Modeling and Simulation of High Dimensional Stochastic Multiscale PDE Systems at the Exascale

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

Kevrekidis, Ioannis

2017-03-22

The thrust of the proposal was to exploit modern data-mining tools in a way that will create a systematic, computer-assisted approach to the representation of random media -- and also to the representation of the solutions of an array of important physicochemical processes that take place in/on such media. A parsimonious representation/parametrization of the random media links directly (via uncertainty quantification tools) to good sampling of the distribution of random media realizations. It also links directly to modern multiscale computational algorithms (like the equation-free approach that has been developed in our group) and plays a crucial role in accelerating themore » scientific computation of solutions of nonlinear PDE models (deterministic or stochastic) in such media – both solutions in particular realizations of the random media, and estimation of the statistics of the solutions over multiple realizations (e.g. expectations).« less

Solving Partial Differential Equations in a data-driven multiprocessor environment

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

Gaudiot, J.L.; Lin, C.M.; Hosseiniyar, M.

1988-12-31

Partial differential equations can be found in a host of engineering and scientific problems. The emergence of new parallel architectures has spurred research in the definition of parallel PDE solvers. Concurrently, highly programmable systems such as data-how architectures have been proposed for the exploitation of large scale parallelism. The implementation of some Partial Differential Equation solvers (such as the Jacobi method) on a tagged token data-flow graph is demonstrated here. Asynchronous methods (chaotic relaxation) are studied and new scheduling approaches (the Token No-Labeling scheme) are introduced in order to support the implementation of the asychronous methods in a data-driven environment.more » New high-level data-flow language program constructs are introduced in order to handle chaotic operations. Finally, the performance of the program graphs is demonstrated by a deterministic simulation of a message passing data-flow multiprocessor. An analysis of the overhead in the data-flow graphs is undertaken to demonstrate the limits of parallel operations in dataflow PDE program graphs.« less

AQUASOL: An efficient solver for the dipolar Poisson–Boltzmann–Langevin equation

PubMed Central

Koehl, Patrice; Delarue, Marc

2010-01-01

The Poisson–Boltzmann (PB) formalism is among the most popular approaches to modeling the solvation of molecules. It assumes a continuum model for water, leading to a dielectric permittivity that only depends on position in space. In contrast, the dipolar Poisson–Boltzmann–Langevin (DPBL) formalism represents the solvent as a collection of orientable dipoles with nonuniform concentration; this leads to a nonlinear permittivity function that depends both on the position and on the local electric field at that position. The differences in the assumptions underlying these two models lead to significant differences in the equations they generate. The PB equation is a second order, elliptic, nonlinear partial differential equation (PDE). Its response coefficients correspond to the dielectric permittivity and are therefore constant within each subdomain of the system considered (i.e., inside and outside of the molecules considered). While the DPBL equation is also a second order, elliptic, nonlinear PDE, its response coefficients are nonlinear functions of the electrostatic potential. Many solvers have been developed for the PB equation; to our knowledge, none of these can be directly applied to the DPBL equation. The methods they use may adapt to the difference; their implementations however are PBE specific. We adapted the PBE solver originally developed by Holst and Saied [J. Comput. Chem. 16, 337 (1995)] to the problem of solving the DPBL equation. This solver uses a truncated Newton method with a multigrid preconditioner. Numerical evidences suggest that it converges for the DPBL equation and that the convergence is superlinear. It is found however to be slow and greedy in memory requirement for problems commonly encountered in computational biology and computational chemistry. To circumvent these problems, we propose two variants, a quasi-Newton solver based on a simplified, inexact Jacobian and an iterative self-consistent solver that is based directly on the PBE solver. While both methods are not guaranteed to converge, numerical evidences suggest that they do and that their convergence is also superlinear. Both variants are significantly faster than the solver based on the exact Jacobian, with a much smaller memory footprint. All three methods have been implemented in a new code named AQUASOL, which is freely available. PMID:20151727

AQUASOL: An efficient solver for the dipolar Poisson-Boltzmann-Langevin equation.

PubMed

Koehl, Patrice; Delarue, Marc

2010-02-14

The Poisson-Boltzmann (PB) formalism is among the most popular approaches to modeling the solvation of molecules. It assumes a continuum model for water, leading to a dielectric permittivity that only depends on position in space. In contrast, the dipolar Poisson-Boltzmann-Langevin (DPBL) formalism represents the solvent as a collection of orientable dipoles with nonuniform concentration; this leads to a nonlinear permittivity function that depends both on the position and on the local electric field at that position. The differences in the assumptions underlying these two models lead to significant differences in the equations they generate. The PB equation is a second order, elliptic, nonlinear partial differential equation (PDE). Its response coefficients correspond to the dielectric permittivity and are therefore constant within each subdomain of the system considered (i.e., inside and outside of the molecules considered). While the DPBL equation is also a second order, elliptic, nonlinear PDE, its response coefficients are nonlinear functions of the electrostatic potential. Many solvers have been developed for the PB equation; to our knowledge, none of these can be directly applied to the DPBL equation. The methods they use may adapt to the difference; their implementations however are PBE specific. We adapted the PBE solver originally developed by Holst and Saied [J. Comput. Chem. 16, 337 (1995)] to the problem of solving the DPBL equation. This solver uses a truncated Newton method with a multigrid preconditioner. Numerical evidences suggest that it converges for the DPBL equation and that the convergence is superlinear. It is found however to be slow and greedy in memory requirement for problems commonly encountered in computational biology and computational chemistry. To circumvent these problems, we propose two variants, a quasi-Newton solver based on a simplified, inexact Jacobian and an iterative self-consistent solver that is based directly on the PBE solver. While both methods are not guaranteed to converge, numerical evidences suggest that they do and that their convergence is also superlinear. Both variants are significantly faster than the solver based on the exact Jacobian, with a much smaller memory footprint. All three methods have been implemented in a new code named AQUASOL, which is freely available.

A fast solver for the Helmholtz equation based on the generalized multiscale finite-element method

NASA Astrophysics Data System (ADS)

Fu, Shubin; Gao, Kai

2017-11-01

Conventional finite-element methods for solving the acoustic-wave Helmholtz equation in highly heterogeneous media usually require finely discretized mesh to represent the medium property variations with sufficient accuracy. Computational costs for solving the Helmholtz equation can therefore be considerably expensive for complicated and large geological models. Based on the generalized multiscale finite-element theory, we develop a novel continuous Galerkin method to solve the Helmholtz equation in acoustic media with spatially variable velocity and mass density. Instead of using conventional polynomial basis functions, we use multiscale basis functions to form the approximation space on the coarse mesh. The multiscale basis functions are obtained from multiplying the eigenfunctions of a carefully designed local spectral problem with an appropriate multiscale partition of unity. These multiscale basis functions can effectively incorporate the characteristics of heterogeneous media's fine-scale variations, thus enable us to obtain accurate solution to the Helmholtz equation without directly solving the large discrete system formed on the fine mesh. Numerical results show that our new solver can significantly reduce the dimension of the discrete Helmholtz equation system, and can also obviously reduce the computational time.

Uncertainty Quantification of Non-linear Oscillation Triggering in a Multi-injector Liquid-propellant Rocket Combustion Chamber

NASA Astrophysics Data System (ADS)

Popov, Pavel; Sideris, Athanasios; Sirignano, William

2014-11-01

We examine the non-linear dynamics of the transverse modes of combustion-driven acoustic instability in a liquid-propellant rocket engine. Triggering can occur, whereby small perturbations from mean conditions decay, while larger disturbances grow to a limit-cycle of amplitude that may compare to the mean pressure. For a deterministic perturbation, the system is also deterministic, computed by coupled finite-volume solvers at low computational cost for a single realization. The randomness of the triggering disturbance is captured by treating the injector flow rates, local pressure disturbances, and sudden acceleration of the entire combustion chamber as random variables. The combustor chamber with its many sub-fields resulting from many injector ports may be viewed as a multi-scale complex system wherein the developing acoustic oscillation is the emergent structure. Numerical simulation of the resulting stochastic PDE system is performed using the polynomial chaos expansion method. The overall probability of unstable growth is assessed in different regions of the parameter space. We address, in particular, the seven-injector, rectangular Purdue University experimental combustion chamber. In addition to the novel geometry, new features include disturbances caused by engine acceleration and unsteady thruster nozzle flow.

A multi-scale network method for two-phase flow in porous media

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

Khayrat, Karim, E-mail: khayratk@ifd.mavt.ethz.ch; Jenny, Patrick

Pore-network models of porous media are useful in the study of pore-scale flow in porous media. In order to extract macroscopic properties from flow simulations in pore-networks, it is crucial the networks are large enough to be considered representative elementary volumes. However, existing two-phase network flow solvers are limited to relatively small domains. For this purpose, a multi-scale pore-network (MSPN) method, which takes into account flow-rate effects and can simulate larger domains compared to existing methods, was developed. In our solution algorithm, a large pore network is partitioned into several smaller sub-networks. The algorithm to advance the fluid interfaces withinmore » each subnetwork consists of three steps. First, a global pressure problem on the network is solved approximately using the multiscale finite volume (MSFV) method. Next, the fluxes across the subnetworks are computed. Lastly, using fluxes as boundary conditions, a dynamic two-phase flow solver is used to advance the solution in time. Simulation results of drainage scenarios at different capillary numbers and unfavourable viscosity ratios are presented and used to validate the MSPN method against solutions obtained by an existing dynamic network flow solver.« less

Xyce

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

Thomquist, Heidi K.; Fixel, Deborah A.; Fett, David Brian

The Xyce Parallel Electronic Simulator simulates electronic circuit behavior in DC, AC, HB, MPDE and transient mode using standard analog (DAE) and/or device (PDE) device models including several age and radiation aware devices. It supports a variety of computing platforms (both serial and parallel) computers. Lastly, it uses a variety of modern solution algorithms dynamic parallel load-balancing and iterative solvers.

Equation-free and variable free modeling for complex/multiscale systems. Coarse-grained computation in science and engineering using fine-grained models

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

Kevrekidis, Ioannis G.

The work explored the linking of modern developing machine learning techniques (manifold learning and in particular diffusion maps) with traditional PDE modeling/discretization/scientific computation techniques via the equation-free methodology developed by the PI. The result (in addition to several PhD degrees, two of them by CSGF Fellows) was a sequence of strong developments - in part on the algorithmic side, linking data mining with scientific computing, and in part on applications, ranging from PDE discretizations to molecular dynamics and complex network dynamics.

IGA-ADS: Isogeometric analysis FEM using ADS solver

NASA Astrophysics Data System (ADS)

Łoś, Marcin M.; Woźniak, Maciej; Paszyński, Maciej; Lenharth, Andrew; Hassaan, Muhamm Amber; Pingali, Keshav

2017-08-01

In this paper we present a fast explicit solver for solution of non-stationary problems using L2 projections with isogeometric finite element method. The solver has been implemented within GALOIS framework. It enables parallel multi-core simulations of different time-dependent problems, in 1D, 2D, or 3D. We have prepared the solver framework in a way that enables direct implementation of the selected PDE and corresponding boundary conditions. In this paper we describe the installation, implementation of exemplary three PDEs, and execution of the simulations on multi-core Linux cluster nodes. We consider three case studies, including heat transfer, linear elasticity, as well as non-linear flow in heterogeneous media. The presented package generates output suitable for interfacing with Gnuplot and ParaView visualization software. The exemplary simulations show near perfect scalability on Gilbert shared-memory node with four Intel® Xeon® CPU E7-4860 processors, each possessing 10 physical cores (for a total of 40 cores).

Computational Electromagnetics

DTIC Science & Technology

2011-02-20

finite differences use the continuation method instead, and have been shown to lead to unconditionally stable numerics for a wide range of realistic PDE...best previous solvers were restricted to two-dimensional (range and height) refractive index variations. The numerical method we introduced...however, is such that even its solution on the basis of Rytov’s method gives rise to extremely high computational costs. We thus resort to

Multi-Dimensional Quantum Tunneling and Transport Using the Density-Gradient Model

NASA Technical Reports Server (NTRS)

Biegel, Bryan A.; Yu, Zhi-Ping; Ancona, Mario; Rafferty, Conor; Saini, Subhash (Technical Monitor)

1999-01-01

We show that quantum effects are likely to significantly degrade the performance of MOSFETs (metal oxide semiconductor field effect transistor) as these devices are scaled below 100 nm channel length and 2 nm oxide thickness over the next decade. A general and computationally efficient electronic device model including quantum effects would allow us to monitor and mitigate these effects. Full quantum models are too expensive in multi-dimensions. Using a general but efficient PDE solver called PROPHET, we implemented the density-gradient (DG) quantum correction to the industry-dominant classical drift-diffusion (DD) model. The DG model efficiently includes quantum carrier profile smoothing and tunneling in multi-dimensions and for any electronic device structure. We show that the DG model reduces DD model error from as much as 50% down to a few percent in comparison to thin oxide MOS capacitance measurements. We also show the first DG simulations of gate oxide tunneling and transverse current flow in ultra-scaled MOSFETs. The advantages of rapid model implementation using the PDE solver approach will be demonstrated, as well as the applicability of the DG model to any electronic device structure.

Creating Weather System Ensembles Through Synergistic Process Modeling and Machine Learning

NASA Astrophysics Data System (ADS)

Chen, B.; Posselt, D. J.; Nguyen, H.; Wu, L.; Su, H.; Braverman, A. J.

2017-12-01

Earth's weather and climate are sensitive to a variety of control factors (e.g., initial state, forcing functions, etc). Characterizing the response of the atmosphere to a change in initial conditions or model forcing is critical for weather forecasting (ensemble prediction) and climate change assessment. Input - response relationships can be quantified by generating an ensemble of multiple (100s to 1000s) realistic realizations of weather and climate states. Atmospheric numerical models generate simulated data through discretized numerical approximation of the partial differential equations (PDEs) governing the underlying physics. However, the computational expense of running high resolution atmospheric state models makes generation of more than a few simulations infeasible. Here, we discuss an experiment wherein we approximate the numerical PDE solver within the Weather Research and Forecasting (WRF) Model using neural networks trained on a subset of model run outputs. Once trained, these neural nets can produce large number of realization of weather states from a small number of deterministic simulations with speeds that are orders of magnitude faster than the underlying PDE solver. Our neural network architecture is inspired by the governing partial differential equations. These equations are location-invariant, and consist of first and second derivations. As such, we use a 3x3 lon-lat grid of atmospheric profiles as the predictor in the neural net to provide the network the information necessary to compute the first and second moments. Results indicate that the neural network algorithm can approximate the PDE outputs with high degree of accuracy (less than 1% error), and that this error increases as a function of the prediction time lag.

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

Overcoming Challenges in Kinetic Modeling of Magnetized Plasmas and Vacuum Electronic Devices

NASA Astrophysics Data System (ADS)

Omelchenko, Yuri; Na, Dong-Yeop; Teixeira, Fernando

2017-10-01

We transform the state-of-the art of plasma modeling by taking advantage of novel computational techniques for fast and robust integration of multiscale hybrid (full particle ions, fluid electrons, no displacement current) and full-PIC models. These models are implemented in 3D HYPERS and axisymmetric full-PIC CONPIC codes. HYPERS is a massively parallel, asynchronous code. The HYPERS solver does not step fields and particles synchronously in time but instead executes local variable updates (events) at their self-adaptive rates while preserving fundamental conservation laws. The charge-conserving CONPIC code has a matrix-free explicit finite-element (FE) solver based on a sparse-approximate inverse (SPAI) algorithm. This explicit solver approximates the inverse FE system matrix (``mass'' matrix) using successive sparsity pattern orders of the original matrix. It does not reduce the set of Maxwell's equations to a vector-wave (curl-curl) equation of second order but instead utilizes the standard coupled first-order Maxwell's system. We discuss the ability of our codes to accurately and efficiently account for multiscale physical phenomena in 3D magnetized space and laboratory plasmas and axisymmetric vacuum electronic devices.

A multiscale approach to modelling electrochemical processes occurring across the cell membrane with application to transmission of action potentials.

PubMed

Richardson, G

2009-09-01

By application of matched asymptotic expansions, a simplified partial differential equation (PDE) model for the dynamic electrochemical processes occurring in the vicinity of a membrane, as ions selectively permeate across it, is formally derived from the Poisson-Nernst-Planck equations of electrochemistry. It is demonstrated that this simplified model reduces itself, in the limit of a long thin axon, to the cable equation used by Hodgkin and Huxley to describe the propagation of action potentials in the unmyelinated squid giant axon. The asymptotic reduction from the simplified PDE model to the cable equation leads to insights that are not otherwise apparent; these include an explanation of why the squid giant axon attains a diameter in the region of 1 mm. The simplified PDE model has more general application than the Hodgkin-Huxley cable equation and can, e.g. be used to describe action potential propagation in myelinated axons and neuronal cell bodies.

Solution of elliptic partial differential equations by fast Poisson solvers using a local relaxation factor. 1: One-step method

NASA Technical Reports Server (NTRS)

Chang, S. C.

1986-01-01

An algorithm for solving a large class of two- and three-dimensional nonseparable elliptic partial differential equations (PDE's) is developed and tested. It uses a modified D'Yakanov-Gunn iterative procedure in which the relaxation factor is grid-point dependent. It is easy to implement and applicable to a variety of boundary conditions. It is also computationally efficient, as indicated by the results of numerical comparisons with other established methods. Furthermore, the current algorithm has the advantage of possessing two important properties which the traditional iterative methods lack; that is: (1) the convergence rate is relatively insensitive to grid-cell size and aspect ratio, and (2) the convergence rate can be easily estimated by using the coefficient of the PDE being solved.

Multiscale Modeling of Hall Thrusters. Chapter 7: Plume Modeling

DTIC Science & Technology

2012-03-06

Quasineutral Potential Fix Finally, a ”quasi-neutral” switch has been implemented in the Draco Gauss - Seidel Solver. Implementation in the PCG solver is...unlimited. 4 (a) (b) Figure 7.2: Potential solution obtained for a single and multiple (16) zones Hence, part of the development effort went into...be seen from this plot, the two solutions are identical. The division of mesh into multiple zones had another benefit for parallel compu- tations

Multiscale Mathematics for Biomass Conversion to Renewable Hydrogen

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

Plechac, Petr; Vlachos, Dionisios; Katsoulakis, Markos

2013-09-05

The overall objective of this project is to develop multiscale models for understanding and eventually designing complex processes for renewables. To the best of our knowledge, our work is the first attempt at modeling complex reacting systems, whose performance relies on underlying multiscale mathematics. Our specific application lies at the heart of biofuels initiatives of DOE and entails modeling of catalytic systems, to enable economic, environmentally benign, and efficient conversion of biomass into either hydrogen or valuable chemicals. Specific goals include: (i) Development of rigorous spatio-temporal coarse-grained kinetic Monte Carlo (KMC) mathematics and simulation for microscopic processes encountered in biomassmore » transformation. (ii) Development of hybrid multiscale simulation that links stochastic simulation to a deterministic partial differential equation (PDE) model for an entire reactor. (iii) Development of hybrid multiscale simulation that links KMC simulation with quantum density functional theory (DFT) calculations. (iv) Development of parallelization of models of (i)-(iii) to take advantage of Petaflop computing and enable real world applications of complex, multiscale models. In this NCE period, we continued addressing these objectives and completed the proposed work. Main initiatives, key results, and activities are outlined.« less

The multiscale expansions of difference equations in the small lattice spacing regime, and a vicinity and integrability test: I

NASA Astrophysics Data System (ADS)

Santini, Paolo Maria

2010-01-01

We propose an algorithmic procedure (i) to study the 'distance' between an integrable PDE and any discretization of it, in the small lattice spacing epsilon regime, and, at the same time, (ii) to test the (asymptotic) integrability properties of such discretization. This method should provide, in particular, useful and concrete information on how good is any numerical scheme used to integrate a given integrable PDE. The procedure, illustrated on a fairly general ten-parameter family of discretizations of the nonlinear Schrödinger equation, consists of the following three steps: (i) the construction of the continuous multiscale expansion of a generic solution of the discrete system at all orders in epsilon, following Degasperis et al (1997 Physica D 100 187-211) (ii) the application, to such an expansion, of the Degasperis-Procesi (DP) integrability test (Degasperis A and Procesi M 1999 Asymptotic integrability Symmetry and Perturbation Theory, SPT98, ed A Degasperis and G Gaeta (Singapore: World Scientific) pp 23-37 Degasperis A 2001 Multiscale expansion and integrability of dispersive wave equations Lectures given at the Euro Summer School: 'What is integrability?' (Isaac Newton Institute, Cambridge, UK, 13-24 August); Integrability (Lecture Notes in Physics vol 767) ed A Mikhailov (Berlin: Springer)), to test the asymptotic integrability properties of the discrete system and its 'distance' from its continuous limit; (iii) the use of the main output of the DP test to construct infinitely many approximate symmetries and constants of motion of the discrete system, through novel and simple formulas.

Array-based Hierarchical Mesh Generation in Parallel

DOE PAGES

Ray, Navamita; Grindeanu, Iulian; Zhao, Xinglin; ...

2015-11-03

In this paper, we describe an array-based hierarchical mesh generation capability through uniform refinement of unstructured meshes for efficient solution of PDE's using finite element methods and multigrid solvers. A multi-degree, multi-dimensional and multi-level framework is designed to generate the nested hierarchies from an initial mesh that can be used for a number of purposes such as multi-level methods to generating large meshes. The capability is developed under the parallel mesh framework “Mesh Oriented dAtaBase” a.k.a MOAB. We describe the underlying data structures and algorithms to generate such hierarchies and present numerical results for computational efficiency and mesh quality. Inmore » conclusion, we also present results to demonstrate the applicability of the developed capability to a multigrid finite-element solver.« less

Workload Characterization of CFD Applications Using Partial Differential Equation Solvers

NASA Technical Reports Server (NTRS)

Waheed, Abdul; Yan, Jerry; Saini, Subhash (Technical Monitor)

1998-01-01

Workload characterization is used for modeling and evaluating of computing systems at different levels of detail. We present workload characterization for a class of Computational Fluid Dynamics (CFD) applications that solve Partial Differential Equations (PDEs). This workload characterization focuses on three high performance computing platforms: SGI Origin2000, EBM SP-2, a cluster of Intel Pentium Pro bases PCs. We execute extensive measurement-based experiments on these platforms to gather statistics of system resource usage, which results in workload characterization. Our workload characterization approach yields a coarse-grain resource utilization behavior that is being applied for performance modeling and evaluation of distributed high performance metacomputing systems. In addition, this study enhances our understanding of interactions between PDE solver workloads and high performance computing platforms and is useful for tuning these applications.

Fast Laplace solver approach to pore-scale permeability

NASA Astrophysics Data System (ADS)

Arns, C. H.; Adler, P. M.

2018-02-01

We introduce a powerful and easily implemented method to calculate the permeability of porous media at the pore scale using an approximation based on the Poiseulle equation to calculate permeability to fluid flow with a Laplace solver. The method consists of calculating the Euclidean distance map of the fluid phase to assign local conductivities and lends itself naturally to the treatment of multiscale problems. We compare with analytical solutions as well as experimental measurements and lattice Boltzmann calculations of permeability for Fontainebleau sandstone. The solver is significantly more stable than the lattice Boltzmann approach, uses less memory, and is significantly faster. Permeabilities are in excellent agreement over a wide range of porosities.

BGK-MD, Version 1.0

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

Haack, Jeffrey; Shohet, Gil

2016-12-02

The software implements a heterogeneous multiscale method (HMM), which involves solving a classical molecular dynamics (MD) problem and then computes the entropy production in order to compute the relaxation times towards equilibrium for use in a Bhatnagar-Gross-Krook (BGK) solver.

Dynamic one-dimensional modeling of secondary settling tanks and system robustness evaluation.

PubMed

Li, Ben; Stenstrom, M K

2014-01-01

One-dimensional secondary settling tank models are widely used in current engineering practice for design and optimization, and usually can be expressed as a nonlinear hyperbolic or nonlinear strongly degenerate parabolic partial differential equation (PDE). Reliable numerical methods are needed to produce approximate solutions that converge to the exact analytical solutions. In this study, we introduced a reliable numerical technique, the Yee-Roe-Davis (YRD) method as the governing PDE solver, and compared its reliability with the prevalent Stenstrom-Vitasovic-Takács (SVT) method by assessing their simulation results at various operating conditions. The YRD method also produced a similar solution to the previously developed Method G and Enquist-Osher method. The YRD and SVT methods were also used for a time-to-failure evaluation, and the results show that the choice of numerical method can greatly impact the solution. Reliable numerical methods, such as the YRD method, are strongly recommended.

Solution of elliptic partial differential equations by fast Poisson solvers using a local relaxation factor. 2: Two-step method

NASA Technical Reports Server (NTRS)

Chang, S. C.

1986-01-01

A two-step semidirect procedure is developed to accelerate the one-step procedure described in NASA TP-2529. For a set of constant coefficient model problems, the acceleration factor increases from 1 to 2 as the one-step procedure convergence rate decreases from + infinity to 0. It is also shown numerically that the two-step procedure can substantially accelerate the convergence of the numerical solution of many partial differential equations (PDE's) with variable coefficients.

ICASE Semiannual Report 1 October 1991 - 31 March 1992

DTIC Science & Technology

1992-05-01

who have resident appointments for limited periods of time as well as by visiting and resident consultants. Members of NASA’s research staff may also...performed showing that the full optimization problem can be solved with a computational cost which is only a few times more than that of solving the PDE...The goal is to obtain a solution of the optimization problem in a computational cost which is just a few times (2-3) that of the flow solver. Such a

Efficient solution of ordinary differential equations modeling electrical activity in cardiac cells.

PubMed

Sundnes, J; Lines, G T; Tveito, A

2001-08-01

The contraction of the heart is preceded and caused by a cellular electro-chemical reaction, causing an electrical field to be generated. Performing realistic computer simulations of this process involves solving a set of partial differential equations, as well as a large number of ordinary differential equations (ODEs) characterizing the reactive behavior of the cardiac tissue. Experiments have shown that the solution of the ODEs contribute significantly to the total work of a simulation, and there is thus a strong need to utilize efficient solution methods for this part of the problem. This paper presents how an efficient implicit Runge-Kutta method may be adapted to solve a complicated cardiac cell model consisting of 31 ODEs, and how this solver may be coupled to a set of PDE solvers to provide complete simulations of the electrical activity.

Scalable hierarchical PDE sampler for generating spatially correlated random fields using nonmatching meshes: Scalable hierarchical PDE sampler using nonmatching meshes

DOE PAGES

Osborn, Sarah; Zulian, Patrick; Benson, Thomas; ...

2018-01-30

This work describes a domain embedding technique between two nonmatching meshes used for generating realizations of spatially correlated random fields with applications to large-scale sampling-based uncertainty quantification. The goal is to apply the multilevel Monte Carlo (MLMC) method for the quantification of output uncertainties of PDEs with random input coefficients on general and unstructured computational domains. We propose a highly scalable, hierarchical sampling method to generate realizations of a Gaussian random field on a given unstructured mesh by solving a reaction–diffusion PDE with a stochastic right-hand side. The stochastic PDE is discretized using the mixed finite element method on anmore » embedded domain with a structured mesh, and then, the solution is projected onto the unstructured mesh. This work describes implementation details on how to efficiently transfer data from the structured and unstructured meshes at coarse levels, assuming that this can be done efficiently on the finest level. We investigate the efficiency and parallel scalability of the technique for the scalable generation of Gaussian random fields in three dimensions. An application of the MLMC method is presented for quantifying uncertainties of subsurface flow problems. Here, we demonstrate the scalability of the sampling method with nonmatching mesh embedding, coupled with a parallel forward model problem solver, for large-scale 3D MLMC simulations with up to 1.9·109 unknowns.« less

Scalable hierarchical PDE sampler for generating spatially correlated random fields using nonmatching meshes: Scalable hierarchical PDE sampler using nonmatching meshes

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

Osborn, Sarah; Zulian, Patrick; Benson, Thomas

This work describes a domain embedding technique between two nonmatching meshes used for generating realizations of spatially correlated random fields with applications to large-scale sampling-based uncertainty quantification. The goal is to apply the multilevel Monte Carlo (MLMC) method for the quantification of output uncertainties of PDEs with random input coefficients on general and unstructured computational domains. We propose a highly scalable, hierarchical sampling method to generate realizations of a Gaussian random field on a given unstructured mesh by solving a reaction–diffusion PDE with a stochastic right-hand side. The stochastic PDE is discretized using the mixed finite element method on anmore » embedded domain with a structured mesh, and then, the solution is projected onto the unstructured mesh. This work describes implementation details on how to efficiently transfer data from the structured and unstructured meshes at coarse levels, assuming that this can be done efficiently on the finest level. We investigate the efficiency and parallel scalability of the technique for the scalable generation of Gaussian random fields in three dimensions. An application of the MLMC method is presented for quantifying uncertainties of subsurface flow problems. Here, we demonstrate the scalability of the sampling method with nonmatching mesh embedding, coupled with a parallel forward model problem solver, for large-scale 3D MLMC simulations with up to 1.9·109 unknowns.« less

Parallel multiscale simulations of a brain aneurysm

PubMed Central

Grinberg, Leopold; Fedosov, Dmitry A.; Karniadakis, George Em

2012-01-01

Cardiovascular pathologies, such as a brain aneurysm, are affected by the global blood circulation as well as by the local microrheology. Hence, developing computational models for such cases requires the coupling of disparate spatial and temporal scales often governed by diverse mathematical descriptions, e.g., by partial differential equations (continuum) and ordinary differential equations for discrete particles (atomistic). However, interfacing atomistic-based with continuum-based domain discretizations is a challenging problem that requires both mathematical and computational advances. We present here a hybrid methodology that enabled us to perform the first multi-scale simulations of platelet depositions on the wall of a brain aneurysm. The large scale flow features in the intracranial network are accurately resolved by using the high-order spectral element Navier-Stokes solver εκ αr. The blood rheology inside the aneurysm is modeled using a coarse-grained stochastic molecular dynamics approach (the dissipative particle dynamics method) implemented in the parallel code LAMMPS. The continuum and atomistic domains overlap with interface conditions provided by effective forces computed adaptively to ensure continuity of states across the interface boundary. A two-way interaction is allowed with the time-evolving boundary of the (deposited) platelet clusters tracked by an immersed boundary method. The corresponding heterogeneous solvers ( εκ αr and LAMMPS) are linked together by a computational multilevel message passing interface that facilitates modularity and high parallel efficiency. Results of multiscale simulations of clot formation inside the aneurysm in a patient-specific arterial tree are presented. We also discuss the computational challenges involved and present scalability results of our coupled solver on up to 300K computer processors. Validation of such coupled atomistic-continuum models is a main open issue that has to be addressed in future work. PMID:23734066

SOMAR-LES: A framework for multi-scale modeling of turbulent stratified oceanic flows

NASA Astrophysics Data System (ADS)

Chalamalla, Vamsi K.; Santilli, Edward; Scotti, Alberto; Jalali, Masoud; Sarkar, Sutanu

2017-12-01

A new multi-scale modeling technique, SOMAR-LES, is presented in this paper. Localized grid refinement gives SOMAR (the Stratified Ocean Model with Adaptive Resolution) access to small scales of the flow which are normally inaccessible to general circulation models (GCMs). SOMAR-LES drives a LES (Large Eddy Simulation) on SOMAR's finest grids, forced with large scale forcing from the coarser grids. Three-dimensional simulations of internal tide generation, propagation and scattering are performed to demonstrate this multi-scale modeling technique. In the case of internal tide generation at a two-dimensional bathymetry, SOMAR-LES is able to balance the baroclinic energy budget and accurately model turbulence losses at only 10% of the computational cost required by a non-adaptive solver running at SOMAR-LES's fine grid resolution. This relative cost is significantly reduced in situations with intermittent turbulence or where the location of the turbulence is not known a priori because SOMAR-LES does not require persistent, global, high resolution. To illustrate this point, we consider a three-dimensional bathymetry with grids adaptively refined along the tidally generated internal waves to capture remote mixing in regions of wave focusing. The computational cost in this case is found to be nearly 25 times smaller than that of a non-adaptive solver at comparable resolution. In the final test case, we consider the scattering of a mode-1 internal wave at an isolated two-dimensional and three-dimensional topography, and we compare the results with Legg (2014) numerical experiments. We find good agreement with theoretical estimates. SOMAR-LES is less dissipative than the closure scheme employed by Legg (2014) near the bathymetry. Depending on the flow configuration and resolution employed, a reduction of more than an order of magnitude in computational costs is expected, relative to traditional existing solvers.

Parallel multiscale simulations of a brain aneurysm.

PubMed

Grinberg, Leopold; Fedosov, Dmitry A; Karniadakis, George Em

2013-07-01

Cardiovascular pathologies, such as a brain aneurysm, are affected by the global blood circulation as well as by the local microrheology. Hence, developing computational models for such cases requires the coupling of disparate spatial and temporal scales often governed by diverse mathematical descriptions, e.g., by partial differential equations (continuum) and ordinary differential equations for discrete particles (atomistic). However, interfacing atomistic-based with continuum-based domain discretizations is a challenging problem that requires both mathematical and computational advances. We present here a hybrid methodology that enabled us to perform the first multi-scale simulations of platelet depositions on the wall of a brain aneurysm. The large scale flow features in the intracranial network are accurately resolved by using the high-order spectral element Navier-Stokes solver εκ αr . The blood rheology inside the aneurysm is modeled using a coarse-grained stochastic molecular dynamics approach (the dissipative particle dynamics method) implemented in the parallel code LAMMPS. The continuum and atomistic domains overlap with interface conditions provided by effective forces computed adaptively to ensure continuity of states across the interface boundary. A two-way interaction is allowed with the time-evolving boundary of the (deposited) platelet clusters tracked by an immersed boundary method. The corresponding heterogeneous solvers ( εκ αr and LAMMPS) are linked together by a computational multilevel message passing interface that facilitates modularity and high parallel efficiency. Results of multiscale simulations of clot formation inside the aneurysm in a patient-specific arterial tree are presented. We also discuss the computational challenges involved and present scalability results of our coupled solver on up to 300K computer processors. Validation of such coupled atomistic-continuum models is a main open issue that has to be addressed in future work.

