Gain-scheduled controller synthesis for a nonlinear PDE
NASA Astrophysics Data System (ADS)
Mahdi Hashemi, Seyed; Werner, Herbert
2012-01-01
Linear parameter-varying (LPV) modelling and control of a nonlinear partial differential equation (PDE) is considered in this article. The one-dimensional viscous Burgers' equation is discretised using a finite difference scheme; the boundary conditions are taken as control inputs and the velocities at two grid points are assumed to be measurable. A nonlinear high-order state space model is generated and proper orthogonal decomposition is used for model order reduction. After assessing the accuracy of the reduced model, a low-order functional observer is designed to estimate the reduced states which are linear combinations of the velocities at all grid points. A discrete-time quasi-LPV model that is affine in scheduling parameters is derived based on the reduced model. A polytopic LPV controller is synthesised based on a generalised plant containing the LPV model and the functional observer. More generally, the proposed method can be used to design an LPV controller for a quasi-LPV system with non-measurable scheduling parameters. Simulation results demonstrate the high tracking performance and disturbance and measurement noise rejection capabilities of the designed LPV controller compared with a linear quadratic Gaussian (LQG) controller based on a linearised model.
Luo, Biao; Wu, Huai-Ning
2012-12-01
This paper addresses the approximate optimal control problem for a class of parabolic partial differential equation (PDE) systems with nonlinear spatial differential operators. An approximate optimal control design method is proposed on the basis of the empirical eigenfunctions (EEFs) and neural network (NN). First, based on the data collected from the PDE system, the Karhunen-Loève decomposition is used to compute the EEFs. With those EEFs, the PDE system is formulated as a high-order ordinary differential equation (ODE) system. To further reduce its dimension, the singular perturbation (SP) technique is employed to derive a reduced-order model (ROM), which can accurately describe the dominant dynamics of the PDE system. Second, the Hamilton-Jacobi-Bellman (HJB) method is applied to synthesize an optimal controller based on the ROM, where the closed-loop asymptotic stability of the high-order ODE system can be guaranteed by the SP theory. By dividing the optimal control law into two parts, the linear part is obtained by solving an algebraic Riccati equation, and a new type of HJB-like equation is derived for designing the nonlinear part. Third, a control update strategy based on successive approximation is proposed to solve the HJB-like equation, and its convergence is proved. Furthermore, an NN approach is used to approximate the cost function. Finally, we apply the developed approximate optimal control method to a diffusion-reaction process with a nonlinear spatial operator, and the simulation results illustrate its effectiveness. PMID:22588610
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.
Existence of solutions for a nonlinear PDE with an inverse square potential
NASA Astrophysics Data System (ADS)
Chen, Jianqing
Via Linking theorem and delicate energy estimates, the existence of nontrivial solutions for a nonlinear PDE with an inverse square potential and critical sobolev exponent is proved. This result gives a partial (positive) answer to an open problem proposed in Ferrero and Gazzola (J. Differential Equations 177 (2001) 494).
NASA Astrophysics Data System (ADS)
Unger, André J. A.
2010-02-01
This work is the first installment in a two-part series, and focuses on the development of a numerical PDE approach to price components of a Bermudan-style callable catastrophe (CAT) bond. The bond is based on two underlying stochastic variables; the PCS index which posts quarterly estimates of industry-wide hurricane losses as well as a single-factor CIR interest rate model for the three-month LIBOR. The aggregate PCS index is analogous to losses claimed under traditional reinsurance in that it is used to specify a reinsurance layer. The proposed CAT bond model contains a Bermudan-style call feature designed to allow the reinsurer to minimize their interest rate risk exposure on making substantial fixed coupon payments using capital from the reinsurance premium. Numerical PDE methods are the fundamental strategy for pricing early-exercise constraints, such as the Bermudan-style call feature, into contingent claim models. Therefore, the objective and unique contribution of this first installment in the two-part series is to develop a formulation and discretization strategy for the proposed CAT bond model utilizing a numerical PDE approach. Object-oriented code design is fundamental to the numerical methods used to aggregate the PCS index, and implement the call feature. Therefore, object-oriented design issues that relate specifically to the development of a numerical PDE approach for the component of the proposed CAT bond model that depends on the PCS index and LIBOR are described here. Formulation, numerical methods and code design issues that relate to aggregating the PCS index and introducing the call option are the subject of the companion paper.
Cameron, M.K.; Fomel, S.B.; Sethian, J.A.
2009-01-01
In the present work we derive and study a nonlinear elliptic PDE coming from the problem of estimation of sound speed inside the Earth. The physical setting of the PDE allows us to pose only a Cauchy problem, and hence is ill-posed. However we are still able to solve it numerically on a long enough time interval to be of practical use. We used two approaches. The first approach is a finite difference time-marching numerical scheme inspired by the Lax-Friedrichs method. The key features of this scheme is the Lax-Friedrichs averaging and the wide stencil in space. The second approach is a spectral Chebyshev method with truncated series. We show that our schemes work because of (1) the special input corresponding to a positive finite seismic velocity, (2) special initial conditions corresponding to the image rays, (3) the fact that our finite-difference scheme contains small error terms which damp the high harmonics; truncation of the Chebyshev series, and (4) the need to compute the solution only for a short interval of time. We test our numerical scheme on a collection of analytic examples and demonstrate a dramatic improvement in accuracy in the estimation of the sound speed inside the Earth in comparison with the conventional Dix inversion. Our test on the Marmousi example confirms the effectiveness of the proposed approach.
Weeratunga, S K; Kamath, C
2001-12-20
Removing noise from data is often the first step in data analysis. Denoising techniques should not only reduce the noise, but do so without blurring or changing the location of the edges. Many approaches have been proposed to accomplish this; in this paper, they focus on one such approach, namely the use of non-linear diffusion operators. This approach has been studied extensively from a theoretical viewpoint ever since the 1987 work of Perona and Malik showed that non-linear filters outperformed the more traditional linear Canny edge detector. They complement this theoretical work by investigating the performance of several isotropic diffusion operators on test images from scientific domains. They explore the effects of various parameters such as the choice of diffusivity function, explicit and implicit methods for the discretization of the PDE, and approaches for the spatial discretization of the non-linear operator etc. They also compare these schemes with simple spatial filters and the more complex wavelet-based shrinkage techniques. The empirical results show that, with an appropriate choice of parameters, diffusion-based schemes can be as effective as competitive techniques.
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.
He's Frequency Formulation for Nonlinear Oscillators
ERIC Educational Resources Information Center
Geng, Lei; Cai, Xu-Chu
2007-01-01
Based on an ancient Chinese algorithm, J H He suggested a simple but effective method to find the frequency of a nonlinear oscillator. In this paper, a modified version is suggested to improve the accuracy of the frequency; two examples are given, revealing that the obtained solutions are of remarkable accuracy and are valid for the whole solution…
Geometric nonlinear formulation for thermal-rigid-flexible coupling system
NASA Astrophysics Data System (ADS)
Fan, Wei; Liu, Jin-Yang
2013-10-01
This paper develops geometric nonlinear hybrid formulation for flexible multibody system with large deformation considering thermal effect. Different from the conventional formulation, the heat flux is the function of the rotational angle and the elastic deformation, therefore, the coupling among the temperature, the large overall motion and the elastic deformation should be taken into account. Firstly, based on nonlinear strain-displacement relationship, variational dynamic equations and heat conduction equations for a flexible beam are derived by using virtual work approach, and then, Lagrange dynamics equations and heat conduction equations of the first kind of the flexible multibody system are obtained by leading into the vectors of Lagrange multiplier associated with kinematic and temperature constraint equations. This formulation is used to simulate the thermal included hub-beam system. Comparison of the response between the coupled system and the uncoupled system has revealed the thermal chattering phenomenon. Then, the key parameters for stability, including the moment of inertia of the central body, the incident angle, the damping ratio and the response time ratio, are analyzed. This formulation is also used to simulate a three-link system applied with heat flux. Comparison of the results obtained by the proposed formulation with those obtained by the approximate nonlinear model and the linear model shows the significance of considering all the nonlinear terms in the strain in case of large deformation. At last, applicability of the approximate nonlinear model and the linear model are clarified in detail.
Geometric nonlinear formulation for thermal-rigid-flexible coupling system
NASA Astrophysics Data System (ADS)
Fan, Wei; Liu, Jin-Yang
2013-09-01
This paper develops geometric nonlinear hybrid formulation for flexible multibody system with large deformation considering thermal effect. Different from the conventional formulation, the heat flux is the function of the rotational angle and the elastic deformation, therefore, the coupling among the temperature, the large overall motion and the elastic deformation should be taken into account. Firstly, based on nonlinear strain-displacement relationship, variational dynamic equations and heat conduction equations for a flexible beam are derived by using virtual work approach, and then, Lagrange dynamics equations and heat conduction equations of the first kind of the flexible multibody system are obtained by leading into the vectors of Lagrange multiplier associated with kinematic and temperature constraint equations. This formulation is used to simulate the thermal included hub-beam system. Comparison of the response between the coupled system and the uncoupled system has revealed the thermal chattering phenomenon. Then, the key parameters for stability, including the moment of inertia of the central body, the incident angle, the damping ratio and the response time ratio, are analyzed. This formulation is also used to simulate a three-link system applied with heat flux. Comparison of the results obtained by the proposed formulation with those obtained by the approximate nonlinear model and the linear model shows the significance of considering all the nonlinear terms in the strain in case of large deformation. At last, applicability of the approximate nonlinear model and the linear model are clarified in detail.
Terascale Optimal PDE Simulations
David Keyes
2009-07-28
The Terascale Optimal PDE Solvers (TOPS) Integrated Software Infrastructure Center (ISIC) was created to develop and implement algorithms and support scientific investigations performed by DOE-sponsored researchers. These simulations often involve the solution of partial differential equations (PDEs) on terascale computers. The TOPS Center researched, developed and deployed an integrated toolkit of open-source, optimal complexity solvers for the nonlinear partial differential equations that arise in many DOE application areas, including fusion, accelerator design, global climate change and reactive chemistry. The algorithms created as part of this project were also designed to reduce current computational bottlenecks by orders of magnitude on terascale computers, enabling scientific simulation on a scale heretofore impossible.
Nonlinear stability of a heterogeneous state in a PDE-ODE model for acid-mediated tumor invasion.
