NONOate of arteries incubated for 20 h but augmented the response incubated for 2 h. A greater relaxation to 8-bromo-guanosine 3'5'-cyclic monophosphate occurred in arteries incubated for 20 than for 2 h. The protein level of the dimers but not monomers of PDE5 was reduced by dithiothreitol and unaffected by hydrogen peroxide, accompanied with decreased PDE5 activity and reduced response to DETA NONOate. These results demonstrate that the dimeric but not monomeric status of sGC and PDE5 of coronary arteries are closely related to their activities. The preserved vasodilator response after 20 h incubation may result in part from a synchronous reduction of the dimer levels of sGC and PDE5 as well as an augmented response to cGMP.

Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes

PubMed Central

Hackett, Geoffrey; Jones, Peter W; Strange, Richard C; Ramachandran, Sudarshan

2017-01-01

AIM To determine how statins, testosterone (T) replacement therapy (TRT) and phosphodiesterase 5-inhibitors (PDE5I) influence age related mortality in diabetic men. METHODS We studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual. RESULTS Age was associated with mortality (logistic regression, OR = 1.10, 95%CI: 1.08-1.13, P < 0.001). With all factors included, age (OR = 1.08, 95%CI: 1.06-1.11, P < 0.001), Low T/treated (OR = 0.38, 95%CI: 0.15-0.92, P = 0.033), PDE5I/treated (OR = 0.17, 95%CI: 0.053-0.56, P = 0.004) and statin/treated (OR = 0.59, 95%CI: 0.36-0.97, P = 0.038) were associated with lower mortality. Age related mortality was as described by Gompertz, r2 = 0.881 when Ln (mortality) was plotted against age. The probability of mortality and 95%CI (from logistic regression) of individuals, treated/untreated with the drugs, alone and in combination was plotted against age. Overlap of 95%CI lines was evident with statins and TRT. No overlap was evident with PDE5I alone and with statins and TRT, this suggesting a change in the relationship between age and mortality. CONCLUSION We show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men. PMID:28344753

[Anti-B[a]PDE-DNA formation in lymphomonocytes of humans environmentally exposed to polycyclic aromatic hydrocarbons].

PubMed

Pavanello, S; Pulliero, A; Lai, A; Gaiardo, A; Mastrangelo, G; Clonfero, E

2005-01-01

[Anti-B[a]PDE-DNA formation in lymphomonocytes of humans environmentally exposed to polycyclic aromatic hydrocarbons] We are currently evaluating anti-benzo[a]pyrenediolepoxide-(B[a]PDE)-DNA adduct levels in lymphomonocytes of humans exposed to polycyclic aromatic hydrocarbons (PAHs) to validate this indicator of biologically effective dose in a surrogate tissue. The study protocol (October 2002-June 2005) implies: (a) a signed informed consent by each participant; (b) recruitment of 600 Padua municipal workers during visits at our outpatient clinic; (c) administration of a questionnaire regarding non occupational sources of PAH (B[a]P) exposure; (d) collection of blood (15 ml) and urine (200 ml) samples. Anti-B[a]PDE-DNA adduct levels in lymphomonocytes are detected by HPLC-fluorescence analysis. To date, 438 subjects have been examined (age range 20-62 years; 52% males). We found that: (i) anti-B[a]PDE-DNA adduct levels are significantly lower than those we previously found in coke-oven workers (N=95) occupationally exposed to high levels of PAHs (1.51 +/- 2.68 versus 4.07 +/- 3.78 anti-B[a]PDE-adduct/10(8) nucleotides, p < 0.001; 37% versus 97% positive subjects with > or =1 adduct/10(8) nucleotides; p < 0.001); (ii) smokers (23%) have significantly higher adduct levels than non smokers (p < 0.001); iii) non smokers who consume PAH-rich meals > or =52 times/year (142 subjects, 42%) have significantly increased adduct levels than those <52 times/year (p < 0.01). Dietary and smoking habits did not influence the occupationally-induced adduct levels in coke-oven workers. This is the first study that examines anti-B[a]PDE-DNA adduct levels in a large cohort showing that anti-B[a]PDE-DNA adducts can be detected in humans environmentally exposed to low doses of PAH (B[a]P and are modulated by smoke and dietary habits.

Intraperitoneal Vancomycin Concentrations During Peritoneal Dialysis–Associated Peritonitis: Correlation with Serum Levels

PubMed Central

Fish, Richard; Nipah, Robert; Jones, Chris; Finney, Hazel; Fan, Stanley L.S.

2012-01-01

♦ Background: For the treatment of peritoneal dialysis–associated peritonitis (PDP), it has been suggested that serum concentrations of vancomycin be kept above 12 mg/L – 15 mg/L. However, studies correlating vancomycin concentrations in serum and peritoneal dialysate effluent (PDE) during active infection are sparse. We undertook the present study to investigate this issue and to determine whether achieving the recommended serum level of vancomycin results in therapeutic levels intraperitoneally. ♦ Methods: We studied patients treated with intraperitoneal (IP) vancomycin for non-gram-negative PDP. We gave a single dose (approximately 30 mg/kg) at presentation, and we subsequently measured vancomycin levels in PDE on day 5; we wanted to determine if efflux of vancomycin from serum to PDE during a 4-hour dwell was consistent and resulted in therapeutic levels. ♦ Results: Of the 48 episodes of PDP studied, serum vancomycin concentrations exceeding 12 mg/L were achieved in 98% of patients, but in 11 patients (23%), a PDE vancomycin level below 4 mg/L—the minimal inhibitory concentration (MIC) of many gram-positive organisms—was observed at the end of a 4-hour dwell on day 5. The correlation between the concentrations of vancomycin in serum and PDE (from efflux of antibiotic over 4 hours) was statistically significant, but poor (R2 = 0.18). ♦ Conclusions: Our data support the International Society for Peritoneal Dialysis statement that adequate serum vancomycin concentrations can be achieved with intermittent dosing (single dose every 5 days), but cannot guarantee therapeutic PDE levels in the treatment of PDP. Intermittent dosing of vancomycin may not consistently result in PDE concentrations markedly greater than MIC of many important pathogens. Although the clinical significance of this finding remains to be determined, it may be preferable to give smaller but more frequent doses of PDE vancomycin (continuous dosing) for adults with PDP (as is currently recommended for children). PMID:22045102

[Adenoviral short hairpin RNA targeting phosphodiesterase 5 attenuates cardiac remodeling and cardiac dysfunction following myocardial infarction in mice].

PubMed

Zhang, Jian; Jin, Zhe; Li, Longhu; Gang, Li; Yu, Qin; Wang, Meilan; Song, Ailin; Hong, Bingzhe

2014-04-01

To observe the impact of PDE5shRNA on cardiac remodeling and heart function following myocardial infarction in mice. Myocardial infarction (MI) was induced in mice by left coronary artery ligation. Mice were randomly assigned to sham group (n = 6), PDE5shRNA group (n = 12), common adenovirus group (n = 15) and DMEM group (n = 8). Four weeks post-MI, the survival rate was evaluated. Cardiac function was examined by echocardiography. HE staining and Masson staining were used to evaluate the myocardial infarction size and fibrosis. The number of blood vessels was evaluated by immunohistochemistry, PDE5 protein expression in the left ventricular was detected using Western blot, level of cGMP or PKG activity in the left ventricle was evaluated with ELISA. Four weeks post-MI, all mice survived in the sham group, 3(37%) mice died in the DMEM group, 1 (8%) died in the PDE5shRNA group and 5 died in the common adenovirus group (33%). Infarct size was significantly reduced in PDE5shRNA group compared with the common adenovirus group and DMEM group [(25.4 ± 2.9)% vs. (42.0 ± 3.2)% and (43.4 ± 2.6) %, P < 0.05]. Cardiac function was significantly improved in PDE5shRNA group compared to common adenovirus group and DMEM group[LVFS: (21.1 ± 3.7)% vs. (14.2 ± 2.9)% and (14.22 ± 2.91)%, all P < 0.05; LVEF: (48.2 ± 7.1)% vs. (34.6 ± 6.2)% and (38.1 ± 2.8)%, all P < 0.05; LVESD: (3.87 ± 0.45) mm vs.(4.91 ± 0.62) mm and (4.63 ± 0.37) mm, all P < 0.05]. The blood vessel density was also higher in PDE5shRNA group compared with common adenovirus group (infarct area:14.3 ± 2.0 vs. 6.6 ± 1.2, P < 0.05; periinfarct area: 23.6 ± 2.1 vs. 13.7 ± 2.4, P < 0.05). Compared with common adenovirus group, level of PDE5 was significantly downregulated and level of cGMP or PKG was significantly upregulated in PDE5shRNA group (all P < 0.05). Present study suggests PDE5shRNA improves cardiac function and attenuates cardiac remodeling through reducing infarction size and cardiac fibrosis and these beneficial effects are possibly mediated by activating cGMP/PKG signaling pathway.

Traveling wave to a reaction-hyperbolic system for axonal transport

NASA Astrophysics Data System (ADS)

Huang, Feimin; Li, Xing; Zhang, Yinglong

2017-07-01

In this paper, we study a class of nonlinear reaction-hyperbolic systems modeling the neuronal signal transfer in neuroscience. This reaction-hyperbolic system can be regarded as n × n (n ≥ 2) hyperbolic system with relaxation. We first prove the existence of traveling wave by Gershgorin circle theorem and mathematically describe the neuronal signal transport. Then for a special case n = 2, we show the traveling wave is nonlinearly stable, and obtain the convergence rate simultaneously by a weighted estimate.

Direct Initiation Through Detonation Branching in a Pulsed Detonation Engine

DTIC Science & Technology

2008-03-01

important features noted ................................. 33  Figure 20. GM Quad 4 engine head used as the PDE research engine with the detonation tube...Deflagration to Detonation Transition EF – Engine Frequency FF – Fill Fraction NPT – National Pipe Thread MPT – Male National Pipe Thread PDE – Pulsed... Detonation Engines ( PDE ) has increased greatly in recent years due in part to the potential for increased thermal efficiency derived from constant

Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction.

PubMed

Chen, Si; Knight, Walter E; Yan, Chen

2018-04-23

Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential.

Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center.