Parallel multiscale simulations of a brain aneurysm

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

Grinberg, Leopold; Fedosov, Dmitry A.; Karniadakis, George Em, E-mail: george_karniadakis@brown.edu

2013-07-01

Cardiovascular pathologies, such as a brain aneurysm, are affected by the global blood circulation as well as by the local microrheology. Hence, developing computational models for such cases requires the coupling of disparate spatial and temporal scales often governed by diverse mathematical descriptions, e.g., by partial differential equations (continuum) and ordinary differential equations for discrete particles (atomistic). However, interfacing atomistic-based with continuum-based domain discretizations is a challenging problem that requires both mathematical and computational advances. We present here a hybrid methodology that enabled us to perform the first multiscale simulations of platelet depositions on the wall of a brain aneurysm.more » The large scale flow features in the intracranial network are accurately resolved by using the high-order spectral element Navier–Stokes solver NεκTαr. The blood rheology inside the aneurysm is modeled using a coarse-grained stochastic molecular dynamics approach (the dissipative particle dynamics method) implemented in the parallel code LAMMPS. The continuum and atomistic domains overlap with interface conditions provided by effective forces computed adaptively to ensure continuity of states across the interface boundary. A two-way interaction is allowed with the time-evolving boundary of the (deposited) platelet clusters tracked by an immersed boundary method. The corresponding heterogeneous solvers (NεκTαr and LAMMPS) are linked together by a computational multilevel message passing interface that facilitates modularity and high parallel efficiency. Results of multiscale simulations of clot formation inside the aneurysm in a patient-specific arterial tree are presented. We also discuss the computational challenges involved and present scalability results of our coupled solver on up to 300 K computer processors. Validation of such coupled atomistic-continuum models is a main open issue that has to be addressed in future work.« less

A two-dimensional Riemann solver with self-similar sub-structure - Alternative formulation based on least squares projection

NASA Astrophysics Data System (ADS)

Balsara, Dinshaw S.; Vides, Jeaniffer; Gurski, Katharine; Nkonga, Boniface; Dumbser, Michael; Garain, Sudip; Audit, Edouard

2016-01-01

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 self-similar formulation of Balsara [16] proves especially useful for this purpose. While that work is based on a Galerkin projection, in this paper we present an analogous self-similar formulation that is based on a different interpretation. In the present formulation, we interpret the shock jumps at the boundary of the strongly-interacting state quite literally. The enforcement of the shock jump conditions is done with a least squares projection (Vides, Nkonga and Audit [67]). With that interpretation, we again show that the multidimensional Riemann solver can be endowed with sub-structure. However, we find that the most efficient implementation arises when we use a flux vector splitting and a least squares projection. An alternative formulation that is based on the full characteristic matrices is also presented. The multidimensional Riemann solvers that are demonstrated here use one-dimensional HLLC Riemann solvers as building blocks. Several stringent test problems drawn from hydrodynamics and MHD are presented to show that the method works. Results from structured and unstructured meshes demonstrate the versatility of our method. The reader is also invited to watch a video introduction to multidimensional Riemann solvers on http://www.nd.edu/ dbalsara/Numerical-PDE-Course.

Multiscale modeling and simulation of brain blood flow

NASA Astrophysics Data System (ADS)

Perdikaris, Paris; Grinberg, Leopold; Karniadakis, George Em

2016-02-01

The aim of this work is to present an overview of recent advances in multi-scale modeling of brain blood flow. In particular, we present some approaches that enable the in silico study of multi-scale and multi-physics phenomena in the cerebral vasculature. We discuss the formulation of continuum and atomistic modeling approaches, present a consistent framework for their concurrent coupling, and list some of the challenges that one needs to overcome in achieving a seamless and scalable integration of heterogeneous numerical solvers. The effectiveness of the proposed framework is demonstrated in a realistic case involving modeling the thrombus formation process taking place on the wall of a patient-specific cerebral aneurysm. This highlights the ability of multi-scale algorithms to resolve important biophysical processes that span several spatial and temporal scales, potentially yielding new insight into the key aspects of brain blood flow in health and disease. Finally, we discuss open questions in multi-scale modeling and emerging topics of future research.

TDIGG - TWO-DIMENSIONAL, INTERACTIVE GRID GENERATION CODE

NASA Technical Reports Server (NTRS)

Vu, B. T.

1994-01-01

TDIGG is a fast and versatile program for generating two-dimensional computational grids for use with finite-difference flow-solvers. Both algebraic and elliptic grid generation systems are included. The method for grid generation by algebraic transformation is based on an interpolation algorithm and the elliptic grid generation is established by solving the partial differential equation (PDE). Non-uniform grid distributions are carried out using a hyperbolic tangent stretching function. For algebraic grid systems, interpolations in one direction (univariate) and two directions (bivariate) are considered. These interpolations are associated with linear or cubic Lagrangian/Hermite/Bezier polynomial functions. The algebraic grids can subsequently be smoothed using an elliptic solver. For elliptic grid systems, the PDE can be in the form of Laplace (zero forcing function) or Poisson. The forcing functions in the Poisson equation come from the boundary or the entire domain of the initial algebraic grids. A graphics interface procedure using the Silicon Graphics (GL) Library is included to allow users to visualize the grid variations at each iteration. This will allow users to interactively modify the grid to match their applications. TDIGG is written in FORTRAN 77 for Silicon Graphics IRIS series computers running IRIX. This package requires either MIT's X Window System, Version 11 Revision 4 or SGI (Motif) Window System. A sample executable is provided on the distribution medium. It requires 148K of RAM for execution. The standard distribution medium is a .25 inch streaming magnetic IRIX tape cartridge in UNIX tar format. This program was developed in 1992.

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

NASA Technical Reports Server (NTRS)

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

1997-01-01

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

Multiscale Simulation Framework for Coupled Fluid Flow and Mechanical Deformation

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

Hou, Thomas; Efendiev, Yalchin; Tchelepi, Hamdi

2016-05-24

Our work in this project is aimed at making fundamental advances in multiscale methods for flow and transport in highly heterogeneous porous media. The main thrust of this research is to develop a systematic multiscale analysis and efficient coarse-scale models that can capture global effects and extend existing multiscale approaches to problems with additional physics and uncertainties. A key emphasis is on problems without an apparent scale separation. Multiscale solution methods are currently under active investigation for the simulation of subsurface flow in heterogeneous formations. These procedures capture the effects of fine-scale permeability variations through the calculation of specialized coarse-scalemore » basis functions. Most of the multiscale techniques presented to date employ localization approximations in the calculation of these basis functions. For some highly correlated (e.g., channelized) formations, however, global effects are important and these may need to be incorporated into the multiscale basis functions. Other challenging issues facing multiscale simulations are the extension of existing multiscale techniques to problems with additional physics, such as compressibility, capillary effects, etc. In our project, we explore the improvement of multiscale methods through the incorporation of additional (single-phase flow) information and the development of a general multiscale framework for flows in the presence of uncertainties, compressible flow and heterogeneous transport, and geomechanics. We have considered (1) adaptive local-global multiscale methods, (2) multiscale methods for the transport equation, (3) operator-based multiscale methods and solvers, (4) multiscale methods in the presence of uncertainties and applications, (5) multiscale finite element methods for high contrast porous media and their generalizations, and (6) multiscale methods for geomechanics.« less

Multiscale analysis and computation for flows in heterogeneous media

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

Efendiev, Yalchin; Hou, T. Y.; Durlofsky, L. J.

Our work in this project is aimed at making fundamental advances in multiscale methods for flow and transport in highly heterogeneous porous media. The main thrust of this research is to develop a systematic multiscale analysis and efficient coarse-scale models that can capture global effects and extend existing multiscale approaches to problems with additional physics and uncertainties. A key emphasis is on problems without an apparent scale separation. Multiscale solution methods are currently under active investigation for the simulation of subsurface flow in heterogeneous formations. These procedures capture the effects of fine-scale permeability variations through the calculation of specialized coarse-scalemore » basis functions. Most of the multiscale techniques presented to date employ localization approximations in the calculation of these basis functions. For some highly correlated (e.g., channelized) formations, however, global effects are important and these may need to be incorporated into the multiscale basis functions. Other challenging issues facing multiscale simulations are the extension of existing multiscale techniques to problems with additional physics, such as compressibility, capillary effects, etc. In our project, we explore the improvement of multiscale methods through the incorporation of additional (single-phase flow) information and the development of a general multiscale framework for flows in the presence of uncertainties, compressible flow and heterogeneous transport, and geomechanics. We have considered (1) adaptive local-global multiscale methods, (2) multiscale methods for the transport equation, (3) operator-based multiscale methods and solvers, (4) multiscale methods in the presence of uncertainties and applications, (5) multiscale finite element methods for high contrast porous media and their generalizations, and (6) multiscale methods for geomechanics. Below, we present a brief overview of each of these contributions.« less

Efficient Integration of Coupled Electrical-Chemical Systems in Multiscale Neuronal Simulations

PubMed Central

Brocke, Ekaterina; Bhalla, Upinder S.; Djurfeldt, Mikael; Hellgren Kotaleski, Jeanette; Hanke, Michael

2016-01-01

Multiscale modeling and simulations in neuroscience is gaining scientific attention due to its growing importance and unexplored capabilities. For instance, it can help to acquire better understanding of biological phenomena that have important features at multiple scales of time and space. This includes synaptic plasticity, memory formation and modulation, homeostasis. There are several ways to organize multiscale simulations depending on the scientific problem and the system to be modeled. One of the possibilities is to simulate different components of a multiscale system simultaneously and exchange data when required. The latter may become a challenging task for several reasons. First, the components of a multiscale system usually span different spatial and temporal scales, such that rigorous analysis of possible coupling solutions is required. Then, the components can be defined by different mathematical formalisms. For certain classes of problems a number of coupling mechanisms have been proposed and successfully used. However, a strict mathematical theory is missing in many cases. Recent work in the field has not so far investigated artifacts that may arise during coupled integration of different approximation methods. Moreover, in neuroscience, the coupling of widely used numerical fixed step size solvers may lead to unexpected inefficiency. In this paper we address the question of possible numerical artifacts that can arise during the integration of a coupled system. We develop an efficient strategy to couple the components comprising a multiscale test problem in neuroscience. We introduce an efficient coupling method based on the second-order backward differentiation formula (BDF2) numerical approximation. The method uses an adaptive step size integration with an error estimation proposed by Skelboe (2000). The method shows a significant advantage over conventional fixed step size solvers used in neuroscience for similar problems. We explore different coupling strategies that define the organization of computations between system components. We study the importance of an appropriate approximation of exchanged variables during the simulation. The analysis shows a substantial impact of these aspects on the solution accuracy in the application to our multiscale neuroscientific test problem. We believe that the ideas presented in the paper may essentially contribute to the development of a robust and efficient framework for multiscale brain modeling and simulations in neuroscience. PMID:27672364

Efficient Integration of Coupled Electrical-Chemical Systems in Multiscale Neuronal Simulations.

PubMed

Brocke, Ekaterina; Bhalla, Upinder S; Djurfeldt, Mikael; Hellgren Kotaleski, Jeanette; Hanke, Michael

2016-01-01

Multiscale modeling and simulations in neuroscience is gaining scientific attention due to its growing importance and unexplored capabilities. For instance, it can help to acquire better understanding of biological phenomena that have important features at multiple scales of time and space. This includes synaptic plasticity, memory formation and modulation, homeostasis. There are several ways to organize multiscale simulations depending on the scientific problem and the system to be modeled. One of the possibilities is to simulate different components of a multiscale system simultaneously and exchange data when required. The latter may become a challenging task for several reasons. First, the components of a multiscale system usually span different spatial and temporal scales, such that rigorous analysis of possible coupling solutions is required. Then, the components can be defined by different mathematical formalisms. For certain classes of problems a number of coupling mechanisms have been proposed and successfully used. However, a strict mathematical theory is missing in many cases. Recent work in the field has not so far investigated artifacts that may arise during coupled integration of different approximation methods. Moreover, in neuroscience, the coupling of widely used numerical fixed step size solvers may lead to unexpected inefficiency. In this paper we address the question of possible numerical artifacts that can arise during the integration of a coupled system. We develop an efficient strategy to couple the components comprising a multiscale test problem in neuroscience. We introduce an efficient coupling method based on the second-order backward differentiation formula (BDF2) numerical approximation. The method uses an adaptive step size integration with an error estimation proposed by Skelboe (2000). The method shows a significant advantage over conventional fixed step size solvers used in neuroscience for similar problems. We explore different coupling strategies that define the organization of computations between system components. We study the importance of an appropriate approximation of exchanged variables during the simulation. The analysis shows a substantial impact of these aspects on the solution accuracy in the application to our multiscale neuroscientific test problem. We believe that the ideas presented in the paper may essentially contribute to the development of a robust and efficient framework for multiscale brain modeling and simulations in neuroscience.

Probabilistic numerical methods for PDE-constrained Bayesian inverse problems

NASA Astrophysics Data System (ADS)

Cockayne, Jon; Oates, Chris; Sullivan, Tim; Girolami, Mark

2017-06-01

This paper develops meshless methods for probabilistically describing discretisation error in the numerical solution of partial differential equations. This construction enables the solution of Bayesian inverse problems while accounting for the impact of the discretisation of the forward problem. In particular, this drives statistical inferences to be more conservative in the presence of significant solver error. Theoretical results are presented describing rates of convergence for the posteriors in both the forward and inverse problems. This method is tested on a challenging inverse problem with a nonlinear forward model.

A framework for expanding aqueous chemistry in the Community Multiscale Air Quality (CMAQ) model version 5.1

NASA Astrophysics Data System (ADS)

Fahey, Kathleen M.; Carlton, Annmarie G.; Pye, Havala O. T.; Baek, Jaemeen; Hutzell, William T.; Stanier, Charles O.; Baker, Kirk R.; Wyat Appel, K.; Jaoui, Mohammed; Offenberg, John H.

2017-04-01

This paper describes the development and implementation of an extendable aqueous-phase chemistry option (AQCHEM - KMT(I)) for the Community Multiscale Air Quality (CMAQ) modeling system, version 5.1. Here, the Kinetic PreProcessor (KPP), version 2.2.3, is used to generate a Rosenbrock solver (Rodas3) to integrate the stiff system of ordinary differential equations (ODEs) that describe the mass transfer, chemical kinetics, and scavenging processes of CMAQ clouds. CMAQ's standard cloud chemistry module (AQCHEM) is structurally limited to the treatment of a simple chemical mechanism. This work advances our ability to test and implement more sophisticated aqueous chemical mechanisms in CMAQ and further investigate the impacts of microphysical parameters on cloud chemistry. Box model cloud chemistry simulations were performed to choose efficient solver and tolerance settings, evaluate the implementation of the KPP solver, and assess the direct impacts of alternative solver and kinetic mass transfer on predicted concentrations for a range of scenarios. Month-long CMAQ simulations for winter and summer periods over the US reveal the changes in model predictions due to these cloud module updates within the full chemical transport model. While monthly average CMAQ predictions are not drastically altered between AQCHEM and AQCHEM - KMT, hourly concentration differences can be significant. With added in-cloud secondary organic aerosol (SOA) formation from biogenic epoxides (AQCHEM - KMTI), normalized mean error and bias statistics are slightly improved for 2-methyltetrols and 2-methylglyceric acid at the Research Triangle Park measurement site in North Carolina during the Southern Oxidant and Aerosol Study (SOAS) period. The added in-cloud chemistry leads to a monthly average increase of 11-18 % in cloud SOA at the surface in the eastern United States for June 2013.

On the use of reverse Brownian motion to accelerate hybrid simulations

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

Bakarji, Joseph; Tartakovsky, Daniel M., E-mail: tartakovsky@stanford.edu

Multiscale and multiphysics simulations are two rapidly developing fields of scientific computing. Efficient coupling of continuum (deterministic or stochastic) constitutive solvers with their discrete (stochastic, particle-based) counterparts is a common challenge in both kinds of simulations. We focus on interfacial, tightly coupled simulations of diffusion that combine continuum and particle-based solvers. The latter employs the reverse Brownian motion (rBm), a Monte Carlo approach that allows one to enforce inhomogeneous Dirichlet, Neumann, or Robin boundary conditions and is trivially parallelizable. We discuss numerical approaches for improving the accuracy of rBm in the presence of inhomogeneous Neumann boundary conditions and alternative strategiesmore » for coupling the rBm solver with its continuum counterpart. Numerical experiments are used to investigate the convergence, stability, and computational efficiency of the proposed hybrid algorithm.« less

A consistent modelling methodology for secondary settling tanks in wastewater treatment.

PubMed

Bürger, Raimund; Diehl, Stefan; Nopens, Ingmar

2011-03-01

The aim of this contribution is partly to build consensus on a consistent modelling methodology (CMM) of complex real processes in wastewater treatment by combining classical concepts with results from applied mathematics, and partly to apply it to the clarification-thickening process in the secondary settling tank. In the CMM, the real process should be approximated by a mathematical model (process model; ordinary or partial differential equation (ODE or PDE)), which in turn is approximated by a simulation model (numerical method) implemented on a computer. These steps have often not been carried out in a correct way. The secondary settling tank was chosen as a case since this is one of the most complex processes in a wastewater treatment plant and simulation models developed decades ago have no guarantee of satisfying fundamental mathematical and physical properties. Nevertheless, such methods are still used in commercial tools to date. This particularly becomes of interest as the state-of-the-art practice is moving towards plant-wide modelling. Then all submodels interact and errors propagate through the model and severely hamper any calibration effort and, hence, the predictive purpose of the model. The CMM is described by applying it first to a simple conversion process in the biological reactor yielding an ODE solver, and then to the solid-liquid separation in the secondary settling tank, yielding a PDE solver. Time has come to incorporate established mathematical techniques into environmental engineering, and wastewater treatment modelling in particular, and to use proven reliable and consistent simulation models. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

Perdikaris, Paris, E-mail: parisp@mit.edu; Grinberg, Leopold, E-mail: leopoldgrinberg@us.ibm.com; Karniadakis, George Em, E-mail: george-karniadakis@brown.edu

The aim of this work is to present an overview of recent advances in multi-scale modeling of brain blood flow. In particular, we present some approaches that enable the in silico study of multi-scale and multi-physics phenomena in the cerebral vasculature. We discuss the formulation of continuum and atomistic modeling approaches, present a consistent framework for their concurrent coupling, and list some of the challenges that one needs to overcome in achieving a seamless and scalable integration of heterogeneous numerical solvers. The effectiveness of the proposed framework is demonstrated in a realistic case involving modeling the thrombus formation process takingmore » place on the wall of a patient-specific cerebral aneurysm. This highlights the ability of multi-scale algorithms to resolve important biophysical processes that span several spatial and temporal scales, potentially yielding new insight into the key aspects of brain blood flow in health and disease. Finally, we discuss open questions in multi-scale modeling and emerging topics of future research.« less

Spatial adaptive sampling in multiscale simulation

NASA Astrophysics Data System (ADS)

Rouet-Leduc, Bertrand; Barros, Kipton; Cieren, Emmanuel; Elango, Venmugil; Junghans, Christoph; Lookman, Turab; Mohd-Yusof, Jamaludin; Pavel, Robert S.; Rivera, Axel Y.; Roehm, Dominic; McPherson, Allen L.; Germann, Timothy C.

2014-07-01

In a common approach to multiscale simulation, an incomplete set of macroscale equations must be supplemented with constitutive data provided by fine-scale simulation. Collecting statistics from these fine-scale simulations is typically the overwhelming computational cost. We reduce this cost by interpolating the results of fine-scale simulation over the spatial domain of the macro-solver. Unlike previous adaptive sampling strategies, we do not interpolate on the potentially very high dimensional space of inputs to the fine-scale simulation. Our approach is local in space and time, avoids the need for a central database, and is designed to parallelize well on large computer clusters. To demonstrate our method, we simulate one-dimensional elastodynamic shock propagation using the Heterogeneous Multiscale Method (HMM); we find that spatial adaptive sampling requires only ≈ 50 ×N0.14 fine-scale simulations to reconstruct the stress field at all N grid points. Related multiscale approaches, such as Equation Free methods, may also benefit from spatial adaptive sampling.

Combining cellular automata and Lattice Boltzmann method to model multiscale avascular tumor growth coupled with nutrient diffusion and immune competition.

PubMed

Alemani, Davide; Pappalardo, Francesco; Pennisi, Marzio; Motta, Santo; Brusic, Vladimir

2012-02-28

In the last decades the Lattice Boltzmann method (LB) has been successfully used to simulate a variety of processes. The LB model describes the microscopic processes occurring at the cellular level and the macroscopic processes occurring at the continuum level with a unique function, the probability distribution function. Recently, it has been tried to couple deterministic approaches with probabilistic cellular automata (probabilistic CA) methods with the aim to model temporal evolution of tumor growths and three dimensional spatial evolution, obtaining hybrid methodologies. Despite the good results attained by CA-PDE methods, there is one important issue which has not been completely solved: the intrinsic stochastic nature of the interactions at the interface between cellular (microscopic) and continuum (macroscopic) level. CA methods are able to cope with the stochastic phenomena because of their probabilistic nature, while PDE methods are fully deterministic. Even if the coupling is mathematically correct, there could be important statistical effects that could be missed by the PDE approach. For such a reason, to be able to develop and manage a model that takes into account all these three level of complexity (cellular, molecular and continuum), we believe that PDE should be replaced with a statistic and stochastic model based on the numerical discretization of the Boltzmann equation: The Lattice Boltzmann (LB) method. In this work we introduce a new hybrid method to simulate tumor growth and immune system, by applying Cellular Automata Lattice Boltzmann (CA-LB) approach. Copyright © 2011 Elsevier B.V. All rights reserved.

MUSIC: MUlti-Scale Initial Conditions

NASA Astrophysics Data System (ADS)

Hahn, Oliver; Abel, Tom

2013-11-01

MUSIC generates multi-scale initial conditions with multiple levels of refinements for cosmological ‘zoom-in’ simulations. The code uses an adaptive convolution of Gaussian white noise with a real-space transfer function kernel together with an adaptive multi-grid Poisson solver to generate displacements and velocities following first- (1LPT) or second-order Lagrangian perturbation theory (2LPT). MUSIC achieves rms relative errors of the order of 10-4 for displacements and velocities in the refinement region and thus improves in terms of errors by about two orders of magnitude over previous approaches. In addition, errors are localized at coarse-fine boundaries and do not suffer from Fourier space-induced interference ringing.

Design of a Variational Multiscale Method for Turbulent Compressible Flows

NASA Technical Reports Server (NTRS)

Diosady, Laslo Tibor; Murman, Scott M.

2013-01-01

A spectral-element framework is presented for the simulation of subsonic compressible high-Reynolds-number flows. The focus of the work is maximizing the efficiency of the computational schemes to enable unsteady simulations with a large number of spatial and temporal degrees of freedom. A collocation scheme is combined with optimized computational kernels to provide a residual evaluation with computational cost independent of order of accuracy up to 16th order. The optimized residual routines are used to develop a low-memory implicit scheme based on a matrix-free Newton-Krylov method. A preconditioner based on the finite-difference diagonalized ADI scheme is developed which maintains the low memory of the matrix-free implicit solver, while providing improved convergence properties. Emphasis on low memory usage throughout the solver development is leveraged to implement a coupled space-time DG solver which may offer further efficiency gains through adaptivity in both space and time.

Thermal mathematical modeling of a multicell common pressure vessel nickel-hydrogen battery

NASA Technical Reports Server (NTRS)

Kim, Junbom; Nguyen, T. V.; White, R. E.

1992-01-01

A two-dimensional and time-dependent thermal model of a multicell common pressure vessel (CPV) nickel-hydrogen battery was developed. A finite element solver called PDE/Protran was used to solve this model. The model was used to investigate the effects of various design parameters on the temperature profile within the cell. The results were used to help find a design that will yield an acceptable temperature gradient inside a multicell CPV nickel-hydrogen battery. Steady-state and unsteady-state cases with a constant heat generation rate and a time-dependent heat generation rate were solved.

Building Blocks for Reliable Complex Nonlinear Numerical Simulations

NASA Technical Reports Server (NTRS)

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

2002-01-01

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

Building Blocks for Reliable Complex Nonlinear Numerical Simulations

NASA Technical Reports Server (NTRS)

Yee, H. C.

2005-01-01

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

Building Blocks for Reliable Complex Nonlinear Numerical Simulations. Chapter 2

NASA Technical Reports Server (NTRS)

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

2001-01-01

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

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.

A preliminary investigation of the growth of an aneurysm with a multiscale monolithic Fluid-Structure interaction solver

NASA Astrophysics Data System (ADS)

Cerroni, D.; Manservisi, S.; Pozzetti, G.

2015-11-01

In this work we investigate the potentialities of multi-scale engineering techniques to approach complex problems related to biomedical and biological fields. In particular we study the interaction between blood and blood vessel focusing on the presence of an aneurysm. The study of each component of the cardiovascular system is very difficult due to the fact that the movement of the fluid and solid is determined by the rest of system through dynamical boundary conditions. The use of multi-scale techniques allows us to investigate the effect of the whole loop on the aneurysm dynamic. A three-dimensional fluid-structure interaction model for the aneurysm is developed and coupled to a mono-dimensional one for the remaining part of the cardiovascular system, where a point zero-dimensional model for the heart is provided. In this manner it is possible to achieve rigorous and quantitative investigations of the cardiovascular disease without loosing the system dynamic. In order to study this biomedical problem we use a monolithic fluid-structure interaction (FSI) model where the fluid and solid equations are solved together. The use of a monolithic solver allows us to handle the convergence issues caused by large deformations. By using this monolithic approach different solid and fluid regions are treated as a single continuum and the interface conditions are automatically taken into account. In this way the iterative process characteristic of the commonly used segregated approach, it is not needed any more.

Modelling atmospheric flows with adaptive moving meshes

NASA Astrophysics Data System (ADS)

Kühnlein, Christian; Smolarkiewicz, Piotr K.; Dörnbrack, Andreas

2012-04-01

An anelastic atmospheric flow solver has been developed that combines semi-implicit non-oscillatory forward-in-time numerics with a solution-adaptive mesh capability. A key feature of the solver is the unification of a mesh adaptation apparatus, based on moving mesh partial differential equations (PDEs), with the rigorous formulation of the governing anelastic PDEs in generalised time-dependent curvilinear coordinates. The solver development includes an enhancement of the flux-form multidimensional positive definite advection transport algorithm (MPDATA) - employed in the integration of the underlying anelastic PDEs - that ensures full compatibility with mass continuity under moving meshes. In addition, to satisfy the geometric conservation law (GCL) tensor identity under general moving meshes, a diagnostic approach is proposed based on the treatment of the GCL as an elliptic problem. The benefits of the solution-adaptive moving mesh technique for the simulation of multiscale atmospheric flows are demonstrated. The developed solver is verified for two idealised flow problems with distinct levels of complexity: passive scalar advection in a prescribed deformational flow, and the life cycle of a large-scale atmospheric baroclinic wave instability showing fine-scale phenomena of fronts and internal gravity waves.

High Performance Radiation Transport Simulations on TITAN

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

Baker, Christopher G; Davidson, Gregory G; Evans, Thomas M

2012-01-01

In this paper we describe the Denovo code system. Denovo solves the six-dimensional, steady-state, linear Boltzmann transport equation, of central importance to nuclear technology applications such as reactor core analysis (neutronics), radiation shielding, nuclear forensics and radiation detection. The code features multiple spatial differencing schemes, state-of-the-art linear solvers, the Koch-Baker-Alcouffe (KBA) parallel-wavefront sweep algorithm for inverting the transport operator, a new multilevel energy decomposition method scaling to hundreds of thousands of processing cores, and a modern, novel code architecture that supports straightforward integration of new features. In this paper we discuss the performance of Denovo on the 10--20 petaflop ORNLmore » GPU-based system, Titan. We describe algorithms and techniques used to exploit the capabilities of Titan's heterogeneous compute node architecture and the challenges of obtaining good parallel performance for this sparse hyperbolic PDE solver containing inherently sequential computations. Numerical results demonstrating Denovo performance on early Titan hardware are presented.« less

A physics based multiscale modeling of cavitating flows.

PubMed

Ma, Jingsen; Hsiao, Chao-Tsung; Chahine, Georges L

2017-03-02

Numerical modeling of cavitating bubbly flows is challenging due to the wide range of characteristic lengths of the physics at play: from micrometers (e.g., bubble nuclei radius) to meters (e.g., propeller diameter or sheet cavity length). To address this, we present here a multiscale approach which integrates a Discrete Singularities Model (DSM) for dispersed microbubbles and a two-phase Navier Stokes solver for the bubbly medium, which includes a level set approach to describe large cavities or gaseous pockets. Inter-scale schemes are used to smoothly bridge the two transitioning subgrid DSM bubbles into larger discretized cavities. This approach is demonstrated on several problems including cavitation inception and vapor core formation in a vortex flow, sheet-to-cloud cavitation over a hydrofoil, cavitation behind a blunt body, and cavitation on a propeller. These examples highlight the capabilities of the developed multiscale model in simulating various form of cavitation.

A physics based multiscale modeling of cavitating flows

PubMed Central

Ma, Jingsen; Hsiao, Chao-Tsung; Chahine, Georges L.

2018-01-01

Numerical modeling of cavitating bubbly flows is challenging due to the wide range of characteristic lengths of the physics at play: from micrometers (e.g., bubble nuclei radius) to meters (e.g., propeller diameter or sheet cavity length). To address this, we present here a multiscale approach which integrates a Discrete Singularities Model (DSM) for dispersed microbubbles and a two-phase Navier Stokes solver for the bubbly medium, which includes a level set approach to describe large cavities or gaseous pockets. Inter-scale schemes are used to smoothly bridge the two transitioning subgrid DSM bubbles into larger discretized cavities. This approach is demonstrated on several problems including cavitation inception and vapor core formation in a vortex flow, sheet-to-cloud cavitation over a hydrofoil, cavitation behind a blunt body, and cavitation on a propeller. These examples highlight the capabilities of the developed multiscale model in simulating various form of cavitation. PMID:29720773

A SEMI-LAGRANGIAN TWO-LEVEL PRECONDITIONED NEWTON-KRYLOV SOLVER FOR CONSTRAINED DIFFEOMORPHIC IMAGE REGISTRATION.

PubMed

Mang, Andreas; Biros, George

2017-01-01

We propose an efficient numerical algorithm for the solution of diffeomorphic image registration problems. We use a variational formulation constrained by a partial differential equation (PDE), where the constraints are a scalar transport equation. We use a pseudospectral discretization in space and second-order accurate semi-Lagrangian time stepping scheme for the transport equations. We solve for a stationary velocity field using a preconditioned, globalized, matrix-free Newton-Krylov scheme. We propose and test a two-level Hessian preconditioner. We consider two strategies for inverting the preconditioner on the coarse grid: a nested preconditioned conjugate gradient method (exact solve) and a nested Chebyshev iterative method (inexact solve) with a fixed number of iterations. We test the performance of our solver in different synthetic and real-world two-dimensional application scenarios. We study grid convergence and computational efficiency of our new scheme. We compare the performance of our solver against our initial implementation that uses the same spatial discretization but a standard, explicit, second-order Runge-Kutta scheme for the numerical time integration of the transport equations and a single-level preconditioner. Our improved scheme delivers significant speedups over our original implementation. As a highlight, we observe a 20 × speedup for a two dimensional, real world multi-subject medical image registration problem.

Compatible Spatial Discretizations for Partial Differential Equations

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

Arnold, Douglas, N, ed.

From May 11--15, 2004, the Institute for Mathematics and its Applications held a hot topics workshop on Compatible Spatial Discretizations for Partial Differential Equations. The numerical solution of partial differential equations (PDE) is a fundamental task in science and engineering. The goal of the workshop was to bring together a spectrum of scientists at the forefront of the research in the numerical solution of PDEs to discuss compatible spatial discretizations. We define compatible spatial discretizations as those that inherit or mimic fundamental properties of the PDE such as topology, conservation, symmetries, and positivity structures and maximum principles. A wide varietymore » of discretization methods applied across a wide range of scientific and engineering applications have been designed to or found to inherit or mimic intrinsic spatial structure and reproduce fundamental properties of the solution of the continuous PDE model at the finite dimensional level. A profusion of such methods and concepts relevant to understanding them have been developed and explored: mixed finite element methods, mimetic finite differences, support operator methods, control volume methods, discrete differential forms, Whitney forms, conservative differencing, discrete Hodge operators, discrete Helmholtz decomposition, finite integration techniques, staggered grid and dual grid methods, etc. This workshop seeks to foster communication among the diverse groups of researchers designing, applying, and studying such methods as well as researchers involved in practical solution of large scale problems that may benefit from advancements in such discretizations; to help elucidate the relations between the different methods and concepts; and to generally advance our understanding in the area of compatible spatial discretization methods for PDE. Particular points of emphasis included: + Identification of intrinsic properties of PDE models that are critical for the fidelity of numerical simulations. + Identification and design of compatible spatial discretizations of PDEs, their classification, analysis, and relations. + Relationships between different compatible spatial discretization methods and concepts which have been developed; + Impact of compatible spatial discretizations upon physical fidelity, verification and validation of simulations, especially in large-scale, multiphysics settings. + How solvers address the demands placed upon them by compatible spatial discretizations. This report provides information about the program and abstracts of all the presentations.« less

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.

Physically-enhanced data visualisation: towards real time solution of Partial Differential Equations in 3D domains

NASA Astrophysics Data System (ADS)

Zlotnik, Sergio

2017-04-01

Information provided by visualisation environments can be largely increased if the data shown is combined with some relevant physical processes and the used is allowed to interact with those processes. This is particularly interesting in VR environments where the user has a deep interplay with the data. For example, a geological seismic line in a 3D "cave" shows information of the geological structure of the subsoil. The available information could be enhanced with the thermal state of the region under study, with water-flow patterns in porous rocks or with rock displacements under some stress conditions. The information added by the physical processes is usually the output of some numerical technique applied to solve a Partial Differential Equation (PDE) that describes the underlying physics. Many techniques are available to obtain numerical solutions of PDE (e.g. Finite Elements, Finite Volumes, Finite Differences, etc). Although, all these traditional techniques require very large computational resources (particularly in 3D), making them useless in a real time visualization environment -such as VR- because the time required to compute a solution is measured in minutes or even in hours. We present here a novel alternative for the resolution of PDE-based problems that is able to provide a 3D solutions for a very large family of problems in real time. That is, the solution is evaluated in a one thousands of a second, making the solver ideal to be embedded into VR environments. Based on Model Order Reduction ideas, the proposed technique divides the computational work in to a computationally intensive "offline" phase, that is run only once in a life time, and an "online" phase that allow the real time evaluation of any solution within a family of problems. Preliminary examples of real time solutions of complex PDE-based problems will be presented, including thermal problems, flow problems, wave problems and some simple coupled problems.

Array-based, parallel hierarchical mesh refinement algorithms for unstructured meshes

DOE PAGES

Ray, Navamita; Grindeanu, Iulian; Zhao, Xinglin; ...

2016-08-18

In this paper, we describe an array-based hierarchical mesh refinement capability through uniform refinement of unstructured meshes for efficient solution of PDE's using finite element methods and multigrid solvers. A multi-degree, multi-dimensional and multi-level framework is designed to generate the nested hierarchies from an initial coarse mesh that can be used for a variety of purposes such as in multigrid solvers/preconditioners, to do solution convergence and verification studies and to improve overall parallel efficiency by decreasing I/O bandwidth requirements (by loading smaller meshes and in memory refinement). We also describe a high-order boundary reconstruction capability that can be used tomore » project the new points after refinement using high-order approximations instead of linear projection in order to minimize and provide more control on geometrical errors introduced by curved boundaries.The capability is developed under the parallel unstructured mesh framework "Mesh Oriented dAtaBase" (MOAB Tautges et al. (2004)). We describe the underlying data structures and algorithms to generate such hierarchies in parallel and present numerical results for computational efficiency and effect on mesh quality. Furthermore, we also present results to demonstrate the applicability of the developed capability to study convergence properties of different point projection schemes for various mesh hierarchies and to a multigrid finite-element solver for elliptic problems.« less

Architecting the Finite Element Method Pipeline for the GPU.