Tao, Youshan; Tello, J Ignacio
2016-02-01
This work studies a general reaction-diffusion model for acid-mediated tumor invasion, where tumor cells produce excess acid that primarily kills healthy cells, and thereby invade the microenvironment. The acid diffuses and could be cleared by vasculature, and the healthy and tumor cells are viewed as two species following logistic growth with mutual competition. A key feature of this model is the density-limited diffusion for tumor cells, reflecting that a healthy tissue will spatially constrain a tumor unless shrunk. Under appropriate assumptions on model parameters and on initial data, it is shown that the unique heterogeneous state is nonlinearly stable, which implies a long-term coexistence of the healthy and tumor cells in certain parameter space. Our theoretical result suggests that acidity may play a significant role in heterogeneous tumor progression. PMID:26776259
Entropic and gradient flow formulations for nonlinear diffusion
NASA Astrophysics Data System (ADS)
Dirr, Nicolas; Stamatakis, Marios; Zimmer, Johannes
2016-08-01
Nonlinear diffusion ∂tρ = Δ(Φ(ρ)) is considered for a class of nonlinearities Φ. It is shown that for suitable choices of Φ, an associated Lyapunov functional can be interpreted as thermodynamic entropy. This information is used to derive an associated metric, here called thermodynamic metric. The analysis is confined to nonlinear diffusion obtainable as hydrodynamic limit of a zero range process. The thermodynamic setting is linked to a large deviation principle for the underlying zero range process and the corresponding equation of fluctuating hydrodynamics. For the latter connections, the thermodynamic metric plays a central role.
Partial differential equation transform — Variational formulation and Fourier analysis
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
Garnier, Josselin; Picozzi, Antonio
2010-03-15
This article presents a unified kinetic formulation of partially coherent nonlinear optical waves propagating in a noninstantaneous response Kerr medium. We derive a kinetic equation that combines the weak Langmuir turbulence kinetic equation and a Vlasov-like equation within a general framework: It describes the evolution of the spectrum of a random field that exhibits a quasistationary statistics in the presence of a noninstantaneous nonlinear response. The kinetic equation sheds new light on the dynamics of partially coherent nonlinear waves and allows for a qualitative interpretation of the interplay between the noninstantaneous nonlinearity and the nonstationary statistics of the incoherent field. It is shown that the incoherent modulational instability of a random nonlinear wave can be suppressed by the noninstantaneous nonlinear response. Moreover, incoherent modulational instability can prevent the generation of spectral incoherent solitons.
On high-continuity transfinite element formulations for linear-nonlinear transient thermal problems
NASA Technical Reports Server (NTRS)
Tamma, Kumar K.; Railkar, Sudhir B.
1987-01-01
This paper describes recent developments in the applicability of a hybrid transfinite element methodology with emphasis on high-continuity formulations for linear/nonlinear transient thermal problems. The proposed concepts furnish accurate temperature distributions and temperature gradients making use of a relatively smaller number of degrees of freedom; and the methodology is applicable to linear/nonlinear thermal problems. Characteristic features of the formulations are described in technical detail as the proposed hybrid approach combines the major advantages and modeling features of high-continuity thermal finite elements in conjunction with transform methods and classical Galerkin schemes. Several numerical test problems are evaluated and the results obtained validate the proposed concepts for linear/nonlinear thermal problems.
Self-consistent linearization of non-linear BEM formulations with quadratic convergence
NASA Astrophysics Data System (ADS)
Fernandes, G. R.; de Souza Neto, E. A.
2013-11-01
In this work, a general technique to obtain the self-consistent linearization of non-linear formulations of the boundary element method (BEM) is presented. In the incremental-iterative procedure required to solve the non-linear problem the convergence is quadratic, being the solution obtained from the consistent tangent operator. This technique is applied to non-linear BEM formulations for plates where two independent problems are discussed: the plate bending and the stretching problem. For both problems an equilibrium equation is written in terms of strains and internal forces and then the consistent tangent operator is derived by applying the Newton-Raphson’s scheme. The Von Mises criterion is adopted to govern the elasto-plastic material behaviour checked at points along the plate thickness, although the presented formulations can be used with any non-linear model. Numerical examples are presented showing the accuracy of the results as well as the high convergence rate of the iterative procedure.
SEACAS Theory Manuals: Part 1. Problem Formulation in Nonlinear Solid Mechancis
Attaway, S.W.; Laursen, T.A.; Zadoks, R.I.
1998-08-01
This report gives an introduction to the basic concepts and principles involved in the formulation of nonlinear problems in solid mechanics. By way of motivation, the discussion begins with a survey of some of the important sources of nonlinearity in solid mechanics applications, using wherever possible simple one dimensional idealizations to demonstrate the physical concepts. This discussion is then generalized by presenting generic statements of initial/boundary value problems in solid mechanics, using linear elasticity as a template and encompassing such ideas as strong and weak forms of boundary value problems, boundary and initial conditions, and dynamic and quasistatic idealizations. The notational framework used for the linearized problem is then extended to account for finite deformation of possibly inelastic solids, providing the context for the descriptions of nonlinear continuum mechanics, constitutive modeling, and finite element technology given in three companion reports.
A Green's function formulation for a nonlinear potential flow solution applicable to transonic flow
NASA Technical Reports Server (NTRS)
Baker, A. J.; Fox, C. H., Jr.
1977-01-01
Routine determination of inviscid subsonic flow fields about wing-body-tail configurations employing a Green's function approach for numerical solution of the perturbation velocity potential equation is successfully extended into the high subsonic subcritical flow regime and into the shock-free supersonic flow regime. A modified Green's function formulation, valid throughout a range of Mach numbers including transonic, that takes an explicit accounting of the intrinsic nonlinearity in the parent governing partial differential equations is developed. Some considerations pertinent to flow field predictions in the transonic flow regime are discussed.
CAD of control systems: Application of nonlinear programming to a linear quadratic formulation
NASA Technical Reports Server (NTRS)
Fleming, P.
1983-01-01
The familiar suboptimal regulator design approach is recast as a constrained optimization problem and incorporated in a Computer Aided Design (CAD) package where both design objective and constraints are quadratic cost functions. This formulation permits the separate consideration of, for example, model following errors, sensitivity measures and control energy as objectives to be minimized or limits to be observed. Efficient techniques for computing the interrelated cost functions and their gradients are utilized in conjunction with a nonlinear programming algorithm. The effectiveness of the approach and the degree of insight into the problem which it affords is illustrated in a helicopter regulation design example.
Nonlinear aspects of high heat flux nucleate boiling heat transfer. Part 1, Formulation
Sadasivan, P.; Unal, C.; Nelson, R.
1994-04-01
This paper outlines the essential details of the formulation and numerical implementation of a model used to study nonlinear aspects of the macrolayer-controlled heat transfer process associated with high heat flux nucleate boiling and the critical heat flux. The model addresses the three-dimensional transient conduction heat transfer process within the problem domain comprised of the macrolayer and heater. Heat dissipation from the heater is modeled as the sum of transient transport into the macrolayer, and the heat loss resulting from evaporation of menisci associated with vapor stems.
Modified Eulerian-Lagrangian formulation for hydrodynamic modeling
NASA Astrophysics Data System (ADS)
Sorek, Shaul; Borisov, Vyacheslav
2012-04-01
We present the modified Eulerian-Lagrangian (MEL) formulation, based on non-divergent forms of partial differential balance equations, for simulating transport of extensive quantities in a porous medium. Hydrodynamic derivatives are written in terms of modified velocities for particles propagating phase and component quantities along their respective paths. The particles physically interpreted velocities also address the heterogeneity of the matrix and fluid properties. The MEL formulation is also implemented to parabolic Partial Differential Equations (PDE's) as these are shown to be interchangeable with equivalent PDE's having hyperbolic - parabolic characteristics, without violating the same physical concepts. We prove that the MEL schemes provide a convergent and monotone approximation also to PDE's with discontinuous coefficients. An extension to the Peclet number is presented that also accounts for advective dominant PDE's with no reference to the fluid velocity or even when this velocity is not introduced. In Sorek et al. [27], a mathematical analysis for a linear system of coupled PDE's and an example of nonlinear PDE's, proved that the finite difference MEL, unlike an Eulerian scheme, guaranties the absence of spurious oscillations. Currently, we present notions of monotone interpolation associated with the MEL particle tracking procedure and prove the convergence of the MEL schemes to the original balance equation also for discontinuous coefficients on the basis of difference schemes approximating PDE's. We provide numerical examples, also with highly random fields of permeabilities and/or dispersivities, suggesting that the MEL scheme produces resolutions that are more consistent with the physical phenomenon in comparison to the Eulerian and the Eulerian-Lagrangian (EL) schemes.
NASA Technical Reports Server (NTRS)
Barut, A.; Madenci, Erdogan; Tessler, A.
1997-01-01
This study presents a transient nonlinear finite element analysis within the realm of a multi-body dynamics formulation for determining the dynamic response of a moderately thick laminated shell undergoing a rapid and large rotational motion and nonlinear elastic deformations. Nonlinear strain measure and rotation, as well as 'the transverse shear deformation, are explicitly included in the formulation in order to capture the proper motion-induced stiffness of the laminate. The equations of motion are derived from the virtual work principle. The analysis utilizes a shear deformable shallow shell element along with the co-rotational form of the updated Lagrangian formulation. The shallow shell element formulation is based on the Reissner-Mindlin and Marguerre theory.
A survey of the core-congruential formulation for geometrically nonlinear TL finite elements
NASA Technical Reports Server (NTRS)
Felippa, Carlos A.; Crivelli, Luis A.; Haugen, Bjorn
1994-01-01
This article presents a survey of the core-congruential formulation (CCF) for geometrically nonlinear mechanical finite elements based on the total Lagrangian (TL) kinematic description. Although the key ideas behind the CCF can be traced back to Rajasekaran and Murray in 1973, it has not subsequently received serious attention. The CCF is distinguished by a two-phase development of the finite element stiffness equations. The initial phase developed equations for individual particles. These equations are expressed in terms of displacement gradients as degrees of freedom. The second phase involves congruential-type transformations that eventually binds the element particles of an individual element in terms of its node-displacement degrees of freedom. Two versions of the CCF, labeled direct and generalized, are distinguished. The direct CCF (DCCF) is first described in general form and then applied to the derivation of geometrically nonlinear bar, and plane stress elements using the Green-Lagrange strain measure. The more complex generalized CCF (GCCF) is described and applied to the derivation of 2D and 3D Timoshenko beam elements. Several advantages of the CCF, notably the physically clean separation of material and geometric stiffnesses, and its independence with respect to the ultimate choice of shape functions and element degrees of freedom, are noted. Application examples involving very large motions solved with the 3D beam element display the range of applicability of this formulation, which transcends the kinematic limitations commonly attributed to the TL description.
NASA Astrophysics Data System (ADS)
Soyarslan, C.; Bargmann, S.
2016-06-01
In this paper, we present a thermomechanical framework which makes use of the internal variable theory of thermodynamics for damage-coupled finite viscoplasticity with nonlinear isotropic hardening. Damage evolution, being an irreversible process, generates heat. In addition to its direct effect on material's strength and stiffness, it causes deterioration of the heat conduction. The formulation, following the footsteps of Simó and Miehe (1992), introduces inelastic entropy as an additional state variable. Given a temperature dependent damage dissipation potential, we show that the evolution of inelastic entropy assumes a split form relating to plastic and damage parts, respectively. The solution of the thermomechanical problem is based on the so-called isothermal split. This allows the use of the model in 2D and 3D example problems involving geometrical imperfection triggered necking in an axisymmetric bar and thermally triggered necking of a 3D rectangular bar.
A three-dimensional nonlinear Timoshenko beam based on the core-congruential formulation
NASA Technical Reports Server (NTRS)
Crivelli, Luis A.; Felippa, Carlos A.