PubMed

Freund, Yvonne R; Akama, Tsutomu; Alley, M R K; Antunes, Joana; Dong, Chen; Jarnagin, Kurt; Kimura, Richard; Nieman, James A; Maples, Kirk R; Plattner, Jacob J; Rock, Fernando; Sharma, Rashmi; Singh, Rajeshwar; Sanders, Virginia; Zhou, Yasheen

2012-09-21

We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-α, IL-2, IFN-γ, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Infrared hyperbolic metasurface based on nanostructured van der Waals materials

NASA Astrophysics Data System (ADS)

Li, Peining; Dolado, Irene; Alfaro-Mozaz, Francisco Javier; Casanova, Fèlix; Hueso, Luis E.; Liu, Song; Edgar, James H.; Nikitin, Alexey Y.; Vélez, Saül; Hillenbrand, Rainer

2018-02-01

Metasurfaces with strongly anisotropic optical properties can support deep subwavelength-scale confined electromagnetic waves (polaritons), which promise opportunities for controlling light in photonic and optoelectronic applications. We developed a mid-infrared hyperbolic metasurface by nanostructuring a thin layer of hexagonal boron nitride that supports deep subwavelength-scale phonon polaritons that propagate with in-plane hyperbolic dispersion. By applying an infrared nanoimaging technique, we visualize the concave (anomalous) wavefronts of a diverging polariton beam, which represent a landmark feature of hyperbolic polaritons. The results illustrate how near-field microscopy can be applied to reveal the exotic wavefronts of polaritons in anisotropic materials and demonstrate that nanostructured van der Waals materials can form a highly variable and compact platform for hyperbolic infrared metasurface devices and circuits.

On the Behavior of Eisenstein Series Through Elliptic Degeneration

NASA Astrophysics Data System (ADS)

Garbin, D.; Pippich, A.-M. V.

2009-12-01

Let Γ be a Fuchsian group of the first kind acting on the hyperbolic upper half plane {mathbb{H}}, and let {M = Γbackslash mathbb{H}} be the associated finite volume hyperbolic Riemann surface. If γ is a primitive parabolic, hyperbolic, resp. elliptic element of Γ, there is an associated parabolic, hyperbolic, resp. elliptic Eisenstein series. In this article, we study the limiting behavior of these Eisenstein series on an elliptically degenerating family of finite volume hyperbolic Riemann surfaces. In particular, we prove the following result. The elliptic Eisenstein series associated to a degenerating elliptic element converges up to a factor to the parabolic Eisenstein series associated to the parabolic element which fixes the newly developed cusp on the limit surface.

Hyperbolic metamaterials: new physics behind a classical problem.

PubMed

Drachev, Vladimir P; Podolskiy, Viktor A; Kildishev, Alexander V

2013-06-17

Hyperbolic materials enable numerous surprising applications that include far-field subwavelength imaging, nanolithography, and emission engineering. The wavevector of a plane wave in these media follows the surface of a hyperboloid in contrast to an ellipsoid for conventional anisotropic dielectric. The consequences of hyperbolic dispersion were first studied in the 50's pertaining to the problems of electromagnetic wave propagation in the Earth's ionosphere and in the stratified artificial materials of transmission lines. Recent years have brought explosive growth in optics and photonics of hyperbolic media based on metamaterials across the optical spectrum. Here we summarize earlier theories in the Clemmow's prescription for transformation of the electromagnetic field in hyperbolic media and provide a review of recent developments in this active research area.

Polyhedra and packings from hyperbolic honeycombs.

PubMed

Pedersen, Martin Cramer; Hyde, Stephen T

2018-06-20

We derive more than 80 embeddings of 2D hyperbolic honeycombs in Euclidean 3 space, forming 3-periodic infinite polyhedra with cubic symmetry. All embeddings are "minimally frustrated," formed by removing just enough isometries of the (regular, but unphysical) 2D hyperbolic honeycombs [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text] to allow embeddings in Euclidean 3 space. Nearly all of these triangulated "simplicial polyhedra" have symmetrically identical vertices, and most are chiral. The most symmetric examples include 10 infinite "deltahedra," with equilateral triangular faces, 6 of which were previously unknown and some of which can be described as packings of Platonic deltahedra. We describe also related cubic crystalline packings of equal hyperbolic discs in 3 space that are frustrated analogues of optimally dense hyperbolic disc packings. The 10-coordinated packings are the least "loosened" Euclidean embeddings, although frustration swells all of the hyperbolic disc packings to give less dense arrays than the flat penny-packing even though their unfrustrated analogues in [Formula: see text] are denser.

Boundary causality versus hyperbolicity for spherical black holes in Gauss-Bonnet gravity

NASA Astrophysics Data System (ADS)

Andrade, Tomás; Cáceres, Elena; Keeler, Cynthia

2017-07-01

We explore the constraints boundary causality places on the allowable Gauss-Bonnet gravitational couplings in asymptotically AdS spaces, specifically considering spherical black hole solutions. We additionally consider the hyperbolicity properties of these solutions, positing that hyperbolicity-violating solutions are sick solutions whose causality properties provide no information about the theory they reside in. For both signs of the Gauss-Bonnet coupling, spherical black holes violate boundary causality at smaller absolute values of the coupling than planar black holes do. For negative coupling, as we tune the Gauss-Bonnet coupling away from zero, both spherical and planar black holes violate hyperbolicity before they violate boundary causality. For positive coupling, the only hyperbolicity-respecting spherical black holes which violate boundary causality do not do so appreciably far from the planar bound. Consequently, eliminating hyperbolicity-violating solutions means the bound on Gauss-Bonnet couplings from the boundary causality of spherical black holes is no tighter than that from planar black holes.

Cascades of Particles Moving at Finite Velocity in Hyperbolic Spaces

NASA Astrophysics Data System (ADS)

Cammarota, V.; Orsingher, E.

2008-12-01

A branching process of particles moving at finite velocity over the geodesic lines of the hyperbolic space (Poincaré half-plane and Poincaré disk) is examined. Each particle can split into two particles only once at Poisson spaced times and deviates orthogonally when splitted. At time t, after N( t) Poisson events, there are N( t)+1 particles moving along different geodesic lines. We are able to obtain the exact expression of the mean hyperbolic distance of the center of mass of the cloud of particles. We derive such mean hyperbolic distance from two different and independent ways and we study the behavior of the relevant expression as t increases and for different values of the parameters c (hyperbolic velocity of motion) and λ (rate of reproduction). The mean hyperbolic distance of each moving particle is also examined and a useful representation, as the distance of a randomly stopped particle moving over the main geodesic line, is presented.

Super-Coulombic atom–atom interactions in hyperbolic media

PubMed Central

Cortes, Cristian L.; Jacob, Zubin

2017-01-01

Dipole–dipole interactions, which govern phenomena such as cooperative Lamb shifts, superradiant decay rates, Van der Waals forces and resonance energy transfer rates, are conventionally limited to the Coulombic near-field. Here we reveal a class of real-photon and virtual-photon long-range quantum electrodynamic interactions that have a singularity in media with hyperbolic dispersion. The singularity in the dipole–dipole coupling, referred to as a super-Coulombic interaction, is a result of an effective interaction distance that goes to zero in the ideal limit irrespective of the physical distance. We investigate the entire landscape of atom–atom interactions in hyperbolic media confirming the giant long-range enhancement. We also propose multiple experimental platforms to verify our predicted effect with phonon–polaritonic hexagonal boron nitride, plasmonic super-lattices and hyperbolic meta-surfaces as well. Our work paves the way for the control of cold atoms above hyperbolic meta-surfaces and the study of many-body physics with hyperbolic media. PMID:28120826

Super-Coulombic atom-atom interactions in hyperbolic media

NASA Astrophysics Data System (ADS)

Cortes, Cristian L.; Jacob, Zubin

2017-01-01

Dipole-dipole interactions, which govern phenomena such as cooperative Lamb shifts, superradiant decay rates, Van der Waals forces and resonance energy transfer rates, are conventionally limited to the Coulombic near-field. Here we reveal a class of real-photon and virtual-photon long-range quantum electrodynamic interactions that have a singularity in media with hyperbolic dispersion. The singularity in the dipole-dipole coupling, referred to as a super-Coulombic interaction, is a result of an effective interaction distance that goes to zero in the ideal limit irrespective of the physical distance. We investigate the entire landscape of atom-atom interactions in hyperbolic media confirming the giant long-range enhancement. We also propose multiple experimental platforms to verify our predicted effect with phonon-polaritonic hexagonal boron nitride, plasmonic super-lattices and hyperbolic meta-surfaces as well. Our work paves the way for the control of cold atoms above hyperbolic meta-surfaces and the study of many-body physics with hyperbolic media.

Erectile Dysfunction Medication Use in Veterans Eligible for Medicare Part D.

PubMed

Spencer, Samantha H; Suda, Katie J; Smith, Bridget M; Huo, Zhiping; Bailey, Lauren; Stroupe, Kevin T

2016-07-01

Erectile dysfunction (ED) medications are therapeutically effective and associated with satisfaction. Medicare Part D included ED medications on the formulary during 2006 and inadvertently in 2007-2008. To characterize phosphodiesterase-5 inhibitor (PDE-5) medication use among veterans who were dually eligible for Veterans Affairs (VA) and Medicare Part D benefits. Veterans aged > 66 years who received PDE-5 inhibitors between 2005 and 2009 were included. Veterans were categorized by PDE-5 inhibitor claims: VA-only, Part D-only, or dual users of VA and Part D-reimbursed pharmacies. T-tests and chi-square tests were applied as appropriate. From 2005 to 2009, the majority (85.2%) of veterans used VA benefits exclusively for their PDE-5 inhibitors; 11.4% used Medicare Part D exclusively; and 3.4% were dual users. The Part D-only group was older, more frequently not black, had a VA copay, and had a higher income (P < 0.03). The VA group was more likely to have comorbidities, smoke, and have a history of substance abuse (P < 0.001). With the inception of Medicare Part D in 2006, the number of patients filling prescriptions for PDE-5 inhibitors (-68%) and total number of PDE-5 inhibitor 30-day equivalents dispensed (-86.7%) from the VA decreased. Part D prescriptions increased through 2006 (full coverage period) and 2007 (accidental partial coverage) and decreased in 2008. While Part D accounted for only 10% of PDE-5 inhibitor 30-day equivalents, it equaled 29.2% of dispensed tablets. In October 2007, VA PDE-5 inhibitor use returned to 2005 levels. Implementation of Medicare Part D reduced VA PDE-5 inhibitor acquisition. However, after removal of PDE-5 inhibitors from the Part D formulary, use of VA pharmacies for PDE-5 inhibitors resumed. Medication policies outside the VA can affect medication use. Veterans with access to non-VA health care may obtain medications from the private sector because of VA restrictions. This may be especially true for nonformulary and lifestyle medications. The authors received funding support for this research project from the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service as grant IIR 07-165-2. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or Health Services Research and Development Service. Study concept and design were contributed by Smith and Stroupe, assisted by the other authors. Huo, Bailey, and Stroupe took the lead in data collection, assisted by the other authors. Data interpretation was performed by Spencer and Suda, along with Smith and Stroupe and assisted by Huo and Bailey. The manuscript was primarily written by Spencer and Suda, with assistance from the other authors, and revised by Spencer, along with the other authors.