PubMed

Fu, Zhisong; Lewis, T James; Kirby, Robert M; Whitaker, Ross T

2014-02-01

The finite element method (FEM) is a widely employed numerical technique for approximating the solution of partial differential equations (PDEs) in various science and engineering applications. Many of these applications benefit from fast execution of the FEM pipeline. One way to accelerate the FEM pipeline is by exploiting advances in modern computational hardware, such as the many-core streaming processors like the graphical processing unit (GPU). In this paper, we present the algorithms and data-structures necessary to move the entire FEM pipeline to the GPU. First we propose an efficient GPU-based algorithm to generate local element information and to assemble the global linear system associated with the FEM discretization of an elliptic PDE. To solve the corresponding linear system efficiently on the GPU, we implement a conjugate gradient method preconditioned with a geometry-informed algebraic multi-grid (AMG) method preconditioner. We propose a new fine-grained parallelism strategy, a corresponding multigrid cycling stage and efficient data mapping to the many-core architecture of GPU. Comparison of our on-GPU assembly versus a traditional serial implementation on the CPU achieves up to an 87 × speedup. Focusing on the linear system solver alone, we achieve a speedup of up to 51 × versus use of a comparable state-of-the-art serial CPU linear system solver. Furthermore, the method compares favorably with other GPU-based, sparse, linear solvers.

Fast Multiscale Algorithms for Wave Propagation in Heterogeneous Environments

DTIC Science & Technology

2016-01-07

methods for waves’’, Nonlinear solvers for high- intensity focused ultrasound with application to cancer treatment, AIMS, Palo Alto, 2012. ``Hermite...formulation but different parametrizations. . . . . . . . . . . . 6 4 Density µ(t) at mode 0 for scattering of a plane Gaussian pulse from a sphere. On the...spatiotemporal scales. Two crucial components of the highly-efficient, general-purpose wave simulator we envision are • Reliable, low -cost methods for truncating

Pseudo-time methods for constrained optimization problems governed by PDE

NASA Technical Reports Server (NTRS)

Taasan, Shlomo

1995-01-01

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

Adjoint sensitivity analysis of chaotic dynamical systems with non-intrusive least squares shadowing

NASA Astrophysics Data System (ADS)

Blonigan, Patrick J.

2017-11-01

This paper presents a discrete adjoint version of the recently developed non-intrusive least squares shadowing (NILSS) algorithm, which circumvents the instability that conventional adjoint methods encounter for chaotic systems. The NILSS approach involves solving a smaller minimization problem than other shadowing approaches and can be implemented with only minor modifications to preexisting tangent and adjoint solvers. Adjoint NILSS is demonstrated on a small chaotic ODE, a one-dimensional scalar PDE, and a direct numerical simulation (DNS) of the minimal flow unit, a turbulent channel flow on a small spatial domain. This is the first application of an adjoint shadowing-based algorithm to a three-dimensional turbulent flow.

An efficient three-dimensional Poisson solver for SIMD high-performance-computing architectures

NASA Technical Reports Server (NTRS)

Cohl, H.

1994-01-01

We present an algorithm that solves the three-dimensional Poisson equation on a cylindrical grid. The technique uses a finite-difference scheme with operator splitting. This splitting maps the banded structure of the operator matrix into a two-dimensional set of tridiagonal matrices, which are then solved in parallel. Our algorithm couples FFT techniques with the well-known ADI (Alternating Direction Implicit) method for solving Elliptic PDE's, and the implementation is extremely well suited for a massively parallel environment like the SIMD architecture of the MasPar MP-1. Due to the highly recursive nature of our problem, we believe that our method is highly efficient, as it avoids excessive interprocessor communication.

A Fractional PDE Approach to Turbulent Mixing; Part II: Numerical Simulation

NASA Astrophysics Data System (ADS)

Samiee, Mehdi; Zayernouri, Mohsen

2016-11-01

We propose a generalizing fractional order transport model of advection-diffusion kind with fractional time- and space-derivatives, governing the evolution of passive scalar turbulence. This approach allows one to incorporate the nonlocal and memory effects in the underlying anomalous diffusion i.e., sub-to-standard diffusion to model the trapping of particles inside the eddied, and super-diffusion associated with the sudden jumps of particles from one coherent region to another. For this nonlocal model, we develop a high order numerical (spectral) method in addition to a fast solver, examined in the context of some canonical problems. PhD student, Department of Mechanical Engineering, & Department Computational Mathematics, Science, and Engineering.

Multiscale modeling of mucosal immune responses

PubMed Central

2015-01-01

Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T cell differentiation and tissue level cell-cell interactions was developed to illustrate the capabilities, power and scope of ENISI MSM. Background Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Implementation Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. Conclusion We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut inflammation. Our modeling predictions dissect the mechanisms by which effector CD4+ T cell responses contribute to tissue damage in the gut mucosa following immune dysregulation. PMID:26329787

Multiscale modeling of mucosal immune responses.

PubMed

Mei, Yongguo; Abedi, Vida; Carbo, Adria; Zhang, Xiaoying; Lu, Pinyi; Philipson, Casandra; Hontecillas, Raquel; Hoops, Stefan; Liles, Nathan; Bassaganya-Riera, Josep

2015-01-01

Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut inflammation. Our modeling predictions dissect the mechanisms by which effector CD4+ T cell responses contribute to tissue damage in the gut mucosa following immune dysregulation.Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T cell differentiation and tissue level cell-cell interactions was developed to illustrate the capabilities, power and scope of ENISI MSM.

A framework for expanding aqueous chemistry in the ...

EPA Pesticide Factsheets

This paper describes the development and implementation of an extendable aqueous-phase chemistry option (AQCHEM − KMT(I)) for the Community Multiscale Air Quality (CMAQ) modeling system, version 5.1. Here, the Kinetic PreProcessor (KPP), version 2.2.3, is used to generate a Rosenbrock solver (Rodas3) to integrate the stiff system of ordinary differential equations (ODEs) that describe the mass transfer, chemical kinetics, and scavenging processes of CMAQ clouds. CMAQ's standard cloud chemistry module (AQCHEM) is structurally limited to the treatment of a simple chemical mechanism. This work advances our ability to test and implement more sophisticated aqueous chemical mechanisms in CMAQ and further investigate the impacts of microphysical parameters on cloud chemistry. Box model cloud chemistry simulations were performed to choose efficient solver and tolerance settings, evaluate the implementation of the KPP solver, and assess the direct impacts of alternative solver and kinetic mass transfer on predicted concentrations for a range of scenarios. Month-long CMAQ simulations for winter and summer periods over the US reveal the changes in model predictions due to these cloud module updates within the full chemical transport model. While monthly average CMAQ predictions are not drastically altered between AQCHEM and AQCHEM − KMT, hourly concentration differences can be significant. With added in-cloud secondary organic aerosol (SOA) formation from bio

Final Report for "Implimentation and Evaluation of Multigrid Linear Solvers into Extended Magnetohydrodynamic Codes for Petascale Computing"

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

Srinath Vadlamani; Scott Kruger; Travis Austin

Extended magnetohydrodynamic (MHD) codes are used to model the large, slow-growing instabilities that are projected to limit the performance of International Thermonuclear Experimental Reactor (ITER). The multiscale nature of the extended MHD equations requires an implicit approach. The current linear solvers needed for the implicit algorithm scale poorly because the resultant matrices are so ill-conditioned. A new solver is needed, especially one that scales to the petascale. The most successful scalable parallel processor solvers to date are multigrid solvers. Applying multigrid techniques to a set of equations whose fundamental modes are dispersive waves is a promising solution to CEMM problems.more » For the Phase 1, we implemented multigrid preconditioners from the HYPRE project of the Center for Applied Scientific Computing at LLNL via PETSc of the DOE SciDAC TOPS for the real matrix systems of the extended MHD code NIMROD which is a one of the primary modeling codes of the OFES-funded Center for Extended Magnetohydrodynamic Modeling (CEMM) SciDAC. We implemented the multigrid solvers on the fusion test problem that allows for real matrix systems with success, and in the process learned about the details of NIMROD data structures and the difficulties of inverting NIMROD operators. The further success of this project will allow for efficient usage of future petascale computers at the National Leadership Facilities: Oak Ridge National Laboratory, Argonne National Laboratory, and National Energy Research Scientific Computing Center. The project will be a collaborative effort between computational plasma physicists and applied mathematicians at Tech-X Corporation, applied mathematicians Front Range Scientific Computations, Inc. (who are collaborators on the HYPRE project), and other computational plasma physicists involved with the CEMM project.« less

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.

Multiscale Numerical Methods for Non-Equilibrium Plasma

DTIC Science & Technology

2015-08-01

current paper reports on the implementation of a numerical solver on the Graphic Processing Units (GPUs) to model reactive gas mixtures with detailed...Governing equations The flow ismodeled as amixture of gas specieswhile neglecting viscous effects. The chemical reactions taken place between the gas ...components are to be modeled in great detail. The set of the Euler equations for a reactive gas mixture can be written as: ∂Q ∂t + ∇ · F̄ = Ω̇ (1) where Q

Nektar++: An open-source spectral/ hp element framework

NASA Astrophysics Data System (ADS)

Cantwell, C. D.; Moxey, D.; Comerford, A.; Bolis, A.; Rocco, G.; Mengaldo, G.; De Grazia, D.; Yakovlev, S.; Lombard, J.-E.; Ekelschot, D.; Jordi, B.; Xu, H.; Mohamied, Y.; Eskilsson, C.; Nelson, B.; Vos, P.; Biotto, C.; Kirby, R. M.; Sherwin, S. J.

2015-07-01

Nektar++ is an open-source software framework designed to support the development of high-performance scalable solvers for partial differential equations using the spectral/ hp element method. High-order methods are gaining prominence in several engineering and biomedical applications due to their improved accuracy over low-order techniques at reduced computational cost for a given number of degrees of freedom. However, their proliferation is often limited by their complexity, which makes these methods challenging to implement and use. Nektar++ is an initiative to overcome this limitation by encapsulating the mathematical complexities of the underlying method within an efficient C++ framework, making the techniques more accessible to the broader scientific and industrial communities. The software supports a variety of discretisation techniques and implementation strategies, supporting methods research as well as application-focused computation, and the multi-layered structure of the framework allows the user to embrace as much or as little of the complexity as they need. The libraries capture the mathematical constructs of spectral/ hp element methods, while the associated collection of pre-written PDE solvers provides out-of-the-box application-level functionality and a template for users who wish to develop solutions for addressing questions in their own scientific domains.

A fast Chebyshev method for simulating flexible-wing propulsion

NASA Astrophysics Data System (ADS)

Moore, M. Nicholas J.

2017-09-01

We develop a highly efficient numerical method to simulate small-amplitude flapping propulsion by a flexible wing in a nearly inviscid fluid. We allow the wing's elastic modulus and mass density to vary arbitrarily, with an eye towards optimizing these distributions for propulsive performance. The method to determine the wing kinematics is based on Chebyshev collocation of the 1D beam equation as coupled to the surrounding 2D fluid flow. Through small-amplitude analysis of the Euler equations (with trailing-edge vortex shedding), the complete hydrodynamics can be represented by a nonlocal operator that acts on the 1D wing kinematics. A class of semi-analytical solutions permits fast evaluation of this operator with O (Nlog ⁡ N) operations, where N is the number of collocation points on the wing. This is in contrast to the minimum O (N2) cost of a direct 2D fluid solver. The coupled wing-fluid problem is thus recast as a PDE with nonlocal operator, which we solve using a preconditioned iterative method. These techniques yield a solver of near-optimal complexity, O (Nlog ⁡ N) , allowing one to rapidly search the infinite-dimensional parameter space of all possible material distributions and even perform optimization over this space.

Examination of Wave Speed in Rotating Detonation Engines Using Simplified Computational Fluid Dynamics

NASA Technical Reports Server (NTRS)

Paxson, Daniel E.

2018-01-01

A simplified, two-dimensional, computational fluid dynamic (CFD) simulation, with a reactive Euler solver is used to examine possible causes for the low detonation wave propagation speeds that are consistently observed in air breathing rotating detonation engine (RDE) experiments. Intense, small-scale turbulence is proposed as the primary mechanism. While the solver cannot model this turbulence, it can be used to examine the most likely, and profound effect of turbulence. That is a substantial enlargement of the reaction zone, or equivalently, an effective reduction in the chemical reaction rate. It is demonstrated that in the unique flowfield of the RDE, a reduction in reaction rate leads to a reduction in the detonation speed. A subsequent test of reduced reaction rate in a purely one-dimensional pulsed detonation engine (PDE) flowfield yields no reduction in wave speed. The reasons for this are explained. The impact of reduced wave speed on RDE performance is then examined, and found to be minimal. Two other potential mechanisms are briefly examined. These are heat transfer, and reactive mixture non-uniformity. In the context of the simulation used for this study, both mechanisms are shown to have negligible effect on either wave speed or performance.

Globalized Newton-Krylov-Schwarz Algorithms and Software for Parallel Implicit CFD

NASA Technical Reports Server (NTRS)

Gropp, W. D.; Keyes, D. E.; McInnes, L. C.; Tidriri, M. D.

1998-01-01

Implicit solution methods are important in applications modeled by PDEs with disparate temporal and spatial scales. Because such applications require high resolution with reasonable turnaround, "routine" parallelization is essential. The pseudo-transient matrix-free Newton-Krylov-Schwarz (Psi-NKS) algorithmic framework is presented as an answer. We show that, for the classical problem of three-dimensional transonic Euler flow about an M6 wing, Psi-NKS can simultaneously deliver: globalized, asymptotically rapid convergence through adaptive pseudo- transient continuation and Newton's method-, reasonable parallelizability for an implicit method through deferred synchronization and favorable communication-to-computation scaling in the Krylov linear solver; and high per- processor performance through attention to distributed memory and cache locality, especially through the Schwarz preconditioner. Two discouraging features of Psi-NKS methods are their sensitivity to the coding of the underlying PDE discretization and the large number of parameters that must be selected to govern convergence. We therefore distill several recommendations from our experience and from our reading of the literature on various algorithmic components of Psi-NKS, and we describe a freely available, MPI-based portable parallel software implementation of the solver employed here.

Comparative Study of Advanced Turbulence Models for Turbomachinery

NASA Technical Reports Server (NTRS)

Hadid, Ali H.; Sindir, Munir M.

1996-01-01

A computational study has been undertaken to study the performance of advanced phenomenological turbulence models coded in a modular form to describe incompressible turbulent flow behavior in two dimensional/axisymmetric and three dimensional complex geometry. The models include a variety of two equation models (single and multi-scale k-epsilon models with different near wall treatments) and second moment algebraic and full Reynolds stress closure models. These models were systematically assessed to evaluate their performance in complex flows with rotation, curvature and separation. The models are coded as self contained modules that can be interfaced with a number of flow solvers. These modules are stand alone satellite programs that come with their own formulation, finite-volume discretization scheme, solver and boundary condition implementation. They will take as input (from any generic Navier-Stokes solver) the velocity field, grid (structured H-type grid) and computational domain specification (boundary conditions), and will deliver, depending on the model used, turbulent viscosity, or the components of the Reynolds stress tensor. There are separate 2D/axisymmetric and/or 3D decks for each module considered. The modules are tested using Rocketdyn's proprietary code REACT. The code utilizes an efficient solution procedure to solve Navier-Stokes equations in a non-orthogonal body-fitted coordinate system. The differential equations are discretized over a finite-volume grid using a non-staggered variable arrangement and an efficient solution procedure based on the SIMPLE algorithm for the velocity-pressure coupling is used. The modules developed have been interfaced and tested using finite-volume, pressure-correction CFD solvers which are widely used in the CFD community. Other solvers can also be used to test these modules since they are independently structured with their own discretization scheme and solver methodology. Many of these modules have been independently tested by Professor C.P. Chen and his group at the University of Alabama at Huntsville (UAH) by interfacing them with own flow solver (MAST).

Differential morphology and image processing.

PubMed

Maragos, P

1996-01-01

Image processing via mathematical morphology has traditionally used geometry to intuitively understand morphological signal operators and set or lattice algebra to analyze them in the space domain. We provide a unified view and analytic tools for morphological image processing that is based on ideas from differential calculus and dynamical systems. This includes ideas on using partial differential or difference equations (PDEs) to model distance propagation or nonlinear multiscale processes in images. We briefly review some nonlinear difference equations that implement discrete distance transforms and relate them to numerical solutions of the eikonal equation of optics. We also review some nonlinear PDEs that model the evolution of multiscale morphological operators and use morphological derivatives. Among the new ideas presented, we develop some general 2-D max/min-sum difference equations that model the space dynamics of 2-D morphological systems (including the distance computations) and some nonlinear signal transforms, called slope transforms, that can analyze these systems in a transform domain in ways conceptually similar to the application of Fourier transforms to linear systems. Thus, distance transforms are shown to be bandpass slope filters. We view the analysis of the multiscale morphological PDEs and of the eikonal PDE solved via weighted distance transforms as a unified area in nonlinear image processing, which we call differential morphology, and briefly discuss its potential applications to image processing and computer vision.

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

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

Estep, Donald

2015-11-30

This project addressed the challenge of predictive computational analysis of strongly coupled, highly nonlinear multiphysics systems characterized by multiple physical phenomena that span a large range of length- and time-scales. Specifically, the project was focused on computational estimation of numerical error and sensitivity analysis of computational solutions with respect to variations in parameters and data. In addition, the project investigated the use of accurate computational estimates to guide efficient adaptive discretization. The project developed, analyzed and evaluated new variational adjoint-based techniques for integration, model, and data error estimation/control and sensitivity analysis, in evolutionary multiphysics multiscale simulations.

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

NASA Technical Reports Server (NTRS)

Vigue, Y.

1994-01-01

HEAT.PRO calculates the thermal imbalance force resulting from satellite surface heating. The heated body of a satellite re-radiates energy at a rate that is proportional to its temperature, losing the energy in the form of photons. By conservation of momentum, this momentum flux out of the body creates a reaction force against the radiation surface, and the net thermal force can be observed as a small perturbation that affects long term orbital behavior of the satellite. HEAT.PRO calculates this thermal imbalance force and then determines its effects on satellite orbits, especially where the Earth's shadowing of an orbiting satellite causes periodic changes in the spacecraft's thermal environment. HEAT.PRO implements a finite element method routine called PDE2D which incorporates material properties to determine the solar panel surface temperatures. The nodal temperatures are computed at specified time steps and are used to determine the magnitude and direction of the thermal force on the spacecraft. These calculations are based on the solar panel orientation and satellite's position with respect to the earth and sun. It is necessary to have accurate, current knowledge of surface emissivity, thermal conductivity, heat capacity, and material density. These parameters, which may change due to degradation of materials in the environment of space, influence the nodal temperatures that are computed and thus the thermal force calculations. HEAT.PRO was written in FORTRAN 77 for Cray series computers running UNICOS. The source code contains directives for and is used as input to the required partial differential equation solver, PDE2D. HEAT.PRO is available on a 9-track 1600 BPI magnetic tape in UNIX tar format (standard distribution medium) or a .25 inch streaming magnetic tape cartridge in UNIX tar format. An electronic copy of the documentation in Macintosh Microsoft Word format is included on the distribution tape. HEAT.PRO was developed in 1991. Cray and UNICOS are registered trademarks of Cray Research, Inc. UNIX is a trademark of AT&T Bell Laboratories. PDE2D is available from Granville Sewell, Mathematics Dept., University of Texas at El Paso, El Paso, Texas 79968.

plasmaFoam: An OpenFOAM framework for computational plasma physics and chemistry

NASA Astrophysics Data System (ADS)

Venkattraman, Ayyaswamy; Verma, Abhishek Kumar

2016-09-01

As emphasized in the 2012 Roadmap for low temperature plasmas (LTP), scientific computing has emerged as an essential tool for the investigation and prediction of the fundamental physical and chemical processes associated with these systems. While several in-house and commercial codes exist, with each having its own advantages and disadvantages, a common framework that can be developed by researchers from all over the world will likely accelerate the impact of computational studies on advances in low-temperature plasma physics and chemistry. In this regard, we present a finite volume computational toolbox to perform high-fidelity simulations of LTP systems. This framework, primarily based on the OpenFOAM solver suite, allows us to enhance our understanding of multiscale plasma phenomenon by performing massively parallel, three-dimensional simulations on unstructured meshes using well-established high performance computing tools that are widely used in the computational fluid dynamics community. In this talk, we will present preliminary results obtained using the OpenFOAM-based solver suite with benchmark three-dimensional simulations of microplasma devices including both dielectric and plasma regions. We will also discuss the future outlook for the solver suite.

The Effect of Scale Dependent Discretization on the Progressive Failure of Composite Materials Using Multiscale Analyses

NASA Technical Reports Server (NTRS)

Ricks, Trenton M.; Lacy, Thomas E., Jr.; Pineda, Evan J.; Bednarcyk, Brett A.; Arnold, Steven M.

2013-01-01

A multiscale modeling methodology, which incorporates a statistical distribution of fiber strengths into coupled micromechanics/ finite element analyses, is applied to unidirectional polymer matrix composites (PMCs) to analyze the effect of mesh discretization both at the micro- and macroscales on the predicted ultimate tensile (UTS) strength and failure behavior. The NASA code FEAMAC and the ABAQUS finite element solver were used to analyze the progressive failure of a PMC tensile specimen that initiates at the repeating unit cell (RUC) level. Three different finite element mesh densities were employed and each coupled with an appropriate RUC. Multiple simulations were performed in order to assess the effect of a statistical distribution of fiber strengths on the bulk composite failure and predicted strength. The coupled effects of both the micro- and macroscale discretizations were found to have a noticeable effect on the predicted UTS and computational efficiency of the simulations.

Modeling Complex Biological Flows in Multi-Scale Systems using the APDEC Framework

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

Trebotich, D

We have developed advanced numerical algorithms to model biological fluids in multiscale flow environments using the software framework developed under the SciDAC APDEC ISIC. The foundation of our computational effort is an approach for modeling DNA-laden fluids as ''bead-rod'' polymers whose dynamics are fully coupled to an incompressible viscous solvent. The method is capable of modeling short range forces and interactions between particles using soft potentials and rigid constraints. Our methods are based on higher-order finite difference methods in complex geometry with adaptivity, leveraging algorithms and solvers in the APDEC Framework. Our Cartesian grid embedded boundary approach to incompressible viscousmore » flow in irregular geometries has also been interfaced to a fast and accurate level-sets method within the APDEC Framework for extracting surfaces from volume renderings of medical image data and used to simulate cardio-vascular and pulmonary flows in critical anatomies.« less

Simulation of dilute polymeric fluids in a three-dimensional contraction using a multiscale FENE model

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

Griebel, M., E-mail: griebel@ins.uni-bonn.de, E-mail: ruettgers@ins.uni-bonn.de; Rüttgers, A., E-mail: griebel@ins.uni-bonn.de, E-mail: ruettgers@ins.uni-bonn.de

The multiscale FENE model is applied to a 3D square-square contraction flow problem. For this purpose, the stochastic Brownian configuration field method (BCF) has been coupled with our fully parallelized three-dimensional Navier-Stokes solver NaSt3DGPF. The robustness of the BCF method enables the numerical simulation of high Deborah number flows for which most macroscopic methods suffer from stability issues. The results of our simulations are compared with that of experimental measurements from literature and show a very good agreement. In particular, flow phenomena such as a strong vortex enhancement, streamline divergence and a flow inversion for highly elastic flows are reproduced.more » Due to their computational complexity, our simulations require massively parallel computations. Using a domain decomposition approach with MPI, the implementation achieves excellent scale-up results for up to 128 processors.« less

Modeling complex biological flows in multi-scale systems using the APDEC framework

NASA Astrophysics Data System (ADS)

Trebotich, David

2006-09-01

We have developed advanced numerical algorithms to model biological fluids in multiscale flow environments using the software framework developed under the SciDAC APDEC ISIC. The foundation of our computational effort is an approach for modeling DNA laden fluids as ''bead-rod'' polymers whose dynamics are fully coupled to an incompressible viscous solvent. The method is capable of modeling short range forces and interactions between particles using soft potentials and rigid constraints. Our methods are based on higher-order finite difference methods in complex geometry with adaptivity, leveraging algorithms and solvers in the APDEC Framework. Our Cartesian grid embedded boundary approach to incompressible viscous flow in irregular geometries has also been interfaced to a fast and accurate level-sets method within the APDEC Framework for extracting surfaces from volume renderings of medical image data and used to simulate cardio-vascular and pulmonary flows in critical anatomies.

Multiscale geometric modeling of macromolecules I: Cartesian representation

NASA Astrophysics Data System (ADS)

Xia, Kelin; Feng, Xin; Chen, Zhan; Tong, Yiying; Wei, Guo-Wei

2014-01-01

This paper focuses on the geometric modeling and computational algorithm development of biomolecular structures from two data sources: Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) in the Eulerian (or Cartesian) representation. Molecular surface (MS) contains non-smooth geometric singularities, such as cusps, tips and self-intersecting facets, which often lead to computational instabilities in molecular simulations, and violate the physical principle of surface free energy minimization. Variational multiscale surface definitions are proposed based on geometric flows and solvation analysis of biomolecular systems. Our approach leads to geometric and potential driven Laplace-Beltrami flows for biomolecular surface evolution and formation. The resulting surfaces are free of geometric singularities and minimize the total free energy of the biomolecular system. High order partial differential equation (PDE)-based nonlinear filters are employed for EMDB data processing. We show the efficacy of this approach in feature-preserving noise reduction. After the construction of protein multiresolution surfaces, we explore the analysis and characterization of surface morphology by using a variety of curvature definitions. Apart from the classical Gaussian curvature and mean curvature, maximum curvature, minimum curvature, shape index, and curvedness are also applied to macromolecular surface analysis for the first time. Our curvature analysis is uniquely coupled to the analysis of electrostatic surface potential, which is a by-product of our variational multiscale solvation models. As an expository investigation, we particularly emphasize the numerical algorithms and computational protocols for practical applications of the above multiscale geometric models. Such information may otherwise be scattered over the vast literature on this topic. Based on the curvature and electrostatic analysis from our multiresolution surfaces, we introduce a new concept, the polarized curvature, for the prediction of protein binding sites.

Solution of elliptic PDEs by fast Poisson solvers using a local relaxation factor

NASA Technical Reports Server (NTRS)

Chang, Sin-Chung

1986-01-01

A large class of two- and three-dimensional, nonseparable elliptic partial differential equations (PDEs) is presently solved by means of novel one-step (D'Yakanov-Gunn) and two-step (accelerated one-step) iterative procedures, using a local, discrete Fourier analysis. In addition to being easily implemented and applicable to a variety of boundary conditions, these procedures are found to be computationally efficient on the basis of the results of numerical comparison with other established methods, which lack the present one's: (1) insensitivity to grid cell size and aspect ratio, and (2) ease of convergence rate estimation by means of the coefficient of the PDE being solved. The two-step procedure is numerically demonstrated to outperform the one-step procedure in the case of PDEs with variable coefficients.

Analysis of Aluminum-Nitride SOI for High-Temperature Electronics

NASA Technical Reports Server (NTRS)

Biegel, Bryan A.; Osman, Mohamed A.; Yu, Zhiping

2000-01-01

We use numerical simulation to investigate the high-temperature (up to 500K) operation of SOI MOSFETs with Aluminum-Nitride (AIN) buried insulators, rather than the conventional silicon-dioxide (SiO2). Because the thermal conductivity of AIN is about 100 times that of SiO2, AIN SOI should greatly reduce the often severe self-heating problem of conventional SOI, making SOI potentially suitable for high-temperature applications. A detailed electrothermal transport model is used in the simulations, and solved with a PDE solver called PROPHET In this work, we compare the performance of AIN-based SOI with that of SiO2-based SOI and conventional MOSFETs. We find that AIN SOI does indeed remove the self-heating penalty of SOL However, several device design trade-offs remain, which our simulations highlight.

An Efficient Multiscale Finite-Element Method for Frequency-Domain Seismic Wave Propagation

DOE PAGES

Gao, Kai; Fu, Shubin; Chung, Eric T.

2018-02-13

The frequency-domain seismic-wave equation, that is, the Helmholtz equation, has many important applications in seismological studies, yet is very challenging to solve, particularly for large geological models. Iterative solvers, domain decomposition, or parallel strategies can partially alleviate the computational burden, but these approaches may still encounter nontrivial difficulties in complex geological models where a sufficiently fine mesh is required to represent the fine-scale heterogeneities. We develop a novel numerical method to solve the frequency-domain acoustic wave equation on the basis of the multiscale finite-element theory. We discretize a heterogeneous model with a coarse mesh and employ carefully constructed high-order multiscalemore » basis functions to form the basis space for the coarse mesh. Solved from medium- and frequency-dependent local problems, these multiscale basis functions can effectively capture themedium’s fine-scale heterogeneity and the source’s frequency information, leading to a discrete system matrix with a much smaller dimension compared with those from conventional methods.We then obtain an accurate solution to the acoustic Helmholtz equation by solving only a small linear system instead of a large linear system constructed on the fine mesh in conventional methods.We verify our new method using several models of complicated heterogeneities, and the results show that our new multiscale method can solve the Helmholtz equation in complex models with high accuracy and extremely low computational costs.« less

An Efficient Multiscale Finite-Element Method for Frequency-Domain Seismic Wave Propagation

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

Gao, Kai; Fu, Shubin; Chung, Eric T.

The frequency-domain seismic-wave equation, that is, the Helmholtz equation, has many important applications in seismological studies, yet is very challenging to solve, particularly for large geological models. Iterative solvers, domain decomposition, or parallel strategies can partially alleviate the computational burden, but these approaches may still encounter nontrivial difficulties in complex geological models where a sufficiently fine mesh is required to represent the fine-scale heterogeneities. We develop a novel numerical method to solve the frequency-domain acoustic wave equation on the basis of the multiscale finite-element theory. We discretize a heterogeneous model with a coarse mesh and employ carefully constructed high-order multiscalemore » basis functions to form the basis space for the coarse mesh. Solved from medium- and frequency-dependent local problems, these multiscale basis functions can effectively capture themedium’s fine-scale heterogeneity and the source’s frequency information, leading to a discrete system matrix with a much smaller dimension compared with those from conventional methods.We then obtain an accurate solution to the acoustic Helmholtz equation by solving only a small linear system instead of a large linear system constructed on the fine mesh in conventional methods.We verify our new method using several models of complicated heterogeneities, and the results show that our new multiscale method can solve the Helmholtz equation in complex models with high accuracy and extremely low computational costs.« less

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.

A Multiscale Progressive Failure Modeling Methodology for Composites that Includes Fiber Strength Stochastics

NASA Technical Reports Server (NTRS)

Ricks, Trenton M.; Lacy, Thomas E., Jr.; Bednarcyk, Brett A.; Arnold, Steven M.; Hutchins, John W.

2014-01-01

A multiscale modeling methodology was developed for continuous fiber composites that incorporates a statistical distribution of fiber strengths into coupled multiscale micromechanics/finite element (FE) analyses. A modified two-parameter Weibull cumulative distribution function, which accounts for the effect of fiber length on the probability of failure, was used to characterize the statistical distribution of fiber strengths. A parametric study using the NASA Micromechanics Analysis Code with the Generalized Method of Cells (MAC/GMC) was performed to assess the effect of variable fiber strengths on local composite failure within a repeating unit cell (RUC) and subsequent global failure. The NASA code FEAMAC and the ABAQUS finite element solver were used to analyze the progressive failure of a unidirectional SCS-6/TIMETAL 21S metal matrix composite tensile dogbone specimen at 650 degC. Multiscale progressive failure analyses were performed to quantify the effect of spatially varying fiber strengths on the RUC-averaged and global stress-strain responses and failure. The ultimate composite strengths and distribution of failure locations (predominately within the gage section) reasonably matched the experimentally observed failure behavior. The predicted composite failure behavior suggests that use of macroscale models that exploit global geometric symmetries are inappropriate for cases where the actual distribution of local fiber strengths displays no such symmetries. This issue has not received much attention in the literature. Moreover, the model discretization at a specific length scale can have a profound effect on the computational costs associated with multiscale simulations.models that yield accurate yet tractable results.

Bringing global gyrokinetic turbulence simulations to the transport timescale using a multiscale approach

NASA Astrophysics Data System (ADS)

Parker, Jeffrey B.; LoDestro, Lynda L.; Told, Daniel; Merlo, Gabriele; Ricketson, Lee F.; Campos, Alejandro; Jenko, Frank; Hittinger, Jeffrey A. F.

2018-05-01

The vast separation dividing the characteristic times of energy confinement and turbulence in the core of toroidal plasmas makes first-principles prediction on long timescales extremely challenging. Here we report the demonstration of a multiple-timescale method that enables coupling global gyrokinetic simulations with a transport solver to calculate the evolution of the self-consistent temperature profile. This method, which exhibits resiliency to the intrinsic fluctuations arising in turbulence simulations, holds potential for integrating nonlocal gyrokinetic turbulence simulations into predictive, whole-device models.

ML 3.0 smoothed aggregation user's guide.

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

Sala, Marzio; Hu, Jonathan Joseph; Tuminaro, Raymond Stephen

2004-05-01

ML is a multigrid preconditioning package intended to solve linear systems of equations Az = b where A is a user supplied n x n sparse matrix, b is a user supplied vector of length n and x is a vector of length n to be computed. ML should be used on large sparse linear systems arising from partial differential equation (PDE) discretizations. While technically any linear system can be considered, ML should be used on linear systems that correspond to things that work well with multigrid methods (e.g. elliptic PDEs). ML can be used as a stand-alone package ormore » to generate preconditioners for a traditional iterative solver package (e.g. Krylov methods). We have supplied support for working with the AZTEC 2.1 and AZTECOO iterative package [15]. However, other solvers can be used by supplying a few functions. This document describes one specific algebraic multigrid approach: smoothed aggregation. This approach is used within several specialized multigrid methods: one for the eddy current formulation for Maxwell's equations, and a multilevel and domain decomposition method for symmetric and non-symmetric systems of equations (like elliptic equations, or compressible and incompressible fluid dynamics problems). Other methods exist within ML but are not described in this document. Examples are given illustrating the problem definition and exercising multigrid options.« less

ML 3.1 smoothed aggregation user's guide.

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

Sala, Marzio; Hu, Jonathan Joseph; Tuminaro, Raymond Stephen

2004-10-01

ML is a multigrid preconditioning package intended to solve linear systems of equations Ax = b where A is a user supplied n x n sparse matrix, b is a user supplied vector of length n and x is a vector of length n to be computed. ML should be used on large sparse linear systems arising from partial differential equation (PDE) discretizations. While technically any linear system can be considered, ML should be used on linear systems that correspond to things that work well with multigrid methods (e.g. elliptic PDEs). ML can be used as a stand-alone package ormore » to generate preconditioners for a traditional iterative solver package (e.g. Krylov methods). We have supplied support for working with the Aztec 2.1 and AztecOO iterative package [16]. However, other solvers can be used by supplying a few functions. This document describes one specific algebraic multigrid approach: smoothed aggregation. This approach is used within several specialized multigrid methods: one for the eddy current formulation for Maxwell's equations, and a multilevel and domain decomposition method for symmetric and nonsymmetric systems of equations (like elliptic equations, or compressible and incompressible fluid dynamics problems). Other methods exist within ML but are not described in this document. Examples are given illustrating the problem definition and exercising multigrid options.« less

SOME NEW FINITE DIFFERENCE METHODS FOR HELMHOLTZ EQUATIONS ON IRREGULAR DOMAINS OR WITH INTERFACES

PubMed Central

Wan, Xiaohai; Li, Zhilin

2012-01-01

Solving a Helmholtz equation Δu + λu = f efficiently is a challenge for many applications. For example, the core part of many efficient solvers for the incompressible Navier-Stokes equations is to solve one or several Helmholtz equations. In this paper, two new finite difference methods are proposed for solving Helmholtz equations on irregular domains, or with interfaces. For Helmholtz equations on irregular domains, the accuracy of the numerical solution obtained using the existing augmented immersed interface method (AIIM) may deteriorate when the magnitude of λ is large. In our new method, we use a level set function to extend the source term and the PDE to a larger domain before we apply the AIIM. For Helmholtz equations with interfaces, a new maximum principle preserving finite difference method is developed. The new method still uses the standard five-point stencil with modifications of the finite difference scheme at irregular grid points. The resulting coefficient matrix of the linear system of finite difference equations satisfies the sign property of the discrete maximum principle and can be solved efficiently using a multigrid solver. The finite difference method is also extended to handle temporal discretized equations where the solution coefficient λ is inversely proportional to the mesh size. PMID:22701346

SOME NEW FINITE DIFFERENCE METHODS FOR HELMHOLTZ EQUATIONS ON IRREGULAR DOMAINS OR WITH INTERFACES.