1992-01-01
A three-dimensional, geometrically nonlinear two-node Timoshenkoo beam element based on the total Larangrian description is derived. The element behavior is assumed to be linear elastic, but no restrictions are placed on magnitude of finite rotations. The resulting element has twelve degrees of freedom: six translational components and six rotational-vector components. The formulation uses the Green-Lagrange strains and second Piola-Kirchhoff stresses as energy-conjugate variables and accounts for the bending-stretching and bending-torsional coupling effects without special provisions. The core-congruential formulation (CCF) is used to derived the discrete equations in a staged manner. Core equations involving the internal force vector and tangent stiffness matrix are developed at the particle level. A sequence of matrix transformations carries these equations to beam cross-sections and finally to the element nodal degrees of freedom. The choice of finite rotation measure is made in the next-to-last transformation stage, and the choice of over-the-element interpolation in the last one. The tangent stiffness matrix is found to retain symmetry if the rotational vector is chosen to measure finite rotations. An extensive set of numerical examples is presented to test and validate the present element.
NASA Technical Reports Server (NTRS)
Ungsuwarungsri, T.; Knauss, W. G.
1988-01-01
A numerical method is developed for the determinations of the equilibrium shape of a craze in an infinite elastic plane whose fibrils exhibit very general nonlinear force-displacement behavior. The problem formulation is based on the superposition of the relevant elasticity Green's function; the solution of the resulting nonlinear problem is obtained by using Picard's successive approximation scheme. The model is used to investigate the effect of nonlinear fibril behavior on the mechanics of craze and crack growth, and the results are compared with the Dugdale model.
Evaluation of nonlinear structural dynamic responses using a fast-running spring-mass formulation
Benjamin, A.S.; Altman, B.S.; Gruda, J.D.
1995-03-01
In today`s world, accurate finite-element simulations of large nonlinear systems may require meshes composed of hundreds of thousands of degrees of freedom. Even with today`s fast computers and the promise of ever-faster ones in the future, central processing unit (CPU) expenditures for such problems could be measured in days. Many contemporary engineering problems, such as those found in risk assessment, probabilistic structural analysis, and structural design optimization, cannot tolerate the cost or turnaround time for such CPU-intensive analyses, because these applications require a large number of cases to be run with different inputs. For many risk assessment applications, analysts would prefer running times to be measurable in minutes. There is therefore a need for approximation methods which can solve such problems far more efficiently than the very detailed methods and yet maintain an acceptable degree of accuracy. For this purpose, we have been working on two methods of approximation: neural networks and spring-mass models. This paper presents our work and results to date for spring-mass modeling and analysis, since we are further along in this area than in the neural network formulation. It describes the physical and numerical models contained in a code we developed called STRESS, which stands for ``Spring-mass Transient Response Evaluation for structural Systems``. The paper also presents results for a demonstration problem, and compares these with results obtained for the same problem using PRONTO3D, a state-of-the-art finite element code which was also developed at Sandia.
NASA Astrophysics Data System (ADS)
Choudhury, Raja Roy; Choudhury, Arundhati Roy; Ghose, Mrinal Kanti
2013-09-01
To characterize nonlinear optical fiber, a semi-analytical formulation using variational principle and the Nelder-Mead Simplex method for nonlinear unconstrained minimization is proposed. The number of optimizing parameters in order to optimize core parameter U has been increased to incorporate more flexibility in the formulation of an innovative form of fundamental modal field. This formulation provides accurate analytical expressions for modal dispersion parameter (g) of optical fiber with Kerr nonlinearity. The minimization of core parameter (U), which involves Kerr nonlinearity through the nonstationary expression of propagation constant, is carried out by the Nelder-Mead Simplex method of nonlinear unconstrained minimization, suitable for problems with nonsmooth functions as the method does not require any derivative information. This formulation has less computational burden for calculation of modal parameters than full numerical methods.
Cheng, Kung-Shan; Dewhirst, Mark W.; Stauffer, Paul F.; Das, Shiva
2010-01-01
Purpose: A nonlinear system reconstruction can theoretically provide timely system reconstruction when designing a real-time image-guided adaptive control for multisource heating for hyperthermia. This clinical need motivates an analysis of the essential mathematical characteristics and constraints of such an approach. Methods: The implicit function theorem (IFT), the Karush–Kuhn–Tucker (KKT) necessary condition of optimality, and the Tikhonov–Phillips regularization (TPR) were used to analyze and determine the requirements of the optimal system reconstruction. Two mutually exclusive generic approaches were analyzed to reconstruct the physical system: The traditional full reconstruction and the recently suggested partial reconstruction. Rigorous mathematical analysis based on IFT, KKT, and TPR was provided for all four possible nonlinear reconstructions: (1) Nonlinear noiseless full reconstruction, (2) nonlinear noisy full reconstruction, (3) nonlinear noiseless partial reconstruction, and (4) nonlinear noisy partial reconstruction, when a class of nonlinear formulations of system reconstruction is employed. Results: Effective numerical algorithms for solving each of the aforementioned four nonlinear reconstructions were introduced and formal derivations and analyses were provided. The analyses revealed the necessity of adding regularization when partial reconstruction is used. Regularization provides the theoretical support for one to uniquely reconstruct the optimal system. It also helps alleviate the negative influences of unavoidable measurement noise. Both theoretical analysis and numerical examples showed the importance of having a good initial guess for accomplishing nonlinear system reconstruction. Conclusions: Regularization is mandatory for partial reconstruction to make it well posed. The Tikhonov–Phillips regularized Gauss–Newton algorithm has nice theoretical performance for partial reconstruction of systems with and without noise. The
Formulation of the linear model from the nonlinear simulation for the F18 HARV
NASA Technical Reports Server (NTRS)
Hall, Charles E., Jr.
1991-01-01
The F-18 HARV is a modified F-18 Aircraft which is capable of flying in the post-stall regime in order to achieve superagility. The onset of aerodynamic stall, and continued into the post-stall region, is characterized by nonlinearities in the aerodynamic coefficients. These aerodynamic coefficients are not expressed as analytic functions, but rather in the form of tabular data. The nonlinearities in the aerodynamic coefficients yield a nonlinear model of the aircraft's dynamics. Nonlinear system theory has made many advances, but this area is not sufficiently developed to allow its application to this problem, since many of the theorems are existance theorems and that the systems are composed of analytic functions. Thus, the feedback matrices and the state estimators are obtained from linear system theory techniques. It is important, in order to obtain the correct feedback matrices and state estimators, that the linear description of the nonlinear flight dynamics be as accurate as possible. A nonlinear simulation is run under the Advanced Continuous Simulation Language (ACSL). The ACSL simulation uses FORTRAN subroutines to interface to the look-up tables for the aerodynamic data. ACSL has commands to form the linear representation for the system. Other aspects of this investigation are discussed.
Townsend, Molly T; Sarigul-Klijn, Nesrin
2016-01-01
Simplified material models are commonly used in computational simulation of biological soft tissue as an approximation of the complicated material response and to minimize computational resources. However, the simulation of complex loadings, such as long-duration tissue swelling, necessitates complex models that are not easy to formulate. This paper strives to offer the updated Lagrangian formulation comprehensive procedure of various non-linear material models for the application of finite element analysis of biological soft tissues including a definition of the Cauchy stress and the spatial tangential stiffness. The relationships between water content, osmotic pressure, ionic concentration and the pore pressure stress of the tissue are discussed with the merits of these models and their applications. PMID:26611112
NASA Astrophysics Data System (ADS)
Zeevaert, A. E.
1980-03-01
A mathematical formulation to model the behavior under load of a reinforced soil system, where a fabric is placed over a soft soil and covered with stone for use as a temporary haul road is discussed. This approach is used to improve the behavior of temporary roadways, particularly where very soft soils are encountered. The stress distribution and the load-deformation characteristics of the soil-fabric system for varying geometries and material properties are defined. Included in the mathematical formulation are such features as: nonlinear behavior of the soil and fabric materials, friction parameters of the interface, tension characteristics of the fabric materials, large displacements in finite deformation, "no tension" conditions of the cohesionless materials, and yielding of plastic materials. The mathematical model is a more complete approximation of the actual fabric-soil system than is presently available.
NASA Technical Reports Server (NTRS)
Fleming, P.
1985-01-01
A design technique is proposed for linear regulators in which a feedback controller of fixed structure is chosen to minimize an integral quadratic objective function subject to the satisfaction of integral quadratic constraint functions. Application of a non-linear programming algorithm to this mathematically tractable formulation results in an efficient and useful computer-aided design tool. Particular attention is paid to computational efficiency and various recommendations are made. Two design examples illustrate the flexibility of the approach and highlight the special insight afforded to the designer.
NASA Astrophysics Data System (ADS)
Calef, Matthew T.; Fichtl, Erin D.; Warsa, James S.; Berndt, Markus; Carlson, Neil N.
2013-04-01
We compare a variant of Anderson Mixing with the Jacobian-Free Newton-Krylov and Broyden methods applied to an instance of the k-eigenvalue formulation of the linear Boltzmann transport equation. We present evidence that one variant of Anderson Mixing finds solutions in the fewest number of iterations. We examine and strengthen theoretical results of Anderson Mixing applied to linear problems.
Nonlinear bend stiffener analysis using a simple formulation and finite element method
NASA Astrophysics Data System (ADS)
Tong, Dong Jin; Low, Ying Min; Sheehan, John M.
2011-12-01
Flexible marine risers are commonly used in deepwater floating systems. Bend stiffeners are designed to protect flexible risers against excessive bending at the connection with the hull. The structure is usually analyzed as a cantilever beam subjected to an inclined point load. As deflections are large and the bend stiffener material exhibits nonlinear stress-strain characteristics, geometric and material nonlinearities are important considerations. A new approach has been developed to solve this nonlinear problem. Its main advantage is its simplicity; in fact the present method can be easily implemented on a spreadsheet. Finite element analysis using ABAQUS is performed to validate the method. Solid elements are used for the bend stiffener and flexible pipe. To simulate the near inextensibility of flexible risers, a simple and original idea of using truss elements is proposed. Through a set of validation studies, the present method is found to be in a good agreement with the finite element analysis. Further, parametric studies are performed by using both methods to identify the key parameters and phenomena that are most critical in design. The most important finding is that the common practice of neglecting the internal steel sleeve in the bend stiffener analysis is non-conservative and therefore needs to be reassessed.
NASA Astrophysics Data System (ADS)
Bidikli, Baris; Tatlicioglu, Enver; Zergeroglu, Erkan; Bayrak, Alper
2016-09-01
In this work, we present a novel continuous robust controller for a class of multi-input/multi-output nonlinear systems that contains unstructured uncertainties in their drift vectors and input matrices. The proposed controller compensates uncertainties in the system dynamics and achieves asymptotic tracking while requiring only the knowledge of the sign of the leading principal minors of the input gain matrix. A Lyapunov-based argument backed up with an integral inequality is applied to prove the asymptotic stability of the closed-loop system. Simulation results are presented to illustrate the viability of the proposed method.