SOP conservative (medical and mechanical) treatment of erectile dysfunction.

PubMed

Porst, Hartmut; Burnett, Arthur; Brock, Gerald; Ghanem, Hussein; Giuliano, Francois; Glina, Sidney; Hellstrom, Wayne; Martin-Morales, Antonio; Salonia, Andrea; Sharlip, Ira

2013-01-01

Erectile dysfunction (ED) is the most frequently treated male sexual dysfunction worldwide. ED is a chronic condition that exerts a negative impact on male self-esteem and nearly all life domains including interpersonal, family, and business relationships. The aim of this study is to provide an updated overview on currently used and available conservative treatment options for ED with a special focus on their efficacy, tolerability, safety, merits, and limitations including the role of combination therapies for monotherapy failures. The methods used were PubMed and MEDLINE searches using the following keywords: ED, phosphodiesterase type 5 (PDE5) inhibitors, oral drug therapy, intracavernosal injection therapy, transurethral therapy, topical therapy, and vacuum-erection therapy/constriction devices. Additionally, expert opinions by the authors of this article are included. Level 1 evidence exists that changes in sedentary lifestyle with weight loss and optimal treatment of concomitant diseases/risk factors (e.g., diabetes, hypertension, and dyslipidemia) can either improve ED or add to the efficacy of ED-specific therapies, e.g., PDE5 inhibitors. Level 1 evidence also exists that treatment of hypogonadism with total testosterone < 300 ng/dL (10.4 nmol/L) can either improve ED or add to the efficacy of PDE5 inhibitors. There is level 1 evidence regarding the efficacy and safety of the following monotherapies in a spectrum-wide range of ED populations: PDE5 inhibitors, intracavernosal injection therapy with prostaglandin E1 (PGE1, synonymous alprostadil) or vasoactive intestinal peptide (VIP)/phentolamine, and transurethral PGE1 therapy. There is level 2 evidence regarding the efficacy and safety of the following ED treatments: vacuum-erection therapy in a wide range of ED populations, oral L-arginine (3-5 g), topical PGE1 in special ED populations, intracavernosal injection therapy with papaverine/phentolamine (bimix), or papaverine/phentolamine/PGE1 (trimix) combination mixtures. There is level 3 evidence regarding the efficacy and safety of oral yohimbine in nonorganic ED. There is level 3 evidence that combination therapies of PDE5 inhibitors + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone. There is level 4 evidence showing enhanced efficacy with the combination of vacuum-erection therapy + either PDE5 inhibitor or transurethral PGE1 or intracavernosal injection therapy. There is level 5 evidence (expert opinion) that combination therapy of PDE5 inhibitors + L-arginine or daily dosing of tadalafil + short-acting PDE5 inhibitors pro re nata may rescue PDE5 inhibitor monotherapy failures. There is level 5 evidence (expert opinion) that adding either PDE5 inhibitors or transurethral PGE1 may improve outcome of penile prosthetic surgery regarding soft (cold) glans syndrome. There is level 5 evidence (expert opinion) that the combination of PDE5 inhibitors and dapoxetine is effective and safe in patients suffering from both ED and premature ejaculation. © 2013 International Society for Sexual Medicine.

A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement

PubMed Central

Taylor, Peter N; Panicker, Vijay; Sayers, Adrian; Shields, Beverley; Iqbal, Ahmed; Bremner, Alexandra P; Beilby, John P; Leedman, Peter J; Hattersley, Andrew T; Vaidya, Bijay; Frayling, Timothy; Evans, Jonathan; Tobias, Jonathan H; Timpson, Nicholas J; Walsh, John P; Dayan, Colin M

2011-01-01

Objective Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T4). Design Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T4). Methods Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T3), and T4 levels. Results Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64×10−10 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T4 (P=0.023, −0.07 s.d./allele, 95% CI −0.137, −0.01), no association was seen with free T3 (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T4 in 1981 (−0.068 s.d./allele, 95% CI −0.167, 0.031) and 1994 (−0.07 s.d./allele, 95% CI −0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T4. Conclusion Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T4 levels that are consistent over time and lost in individuals on l-T4. These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid. PMID:21317282

How does pre-dialysis education need to change? Findings from a qualitative study with staff and patients.

PubMed

Combes, Gill; Sein, Kim; Allen, Kerry

2017-11-23

Pre-dialysis education (PDE) is provided to thousands of patients every year, helping them decide which renal replacement therapy (RRT) to choose. However, its effectiveness is largely unknown, with relatively little previous research into patients' views about PDE, and no research into staff views. This study reports findings relevant to PDE from a larger mixed methods study, providing insights into what staff and patients think needs to improve. Semi-structured interviews in four hospitals with 96 clinical and managerial staff and 93 dialysis patients, exploring experiences of and views about PDE, and analysed using thematic framework analysis. Most patients found PDE helpful and staff valued its role in supporting patient decision-making. However, patients wanted to see teaching methods and materials improve and biases eliminated. Staff were less aware than patients of how informal staff-patient conversations can influence patients' treatment decision-making. Many staff felt ill equipped to talk about all treatment options in a balanced and unbiased way. Patient decision-making was found to be complex and patients' abilities to make treatment decisions were adversely affected in the pre-dialysis period by emotional distress. Suggested improvements to teaching methods and educational materials are in line with previous studies and current clinical guidelines. All staff, irrespective of their role, need to be trained about all treatment options so that informal conversations with patients are not biased. The study argues for a more individualised approach to PDE which is more like counselling than education and would demand a higher level of skill and training for specialist PDE staff. The study concludes that even if these improvements are made to PDE, not all patients will benefit, because some find decision-making in the pre-dialysis period too complex or are unable to engage with education due to illness or emotional distress. It is therefore recommended that pre-dialysis treatment decisions are temporary, and that PDE is replaced with on-going RRT education which provides opportunities for personalised education and on-going review of patients' treatment choices. Emotional support to help overcome the distress of the transition to end-stage renal disease will also be essential to ensure all patients can benefit from RRT education.

Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn

PubMed Central

Lakshminrusimha, Satyan; Wedgwood, Stephen; Czech, Lyubov; Gugino, Sylvia F.; Russell, James A.; Farrow, Kathryn N.; Steinhorn, Robin H.

2012-01-01

In the pulmonary vasculature, cGMP levels are regulated by soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). We previously reported that lambs with persistent pulmonary hypertension of the newborn (PPHN) demonstrate increased reactive oxygen species (ROS) and altered sGC and PDE5 activity, with resultant decreased cGMP. The objective of this study was to evaluate the effects of hydrocortisone on pulmonary vascular function, ROS, and cGMP in the ovine ductal ligation model of PPHN. PPHN lambs were ventilated with 100% O2 for 24 h. Six lambs received 5 mg/kg hydrocortisone every 8 h times three doses (PPHN-hiHC), five lambs received 3 mg/kg hydrocortisone followed by 1 mg·kg−1·dose−1 times two doses (PPHN-loHC), and six lambs were ventilated with O2 alone (PPHN). All groups were compared with healthy 1-day spontaneously breathing lambs (1DSB). O2 ventilation of PPHN lambs decreased sGC activity, increased PDE5 activity, and increased ROS vs. 1DSB lambs. Both hydrocortisone doses significantly improved arterial-to-alveolar ratios relative to PPHN lambs, decreased PDE5 activity, and increased cGMP relative to PPHN lambs. High-dose hydrocortisone also increased sGC activity, decreased PDE5 expression, decreased ROS, and increased total vascular SOD activity vs. PPHN lambs. These data suggest that hydrocortisone treatment in clinically relevant doses improves oxygenation and decreases hyperoxia-induced changes in sGC and PDE5 activity, increasing cGMP levels. Hydrocortisone reduces ROS levels in part by increasing SOD activity in PPHN lambs ventilated with 100% O2. We speculate that hydrocortisone increases cGMP by direct effects on sGC and PDE5 expression and by attenuating abnormalities induced by oxidant stress. PMID:22198909

Systematic review and meta-analysis on phosphodiesterase 5 inhibitors and α-adrenoceptor antagonists used alone or combined for treatment of LUTS due to BPH

PubMed Central

Wang, Xing-Huan; Wang, Xiao; Shi, Ming-Jun; Li, Sheng; Liu, Tao; Zhang, Xin-Hua

2015-01-01

The aim of this systematic review is to determine the comparative effectiveness and safety of phosphodiesterase 5 inhibitors (PDE5-Is) and α-blockers used alone or combined for the treatment of lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). An electronic search of PubMed, Cochrane Library and Embase up to January 2014 was performed to identify randomized controlled trials comparing the efficacy and safety of PDE5-Is and α-blockers for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia, which assessed IPSS score, maximum flow rate, postvoided residual urine, quality of life and Erectile Function (IIEF) score as outcomes. Data were analyzed by fixed or random effect models using Cochrane Collaboration review manager software. A total of 12 studies were included. Our novel data demonstrated that there was a trend that α-blockers were more efficacious than PDE5-Is on decreasing IPSS score and increasing maximum flow rate. α-blockers were significantly more effective than PDE5-Is on reduction of postvoided residual urine with a mean difference of 3.67 (95% CI 1.56 to 5.77, P = 0.0006) and PDE5-Is showed greater effect than α-blockers on increasing IIEF score with a mean difference of 9.82 (95% CI 3.80 to 15.85, P = 0.001). In conclusion, our novel data demonstrated that PDE5-Is plus ABs ranked the highest on the improvement of LUTS/BPH. PDE5-Is monotherapy was also effective in this kind of disorder except less reduction of PVR than ABs. In addition, both combined- or mono-therapy were safe. PMID:25994648

Elevated Cyclic AMP Levels in T Lymphocytes Transformed by Human T-Cell Lymphotropic Virus Type 1▿

PubMed Central

Kress, Andrea K.; Schneider, Grit; Pichler, Klemens; Kalmer, Martina; Fleckenstein, Bernhard; Grassmann, Ralph

2010-01-01

Human T-cell lymphotropic virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), transforms CD4+ T cells to permanent growth through its transactivator Tax. HTLV-1-transformed cells share phenotypic properties with memory and regulatory T cells (T-reg). Murine T-reg-mediated suppression employs elevated cyclic AMP (cAMP) levels as a key regulator. This led us to determine cAMP levels in HTLV-1-transformed cells. We found elevated cAMP concentrations as a consistent feature of all HTLV-1-transformed cell lines, including in vitro-HTLV-1-transformed, Tax-transformed, and patient-derived cells. In transformed cells with conditional Tax expression, high cAMP levels coincided with the presence of Tax but were lost without it. However, transient ectopic expression of Tax alone was not sufficient to induce cAMP. We found specific downregulation of the cAMP-degrading phosphodiesterase 3B (PDE3B) in HTLV-1-transformed cells, which was independent of Tax in transient expression experiments. This is in line with the notion that PDE3B transcripts and cAMP levels are inversely correlated. Overexpression of PDE3B led to a decrease of cAMP in HTLV-1-transformed cells. Decreased expression of PDE3B was associated with inhibitory histone modifications at the PDE3B promoter and the PDE3B locus. In summary, Tax transformation and its continuous expression contribute to elevated cAMP levels, which may be regulated through PDE3B suppression. This shows that HTLV-1-transformed cells assume biological features of long-lived T-cell populations that potentially contribute to viral persistence. PMID:20573814