PubMed

Wan, Xiaohai; Li, Zhilin

2012-06-01

Solving a Helmholtz equation Δu + λu = f efficiently is a challenge for many applications. For example, the core part of many efficient solvers for the incompressible Navier-Stokes equations is to solve one or several Helmholtz equations. In this paper, two new finite difference methods are proposed for solving Helmholtz equations on irregular domains, or with interfaces. For Helmholtz equations on irregular domains, the accuracy of the numerical solution obtained using the existing augmented immersed interface method (AIIM) may deteriorate when the magnitude of λ is large. In our new method, we use a level set function to extend the source term and the PDE to a larger domain before we apply the AIIM. For Helmholtz equations with interfaces, a new maximum principle preserving finite difference method is developed. The new method still uses the standard five-point stencil with modifications of the finite difference scheme at irregular grid points. The resulting coefficient matrix of the linear system of finite difference equations satisfies the sign property of the discrete maximum principle and can be solved efficiently using a multigrid solver. The finite difference method is also extended to handle temporal discretized equations where the solution coefficient λ is inversely proportional to the mesh size.

An Immersed Boundary - Adaptive Mesh Refinement solver (IB-AMR) for high fidelity fully resolved wind turbine simulations

NASA Astrophysics Data System (ADS)

Angelidis, Dionysios; Sotiropoulos, Fotis

2015-11-01

The geometrical details of wind turbines determine the structure of the turbulence in the near and far wake and should be taken in account when performing high fidelity calculations. Multi-resolution simulations coupled with an immersed boundary method constitutes a powerful framework for high-fidelity calculations past wind farms located over complex terrains. We develop a 3D Immersed-Boundary Adaptive Mesh Refinement flow solver (IB-AMR) which enables turbine-resolving LES of wind turbines. The idea of using a hybrid staggered/non-staggered grid layout adopted in the Curvilinear Immersed Boundary Method (CURVIB) has been successfully incorporated on unstructured meshes and the fractional step method has been employed. The overall performance and robustness of the second order accurate, parallel, unstructured solver is evaluated by comparing the numerical simulations against conforming grid calculations and experimental measurements of laminar and turbulent flows over complex geometries. We also present turbine-resolving multi-scale LES considering all the details affecting the induced flow field; including the geometry of the tower, the nacelle and especially the rotor blades of a wind tunnel scale turbine. This material is based upon work supported by the Department of Energy under Award Number DE-EE0005482 and the Sandia National Laboratories.

Reliable and efficient solution of genome-scale models of Metabolism and macromolecular Expression

DOE PAGES

Ma, Ding; Yang, Laurence; Fleming, Ronan M. T.; ...

2017-01-18

Currently, Constraint-Based Reconstruction and Analysis (COBRA) is the only methodology that permits integrated modeling of Metabolism and macromolecular Expression (ME) at genome-scale. Linear optimization computes steady-state flux solutions to ME models, but flux values are spread over many orders of magnitude. Data values also have greatly varying magnitudes. Furthermore, standard double-precision solvers may return inaccurate solutions or report that no solution exists. Exact simplex solvers based on rational arithmetic require a near-optimal warm start to be practical on large problems (current ME models have 70,000 constraints and variables and will grow larger). We also developed a quadrupleprecision version of ourmore » linear and nonlinear optimizer MINOS, and a solution procedure (DQQ) involving Double and Quad MINOS that achieves reliability and efficiency for ME models and other challenging problems tested here. DQQ will enable extensive use of large linear and nonlinear models in systems biology and other applications involving multiscale data.« less

A Comparison of Solver Performance for Complex Gastric Electrophysiology Models

PubMed Central

Sathar, Shameer; Cheng, Leo K.; Trew, Mark L.

2016-01-01

Computational techniques for solving systems of equations arising in gastric electrophysiology have not been studied for efficient solution process. We present a computationally challenging problem of simulating gastric electrophysiology in anatomically realistic stomach geometries with multiple intracellular and extracellular domains. The multiscale nature of the problem and mesh resolution required to capture geometric and functional features necessitates efficient solution methods if the problem is to be tractable. In this study, we investigated and compared several parallel preconditioners for the linear systems arising from tetrahedral discretisation of electrically isotropic and anisotropic problems, with and without stimuli. The results showed that the isotropic problem was computationally less challenging than the anisotropic problem and that the application of extracellular stimuli increased workload considerably. Preconditioning based on block Jacobi and algebraic multigrid solvers were found to have the best overall solution times and least iteration counts, respectively. The algebraic multigrid preconditioner would be expected to perform better on large problems. PMID:26736543

Reliable and efficient solution of genome-scale models of Metabolism and macromolecular Expression

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

Ma, Ding; Yang, Laurence; Fleming, Ronan M. T.

Currently, Constraint-Based Reconstruction and Analysis (COBRA) is the only methodology that permits integrated modeling of Metabolism and macromolecular Expression (ME) at genome-scale. Linear optimization computes steady-state flux solutions to ME models, but flux values are spread over many orders of magnitude. Data values also have greatly varying magnitudes. Furthermore, standard double-precision solvers may return inaccurate solutions or report that no solution exists. Exact simplex solvers based on rational arithmetic require a near-optimal warm start to be practical on large problems (current ME models have 70,000 constraints and variables and will grow larger). We also developed a quadrupleprecision version of ourmore » linear and nonlinear optimizer MINOS, and a solution procedure (DQQ) involving Double and Quad MINOS that achieves reliability and efficiency for ME models and other challenging problems tested here. DQQ will enable extensive use of large linear and nonlinear models in systems biology and other applications involving multiscale data.« less

Multiscale Methods for Nuclear Reactor Analysis

NASA Astrophysics Data System (ADS)

Collins, Benjamin S.

The ability to accurately predict local pin powers in nuclear reactors is necessary to understand the mechanisms that cause fuel pin failure during steady state and transient operation. In the research presented here, methods are developed to improve the local solution using high order methods with boundary conditions from a low order global solution. Several different core configurations were tested to determine the improvement in the local pin powers compared to the standard techniques, that use diffusion theory and pin power reconstruction (PPR). Two different multiscale methods were developed and analyzed; the post-refinement multiscale method and the embedded multiscale method. The post-refinement multiscale methods use the global solution to determine boundary conditions for the local solution. The local solution is solved using either a fixed boundary source or an albedo boundary condition; this solution is "post-refinement" and thus has no impact on the global solution. The embedded multiscale method allows the local solver to change the global solution to provide an improved global and local solution. The post-refinement multiscale method is assessed using three core designs. When the local solution has more energy groups, the fixed source method has some difficulties near the interface: however the albedo method works well for all cases. In order to remedy the issue with boundary condition errors for the fixed source method, a buffer region is used to act as a filter, which decreases the sensitivity of the solution to the boundary condition. Both the albedo and fixed source methods benefit from the use of a buffer region. Unlike the post-refinement method, the embedded multiscale method alters the global solution. The ability to change the global solution allows for refinement in areas where the errors in the few group nodal diffusion are typically large. The embedded method is shown to improve the global solution when it is applied to a MOX/LEU assembly interface, the fuel/reflector interface, and assemblies where control rods are inserted. The embedded method also allows for multiple solution levels to be applied in a single calculation. The addition of intermediate levels to the solution improves the accuracy of the method. Both multiscale methods considered here have benefits and drawbacks, but both can provide improvements over the current PPR methodology.

Development of a parallel FE simulator for modeling the whole trans-scale failure process of rock from meso- to engineering-scale

NASA Astrophysics Data System (ADS)

Li, Gen; Tang, Chun-An; Liang, Zheng-Zhao

2017-01-01

Multi-scale high-resolution modeling of rock failure process is a powerful means in modern rock mechanics studies to reveal the complex failure mechanism and to evaluate engineering risks. However, multi-scale continuous modeling of rock, from deformation, damage to failure, has raised high requirements on the design, implementation scheme and computation capacity of the numerical software system. This study is aimed at developing the parallel finite element procedure, a parallel rock failure process analysis (RFPA) simulator that is capable of modeling the whole trans-scale failure process of rock. Based on the statistical meso-damage mechanical method, the RFPA simulator is able to construct heterogeneous rock models with multiple mechanical properties, deal with and represent the trans-scale propagation of cracks, in which the stress and strain fields are solved for the damage evolution analysis of representative volume element by the parallel finite element method (FEM) solver. This paper describes the theoretical basis of the approach and provides the details of the parallel implementation on a Windows - Linux interactive platform. A numerical model is built to test the parallel performance of FEM solver. Numerical simulations are then carried out on a laboratory-scale uniaxial compression test, and field-scale net fracture spacing and engineering-scale rock slope examples, respectively. The simulation results indicate that relatively high speedup and computation efficiency can be achieved by the parallel FEM solver with a reasonable boot process. In laboratory-scale simulation, the well-known physical phenomena, such as the macroscopic fracture pattern and stress-strain responses, can be reproduced. In field-scale simulation, the formation process of net fracture spacing from initiation, propagation to saturation can be revealed completely. In engineering-scale simulation, the whole progressive failure process of the rock slope can be well modeled. It is shown that the parallel FE simulator developed in this study is an efficient tool for modeling the whole trans-scale failure process of rock from meso- to engineering-scale.

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.

A Computational Framework for Efficient Low Temperature Plasma Simulations

NASA Astrophysics Data System (ADS)

Verma, Abhishek Kumar; Venkattraman, Ayyaswamy

2016-10-01

Over the past years, scientific computing has emerged as an essential tool for the investigation and prediction of low temperature plasmas (LTP) applications which includes electronics, nanomaterial synthesis, metamaterials etc. To further explore the LTP behavior with greater fidelity, we present a computational toolbox developed to perform LTP simulations. This framework will allow us to enhance our understanding of multiscale plasma phenomenon using high performance computing tools mainly based on OpenFOAM FVM distribution. Although aimed at microplasma simulations, the modular framework is able to perform multiscale, multiphysics simulations of physical systems comprises of LTP. Some salient introductory features are capability to perform parallel, 3D simulations of LTP applications on unstructured meshes. Performance of the solver is tested based on numerical results assessing accuracy and efficiency of benchmarks for problems in microdischarge devices. Numerical simulation of microplasma reactor at atmospheric pressure with hemispherical dielectric coated electrodes will be discussed and hence, provide an overview of applicability and future scope of this framework.

Multiscale simulation of DC corona discharge and ozone generation from nanostructures

NASA Astrophysics Data System (ADS)

Wang, Pengxiang

Atmospheric direct current (dc) corona discharge from micro-sized objects has been widely used as an ion source in many devices, such as photocopiers, laser printers, and electronic air cleaners. Shrinking the size of the discharge electrode to the nanometer range (e.g., through the use of carbon nanotubes or CNTs) is expected to lead to a significant reduction in power consumption and detrimental ozone production in these devices. The objectives of this study are to unveil the fundamental physics of the nanoscale corona discharge and to evaluate its performance and ozone production through numerical models. The extremely small size of CNTs presents considerable complexity and challenges in modeling CNT corona discharges. A hybrid multiscale model, which combines a kinetic particle-in-cell plus Monte Carlo collision (PIC-MCC) model and a continuum model, is developed to simulate the corona discharge from nanostructures. The multiscale model is developed in several steps. First, a pure PIC-MCC model is developed and PIC-MCC simulations of corona plasma from micro-sized electrode with same boundary conditions as prior model are performed to validate the PIC-MCC scheme. The agreement between the PIC-MCC model and the prior continuum model indicates the validity of the PIC-MCC scheme. The validated PIC-MCC scheme is then coupled with a continuum model to simulate the corona discharge from a micro-sized electrode. Unlike the prior continuum model which only predicts the corona plasma region, the hybrid model successfully predicts the self-consistent discharge process in the entire corona discharge gap that includes both corona plasma region and unipolar ion region. The voltage-current density curves obtained by the hybrid model agree well with analytical prediction and experimental results. The hybrid modeling approach, which combines the accuracy of a kinetic model and the efficiency of a continuum model, is thus validated for modeling dc corona discharges. For simulation of corona discharges from nanostructures, a one-dimensional (1-D) multiscale model is used due to the prohibitive computational expense associated with two-dimensional (2-D) modeling. Near the nanoscale discharge electrode surface, a kinetic model based on PIC-MCC is used due to a relatively large Knudsen number in this region. Far away from the nanoscale discharge electrode, a continuum model is used since the Knudsen number is very small there. The multiscale modeling results are compared with experimental data. The quantitative agreement in positive discharges and qualitative agreement in negative discharges validate the modeling approach. The mechanism of sustaining the discharge process from nanostructures is revealed and is found to be different from that of discharge from micro- or macro-sized electrodes. Finally, the corona plasma model is combined with a plasma chemistry model and a transport model to predict the ozone production from the nanoscale corona. The dependence of ozone production on the applied potential and air velocity is studied. The electric field distribution in a 2-D multiscale domain (from nanoscale to microscale) is predicted by solving the Poisson's equation using a finite difference scheme. The discretized linear equations are solved using a multigrid method under the framework of PETSc on a paralleled supercomputer. Although the Poisson solver is able to resolve the multiscale field, the prohibitively long computation time limits the use of a 2-D solver in the current PIC-MCC scheme.

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.

Advances in modelling of biomimetic fluid flow at different scales

PubMed Central

2011-01-01

The biomimetic flow at different scales has been discussed at length. The need of looking into the biological surfaces and morphologies and both geometrical and physical similarities to imitate the technological products and processes has been emphasized. The complex fluid flow and heat transfer problems, the fluid-interface and the physics involved at multiscale and macro-, meso-, micro- and nano-scales have been discussed. The flow and heat transfer simulation is done by various CFD solvers including Navier-Stokes and energy equations, lattice Boltzmann method and molecular dynamics method. Combined continuum-molecular dynamics method is also reviewed. PMID:21711847

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.

An efficient mixed-precision, hybrid CPU-GPU implementation of a nonlinearly implicit one-dimensional particle-in-cell algorithm

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

Chen, Guangye; Chacon, Luis; Barnes, Daniel C

2012-01-01

Recently, a fully implicit, energy- and charge-conserving particle-in-cell method has been developed for multi-scale, full-f kinetic simulations [G. Chen, et al., J. Comput. Phys. 230, 18 (2011)]. The method employs a Jacobian-free Newton-Krylov (JFNK) solver and is capable of using very large timesteps without loss of numerical stability or accuracy. A fundamental feature of the method is the segregation of particle orbit integrations from the field solver, while remaining fully self-consistent. This provides great flexibility, and dramatically improves the solver efficiency by reducing the degrees of freedom of the associated nonlinear system. However, it requires a particle push per nonlinearmore » residual evaluation, which makes the particle push the most time-consuming operation in the algorithm. This paper describes a very efficient mixed-precision, hybrid CPU-GPU implementation of the implicit PIC algorithm. The JFNK solver is kept on the CPU (in double precision), while the inherent data parallelism of the particle mover is exploited by implementing it in single-precision on a graphics processing unit (GPU) using CUDA. Performance-oriented optimizations, with the aid of an analytical performance model, the roofline model, are employed. Despite being highly dynamic, the adaptive, charge-conserving particle mover algorithm achieves up to 300 400 GOp/s (including single-precision floating-point, integer, and logic operations) on a Nvidia GeForce GTX580, corresponding to 20 25% absolute GPU efficiency (against the peak theoretical performance) and 50-70% intrinsic efficiency (against the algorithm s maximum operational throughput, which neglects all latencies). This is about 200-300 times faster than an equivalent serial CPU implementation. When the single-precision GPU particle mover is combined with a double-precision CPU JFNK field solver, overall performance gains 100 vs. the double-precision CPU-only serial version are obtained, with no apparent loss of robustness or accuracy when applied to a challenging long-time scale ion acoustic wave simulation.« less

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

Online learning in optical tomography: a stochastic approach

NASA Astrophysics Data System (ADS)

Chen, Ke; Li, Qin; Liu, Jian-Guo

2018-07-01

We study the inverse problem of radiative transfer equation (RTE) using stochastic gradient descent method (SGD) in this paper. Mathematically, optical tomography amounts to recovering the optical parameters in RTE using the incoming–outgoing pair of light intensity. We formulate it as a PDE-constraint optimization problem, where the mismatch of computed and measured outgoing data is minimized with same initial data and RTE constraint. The memory and computation cost it requires, however, is typically prohibitive, especially in high dimensional space. Smart iterative solvers that only use partial information in each step is called for thereafter. Stochastic gradient descent method is an online learning algorithm that randomly selects data for minimizing the mismatch. It requires minimum memory and computation, and advances fast, therefore perfectly serves the purpose. In this paper we formulate the problem, in both nonlinear and its linearized setting, apply SGD algorithm and analyze the convergence performance.

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

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

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

Micro-Macro Simulation of Viscoelastic Fluids in Three Dimensions

NASA Astrophysics Data System (ADS)

Rüttgers, Alexander; Griebel, Michael

2012-11-01

The development of the chemical industry resulted in various complex fluids that cannot be correctly described by classical fluid mechanics. For instance, this includes paint, engine oils with polymeric additives and toothpaste. We currently perform multiscale viscoelastic flow simulations for which we have coupled our three-dimensional Navier-Stokes solver NaSt3dGPF with the stochastic Brownian configuration field method on the micro-scale. In this method, we represent a viscoelastic fluid as a dumbbell system immersed in a three-dimensional Newtonian liquid which leads to a six-dimensional problem in space. The approach requires large computational resources and therefore depends on an efficient parallelisation strategy. Our flow solver is parallelised with a domain decomposition approach using MPI. It shows excellent scale-up results for up to 128 processors. In this talk, we present simulation results for viscoelastic fluids in square-square contractions due to their relevance for many engineering applications such as extrusion. Another aspect of the talk is the parallel implementation in NaSt3dGPF and the parallel scale-up and speed-up behaviour.

solveME: fast and reliable solution of nonlinear ME models.

PubMed

Yang, Laurence; Ma, Ding; Ebrahim, Ali; Lloyd, Colton J; Saunders, Michael A; Palsson, Bernhard O

2016-09-22

Genome-scale models of metabolism and macromolecular expression (ME) significantly expand the scope and predictive capabilities of constraint-based modeling. ME models present considerable computational challenges: they are much (>30 times) larger than corresponding metabolic reconstructions (M models), are multiscale, and growth maximization is a nonlinear programming (NLP) problem, mainly due to macromolecule dilution constraints. Here, we address these computational challenges. We develop a fast and numerically reliable solution method for growth maximization in ME models using a quad-precision NLP solver (Quad MINOS). Our method was up to 45 % faster than binary search for six significant digits in growth rate. We also develop a fast, quad-precision flux variability analysis that is accelerated (up to 60× speedup) via solver warm-starts. Finally, we employ the tools developed to investigate growth-coupled succinate overproduction, accounting for proteome constraints. Just as genome-scale metabolic reconstructions have become an invaluable tool for computational and systems biologists, we anticipate that these fast and numerically reliable ME solution methods will accelerate the wide-spread adoption of ME models for researchers in these fields.

A Generalized Perturbation Theory Solver In Rattlesnake Based On PETSc With Application To TREAT Steady State Uncertainty Quantification

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

Schunert, Sebastian; Wang, Congjian; Wang, Yaqi

Rattlesnake and MAMMOTH are the designated TREAT analysis tools currently being developed at the Idaho National Laboratory. Concurrent with development of the multi-physics, multi-scale capabilities, sensitivity analysis and uncertainty quantification (SA/UQ) capabilities are required for predicitive modeling of the TREAT reactor. For steady-state SA/UQ, that is essential for setting initial conditions for the transients, generalized perturbation theory (GPT) will be used. This work describes the implementation of a PETSc based solver for the generalized adjoint equations that constitute a inhomogeneous, rank deficient problem. The standard approach is to use an outer iteration strategy with repeated removal of the fundamental modemore » contamination. The described GPT algorithm directly solves the GPT equations without the need of an outer iteration procedure by using Krylov subspaces that are orthogonal to the operator’s nullspace. Three test problems are solved and provide sufficient verification for the Rattlesnake’s GPT capability. We conclude with a preliminary example evaluating the impact of the Boron distribution in the TREAT reactor using perturbation theory.« less

SPH simulations of WBC adhesion to the endothelium: the role of haemodynamics and endothelial binding kinetics.

PubMed

Gholami, Babak; Comerford, Andrew; Ellero, Marco

2015-11-01

A multiscale Lagrangian particle solver introduced in our previous work is extended to model physiologically realistic near-wall cell dynamics. Three-dimensional simulation of particle trajectories is combined with realistic receptor-ligand adhesion behaviour to cover full cell interactions in the vicinity of the endothelium. The selected stochastic adhesion model, which is based on a Monte Carlo acceptance-rejection method, fits in our Lagrangian framework and does not compromise performance. Additionally, appropriate inflow/outflow boundary conditions are implemented for our SPH solver to enable realistic pulsatile flow simulation. The model is tested against in-vitro data from a 3D geometry with a stenosis and sudden expansion. In both steady and pulsatile flow conditions, results show close agreement with the experimental ones. Furthermore we demonstrate, in agreement with experimental observations, that haemodynamics alone does not account for adhesion of white blood cells, in this case U937 monocytic human cells. Our findings suggest that the current framework is fully capable of modelling cell dynamics in large arteries in a realistic and efficient manner.

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.

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.

A multiphysics and multiscale software environment for modeling astrophysical systems

NASA Astrophysics Data System (ADS)

Portegies Zwart, Simon; McMillan, Steve; Harfst, Stefan; Groen, Derek; Fujii, Michiko; Nualláin, Breanndán Ó.; Glebbeek, Evert; Heggie, Douglas; Lombardi, James; Hut, Piet; Angelou, Vangelis; Banerjee, Sambaran; Belkus, Houria; Fragos, Tassos; Fregeau, John; Gaburov, Evghenii; Izzard, Rob; Jurić, Mario; Justham, Stephen; Sottoriva, Andrea; Teuben, Peter; van Bever, Joris; Yaron, Ofer; Zemp, Marcel

2009-05-01

We present MUSE, a software framework for combining existing computational tools for different astrophysical domains into a single multiphysics, multiscale application. MUSE facilitates the coupling of existing codes written in different languages by providing inter-language tools and by specifying an interface between each module and the framework that represents a balance between generality and computational efficiency. This approach allows scientists to use combinations of codes to solve highly coupled problems without the need to write new codes for other domains or significantly alter their existing codes. MUSE currently incorporates the domains of stellar dynamics, stellar evolution and stellar hydrodynamics for studying generalized stellar systems. We have now reached a "Noah's Ark" milestone, with (at least) two available numerical solvers for each domain. MUSE can treat multiscale and multiphysics systems in which the time- and size-scales are well separated, like simulating the evolution of planetary systems, small stellar associations, dense stellar clusters, galaxies and galactic nuclei. In this paper we describe three examples calculated using MUSE: the merger of two galaxies, the merger of two evolving stars, and a hybrid N-body simulation. In addition, we demonstrate an implementation of MUSE on a distributed computer which may also include special-purpose hardware, such as GRAPEs or GPUs, to accelerate computations. The current MUSE code base is publicly available as open source at http://muse.li.

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

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

Multiscale Failure Analysis of Laminated Composite Panels Subjected to Blast Loading Using FEAMAC/Explicit

NASA Technical Reports Server (NTRS)

Pineda, Evan J.; Waas, Anthony M.; Berdnarcyk, Brett A.; Arnold, Steven M.; Collier, Craig S.

2009-01-01

This preliminary report demonstrates the capabilities of the recently developed software implementation that links the Generalized Method of Cells to explicit finite element analysis by extending a previous development which tied the generalized method of cells to implicit finite elements. The multiscale framework, which uses explicit finite elements at the global-scale and the generalized method of cells at the microscale is detailed. This implementation is suitable for both dynamic mechanics problems and static problems exhibiting drastic and sudden changes in material properties, which often encounter convergence issues with commercial implicit solvers. Progressive failure analysis of stiffened and un-stiffened fiber-reinforced laminates subjected to normal blast pressure loads was performed and is used to demonstrate the capabilities of this framework. The focus of this report is to document the development of the software implementation; thus, no comparison between the results of the models and experimental data is drawn. However, the validity of the results are assessed qualitatively through the observation of failure paths, stress contours, and the distribution of system energies.

Data Assimilation and Propagation of Uncertainty in Multiscale Cardiovascular Simulation

NASA Astrophysics Data System (ADS)

Schiavazzi, Daniele; Marsden, Alison

2015-11-01

Cardiovascular modeling is the application of computational tools to predict hemodynamics. State-of-the-art techniques couple a 3D incompressible Navier-Stokes solver with a boundary circulation model and can predict local and peripheral hemodynamics, analyze the post-operative performance of surgical designs and complement clinical data collection minimizing invasive and risky measurement practices. The ability of these tools to make useful predictions is directly related to their accuracy in representing measured physiologies. Tuning of model parameters is therefore a topic of paramount importance and should include clinical data uncertainty, revealing how this uncertainty will affect the predictions. We propose a fully Bayesian, multi-level approach to data assimilation of uncertain clinical data in multiscale circulation models. To reduce the computational cost, we use a stable, condensed approximation of the 3D model build by linear sparse regression of the pressure/flow rate relationship at the outlets. Finally, we consider the problem of non-invasively propagating the uncertainty in model parameters to the resulting hemodynamics and compare Monte Carlo simulation with Stochastic Collocation approaches based on Polynomial or Multi-resolution Chaos expansions.

A Multiphysics and Multiscale Software Environment for Modeling Astrophysical Systems

NASA Astrophysics Data System (ADS)

Portegies Zwart, Simon; McMillan, Steve; O'Nualláin, Breanndán; Heggie, Douglas; Lombardi, James; Hut, Piet; Banerjee, Sambaran; Belkus, Houria; Fragos, Tassos; Fregeau, John; Fuji, Michiko; Gaburov, Evghenii; Glebbeek, Evert; Groen, Derek; Harfst, Stefan; Izzard, Rob; Jurić, Mario; Justham, Stephen; Teuben, Peter; van Bever, Joris; Yaron, Ofer; Zemp, Marcel

We present MUSE, a software framework for tying together existing computational tools for different astrophysical domains into a single multiphysics, multiscale workload. MUSE facilitates the coupling of existing codes written in different languages by providing inter-language tools and by specifying an interface between each module and the framework that represents a balance between generality and computational efficiency. This approach allows scientists to use combinations of codes to solve highly-coupled problems without the need to write new codes for other domains or significantly alter their existing codes. MUSE currently incorporates the domains of stellar dynamics, stellar evolution and stellar hydrodynamics for a generalized stellar systems workload. MUSE has now reached a "Noah's Ark" milestone, with two available numerical solvers for each domain. MUSE can treat small stellar associations, galaxies and everything in between, including planetary systems, dense stellar clusters and galactic nuclei. Here we demonstrate an examples calculated with MUSE: the merger of two galaxies. In addition we demonstrate the working of MUSE on a distributed computer. The current MUSE code base is publicly available as open source at http://muse.li.

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.

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

Convergence of the Graph Allen-Cahn Scheme

NASA Astrophysics Data System (ADS)

Luo, Xiyang; Bertozzi, Andrea L.

2017-05-01

The graph Laplacian and the graph cut problem are closely related to Markov random fields, and have many applications in clustering and image segmentation. The diffuse interface model is widely used for modeling in material science, and can also be used as a proxy to total variation minimization. In Bertozzi and Flenner (Multiscale Model Simul 10(3):1090-1118, 2012), an algorithm was developed to generalize the diffuse interface model to graphs to solve the graph cut problem. This work analyzes the conditions for the graph diffuse interface algorithm to converge. Using techniques from numerical PDE and convex optimization, monotonicity in function value and convergence under an a posteriori condition are shown for a class of schemes under a graph-independent stepsize condition. We also generalize our results to incorporate spectral truncation, a common technique used to save computation cost, and also to the case of multiclass classification. Various numerical experiments are done to compare theoretical results with practical performance.

Workflows for Full Waveform Inversions

NASA Astrophysics Data System (ADS)

Boehm, Christian; Krischer, Lion; Afanasiev, Michael; van Driel, Martin; May, Dave A.; Rietmann, Max; Fichtner, Andreas

2017-04-01

Despite many theoretical advances and the increasing availability of high-performance computing clusters, full seismic waveform inversions still face considerable challenges regarding data and workflow management. While the community has access to solvers which can harness modern heterogeneous computing architectures, the computational bottleneck has fallen to these often manpower-bounded issues that need to be overcome to facilitate further progress. Modern inversions involve huge amounts of data and require a tight integration between numerical PDE solvers, data acquisition and processing systems, nonlinear optimization libraries, and job orchestration frameworks. To this end we created a set of libraries and applications revolving around Salvus (http://salvus.io), a novel software package designed to solve large-scale full waveform inverse problems. This presentation focuses on solving passive source seismic full waveform inversions from local to global scales with Salvus. We discuss (i) design choices for the aforementioned components required for full waveform modeling and inversion, (ii) their implementation in the Salvus framework, and (iii) how it is all tied together by a usable workflow system. We combine state-of-the-art algorithms ranging from high-order finite-element solutions of the wave equation to quasi-Newton optimization algorithms using trust-region methods that can handle inexact derivatives. All is steered by an automated interactive graph-based workflow framework capable of orchestrating all necessary pieces. This naturally facilitates the creation of new Earth models and hopefully sparks new scientific insights. Additionally, and even more importantly, it enhances reproducibility and reliability of the final results.

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

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

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.

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

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

The pseudo-compartment method for coupling partial differential equation and compartment-based models of diffusion.

PubMed

Yates, Christian A; Flegg, Mark B

2015-05-06

Spatial reaction-diffusion models have been employed to describe many emergent phenomena in biological systems. The modelling technique most commonly adopted in the literature implements systems of partial differential equations (PDEs), which assumes there are sufficient densities of particles that a continuum approximation is valid. However, owing to recent advances in computational power, the simulation and therefore postulation, of computationally intensive individual-based models has become a popular way to investigate the effects of noise in reaction-diffusion systems in which regions of low copy numbers exist. The specific stochastic models with which we shall be concerned in this manuscript are referred to as 'compartment-based' or 'on-lattice'. These models are characterized by a discretization of the computational domain into a grid/lattice of 'compartments'. Within each compartment, particles are assumed to be well mixed and are permitted to react with other particles within their compartment or to transfer between neighbouring compartments. Stochastic models provide accuracy, but at the cost of significant computational resources. For models that have regions of both low and high concentrations, it is often desirable, for reasons of efficiency, to employ coupled multi-scale modelling paradigms. In this work, we develop two hybrid algorithms in which a PDE in one region of the domain is coupled to a compartment-based model in the other. Rather than attempting to balance average fluxes, our algorithms answer a more fundamental question: 'how are individual particles transported between the vastly different model descriptions?' First, we present an algorithm derived by carefully redefining the continuous PDE concentration as a probability distribution. While this first algorithm shows very strong convergence to analytical solutions of test problems, it can be cumbersome to simulate. Our second algorithm is a simplified and more efficient implementation of the first, it is derived in the continuum limit over the PDE region alone. We test our hybrid methods for functionality and accuracy in a variety of different scenarios by comparing the averaged simulations with analytical solutions of PDEs for mean concentrations. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

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.

Deterministic Mean-Field Ensemble Kalman Filtering

DOE PAGES

Law, Kody J. H.; Tembine, Hamidou; Tempone, Raul

2016-05-03

The proof of convergence of the standard ensemble Kalman filter (EnKF) from Le Gland, Monbet, and Tran [Large sample asymptotics for the ensemble Kalman filter, in The Oxford Handbook of Nonlinear Filtering, Oxford University Press, Oxford, UK, 2011, pp. 598--631] is extended to non-Gaussian state-space models. In this paper, a density-based deterministic approximation of the mean-field limit EnKF (DMFEnKF) is proposed, consisting of a PDE solver and a quadrature rule. Given a certain minimal order of convergence κ between the two, this extends to the deterministic filter approximation, which is therefore asymptotically superior to standard EnKF for dimension d

CPDES3: A preconditioned conjugate gradient solver for linear asymmetric matrix equations arising from coupled partial differential equations in three dimensions

NASA Astrophysics Data System (ADS)

Anderson, D. V.; Koniges, A. E.; Shumaker, D. E.

1988-11-01

Many physical problems require the solution of coupled partial differential equations on three-dimensional domains. When the time scales of interest dictate an implicit discretization of the equations a rather complicated global matrix system needs solution. The exact form of the matrix depends on the choice of spatial grids and on the finite element or finite difference approximations employed. CPDES3 allows each spatial operator to have 7, 15, 19, or 27 point stencils and allows for general couplings between all of the component PDE's and it automatically generates the matrix structures needed to perform the algorithm. The resulting sparse matrix equation is solved by either the preconditioned conjugate gradient (CG) method or by the preconditioned biconjugate gradient (BCG) algorithm. An arbitrary number of component equations are permitted only limited by available memory. In the sub-band representation used, we generate an algorithm that is written compactly in terms of indirect induces which is vectorizable on some of the newer scientific computers.

CPDES2: A preconditioned conjugate gradient solver for linear asymmetric matrix equations arising from coupled partial differential equations in two dimensions

NASA Astrophysics Data System (ADS)

Anderson, D. V.; Koniges, A. E.; Shumaker, D. E.

1988-11-01

Many physical problems require the solution of coupled partial differential equations on two-dimensional domains. When the time scales of interest dictate an implicit discretization of the equations a rather complicated global matrix system needs solution. The exact form of the matrix depends on the choice of spatial grids and on the finite element or finite difference approximations employed. CPDES2 allows each spatial operator to have 5 or 9 point stencils and allows for general couplings between all of the component PDE's and it automatically generates the matrix structures needed to perform the algorithm. The resulting sparse matrix equation is solved by either the preconditioned conjugate gradient (CG) method or by the preconditioned biconjugate gradient (BCG) algorithm. An arbitrary number of component equations are permitted only limited by available memory. In the sub-band representation used, we generate an algorithm that is written compactly in terms of indirect indices which is vectorizable on some of the newer scientific computers.