A stabilized complementarity formulation for nonlinear analysis of 3D bimodular materials
NASA Astrophysics Data System (ADS)
Zhang, L.; Zhang, H. W.; Wu, J.; Yan, B.
2016-06-01
Bi-modulus materials with different mechanical responses in tension and compression are often found in civil, composite, and biological engineering. Numerical analysis of bimodular materials is strongly nonlinear and convergence is usually a problem for traditional iterative schemes. This paper aims to develop a stabilized computational method for nonlinear analysis of 3D bimodular materials. Based on the parametric variational principle, a unified constitutive equation of 3D bimodular materials is proposed, which allows the eight principal stress states to be indicated by three parametric variables introduced in the principal stress directions. The original problem is transformed into a standard linear complementarity problem (LCP) by the parametric virtual work principle and a quadratic programming algorithm is developed by solving the LCP with the classic Lemke's algorithm. Update of elasticity and stiffness matrices is avoided and, thus, the proposed algorithm shows an excellent convergence behavior compared with traditional iterative schemes. Numerical examples show that the proposed method is valid and can accurately analyze mechanical responses of 3D bimodular materials. Also, stability of the algorithm is greatly improved.
A stabilized complementarity formulation for nonlinear analysis of 3D bimodular materials
NASA Astrophysics Data System (ADS)
Zhang, L.; Zhang, H. W.; Wu, J.; Yan, B.
2015-10-01
Bi-modulus materials with different mechanical responses in tension and compression are often found in civil, composite, and biological engineering. Numerical analysis of bimodular materials is strongly nonlinear and convergence is usually a problem for traditional iterative schemes. This paper aims to develop a stabilized computational method for nonlinear analysis of 3D bimodular materials. Based on the parametric variational principle, a unified constitutive equation of 3D bimodular materials is proposed, which allows the eight principal stress states to be indicated by three parametric variables introduced in the principal stress directions. The original problem is transformed into a standard linear complementarity problem (LCP) by the parametric virtual work principle and a quadratic programming algorithm is developed by solving the LCP with the classic Lemke's algorithm. Update of elasticity and stiffness matrices is avoided and, thus, the proposed algorithm shows an excellent convergence behavior compared with traditional iterative schemes. Numerical examples show that the proposed method is valid and can accurately analyze mechanical responses of 3D bimodular materials. Also, stability of the algorithm is greatly improved.
NASA Astrophysics Data System (ADS)
Yin, Sisi; Nishi, Tatsushi
2014-11-01
Quantity discount policy is decision-making for trade-off prices between suppliers and manufacturers while production is changeable due to demand fluctuations in a real market. In this paper, quantity discount models which consider selection of contract suppliers, production quantity and inventory simultaneously are addressed. The supply chain planning problem with quantity discounts under demand uncertainty is formulated as a mixed-integer nonlinear programming problem (MINLP) with integral terms. We apply an outer-approximation method to solve MINLP problems. In order to improve the efficiency of the proposed method, the problem is reformulated as a stochastic model replacing the integral terms by using a normalisation technique. We present numerical examples to demonstrate the efficiency of the proposed method.
NASA Astrophysics Data System (ADS)
Ramadan, Omar
2015-09-01
In this paper, systematic wave-equation finite difference time domain (WE-FDTD) formulations are presented for modeling electromagnetic wave-propagation in linear and nonlinear dispersive materials. In the proposed formulations, the complex conjugate pole residue (CCPR) pairs model is adopted in deriving a unified dispersive WE-FDTD algorithm that allows modeling different dispersive materials, such as Debye, Drude and Lorentz, in the same manner with the minimal additional auxiliary variables. Moreover, the proposed formulations are incorporated with the wave-equation perfectly matched layer (WE-PML) to construct a material independent mesh truncating technique that can be used for modeling general frequency-dependent open region problems. Several numerical examples involving linear and nonlinear dispersive materials are included to show the validity of the proposed formulations.
NASA Technical Reports Server (NTRS)
Rismantab-Sany, J.; Chang, B.; Shabana, A. A.
1989-01-01
A total Lagrangian finite element formulation for the deformable bodies in multibody mechanical systems that undergo finite relative rotations is developed. The deformable bodies are discretized using finite element methods. The shape functions that are used to describe the displacement field are required to include the rigid body modes that describe only large translational displacements. This does not impose any limitations on the technique because most commonly used shape functions satisfy this requirement. The configuration of an element is defined using four sets of coordinate systems: Body, Element, Intermediate element, Global. The body coordinate system serves as a unique standard for the assembly of the elements forming the deformable body. The element coordinate system is rigidly attached to the element and therefore it translates and rotates with the element. The intermediate element coordinate system, whose axes are initially parallel to the element axes, has an origin which is rigidly attached to the origin of the body coordinate system and is used to conveniently describe the configuration of the element in undeformed state with respect to the body coordinate system.
Demirbas, Didem; Wyman, Arlene R.; Shimizu-Albergine, Masami; Cakici, Ozgur; Beavo, Joseph A.; Hoffman, Charles S.
2013-01-01
A cell-based high-throughput screen (HTS) was developed to detect phosphodiesterase 8 (PDE8) and PDE4/8 combination inhibitors. By replacing the Schizosaccharomyces pombe PDE gene with the murine PDE8A1 gene in strains lacking adenylyl cyclase, we generated strains whose protein kinase A (PKA)-stimulated growth in 5-fluoro orotic acid (5FOA) medium reflects PDE8 activity. From our previously-identified PDE4 and PDE7 inhibitors, we identified a PDE4/8 inhibitor that allowed us to optimize screening conditions. Of 222,711 compounds screened, ∼0.2% displayed composite Z scores of >20. Additional yeast-based assays using the most effective 367 compounds identified 30 candidates for further characterization. Among these, compound BC8-15 displayed the lowest IC50 value for both PDE4 and PDE8 inhibition in in vitro enzyme assays. This compound also displays significant activity against PDE10A and PDE11A. BC8-15 elevates steroidogenesis in mouse Leydig cells as a single pharmacological agent. Assays using BC8-15 and two structural derivatives support a model in which PDE8 is a primary regulator of testosterone production by Leydig cells, with an additional role for PDE4 in this process. BC8-15, BC8-15A, and BC8-15C, which are commercially available compounds, display distinct patterns of activity against PDE4, PDE8, PDE10A, and PDE11A, representing a chemical toolkit that could be used to examine the biological roles of these enzymes in cell culture systems. PMID:23967182
Biomolecular surface construction by PDE transform.
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
Galindo-Tovar, Alejandro; Vargas, María Luisa; Kaumann, Alberto J
2016-02-01
Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial β1- and β2-adrenoceptors despite the high content of sinoatrial cAMP. The function of PDE2 is, however, uncertain. Prostaglandin PGE1 elicits sinoatrial tachycardia through EP receptors, but the control by phosphodiesterases is unknown. We investigated on spontaneously beating right atria of mice the effects of the PDE2 inhibitors Bay 60-7550 and EHNA on basal beating and the tachycardia produced by noradrenaline (3 nM) and PGE1 (1 μM). Bay 60-7550 (1 μM), but not EHNA (10 μM), increased basal sinoatrial beating. EHNA also failed to produce tachycardia in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin (10 μM), remaining inconclusive whether PDE2 reduces basal sinoatrial beating. Rolipram (10 μM) and cilostamide (300 nM) caused moderate tachycardia. The tachycardia evoked by Bay 60-7550 was similar in the absence and presence of rolipram. Noradrenaline elicited stable tachycardia that was not increased by Bay 60-7550. A stable tachycardia caused by PGE1 was not increased by the inhibitors of PDE2, PDE3, and PDE4. Unlike PDE3 and PDE4 which reduce murine basal sinoatrial beating, a possible effect of PDE2 needs further research. The stable tachycardia produced by noradrenaline and PGE1, together with the lack potentiation by the inhibitors of PDE2, PDE3, and PDE4, suggests that cAMP generated at the receptor compartments is hardly hydrolyzed by these phophodiesterases. Evidence from human volunteers is consistent with this proposal. PMID:26531832
Parallels between control PDE's and systems of ODE's
NASA Technical Reports Server (NTRS)
Hunt, L. R.; Villarreal, Ramiro
1988-01-01
System theorists understand that the same mathematical objects which determine controllability for nonlinear control systems of ordinary differential equations (ODEs) also determine hypoellipticity for linear partial differential equations (PDEs). Moreover, almost any study of ODE systems begins with linear systems. It is remarkable that Hormander's paper on hypoellipticity of second order linear p.d.e.'s starts with equations due to Kolmogorov, which are shown to be analogous to the linear PDEs. Eigenvalue placement by state feedback for a controllable linear system can be paralled for a Kolmogorov equation if an appropriate type of feedback is introduced. Results concerning transformations of nonlinear systems to linear systems are similar to results for transforming a linear PDE to a Kolmogorov equation.
Momentum Diffusivity Estimation via PDE-Constrained Optimization
NASA Astrophysics Data System (ADS)
Xu, C.; Ou, Y.; Schuster, E.; Humphreys, D. A.; Walker, M. L.; Casper, T. A.; Meyer, W. H.
2008-11-01
Several experiments around the world have demonstrated that plasma rotation can improve plasma stability and enhance confinement. It has been shown [1] that the critical rotation speed for stabilization is a function of the rotation profile shape, implying a radially distributed stabilizing mechanism. Modeling of the rotational profile dynamics is limited by poor knowledge of the momentum diffusivity coefficient. In this work we use toroidal angular velocity data from experiments where the torque is modulated using neutral beams, and we employ optimization techniques to estimate the momentum diffusivity coefficient for the angular momentum partial differential equation (PDE) that best fits the experimental data. To further investigate the nonlinear dependence of the momentum diffusivity on other physical variables such as temperatures and densities, we introduce techniques from nonlinear regression and machine learning. 6pt [1] A.C. Sontag, et al., Nucl. Fusion 47, 1005 (2007).