Low-Intensity Extracorporeal Shockwave Therapy Can Improve Erectile Function in Patients Who Failed to Respond to Phosphodiesterase Type 5 Inhibitors

PubMed Central

Tsai, Chia-Chun; Wang, Chii-Jye; Lee, Yung-Chin; Kuo, Yen-Ting; Lin, Hsiao-Hua; Li, Ching-Chia; Wu, Wen-Jeng; Liu, Chia-Chu

2017-01-01

Managing patients with erectile dysfunction (ED) who failed to respond to phosphodiesterase type 5 inhibitors (PDE5is) is a challenging task. Recently, low-intensity extracorporeal shockwave therapy (LI-ESWT) was reported to improve ED by enhancing perfusion of the penis. The current study was performed to evaluate whether combined treatment with LI-ESWT and PDE5is can restore erectile function in patients who failed to respond to PDE5is alone. This was an open-label single-arm prospective study. ED patients with an erection hardness score (EHS) ≦2 under a maximal dosage of PDE5is were enrolled. Sociodemographic information and detailed medical history were recorded. LI-ESWT treatment consisted of 3,000 shockwaves once weekly for 12 weeks. All patients continued their regular PDE5is use. The EHS and the 5-item version of the International Index of Erectile Function (IIEF-5) were used to evaluate the change in erectile function 1 and 3 months after LI-ESWT. A total of 52 patients were enrolled. After LI-ESWT treatment, 35 of the 52 patients (67.3%) could achieve an erection hard enough for intercourse (EHS ≧ 3) under PDE5is use at the 1-month follow-up. Initial severity of ED was the only significant predictor of a successful response (EHS1: 35.7% vs. EHS2: 78.9%, p = .005). Thirty-three of the 35 (94.3%) subjects who responded to LI-ESWT could still maintain their erectile function at the 3-month follow-up. LI-ESWT can serve as a salvage therapy for ED patients who failed to respond to PDE5is. Initial severity of ED was an important predictor of a successful response. PMID:28884638

Inhibition of Adrenergic and Non-Adrenergic Smooth Muscle Contraction in the Human Prostate by the Phosphodiesterase 10-Selective Inhibitor TC-E 5005.

PubMed

Hennenberg, Martin; Schott, Melanie; Kan, Aysenur; Keller, Patrick; Tamalunas, Alexander; Ciotkowska, Anna; Rutz, Beata; Wang, Yiming; Strittmatter, Frank; Herlemann, Annika; Yu, Qingfeng; Stief, Christian G; Gratzke, Christian

2016-11-01

The phosphodiesterase (PDE) 5 inhibitor tadalafil is available for treatment of male lower urinary tract symptoms (LUTS), while the role of other PDE isoforms for prostate smooth muscle tone is still unknown. Here, we examined effects of the PDE10-selective inhibitor TC-E 5005 on smooth muscle contraction in human prostate tissue. Prostate samples were obtained from patients undergoing radical prostatectomy. Expression of PDE10 was addressed by RT-PCR, Western blot, and fluorescence staining with different markers. Effects of TC-E 5005 and tadalafil on contraction, and relaxation of prostate strips were studied via organ bath. PDE10A was detectable by RT-PCR, Western blot, and fluorescence staining in prostate tissues. Colocalization with markers suggested expression of PDE10A in smooth muscle cells and catecholaminergic nerves. Norepinephrine, the α1 -adrenergic agonist phenylephrine, the thromboxane A2 analogue U46619, and endothelins 1-3 induced concentration-dependent contractions of prostate strips, while electric field stimulation (EFS) induced frequence-dependent contractions. Application of TC-E 5005 (500 nM) caused significant inhibition of norepinephrine-, phenylephrine-, and endothelin-3-induced contractions. Inhibition of EFS-induced contractions by TC-E 5005 ranged around 50%, resembling inhibition of EFS-induced contractions by tadalafil (10 μM). The prostacyclin analog treprostinil and the nitric oxide donor DEA NONOate induced relaxations of precontracted prostate strips, which were significantly amplified by TCE 5005. The PDE10-selective inhibitor TC-E 5005 inhibits adrenergic and neurogenic smooth muscle contractions in the human prostate. TC-E 5005 inhibits neurogenic contractions with similar efficacy than tadalafil, so that urodynamic effects in vivo appear possible. Prostate 76:1364-1374, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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

NASA Astrophysics Data System (ADS)

AllahTavakoli, Yahya; Safari, Abdolreza; Vaníček, Petr

2016-12-01

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

Dextran Sulfate Sodium-Induced Colonic Histopathology, but not Altered Epithelial Ion Transport, Is Reduced by Inhibition of Phosphodiesterase Activity

PubMed Central

Diaz-Granados, Natalia; Howe, Kathryn; Lu, Jun; McKay, Derek M.

2000-01-01

Inhibition of phosphodiesterase (PDE) activity is beneficial in models of arthritis and airway inflammation. Here we assessed the ability of PDE inhibitors to modulate colitis by exposing mice to 4% (w/v) dextran sulfate sodium (DSS) drinking water for 5 days with or without rolipram, an inhibitor of PDE type 4, or the nonselective PDE inhibitor, pentoxifylline (both at 5 mg/kg, i.p., twice daily). Controls received saline, vehicle, or drug only. Colonic histology, myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels, and epithelial ion transport (baseline and stimulated by electrical nerve stimulation, carbachol, and forskolin) were examined. DSS-treated mice displayed a variable diarrhea, significant histopathology in the mid-distal colon, elevated MPO activity, and reduced (>50%) responses to all three pro-secretory stimuli. Treatment with rolipram, and to a lesser extent pentoxifylline, significantly reduced the severity of the colonic histopathology and MPO levels. Neither PDE inhibitor had any affect on the diminished ion transport events caused by DSS-induced colitis. However, although stimulated ion transport events were still reduced 3 days after DSS treatment, colonic segments from DSS + rolipram-treated mice displayed enhanced recovery in their secretory responsiveness, particularly to carbachol. These findings indicate that specific PDE4 inhibition can significantly reduce the tissue damage that accompanies colitis and enhance recovery of normal colonic function. PMID:10854237

Inhibition of phosphodiesterase-4 decreases ethanol intake in mice.

PubMed

Hu, Wei; Lu, Tina; Chen, Alan; Huang, Ying; Hansen, Rolf; Chandler, L Judson; Zhang, Han-Ting

2011-11-01

Cyclic AMP (cAMP)-protein kinase A signaling has been implicated in the regulation of ethanol consumption. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cAMP and plays a critical role in controlling intracellular cAMP levels in the brain. However, the role of PDE4 in ethanol consumption remains unknown. The objective of this study is to examine whether PDE4 was involved in regulating ethanol intake. The two-bottle choice paradigm was used to assess intake of ethanol, sucrose, and quinine in C57BL/6J mice treated with the selective PDE4 inhibitor rolipram or Ro 20-1724; locomotor activity was also monitored using the open-field test in mice treated with rolipram. Administration (i.p.) of either rolipram (0.25 and 0.5 mg/kg) or Ro 20-1724 (10 mg/kg) reduced ethanol intake and preference by 60-80%, but did not alter total fluid intake. In contrast, rolipram even at the higher dose of 0.5 mg/kg was not able to affect intake of sucrose or quinine, alcohol-induced sedation, or blood ethanol elimination. At 0.5 mg/kg, rolipram did decrease locomotor activity, but the effect only lasted for approximately 40 min, which did not likely affect behavior of ethanol drinking. These results suggest that PDE4 is a novel target for drugs that reduce ethanol intake; PDE4 inhibitors may be used for treatment of alcohol dependence.

A Few New 2+1-Dimensional Nonlinear Dynamics and the Representation of Riemann Curvature Tensors

NASA Astrophysics Data System (ADS)

Wang, Yan; Zhang, Yufeng; Zhang, Xiangzhi

2016-09-01

We first introduced a linear stationary equation with a quadratic operator in ∂x and ∂y, then a linear evolution equation is given by N-order polynomials of eigenfunctions. As applications, by taking N=2, we derived a (2+1)-dimensional generalized linear heat equation with two constant parameters associative with a symmetric space. When taking N=3, a pair of generalized Kadomtsev-Petviashvili equations with the same eigenvalues with the case of N=2 are generated. Similarly, a second-order flow associative with a homogeneous space is derived from the integrability condition of the two linear equations, which is a (2+1)-dimensional hyperbolic equation. When N=3, the third second flow associative with the homogeneous space is generated, which is a pair of new generalized Kadomtsev-Petviashvili equations. Finally, as an application of a Hermitian symmetric space, we established a pair of spectral problems to obtain a new (2+1)-dimensional generalized Schrödinger equation, which is expressed by the Riemann curvature tensors.

Evolution of inviscid Kelvin-Helmholtz instability from a piecewise linear shear layer

NASA Astrophysics Data System (ADS)

Guha, Anirban; Rahmani, Mona; Lawrence, Gregory

2012-11-01

Here we study the evolution of 2D, inviscid Kelvin-Helmholtz instability (KH) ensuing from a piecewise linear shear layer. Although KH pertaining to smooth shear layers (eg. Hyperbolic tangent profile) has been thorough investigated in the past, very little is known about KH resulting from sharp shear layers. Pozrikidis and Higdon (1985) have shown that piecewise shear layer evolves into elliptical vortex patches. This non-linear state is dramatically different from the well known spiral-billow structure of KH. In fact, there is a little acknowledgement that elliptical vortex patches can represent non-linear KH. In this work, we show how such patches evolve through the interaction of vorticity waves. Our work is based on two types of computational methods (i) Contour Dynamics: a boundary-element method which tracks the evolution of the contour of a vortex patch using Lagrangian marker points, and (ii) Direct Numerical Simulation (DNS): an Eulerian pseudo-spectral method heavily used in studying hydrodynamic instability and turbulence.

Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.

PubMed

Goto, Taiji; Shiina, Akiko; Yoshino, Toshiharu; Mizukami, Kiyoshi; Hirahara, Kazuki; Suzuki, Osamu; Sogawa, Yoshitaka; Takahashi, Tomoko; Mikkaichi, Tsuyoshi; Nakao, Naoki; Takahashi, Mizuki; Hasegawa, Masashi; Sasaki, Shigeki

2013-11-15

5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200 nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3 nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16 mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-α) production in mouse splenocytes (IC50=0.21 nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0 mg/kg, i.t.). Copyright © 2013 Elsevier Ltd. All rights reserved.