Deterministic Mean-Field Ensemble Kalman Filtering

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

Law, Kody J. H.; Tembine, Hamidou; Tempone, Raul

The proof of convergence of the standard ensemble Kalman filter (EnKF) from Le Gland, Monbet, and Tran [Large sample asymptotics for the ensemble Kalman filter, in The Oxford Handbook of Nonlinear Filtering, Oxford University Press, Oxford, UK, 2011, pp. 598--631] is extended to non-Gaussian state-space models. In this paper, a density-based deterministic approximation of the mean-field limit EnKF (DMFEnKF) is proposed, consisting of a PDE solver and a quadrature rule. Given a certain minimal order of convergence κ between the two, this extends to the deterministic filter approximation, which is therefore asymptotically superior to standard EnKF for dimension d

Adaptive Skin Meshes Coarsening for Biomolecular Simulation

PubMed Central

Shi, Xinwei; Koehl, Patrice

2011-01-01

In this paper, we present efficient algorithms for generating hierarchical molecular skin meshes with decreasing size and guaranteed quality. Our algorithms generate a sequence of coarse meshes for both the surfaces and the bounded volumes. Each coarser surface mesh is adaptive to the surface curvature and maintains the topology of the skin surface with guaranteed mesh quality. The corresponding tetrahedral mesh is conforming to the interface surface mesh and contains high quality tetrahedral that decompose both the interior of the molecule and the surrounding region (enclosed in a sphere). Our hierarchical tetrahedral meshes have a number of advantages that will facilitate fast and accurate multigrid PDE solvers. Firstly, the quality of both the surface triangulations and tetrahedral meshes is guaranteed. Secondly, the interface in the tetrahedral mesh is an accurate approximation of the molecular boundary. In particular, all the boundary points lie on the skin surface. Thirdly, our meshes are Delaunay meshes. Finally, the meshes are adaptive to the geometry. PMID:21779137

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.

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.

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.

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.

Technique for Calculating Solution Derivatives With Respect to Geometry Parameters in a CFD Code

NASA Technical Reports Server (NTRS)

Mathur, Sanjay

2011-01-01

A solution has been developed to the challenges of computation of derivatives with respect to geometry, which is not straightforward because these are not typically direct inputs to the computational fluid dynamics (CFD) solver. To overcome these issues, a procedure has been devised that can be used without having access to the mesh generator, while still being applicable to all types of meshes. The basic approach is inspired by the mesh motion algorithms used to deform the interior mesh nodes in a smooth manner when the surface nodes, for example, are in a fluid structure interaction problem. The general idea is to model the mesh edges and nodes as constituting a spring-mass system. Changes to boundary node locations are propagated to interior nodes by allowing them to assume their new equilibrium positions, for instance, one where the forces on each node are in balance. The main advantage of the technique is that it is independent of the volumetric mesh generator, and can be applied to structured, unstructured, single- and multi-block meshes. It essentially reduces the problem down to defining the surface mesh node derivatives with respect to the geometry parameters of interest. For analytical geometries, this is quite straightforward. In the more general case, one would need to be able to interrogate the underlying parametric CAD (computer aided design) model and to evaluate the derivatives either analytically, or by a finite difference technique. Because the technique is based on a partial differential equation (PDE), it is applicable not only to forward mode problems (where derivatives of all the output quantities are computed with respect to a single input), but it could also be extended to the adjoint problem, either by using an analytical adjoint of the PDE or a discrete analog.

A PDE Sensitivity Equation Method for Optimal Aerodynamic Design

NASA Technical Reports Server (NTRS)

Borggaard, Jeff; Burns, John

1996-01-01

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

An optimization-based approach for high-order accurate discretization of conservation laws with discontinuous solutions

NASA Astrophysics Data System (ADS)

Zahr, M. J.; Persson, P.-O.

2018-07-01

This work introduces a novel discontinuity-tracking framework for resolving discontinuous solutions of conservation laws with high-order numerical discretizations that support inter-element solution discontinuities, such as discontinuous Galerkin or finite volume methods. The proposed method aims to align inter-element boundaries with discontinuities in the solution by deforming the computational mesh. A discontinuity-aligned mesh ensures the discontinuity is represented through inter-element jumps while smooth basis functions interior to elements are only used to approximate smooth regions of the solution, thereby avoiding Gibbs' phenomena that create well-known stability issues. Therefore, very coarse high-order discretizations accurately resolve the piecewise smooth solution throughout the domain, provided the discontinuity is tracked. Central to the proposed discontinuity-tracking framework is a discrete PDE-constrained optimization formulation that simultaneously aligns the computational mesh with discontinuities in the solution and solves the discretized conservation law on this mesh. The optimization objective is taken as a combination of the deviation of the finite-dimensional solution from its element-wise average and a mesh distortion metric to simultaneously penalize Gibbs' phenomena and distorted meshes. It will be shown that our objective function satisfies two critical properties that are required for this discontinuity-tracking framework to be practical: (1) possesses a local minima at a discontinuity-aligned mesh and (2) decreases monotonically to this minimum in a neighborhood of radius approximately h / 2, whereas other popular discontinuity indicators fail to satisfy the latter. Another important contribution of this work is the observation that traditional reduced space PDE-constrained optimization solvers that repeatedly solve the conservation law at various mesh configurations are not viable in this context since severe overshoot and undershoot in the solution, i.e., Gibbs' phenomena, may make it impossible to solve the discrete conservation law on non-aligned meshes. Therefore, we advocate a gradient-based, full space solver where the mesh and conservation law solution converge to their optimal values simultaneously and therefore never require the solution of the discrete conservation law on a non-aligned mesh. The merit of the proposed method is demonstrated on a number of one- and two-dimensional model problems including the L2 projection of discontinuous functions, Burgers' equation with a discontinuous source term, transonic flow through a nozzle, and supersonic flow around a bluff body. We demonstrate optimal O (h p + 1) convergence rates in the L1 norm for up to polynomial order p = 6 and show that accurate solutions can be obtained on extremely coarse meshes.

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

A multiscale SPH particle model of the near-wall dynamics of leukocytes in flow.

PubMed

Gholami, Babak; Comerford, Andrew; Ellero, Marco

2014-01-01

A novel multiscale Lagrangian particle solver based on SPH is developed with the intended application of leukocyte transport in large arteries. In such arteries, the transport of leukocytes and red blood cells can be divided into two distinct regions: the bulk flow and the near-wall region. In the bulk flow, the transport can be modeled on a continuum basis as the transport of passive scalar concentrations. Whereas in the near-wall region, specific particle tracking of the leukocytes is required and lubrication forces need to be separately taken into account. Because of large separation of spatio-temporal scales involved in the problem, simulations of red blood cells and leukocytes are handled separately. In order to take the exchange of leukocytes between the bulk fluid and the near-wall region into account, solutions are communicated through coupling of conserved quantities at the interface between these regions. Because the particle tracking is limited to those leukocytes lying in the near-wall region only, our approach brings considerable speedup to the simulation of leukocyte circulation in a test geometry of a backward-facing step, which encompasses many flow features observed in vivo. Copyright © 2013 John Wiley & Sons, Ltd.

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

Robust parallel iterative solvers for linear and least-squares problems, Final Technical Report

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

Saad, Yousef

2014-01-16

The primary goal of this project is to study and develop robust iterative methods for solving linear systems of equations and least squares systems. The focus of the Minnesota team is on algorithms development, robustness issues, and on tests and validation of the methods on realistic problems. 1. The project begun with an investigation on how to practically update a preconditioner obtained from an ILU-type factorization, when the coefficient matrix changes. 2. We investigated strategies to improve robustness in parallel preconditioners in a specific case of a PDE with discontinuous coefficients. 3. We explored ways to adapt standard preconditioners formore » solving linear systems arising from the Helmholtz equation. These are often difficult linear systems to solve by iterative methods. 4. We have also worked on purely theoretical issues related to the analysis of Krylov subspace methods for linear systems. 5. We developed an effective strategy for performing ILU factorizations for the case when the matrix is highly indefinite. The strategy uses shifting in some optimal way. The method was extended to the solution of Helmholtz equations by using complex shifts, yielding very good results in many cases. 6. We addressed the difficult problem of preconditioning sparse systems of equations on GPUs. 7. A by-product of the above work is a software package consisting of an iterative solver library for GPUs based on CUDA. This was made publicly available. It was the first such library that offers complete iterative solvers for GPUs. 8. We considered another form of ILU which blends coarsening techniques from Multigrid with algebraic multilevel methods. 9. We have released a new version on our parallel solver - called pARMS [new version is version 3]. As part of this we have tested the code in complex settings - including the solution of Maxwell and Helmholtz equations and for a problem of crystal growth.10. As an application of polynomial preconditioning we considered the problem of evaluating f(A)v which arises in statistical sampling. 11. As an application to the methods we developed, we tackled the problem of computing the diagonal of the inverse of a matrix. This arises in statistical applications as well as in many applications in physics. We explored probing methods as well as domain-decomposition type methods. 12. A collaboration with researchers from Toulouse, France, considered the important problem of computing the Schur complement in a domain-decomposition approach. 13. We explored new ways of preconditioning linear systems, based on low-rank approximations.« less

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.

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.

GPU surface extraction using the closest point embedding

NASA Astrophysics Data System (ADS)

Kim, Mark; Hansen, Charles

2015-01-01

Isosurface extraction is a fundamental technique used for both surface reconstruction and mesh generation. One method to extract well-formed isosurfaces is a particle system; unfortunately, particle systems can be slow. In this paper, we introduce an enhanced parallel particle system that uses the closest point embedding as the surface representation to speedup the particle system for isosurface extraction. The closest point embedding is used in the Closest Point Method (CPM), a technique that uses a standard three dimensional numerical PDE solver on two dimensional embedded surfaces. To fully take advantage of the closest point embedding, it is coupled with a Barnes-Hut tree code on the GPU. This new technique produces well-formed, conformal unstructured triangular and tetrahedral meshes from labeled multi-material volume datasets. Further, this new parallel implementation of the particle system is faster than any known methods for conformal multi-material mesh extraction. The resulting speed-ups gained in this implementation can reduce the time from labeled data to mesh from hours to minutes and benefits users, such as bioengineers, who employ triangular and tetrahedral meshes

Grid generation for the solution of partial differential equations

NASA Technical Reports Server (NTRS)

Eiseman, Peter R.; Erlebacher, Gordon

1989-01-01

A general survey of grid generators is presented with a concern for understanding why grids are necessary, how they are applied, and how they are generated. After an examination of the need for meshes, the overall applications setting is established with a categorization of the various connectivity patterns. This is split between structured grids and unstructured meshes. Altogether, the categorization establishes the foundation upon which grid generation techniques are developed. The two primary categories are algebraic techniques and partial differential equation techniques. These are each split into basic parts, and accordingly are individually examined in some detail. In the process, the interrelations between the various parts are accented. From the established background in the primary techniques, consideration is shifted to the topic of interactive grid generation and then to adaptive meshes. The setting for adaptivity is established with a suitable means to monitor severe solution behavior. Adaptive grids are considered first and are followed by adaptive triangular meshes. Then the consideration shifts to the temporal coupling between grid generators and PDE-solvers. To conclude, a reflection upon the discussion, herein, is given.

Grid generation for the solution of partial differential equations

NASA Technical Reports Server (NTRS)

Eiseman, Peter R.; Erlebacher, Gordon

1987-01-01

A general survey of grid generators is presented with a concern for understanding why grids are necessary, how they are applied, and how they are generated. After an examination of the need for meshes, the overall applications setting is established with a categorization of the various connectivity patterns. This is split between structured grids and unstructured meshes. Altogether, the categorization establishes the foundation upon which grid generation techniques are developed. The two primary categories are algebraic techniques and partial differential equation techniques. These are each split into basic parts, and accordingly are individually examined in some detail. In the process, the interrelations between the various parts are accented. From the established background in the primary techniques, consideration is shifted to the topic of interactive grid generation and then to adaptive meshes. The setting for adaptivity is established with a suitable means to monitor severe solution behavior. Adaptive grids are considered first and are followed by adaptive triangular meshes. Then the consideration shifts to the temporal coupling between grid generators and PDE-solvers. To conclude, a reflection upon the discussion, herein, is given.

Dynamic one-dimensional modeling of secondary settling tanks and design impacts of sizing decisions.

PubMed

Li, Ben; Stenstrom, Michael K

2014-03-01

As one of the most significant components in the activated sludge process (ASP), secondary settling tanks (SSTs) can be investigated with mathematical models to optimize design and operation. This paper takes a new look at the one-dimensional (1-D) SST model by analyzing and considering the impacts of numerical problems, especially the process robustness. An improved SST model with Yee-Roe-Davis technique as the PDE solver is proposed and compared with the widely used Takács model to show its improvement in numerical solution quality. The improved and Takács models are coupled with a bioreactor model to reevaluate ASP design basis and several popular control strategies for economic plausibility, contaminant removal efficiency and system robustness. The time-to-failure due to rising sludge blanket during overloading, as a key robustness indicator, is analyzed to demonstrate the differences caused by numerical issues in SST models. The calculated results indicate that the Takács model significantly underestimates time to failure, thus leading to a conservative design. Copyright © 2013 Elsevier Ltd. All rights reserved.

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.

Whistler wave generation by electron temperature anisotropy during asymmetric magnetic reconnection in space

NASA Astrophysics Data System (ADS)

Swerdlow, Josh; Yoo, Jongsoo; Kim, Eun-Hwa; Yamada, Masaaki; Ji, Hantao

2017-10-01

Generation of whistler waves during asymmetric reconnection is studied by analyzing data from a MMS (Magnetospheric Multiscale) event. In particular, the possible role of electron temperature anisotropy in excitation of whistler waves on the magnetosphere side is discussed. The local electron distribution function is fitted into a sum of bi-Maxwellian distribution functions. Then, the dispersion relation solver, WHAMP (waves in homogeneous, anisotropic, multicomponent plasmas), is used to obtain the local dispersion relation and growth rate of the whistler waves. We compare the theoretical calculations with the measured dispersion relation. This work was made possible by funding from the Department of Energy for the Summer Undergraduate Laboratory Internship (SULI) program. This work is supported by the US DOE Contract No. DE-AC02-09CH11466.

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.

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

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

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

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.

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

Besse, Nicolas; Latu, Guillaume; Ghizzo, Alain

In this paper we present a new method for the numerical solution of the relativistic Vlasov-Maxwell system on a phase-space grid using an adaptive semi-Lagrangian method. The adaptivity is performed through a wavelet multiresolution analysis, which gives a powerful and natural refinement criterion based on the local measurement of the approximation error and regularity of the distribution function. Therefore, the multiscale expansion of the distribution function allows to get a sparse representation of the data and thus save memory space and CPU time. We apply this numerical scheme to reduced Vlasov-Maxwell systems arising in laser-plasma physics. Interaction of relativistically strongmore » laser pulses with overdense plasma slabs is investigated. These Vlasov simulations revealed a rich variety of phenomena associated with the fast particle dynamics induced by electromagnetic waves as electron trapping, particle acceleration, and electron plasma wavebreaking. However, the wavelet based adaptive method that we developed here, does not yield significant improvements compared to Vlasov solvers on a uniform mesh due to the substantial overhead that the method introduces. Nonetheless they might be a first step towards more efficient adaptive solvers based on different ideas for the grid refinement or on a more efficient implementation. Here the Vlasov simulations are performed in a two-dimensional phase-space where the development of thin filaments, strongly amplified by relativistic effects requires an important increase of the total number of points of the phase-space grid as they get finer as time goes on. The adaptive method could be more useful in cases where these thin filaments that need to be resolved are a very small fraction of the hyper-volume, which arises in higher dimensions because of the surface-to-volume scaling and the essentially one-dimensional structure of the filaments. Moreover, the main way to improve the efficiency of the adaptive method is to increase the local character in phase-space of the numerical scheme, by considering multiscale reconstruction with more compact support and by replacing the semi-Lagrangian method with more local - in space - numerical scheme as compact finite difference schemes, discontinuous-Galerkin method or finite element residual schemes which are well suited for parallel domain decomposition techniques.« less

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.

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.

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.

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.

Variable High Order Multiblock Overlapping Grid Methods for Mixed Steady and Unsteady Multiscale Viscous Flows

NASA Technical Reports Server (NTRS)

Sjogreen, Bjoern; Yee, H. C.

2007-01-01

Flows containing steady or nearly steady strong shocks in parts of the flow field, and unsteady turbulence with shocklets on other parts of the flow field are difficult to capture accurately and efficiently employing the same numerical scheme even under the multiblock grid or adaptive grid refinement framework. On one hand, sixth-order or higher shock-capturing methods are appropriate for unsteady turbulence with shocklets. On the other hand, lower order shock-capturing methods are more effective for strong steady shocks in terms of convergence. In order to minimize the shortcomings of low order and high order shock-capturing schemes for the subject flows,a multi- block overlapping grid with different orders of accuracy on different blocks is proposed. Test cases to illustrate the performance of the new solver are included.

Spectral solver for multi-scale plasma physics simulations with dynamically adaptive number of moments

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

Vencels, Juris; Delzanno, Gian Luca; Johnson, Alec

2015-06-01

A spectral method for kinetic plasma simulations based on the expansion of the velocity distribution function in a variable number of Hermite polynomials is presented. The method is based on a set of non-linear equations that is solved to determine the coefficients of the Hermite expansion satisfying the Vlasov and Poisson equations. In this paper, we first show that this technique combines the fluid and kinetic approaches into one framework. Second, we present an adaptive strategy to increase and decrease the number of Hermite functions dynamically during the simulation. The technique is applied to the Landau damping and two-stream instabilitymore » test problems. Performance results show 21% and 47% saving of total simulation time in the Landau and two-stream instability test cases, respectively.« less

Bringing global gyrokinetic turbulence simulations to the transport timescale using a multiscale approach

NASA Astrophysics Data System (ADS)

Parker, Jeffrey; Lodestro, Lynda; Told, Daniel; Merlo, Gabriele; Ricketson, Lee; Campos, Alejandro; Jenko, Frank; Hittinger, Jeffrey

2017-10-01

Predictive whole-device simulation models will play an increasingly important role in ensuring the success of fusion experiments and accelerating the development of fusion energy. In the core of tokamak plasmas, a separation of timescales between turbulence and transport makes a single direct simulation of both processes computationally expensive. We present the first demonstration of a multiple-timescale method coupling global gyrokinetic simulations with a transport solver to calculate the self-consistent, steady-state temperature profile. Initial results are highly encouraging, with the coupling method appearing robust to the difficult problem of turbulent fluctuations. The method holds potential for integrating first-principles turbulence simulations into whole-device models and advancing the understanding of global plasma behavior. Work supported by US DOE under Contract DE-AC52-07NA27344 and the Exascale Computing Project (17-SC-20-SC).

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

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.

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.

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.

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.

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…

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

Status and future of MUSE

NASA Astrophysics Data System (ADS)

Harfst, S.; Portegies Zwart, S.; McMillan, S.

2008-12-01

We present MUSE, a software framework for combining existing computational tools from different astrophysical domains into a single multi-physics, multi-scale application. MUSE facilitates the coupling of existing codes written in different languages by providing inter-language tools and by specifying an interface between each module and the framework that represents a balance between generality and computational efficiency. This approach allows scientists to use combinations of codes to solve highly-coupled problems without the need to write new codes for other domains or significantly alter their existing codes. MUSE currently incorporates the domains of stellar dynamics, stellar evolution and stellar hydrodynamics for studying generalized stellar systems. We have now reached a ``Noah's Ark'' milestone, with (at least) two available numerical solvers for each domain. MUSE can treat multi-scale and multi-physics systems in which the time- and size-scales are well separated, like simulating the evolution of planetary systems, small stellar associations, dense stellar clusters, galaxies and galactic nuclei. In this paper we describe two examples calculated using MUSE: the merger of two galaxies and an N-body simulation with live stellar evolution. In addition, we demonstrate an implementation of MUSE on a distributed computer which may also include special-purpose hardware, such as GRAPEs or GPUs, to accelerate computations. The current MUSE code base is publicly available as open source at http://muse.li.

Multiscale Airflow Model and Aerosol Deposition in Healthy and Emphysematous Rat Lungs

NASA Astrophysics Data System (ADS)

Oakes, Jessica; Marsden, Alison; Grandmont, Celine; Darquenne, Chantal; Vignon-Clementel, Irene

2012-11-01

The fate of aerosol particles in healthy and emphysematic lungs is needed to determine the toxic or therapeutic effects of inhalable particles. In this study we used a multiscale numerical model that couples a 0D resistance and capacitance model to 3D airways generated from MR images. Airflow simulations were performed using an in-house 3D finite element solver (SimVascular, simtk.org). Seven simulations were performed; 1 healthy, 1 uniform emphysema and 5 different cases of heterogeneous emphysema. In the heterogeneous emphysema cases the disease was confined to a single lobe. As a post processing step, 1 micron diameter particles were tracked in the flow field using Lagrangian particle tracking. The simulation results showed that the inhaled flow distribution was equal for the healthy and uniform emphysema cases. However, in the heterogeneous emphysema cases the delivery of inhaled air was larger in the diseased lobe. Additionally, there was an increase in delivery of aerosol particles to the diseased lobe. This suggests that as the therapeutic particles would reach the diseased areas of the lung, while toxic particles would increasingly harm the lung. The 3D-0D model described here is the first of its kind to be used to study healthy and emphysematic lungs. NSF Graduate Fellowship (Oakes), Burroughs Wellcome Fund (Marsden, Oakes) 1R21HL087805-02 from NHLBI at NIH, INRIA Team Grant.

Multiscale modeling of a Chemofilter device for filtering chemotherapy toxins from blood

NASA Astrophysics Data System (ADS)

Maani, Nazanin; Beyhaghi, Saman; Yee, Daryl; Nosonovsky, Micheal; Greer, Julia; Hetts, Steven; Rayz, Vitaliy

2016-11-01

Purpose: Chemotherapy drugs injected intra-arterially to treat cancer can cause systemic toxic effects. A catheter-based Chemofilter device, temporarily deployed in a vein during the procedure can filter excessive drug from the blood thus reducing chemotherapy side-effects. CFD modeling is used to design the membrane of the Chemofilter in order to optimize its hemodynamic performance. Methods: Multiscale approach is used to model blood flow through the Chemofilter. The toxins bind to the Chemofilter's membrane formed by a lattice of numerous micro cells deployed in a blood vessel of much larger size. A detailed model of the flow through a 2x2 microcell matrix with periodic boundary conditions is used to determine the permeability of the membrane. The results are used to simulate the flow through the whole device modeled as a uniform porous membrane. The finite-volume solver Fluent is used to obtain the numerical solution. Results: The micro cell matrix has a porosity of 0.92. The pressure drop across the resolved microcells was found to be 630 Pa, resulting in the permeability of 6.21 x10-11 m2 in the normal direction. These values were used to optimize the device geometry in order to increase the contact area of the membrane, while minimizing its obstruction to the flow. NIH NCI R01CA194533.

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.

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

Automatic Thread-Level Parallelization in the Chombo AMR Library

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

Christen, Matthias; Keen, Noel; Ligocki, Terry

2011-05-26

The increasing on-chip parallelism has some substantial implications for HPC applications. Currently, hybrid programming models (typically MPI+OpenMP) are employed for mapping software to the hardware in order to leverage the hardware?s architectural features. In this paper, we present an approach that automatically introduces thread level parallelism into Chombo, a parallel adaptive mesh refinement framework for finite difference type PDE solvers. In Chombo, core algorithms are specified in the ChomboFortran, a macro language extension to F77 that is part of the Chombo framework. This domain-specific language forms an already used target language for an automatic migration of the large number ofmore » existing algorithms into a hybrid MPI+OpenMP implementation. It also provides access to the auto-tuning methodology that enables tuning certain aspects of an algorithm to hardware characteristics. Performance measurements are presented for a few of the most relevant kernels with respect to a specific application benchmark using this technique as well as benchmark results for the entire application. The kernel benchmarks show that, using auto-tuning, up to a factor of 11 in performance was gained with 4 threads with respect to the serial reference implementation.« less

Quantitative modeling and optimization of magnetic tweezers.

PubMed

Lipfert, Jan; Hao, Xiaomin; Dekker, Nynke H

2009-06-17

Magnetic tweezers are a powerful tool to manipulate single DNA or RNA molecules and to study nucleic acid-protein interactions in real time. Here, we have modeled the magnetic fields of permanent magnets in magnetic tweezers and computed the forces exerted on superparamagnetic beads from first principles. For simple, symmetric geometries the magnetic fields can be calculated semianalytically using the Biot-Savart law. For complicated geometries and in the presence of an iron yoke, we employ a finite-element three-dimensional PDE solver to numerically solve the magnetostatic problem. The theoretical predictions are in quantitative agreement with direct Hall-probe measurements of the magnetic field and with measurements of the force exerted on DNA-tethered beads. Using these predictive theories, we systematically explore the effects of magnet alignment, magnet spacing, magnet size, and of adding an iron yoke to the magnets on the forces that can be exerted on tethered particles. We find that the optimal configuration for maximal stretching forces is a vertically aligned pair of magnets, with a minimal gap between the magnets and minimal flow cell thickness. Following these principles, we present a configuration that allows one to apply > or = 40 pN stretching forces on approximately 1-microm tethered beads.

Quantitative Modeling and Optimization of Magnetic Tweezers

PubMed Central

Lipfert, Jan; Hao, Xiaomin; Dekker, Nynke H.

2009-01-01

Abstract Magnetic tweezers are a powerful tool to manipulate single DNA or RNA molecules and to study nucleic acid-protein interactions in real time. Here, we have modeled the magnetic fields of permanent magnets in magnetic tweezers and computed the forces exerted on superparamagnetic beads from first principles. For simple, symmetric geometries the magnetic fields can be calculated semianalytically using the Biot-Savart law. For complicated geometries and in the presence of an iron yoke, we employ a finite-element three-dimensional PDE solver to numerically solve the magnetostatic problem. The theoretical predictions are in quantitative agreement with direct Hall-probe measurements of the magnetic field and with measurements of the force exerted on DNA-tethered beads. Using these predictive theories, we systematically explore the effects of magnet alignment, magnet spacing, magnet size, and of adding an iron yoke to the magnets on the forces that can be exerted on tethered particles. We find that the optimal configuration for maximal stretching forces is a vertically aligned pair of magnets, with a minimal gap between the magnets and minimal flow cell thickness. Following these principles, we present a configuration that allows one to apply ≥40 pN stretching forces on ≈1-μm tethered beads. PMID:19527664

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.

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).

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.

Fluid preconditioning for Newton–Krylov-based, fully implicit, electrostatic particle-in-cell simulations

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

Chen, G., E-mail: gchen@lanl.gov; Chacón, L.; Leibs, C.A.

2014-02-01

A recent proof-of-principle study proposes an energy- and charge-conserving, nonlinearly implicit electrostatic particle-in-cell (PIC) algorithm in one dimension [9]. The algorithm in the reference employs an unpreconditioned Jacobian-free Newton–Krylov method, which ensures nonlinear convergence at every timestep (resolving the dynamical timescale of interest). Kinetic enslavement, which is one key component of the algorithm, not only enables fully implicit PIC as a practical approach, but also allows preconditioning the kinetic solver with a fluid approximation. This study proposes such a preconditioner, in which the linearized moment equations are closed with moments computed from particles. Effective acceleration of the linear GMRES solvemore » is demonstrated, on both uniform and non-uniform meshes. The algorithm performance is largely insensitive to the electron–ion mass ratio. Numerical experiments are performed on a 1D multi-scale ion acoustic wave test problem.« less

The Center for Multiscale Plasma Dynamics, Final Report

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

Gombosi, Tamas I.

The University of Michigan participated in the joint UCLA/Maryland fusion science center focused on plasma physics problems for which the traditional separation of the dynamics into microscale and macroscale processes breaks down. These processes involve large scale flows and magnetic fields tightly coupled to the small scale, kinetic dynamics of turbulence, particle acceleration and energy cascade. The interaction between these vastly disparate scales controls the evolution of the system. The enormous range of temporal and spatial scales associated with these problems renders direct simulation intractable even in computations that use the largest existing parallel computers. Our efforts focused on twomore » main problems: the development of Hall MHD solvers on solution adaptive grids and the development of solution adaptive grids using generalized coordinates so that the proper geometry of inertial confinement can be taken into account and efficient refinement strategies can be obtained.« less

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.

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

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.

Low-energy effective Hamiltonians for correlated electron systems beyond density functional theory

NASA Astrophysics Data System (ADS)

Hirayama, Motoaki; Miyake, Takashi; Imada, Masatoshi; Biermann, Silke

2017-08-01

We propose a refined scheme of deriving an effective low-energy Hamiltonian for materials with strong electronic Coulomb correlations beyond density functional theory (DFT). By tracing out the electronic states away from the target degrees of freedom in a controlled way by a perturbative scheme, we construct an effective Hamiltonian for a restricted low-energy target space incorporating the effects of high-energy degrees of freedom in an effective manner. The resulting effective Hamiltonian can afterwards be solved by accurate many-body solvers. We improve this "multiscale ab initio scheme for correlated electrons" (MACE) primarily in two directions by elaborating and combining two frameworks developed by Hirayama et al. [M. Hirayama, T. Miyake, and M. Imada, Phys. Rev. B 87, 195144 (2013), 10.1103/PhysRevB.87.195144] and Casula et al. [M. Casula, P. Werner, L. Vaugier, F. Aryasetiawan, T. Miyake, A. J. Millis, and S. Biermann, Phys. Rev. Lett. 109, 126408 (2012), 10.1103/PhysRevLett.109.126408]: (1) Double counting of electronic correlations between the DFT and the low-energy solver is avoided by using the constrained G W scheme; and (2) the frequency dependent interactions emerging from the partial trace summation are successfully separated into a nonlocal part that is treated following ideas by Hirayama et al. and a local part treated nonperturbatively in the spirit of Casula et al. and are incorporated into the renormalization of the low-energy dispersion. The scheme is favorably tested on the example of SrVO3.

On the use of kinetic energy preserving DG-schemes for large eddy simulation

NASA Astrophysics Data System (ADS)

Flad, David; Gassner, Gregor

2017-12-01

Recently, element based high order methods such as Discontinuous Galerkin (DG) methods and the closely related flux reconstruction (FR) schemes have become popular for compressible large eddy simulation (LES). Element based high order methods with Riemann solver based interface numerical flux functions offer an interesting dispersion dissipation behavior for multi-scale problems: dispersion errors are very low for a broad range of scales, while dissipation errors are very low for well resolved scales and are very high for scales close to the Nyquist cutoff. In some sense, the inherent numerical dissipation caused by the interface Riemann solver acts as a filter of high frequency solution components. This observation motivates the trend that element based high order methods with Riemann solvers are used without an explicit LES model added. Only the high frequency type inherent dissipation caused by the Riemann solver at the element interfaces is used to account for the missing sub-grid scale dissipation. Due to under-resolution of vortical dominated structures typical for LES type setups, element based high order methods suffer from stability issues caused by aliasing errors of the non-linear flux terms. A very common strategy to fight these aliasing issues (and instabilities) is so-called polynomial de-aliasing, where interpolation is exchanged with projection based on an increased number of quadrature points. In this paper, we start with this common no-model or implicit LES (iLES) DG approach with polynomial de-aliasing and Riemann solver dissipation and review its capabilities and limitations. We find that the strategy gives excellent results, but only when the resolution is such, that about 40% of the dissipation is resolved. For more realistic, coarser resolutions used in classical LES e.g. of industrial applications, the iLES DG strategy becomes quite inaccurate. We show that there is no obvious fix to this strategy, as adding for instance a sub-grid-scale models on top doesn't change much or in worst case decreases the fidelity even more. Finally, the core of this work is a novel LES strategy based on split form DG methods that are kinetic energy preserving. The scheme offers excellent stability with full control over the amount and shape of the added artificial dissipation. This premise is the main idea of the work and we will assess the LES capabilities of the novel split form DG approach when applied to shock-free, moderate Mach number turbulence. We will demonstrate that the novel DG LES strategy offers similar accuracy as the iLES methodology for well resolved cases, but strongly increases fidelity in case of more realistic coarse resolutions.

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.

Tinker-HP: a massively parallel molecular dynamics package for multiscale simulations of large complex systems with advanced point dipole polarizable force fields.

PubMed

Lagardère, Louis; Jolly, Luc-Henri; Lipparini, Filippo; Aviat, Félix; Stamm, Benjamin; Jing, Zhifeng F; Harger, Matthew; Torabifard, Hedieh; Cisneros, G Andrés; Schnieders, Michael J; Gresh, Nohad; Maday, Yvon; Ren, Pengyu Y; Ponder, Jay W; Piquemal, Jean-Philip

2018-01-28

We present Tinker-HP, a massively MPI parallel package dedicated to classical molecular dynamics (MD) and to multiscale simulations, using advanced polarizable force fields (PFF) encompassing distributed multipoles electrostatics. Tinker-HP is an evolution of the popular Tinker package code that conserves its simplicity of use and its reference double precision implementation for CPUs. Grounded on interdisciplinary efforts with applied mathematics, Tinker-HP allows for long polarizable MD simulations on large systems up to millions of atoms. We detail in the paper the newly developed extension of massively parallel 3D spatial decomposition to point dipole polarizable models as well as their coupling to efficient Krylov iterative and non-iterative polarization solvers. The design of the code allows the use of various computer systems ranging from laboratory workstations to modern petascale supercomputers with thousands of cores. Tinker-HP proposes therefore the first high-performance scalable CPU computing environment for the development of next generation point dipole PFFs and for production simulations. Strategies linking Tinker-HP to Quantum Mechanics (QM) in the framework of multiscale polarizable self-consistent QM/MD simulations are also provided. The possibilities, performances and scalability of the software are demonstrated via benchmarks calculations using the polarizable AMOEBA force field on systems ranging from large water boxes of increasing size and ionic liquids to (very) large biosystems encompassing several proteins as well as the complete satellite tobacco mosaic virus and ribosome structures. For small systems, Tinker-HP appears to be competitive with the Tinker-OpenMM GPU implementation of Tinker. As the system size grows, Tinker-HP remains operational thanks to its access to distributed memory and takes advantage of its new algorithmic enabling for stable long timescale polarizable simulations. Overall, a several thousand-fold acceleration over a single-core computation is observed for the largest systems. The extension of the present CPU implementation of Tinker-HP to other computational platforms is discussed.

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.

Determination of the diffusivity, dispersion, skewness and kurtosis in heterogeneous porous flow. Part I: Analytical solutions with the extended method of moments.

NASA Astrophysics Data System (ADS)

Ginzburg, Irina; Vikhansky, Alexander

2018-05-01

The extended method of moments (EMM) is elaborated in recursive algorithmic form for the prediction of the effective diffusivity, the Taylor dispersion dyadic and the associated longitudinal high-order coefficients in mean-concentration profiles and residence-time distributions. The method applies in any streamwise-periodic stationary d-dimensional velocity field resolved in the piecewise continuous heterogeneous porosity field. It is demonstrated that EMM reduces to the method of moments and the volume-averaging formulation in microscopic velocity field and homogeneous soil, respectively. The EMM simultaneously constructs two systems of moments, the spatial and the temporal, without resorting to solving of the high-order upscaled PDE. At the same time, the EMM is supported with the reconstruction of distribution from its moments, allowing to visualize the deviation from the classical ADE solution. The EMM can be handled by any linear advection-diffusion solver with explicit mass-source and diffusive-flux jump condition on the solid boundary and permeable interface. The prediction of the first four moments is decisive in the optimization of the dispersion, asymmetry, peakedness and heavy-tails of the solute distributions, through an adequate design of the composite materials, wetlands, chemical devices or oil recovery. The symbolic solutions for dispersion, skewness and kurtosis are constructed in basic configurations: diffusion process and Darcy flow through two porous blocks in "series", straight and radial Poiseuille flow, porous flow governed by the Stokes-Brinkman-Darcy channel equation and a fracture surrounded by penetrable diffusive matrix or embedded in porous flow. We examine the moments dependency upon porosity contrast, aspect ratio, Péclet and Darcy numbers, but also for their response on the effective Brinkman viscosity applied in flow modeling. Two numerical Lattice Boltzmann algorithms, a direct solver of the microscopic ADE in heterogeneous structure and a novel scheme for EMM numerical formulation, are called for validation of the constructed analytical predictions.