Abusnina, Abdurazzag; Keravis, Thérèse; Zhou, Qingwei; Justiniano, Hélène; Lobstein, Annelise; Lugnier, Claire
2015-02-01
Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis by stimulating endothelial cells. Increase in cyclic AMP (cAMP) level inhibits VEGF-induced endothelial cell proliferation and migration. Cyclic nucleotide phosphodiesterases (PDEs), which specifically hydrolyse cyclic nucleotides, are critical in the regulation of this signal transduction. We have previously reported that PDE2 and PDE4 up-regulations in human umbilical vein endothelial cells (HUVECs) are implicated in VEGF-induced angiogenesis and that inhibition of PDE2 and PDE4 activities prevents the development of the in vitro angiogenesis by increasing cAMP level, as well as the in vivo chicken embryo angiogenesis. We have also shown that polyphenols are able to inhibit PDEs. The curcumin having anti-cancer properties, the present study investigated whether PDE2 and PDE4 inhibitors and curcumin could have similar in vivo anti-tumour properties and whether the anti-angiogenic effects of curcumin are mediated by PDEs. Both PDE2/PDE4 inhibitor association and curcumin significantly inhibited in vivo tumour growth in C57BL/6N mice. In vitro, curcumin inhibited basal and VEGF-stimulated HUVEC proliferation and migration and delayed cell cycle progression at G0/G1, similarly to the combination of selective PDE2 and PDE4 inhibitors. cAMP levels in HUVECs were significantly increased by curcumin, similarly to rolipram (PDE4 inhibitor) and BAY-60-550 (PDE2 inhibitor) association, indicating cAMP-PDE inhibitions. Moreover, curcumin was able to inhibit VEGF-induced cAMP-PDE activity without acting on cGMP-PDE activity and to modulate PDE2 and PDE4 expressions in HUVECs. The present results suggest that curcumin exerts its in vitro anti-angiogenic and in vivo anti-tumour properties through combined PDE2 and PDE4 inhibition. PMID:25230992
Spillover, nonlinearity, and flexible structures
NASA Technical Reports Server (NTRS)
Bass, Robert W.; Zes, Dean
1991-01-01
Many systems whose evolution in time is governed by Partial Differential Equations (PDEs) are linearized around a known equilibrium before Computer Aided Control Engineering (CACE) is considered. In this case, there are infinitely many independent vibrational modes, and it is intuitively evident on physical grounds that infinitely many actuators would be needed in order to control all modes. A more precise, general formulation of this grave difficulty (spillover problem) is due to A.V. Balakrishnan. A possible route to circumvention of this difficulty lies in leaving the PDE in its original nonlinear form, and adding the essentially finite dimensional control action prior to linearization. One possibly applicable technique is the Liapunov Schmidt rigorous reduction of singular infinite dimensional implicit function problems to finite dimensional implicit function problems. Omitting details of Banach space rigor, the formalities of this approach are given.
PDE-10A inhibitors as insulin secretagogues.
Cantin, Louis-David; Magnuson, Steven; Gunn, David; Barucci, Nicole; Breuhaus, Marina; Bullock, William H; Burke, Jennifer; Claus, Thomas H; Daly, Michelle; Decarr, Lynn; Gore-Willse, Ann; Hoover-Litty, Helana; Kumarasinghe, Ellalahewage S; Li, Yaxin; Liang, Sidney X; Livingston, James N; Lowinger, Timothy; Macdougall, Margit; Ogutu, Herbert O; Olague, Alan; Ott-Morgan, Ronda; Schoenleber, Robert W; Tersteegen, Adrian; Wickens, Philip; Zhang, Zhonghua; Zhu, Jian; Zhu, Lei; Sweet, Laurel J
2007-05-15
Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured. PMID:17400452
Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases.
Abbott-Banner, Katharine H; Page, Clive P
2014-05-01
Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti-inflammatory (PDE4) and bifunctional bronchodilator/anti-inflammatory (PDE3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose-limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE4 inhibitor, the orally active roflumilast-n-oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non-selective for either PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with subtype specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE3 or PDE4 alone, given the potential positive interactions with regard to anti-inflammatory and bronchodilator effects that have been observed pre-clinically with dual inhibition of PDE3 and PDE4 compared with inhibition of either isozyme alone. This MiniReview will summarize recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis. PMID:24517491
NASA Technical Reports Server (NTRS)
Graf, Wiley E.
1991-01-01
A mixed formulation is chosen to overcome deficiencies of the standard displacement-based shell model. Element development is traced from the incremental variational principle on through to the final set of equilibrium equations. Particular attention is paid to developing specific guidelines for selecting the optimal set of strain parameters. A discussion of constraint index concepts and their predictive capability related to locking is included. Performance characteristics of the elements are assessed in a wide variety of linear and nonlinear plate/shell problems. Despite limiting the study to geometric nonlinear analysis, a substantial amount of additional insight concerning the finite element modeling of thin plate/shell structures is provided. For example, in nonlinear analysis, given the same mesh and load step size, mixed elements converge in fewer iterations than equivalent displacement-based models. It is also demonstrated that, in mixed formulations, lower order elements are preferred. Additionally, meshes used to obtain accurate linear solutions do not necessarily converge to the correct nonlinear solution. Finally, a new form of locking was identified associated with employing elements designed for biaxial bending in uniaxial bending applications.
Erdogan, S; Houslay, M D
1997-01-01
The cAMP phosphodiesterase (PDE) 3 and PDE4 isoforms provide the major cAMP-hydrolysing PDE activities in Jurkat T-cells, with additional contributions from the PDE1 and PDE2 isoforms. Challenge of cells with the adenylate cyclase activator forskolin led to a rapid, albeit transient, increase in PDE3 activity occurring over the first 45 min, followed by a sustained increase in PDE3 activity which began after approximately 3 h and continued for at least 24 h. Only this second phase of increase in PDE3 activity was blocked by the transcriptional inhibitor actinomycin D. After approximately 3 h of exposure to forskolin, PDE4 activity had increased, via a process that could be inhibited by actinomycin D, and it remained elevated for at least a 24 h period. Such actions of forskolin were mimicked by cholera toxin and 8-bromo-cAMP. Forskolin increased intracellular cAMP concentrations in a time-dependent fashion and its action was enhanced when PDE induction was blocked with actinomycin D. Reverse transcription (RT)-PCR analysis, using generic primers designed to detect transcripts representing enzymically active products of the four PDE4 genes, identified transcripts for PDE4A and PDE4D but not for PDE4B or PDE4C in untreated Jurkat T-cells. Forskolin treatment did not induce transcripts for either PDE4B or PDE4C; however, it reduced the RT-PCR signal for PDE4A transcripts and markedly enhanced that for PDE4D transcripts. Using RT-PCR primers for PDE4 splice variants, a weak signal for PDE4D1 was evident in control cells whereas, in forskolin-treated cells, clear signals for both PDE4D1 and PDE4D2 were detected. RT-PCR analysis of the PDE4A species indicated that it was not the PDE4A isoform PDE-46 (PDE4A4B). Immunoblotting of control cells for PDE4 forms identified a single PDE4A species of approximately 118 kDa, which migrated distinctly from the PDE4A4B isoform PDE-46, with immunoprecipitation analyses showing that it provided all of the PDE4 activity in control
NASA Astrophysics Data System (ADS)
Krak, Michael D.; Dreyer, Jason T.; Singh, Rajendra
2016-03-01
A vehicle clutch damper is intentionally designed to contain multiple discontinuous non-linearities, such as multi-staged springs, clearances, pre-loads, and multi-staged friction elements. The main purpose of this practical torsional device is to transmit a wide range of torque while isolating torsional vibration between an engine and transmission. Improved understanding of the dynamic behavior of the device could be facilitated by laboratory measurement, and thus a refined vibratory experiment is proposed. The experiment is conceptually described as a single degree of freedom non-linear torsional system that is excited by an external step torque. The single torsional inertia (consisting of a shaft and torsion arm) is coupled to ground through parallel production clutch dampers, which are characterized by quasi-static measurements provided by the manufacturer. Other experimental objectives address physical dimensions, system actuation, flexural modes, instrumentation, and signal processing issues. Typical measurements show that the step response of the device is characterized by three distinct non-linear regimes (double-sided impact, single-sided impact, and no-impact). Each regime is directly related to the non-linear features of the device and can be described by peak angular acceleration values. Predictions of a simplified single degree of freedom non-linear model verify that the experiment performs well and as designed. Accordingly, the benchmark measurements could be utilized to validate non-linear models and simulation codes, as well as characterize dynamic parameters of the device including its dissipative properties.
Moment equations for a piecewise deterministic PDE
NASA Astrophysics Data System (ADS)
Bressloff, Paul C.; Lawley, Sean D.
2015-03-01
We analyze a piecewise deterministic PDE consisting of the diffusion equation on a finite interval Ω with randomly switching boundary conditions and diffusion coefficient. We proceed by spatially discretizing the diffusion equation using finite differences and constructing the Chapman-Kolmogorov (CK) equation for the resulting finite-dimensional stochastic hybrid system. We show how the CK equation can be used to generate a hierarchy of equations for the r-th moments of the stochastic field, which take the form of r-dimensional parabolic PDEs on {{Ω }r} that couple to lower order moments at the boundaries. We explicitly solve the first and second order moment equations (r = 2). We then describe how the r-th moment of the stochastic PDE can be interpreted in terms of the splitting probability that r non-interacting Brownian particles all exit at the same boundary; although the particles are non-interacting, statistical correlations arise due to the fact that they all move in the same randomly switching environment. Hence the stochastic diffusion equation describes two levels of randomness: Brownian motion at the individual particle level and a randomly switching environment. Finally, in the limit of fast switching, we use a quasi-steady state approximation to reduce the piecewise deterministic PDE to an SPDE with multiplicative Gaussian noise in the bulk and a stochastically-driven boundary.
Assessing the emetic potential of PDE4 inhibitors in rats.
Robichaud, A; Savoie, C; Stamatiou, P B; Lachance, N; Jolicoeur, P; Rasori, R; Chan, C C
2002-01-01
1. Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha(2)-adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors. 2. Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg kg(-1), i.m.) and ketamine (10 mg kg(-1), i.m.). PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline) - PDE4 inhibitor: 0.01 - 3 mg kg(-1)), like MK-912 (alpha(2)-adrenoceptor antagonist: 0.01 - 3 mg kg(-1)), dose-dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1 - 10 mg kg(-1)). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors. 3. Neither MK-912 (3 mg kg(-1)) nor PMNPQ (0.1 - 1 mg kg(-1)) altered the duration of anaesthesia induced via a non-alpha(2)-adrenoceptor pathway (sodium pentobarbitone 50 mg kg(-1), i.p.). 4. Central NK(1) receptors are involved in PDE4 inhibitor-induced emesis. Consistently, [sar(9), Met(O(2))(11)]-substance P (NK(1) receptor agonist, 6 microg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. 5. In summary, this model is functionally coupled to PDE4, specific to alpha(2)-adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats. PMID:11786486
Chen, Zheng; Jagannathan, Sarangapani
2008-01-01
In this paper, we consider the use of nonlinear networks towards obtaining nearly optimal solutions to the control of nonlinear discrete-time (DT) systems. The method is based on least squares successive approximation solution of the generalized Hamilton-Jacobi-Bellman (GHJB) equation which appears in optimization problems. Successive approximation using the GHJB has not been applied for nonlinear DT systems. The proposed recursive method solves the GHJB equation in DT on a well-defined region of attraction. The definition of GHJB, pre-Hamiltonian function, HJB equation, and method of updating the control function for the affine nonlinear DT systems under small perturbation assumption are proposed. A neural network (NN) is used to approximate the GHJB solution. It is shown that the result is a closed-loop control based on an NN that has been tuned a priori in offline mode. Numerical examples show that, for the linear DT system, the updated control laws will converge to the optimal control, and for nonlinear DT systems, the updated control laws will converge to the suboptimal control. PMID:18269941
Mehraeen, Shahab; Dierks, Travis; Jagannathan, S; Crow, Mariesa L
2013-12-01
In this paper, the nearly optimal solution for discrete-time (DT) affine nonlinear control systems in the presence of partially unknown internal system dynamics and disturbances is considered. The approach is based on successive approximate solution of the Hamilton-Jacobi-Isaacs (HJI) equation, which appears in optimal control. Successive approximation approach for updating control and disturbance inputs for DT nonlinear affine systems are proposed. Moreover, sufficient conditions for the convergence of the approximate HJI solution to the saddle point are derived, and an iterative approach to approximate the HJI equation using a neural network (NN) is presented. Then, the requirement of full knowledge of the internal dynamics of the nonlinear DT system is relaxed by using a second NN online approximator. The result is a closed-loop optimal NN controller via offline learning. A numerical example is provided illustrating the effectiveness of the approach. PMID:24273142
NASA Astrophysics Data System (ADS)
Dantu, Subbarao; Uma, R.