PDE3A mutations cause autosomal dominant hypertension with brachydactyly.

PubMed

Maass, Philipp G; Aydin, Atakan; Luft, Friedrich C; Schächterle, Carolin; Weise, Anja; Stricker, Sigmar; Lindschau, Carsten; Vaegler, Martin; Qadri, Fatimunnisa; Toka, Hakan R; Schulz, Herbert; Krawitz, Peter M; Parkhomchuk, Dmitri; Hecht, Jochen; Hollfinger, Irene; Wefeld-Neuenfeld, Yvette; Bartels-Klein, Eireen; Mühl, Astrid; Kann, Martin; Schuster, Herbert; Chitayat, David; Bialer, Martin G; Wienker, Thomas F; Ott, Jürg; Rittscher, Katharina; Liehr, Thomas; Jordan, Jens; Plessis, Ghislaine; Tank, Jens; Mai, Knut; Naraghi, Ramin; Hodge, Russell; Hopp, Maxwell; Hattenbach, Lars O; Busjahn, Andreas; Rauch, Anita; Vandeput, Fabrice; Gong, Maolian; Rüschendorf, Franz; Hübner, Norbert; Haller, Hermann; Mundlos, Stefan; Bilginturan, Nihat; Movsesian, Matthew A; Klussmann, Enno; Toka, Okan; Bähring, Sylvia

2015-06-01

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.

Is PDE4 too difficult a drug target?

PubMed

Higgs, Gerry

2010-05-01

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

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

NASA Technical Reports Server (NTRS)

1980-01-01

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tian, Yuanyuan; Cui, Wenjun; Huang, Manna

Cyclic nucleotide phosphodiesterases (PDEs) decompose second messengers cAMP and cGMP that play critical roles in many physiological processes. PDE1 of Saccharomyces cerevisiae has been subcloned and expressed in Escherichia coli. Recombinant yPDE1 has a K M of 110 μM and a k cat of 16.9 s⁻¹ for cAMP and a K M of 105 μM and a k cat of 11.8 s₅⁻¹ for cGMP. Thus, the specificity constant (k cat/K McAMP)/(k cat/K M cGMP) of 1.4 indicates a dual specificity of yPDE1 for hydrolysis of both cAMP and cGMP. The crystal structures of unliganded yPDE1 and its complex with GMPmore » at 1.31 Å resolution reveal a new structural folding that is different from those of human PDEs but is partially similar to that of some other metalloenzymes such as metallo-β-lactamase. In spite of their different structures and divalent metals, yPDE1 and human PDEs may share a common mechanism for hydrolysis of cAMP and cGMP.« less

Using CLIPS in the domain of knowledge-based massively parallel programming

NASA Technical Reports Server (NTRS)

Dvorak, Jiri J.

1994-01-01

The Program Development Environment (PDE) is a tool for massively parallel programming of distributed-memory architectures. Adopting a knowledge-based approach, the PDE eliminates the complexity introduced by parallel hardware with distributed memory and offers complete transparency in respect of parallelism exploitation. The knowledge-based part of the PDE is realized in CLIPS. Its principal task is to find an efficient parallel realization of the application specified by the user in a comfortable, abstract, domain-oriented formalism. A large collection of fine-grain parallel algorithmic skeletons, represented as COOL objects in a tree hierarchy, contains the algorithmic knowledge. A hybrid knowledge base with rule modules and procedural parts, encoding expertise about application domain, parallel programming, software engineering, and parallel hardware, enables a high degree of automation in the software development process. In this paper, important aspects of the implementation of the PDE using CLIPS and COOL are shown, including the embedding of CLIPS with C++-based parts of the PDE. The appropriateness of the chosen approach and of the CLIPS language for knowledge-based software engineering are discussed.

Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling

PubMed Central

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

2016-01-01

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

Lift of noninvariant solutions of heavenly equations from three to four dimensions and new ultra-hyperbolic metrics

NASA Astrophysics Data System (ADS)

Malykh, A. A.; Nutku, Y.; Sheftel, M. B.

2007-08-01

We demonstrate that partner symmetries provide a lift of noninvariant solutions of the three-dimensional Boyer-Finley equation to noninvariant solutions of the four-dimensional hyperbolic complex Monge-Ampère equation. The lift is applied to noninvariant solutions of the Boyer-Finley equation, obtained earlier by the method of group foliation, to yield noninvariant solutions of the hyperbolic complex Monge-Ampère equation. Using these solutions we construct new Ricci-flat ultra-hyperbolic metrics with non-zero curvature tensor that have no Killing vectors.

On the lagrangian 1-form structure of the hyperbolic calogero-moser system

NASA Astrophysics Data System (ADS)

Jairuk, Umpon; Tanasittikosol, Monsit; Yoo-Kong, Sikarin

2017-06-01

In this work, we present the Lagrangian 1-form structure of the hyperbolic Calogero-Moser system in both discrete-time level and continuous-time level. The discrete-time hyperbolic Calogero-Moser system is obtained by considering pole reduction of the semi-discrete Kadomtsev-Petviashvili (KP) equation. Furthermore, it is shown that the hyperbolic Calogero-Moser system possesses the key relation, known as the discrete-time closure relation. This relation is a consequence of the compatibility property of the temporal Lax matrices. The continuous-time hierarchy of the hyperbolic Calogero-Moser system is obtained by taking two successive continuum limits, namely, the skewed limit and full limit. With these successive limits, the continuous-time closure relation is also obtained and is shown to hold at the continuous level.

Advantages of multigrid methods for certifying the accuracy of PDE modeling

NASA Technical Reports Server (NTRS)

Forester, C. K.

1981-01-01

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

Oscillatory instability of a self-rewetting film driven by thermal modulation

NASA Astrophysics Data System (ADS)

Batson, William; Agnon, Yehuda; Oron, Alex

2016-11-01

Here we consider the self-rewetting fluids (SRWFs) that exhibit a well-defined minimum surface tension with respect to temperature, in contrast to those where surface tension decreases linearly. Utilization of SRWFs has grown significantly in the past decade, due to observations that heat transfer is enhanced in applications such as film boiling and pulsating heat pipes. With similar applications in mind, we investigate the dynamics of a thin SRWF film which is subjected to a temperature modulation in the bounding gas. A model is developed within the framework of the long-wave approximation, and a time-averaged thermocapillary driving force for destabilization is uncovered for SRWFs that results from the nonlinear surface tension. Linear analysis of the nonlinear PDE for the film thickness is used to determine the critical conditions at which this driving force destabilizes the film, and, numerical integration of this evolution equation reveals that linearly unstable perturbations saturate to regular periodic solutions (when the modulational frequency is set properly). Properties of these flows such as bifurcation and long-domain flows, where multiple unstable linear modes interact, will also be discussed.

Radiosynthesis and initial characterization of a PDE10A specific PET tracer [18F]AMG 580 in non-human primates.

PubMed

Hwang, Dah-Ren; Hu, Essa; Allen, Jennifer R; Davis, Carl; Treanor, James; Miller, Silke; Chen, Hang; Shi, Bingzhi; Narayanan, Tanjorie K; Barret, Olivier; Alagille, David; Yu, Zhigang; Slifstein, Mark

2015-08-01

Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important second messengers for neurotransmission. Inhibition of PDE10A has been identified as a potential target for treatment of various neuropsychiatric disorders. To assist drug development, we have identified a selective PDE10A positron emission tomography (PET) tracer, AMG 580. We describe here the radiosynthesis of [(18)F]AMG 580 and in vitro and in vivo characterization results. The potency and selectivity were determined by in vitro assay using [(3)H]AMG 580 and baboon brain tissues. [(18)F]AMG 580 was prepared by a 1-step [(18)F]fluorination procedure. Dynamic brain PET scans were performed in non-human primates. Regions-of-interest were defined on individuals' MRIs and transferred to the co-registered PET images. Data were analyzed using two tissue compartment analysis (2TC), Logan graphical (Logan) analysis with metabolite-corrected input function and the simplified reference tissue model (SRTM) method. A PDE10A inhibitor and unlabeled AMG 580 were used to demonstrate the PDE10A specificity. KD was estimated by Scatchard analysis of high and low affinity PET scans. AMG 580 has an in vitro KD of 71.9 pM. Autoradiography showed specific uptake in striatum. Mean activity of 121 ± 18 MBq was used in PET studies. In Rhesus, the baseline BPND for putamen and caudate was 3.38 and 2.34, respectively, via 2TC, and 3.16, 2.34 via Logan, and 2.92, and 2.01 via SRTM. A dose dependent decrease of BPND was observed by the pre-treatment with a PDE10A inhibitor. In baboons, 0.24 mg/kg dose of AMG 580 resulted in about 70% decrease of BPND. The in vivo KD of [(18)F]AMG 580 was estimated to be around 0.44 nM in baboons. [(18)F]AMG 580 is a selective and potent PDE10A PET tracer with excellent specific striatal binding in non-human primates. It warrants further evaluation in humans. Copyright © 2015 Elsevier Inc. All rights reserved.

Reverse engineering of aircraft wing data using a partial differential equation surface model

NASA Astrophysics Data System (ADS)

Huband, Jacalyn Mann

Reverse engineering is a multi-step process used in industry to determine a production representation of an existing physical object. This representation is in the form of mathematical equations that are compatible with computer-aided design and computer-aided manufacturing (CAD/CAM) equipment. The four basic steps to the reverse engineering process are data acquisition, data separation, surface or curve fitting, and CAD/CAM production. The surface fitting step determines the design representation of the object, and thus is critical to the success or failure of the reverse engineering process. Although surface fitting methods described in the literature are used to model a variety of surfaces, they are not suitable for reversing aircraft wings. In this dissertation, we develop and demonstrate a new strategy for reversing a mathematical representation of an aircraft wing. The basis of our strategy is to take an aircraft design model and determine if an inverse model can be derived. A candidate design model for this research is the partial differential equation (PDE) surface model, proposed by Bloor and Wilson and used in the Rapid Airplane Parameter Input Design (RAPID) tool at the NASA-LaRC Geolab. There are several basic mathematical problems involved in reversing the PDE surface model: (i) deriving a computational approximation of the surface function; (ii) determining a radial parametrization of the wing; (iii) choosing mathematical models or classes of functions for representation of the boundary functions; (iv) fitting the boundary data points by the chosen boundary functions; and (v) simultaneously solving for the axial parameterization and the derivative boundary functions. The study of the techniques to solve the above mathematical problems has culminated in a reverse PDE surface model and two reverse PDE surface algorithms. One reverse PDE surface algorithm recovers engineering design parameters for the RAPID tool from aircraft wing data and the other generates a PDE surface model with spline boundary functions from an arbitrary set of grid points. Our numerical tests show that the reverse PDE surface model and the reverse PDE surface algorithms can be used for the reverse engineering of aircraft wing data.