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.

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.

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.

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

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.

Multiscale Multilevel Approach to Solution of Nanotechnology Problems

NASA Astrophysics Data System (ADS)

Polyakov, Sergey; Podryga, Viktoriia

2018-02-01

The paper is devoted to a multiscale multilevel approach for the solution of nanotechnology problems on supercomputer systems. The approach uses the combination of continuum mechanics models and the Newton dynamics for individual particles. This combination includes three scale levels: macroscopic, mesoscopic and microscopic. For gas-metal technical systems the following models are used. The quasihydrodynamic system of equations is used as a mathematical model at the macrolevel for gas and solid states. The system of Newton equations is used as a mathematical model at the mesoand microlevels; it is written for nanoparticles of the medium and larger particles moving in the medium. The numerical implementation of the approach is based on the method of splitting into physical processes. The quasihydrodynamic equations are solved by the finite volume method on grids of different types. The Newton equations of motion are solved by Verlet integration in each cell of the grid independently or in groups of connected cells. In the framework of the general methodology, four classes of algorithms and methods of their parallelization are provided. The parallelization uses the principles of geometric parallelism and the efficient partitioning of the computational domain. A special dynamic algorithm is used for load balancing the solvers. The testing of the developed approach was made by the example of the nitrogen outflow from a balloon with high pressure to a vacuum chamber through a micronozzle and a microchannel. The obtained results confirm the high efficiency of the developed methodology.

The Effect of Fiber Strength Stochastics and Local Fiber Volume Fraction on Multiscale Progressive Failure of Composites

NASA Technical Reports Server (NTRS)

Ricks, Trenton M.; Lacy, Jr., Thomas E.; Bednarcyk, Brett A.; Arnold, Steven M.

2013-01-01

Continuous fiber unidirectional polymer matrix composites (PMCs) can exhibit significant local variations in fiber volume fraction as a result of processing conditions that can lead to further local differences in material properties and failure behavior. In this work, the coupled effects of both local variations in fiber volume fraction and the empirically-based statistical distribution of fiber strengths on the predicted longitudinal modulus and local tensile strength of a unidirectional AS4 carbon fiber/ Hercules 3502 epoxy composite were investigated using the special purpose NASA Micromechanics Analysis Code with Generalized Method of Cells (MAC/GMC); local effective composite properties were obtained by homogenizing the material behavior over repeating units cells (RUCs). The predicted effective longitudinal modulus was relatively insensitive to small (8%) variations in local fiber volume fraction. The composite tensile strength, however, was highly dependent on the local distribution in fiber strengths. The RUC-averaged constitutive response can be used to characterize lower length scale material behavior within a multiscale analysis framework that couples the NASA code FEAMAC and the ABAQUS finite element solver. Such an approach can be effectively used to analyze the progressive failure of PMC structures whose failure initiates at the RUC level. Consideration of the effect of local variations in constituent properties and morphologies on progressive failure of PMCs is a central aspect of the application of Integrated Computational Materials Engineering (ICME) principles for composite materials.

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.

Bayesian Inference of High-Dimensional Dynamical Ocean Models

NASA Astrophysics Data System (ADS)

Lin, J.; Lermusiaux, P. F. J.; Lolla, S. V. T.; Gupta, A.; Haley, P. J., Jr.

2015-12-01

This presentation addresses a holistic set of challenges in high-dimension ocean Bayesian nonlinear estimation: i) predict the probability distribution functions (pdfs) of large nonlinear dynamical systems using stochastic partial differential equations (PDEs); ii) assimilate data using Bayes' law with these pdfs; iii) predict the future data that optimally reduce uncertainties; and (iv) rank the known and learn the new model formulations themselves. Overall, we allow the joint inference of the state, equations, geometry, boundary conditions and initial conditions of dynamical models. Examples are provided for time-dependent fluid and ocean flows, including cavity, double-gyre and Strait flows with jets and eddies. The Bayesian model inference, based on limited observations, is illustrated first by the estimation of obstacle shapes and positions in fluid flows. Next, the Bayesian inference of biogeochemical reaction equations and of their states and parameters is presented, illustrating how PDE-based machine learning can rigorously guide the selection and discovery of complex ecosystem models. Finally, the inference of multiscale bottom gravity current dynamics is illustrated, motivated in part by classic overflows and dense water formation sites and their relevance to climate monitoring and dynamics. This is joint work with our MSEAS group at MIT.

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

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.

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.

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.

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.

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

[Update of PDE5 inhibitors as treatment of ED].

PubMed

Lu, Yong-ning; Chen, Bin

2005-07-01

Erectile dysfunction is a common ailment in middle-aged and old men. The management of ED has entered a new stage since sildenafil was used to treat ED in 1998. Sildenafil became the first-line treatment for its efficacy and safety. In recent years, new PDE5 inhibitors--vardenafil and tadalafil came into market in succession, providing more options available for oral therapy. This review is about the development of preclinical and clinical medicine research on the three PDE5 inhibitors, and provide information for clinical choices.

A new adaptive mesh refinement strategy for numerically solving evolutionary PDE's

NASA Astrophysics Data System (ADS)

Burgarelli, Denise; Kischinhevsky, Mauricio; Biezuner, Rodney Josue

2006-11-01

A graph-based implementation of quadtree meshes for dealing with adaptive mesh refinement (AMR) in the numerical solution of evolutionary partial differential equations is discussed using finite volume methods. The technique displays a plug-in feature that allows replacement of a group of cells in any region of interest for another one with arbitrary refinement, and with only local changes occurring in the data structure. The data structure is also specially designed to minimize the number of operations needed in the AMR. Implementation of the new scheme allows flexibility in the levels of refinement of adjacent regions. Moreover, storage requirements and computational cost compare competitively with mesh refinement schemes based on hierarchical trees. Low storage is achieved for only the children nodes are stored when a refinement takes place. These nodes become part of a graph structure, thus motivating the denomination autonomous leaves graph (ALG) for the new scheme. Neighbors can then be reached without accessing their parent nodes. Additionally, linear-system solvers based on the minimization of functionals can be easily employed. ALG was not conceived with any particular problem or geometry in mind and can thus be applied to the study of several phenomena. Some test problems are used to illustrate the effectiveness of the technique.

Influence of erectile dysfunction course on its progress and efficacy of treatment with phosphodiesterase type 5 inhibitors.

PubMed

Liu, De-Feng; Jiang, Hui; Hong, Kai; Zhao, Lian-Ming; Tang, Wen-Hao; Ma, Lu-Lin

2010-11-01

Erectile dysfunction (ED) is a common impairment among older men, and the prevalence rates increase sharply after age of 60 years. Most studies have focused on the prevalence rate or dangerous factors. The aim of this study was to investigate the basic epidemiologic data about ED patients with different ED courses. The purpose of this research was to understand the therapeutic effect of phosphodiesterase type 5 inhibitor (PDE5-I) and see how and why the ED course impact the progress of ED and the therapeutic effect of PDE5-I treatment. From June 2008 to June 2009, 4252 questionnaires (Quality of Erection Questionnaire, QEQ) were gathered from 46 centers by urology or andrology doctors all around China. Patients with ED (age ≥ 20 years) filled in first half of the questionnaires when they came for the first time, and then completed the second half 4 weeks after PDE5-I therapy. ED courses of most patients were less than 5 years (< 5 years, 74.0%; 5 - 10 years 20.8%; > 10 years, 5.2%). As ED course increasing, the incidence of the risk factors of ED, such as smoking, drinking, hypertension, diabetes, heart disease and hyperlipidemia also increase (P ≤ 0.01). PDE5-I was effective in improving the quality of sexual activities (P ≤ 0.01). Administration of PDE5-I improves satisfaction, enjoyment and frequency of sexual activities. The longer the ED course, the worse the therapeutic effect (< 5 years, 96.1%; 5 - 10 years, 94.9%; > 10 years, 89.0%) (P ≤ 0.01). The ED course greatly affected the therapeutic effect of PDE5-1, the patients with ED should consult doctor at early stage of the disease. Administration of PDE5-I effectively improves the penile erection and the quality of sexual life of the patients hence should be considered as first-line medicine in the treatment of ED.

Calcium-dependent phosphodiesterase 1C inhibits renin release from isolated juxtaglomerular cells

PubMed Central

Ortiz-Capisano, M. Cecilia; Liao, Tang-Dong; Ortiz, Pablo A.

2009-01-01

Renin release from the juxtaglomerular (JG) cell is stimulated by the second messenger cAMP and inhibited by calcium. We previously showed JG cells contain a calcium sensing receptor (CaSR), which, when stimulated, decreases cAMP formation and inhibits renin release. We hypothesize CaSR activation decreases cAMP and renin release, in part, by stimulating a calcium calmodulin-activated phosphodiesterase 1 (PDE1). We incubated our primary culture of JG cells with two selective PDE1 inhibitors [8-methoxymethil-IBMX (8-MM-IBMX; 20 μM) and vinpocetine (40 μM)] and the calmodulin inhibitor W-7 (10 μM) and measured cAMP and renin release. Stimulation of the JG cell CaSR with the calcimimetic cinacalcet (1 μM) resulted in decreased cAMP from a basal of 1.13 ± 0.14 to 0.69 ± 0.08 pM/mg protein (P < 0.001) and in renin release from 0.89 ± 0.16 to 0.38 ± 0.08 μg ANG I/ml·h−1·mg protein−1 (P < 0.001). However, the addition of 8-MM-IBMX with cinacalcet returned both cAMP (1.10 ± 0.19 pM/mg protein) and renin (0.57 ± 0.16 μg ANG I/ml·h−1·mg protein−1) to basal levels. Similar results were obtained with vinpocetine, and also with W-7. Combining 8-MM-IBMX and W-7 had no additive effect. To determine which PDE1 isoform is involved, we performed Western blot analysis for PDE1A, B, and C. Only Western blot analysis for PDE1C showed a characteristic band apparent at 80 kDa. Immunofluorescence showed cytoplasmic distribution of PDE1C and renin in the JG cells. In conclusion, PDE1C is expressed in isolated JG cells, and contributes to calcium's inhibitory modulation of renin release from JG cells. PMID:19741056

Luteinizing hormone signaling phosphorylates and activates the cyclic GMP phosphodiesterase PDE5 in mouse ovarian follicles, contributing an additional component to the hormonally induced decrease in cyclic GMP that reinitiates meiosis.

PubMed

Egbert, Jeremy R; Yee, Siu-Pok; Jaffe, Laurinda A

2018-03-01

Prior to birth, oocytes within mammalian ovarian follicles initiate meiosis, but then arrest in prophase until puberty, when with each reproductive cycle, one or more follicles are stimulated by luteinizing hormone (LH) to resume meiosis in preparation for fertilization. Within preovulatory follicles, granulosa cells produce high levels of cGMP, which diffuses into the oocyte to maintain meiotic arrest. LH signaling restarts meiosis by rapidly lowering the levels of cGMP in the follicle and oocyte. Part of this decrease is mediated by the dephosphorylation and inactivation the NPR2 guanylyl cyclase in response to LH, but the mechanism for the remainder of the cGMP decrease is unknown. At least one cGMP phosphodiesterase, PDE5, is activated by LH signaling, which would contribute to lowering cGMP. PDE5 exhibits increased cGMP-hydrolytic activity when phosphorylated on serine 92, and we recently demonstrated that LH signaling phosphorylates PDE5 on this serine and increases its activity in rat follicles. To test the extent to which this mechanism contributes to the cGMP decrease that restarts meiosis, we generated a mouse line in which serine 92 was mutated to alanine (Pde5-S92A), such that it cannot be phosphorylated. Here we show that PDE5 phosphorylation is required for the LH-induced increase in cGMP-hydrolytic activity, but that this increase has only a modest effect on the LH-induced cGMP decrease in mouse follicles, and does not affect the timing of meiotic resumption. Though we show that the activation of PDE5 is among the mechanisms contributing to the cGMP decrease, these results suggest that another cGMP phosphodiesterase is also activated by LH signaling. Copyright © 2018 Elsevier Inc. All rights reserved.

Thrust Measurements for a Pulse Detonation Engine Driven Ejector

NASA Technical Reports Server (NTRS)

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

2005-01-01

Results of an experimental effort on pulse detonation driven ejectors aimed at probing different aspects of PDE ejector processes, are presented and discussed. The PDE was operated using ethylene as the fuel and an equimolar oxygen/nitrogen mixture as the oxidizer at an equivalence ratio of one. The thrust measurements for the PDE alone are in excellent agreement with experimental and modeling results reported in the literature and serve as a Baseline for the ejector studies. These thrust measurements were then used as a basis for quantifying thrust augmentation for various PDE/ejector setups using 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. 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.

Fourth-order partial differential equation noise removal on welding images

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

Halim, Suhaila Abd; Ibrahim, Arsmah; Sulong, Tuan Nurul Norazura Tuan

2015-10-22

Partial differential equation (PDE) has become one of the important topics in mathematics and is widely used in various fields. It can be used for image denoising in the image analysis field. In this paper, a fourth-order PDE is discussed and implemented as a denoising method on digital images. The fourth-order PDE is solved computationally using finite difference approach and then implemented on a set of digital radiographic images with welding defects. The performance of the discretized model is evaluated using Peak Signal to Noise Ratio (PSNR). Simulation is carried out on the discretized model on different level of Gaussianmore » noise in order to get the maximum PSNR value. The convergence criteria chosen to determine the number of iterations required is measured based on the highest PSNR value. Results obtained show that the fourth-order PDE model produced promising results as an image denoising tool compared with median filter.« less

Novel PDE4 Inhibitors Derived from Chinese Medicine Forsythia

PubMed Central

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

2014-01-01

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

Free-form geometric modeling by integrating parametric and implicit PDEs.

PubMed

Du, Haixia; Qin, Hong

2007-01-01

Parametric PDE techniques, which use partial differential equations (PDEs) defined over a 2D or 3D parametric domain to model graphical objects and processes, can unify geometric attributes and functional constraints of the models. PDEs can also model implicit shapes defined by level sets of scalar intensity fields. In this paper, we present an approach that integrates parametric and implicit trivariate PDEs to define geometric solid models containing both geometric information and intensity distribution subject to flexible boundary conditions. The integrated formulation of second-order or fourth-order elliptic PDEs permits designers to manipulate PDE objects of complex geometry and/or arbitrary topology through direct sculpting and free-form modeling. We developed a PDE-based geometric modeling system for shape design and manipulation of PDE objects. The integration of implicit PDEs with parametric geometry offers more general and arbitrary shape blending and free-form modeling for objects with intensity attributes than pure geometric models.

Review on factors affecting the performance of pulse detonation engine

NASA Astrophysics Data System (ADS)

Tripathi, Saurabh; Pandey, Krishna Murari

2018-04-01

Now a day's rocket engines (air-breathing type) are being used for aerospace purposes but the studies have shown that these are less efficient, so alternatives are being searched for these. Pulse Detonation Engine (PDE) is one such efficient engine which can replace the rocket engines. In this review paper, different researches have been cited. As can be observed from various researches, insertion of obstacles is better. Deflagration to Detonation(DDT) transition process is found to be most important factor. So a lot of researches are being done considering this DDT chamber. Also, the ignition chamber and ejector were found to improve the effectiveness of PDE. The PDE works with a range of Mach 0-4. Flame acceleration is also found to increase the DDT process. Use of valve and valveless engine has also been compared. Various other factors have been focused in this review paper which is found to boost PDE performance.

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

NASA Astrophysics Data System (ADS)

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

2010-09-01

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

Selective inhibition of phosphodiesterase 5 enhances glutamatergic synaptic plasticity and memory in mice.

PubMed

Uthayathas, Subramaniam; Parameshwaran, Kodeeswaran; Karuppagounder, Senthilkumar S; Ahuja, Manuj; Dhanasekaran, Muralikrishnan; Suppiramaniam, Vishnu

2013-11-01

Phosphodiesterases (PDEs) belong to a family of proteins that control metabolism of cyclic nucleotides. Targeting PDE5, for enhancing cellular function, is one of the therapeutic strategies for male erectile dysfunction. We have investigated whether in vivo inhibition of PDE5, which is expressed in several brain regions, will enhance memory and synaptic transmission in the hippocampus of healthy mice. We have found that acute administration of sildenafil, a specific PDE5 inhibitor, enhanced hippocampus-dependent memory tasks. To elucidate the underlying mechanism in the memory enhancement, effects of sildenafil on long-term potentiation (LTP) were measured. The level of LTP was significantly elevated, with concomitant increases in basal synaptic transmission, in mice treated with sildenafil (1 mg/kg/day) for 15 days compared to control mice. These results suggest that moderate PDE5 inhibition enhances memory by increasing synaptic plasticity and transmission in the hippocampus. Copyright © 2013 Wiley Periodicals, Inc.

FWT2D: A massively parallel program for frequency-domain full-waveform tomography of wide-aperture seismic data—Part 1: Algorithm

NASA Astrophysics Data System (ADS)

Sourbier, Florent; Operto, Stéphane; Virieux, Jean; Amestoy, Patrick; L'Excellent, Jean-Yves

2009-03-01

This is the first paper in a two-part series that describes a massively parallel code that performs 2D frequency-domain full-waveform inversion of wide-aperture seismic data for imaging complex structures. Full-waveform inversion methods, namely quantitative seismic imaging methods based on the resolution of the full wave equation, are computationally expensive. Therefore, designing efficient algorithms which take advantage of parallel computing facilities is critical for the appraisal of these approaches when applied to representative case studies and for further improvements. Full-waveform modelling requires the resolution of a large sparse system of linear equations which is performed with the massively parallel direct solver MUMPS for efficient multiple-shot simulations. Efficiency of the multiple-shot solution phase (forward/backward substitutions) is improved by using the BLAS3 library. The inverse problem relies on a classic local optimization approach implemented with a gradient method. The direct solver returns the multiple-shot wavefield solutions distributed over the processors according to a domain decomposition driven by the distribution of the LU factors. The domain decomposition of the wavefield solutions is used to compute in parallel the gradient of the objective function and the diagonal Hessian, this latter providing a suitable scaling of the gradient. The algorithm allows one to test different strategies for multiscale frequency inversion ranging from successive mono-frequency inversion to simultaneous multifrequency inversion. These different inversion strategies will be illustrated in the following companion paper. The parallel efficiency and the scalability of the code will also be quantified.

Effect of Phosphodiesterase in Regulating the Activity of Lysosomes in the HeLa Cell Line.

PubMed

Hong, Eun-Seon; Kim, Bit-Na; Kim, Yang-Hoon; Min, Jiho

2017-02-28

The transport of lysosomal enzymes into the lysosomes depends on the phosphorylation of their chains and the binding of the phosphorylated residues to mannose-6-phosphate receptors. The efficiency of separation depends more on the phosphodiesterases (PDEs) than on the activity of the phosphorylation of mannose residues and can be determined in vitro. PDEs play important roles in regulation of the activation of lysosomes. The expression of proteins was confirmed by western blotting. All PDE4 series protein expression was reduced in high concentrations of rolipram. As a result of observing the fluorescence intensity after rolipram treatment, the lysosomal enzyme was activated at low concentrations and suppressed at high concentrations. High concentrations of rolipram recovered the original function. Antimicrobial activity was not shown in either 10 or 100 µ concentrations of rolipram in treated HeLa cells in vitro. However, the higher anticancer activity at lower rolipram concentration was shown in lysosomal enzyme treated with 10 µ of rolipram. The anticancer activity was confirmed through cathepsin B and D assay. Tranfection allowed examination of the relationship between PDE4 and lysosomal activity in more detail. Protein expression was confirmed to be reduced. Fluorescence intensity showed decreased activity of lysosomes and ROS in cells transfected with the antisense sequences of PDE4 A, B, C, and D. PDE4A showed anticancer activity, whereas lysosome from cells transfected with the antisense sequences of PDE4 B, C, and D had decreased anticancer activity. These results showed the PDE4 A, B, C, and D are conjunctly related with lysosomal activity.

Quercetin acutely relaxes airway smooth muscle and potentiates β-agonist-induced relaxation via dual phosphodiesterase inhibition of PLCβ and PDE4

PubMed Central

Emala, Charles W.

2013-01-01

Asthma is a disease of the airways with symptoms including exaggerated airway narrowing and airway inflammation. Early asthma therapies used methylxanthines to relieve symptoms, in part, by inhibiting cyclic nucleotide phosphodiesterases (PDEs), the enzyme responsible for degrading cAMP. The classification of tissue-specific PDE subtypes and the clinical introduction of PDE-selective inhibitors for chronic obstructive pulmonary disease (i.e., roflumilast) have reopened the possibility of using PDE inhibition in the treatment of asthma. Quercetin is a naturally derived PDE4-selective inhibitor found in fruits, vegetables, and tea. We hypothesized that quercetin relaxes airway smooth muscle via cAMP-mediated pathways and augments β-agonist relaxation. Tracheal rings from male A/J mice were mounted in myographs and contracted with acetylcholine (ACh). Addition of quercetin (100 nM-1 mM) acutely and concentration-dependently relaxed airway rings precontracted with ACh. In separate studies, pretreatment with quercetin (100 μM) prevented force generation upon exposure to ACh. In additional studies, quercetin (50 μM) significantly potentiated isoproterenol-induced relaxations. In in vitro assays, quercetin directly attenuated phospholipase C activity, decreased inositol phosphate synthesis, and decreased intracellular calcium responses to Gq-coupled agonists (histamine or bradykinin). Finally, nebulization of quercetin (100 μM) in an in vivo model of airway responsiveness significantly attenuated methacholine-induced increases in airway resistance. These novel data show that the natural PDE4-selective inhibitor quercetin may provide therapeutic relief of asthma symptoms and decrease reliance on short-acting β-agonists. PMID:23873842

Insight into the Phosphodiesterase Mechanism from Combined QM/MM Free Energy Simulations

PubMed Central

Wong, Kin-Yiu; Gao, Jiali

2011-01-01

Summary Molecular dynamics simulations employing a combined quantum mechanical and molecular mechanical potential have been carried out to elucidate the reaction mechanism of the hydrolysis of a cyclic nucleotide cAMP substrate by phosphodiesterase 4B (PDE4B). PDE4B is a member of the PDE superfamily of enzymes that play crucial roles in cellular signal transduction. We have determined a two-dimensional potential of mean force for the coupled phosphoryl bond cleavage and proton transfer through a general acid catalysis mechanism in PDE4B. The results indicate that the ring-opening process takes place through an SN2 reaction mechanism, followed by a proton transfer to stabilize the leaving group. The computed free energy of activation for the PDE4B-catalyzed cAMP hydrolysis is about 13 kcal/mol and an overall reaction free energy is about −17 kcal/mol, both in accord with experimental results. In comparison with the uncatalyzed reaction in water, the enzyme PDE4B provides a strong stabilization of the transition state, lowering the free energy barrier by 14 kcal/mol. We found that the proton transfer from the general acid residue His234 to the O3' oxyanion of the ribosyl leaving group lags behind the nucleophilic attack, resulting in a shallow minimum on the free energy surface. A key contributing factor to transition state stabilization is the elongation of the distance between the divalent metal ions Zn2+ and Mg2+ in the active site as the reaction proceeds from the Michaelis complex to the transition state. PMID:21595828

Epac1, PDE4, and PKC protein expression and their association with AKAP95, Cx43, and cyclinD2/E1 in breast cancer tissues.

PubMed

Huang, Ping; Sun, Qian; Zhuang, Wenxin; Peng, Kuan; Wang, Dai; Yao, Youliang; Guo, Dongbei; Zhang, Lu; Shen, Chuhan; Sun, Mengyun; Tang, Chaoying; Teng, Bogang; Zhang, Yongxing

2017-09-01

This study was conducted to investigate the exchange protein directly activated by cAMP (Epac1), PDE4, and PKC expression in breast cancer tissues, and the correlation between these proteins and AKAP95, Cx43, cyclin D2, and cyclin E1. PV-9000 two-step immunohistochemistry was used to analyze protein expression. The positive rate of Epac1 protein expression in breast cancer tissues (58%) was higher than in para-carcinoma tissues (10%) (P < 0.05). There were no significant differences in the positive rates of PDE4 and PKC expression between breast cancer and para-carcinoma tissues (P > 0.05). The positive expression rate of PDE4 was higher in the P53 protein positive group compared to the P53 negative group (P < 0.05). Correlations between Epac1 and cyclin D2, PDE4 and cyclin D2, AKAP95 and PKC, Cx43 and PKC, and cyclin D2 and PKC proteins were observed (P < 0.05). Epac1 expression in breast cancer tissues was increased, suggesting that the protein may be involved in the development of breast cancer. Correlations between Epac1 and cyclin D2, PDE4 and cyclin D2, AKAP95 and PKC, Cx43 and PKC, and cyclin D2 and PKC proteins suggested synergistic effects among these proteins in the development of breast cancer. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival.

PubMed

Medina-Rodríguez, E M; Arenzana, F J; Pastor, J; Redondo, M; Palomo, V; García de Sola, R; Gil, C; Martínez, A; Bribián, A; de Castro, F

2013-09-01

During the development of the central nervous system (CNS), oligodendrocyte precursors (OPCs) are generated in specific sites within the neural tube and then migrate to colonize the entire CNS, where they differentiate into myelin-forming oligodendrocytes. Demyelinating diseases such as multiple sclerosis (MS) are characterized by the death of these cells. The CNS reacts to demyelination and by promoting spontaneous remyelination, an effect mediated by endogenous OPCs, cells that represent approximately 5-7 % of the cells in the adult brain. Numerous factors influence oligodendrogliogenesis and oligodendrocyte differentiation, including morphogens, growth factors, chemotropic molecules, extracellular matrix proteins, and intracellular cAMP levels. Here, we show that during development and in early adulthood, OPCs in the murine cerebral cortex contain phosphodiesterase-7 (PDE7) that metabolizes cAMP. We investigated the effects of different PDE7 inhibitors (the well-known BRL-50481 and two new ones, TC3.6 and VP1.15) on OPC proliferation, survival, and differentiation. While none of the PDE7 inhibitors analyzed altered OPC proliferation, TC3.6 and VP1.15 enhanced OPC survival and differentiation, processes in which ERK intracellular signaling played a key role. PDE7 expression was also observed in OPCs isolated from adult human brains and the differentiation of these OPCs into more mature oligodendroglial phenotypes was accelerated by treatment with both new PDE7 inhibitors. These findings reveal new roles for PDE7 in regulating OPC survival and differentiation during brain development and in adulthood, and they may further our understanding of myelination and facilitate the development of therapeutic remyelination strategies for the treatment of MS.

[Masturbation device (EGG) as a new penile rehabilitation tool: a pilot study].

PubMed

Sato, Yoshikazu; Tanda, Hitoshi; Nakajima, Hisao; Nitta, Toshikazu; Akagashi, Keigo; Hanzawa, Tatsuo; Tobe, Musashi; Haga, Kazunori; Uchida, Kosuke; Honma, Ichiya

2013-05-01

Erectile dysfunction following radical prostatectomy (RP) is still a significant burden as a post-operative morbidity, despite advances in nerve-sparing techniques and penile (erectile function) rehabilitation (PR) programs. We assessed the effects of stimulation with the masturbation device "EGG" on enhancement of erectile response along with administration of phospho diesterase type 5 inhibitor. We also studied the change of self-esteem and motivation for continuation of PR after stimulation with EGG. Eight nonresponders for PDE5-I who underwent retropubic RP were enrolled. Patients' median age was 71.5 years old. No patients received adjuvant therapy for prostate cancer. The patients' erectile response in the penile rehabilitation session (masturbation) with PDE5-I＋manual stimulation and PDE5-I＋stimulation with EGG were evaluated by erection hardness score (EHS). Changes of self-esteem and motivation for penile rehabilitation were assessed by the self-esteem subscale of the Self-Esteem and Relationship (SEAR) questionnaire and one original question, respectively. PDE5-I ＋ stimulation with EGG significantly enhanced EHS compared to PDE5-I＋manual stimulation in the eight patients (p＝0.027). Transformed score of self-esteem subscale score of SEAR questionnaire was significantly increased in the PR session with EGG compared to the PR session with manual stimulation (p＝0.043). Six patients who showed a better erectile response with EGG retained motivation for continuation of PR. PDE5-I＋stimulation with EGG improved the erectile response in post-RP patients. EGG as a masturbation device may have a potential for contribution to successful PR.

Investigation of Sustained Detonation Devices: the Pulse Detonation Engine-Crossover System and the Rotating Detonation Engine System

NASA Astrophysics Data System (ADS)

Driscoll, Robert B.

An experimental study is conducted on a Pulse Detonation Engine-Crossover System to investigate the feasibility of repeated, shock-initiated combustion and characterize the initiation performance. A PDE-crossover system can decrease deflagration-to-detonation transition length while employing a single spark source to initiate a multi-PDE system. Visualization of a transferred shock wave propagating through a clear channel reveals a complex shock train behind the leading shock. Shock wave Mach number and decay rate remains constant for varying crossover tube geometries and operational frequencies. A temperature gradient forms within the crossover tube due to forward flow of high temperature ionized gas into the crossover tube from the driver PDE and backward flow of ionized gas into the crossover tube from the driven PDE, which can cause intermittent auto-ignition of the driver PDE. Initiation performance in the driven PDE is strongly dependent on initial driven PDE skin temperature in the shock wave reflection region. An array of detonation tubes connected with crossover tubes is developed using optimized parameters and successful operation utilizing shock-initiated combustion through shock wave reflection is achieved and sustained. Finally, an air-breathing, PDE-Crossover System is developed to characterize the feasibility of shock-initiated combustion within an air-breathing pulse detonation engine. The initiation effectiveness of shock-initiated combustion is compared to spark discharge and detonation injection through a pre-detonator. In all cases, shock-initiated combustion produces improved initiation performance over spark discharge and comparable detonation transition run-up lengths relative to pre-detonator initiation. A computational study characterizes the mixing processes and injection flow field within a rotating detonation engine. Injection parameters including reactant flow rate, reactant injection area, placement of the fuel injection, and fuel injection distribution are varied to assess the impact on mixing. Decreasing reactant injection areas improves fuel penetration into the cross-flowing air stream, enhances turbulent diffusion of the fuel within the annulus, and increases local equivalence ratio and fluid mixedness. Staggering fuel injection holes produces a decrease in mixing when compared to collinear fuel injection. Finally, emulating nozzle integration by increasing annulus back-pressure increases local equivalence ratio in the injection region due to increased convection residence time.

Synergistic effects of BAY 60-4552 and vardenafil on relaxation of corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure.

PubMed

Albersen, Maarten; Linsen, Loes; Tinel, Hanna; Sandner, Peter; Van Renterghem, Koenraad

2013-05-01

Overall efficacy rates of phosphodiesterase type 5 inhibitors (PDE5-i) for erectile dysfunction (ED) are 60-70%. PDE5-i treatment failures currently have to resort to invasive treatment options for restoration of erectile function. AIMS.: To assess changes in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase (PKG) pathway in human corpus cavernosum (HCC) of PDE5-i nonresponders compared with healthy controls. To evaluate the effects of BAY 60-4552, a stimulator of soluble guanylate cyclase (sGC), and vardenafil on relaxation of HCC strips from PDE5-i nonresponders. mRNA expression, morphological localization of the NO/cGMP/PKG pathway, and relaxant capacity of both compounds alone or combined. Analysis of variance, t-test or Mann-Whitney test based upon number of groups and normality of data. HCC tissues were harvested after consent from individuals undergoing penile prosthesis implantation (patients) and potent patients undergoing transurethral surgery (healthy controls, needle biopsy). HCC tissues of patients were compared with those of healthy controls for the expression of mRNA coding for PDE5A, eNOS, PKGα1, PKG2, sGCα1, sGCα2, sGCβ1, sGCβ2, α-smooth muscle actin (aSMA) and β-actin by quantitative polymerase chain reaction (qPCR). The respective proteins were localized using immunofluorescence. Tissue strips of patients were precontracted with phenylepinephrine followed by incubation with 1 μM of either vardenafil or BAY 60-4552, or both simultaneously. The main targets in the NO/cGMP/sGC pathway were downregulated in PDE5-i nonresponders. The pathway was morphologically located to HCC smooth muscle, of which the overall content was preserved in ED patients based on aSMA expression. BAY 60-4552 and vardenafil have synergistic effects on relaxation of HCC of PDE5-i nonresponders. The main limitation is the small amount of control tissue precluding functional testing on these samples. Despite downregulation of the NO/cGMP/PKG pathway, combining BAY 60-4552 with vardenafil significantly enhanced relaxation HCC strips of PDE5-i nonresponders. © 2013 International Society for Sexual Medicine.

A Numerical Study of Mesh Adaptivity in Multiphase Flows with Non-Newtonian Fluids

NASA Astrophysics Data System (ADS)

Percival, James; Pavlidis, Dimitrios; Xie, Zhihua; Alberini, Federico; Simmons, Mark; Pain, Christopher; Matar, Omar

2014-11-01

We present an investigation into the computational efficiency benefits of dynamic mesh adaptivity in the numerical simulation of transient multiphase fluid flow problems involving Non-Newtonian fluids. Such fluids appear in a range of industrial applications, from printing inks to toothpastes and introduce new challenges for mesh adaptivity due to the additional ``memory'' of viscoelastic fluids. Nevertheless, the multiscale nature of these flows implies huge potential benefits for a successful implementation. The study is performed using the open source package Fluidity, which couples an unstructured mesh control volume finite element solver for the multiphase Navier-Stokes equations to a dynamic anisotropic mesh adaptivity algorithm, based on estimated solution interpolation error criteria, and conservative mesh-to-mesh interpolation routine. The code is applied to problems involving rheologies ranging from simple Newtonian to shear-thinning to viscoelastic materials and verified against experimental data for various industrial and microfluidic flows. This work was undertaken as part of the EPSRC MEMPHIS programme grant EP/K003976/1.

Molecular dynamics simulations in hybrid particle-continuum schemes: Pitfalls and caveats

NASA Astrophysics Data System (ADS)

Stalter, S.; Yelash, L.; Emamy, N.; Statt, A.; Hanke, M.; Lukáčová-Medvid'ová, M.; Virnau, P.

2018-03-01

Heterogeneous multiscale methods (HMM) combine molecular accuracy of particle-based simulations with the computational efficiency of continuum descriptions to model flow in soft matter liquids. In these schemes, molecular simulations typically pose a computational bottleneck, which we investigate in detail in this study. We find that it is preferable to simulate many small systems as opposed to a few large systems, and that a choice of a simple isokinetic thermostat is typically sufficient while thermostats such as Lowe-Andersen allow for simulations at elevated viscosity. We discuss suitable choices for time steps and finite-size effects which arise in the limit of very small simulation boxes. We also argue that if colloidal systems are considered as opposed to atomistic systems, the gap between microscopic and macroscopic simulations regarding time and length scales is significantly smaller. We propose a novel reduced-order technique for the coupling to the macroscopic solver, which allows us to approximate a non-linear stress-strain relation efficiently and thus further reduce computational effort of microscopic simulations.