2000-10-01
The nonlinear Schrodinger equation in cylindrical geometry with saturating nonlinearity like the ponderomotive or relativistic nonlinearity in a plasma is analysed with the help of Symmetry Group Analysis. The symmetry group of the equation is deduced and a fiber-preserving subgroup of linear transformations are identified that leave such a nonlinear Schrodinger equation invariant. The MACSYMA-based Lie algebra of the symmetry group is realized to the extent possible. The theory results in an ordinary differential equation apart from a dictated beam profile. The resulting ordinary differential equation for self-focusing is compared with similar equations obtained from other existing theories of self-focusing in cylindrical geometry like the modified paraxial theory based on harmonic-oscillator basis, the moments theory and the variational theory . New types of solutions are identified and the limitations of the different methods are indicated.Acknowledgements: Financial assistance of CSIR(India)(Research Project,03(0815)/97/ EMR-II) for this work is acknowledged.
[Progress in PDE4 targeted therapy for inflammatory diseases].
Song, Shun-de; Tang, Hui-fang
2014-05-01
cAMP-specific phosphodiesterase type 4 (PDE4) is one of the hot targets for treatment of inflammatory diseases. PDE4 inhibitors can suppress inflammation by increasing the concentration of cAMP in inflammatory cells. The efficacy and safety evaluations of several PDE4 inhibitors are currently carried on in clinical trials, for example GSK256066 in asthma, roflumilast and GSK256066 in chronic obstructive pulmonary disease, tetomilast in inflammatory bowel disease, and apremilast in dermatitis and arthritis etc. This article reviews the recent progress on PDE4-targeted therapy for inflammatory diseases. PMID:24998661
Vang, Amanda G.; Basole, Chaitali; Dong, Hongli; Nguyen, Rebecca K.; Housley, William; Guernsey, Linda; Adami, Alexander J.; Thrall, Roger S.; Clark, Robert B.; Epstein, Paul M.; Brocke, Stefan
2016-01-01
Abolishing the inhibitory signal of intracellular cAMP is a prerequisite for effector T (Teff) cell function. The regulation of cAMP within leukocytes critically depends on its degradation by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE8A, a PDE isoform with 40–100-fold greater affinity for cAMP than PDE4, is selectively expressed in Teff vs. regulatory T (Treg) cells and controls CD4+ Teff cell adhesion and chemotaxis. Here, we determined PDE8A expression and function in CD4+ Teff cell populations in vivo. Using magnetic bead separation to purify leukocyte populations from the lung draining hilar lymph node (HLN) in a mouse model of ovalbumin-induced allergic airway disease (AAD), we found by Western immunoblot and quantitative (q)RT-PCR that PDE8A protein and gene expression are enhanced in the CD4+ T cell fraction over the course of the acute inflammatory disease and recede at the late tolerant non-inflammatory stage. To evaluate PDE8A as a potential drug target, we compared the selective and combined effects of the recently characterized highly potent PDE8-selective inhibitor PF-04957325 with the PDE4-selective inhibitor piclamilast (PICL). As previously shown, PF-04957325 suppresses T cell adhesion to endothelial cells. In contrast, we found that PICL alone increased firm T cell adhesion to endothelial cells by ~20% and significantly abrogated the inhibitory effect of PF-04957325 on T cell adhesion by over 50% when cells were co-exposed to PICL and PF-04957325. Despite its robust effect on T cell adhesion, PF-04957325 was over two orders of magnitude less efficient than PICL in suppressing polyclonal Teff cell proliferation, and showed no effect on cytokine gene expression in these cells. More importantly, PDE8 inhibition did not suppress proliferation and cytokine production of myelin-antigen reactive proinflammatory Teff cells in vivo and in vitro. Thus, targeting PDE8 through PF-04957325 selectively regulates Teff cell
Vang, Amanda G; Basole, Chaitali; Dong, Hongli; Nguyen, Rebecca K; Housley, William; Guernsey, Linda; Adami, Alexander J; Thrall, Roger S; Clark, Robert B; Epstein, Paul M; Brocke, Stefan
2016-01-01
Abolishing the inhibitory signal of intracellular cAMP is a prerequisite for effector T (Teff) cell function. The regulation of cAMP within leukocytes critically depends on its degradation by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE8A, a PDE isoform with 40-100-fold greater affinity for cAMP than PDE4, is selectively expressed in Teff vs. regulatory T (Treg) cells and controls CD4(+) Teff cell adhesion and chemotaxis. Here, we determined PDE8A expression and function in CD4(+) Teff cell populations in vivo. Using magnetic bead separation to purify leukocyte populations from the lung draining hilar lymph node (HLN) in a mouse model of ovalbumin-induced allergic airway disease (AAD), we found by Western immunoblot and quantitative (q)RT-PCR that PDE8A protein and gene expression are enhanced in the CD4(+) T cell fraction over the course of the acute inflammatory disease and recede at the late tolerant non-inflammatory stage. To evaluate PDE8A as a potential drug target, we compared the selective and combined effects of the recently characterized highly potent PDE8-selective inhibitor PF-04957325 with the PDE4-selective inhibitor piclamilast (PICL). As previously shown, PF-04957325 suppresses T cell adhesion to endothelial cells. In contrast, we found that PICL alone increased firm T cell adhesion to endothelial cells by ~20% and significantly abrogated the inhibitory effect of PF-04957325 on T cell adhesion by over 50% when cells were co-exposed to PICL and PF-04957325. Despite its robust effect on T cell adhesion, PF-04957325 was over two orders of magnitude less efficient than PICL in suppressing polyclonal Teff cell proliferation, and showed no effect on cytokine gene expression in these cells. More importantly, PDE8 inhibition did not suppress proliferation and cytokine production of myelin-antigen reactive proinflammatory Teff cells in vivo and in vitro. Thus, targeting PDE8 through PF-04957325 selectively regulates Teff
Favot, Laure; Keravis, Thérèse; Lugnier, Claire
2004-09-01
Endothelial cell proliferation in response to VEGF plays an important role in physiological and pathological angiogenesis. The role of PDE2 and PDE4 in VEGF-induced proliferation in HUVEC was investigated: 1) VEGF increased cAMP-hydrolytic activity by up-regulating the expression of PDE2 and PDE4 isozymes; 2) VEGF increased progression in cell cycle with an increase in p42/p44 MAP kinase, cyclin A and cyclin D1 expressions and with a decrease in p21 waf1/cip1 and p27 kip1 expressions; 3) EHNA (20 micro M), a selective PDE2 inhibitor, RP73401 (10 micro M), a selective PDE4 inhibitor blocked the VEGF-induced increase in p42/p44 MAP kinase expression; 4) RP73401, but not EHNA, blocked the VEGF-induced increase in cyclin A and decrease in p27 kip1 expressions; 5) EHNA, contrary to RP73401, enhanced the VEGF-induced increase of cyclin A and decrease of p27 kip1. 6) EHNA and RP73401 together blocked the VEGF-induced increase in cyclin D1 and decrease in p21 waf1/cip1 expressions; 7) Inhibition of VEGF-upregulated PDE2 and PDE4 reversed the VEGF-induced alterations in cell cycle protein expression, bringing back endothelial cells to a non-proliferating status. Consequently, PDE2 and PDE4 inhibitions were able to inhibit VEGF-induced endothelial cell proliferation by restoring cell cycle key protein expression, and might thus be useful in excessive angiogenesis. Furthermore, the differences between PDE2 and PDE4 effects may suggest compartmentalized effects. PMID:15351862
NASA Astrophysics Data System (ADS)
Glatzel, W.; Chernigovski, S.
2016-04-01
The simulation of finite amplitude stellar pulsations and the theoretical determination of the final fate of violently unstable stellar models require the complete consideration of the mechanics and thermodynamics of a star. In particular, non-linear effects need to be taken into account. Numerical methods for the study of non-linear pulsations are available so far only for spherically symmetric radial pulsations. This paper is meant as a first step towards a numerical scheme which allows for the representation of non-radial non-linear stellar pulsations. A characteristic of stellar pulsations are dominant gravitational and thermal energies exceeding the kinetic energy by several orders of magnitude. As a consequence, numerical simulations of stellar pulsations require an extremely high accuracy, which can be met only by sophisticated intrinsically strictly conservative numerical schemes. Whether gravity can be represented numerically in a fully conservative way is the subject of this study. A fully conservative discrete form of gravity is derived explicitly and proven to satisfy all common conservation laws intrinsically.
PDE4B as a microglia target to reduce neuroinflammation.
Pearse, Damien D; Hughes, Zoë A
2016-10-01
The importance of microglia in immune homeostasis within the brain is undisputed. Their role in a diversity of neurological and psychiatric diseases as well as CNS injury is the subject of much investigation. Cyclic adenosine monophosphate (AMP) is a critical regulator of microglia homeostasis; as the predominant negative modulator of cyclic AMP signaling within microglia, phosphodiesterase 4 (PDE4) represents a promising target for modulating immune function. PDE4 expression is regulated by inflammation, and in turn, PDE4 inhibition can alter microglia reactivity. As the prototypic PDE4 inhibitor, rolipram, was tested clinically in the 1980s, drug discovery and clinical development of PDE4 inhibitors have been severely hampered by tolerability issues involving nausea and emesis. The two PDE4 inhibitors approved for peripheral inflammatory disorders (roflumilast and apremilast) lack brain penetration and are dose-limited by side effects making them unsuitable for modulating microglial function. Subtype selective inhibitors targeting PDE4B are of high interest given the critical role PDE4B plays in immune function versus the association of PDE4D with nausea and emesis. The challenges and requirements for successful development of a novel brain-penetrant PDE4B inhibitor are discussed in the context of early clinical development strategies. Furthermore, the challenges of monitoring the state of microglia in vivo are highlighted, including a description of the currently available tools and their limitations. Continued drug discovery efforts to identify safe and well-tolerated, brain-penetrant PDE4 inhibitors are a reflection of the confidence in the rationale for modulation of this target to produce meaningful therapeutic benefit in a wide range of neurological conditions and injury. GLIA 2016;64:1698-1709. PMID:27038323
NASA Technical Reports Server (NTRS)
Simitses, George J.; Carlson, Robert L.; Riff, Richard
1991-01-01
The object of the research reported herein was to develop a general mathematical model and solution methodologies for analyzing the structural response of thin, metallic shell structures under large transient, cyclic, or static thermomechanical loads. Among the system responses associated with these loads and conditions are thermal buckling, creep buckling, and ratcheting. Thus geometric and material nonlinearities (of high order) can be anticipated and must be considered in developing the mathematical model. The methodology is demonstrated through different problems of extension, shear, and of planar curved beams. Moreover, importance of the inclusion of large strain is clearly demonstrated, through the chosen applications.