OPC-13013, a cyclic nucleotide phosphodiesterase type III, inhibitor, inhibits cell proliferation and transdifferentiation of cultured rat hepatic stellate cells.

PubMed

Shimizu, E; Kobayashi, Y; Oki, Y; Kawasaki, T; Yoshimi, T; Nakamura, H

1999-01-01

Activated hepatic stellate cells (HSC; lipocytes; Ito cells) proliferate and are responsible for extracellular matrix synthesis during hepatic fibrogenesis. During activation, HSC undergo transdifferentiation into myofibroblasts expressing alpha-smooth muscle actin (alpha-SMA). Adenosine 3', 5'-cyclic monophosphate (cyclic AMP) is an ubiquitous intracellular signaling molecule, and is upregulated by the activation of adenylate cyclase and downregulated via hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). Recently, increased intracellular cyclic AMP has been shown to inhibit HSC activation. The aim of the current study was to determine the effects of inhibition of PDEs on cell proliferation and transdifferentiation in cultured rat HSC. Cell proliferation was determined by [3H]thymidine incorporation, and Western blot analysis was performed for detection of alpha-SMA, a phenotypic marker of transdifferentiation into myofibroblast. When the cells were exposed to 3-isobutyl-1-methylxanthine (IBMX; 50-1000 microM), a nonselective PDE inhibitor, serum-stimulated [3H]thymidine incorporation was suppressed in a dose-dependent manner with a maximum inhibition of 66% at a concentration of 500 microM OPC-13013 (1-60 microM), a selective PDE III isoenzyme inhibitor, induced a dose-dependent inhibitory effect on serum-stimulated DNA synthesis that reached a maximum inhibition of 95% at a concentration of 60 microM, while neither 8-methoxymethyl-3-isobutyl-1-methylxanthine (8-MMX), a PDE I isoenzyme inhibitor, nor Ro-20-1724, a PDE IV isoenzyme inhibitor, had an inhibitory effect. Western blot analysis revealed that IBMX or OPC-13013 decreased alpha-SMA expression, while other selective PDE isoenzyme inhibitors did not have a suppressive effect. IBMX, OPC-13013 or Ro-20-1724, but not 8-MMX augmented forskolin-induced increase in intracellular cyclic AMP levels although cyclic AMP levels were not affected by treatment with any of these PDE inhibitors alone. These data indicate that inhibition of PDEs, especially PDE III isoenzyme, can produce an inhibitory effect on HSC activation. The PDE III isoenzyme may contribute to the regulation of HSC activation during fibrogenesis. In addition, OPC-13013 may have the potential to inhibit initiation and progression of hepatic fibrosis by interfering with HSC activation.

Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes

PubMed Central

Shi, Qian; Li, Minghui; Mika, Delphine; Fu, Qin; Kim, Sungjin; Phan, Jason; Shen, Ao; Vandecasteele, Gregoire; Xiang, Yang K.

2017-01-01

Aims Cardiac β-adrenergic receptor (βAR) signalling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between βARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists. Methods and results Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists. Activation of Gs-coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and Gq-coupled α1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of β1AR and β2AR at putative protein kinase A (PKA) phosphorylation sites; but activation of Gi-coupled α2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote β2AR phosphorylation effectively inhibit βAR agonist isoproterenol-induced PKA phosphorylation of phospholamban and contractile function in ventricular cardiomyocytes. Heterologous GPCR stimuli have minimal to small effect on isoproterenol-induced β2AR activation and G-protein coupling for cyclic adenosine monophosphate (cAMP) production. However, these GPCR stimuli significantly promote phosphorylation of phosphodiesterase 4D (PDE4D), and recruit PDE4D to the phosphorylated β2AR in a β-arrestin 2 dependent manner without promoting β2AR endocytosis. The increased binding between β2AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in β2AR, inhibition of PDE4, or genetic ablation of PDE4D or β-arrestin 2 abolishes this heterologous inhibitory effect. Ablation of β-arrestin 2 or PDE4D gene also rescues β-adrenergic stimuli-induced myocyte contractile function. Conclusions These data reveal essential roles of β-arrestin 2 and PDE4D in a common mechanism for heterologous desensitization of cardiac βARs under hormonal stimulation, which is associated with impaired cardiac function during the development of pathophysiological conditions. PMID:28339772

Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes.

PubMed

Shi, Qian; Li, Minghui; Mika, Delphine; Fu, Qin; Kim, Sungjin; Phan, Jason; Shen, Ao; Vandecasteele, Gregoire; Xiang, Yang K

2017-05-01

Cardiac β-adrenergic receptor (βAR) signalling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between βARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists. Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists. Activation of Gs-coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and Gq-coupled α1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of β1AR and β2AR at putative protein kinase A (PKA) phosphorylation sites; but activation of Gi-coupled α2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote β2AR phosphorylation effectively inhibit βAR agonist isoproterenol-induced PKA phosphorylation of phospholamban and contractile function in ventricular cardiomyocytes. Heterologous GPCR stimuli have minimal to small effect on isoproterenol-induced β2AR activation and G-protein coupling for cyclic adenosine monophosphate (cAMP) production. However, these GPCR stimuli significantly promote phosphorylation of phosphodiesterase 4D (PDE4D), and recruit PDE4D to the phosphorylated β2AR in a β-arrestin 2 dependent manner without promoting β2AR endocytosis. The increased binding between β2AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in β2AR, inhibition of PDE4, or genetic ablation of PDE4D or β-arrestin 2 abolishes this heterologous inhibitory effect. Ablation of β-arrestin 2 or PDE4D gene also rescues β-adrenergic stimuli-induced myocyte contractile function. These data reveal essential roles of β-arrestin 2 and PDE4D in a common mechanism for heterologous desensitization of cardiac βARs under hormonal stimulation, which is associated with impaired cardiac function during the development of pathophysiological conditions. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

Adherence to Phosphodiesterase Type 5 Inhibitors in the Treatment of Erectile Dysfunction in Long-Term Users: How Do Men Use the Inhibitors?

PubMed Central

Carvalheira, Ana; Forjaz, Vera; Pereira, Nuno Monteiro

2014-01-01

Introduction The high effectiveness of phosphodiesterase type 5 inhibitors (PDE5-i) in the treatment of erectile dysfunction (ED) has been demonstrated. However, previous research shows that PDE5-i treatments have high discontinuation rates. Aim The main goals of this study were to (i) characterize the way men use PDE5-i and (ii) analyze the adherence to treatment, identifying the factors that influence PDE5-i use. Methods A total of 148 men with clinical diagnosis for ED who maintained the treatment with PDE5-i for over 3 years were interviewed. Interviews concerning their ongoing treatment were carried out using a standardized questionnaire with quantitative and qualitative items. Main Outcome Measures Physiological measures included the intracavernous alprostadil injection test, associated with penile rigidometry and penile Doppler ultrasound. The qualitative measure included two questions: “Do you use the drug in every sexual intercourse?” and “How do you use the inhibitor?” Results ED causes were classified as venogenic (31%), arteriogenic (23%), psychogenic (18%), iatrogenic (13%), neurogenic (8%), and diabetic (7%). Participation rate was 71.8%. Of the 148 patients studied, 75% claimed not to use PDE5-i in every intercourse. Most used tadalafil (66%), followed by sildenafil (20%), vardenafil (10%), and 4% alternated the type of medicine. Four main categories emerged concerning the factors that determine the intake of PDE5-i in some intercourse situations and not in others: (i) psychological factors; (ii) medication-related factors; (iii) circumstantial factors; and (iv) relational factors. Conclusion The analysis of men's narratives revealed a combination of factors that influence the adherence to PDE5-i. The psychological and medication-related factors were the most prevalent. This study highlighted the importance of taking these factors into account, both at the time of prescription and during the follow-up in order to improve adherence. Carvalheira A, Forjaz V, and Pereira NM. Adherence to phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction in long-term users: How do men use the inhibitors? Sex Med 2014;2:96–102. PMID:25356304

Decision tree analyses of key patient characteristics in Middle Eastern/North African and Latin American men treated with long-acting and short-acting PDE5 inhibitors for erectile dysfunction.

PubMed

Rubio-Aurioles, Eusebio; El-Meliegy, Amr; Abdulwahed, Samer; Henneges, Carsten; Sorsaburu, Sebastian; Gurbuz, Sirel

2015-02-01

Phosphodiesterase type 5 (PDE5) inhibitors have discontinuation rates as high as 60% in men with erectile dysfunction. Treatment satisfaction has been significantly associated with treatment continuation. Understanding key characteristics in terms of treatment preference, relationship, and lifestyle issues could provide direction on how to improve compliance with PDE5 inhibitor treatment globally. The objective was to identify subgroups of interest in the pooled database of two observational studies conducted in Latin America (LA) and Middle East/North Africa (MENA) exploring patient characteristics and prescription of either a long- or short-acting PDE5 inhibitor at baseline. Two identical prospective, non-interventional, observational, studies in MENA (N = 493) and LA (N = 511) treated men with an 'on demand' (pro re nata, PRN) PDE5 inhibitor (sildenafil, tadalafil, vardenafil, or lodenafil) during 6 months. In this post-hoc meta-analysis of two observational studies with equal design, pooled data were analyzed to determine patient characteristics and PDE5 inhibitor prescribed/used most likely to be associated with patient expectations, satisfaction, self-esteem, and patient-partner relationships. Decision tree analyses, with and without weighting, were used to identify and describe key features. In each analysis of patient expectations, patient-partner relationship, and self-esteem, we describe the two major subgroups at baseline for each decision tree. Analyses of patient expectations and sexual self-esteem revealed that patients prescribed long-acting PDE5 inhibitors (59%) highlighted the importance of treatment effect duration, second to partner satisfaction with treatment, while patients prescribed short-acting PDE5 inhibitors (32%) placed less importance on treatment effect duration but considerable importance on treatment effect lasting until intercourse completion. Further insights regarding patients, partner relationship characteristics, and treatment expectations were identified. Our analyses have described key characteristics, such as self- and partner perceptions, sexual attitudes, and treatment expectations in relation to the patients' country and prescribed treatment, which might guide treatment decisions in MENA and LA men with ED.

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.