WAKES: Wavelet Adaptive Kinetic Evolution Solvers

NASA Astrophysics Data System (ADS)

Mardirian, Marine; Afeyan, Bedros; Larson, David

2016-10-01

We are developing a general capability to adaptively solve phase space evolution equations mixing particle and continuum techniques in an adaptive manner. The multi-scale approach is achieved using wavelet decompositions which allow phase space density estimation to occur with scale dependent increased accuracy and variable time stepping. Possible improvements on the SFK method of Larson are discussed, including the use of multiresolution analysis based Richardson-Lucy Iteration, adaptive step size control in explicit vs implicit approaches. Examples will be shown with KEEN waves and KEEPN (Kinetic Electrostatic Electron Positron Nonlinear) waves, which are the pair plasma generalization of the former, and have a much richer span of dynamical behavior. WAKES techniques are well suited for the study of driven and released nonlinear, non-stationary, self-organized structures in phase space which have no fluid, limit nor a linear limit, and yet remain undamped and coherent well past the drive period. The work reported here is based on the Vlasov-Poisson model of plasma dynamics. Work supported by a Grant from the AFOSR.

Numerical prediction of pollutant dispersion and transport in an atmospheric boundary layer

NASA Astrophysics Data System (ADS)

Zeoli, Stéphanie; Bricteux, Laurent; Mech. Eng. Dpt. Team

2014-11-01

The ability to accurately predict concentration levels of air pollutant released from point sources is required in order to determine their environmental impact. A wall modeled large-eddy simulation (WMLES) of the ABL is performed using the OpenFoam based solver SOWFA (Churchfield and Lee, NREL). It uses Boussinesq approximation for buoyancy effects and takes into account Coriolis forces. A synthetic eddy method is proposed to properly model turbulence inlet velocity boundary conditions. This method will be compared with the standard pressure gradient forcing. WMLES are usually performed using a standard Smagorinsky model or its dynamic version. It is proposed here to investigate a subgrid scale (SGS) model with a better spectral behavior. To this end, a regularized variational multiscale (RVMs) model (Jeanmart and Winckelmans, 2007) is implemented together with standard wall function in order to preserve the dynamics of the large scales within the Ekman layer. The influence of the improved SGS model on the wind simulation and scalar transport will be discussed based on turbulence diagnostics.

An adaptive, implicit, conservative, 1D-2V multi-species Vlasov-Fokker-Planck multi-scale solver in planar geometry

NASA Astrophysics Data System (ADS)

Taitano, W. T.; Chacón, L.; Simakov, A. N.

2018-07-01

We consider a 1D-2V Vlasov-Fokker-Planck multi-species ionic description coupled to fluid electrons. We address temporal stiffness with implicit time stepping, suitably preconditioned. To address temperature disparity in time and space, we extend the conservative adaptive velocity-space discretization scheme proposed in [Taitano et al., J. Comput. Phys., 318, 391-420, (2016)] to a spatially inhomogeneous system. In this approach, we normalize the velocity-space coordinate to a temporally and spatially varying local characteristic speed per species. We explicitly consider the resulting inertial terms in the Vlasov equation, and derive a discrete formulation that conserves mass, momentum, and energy up to a prescribed nonlinear tolerance upon convergence. Our conservation strategy employs nonlinear constraints to enforce these properties discretely for both the Vlasov operator and the Fokker-Planck collision operator. Numerical examples of varying degrees of complexity, including shock-wave propagation, demonstrate the favorable efficiency and accuracy properties of the scheme.

Numerical investigation of spray ignition of a multi-component fuel surrogate

NASA Astrophysics Data System (ADS)

Backer, Lara; Narayanaswamy, Krithika; Pepiot, Perrine

2014-11-01

Simulating turbulent spray ignition, an important process in engine combustion, is challenging, since it combines the complexity of multi-scale, multiphase turbulent flow modeling with the need for an accurate description of chemical kinetics. In this work, we use direct numerical simulation to investigate the role of the evaporation model on the ignition characteristics of a multi-component fuel surrogate, injected as droplets in a turbulent environment. The fuel is represented as a mixture of several components, each one being representative of a different chemical class. A reduced kinetic scheme for the mixture is extracted from a well-validated detailed chemical mechanism, and integrated into the multiphase turbulent reactive flow solver NGA. Comparisons are made between a single-component evaporation model, in which the evaporating gas has the same composition as the liquid droplet, and a multi-component model, where component segregation does occur. In particular, the corresponding production of radical species, which are characteristic of the ignition of individual fuel components, is thoroughly analyzed.

Fully implicit adaptive mesh refinement solver for 2D MHD

NASA Astrophysics Data System (ADS)

Philip, B.; Chacon, L.; Pernice, M.

2008-11-01

Application of implicit adaptive mesh refinement (AMR) to simulate resistive magnetohydrodynamics is described. Solving this challenging multi-scale, multi-physics problem can improve understanding of reconnection in magnetically-confined plasmas. AMR is employed to resolve extremely thin current sheets, essential for an accurate macroscopic description. Implicit time stepping allows us to accurately follow the dynamical time scale of the developing magnetic field, without being restricted by fast Alfven time scales. At each time step, the large-scale system of nonlinear equations is solved by a Jacobian-free Newton-Krylov method together with a physics-based preconditioner. Each block within the preconditioner is solved optimally using the Fast Adaptive Composite grid method, which can be considered as a multiplicative Schwarz method on AMR grids. We will demonstrate the excellent accuracy and efficiency properties of the method with several challenging reduced MHD applications, including tearing, island coalescence, and tilt instabilities. B. Philip, L. Chac'on, M. Pernice, J. Comput. Phys., in press (2008)

Effects of selective phosphodiesterases-4 inhibitors on learning and memory: a review of recent research.

PubMed

Peng, Sheng; Sun, Haiyan; Zhang, Xiaoqing; Liu, Gongjian; Wang, Guanglei

2014-09-01

Phosphodiesterase-4 (PDE-4) regulates the intracellular level of cyclic adenosine monophosphate. Recent studies demonstrated that PDE-4 inhibitors can counteract deficits in long-term memory caused by aging or increased expression of mutant forms of human amyloid precursor proteins, and can influence the process of memory function and cognitive enhancement. Therapeutics, such as ketamine, a drug used in clinical anesthesia, can also cause memory deficits as adverse effects. Targeting PDE-4 with selective inhibitors may offer a novel therapeutic strategy to prevent, slow the progress, and, eventually, treat memory deficits.

Cloning and expression of cDNA for a human low-K sub m , rolipram-sensitive cyclic AMP phosphodiesterase

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

Livi, G.P.; McHale, M.J.; Sathe, G.M.

1990-06-01

The authors have isolated cDNA clones representing cyclic AMP (cAMP)-specific phosphodiesterases (PDEases) from a human monocyte cDNA library. One cDNA clone (hPDE-1) defines a large open reading frame of ca. 2.1 kilobases, predicting a 686-amino-acid, ca. 77-kilodalton protein which contains significant homology to both rat brain and {ital Drosophila} cAMP PDEases, especially within an internal conserved domain of ca. 270 residues. Amino acid sequence divergence exists at the NH{sub 2} terminus and also within a 40- to 100-residue domain near the COOH-terminal end. hPDE-1 hybridizes to a major 4.8-kilobase mRNA transcript from both human monocytes and placenta. The coding regionmore » of hPDE-1 was engineered for expression in COS-1 cells, resulting in the overproduction of cAMP PDEase activity. The hPDE-1 recombinant gene product was identified as a low-{ital K{sub m}} cAMP phosphodiesterase on the basis of several biochemical properties including selective inhibition by the antidepressant drug rolipram. Known inhibitors of other PDEases (cGMP-specific PDEase, cGMP-inhibited PDEase) had little or no effect on the hPDE-1 recombinant gene product.« less

The Feasibility of Applying AC Driven Low-Temperature Plasma for Multi-Cycle Detonation Initiation

NASA Astrophysics Data System (ADS)

Zheng, Dianfeng

2016-11-01

Ignition is a key system in pulse detonation engines (PDE). As advanced ignition methods, nanosecond pulse discharge low-temperature plasma ignition is used in some combustion systems, and continuous alternating current (AC) driven low-temperature plasma using dielectric barrier discharge (DBD) is used for the combustion assistant. However, continuous AC driven plasmas cannot be used for ignition in pulse detonation engines. In this paper, experimental and numerical studies of pneumatic valve PDE using an AC driven low-temperature plasma igniter were described. The pneumatic valve was jointly designed with the low-temperature plasma igniter, and the numerical simulation of the cold-state flow field in the pneumatic valve showed that a complex flow in the discharge area, along with low speed, was beneficial for successful ignition. In the experiments ethylene was used as the fuel and air as oxidizing agent, ignition by an AC driven low-temperature plasma achieved multi-cycle intermittent detonation combustion on a PDE, the working frequency of the PDE reached 15 Hz and the peak pressure of the detonation wave was approximately 2.0 MPa. The experimental verifications of the feasibility in PDE ignition expanded the application field of AC driven low-temperature plasma. supported by National Natural Science Foundation of China (No. 51176001)

A multi-scale convolutional neural network for phenotyping high-content cellular images.

PubMed

Godinez, William J; Hossain, Imtiaz; Lazic, Stanley E; Davies, John W; Zhang, Xian

2017-07-01

Identifying phenotypes based on high-content cellular images is challenging. Conventional image analysis pipelines for phenotype identification comprise multiple independent steps, with each step requiring method customization and adjustment of multiple parameters. Here, we present an approach based on a multi-scale convolutional neural network (M-CNN) that classifies, in a single cohesive step, cellular images into phenotypes by using directly and solely the images' pixel intensity values. The only parameters in the approach are the weights of the neural network, which are automatically optimized based on training images. The approach requires no a priori knowledge or manual customization, and is applicable to single- or multi-channel images displaying single or multiple cells. We evaluated the classification performance of the approach on eight diverse benchmark datasets. The approach yielded overall a higher classification accuracy compared with state-of-the-art results, including those of other deep CNN architectures. In addition to using the network to simply obtain a yes-or-no prediction for a given phenotype, we use the probability outputs calculated by the network to quantitatively describe the phenotypes. This study shows that these probability values correlate with chemical treatment concentrations. This finding validates further our approach and enables chemical treatment potency estimation via CNNs. The network specifications and solver definitions are provided in Supplementary Software 1. william_jose.godinez_navarro@novartis.com or xian-1.zhang@novartis.com. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

A paradigm for modeling and computation of gas dynamics

NASA Astrophysics Data System (ADS)

Xu, Kun; Liu, Chang

2017-02-01

In the continuum flow regime, the Navier-Stokes (NS) equations are usually used for the description of gas dynamics. On the other hand, the Boltzmann equation is applied for the rarefied flow. These two equations are based on distinguishable modeling scales for flow physics. Fortunately, due to the scale separation, i.e., the hydrodynamic and kinetic ones, both the Navier-Stokes equations and the Boltzmann equation are applicable in their respective domains. However, in real science and engineering applications, they may not have such a distinctive scale separation. For example, around a hypersonic flying vehicle, the flow physics at different regions may correspond to different regimes, where the local Knudsen number can be changed significantly in several orders of magnitude. With a variation of flow physics, theoretically a continuous governing equation from the kinetic Boltzmann modeling to the hydrodynamic Navier-Stokes dynamics should be used for its efficient description. However, due to the difficulties of a direct modeling of flow physics in the scale between the kinetic and hydrodynamic ones, there is basically no reliable theory or valid governing equations to cover the whole transition regime, except resolving flow physics always down to the mean free path scale, such as the direct Boltzmann solver and the Direct Simulation Monte Carlo (DSMC) method. In fact, it is an unresolved problem about the exact scale for the validity of the NS equations, especially in the small Reynolds number cases. The computational fluid dynamics (CFD) is usually based on the numerical solution of partial differential equations (PDEs), and it targets on the recovering of the exact solution of the PDEs as mesh size and time step converging to zero. This methodology can be hardly applied to solve the multiple scale problem efficiently because there is no such a complete PDE for flow physics through a continuous variation of scales. For the non-equilibrium flow study, the direct modeling methods, such as DSMC, particle in cell, and smooth particle hydrodynamics, play a dominant role to incorporate the flow physics into the algorithm construction directly. It is fully legitimate to combine the modeling and computation together without going through the process of constructing PDEs. In other words, the CFD research is not only to obtain the numerical solution of governing equations but to model flow dynamics as well. This methodology leads to the unified gas-kinetic scheme (UGKS) for flow simulation in all flow regimes. Based on UGKS, the boundary for the validation of the Navier-Stokes equations can be quantitatively evaluated. The combination of modeling and computation provides a paradigm for the description of multiscale transport process.

Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum.

PubMed

Toque, Haroldo A; Teixeira, Cleber E; Lorenzetti, Raquel; Okuyama, Cristina E; Antunes, Edson; De Nucci, Gilberto

2008-09-04

Nitrergic nerves and endothelial cells release nitric oxide (NO) in the corpus cavernosum, a key mediator that stimulates soluble guanylyl cyclase to increase cGMP levels causing penile erection. Phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, prolong the NO effects by inhibiting cGMP breakdown. Here, we report a novel PDE5 inhibitor, lodenafil carbonate, (Bis-(2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl}-ethyl)carbonate) that is a dimer of lodenafil. We therefore aimed to compare the effects of sildenafil, lodenafil and lodenafil carbonate on in vitro human and rabbit cavernosal relaxations, activity of crude PDE extracts from human platelets, as well as stability and metabolic studies in rat, dog and human plasma. Pharmacokinetic evaluations after intravenous and oral administration were performed in male beagles. Functional experiments were conducted using organ bath techniques. Pharmacokinetics was studied in beagles by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), following oral or intravascular administration. All PDE5 inhibitors tested concentration-dependently relaxed (0.001-100 microM) phenylephrine-precontracted rabbit and human corpus cavernosum. The cavernosal relaxations evoked by either acetylcholine (0.01-100 microM) or electrical field stimulation (EFS, 1-20 Hz) were markedly potentiated by sildenafil, lodenafil and lodenafil carbonate. Lodenafil carbonate was more potent to inhibit the cGMP hydrolysis in PDE extracts compared with lodenafil and sildenafil. Following intravascular and single oral administration of lodenafil carbonate, only lodenafil and norlodenafil were detected in vivo. These results indicate that lodenafil carbonate works as a prodrug, being lodenafil the active moiety of lodenafil carbonate.

PDE5 inhibitor treatment persistence and adherence in Brazilian men: post-hoc analyses from a 6-month, prospective, observational study.

PubMed

Cairoli, Carlos; Reyes, Luis Antonio; Henneges, Carsten; Sorsaburu, Sebastian

2014-01-01

Characterize persistence and adherence to phosphodiesterase type - 5 inhibitor (PDE5I) on-demand therapy over 6 months among Brazilian men in an observational, non-interventional study of Latin American men naïve to PDE5Is with erectile dysfunction (ED). Men were prescribed PDE5Is per routine clinical practice. Persistence was defined as using ≥ 1 dose during the previous 4 - weeks, and adherence as following dosing instructions for the most recent dose, assessed using the Persistence and Adherence Questionnaire. Other measures included the Self - Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence/adherence. 104 Brazilian men were enrolled; mean age by treatment was 53 to 59 years, and most presented with moderate ED (61.7%). The prescribed PDE5I was sildenafil citrate for 50 (48.1%), tadalafil for 36 (34.6%), vardenafil for 15 (14.4%), and lodenafil for 3 patients (2.9%). Overall treatment persistence was 69.2% and adherence was 70.2%; both were numerically higher with tadalafil (75.0%) versus sildenafil or vardenafil (range 60.0% to 68.0%). Potential associations of persistence and/or adherence were observed with education level, ED etiology, employment status, and coronary artery disease. Improvements in all IIEF domain scores, and both SEAR domain scores were observed for all treatments. Study limitations included the observational design, brief duration, dependence on patient self - reporting, and limited sample size. Approximately two-thirds of PDE5I-naive, Brazilian men with ED were treatment persistent and adherent after 6 months. Further study is warranted to improve long-term outcomes of ED treatment.

Comparison of phosphodiesterase 10A, dopamine receptors D1 and D2 and dopamine transporter ligand binding in the striatum of the R6/2 and BACHD mouse models of Huntington's disease.

PubMed

Miller, Silke; Hill Della Puppa, Geraldine; Reidling, Jack; Marcora, Edoardo; Thompson, Leslie M; Treanor, James

2014-01-01

Phosphodiesterase 10A (PDE10A) is expressed at high levels in the striatum and has been proposed both as a biomarker for Huntington's disease pathology and as a target for intervention. PDE10A radiotracers have been successfully used to measure changes in binding density in Huntington's disease patients, but little is known about PDE10A binding in mouse models that are used extensively to model pathology and test therapeutic interventions. Our study investigated changes in PDE10A binding using the selective tracer 3H-7980 at specific ages of two Huntington's disease transgenic mouse models: R6/2, a short-lived model carrying exon-1 of mutant HTT and BACHD, a longer-lived model carrying full-length mutant HTT. PDE10A binding was compared to binding of known markers of striatal atrophy in Huntington's disease, e.g. dopamine transporter (DAT) and dopamine receptors D1 and D2. We found that in the R6/2 model at 6 weeks of age, mice showed high variability of binding, however binding of all ligands was significantly decreased at 8 and 12 weeks of age. In contrast, no changes were detectable in the BACHD model at 8, 10 or 12 month of age. These findings suggest that radiotracer binding of PDE10A, DAT, D1 and D2 receptor in the R6/2 model may be a good indicator of striatal pathological changes that are observed in Huntington's disease patients, and that the first 12 months in the BACHD model may be more reflective of early stages of the disease.

Identification of cytosolic phosphodiesterases in the erythrocyte: A possible role for PDE5

PubMed Central

Adderley, Shaquria P.; Thuet, Kelly M.; Sridharan, Meera; Bowles, Elizabeth A.; Stephenson, Alan H.; Ellsworth, Mary L.; Sprague, Randy S.

2011-01-01

Summary Background Within erythrocytes (RBCs), cAMP levels are regulated by phosphodiesterases (PDEs). Increases in cAMP and ATP release associated with activation of β-adrenergic receptors (βARs) and prostacyclin receptors (IPRs) are regulated by PDEs 2, 4 and PDE 3, respectively. Here we establish the presence of cytosolic PDEs in RBCs and determine a role for PDE5 in regulating levels of cGMP. Material/Methods Purified cytosolic proteins were obtained from isolated human RBCs and western analysis was performed using antibodies against PDEs 3A, 4 and 5. Rabbit RBCs were incubated with dbcGMP, a cGMP analog, to determine the effect of cGMP on cAMP levels. To determine if cGMP affects receptor-mediated increases in cAMP, rabbit RBCs were incubated with dbcGMP prior to addition of isoproterenol (ISO), a βAR receptor agonist. To demonstrate that endogenous cGMP produces the same effect, rabbit and human RBCs were incubated with SpNONOate (SpNO), a nitric oxide donor, and YC1, a direct activator of soluble guanylyl cyclase (sGC), in the absence and presence of a selective PDE5 inhibitor, zaprinast (ZAP). Results Western analysis identified PDEs 3A, 4D and 5A. dbcGMP produced a concentration dependent increase in cAMP and ISO-induced increases in cAMP were potentiated by dbcGMP. In addition, incubation with YC1 and SpNO in the presence of ZAP potentiated βAR-induced increases in cAMP. Conclusions PDEs 2, 3A and 5 are present in the cytosol of human RBCs. PDE5 activity in RBCs regulates cGMP levels. Increases in intracellular cGMP augment cAMP levels. These studies suggest a novel role for PDE5 in erythrocytes. PMID:21525805

Hand drawing of pencil electrodes on paper platforms for contactless conductivity detection of inorganic cations in human tear samples using electrophoresis chips.

PubMed

Chagas, Cyro L S; Costa Duarte, Lucas; Lobo-Júnior, Eulício O; Piccin, Evandro; Dossi, Nicolò; Coltro, Wendell K T

2015-08-01

This paper describes for the first time the fabrication of pencil drawn electrodes (PDE) on paper platforms for capacitively coupled contactless conductivity detection (C(4) D) on electrophoresis microchips. PDE-C(4) D devices were attached on PMMA electrophoresis chips and used for detection of K(+) and Na(+) in human tear samples. PDE-C(4) D devices were produced on office paper and chromatographic paper platforms and their performance were thoroughly investigated using a model mixture containing K(+) , Na(+) , and Li(+) . In comparison with chromatographic paper, PDE-C(4) D fabricated on office paper has exhibited better performance due to its higher electrical conductivity. Furthermore, the detector response was similar to that recorded with electrodes prepared with copper adhesive tape. The fabrication of PDE-C(4) D on office paper has offered great advantages including extremely low cost (< $ 0.004 per unit), reduced fabrication time (< 5 min), and minimal instrumentation (pencil and paper). The proposed electrodes demonstrated excellent analytical performance with good reproducibility. For an inter-PDE comparison (n = 7), the RSD values for migration time, peak area, and separation efficiency were lower than 2.5, 10.5, and 14%, respectively. The LOD's achieved for K(+) , Na(+) , and Li(+) were 4.9, 6.8, and 9.0 μM, respectively. The clinical feasibility of the proposed approach was successfully demonstrated with the quantitative analysis of K(+) and Na(+) in tear samples. The concentration levels found for K(+) and Na(+) were, respectively, 20.8 ± 0.1 mM and 101.2 ± 0.1 mM for sample #1, and 20.4 ± 0.1 mM and 111.4 ± 0.1 mM for sample #2. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Regulation of ecto-apyrase CD39 (ENTPD1) expression by phosphodiesterase III (PDE3)

PubMed Central

Baek, Amy E.; Kanthi, Yogendra; Sutton, Nadia R.; Liao, Hui; Pinsky, David J.

2013-01-01

The ectoenzyme CD39 suppresses thrombosis and inflammation by suppressing ATP and ADP to AMP. However, mechanisms of CD39 transcriptional and post-translational regulation are not well known. Here we show that CD39 levels are modulated by inhibition of phosphodiesterase 3 (PDE3). RAW macrophages and human umbilical vein endothelial cells (HUVECs) were treated with the PDE3 inhibitors cilostazol and milrinone, then analyzed using qRT-PCR, immunoprecipitation/Western blot, immunofluorescent staining, radio-thin-layer chromatography, a malachite green assay, and ELISA. HUVECs expressed elevated CD39 protein (2-fold [P<0.05] for cilostazol and 2.5-fold [P<0.01] for milrinone), while macrophage CD39 mRNA and protein were both elevated after PDE3 inhibition. HUVEC ATPase activity increased by 25% with cilostazol and milrinone treatment (P<0.05 and P<0.01, respectively), as did ADPase activity (47% and 61%, P<0.001). There was also a dose-dependent elevation of soluble CD39 after treatment with 8-Br-cAMP, with maximal elevation of 60% more CD39 present compared to controls (1 mM, P<0.001). Protein harvested after 8-Br-cAMP treatment showed that ubiquitination of CD39 was decreased by 43% compared to controls. A DMSO or PBS vehicle control was included for each experiment based on solubility of cilostazol, milrinone, and 8-Br-cAMP. These results indicate that PDE3 inhibition regulates endothelial CD39 at a post-translational level.—Baek, A. E., Kanthi, Y., Sutton, N. R., Liao, H., Pinsky, D. J. Regulation of ecto-apyrase CD39 (ENTPD1) expression by phosphodiesterase III (PDE3). PMID:23901069

Synergistic effect between 5-HT4 receptor agonist and phosphodiesterase 4-inhibitor in releasing acetylcholine in pig gastric circular muscle in vitro.

PubMed

Lefebvre, Romain A; Van Colen, Inge; Pauwelyn, Vicky; De Maeyer, Joris H

2016-06-15

5-HT4 receptor agonists have a gastroprokinetic effect by facilitating acetylcholine release from cholinergic nerves innervating gastrointestinal smooth muscle. The role of phosphodiesterase (PDE) 4 in the signal transduction pathway of the 5-HT4 receptors located on the cholinergic neurons towards the circular muscle layer in pig stomach was investigated by analysis of acetylcholine release. Circular muscle strips were prepared from pig proximal stomach and tritium outflow, induced by electrical field stimulation, was studied as a marker for acetylcholine release after incubation with [(3)H]-choline. The PDE4-inhibitor roflumilast concentration-dependently (0.1-1µM) enhanced the facilitating effect of a submaximally effective concentration of the 5-HT4 receptor agonist prucalopride (0.01µM) on electrically induced acetylcholine release. Roflumilast (0.3µM) enhanced acetylcholine release per se but in the combined presence of roflumilast and prucalopride, acetylcholine release was enhanced more than the sum of the effect of the 2 compounds alone. The 5-HT4 receptor agonist velusetrag concentration-dependently (0.01-0.1µM) enhanced acetylcholine release; the effect of the minimally effective concentration (0.01µM) was significantly enhanced by 1µM of the PDE4-inhibitor rolipram, again to a level higher than the sum of the effect of the 2 compounds alone. The synergistic effect between 5-HT4 receptor agonists and PDE4-inhibitors demonstrates that the intracellular pathway of the 5-HT4 receptors located on cholinergic neurons towards pig gastric circular muscle is controlled by PDE4. Combining a 5-HT4 receptor agonist with a PDE4-inhibitor might thus enhance its gastroprokinetic effect. Copyright © 2016 Elsevier B.V. All rights reserved.

The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents.

PubMed

Gentzel, Renee C; Toolan, Dawn; Roberts, Rhonda; Koser, Amy Jo; Kandebo, Monika; Hershey, James; Renger, John J; Uslaner, Jason; Smith, Sean M

2015-12-01

Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c-fos, egr-1, and arc in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2-neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3-30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor. Copyright © 2015. Published by Elsevier Ltd.

Cardiac Hypertrophy Is Inhibited by a Local Pool of cAMP Regulated by Phosphodiesterase 2.

PubMed

Zoccarato, Anna; Surdo, Nicoletta C; Aronsen, Jan M; Fields, Laura A; Mancuso, Luisa; Dodoni, Giuliano; Stangherlin, Alessandra; Livie, Craig; Jiang, He; Sin, Yuan Yan; Gesellchen, Frank; Terrin, Anna; Baillie, George S; Nicklin, Stuart A; Graham, Delyth; Szabo-Fresnais, Nicolas; Krall, Judith; Vandeput, Fabrice; Movsesian, Matthew; Furlan, Leonardo; Corsetti, Veronica; Hamilton, Graham; Lefkimmiatis, Konstantinos; Sjaastad, Ivar; Zaccolo, Manuela

2015-09-25

Chronic elevation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodeling and cardiac hypertrophy. However, enhancement of particular aspects of cAMP/protein kinase A signaling seems to be beneficial for the failing heart. cAMP is a pleiotropic second messenger with the ability to generate multiple functional outcomes in response to different extracellular stimuli with strict fidelity, a feature that relies on the spatial segregation of the cAMP pathway components in signaling microdomains. How individual cAMP microdomains affect cardiac pathophysiology remains largely to be established. The cAMP-degrading enzymes phosphodiesterases (PDEs) play a key role in shaping local changes in cAMP. Here we investigated the effect of specific inhibition of selected PDEs on cardiac myocyte hypertrophic growth. Using pharmacological and genetic manipulation of PDE activity, we found that the rise in cAMP resulting from inhibition of PDE3 and PDE4 induces hypertrophy, whereas increasing cAMP levels via PDE2 inhibition is antihypertrophic. By real-time imaging of cAMP levels in intact myocytes and selective displacement of protein kinase A isoforms, we demonstrate that the antihypertrophic effect of PDE2 inhibition involves the generation of a local pool of cAMP and activation of a protein kinase A type II subset, leading to phosphorylation of the nuclear factor of activated T cells. Different cAMP pools have opposing effects on cardiac myocyte cell size. PDE2 emerges as a novel key regulator of cardiac hypertrophy in vitro and in vivo, and its inhibition may have therapeutic applications. © 2015 American Heart Association, Inc.

The PDE4 inhibitor CHF-6001 and LAMAs inhibit bronchoconstriction-induced remodeling in lung slices.

PubMed

Kistemaker, Loes E M; Oenema, Tjitske A; Baarsma, Hoeke A; Bos, I Sophie T; Schmidt, Martina; Facchinetti, Fabrizio; Civelli, Maurizio; Villetti, Gino; Gosens, Reinoud

2017-09-01

Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced remodeling. Because of the different mechanism of action of PDE4 inhibitors and anticholinergics, we hypothesized functional interactions of these two drug classes. Guinea pig precision-cut lung slices were preincubated with the PDE4 inhibitors CHF-6001 or roflumilast and/or the anticholinergics tiotropium or glycopyorrolate, followed by stimulation with methacholine (10 μM) or TGF-β 1 (2 ng/ml) for 48 h. The inhibitory effects on airway smooth muscle remodeling, airway contraction, and TGF-β release were investigated. Methacholine-induced protein expression of smooth muscle-myosin was fully inhibited by CHF-6001 (0.3-100 nM), whereas roflumilast (1 µM) had smaller effects. Tiotropium and glycopyrrolate fully inhibited methacholine-induced airway remodeling (0.1-30 nM). The combination of CHF-6001 and tiotropium or glycopyrrolate, in concentrations partially effective by themselves, fully inhibited methacholine-induced remodeling in combination. CHF-6001 did not affect airway closure and had limited effects on TGF-β 1 -induced remodeling, but rather, it inhibited methacholine-induced TGF-β release. The PDE4 inhibitor CHF-6001, and to a lesser extent roflumilast, and the LAMAs tiotropium and glycopyrrolate inhibit bronchoconstriction-induced remodeling. The combination of CHF-6001 and anticholinergics was more effective than the individual compounds. This cooperativity might be explained by the distinct mechanisms of action inhibiting TGF-β release and bronchoconstriction. Copyright © 2017 the American Physiological Society.

Administration of PDE4 Inhibitors Suppressed the Pannus-Like Inflammation by Inhibition of Cytokine Production by Macrophages and Synovial Fibroblast Proliferation

PubMed Central

Kobayashi, Katsuya; Suda, Toshio; Manabe, Haruhiko; Miki, Ichiro

2007-01-01

A marked proliferation of synovial fibroblasts in joints leads to pannus formation in rheumatoid arthritis (RA). Various kinds of cytokines are produced in the pannus. The purpose of this study is to elucidate the effects of phosphodiesterase 4 (PDE4) inhibitors in a new animal model for the evaluation of pannus formation and cytokine production in the pannus. Mice sensitized with methylated bovine serum albumin (mBSA) were challenged by subcutaneous implantation of a membrane filter soaked in mBSA solution in the back of the mice. Drugs were orally administered for 10 days. The granuloma formed around the filter was collected on day 11. It was chopped into pieces and cultured in vitro for 24 hr. The cytokines were measured in the supernatants. The type of cytokines produced in the granuloma was quite similar to those produced in pannus in RA. Both PDE4 inhibitors, KF66490 and SB207499, suppressed the production of IL-1β, TNF-α, and IL-12, and the increase in myeloperoxidase activity, a marker enzyme for neutrophils and hydroxyproline content. Compared to leflunomide, PDE4 inhibitors more strongly suppressed IL-12 production and the increase in myeloperoxidase activity. PDE4 inhibitors also inhibited lipopolysaccharide-induced TNF-α and IL-12 production from thioglycolate-induced murine peritoneal macrophages and the proliferation of rat synovial fibroblasts. These results indicate this model makes it easy to evaluate the effect of drugs on various cytokine productions in a granuloma without any purification step and may be a relevant model for evaluating novel antirheumatic drugs on pannus formation in RA. PDE4 inhibitors could have therapeutic effects on pannus formation in RA by inhibition of cytokine production by macrophages and synovial fibroblast proliferation. PMID:18274640

Administration of PDE4 inhibitors suppressed the pannus-like inflammation by inhibition of cytokine production by macrophages and synovial fibroblast proliferation.

PubMed

Kobayashi, Katsuya; Suda, Toshio; Manabe, Haruhiko; Miki, Ichiro

2007-01-01

A marked proliferation of synovial fibroblasts in joints leads to pannus formation in rheumatoid arthritis (RA). Various kinds of cytokines are produced in the pannus. The purpose of this study is to elucidate the effects of phosphodiesterase 4 (PDE4) inhibitors in a new animal model for the evaluation of pannus formation and cytokine production in the pannus. Mice sensitized with methylated bovine serum albumin (mBSA) were challenged by subcutaneous implantation of a membrane filter soaked in mBSA solution in the back of the mice. Drugs were orally administered for 10 days. The granuloma formed around the filter was collected on day 11. It was chopped into pieces and cultured in vitro for 24 hr. The cytokines were measured in the supernatants. The type of cytokines produced in the granuloma was quite similar to those produced in pannus in RA. Both PDE4 inhibitors, KF66490 and SB207499, suppressed the production of IL-1beta, TNF-alpha, and IL-12, and the increase in myeloperoxidase activity, a marker enzyme for neutrophils and hydroxyproline content. Compared to leflunomide, PDE4 inhibitors more strongly suppressed IL-12 production and the increase in myeloperoxidase activity. PDE4 inhibitors also inhibited lipopolysaccharide-induced TNF-alpha and IL-12 production from thioglycolate-induced murine peritoneal macrophages and the proliferation of rat synovial fibroblasts. These results indicate this model makes it easy to evaluate the effect of drugs on various cytokine productions in a granuloma without any purification step and may be a relevant model for evaluating novel antirheumatic drugs on pannus formation in RA. PDE4 inhibitors could have therapeutic effects on pannus formation in RA by inhibition of cytokine production by macrophages and synovial fibroblast proliferation.

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

PubMed

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

2017-02-15

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

Synthetic phosphodiesterase-5-inhibitors use/abuse and interest of hair testing: reporting of a rape case.

PubMed

Duez, Mathieu; Etter, Matthieu; Klinger, Nadine; Cirimele, Vincent

2014-06-01

If classic phosphodiesterase-5 (PDE-5) inhibitors are well known, new synthetic PDE-5 analogues are of more recent introduction. Some of them have already been tested in dietary supplements. We describe here a rape case following the consumption of pills bought on the Internet and containing new synthetic PDE-5 inhibitors. The assailant declared that he lost control after ingesting these pills for the first time. Analyses of conventional matrices (blood, urine) don't allow us to highlight the intake of any substances in relation to this offence due to late sampling (5 days after the offence). Therefore, we have developed an analytical approach to test for PDE-5 inhibitors in hair including the two new synthetic PDE-5 inhibitors analogues - thiosildenafil and hydroxythiohomosildenafil - previously identified in the pills. This new method was validated and applied to the hair samples of the victim and the suspect. Analyses were conducted using a liquid/liquid extraction followed by liquid chromatography coupled with a mass spectrometer in multiple reaction monitoring mode detection. The 2-centimetre proximal hair section of the suspect revealed the presence of thiosildenafil (48 pg/mg), hydroxythiohomosildenafil (24 pg/mg), and sildenafil (7.5 pg/mg). To our knowledge, it is the first time that these two new synthetic PDE-5 inhibitors were detected in biological samples and especially in hair. Complementary investigations showed that a single pill taken by a volunteer provided similar levels in thiosildenafil (35 pg/mg), hydroxythiohomosildenafil (17 pg/mg), and sildenafil (8 pg/mg) to those found in the previous case described here. Copyright © 2014 John Wiley & Sons, Ltd.

PDE5 inhibitors blunt inflammation in human BPH: a potential mechanism of action for PDE5 inhibitors in LUTS.