Kraynik, Stephen M.; Miyaoka, Robert S.
2013-01-01
Brown adipose tissue (BAT) is a highly thermogenic organ that converts lipids and glucose into heat. Many of the metabolic and gene transcriptional hallmarks of BAT activation, namely increased lipolysis, uncoupling protein-1 (UCP1) mRNA, and glucose uptake, are regulated by the adrenergic second messenger, cAMP. Cyclic nucleotide phosphodiesterases (PDEs) catalyze the breakdown of cAMP, thereby regulating the magnitude and duration of this signaling molecule. In the absence of adrenergic stimulus, we found that it required a combination of a PDE3 and a PDE4 inhibitor to fully induce UCP1 mRNA and lipolysis in brown adipocytes, whereas neither PDE inhibitor alone had any substantial effect under basal conditions. Under submaximal β-adrenoceptor stimulation of brown adipocytes, a PDE3 inhibitor alone could potentiate induction of UCP1 mRNA, whereas a PDE4 inhibitor alone could augment lipolysis, indicating differential roles for each of these two PDEs. Neither induction of UCP1 nor lipolysis was altered by inhibition of PDE1, PDE2, or PDE8A. Finally, when injected into mice, the combination of PDE3 and PDE4 inhibitors stimulated glucose uptake in BAT under thermoneutral and fasted conditions, a response that was further potentiated by the global ablation of PDE8A. Taken together, these data reveal that multiple PDEs work in concert to regulate three of the important pathways leading to BAT activation, a finding that may provide an improved conceptual basis for the development of therapies for obesity-related diseases. PMID:23493317
Multithreaded Model for Dynamic Load Balancing Parallel Adaptive PDE Computations
NASA Technical Reports Server (NTRS)
Chrisochoides, Nikos
1995-01-01
We present a multithreaded model for the dynamic load-balancing of numerical, adaptive computations required for the solution of Partial Differential Equations (PDE's) on multiprocessors. Multithreading is used as a means of exploring concurrency in the processor level in order to tolerate synchronization costs inherent to traditional (non-threaded) parallel adaptive PDE solvers. Our preliminary analysis for parallel, adaptive PDE solvers indicates that multithreading can be used an a mechanism to mask overheads required for the dynamic balancing of processor workloads with computations required for the actual numerical solution of the PDE's. Also, multithreading can simplify the implementation of dynamic load-balancing algorithms, a task that is very difficult for traditional data parallel adaptive PDE computations. Unfortunately, multithreading does not always simplify program complexity, often makes code re-usability not an easy task, and increases software complexity.
The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5.
Wallis, R M
1999-10-01
Sildenafil (1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d]pyrimidin-5-yl) phenylsulphonyl]-4-methylpiperazine) has been shown to be an effective oral treatment for male erectile dysfunction. Sildenafil is a potent competitive inhibitor of PDE5 (IC50 3.5 nM) and is selective over PDE1 to 4 (80 to 19,000-fold) and retinal PDE6 (10-fold). Sildenafil enhanced cGMP accumulation driven with sodium nitroprusside in the corpus cavernosum of rabbits without affecting cAMP formulation. In the absence of nitric oxide drive, sildenafil had no functional effect on the human and rabbit isolated corpus cavernosum, but potently potentiated the relaxant effects of nitric oxide on these tissues. In the anaesthetised dog, sildenafil (ED50: 12 to 16 micrograms/kg i.v.) enhanced the increase in intracavernosal pressure induced by electrical stimulation of the pelvic nerve or intracavernosal injection of sodium nitroprusside in the absence of meaningful effects on blood pressure. Consistent with its mode of action, sildenafil potentiated the vasorelaxant effects of glyceryl trinitrate on rabbit isolated aortic rings. However, unlike milrinone, sildenafil had no inotropic effects on the dog isolated trabeculae carneae. Thus it is unlikely to have the deleterious effects on cardiac function associated with PDE3 inhibitors. As a consequence of inhibition of PDE6 in the retina, sildenafil (1 to 100 microM) altered the kinetics of the light response of the dog isolated retina. In the anaesthetised dog, sildenafil modified the a- and b-wave of the electroretinogram induced by a flash of blue light. These effects were proportional to plasma concentrations, were fully reversible and only occurred following plasma concentrations higher (approximately 30-fold) than those active on intracavernosal pressure. These studies have shown that sildenafil is a potent and selective inhibitor of PDE5. It enhances the effect of nitric oxide on the corpus cavernosum and has been shown
PDE regularization for Bayesian reconstruction of emission tomography
NASA Astrophysics Data System (ADS)
Wang, Zhentian; Zhang, Li; Xing, Yuxiang; Zhao, Ziran
2008-03-01
The aim of the present study is to investigate a type of Bayesian reconstruction which utilizes partial differential equations (PDE) image models as regularization. PDE image models are widely used in image restoration and segmentation. In a PDE model, the image can be viewed as the solution of an evolutionary differential equation. The variation of the image can be regard as a descent of an energy function, which entitles us to use PDE models in Bayesian reconstruction. In this paper, two PDE models called anisotropic diffusion are studied. Both of them have the characteristics of edge-preserving and denoising like the popular median root prior (MRP). We use PDE regularization with an Ordered Subsets accelerated Bayesian one step late (OSL) reconstruction algorithm for emission tomography. The OS accelerated OSL algorithm is more practical than a non-accelerated one. The proposed algorithm is called OSEM-PDE. We validated the OSEM-PDE using a Zubal phantom in numerical experiments with attenuation correction and quantum noise considered, and the results are compared with OSEM and an OS version of MRP (OSEM-MRP) reconstruction. OSEM-PDE shows better results both in bias and variance. The reconstruction images are smoother and have sharper edges, thus are more applicable for post processing such as segmentation. We validate this using a k-means segmentation algorithm. The classic OSEM is not convergent especially in noisy condition. However, in our experiment, OSEM-PDE can benefit from OS acceleration and keep stable and convergent while OSEM-MRP failed to converge.
Continuous Medial Representation of Brain Structures Using the Biharmonic PDE
Yushkevich, Paul A.
2009-01-01
A new approach for constructing deformable continuous medial models for anatomical structures is presented. Medial models describe geometrical objects by first specifying the skeleton of the object and then deriving the boundary surface corresponding to the skeleton. However, an arbitrary specification of a skeleton will not be “Valid” unless a certain set of sufficient conditions is satisfied. The most challenging of these is the non-linear equality constraint that must hold along the boundaries of the manifolds forming the skeleton. The main contribution of this paper is to leverage the biharmonic partial differential equation as a mapping from a codimension-0 subset of Euclidean space to the space of skeletons that satisfy the equality constraint. The PDE supports robust numerical solution on freeform triangular meshes, providing additional flexibility for shape modeling. The approach is evaluated by generating continuous medial models for a large dataset of hippocampus shapes. Generalizations to modeling more complex shapes and to representing branching skeletons are demonstrated. PMID:19059348
NASA Technical Reports Server (NTRS)
Fisher, Travis C.; Carpenter, Mark H.; Nordstroem, Jan; Yamaleev, Nail K.; Swanson, R. Charles
2011-01-01
Simulations of nonlinear conservation laws that admit discontinuous solutions are typically restricted to discretizations of equations that are explicitly written in divergence form. This restriction is, however, unnecessary. Herein, linear combinations of divergence and product rule forms that have been discretized using diagonal-norm skew-symmetric summation-by-parts (SBP) operators, are shown to satisfy the sufficient conditions of the Lax-Wendroff theorem and thus are appropriate for simulations of discontinuous physical phenomena. Furthermore, special treatments are not required at the points that are near physical boundaries (i.e., discrete conservation is achieved throughout the entire computational domain, including the boundaries). Examples are presented of a fourth-order, SBP finite-difference operator with second-order boundary closures. Sixth- and eighth-order constructions are derived, and included in E. Narrow-stencil difference operators for linear viscous terms are also derived; these guarantee the conservative form of the combined operator.
Assessing the emetic potential of PDE4 inhibitors in rats
Robichaud, A; Savoie, C; Stamatiou, P B; Lachance, N; Jolicoeur, P; Rasori, R; Chan, C C
2002-01-01
Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha2-adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors.Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg kg−1, i.m.) and ketamine (10 mg kg−1, i.m.) PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline) – PDE4 inhibitor: 0.01 – 3 mg kg−1), like MK-912 (alpha2-adrenoceptor antagonist: 0.01 – 3 mg kg−1), dose-dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1 – 10 mg kg−1). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors.Neither MK-912 (3 mg kg−1) nor PMNPQ (0.1 – 1 mg kg−1) altered the duration of anaesthesia induced via a non-alpha2-adrenoceptor pathway (sodium pentobarbitone 50 mg kg−1, i.p.)Central NK1 receptors are involved in PDE4 inhibitor-induced emesis. Consistently, [sar9, Met(O2)11]-substance P (NK1 receptor agonist, 6 μg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine.In summary, this model is functionally coupled to PDE4, specific to alpha2-adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats. PMID:11786486
PDE Nozzle Optimization Using a Genetic Algorithm
NASA Technical Reports Server (NTRS)
Billings, Dana; Turner, James E. (Technical Monitor)
2000-01-01
Genetic algorithms, which simulate evolution in natural systems, have been used to find solutions to optimization problems that seem intractable to standard approaches. In this study, the feasibility of using a GA to find an optimum, fixed profile nozzle for a pulse detonation engine (PDE) is demonstrated. The objective was to maximize impulse during the detonation wave passage and blow-down phases of operation. Impulse of each profile variant was obtained by using the CFD code Mozart/2.0 to simulate the transient flow. After 7 generations, the method has identified a nozzle profile that certainly is a candidate for optimum solution. The constraints on the generality of this possible solution remain to be clarified.
NASA Astrophysics Data System (ADS)
Sayanjali, M.; Pourtakdoust, Seid H.
2015-05-01
This paper investigates the problem of optimal transfer trajectory design towards the L2 centered Halo orbit of the Sun-Earth three body system, where the initial launch is to start from a low Earth parking orbit (LEO). The proposed optimal transfer trajectory consists of an active part with low-thrust propulsion and a passive coasting part with no thrust or fuel consumption. In this respect a pseudo-stable manifold (SM) is initially determined through backward time integration of the bicircular four body (BCFB) equations of motion, whose initial states are obtained via stable manifolds of the restricted three body problem (R3BP). The optimal transfer trajectories are extracted via a hybrid direct-indirect optimization formulation applied on both R3BP as well as the BCFB models for comparative purposes. The optimal transfer trajectories are designed and analyzed for different Halo injection points (HOI), different Moon's final anomaly (FMA) and also for different locations of the burn-out conditions.