Spillover, nonlinearity, and flexible structures

NASA Technical Reports Server (NTRS)

Bass, Robert W.; Zes, Dean

1991-01-01

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

"That's Really Clever!" Ironic Hyperbole Understanding in Children

ERIC Educational Resources Information Center

Aguert, Marc; Le Vallois, Coralie; Martel, Karine; Laval, Virginie

2018-01-01

Hyperbole supports irony comprehension in adults by heightening the contrast between what is said and the actual situation. Because young children do not perceive the communication situation as a whole, but rather give precedence to either the utterance or the context, we predicted that hyperbole would reduce irony comprehension in six-year-olds…

Hyperbolicity measures democracy in real-world networks

NASA Astrophysics Data System (ADS)

Borassi, Michele; Chessa, Alessandro; Caldarelli, Guido

2015-09-01

In this work, we analyze the hyperbolicity of real-world networks, a geometric quantity that measures if a space is negatively curved. We provide two improvements in our understanding of this quantity: first of all, in our interpretation, a hyperbolic network is "aristocratic", since few elements "connect" the system, while a non-hyperbolic network has a more "democratic" structure with a larger number of crucial elements. The second contribution is the introduction of the average hyperbolicity of the neighbors of a given node. Through this definition, we outline an "influence area" for the vertices in the graph. We show that in real networks the influence area of the highest degree vertex is small in what we define "local" networks (i.e., social or peer-to-peer networks), and large in "global" networks (i.e., power grid, metabolic networks, or autonomous system networks).

The Linear Quadratic Optimal Control Problem for Infinite Dimensional Systems with Unbounded Input and Output Operators.

DTIC Science & Technology

1984-01-01

5.5) respectively (5.3) and (5.8) which means that u(t) - 0 respectively v(t) - 0 for t > o. The evolution of the systems (5.1) and (5.3) in terms ...input/output delays; and b) the general theory is presented in such a way that it applies to both . . ... ..- Lr parabolic and hyperbolic I P9es as...particular emphasis is placed on the development of the duality theory by means of two different state concepts. The resulting evolution equations

On Compressible Vortex Sheets

NASA Astrophysics Data System (ADS)

Secchi, Paolo

2005-05-01

We introduce the main known results of the theory of incompressible and compressible vortex sheets. Moreover, we present recent results obtained by the author with J. F. Coulombel about supersonic compressible vortex sheets in two space dimensions. The problem is a nonlinear free boundary hyperbolic problem with two difficulties: the free boundary is characteristic and the Lopatinski condition holds only in a weak sense, yielding losses of derivatives. Under a supersonic condition that precludes violent instabilities, we prove an energy estimate for the boundary value problem obtained by linearization around an unsteady piecewise solution.

Relation of phosphodiesterase type 5 inhibitors and malignant melanoma: a meta-analysis and systematic review.

PubMed

Wang, Jie; Shen, Yigen; Wang, Jiaoni; Xue, Yangjing; Liao, Lianming; Thapa, Saroj; Ji, Kangting

2017-07-11

Data on the association between using PDE5 inhibitors and malignant melanoma are conflicting. To estimate the relation of using PDE5 inhibitors with risk of malignant melanoma, Medline (Ovid) and Embase (Ovid) databases were searched up to February 2017, and a random effects model was used to calculate the summary risk estimates. Five observational studies were included. Five studies reports encompassed a total of 15,979 melanoma cases occurring among 1, 188,414 participants. The pooled multivariable-adjusted RR of melanoma in patients with using PDE5 inhibitors was 1.12 (95% CI: 1.03-1.21, I2 = 0.48). Findings from this systematic review support that PDE5 inhibitor use is associated with increased risk of melanoma in ED patients, the result remains inclusive and warrants further study in the future.

Roth spots in pyridoxine dependent epilepsy

PubMed Central

Bok, Levinus A; Halbertsma, Feico; Kerkhoff, Frank; Jakobs, Cornelis; Duijsters, Carola; Willemsen, Michèl

2011-01-01

Pyridoxine dependent epilepsy (PDE) is a rare metabolic defect in the degradation of lysine. The authors report a patient with metabolic and DNA confirmed PDE, on the fifth day of life ophthalmoscopy showed bilateral multiple white centred retinal haemorrhages, so called Roth spots. Roth spots are non-specific haemorrhagic signs that occur in a variety of conditions of acute systemic insults in homeostasis – most often infections- which relate to retinal capillary damage and the ensuing reparative process. No biochemical or microbiological signs of infection were present in blood and liquor. MRI of the brain showed an abnormal diffusion signal with increased apparent diffusion coefficient and little blood around the tentorium. The knowledge of the pathogenesis of PDE is still limited. The presence of Roth spots is suggestive for a pathogenic mechanism of vasogenic damage in PDE. PMID:22688935

PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.

PubMed

Nelson, Michael D; Rader, Florian; Tang, Xiu; Tavyev, Jane; Nelson, Stanley F; Miceli, M Carrie; Elashoff, Robert M; Sweeney, H Lee; Victor, Ronald G

2014-06-10

To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis. © 2014 American Academy of Neurology.

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

PubMed

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

2015-11-05

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-rs(b)) 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.

On locally and nonlocally related potential systems

NASA Astrophysics Data System (ADS)

Cheviakov, Alexei F.; Bluman, George W.

2010-07-01

For any partial differential equation (PDE) system, a local conservation law yields potential equations in terms of some potential variable, which normally is a nonlocal variable. The current paper examines situations when such a potential variable is a local variable, i.e., is a function of the independent and dependent variables of a given PDE system, and their derivatives. In the case of two independent variables, a simple necessary and sufficient condition is presented for the locality of such a potential variable, and this is illustrated by several examples. As a particular example, two-dimensional reductions of equilibrium equations for fluid and plasma dynamics are considered. It is shown that such reductions with respect to helical, axial, and translational symmetries have conservation laws which yield local potential variables. This leads to showing that the well-known Johnson-Frieman-Kruskal-Oberman (JFKO) and Bragg-Hawthorne (Grad-Shafranov) equations are locally related to the corresponding helically and axially symmetric PDE systems of fluid/plasma dynamics. For the axially symmetric case, local symmetry classifications and arising invariant solutions are compared for the original PDE system and the Bragg-Hawthorne (potential) equation. The potential equation is shown to have additional symmetries, denoted as restricted symmetries. Restricted symmetries leave invariant a family of solutions of a given PDE system but not the whole solution manifold, and hence are not symmetries of the given PDE system. Corresponding reductions are shown to yield solutions, which are not obtained as invariant solutions from local symmetry reduction.

Functional characterization of the human phosphodiesterase 7A1 promoter.

PubMed Central

Torras-Llort, Mònica; Azorín, Fernando

2003-01-01

In this paper, the human phosphodiesterase 7A1 (h PDE7A1 ) promoter region was identified and functionally characterized. Transient transfection experiments indicated that a 2.9 kb fragment of the h PDE7A1 5'-flanking region, to position -2907, has strong promoter activity in Jurkat T-cells. Deletion analysis showed that the proximal region, up to position -988, contains major cis -regulatory elements of the h PDE7A1 promoter. This minimal promoter region contains a regulatory CpG island which is essential for promoter activity. The CpG island contains three potential cAMP-response-element-binding protein (CREB)-binding sites that, as judged by in vivo dimethyl sulphate (DMS) footprinting, are occupied in Jurkat T-cells. Moreover, over-expression of CREB results in increased promoter activity, but, on the other hand, promoter activity decreases when a dominant-negative form of CREB (KCREB) is over-expressed. In vivo DMS footprinting strongly indicates that other transcription factors, such Ets-2, nuclear factor of activated T-cells 1 (NFAT-1) and nuclear factor kappaB (NF-kappaB), might also contribute to the regulation of h PDE7A1 promoter. Finally, h PDE7A1 promoter was found to be induced by treatment with PMA, but not by treatment with dibutyryl cAMP or forskolin. These results provide insights into the factors and mechanisms that regulate expression of the h PDE7A gene. PMID:12737631

Classification of Tidal Disruption Events Based on Stellar Orbital Properties

NASA Astrophysics Data System (ADS)

Hayasaki, Kimitake; Zhong, Shiyan; Li, Shuo; Berczik, Peter; Spurzem, Rainer

2018-03-01

We study the rates of tidal disruption of stars on bound to unbound orbits by intermediate-mass to supermassive black holes using high-accuracy direct N-body experiments. Stars from the star cluster approaching the black hole can have three types of orbit: eccentric, parabolic, and hyperbolic. Since the mass fallback rate shows different variabilities depending on the orbital type, we can classify tidal disruption events (TDEs) into three main categories: eccentric, parabolic, and hyperbolic. The respective TDEs are characterized by two critical values of the orbital eccentricity: the lower critical eccentricity is the one below which stars on eccentric orbits cause finite, intense accretion, and the upper critical eccentricity is the one above which stars on hyperbolic orbits cause no accretion. Moreover, we find that parabolic TDEs can be divided into three subclasses: precisely parabolic, marginally eccentric, and marginally hyperbolic. We analytically derive that the mass fallback rate of marginally eccentric TDEs can be flatter and slightly higher than the standard fallback rate proportional to t ‑5/3, whereas it can be flatter and lower for marginally hyperbolic TDEs. We confirm using N-body experiments that only a few eccentric, precisely parabolic, and hyperbolic TDEs can occur in a spherical stellar system with a single intermediate-mass to supermassive black hole. A substantial fraction of the stars approaching the black hole would cause marginally eccentric or marginally hyperbolic TDEs.

Is chronic inhibition of phosphodiesterase type 5 cardioprotective and safe? A meta-analysis of randomized controlled trials.

PubMed

Giannetta, Elisa; Feola, Tiziana; Gianfrilli, Daniele; Pofi, Riccardo; Dall'Armi, Valentina; Badagliacca, Roberto; Barbagallo, Federica; Lenzi, Andrea; Isidori, Andrea M

2014-10-20

The myocardial effects of phosphodiesterase type 5 inhibitors (PDE5i) have recently received consideration in several preclinical studies. The risk/benefit ratio in humans remains unclear. We performed a meta-analysis of randomized, placebo-controlled trials (RCTs) to evaluate the efficacy and safety of PDE5i on cardiac morphology and function. From March 2012 to December 2013 (update: May 2014), we searched English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and SCOPUS-selecting RCTs of continuous PDE5i administration that reported cardiovascular outcomes: cardiac geometry and performance, afterload, endothelial function and safety. The pooled estimate of a weighted mean difference between treatment and placebo was obtained for all outcomes using a random effects model. A test for heterogeneity was performed and the I2 statistic calculated. Overall, 1,622 subjects were treated, with 954 randomized to PDE5i and 772 to placebo in 24 RCTs. According to our analysis, sustained PDE5 inhibition produced: (1) an anti-remodeling effect by reducing cardiac mass (-12.21 g/m2, 95% confidence interval (CI): -18.85; -5.57) in subjects with left ventricular hypertrophy (LVH) and by increasing end-diastolic volume (5.00 mL/m2; 95% CI: 3.29; 6.71) in non-LVH patients; (2) an improvement in cardiac performance by increasing cardiac index (0.30 L/min/m2, 95% CI: 0.202; 0.406) and ejection fraction (3.56%, 95% CI: 1.79; 5.33). These effects are parallel to a decline of N-terminal-pro brain natriuretic peptide (NT-proBNP) in subjects with severe LVH (-486.7 pg/ml, 95% CI: -712; -261). PDE5i administration also produced: (3) no changes in afterload parameters and (4) an improvement in flow-mediated vasodilation (3.31%, 95% CI: 0.53; 6.08). Flushing, headache, epistaxis and gastric symptoms were the commonest side effects. This meta-analysis suggests for the first time that PDE5i have anti-remodeling properties and improve cardiac inotropism, independently of afterload changes, with a good safety profile. Given the reproducibility of the findings and tolerability across different populations, PDE5i could be reasonably offered to men with cardiac hypertrophy and early stage heart failure. Given the limited gender data, a larger trial on the sex-specific response to long-term PDE5i treatment is required.