PubMed

Vignozzi, Linda; Gacci, Mauro; Cellai, Ilaria; Morelli, Annamaria; Maneschi, Elena; Comeglio, Paolo; Santi, Raffaella; Filippi, Sandra; Sebastianelli, Arcangelo; Nesi, Gabriella; Serni, Sergio; Carini, Marco; Maggi, Mario

2013-09-01

Metabolic syndrome (MetS) and benign prostate hyperplasia (BPH)/low urinary tract symptoms (LUTS) are often comorbid. Chronic inflammation is one of the putative links between these diseases. Phosphodiesterase type 5 inhibitors (PDE5i) are recognized as an effective treatment of BPH-related LUTS. One proposed mechanism of action of PDE5 is the inhibition of intraprostatic inflammation. In this study we investigate whether PDE5i could blunt inflammation in the human prostate. Evaluation of the effect of tadalafil and vardenafil on secretion of interleukin 8 (IL-8, a surrogate marker of prostate inflammation) by human myofibroblast prostatic cells (hBPH) exposed to different inflammatory stimuli. We preliminary evaluate histological features of prostatic inflammatory infiltrates in BPH patients enrolled in a randomized, double bind, placebo controlled study aimed at investigating the efficacy of vardenafil (10 mg/day, for 12 weeks) on BPH/LUTS. In vitro treatment with tadalafil or vardenafil on hBPH reduced IL-8 secretion induced by either TNFα or metabolic factors, including oxidized low-density lipoprotein, oxLDL, to the same extent as a PDE5-insensitive PKG agonist Sp-8-Br-PET-cGMP. These effects were reverted by the PKG inhibitor KT5823, suggesting a cGMP/PKG-dependency. Treatment with tadalafil or vardenafil significantly suppressed oxLDL receptor (LOX-1) expression. Histological evaluation of anti-CD45 staining (CD45 score) in prostatectomy specimens of BPH patients showed a positive association with MetS severity. Reduced HDL-cholesterol and elevated triglycerides were the only MetS factors significantly associated with CD45 score. In the MetS cohort there was a significant lower CD45 score in the vardenafil-arm versus the placebo-one. © 2013 Wiley Periodicals, Inc.

Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.

PubMed

Aversa, A; Fittipaldi, S; Bimonte, V M; Wannenes, F; Papa, V; Francomano, D; Greco, E A; Lenzi, A; Migliaccio, S

2016-02-01

Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD). Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression. Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation. Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

Insight into the phosphodiesterase mechanism from combined QM/MM free energy simulations.

PubMed

Wong, Kin-Yiu; Gao, Jiali

2011-07-01

Molecular dynamics simulations employing a combined quantum mechanical and molecular mechanical potential have been carried out to elucidate the reaction mechanism of the hydrolysis of a cyclic nucleotide cAMP substrate by phosphodiesterase 4B (PDE4B). PDE4B is a member of the PDE superfamily of enzymes that play crucial roles in cellular signal transduction. We have determined a two-dimensional potential of mean force (PMF) for the coupled phosphoryl bond cleavage and proton transfer through a general acid catalysis mechanism in PDE4B. The results indicate that the ring-opening process takes place through an S(N)2 reaction mechanism, followed by a proton transfer to stabilize the leaving group. The computed free energy of activation for the PDE4B-catalyzed cAMP hydrolysis is about 13 kcal·mol(-1) and an overall reaction free energy is about -17 kcal·mol(-1), both in accord with experimental results. In comparison with the uncatalyzed reaction in water, the enzyme PDE4B provides a strong stabilization of the transition state, lowering the free energy barrier by 14 kcal·mol(-1). We found that the proton transfer from the general acid residue His234 to the O3' oxyanion of the ribosyl leaving group lags behind the nucleophilic attack, resulting in a shallow minimum on the free energy surface. A key contributing factor to transition state stabilization is the elongation of the distance between the divalent metal ions Zn(2+) and Mg(2+) in the active site as the reaction proceeds from the Michaelis complex to the transition state. © 2011 The Authors Journal compilation © 2011 FEBS.

Toward Understanding Business Student Professional Development Engagement

ERIC Educational Resources Information Center

Blau, Gary; Blessley, Misty; Kunkle, Matthew; Schirmer, Michael; Regan, Laureen

2017-01-01

Professional development engagement (PDE) is defined as the level of perceived undergraduate engagement in professional development activities. An 11-item measure of PDE exhibited a good reliability. Using a complete data sample of 467 graduating business undergraduates, four variable sets (student background or precollege variables,…

Phosphodiesterase from Daboia russelli russelli venom: purification, partial characterization and inhibition of platelet aggregation.

PubMed

Mitra, Jyotirmoy; Bhattacharyya, Debasish

2014-09-01

Phosphodiesterases (PDEs) belong to a super-family of enzymes that have multiple roles in the metabolism of extracellular nucleotides and regulation of nucleotide-based intercellular signalling. A PDE from Russell's viper (Daboia russelli russelli) venom (DR-PDE) was purified by gel filtration, ion exchange and affinity chromatographies. Homogeneity of the preparation was verified by SDS-PAGE, SE-HPLC and mass spectrometry. It was free from 5'-nucleotidase, alkaline phosphatase and protease activities. Identity of the enzyme was ensured from partial sequence homology with other PDEs. DR-PDE was inactivated by polyvalent anti-venom serum and metal chelators. The enzyme was partially inhibited by the root extracts of four medicinal plants but remained unaffected by inhibitors of intracellular PDEs. DR-PDE hydrolyses ADP and thus, strongly inhibits ADP-induced platelet aggregation in human platelet rich plasma. This study leads to better understanding of a component of Russell's viper venom that affects homoeostatic system of the victim. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF.

PubMed

Puerta, Elena; Hervias, Isabel; Barros-Miñones, Lucía; Jordan, Joaquin; Ricobaraza, Ana; Cuadrado-Tejedor, Mar; García-Osta, Ana; Aguirre, Norberto

2010-05-01

In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD. Copyright 2010 Elsevier Inc. All rights reserved.

Approaches to Cycle Analysis and Performance Metrics

NASA Technical Reports Server (NTRS)

Parson, Daniel E.

2003-01-01

The following notes were prepared as part of an American Institute of Aeronautics and Astronautics (AIAA) sponsored short course entitled Air Breathing Pulse Detonation Engine (PDE) Technology. The course was presented in January of 2003, and again in July of 2004 at two different AIAA meetings. It was taught by seven instructors, each of whom provided information on particular areas of PDE research. These notes cover two areas. The first is titled Approaches to Cycle Analysis and Performance Metrics. Here, the various methods of cycle analysis are introduced. These range from algebraic, thermodynamic equations, to single and multi-dimensional Computational Fluid Dynamic (CFD) solutions. Also discussed are the various means by which performance is measured, and how these are applied in a device which is fundamentally unsteady. The second topic covered is titled PDE Hybrid Applications. Here the concept of coupling a PDE to a conventional turbomachinery based engine is explored. Motivation for such a configuration is provided in the form of potential thermodynamic benefits. This is accompanied by a discussion of challenges to the technology.

Systematic Review and Meta-Analysis of the Use of Phosphodiesterase Type 5 Inhibitors for Treatment of Erectile Dysfunction following Bilateral Nerve-Sparing Radical Prostatectomy

PubMed Central

Wang, Xiao; Wang, Xinghuan; Liu, Tao; He, Qianwen; Wang, Yipeng; Zhang, Xinhua

2014-01-01

Prostate cancer is relatively common cancer occurring in males. Radical prostatectomy (RP) is the most effective treatment for a localized tumor but erectile dysfunction (ED) is common complication, even when bilateral nerve-sparing RP (BNSRP) is performed. Clinical trials have shown varied effectiveness of phosphodiesterase type-5 inhibitors (PDE5-Is) for treatment of post-BNSRP ED, but there remains controversy over the application of this treatment and no formal systematic review and meta-analysis for the use of PDE5-Is for this condition has been conducted. This review was to systematically assess the efficacy and safety of oral PDE5-Is for post-BNSRP ED. A database search was conducted to identify randomized controlled trials (RCTs). The comparative efficacy of treatments was analyzed by fixed or random effect modeling. Erectile function was measured using the International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP) question-2, 3 and the Global Assessment Question (GAQ). The rate and incidence of adverse events (AEs) were determined. The quality of included studies was appraised using the Cochrane Collaboration bias appraisal tool. Eight RCTs were included in the analyses. PDE5-Is were effective for treating post-BNSRP ED compared to placebo when erectile function was determined using the IIEF score [mean difference (MD) 5.63, 95% confidence interval (CI) (4.26–6.99)], SEP-2 [relative risk (RR) 1.63, 95% CI (1.18–2.25) ], SEP-3 [RR 2.00, 95% CI (1.27–3.15) ] and GAQ [RR 3.35, 95% CI (2.68–4.67) ]. The subgroup analysis could find a trend that longer treatment duration, higher dosage, on-demand dosing, sildenafil and mild ED are associated with more responsiveness to PDE5-Is. PDE5-Is were overall well tolerated with headache being the most commonly reported AE. Our data provides compelling evidence for the use of PDE5-Is as a primary treatment for post-BNSRP ED. However, further studies are required to optomize usage parameters (such as dosage and duration of treatment). PMID:24618671

A 6 month, prospective, observational study of PDE5 inhibitor treatment persistence and adherence in Latin American men with erectile dysfunction.

PubMed

Rubio-Aurioles, Eusebio; Reyes, Luis Antonio; Borregales, Leonardo; Cairoli, Carlos; Sorsaburu, Sebastian

2013-06-01

To assess persistence/adherence rates of phosphodiesterase type-5 inhibitor (PDE5I) on-demand dosing in Latin American men with erectile dysfunction (ED), and explore patient characteristics and treatment factors that may be predictive for PDE5I persistence and adherence. Men from Brazil, Mexico, and Venezuela with ED who were naïve to PDE5Is were prescribed sildenafil, tadalafil, vardenafil, or lodenafil on-demand dosing and asked to provide information about PDE5I use at baseline and at 1, 3, and 6 months. Patients were persistent if they used ≥1 dose during the 4 week period prior to each evaluation. Patients were adherent if they complied with dosing instructions during most recent dose. Main outcome measures included Persistence and Adherence Questionnaire (PAQ), Partner Relationship Questionnaire (PRQ), Self-Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence and adherence. A total of 511 men were enrolled; most had mild to moderate ED (77.1%); 317 patients (62.0%) were prescribed tadalafil, 116 (22.7%) sildenafil, 75 (14.7%) vardenafil, and 3 (0.6%) lodenafil (not further analyzed). A total of 340 patients (66.5%) were 'persistent' at 6 months; 345 (67.5%) were 'adherent'. Persistence and adherence were associated with age, education level, and ED duration. Reasons for non-persistence included medication cost and lack of efficacy. Study limitations included its design, brief observation period, its bias observed toward tadalafil selection; its dependence on patient self-reporting, limited number of factors that were analyzed for persistence/adherence association, its small number of participating patients and Latin American countries, and inherent differences in PDE5I preference and medical practices. Approximately two-thirds of PDE5I-naïve, Latin American men with ED were persistent and adherent after 6 months of therapy. Factors like education level, ED severity, and ED duration were associated with persistence and adherence; additional study is warranted to investigate the predictive value of these factors.

Penile Low Intensity Shock Wave Treatment is Able to Shift PDE5i Nonresponders to Responders: A Double-Blind, Sham Controlled Study.

PubMed

Kitrey, Noam D; Gruenwald, Ilan; Appel, Boaz; Shechter, Arik; Massarwa, Omar; Vardi, Yoram

2016-05-01

We performed sham controlled evaluation of penile low intensity shock wave treatment effect in patients unable to achieve sexual intercourse using PDE5i (phosphodiesterase type 5 inhibitor). This prospective, randomized, double-blind, sham controlled study was done in patients with vasculogenic erectile dysfunction who stopped using PDE5i due to no efficacy. All patients had an erection hardness score of 2 or less with PDE5i. A total of 58 patients were randomized, including 37 treated with low intensity shock waves (12 sessions of 1,500 pulses of 0.09 mJ/mm(2) at 120 shock waves per minute) and 18 treated with a sham probe. In the sham group 16 patients underwent low intensity shock wave treatment 1 month after sham treatment. All patients were evaluated at baseline and 1 month after the end of treatment using validated erectile dysfunction questionnaires and the flow mediated dilatation technique for penile endothelial function. Erectile function was evaluated while patients were receiving PDE5i. In the low intensity shock wave treatment group and the sham group 54.1% and 0% of patients, respectively, achieved erection hard enough for vaginal penetration, that is an EHS (Erection Hardness Score) of 3 (p <0.0001). According to changes in the IIEF-EF (International Index of Erectile Function-Erectile Function) score treatment was effective in 40.5% of men who received low intensity shock wave treatment but in none in the sham group (p = 0.001). Of patients treated with shock waves after sham treatment 56.3% achieved erection hard enough for penetration (p <0.005). Low intensity shock wave treatment is effective even in patients with severe erectile dysfunction who are PDE5i nonresponders. After treatment about half of them were able to achieve erection hard enough for penetration with PDE5i. Longer followup is needed to establish the place of low intensity shock wave treatment in these challenging cases. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Course-, dose-, and stage-dependent toxic effects of prenatal dexamethasone exposure on fetal articular cartilage development.

PubMed

Chen, Ze; Zhao, Zhe; Li, Yunzepeng; Zhang, Xingyu; Li, Bin; Chen, Liaobin; Wang, Hui

2018-04-01

Dexamethasone, a synthetic long-acting glucocorticoid, is routinely used for treating mothers at risk for preterm delivery. However, intrauterine overexposure to glucocorticoids induces low birth weight and cartilage dysplasia in offspring. Also, the "critical window" and safe dose of this treatment are largely unknown. This study investigated the course-, dose-, and stage-dependent toxic effects and the possible mechanisms of prenatal dexamethasone exposure (PDE) on fetal development and articular cartilage development. Pregnant mice (C57BL/6) received subcutaneous injection of dexamethasone (0.8 mg/kg d) once on gestational day (GD) 15 or once a day from GD 15 to 17, or received various doses of dexamethasone (0, 0.2, 0.8, and 1.2 mg/kg d) on GD 15-17, or received dexamethasone (0.8 mg/kg d) at early stage (GD 12-14) or late stage of pregnancy (GD 15-17). Offspring's knee joints were harvested at birth for morphological analyses and detection of gene expression. Repeated PDE significantly suppressed fetal and articular cartilage development, which were characterized by decreased body weight and body length, coarse articular cartilage surfaces, and reduced gene and protein expression of Col2a1 and aggrecan. For those newborns treated with repeated PDE at different doses, the toxic effects on fetal and articular cartilage development were observed at doses of 0.8 and 1.2 mg/kg d, whereas no obvious toxic effects were observed at the dose of 0.2 mg/kg d. Moreover, PDE at 0.8 mg/kg d during the early embryonic stage induced stronger toxic effects on fetal and articular cartilage development, compared with PDE during the late embryonic stage. Detection of gene expression showed that the TGFβ signaling pathway in the articular cartilage was down-regulated after PDE. Taken together, PDE induces fetal developmental toxicity and articular cartilage developmental toxicity in a course-, dose-, and stage-dependent manner. Copyright © 2018 Elsevier B.V. All rights reserved.

Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases.

PubMed

Kalash, Leen; Val, Cristina; Azuaje, Jhonny; Loza, María I; Svensson, Fredrik; Zoufir, Azedine; Mervin, Lewis; Ladds, Graham; Brea, José; Glen, Robert; Sotelo, Eddy; Bender, Andreas

2017-12-30

Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical effect. In particular, suitable compounds may be useful in treating neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at the adenosine A 1 and A 2A receptors (A 1 R and A 2A R) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible ligands that bind to A 1 and A 2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic approach employing in silico target prediction and docking, which may be generally applicable to multi-target compound design at several target classes. This approach has identified 2-aminopyridine-3-carbonitriles as the first multi-target ligands at A 1 R, A 2A R and PDE10A, by showing agreement between the ligand and structure based predictions at these targets. The series were synthesized via an efficient one-pot scheme and validated pharmacologically as A 1 R/A 2A R-PDE10A ligands, with IC 50 values of 2.4-10.0 μM at PDE10A and K i values of 34-294 nM at A 1 R and/or A 2A R. Furthermore, selectivity profiling of the synthesized 2-amino-pyridin-3-carbonitriles against other subtypes of both protein families showed that the multi-target ligand 8 exhibited a minimum of twofold selectivity over all tested off-targets. In addition, both compounds 8 and 16 exhibited the desired multi-target profile, which could be considered for further functional efficacy assessment, analog modification for the improvement of selectivity towards A 1 R, A 2A R and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels.

The effects of the combined use of a PDE5 inhibitor and medications for hypertension, lower urinary tract symptoms and dyslipidemia on corporal tissue tone.

PubMed

Lee, J H; Chae, M R; Park, J K; Jeon, J H; Lee, S W

2012-01-01

ED is closely associated with its comorbidities (hypertension, dyslipidemia and lower urinary tract symptoms (LUTS)). Therefore, several drugs have been prescribed simultaneously with PDE5 inhibitors. If a specific medication for ED comorbidities has enhancing effects on PDE5 inhibitors, it offers alternative combination therapy in nonresponders to monotherapy with PDE5 inhibitors and allows clinicians to treat ED and its comorbidities simultaneously. To establish theoretical basis of choosing an appropriate medication for ED and concomitant disease, we examined the effects combining a PDE5 inhibitor with representative drugs for hypertension, dyslipidemia and LUTS on relaxing the corpus cavernosum of rabbits using the organ-bath technique. The effect of mirodenafil on relaxing phenylephrine-induced cavernosal contractions was significantly enhanced by the presence of 10(-4) M losartan, 10(-6) M nifedipine, 10(-6) M amlodipine, 10(-7) M doxazosin and 10(-9) M tamsulosin (P<0.05). The maximum relaxation effects were 47.2±3.8%, 57.6±2.6%, 64.0±3.7%, 76.1±5.7% and 71.7±5.4%, respectively. Enalapril and simvastatin had no enhancing effects. The relaxation induced by sodium nitroprusside alone (39.0±4.0%) was significantly enhanced in the presence of the 10(-4) M losartan (66.0±6.0%, P<0.05). Tetraethylammonium (1 mM) significantly inhibited the enhancement effects of tamsulosin and doxazosin on mirodenafil-induced relaxation (doxazosin: 76.1±5.7% vs 45.3±2.3%; tamsulosin: 71.7±5.4% vs 48.1±3.5%). On the basis of these findings, losartan seemed to induce synergistic effects through an interaction with nitric oxide. In addition, K(+) channel activation could be one of the mechanisms for the synergistic effect of combining mirodenafil with doxazosin or tamsulosin. We believe that the combination of a PDE5 inhibitor with losartan, nifedipine, amlodipine, doxazosin or tamsulosin could be a pharmacologic strategy for simultaneously treating ED and its comorbidities and increasing response rates to PDE5 inhibitors.

Off-Target Effect of Sildenafil on Postsurgical Erectile Dysfunction: Alternate Pathways and Localized Delivery System.

PubMed

Salmasi, Amirali; Lee, Geun Taek; Patel, Neal; Goyal, Ritu; Dinizo, Michael; Kwon, Young Suk; Modi, Part K; Faiena, Izak; Kim, Hee-Jin; Lee, Nara; Hannan, Johanna L; Kohn, Joachim; Kim, Isaac Yi

2016-12-01

There is no consensus on the best oral phosphodiesterase type 5 inhibitor (PDE5I) for patients undergoing penile rehabilitation after surgical nerve injury. To determine the mechanism of PDE5I on cultured neuronal cells and the effectiveness of local drug delivery using nanospheres (NSPs) to sites of nerve injury in a rat model of bilateral cavernous nerve injury (BCNI). The effects of sildenafil, tadalafil, and vardenafil on cyclic adenosine monophosphate, cyclic guanosine monophosphate, and cell survival after exposure to hypoxia and H 2 O 2 were measured in PC12, SH-SY5Y, and NTERA-2 (NT2) cell cultures. The effects of phosphodiesterase type 4 inhibitor (PDE4I) and PDE5I on neuronal cell survival were evaluated. Male rats underwent BCNI and were untreated (BCNI), immediately treated with application of empty NSPs (BCNI + NSP), NSPs containing sildenafil (Sild + NSP), or NSPs containing rolipram (Rol + NSP). Viability of neuronal cells was measured. Intracavernous pressure changes after cavernous nerve electrostimulation and expression of neurofilament, nitric oxide synthase, and actin in mid-shaft of penis were analyzed 14 days after injury. Sildenafil and rolipram significantly decreased cell death after exposure to H 2 O 2 and hypoxia in PC12, SH-SY5Y, and NT2 cells. PC12 cells did not express PDE5 and knockdown of PDE4 significantly increased cell viability in PC12, SH-SY5Y, and NT2 cells exposed to hypoxia. The ratio of intracavernous pressure to mean arterial pressure and expression of penile neurofilament, nitric oxide synthase, and actin were significantly higher in the Sild + NSP and Rol + NSP groups than in the BCNI and BCNI + NSP groups. Limitations included analysis in only two PDE families using only a single dose. Sildenafil showed the most profound neuroprotective effect compared with tadalafil and vardenafil. Sildenafil- or rolipram-loaded NSP delivery to the site of nerve injury prevented erectile dysfunction and led to increased neurofilament, nitric oxide synthase, smooth muscle content in rat penile tissue after BCNI. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

The U.S. Army Person-Event Data Environment: A Military-Civilian Big Data Enterprise.

PubMed

Vie, Loryana L; Scheier, Lawrence M; Lester, Paul B; Ho, Tiffany E; Labarthe, Darwin R; Seligman, Martin E P

2015-06-01

This report describes a groundbreaking military-civilian collaboration that benefits from an Army and Department of Defense (DoD) big data business intelligence platform called the Person-Event Data Environment (PDE). The PDE is a consolidated data repository that contains unclassified but sensitive manpower, training, financial, health, and medical records covering U.S. Army personnel (Active Duty, Reserve, and National Guard), civilian contractors, and military dependents. These unique data assets provide a veridical timeline capturing each soldier's military experience from entry to separation from the armed forces. The PDE was designed to afford unprecedented cost-efficiencies by bringing researchers and military scientists to a single computerized repository rather than porting vast data resources to individual laboratories. With funding from the Robert Wood Johnson Foundation, researchers from the University of Pennsylvania Positive Psychology Center joined forces with the U.S. Army Research Facilitation Laboratory, forming the scientific backbone of the military-civilian collaboration. This unparalleled opportunity was necessitated by a growing need to learn more about relations between psychological and health assets and health outcomes, including healthcare utilization and costs-issues of major importance for both military and civilian population health. The PDE represents more than 100 times the population size and many times the number of linked variables covered by the nation's leading sources of population health data (e.g., the National Health and Nutrition Examination Survey). Following extensive Army vetting procedures, civilian researchers can mine the PDE's trove of information using a suite of statistical packages made available in a Citrix Virtual Desktop. A SharePoint collaboration and governance management environment ensures user compliance with federal and DoD regulations concerning human subjects' protections and also provides a secure portal for multisite collaborations. Taking similarities and differences between military and civilian populations into account, PDE studies can provide much more detailed insight into health-related questions of broad societal concern. Finding ways to make the rich repository of digitized information in the PDE available through military-civilian collaboration can help solve critical medical and behavioral issues affecting the health and well-being of our nations' military and civilian populations.

Longtime dynamics of the PDE model for the motion toward light of bacterial colonies

NASA Astrophysics Data System (ADS)

Taranets, R.; Chugunova, M.

2018-03-01

We study stationary solutions and longtime dynamics of the PDE model for cyanobacteria motion, which was recently proposed by Chavy-Waddy and Kolokolnikov (2016 Nonlinearity 29 3174). For different values of the parameter α, which controls the extent of the aggregate, we analyse a family of corresponding steady states and their stability (considering symmetric and non-symmetric cases separately). We derive the rate of convergence toward steady states, show existence of weak nonnegative solutions, and we also discover that the value α = 3 is a special case for this PDE model. Using numerical simulations we compare different regimes and illustrate convergence toward steady states.

Phosphodiesterase inhibitors. Part 6: design, synthesis, and structure-activity relationships of PDE4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory activity.

PubMed

Kojima, Akihiko; Takita, Satoshi; Sumiya, Tatsunobu; Ochiai, Koji; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Kohno, Yasushi

2013-10-01

We previously identified KCA-1490 [(-)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model. Copyright © 2013 Elsevier Ltd. All rights reserved.

Estimating varying coefficients for partial differential equation models.

PubMed

Zhang, Xinyu; Cao, Jiguo; Carroll, Raymond J

2017-09-01

Partial differential equations (PDEs) are used to model complex dynamical systems in multiple dimensions, and their parameters often have important scientific interpretations. In some applications, PDE parameters are not constant but can change depending on the values of covariates, a feature that we call varying coefficients. We propose a parameter cascading method to estimate varying coefficients in PDE models from noisy data. Our estimates of the varying coefficients are shown to be consistent and asymptotically normally distributed. The performance of our method is evaluated by a simulation study and by an empirical study estimating three varying coefficients in a PDE model arising from LIDAR data. © 2017, The International Biometric Society.

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.

Tinker-HP: a massively parallel molecular dynamics package for multiscale simulations of large complex systems with advanced point dipole polarizable force fields† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc04531j

PubMed Central

Lagardère, Louis; Jolly, Luc-Henri; Lipparini, Filippo; Aviat, Félix; Stamm, Benjamin; Jing, Zhifeng F.; Harger, Matthew; Torabifard, Hedieh; Cisneros, G. Andrés; Schnieders, Michael J.; Gresh, Nohad; Maday, Yvon; Ren, Pengyu Y.; Ponder, Jay W.

2017-01-01

We present Tinker-HP, a massively MPI parallel package dedicated to classical molecular dynamics (MD) and to multiscale simulations, using advanced polarizable force fields (PFF) encompassing distributed multipoles electrostatics. Tinker-HP is an evolution of the popular Tinker package code that conserves its simplicity of use and its reference double precision implementation for CPUs. Grounded on interdisciplinary efforts with applied mathematics, Tinker-HP allows for long polarizable MD simulations on large systems up to millions of atoms. We detail in the paper the newly developed extension of massively parallel 3D spatial decomposition to point dipole polarizable models as well as their coupling to efficient Krylov iterative and non-iterative polarization solvers. The design of the code allows the use of various computer systems ranging from laboratory workstations to modern petascale supercomputers with thousands of cores. Tinker-HP proposes therefore the first high-performance scalable CPU computing environment for the development of next generation point dipole PFFs and for production simulations. Strategies linking Tinker-HP to Quantum Mechanics (QM) in the framework of multiscale polarizable self-consistent QM/MD simulations are also provided. The possibilities, performances and scalability of the software are demonstrated via benchmarks calculations using the polarizable AMOEBA force field on systems ranging from large water boxes of increasing size and ionic liquids to (very) large biosystems encompassing several proteins as well as the complete satellite tobacco mosaic virus and ribosome structures. For small systems, Tinker-HP appears to be competitive with the Tinker-OpenMM GPU implementation of Tinker. As the system size grows, Tinker-HP remains operational thanks to its access to distributed memory and takes advantage of its new algorithmic enabling for stable long timescale polarizable simulations. Overall, a several thousand-fold acceleration over a single-core computation is observed for the largest systems. The extension of the present CPU implementation of Tinker-HP to other computational platforms is discussed. PMID:29732110

Is it Code Imperfection or 'garbage in Garbage Out'? Outline of Experiences from a Comprehensive Adr Code Verification

NASA Astrophysics Data System (ADS)

Zamani, K.; Bombardelli, F. A.

2013-12-01

ADR equation describes many physical phenomena of interest in the field of water quality in natural streams and groundwater. In many cases such as: density driven flow, multiphase reactive transport, and sediment transport, either one or a number of terms in the ADR equation may become nonlinear. For that reason, numerical tools are the only practical choice to solve these PDEs. All numerical solvers developed for transport equation need to undergo code verification procedure before they are put in to practice. Code verification is a mathematical activity to uncover failures and check for rigorous discretization of PDEs and implementation of initial/boundary conditions. In the context computational PDE verification is not a well-defined procedure on a clear path. Thus, verification tests should be designed and implemented with in-depth knowledge of numerical algorithms and physics of the phenomena as well as mathematical behavior of the solution. Even test results need to be mathematically analyzed to distinguish between an inherent limitation of algorithm and a coding error. Therefore, it is well known that code verification is a state of the art, in which innovative methods and case-based tricks are very common. This study presents full verification of a general transport code. To that end, a complete test suite is designed to probe the ADR solver comprehensively and discover all possible imperfections. In this study we convey our experiences in finding several errors which were not detectable with routine verification techniques. We developed a test suit including hundreds of unit tests and system tests. The test package has gradual increment in complexity such that tests start from simple and increase to the most sophisticated level. Appropriate verification metrics are defined for the required capabilities of the solver as follows: mass conservation, convergence order, capabilities in handling stiff problems, nonnegative concentration, shape preservation, and spurious wiggles. Thereby, we provide objective, quantitative values as opposed to subjective qualitative descriptions as 'weak' or 'satisfactory' agreement with those metrics. We start testing from a simple case of unidirectional advection, then bidirectional advection and tidal flow and build up to nonlinear cases. We design tests to check nonlinearity in velocity, dispersivity and reactions. For all of the mentioned cases we conduct mesh convergence tests. These tests compare the results' order of accuracy versus the formal order of accuracy of discretization. The concealing effect of scales (Peclet and Damkohler numbers) on the mesh convergence study and appropriate remedies are also discussed. For the cases in which the appropriate benchmarks for mesh convergence study are not available we utilize Symmetry, Complete Richardson Extrapolation and Method of False Injection to uncover bugs. Detailed discussions of capabilities of the mentioned code verification techniques are given. Auxiliary subroutines for automation of the test suit and report generation are designed. All in all, the test package is not only a robust tool for code verification but also it provides comprehensive insight on the ADR solvers capabilities. Such information is essential for any rigorous computational modeling of ADR equation for surface/subsurface pollution transport.

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

PubMed Central

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

2015-01-01

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

In Silico Investigations of Chemical Constituents of Clerodendrum colebrookianum in the Anti-Hypertensive Drug Targets: ROCK, ACE, and PDE5.

PubMed

Arya, Hemant; Syed, Safiulla Basha; Singh, Sorokhaibam Sureshkumar; Ampasala, Dinakar R; Coumar, Mohane Selvaraj

2017-06-16

Understanding the molecular mode of action of natural product is a key step for developing drugs from them. In this regard, this study is aimed to understand the molecular-level interactions of chemical constituents of Clerodendrum colebrookianum Walp., with anti-hypertensive drug targets using computational approaches. The plant has ethno-medicinal importance for the treatment of hypertension and reported to show activity against anti-hypertensive drug targets-Rho-associated coiled-coil protein kinase (ROCK), angiotensin-converting enzyme, and phosphodiesterase 5 (PDE5). Docking studies showed that three chemical constituents (acteoside, martinoside, and osmanthuside β6) out of 21 reported from the plant to interact with the anti-hypertensive drug targets with good glide score. In addition, they formed H-bond interactions with the key residues Met156/Met157 of ROCK I/ROCK II and Gln817 of PDE5. Further, molecular dynamics (MD) simulation of protein-ligand complexes suggest that H-bond interactions between acteoside/osmanthuside β6 and Met156/Met157 (ROCK I/ROCK II), acteoside and Gln817 (PDE5) were stable. The present investigation suggests that the anti-hypertensive activity of the plant is due to the interaction of acteoside and osmanthuside β6 with ROCK and PDE5 drug targets. The identified molecular mode of binding of the plant constituents could help to design new drugs to treat hypertension.

A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss.

PubMed

Wang, Li; Feng, Yong; Yan, Denise; Qin, Litao; Grati, M'hamed; Mittal, Rahul; Li, Tao; Sundhari, Abhiraami Kannan; Liu, Yalan; Chapagain, Prem; Blanton, Susan H; Liao, Shixiu; Liu, Xuezhong

2018-06-02

Identification of genes with variants causing non-syndromic hearing loss (NSHL) is challenging due to genetic heterogeneity. The difficulty is compounded by technical limitations that in the past prevented comprehensive gene identification. Recent advances in technology, using targeted capture and next-generation sequencing (NGS), is changing the face of gene identification and making it possible to rapidly and cost-effectively sequence the whole human exome. Here, we characterize a five-generation Chinese family with progressive, postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining population-specific mutation arrays, targeted deafness genes panel, whole exome sequencing (WES), we identified PDE1C (Phosphodiesterase 1C) c.958G>T (p.A320S) as the disease-associated variant. Structural modeling insights into p.A320S strongly suggest that the sequence alteration will likely affect the substrate-binding pocket of PDE1C. By whole-mount immunofluorescence on postnatal day 3 mouse cochlea, we show its expression in outer (OHC) and inner (IHC) hair cells cytosol co-localizing with Lamp-1 in lysosomes. Furthermore, we provide evidence that the variant alters the PDE1C hydrolytic activity for both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Collectively, our findings indicate that the c.958G>T variant in PDE1C may disrupt the cross talk between cGMP-signaling and cAMP pathways in Ca 2+ homeostasis.

Combination therapy for erectile dysfunction: an update review.

PubMed

Dhir, Rohit R; Lin, Hao-Cheng; Canfield, Steven E; Wang, Run

2011-05-01

The introduction of oral phosphodiesterase-5 inhibitors (PDE5Is) in the late 1990s and early 2000s revolutionized the field of sexual medicine and PDE5Is are currently first-line monotherapy for erectile dysfunction (ED). However, a significant proportion of patients with complex ED will be therapeutic non-responders to PDE5I monotherapy. Combination therapy has recently been adopted for more refractory cases of ED, but a critical evaluation of current combination therapies is lacking. A thorough PubMed and Cochrane Library search was conducted focusing on the effectiveness of combination therapies for ED in therapeutic non-responders to PDE5I therapy. Journal articles spanning the time period between January 1990 and December 2010 were reviewed. Criteria included all pertinent review articles, randomized controlled trials, cohort studies and retrospective analyses. References from retrieved articles were also manually scanned for additional relevant publications. Published combination therapies include PDE5I plus vacuum erectile device (VED), intraurethral medication, intracavernosal injection (ICI), androgen supplement, α-blocker or miscellaneous combinations. Based on this review, some of these combination treatments appeared to be quite effective in preliminary testing. Caution must be advised, however, as the majority of combination therapy articles in the last decade have numerous limitations including study biases and small subject size. Regardless of limitations, present combination therapy research provides a solid foundation for future studies in complex ED management.

A study of the management of erectile dysfunction in general practice.

PubMed

Griffiths, L; Bush, N; Mottram, D; Armstrong, D

2005-06-01

The Department of Health issued guidelines for the NHS treatment of erectile dysfunction (ED) with phosphodiesterase type 5 inhibitors (PDE 5 inhibitors) in 1999. There has been an increasing trend in the prescribing of PDE 5 inhibitors within Bebington and West Wirral Primary Care Trust (PCT) over the 3-year period from February 2001 to January 2004. The objective of the study was to investigate implementation of Government guidelines on prescribing of PDE 5 inhibitors for ED and the cost of prescribing outside these guidelines. Practice data were collected for all patients prescribed a PDE 5 inhibitor in 16 surgeries within Bebington and West Wirral Primary Care Trust, from November 2002 to December 2003. The data were evaluated with respect to adherence to UK Government guidelines. Analysis was made on the cost to the PCT with respect to treatment provided outside the guidelines. Prescribing for 78% of patients was within Government guidelines. With respect to frequency of prescribing, 89% of patients in the PCT received less than or equal to the recommended frequency of one tablet per week. The percentage range for practices was 67-100%. The cost to the PCT for PDE 5 inhibitor treatment provided outside the guidelines was 19,060 pounds sterling over the period of study. Prescribers generally follow Government guidelines, however, stricter adherence to guidelines could result in more efficient use of National Health Service resources.