Patterns of age related changes for phosphodiesterase type-10A in comparison with dopamine D2/3 receptors and sub-cortical volumes in the human basal ganglia: A PET study with 18F-MNI-659 and 11C-raclopride with correction for partial volume effect.

PubMed

Fazio, Patrik; Schain, Martin; Mrzljak, Ladislav; Amini, Nahid; Nag, Sangram; Al-Tawil, Nabil; Fitzer-Attas, Cheryl J; Bronzova, Juliana; Landwehrmeyer, Bernhard; Sampaio, Cristina; Halldin, Christer; Varrone, Andrea

2017-05-15

Phosphodiesterase 10A enzyme (PDE10A) is an important striatal target that has been shown to be affected in patients with neurodegenerative disorders, particularly Huntington´s disease (HD). PDE10A is expressed on striatal neurones in basal ganglia where other known molecular targets are enriched such as dopamine D 2/3 receptors (D 2/3 R). The aim of this study was to examine the availability of PDE10A enzyme in relation with age and gender and to compare those changes with those related to D 2/3 R and volumes in different regions of the basal ganglia. As a secondary objective we examined the relative distribution of D 2/3 R and PDE10A enzyme in the striatum and globus pallidus. Forty control subjects (20F/20M; age: 44±11y, age range 27-69) from an ongoing positron emission tomography (PET) study in HD gene expansion carriers were included. Subjects were examined with PET using the high-resolution research tomograph (HRRT) and with 3T magnetic resonance imaging (MRI). The PDE10A radioligand 18 F-MNI-659 and D 2/3 R radioligand 11 C-raclopride were used. The outcome measure was the binding potential (BP ND ) estimated with the two-tissue compartment model ( 18 F-MNI-659) and the simplified reference tissue model ( 11 C-raclopride) using the cerebellum as reference region. The PET data were corrected for partial volume effects. In the striatum, PDE10A availability showed a significant age-related decline that was larger compared to the age-related decline of D 2/3 R availability and to the age-related decline of volumes measured with MRI. In the globus pallidus, a less pronounced decline of PDE10A availability was observed, whereas D 2/3 R availability and volumes seemed to be rather stable with aging. The distribution of the PDE10A enzyme was different from the distribution of D 2/3 R, with higher availability in the globus pallidus. These results indicate that aging is associated with a considerable physiological reduction of the availability of PDE10A enzyme in the striatum. Moreover as result of the analysis, in the striatum for both the molecular targets, we observed a gender effect with higher BP ND the female group. Copyright © 2017 Elsevier Inc. All rights reserved.

Delay, Probability, and Social Discounting in a Public Goods Game

ERIC Educational Resources Information Center

Jones, Bryan A.; Rachlin, Howard

2009-01-01

A human social discount function measures the value to a person of a reward to another person at a given social distance. Just as delay discounting is a hyperbolic function of delay, and probability discounting is a hyperbolic function of odds-against, social discounting is a hyperbolic function of social distance. Experiment 1 obtained individual…

Thrust Augmentation Measurements for a Pulse Detonation Engine Driven Ejector

NASA Technical Reports Server (NTRS)

Pal, S.; Santoro, Robert J.; Shehadeh, R.; Saretto, S.; Lee, S.-Y.

2005-01-01

Thrust augmentation results of an ongoing study of pulse detonation engine driven ejectors are presented and discussed. The experiments were conducted using a pulse detonation engine (PDE) setup with various ejector configurations. The PDE used in these experiments utilizes ethylene (C2H4) as the fuel, and an equi-molar mixture of oxygen and nitrogen as the oxidizer at an equivalence ratio of one. High fidelity thrust measurements were made using an integrated spring damper system. The baseline thrust of the PDE engine was first measured and agrees with experimental and modeling results found in the literature. Thrust augmentation measurements were then made for constant diameter ejectors. The parameter space for the study included ejector length, PDE tube exit to ejector tube inlet overlap distance, and straight versus rounded ejector inlets. The relationship between the thrust augmentation results and various physical phenomena is described. To further understand the flow dynamics, shadow graph images of the exiting shock wave front from the PDE were also made. For the studied parameter space, the results showed a maximum augmentation of 40%. Further increase in augmentation is possible if the geometry of the ejector is tailored, a topic currently studied by numerous groups in the field.

Toward the identification of the cardiac cGMP inhibited-phosphodiesterase catalytic site

NASA Astrophysics Data System (ADS)

Fossa, Paola; Boggia, Raffaella; Mosti, Luisa

1998-07-01

Cyclic nucleotide phosphodiesterases (PDEs) comprise a complex group of enzymes; five major PDE families or classes with distinctive properties have been identified. Among these a great deal of interest has recently been focused on the so called cGMP-inhibited low Km cAMP phosphodiesterase (cGI PDE) or PDE III. A number of positive inotropic agents, including the well-known milrinone, display a specific inhibition of PDE III as primary mechanism of action. Recent studies have been carried out to develop a pharmacophore model of the PDE III active site. We therefore performed molecular modelling and 3D-SAR studies so as to better define structural requirements for potent and selective enzymatic inhibition. The DISCO (DIStance COmparison) strategy has been applied on a set of compounds taken from literature and a milrinone analogue previously synthesized by us, all of which are characterized by a marked inotropic effect but with varying degrees of enzyme selectivity. A common pharmacophoric model was derived, validated and considered as starting point to perform a 3D-SAR study using the GRID force field and PCA (Principal Component Analysis) with the aim of rationally designing more selective inhibitors. This paper presents the results of this theoretical approach.

Application of dry elixir system to oriental traditional medicine: taste masking of peonjahwan by coated dry elixir.

PubMed

Choi, H G; Kim, C K

2000-02-01

Peonjahwan, an oriental traditional medicine composed of crude herbal drugs and animal tissues is bitter and poorly water-soluble. To mask the bitterness of peonjahwan and enhance the release of bilirubin, one of the crude active ingredients of peonjahwan, peonja dry elixir (PDE), was prepared using a spray-dryer after extracting the crude materials in ethanol-water solution. Coated peonja dry elixir (CPDE) was then prepared by coating the PDE with Eudragit acrylic resin. Panel assessed bitterness and release test of bilirubin from PDE and CPDE were carried out and compared with peonjahwan alone. PDE was found to have little effect upon the reduction of the bitterness of peonjahwan. However, the bitterness of CPDE was found to reduce to 1/4 of that of peonjahwan due to the encapsulation of crude active ingredients by the dextrin and Eudragit shell (P<0.05). The release rate of bilirubin from PDE and CPDE for 60 min increased about 3.5- and 2.5- fold, respectively, compared to peonjahwan at pH 1.2. It is concluded that CPDE, which masked the bitterness of peonjahwan and enhanced the release of bilirubin, is a preferable delivery system for peonjahwan.

Dual specificity and novel structural folding of yeast phosphodiesterase-1 for hydrolysis of second messengers cyclic adenosine and guanosine 3',5'-Monophosphate

DOE PAGES

Tian, Yuanyuan; Cui, Wenjun; Huang, Manna; ...

2014-08-05

Cyclic nucleotide phosphodiesterases (PDEs) decompose second messengers cAMP and cGMP that play critical roles in many physiological processes. PDE1 of Saccharomyces cerevisiae has been subcloned and expressed in Escherichia coli. Recombinant yPDE1 has a K M of 110 μM and a k cat of 16.9 s⁻¹ for cAMP and a K M of 105 μM and a k cat of 11.8 s₅⁻¹ for cGMP. Thus, the specificity constant (k cat/K McAMP)/(k cat/K M cGMP) of 1.4 indicates a dual specificity of yPDE1 for hydrolysis of both cAMP and cGMP. The crystal structures of unliganded yPDE1 and its complex with GMPmore » at 1.31 Å resolution reveal a new structural folding that is different from those of human PDEs but is partially similar to that of some other metalloenzymes such as metallo-β-lactamase. In spite of their different structures and divalent metals, yPDE1 and human PDEs may share a common mechanism for hydrolysis of cAMP and cGMP.« less

Critical time scales for advection-diffusion-reaction processes.

PubMed

Ellery, Adam J; Simpson, Matthew J; McCue, Scott W; Baker, Ruth E

2012-04-01

The concept of local accumulation time (LAT) was introduced by Berezhkovskii and co-workers to give a finite measure of the time required for the transient solution of a reaction-diffusion equation to approach the steady-state solution [A. M. Berezhkovskii, C. Sample, and S. Y. Shvartsman, Biophys. J. 99, L59 (2010); A. M. Berezhkovskii, C. Sample, and S. Y. Shvartsman, Phys. Rev. E 83, 051906 (2011)]. Such a measure is referred to as a critical time. Here, we show that LAT is, in fact, identical to the concept of mean action time (MAT) that was first introduced by McNabb [A. McNabb and G. C. Wake, IMA J. Appl. Math. 47, 193 (1991)]. Although McNabb's initial argument was motivated by considering the mean particle lifetime (MPLT) for a linear death process, he applied the ideas to study diffusion. We extend the work of these authors by deriving expressions for the MAT for a general one-dimensional linear advection-diffusion-reaction problem. Using a combination of continuum and discrete approaches, we show that MAT and MPLT are equivalent for certain uniform-to-uniform transitions; these results provide a practical interpretation for MAT by directly linking the stochastic microscopic processes to a meaningful macroscopic time scale. We find that for more general transitions, the equivalence between MAT and MPLT does not hold. Unlike other critical time definitions, we show that it is possible to evaluate the MAT without solving the underlying partial differential equation (pde). This makes MAT a simple and attractive quantity for practical situations. Finally, our work explores the accuracy of certain approximations derived using MAT, showing that useful approximations for nonlinear kinetic processes can be obtained, again without treating the governing pde directly.