Novel mutations in PDE6B causing human retinitis pigmentosa
Cheng, Lu-Lu; Han, Ru-Yi; Yang, Fa-Yu; Yu, Xin-Ping; Xu, Jin-Ling; Min, Qing-Jie; Tian, Jie; Ge, Xiang-Lian; Zheng, Si-Si; Lin, Ye-Wen; Zheng, Yi-Han; Qu, Jia; Gu, Feng
2016-01-01
AIM To identify the genetic defects of a Chinese patient with sporadic retinitis pigmentosa (RP). METHODS Ophthalmologic examinations were performed on the sporadic RP patient, 144 genes associated with retinal diseases were scanned with capture next generation sequencing (CNGS) approach. Two heterozygous mutations in PDE6B were confirmed in the pedigree by Sanger sequencing subsequently. The carrier frequency of PDE6B mutations of reported PDE6B mutations based on the available two public exome databases (1000 Genomes Project and ESP6500 Genomes Project) and one in-house exome database was investigated. RESULTS We identified compound heterozygosity of two novel nonsense mutations c.1133G>A (p.W378X) and c.2395C>T (p.R799X) in PDE6B, one reported causative gene for RP. Neither of the two mutations in our study was presented in three exome databases. Two mutations (p.R74C and p.T604I) in PDE6B have relatively high frequencies in the ESP6500 and in-house databases, respectively, while no common dominant mutation in each of the database or across all databases. CONCLUSION We demonstrates that compound heterozygosity of two novel nonsense mutations in PDE6B could lead to RP. These results collectively point to enormous potential of next-generation sequencing in determining the genetic etiology of RP and how various mutations in PDE6B contribute to the genetic heterogeneity of RP. PMID:27588261
NASA Astrophysics Data System (ADS)
Stein, David B.; Guy, Robert D.; Thomases, Becca
2016-01-01
The Immersed Boundary method is a simple, efficient, and robust numerical scheme for solving PDE in general domains, yet it only achieves first-order spatial accuracy near embedded boundaries. In this paper, we introduce a new high-order numerical method which we call the Immersed Boundary Smooth Extension (IBSE) method. The IBSE method achieves high-order accuracy by smoothly extending the unknown solution of the PDE from a given smooth domain to a larger computational domain, enabling the use of simple Cartesian-grid discretizations (e.g. Fourier spectral methods). The method preserves much of the flexibility and robustness of the original IB method. In particular, it requires minimal geometric information to describe the boundary and relies only on convolution with regularized delta-functions to communicate information between the computational grid and the boundary. We present a fast algorithm for solving elliptic equations, which forms the basis for simple, high-order implicit-time methods for parabolic PDE and implicit-explicit methods for related nonlinear PDE. We apply the IBSE method to solve the Poisson, heat, Burgers', and Fitzhugh-Nagumo equations, and demonstrate fourth-order pointwise convergence for Dirichlet problems and third-order pointwise convergence for Neumann problems.
NASA Astrophysics Data System (ADS)
Stevens, D.; Power, H.; Meng, C. Y.; Howard, D.; Cliffe, K. A.
2013-12-01
This work proposes an alternative decomposition for local scalable meshless RBF collocation. The proposed method operates on a dataset of scattered nodes that are placed within the solution domain and on the solution boundary, forming a small RBF collocation system around each internal node. Unlike other meshless local RBF formulations that are based on a generalised finite difference (RBF-FD) principle, in the proposed "finite collocation" method the solution of the PDE is driven entirely by collocation of PDE governing and boundary operators within the local systems. A sparse global collocation system is obtained not by enforcing the PDE governing operator, but by assembling the value of the field variable in terms of the field value at neighbouring nodes. In analogy to full-domain RBF collocation systems, communication between stencils occurs only over the stencil periphery, allowing the PDE governing operator to be collocated in an uninterrupted manner within the stencil interior. The local collocation of the PDE governing operator allows the method to operate on centred stencils in the presence of strong convective fields; the reconstruction weights assigned to nodes in the stencils being automatically adjusted to represent the flow of information as dictated by the problem physics. This "implicit upwinding" effect mitigates the need for ad-hoc upwinding stencils in convective dominant problems. Boundary conditions are also enforced within the local collocation systems, allowing arbitrary boundary operators to be imposed naturally within the solution construction. The performance of the method is assessed using a large number of numerical examples with two steady PDEs; the convection-diffusion equation, and the Lamé-Navier equations for linear elasticity. The method exhibits high-order convergence in each case tested (greater than sixth order), and the use of centred stencils is demonstrated for convective-dominant problems. In the case of linear elasticity
Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease
Banner, Katharine H; Press, Neil J
2009-01-01
Phosphodiesterase (PDE)4, and to a lesser extent, PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for diseases including chronic obstructive pulmonary disease. Indeed, ibudilast and theophylline are utilized clinically, and roflumilast is in late-stage clinical development. Unfortunately, however many PDE4 and dual PDE3/4 inhibitors have failed in early development due to low therapeutic ratios. The majority of these compounds are however orally administered and non-selective for either PDE3(A, B) or PDE4(A, B, C, D) subtypes. Developing an inhaled dual PDE3/4 inhibitor with subtype specificity may represent one strategy to improve the therapeutic index. Indeed combined inhibition of PDE3 and PDE4 inhibitor has additive and synergistic anti-inflammatory and bronchodilatory effects versus inhibition of either PDE3 or PDE4 alone. Given that synergy has been seen in terms of efficacy end points, an obvious concern is that synergy may also be observed in side effects. Interestingly, however, no synergy or additive effects with a combination of a PDE3 and PDE4 inhibitor in a cardiomyocyte assay were observed. This review will summarize the rationale for developing an inhaled dual PDE3/4 inhibitor, as a treatment for chronic obstructive pulmonary disease together with recent advances in trying to understand the pathogenesis of PDE inhibitor-induced mesenteric vasculitis (a key potential dose-limiting side effect of these agents), highlighting potential early and sensitive predictive biomarkers. PMID:19508401
RACK1 and β-arrestin2 attenuate dimerization of PDE4 cAMP phosphodiesterase PDE4D5.
Bolger, Graeme B
2016-07-01
PDE4 family cAMP-selective cyclic nucleotide phosphodiesterases are important in the regulation of cAMP abundance in numerous systems, and thereby play an important role in the regulation of PKA and EPAC activity and the phosphorylation of CREB. We have used the yeast 2-hybrid system to demonstrate recently that long PDE4 isoforms form homodimers, consistent with data obtained recently by structural studies. The long PDE4 isoform PDE4D5 interacts selectively with β-arrestin2, implicated in the regulation of G-protein-coupled receptors and other cell signaling components, and also with the β-propeller protein RACK1. In the present study, we use 2-hybrid approaches to demonstrate that RACK1 and β-arrestin2 inhibit the dimerization of PDE4D5. We also show that serine-to-alanine mutations at PKA and ERK1/2 phosphorylation sites on PDE4D5 detectably ablate dimerization. Conversely, phospho-mimic serine-to-aspartate mutations at the MK2 and oxidative stress kinase sites ablate dimerization. Analysis of PDE4D5 that is locked into the dimeric configuration by the formation of a trans disulfide bond between Ser261 and Ser602 shows that RACK1 interacts strongly with both the monomeric and dimeric forms, but that β-arrestin2 interacts exclusively with the monomeric form. This is consistent with the concept that β-arrestin2 can preferentially recruit the monomeric, or "open," form of PDE4D5 to β2-adrenergic receptors, where it can regulate cAMP signaling. PMID:26257302
NASA Technical Reports Server (NTRS)
Hunt, L. R.; Villarreal, Ramiro
1987-01-01
System theorists understand that the same mathematical objects which determine controllability for nonlinear control systems of ordinary differential equations (ODEs) also determine hypoellipticity for linear partial differentail equations (PDEs). Moreover, almost any study of ODE systems begins with linear systems. It is remarkable that Hormander's paper on hypoellipticity of second order linear p.d.e.'s starts with equations due to Kolmogorov, which are shown to be analogous to the linear PDEs. Eigenvalue placement by state feedback for a controllable linear system can be paralleled for a Kolmogorov equation if an appropriate type of feedback is introduced. Results concerning transformations of nonlinear systems to linear systems are similar to results for transforming a linear PDE to a Kolmogorov equation.
2d PDE Linear Symmetric Matrix Solver
Energy Science and Technology Software Center (ESTSC)
1983-10-01
ICCG2 (Incomplete Cholesky factorized Conjugate Gradient algorithm for 2d symmetric problems) was developed to solve a linear symmetric matrix system arising from a 9-point discretization of two-dimensional elliptic and parabolic partial differential equations found in plasma physics applications, such as resistive MHD, spatial diffusive transport, and phase space transport (Fokker-Planck equation) problems. These problems share the common feature of being stiff and requiring implicit solution techniques. When these parabolic or elliptic PDE''s are discretized withmore » finite-difference or finite-element methods,the resulting matrix system is frequently of block-tridiagonal form. To use ICCG2, the discretization of the two-dimensional partial differential equation and its boundary conditions must result in a block-tridiagonal supermatrix composed of elementary tridiagonal matrices. The incomplete Cholesky conjugate gradient algorithm is used to solve the linear symmetric matrix equation. Loops are arranged to vectorize on the Cray1 with the CFT compiler, wherever possible. Recursive loops, which cannot be vectorized, are written for optimum scalar speed. For matrices lacking symmetry, ILUCG2 should be used. Similar methods in three dimensions are available in ICCG3 and ILUCG3. A general source containing extensions and macros, which must be processed by a pre-compiler to obtain the standard FORTRAN source, is provided along with the standard FORTRAN source because it is believed to be more readable. The pre-compiler is not included, but pre-compilation may be performed by a text editor as described in the UCRL-88746 Preprint.« less
2d PDE Linear Asymmetric Matrix Solver
Energy Science and Technology Software Center (ESTSC)
1983-10-01
ILUCG2 (Incomplete LU factorized Conjugate Gradient algorithm for 2d problems) was developed to solve a linear asymmetric matrix system arising from a 9-point discretization of two-dimensional elliptic and parabolic partial differential equations found in plasma physics applications, such as plasma diffusion, equilibria, and phase space transport (Fokker-Planck equation) problems. These equations share the common feature of being stiff and requiring implicit solution techniques. When these parabolic or elliptic PDE''s are discretized with finite-difference or finite-elementmore » methods, the resulting matrix system is frequently of block-tridiagonal form. To use ILUCG2, the discretization of the two-dimensional partial differential equation and its boundary conditions must result in a block-tridiagonal supermatrix composed of elementary tridiagonal matrices. A generalization of the incomplete Cholesky conjugate gradient algorithm is used to solve the matrix equation. Loops are arranged to vectorize on the Cray1 with the CFT compiler, wherever possible. Recursive loops, which cannot be vectorized, are written for optimum scalar speed. For problems having a symmetric matrix ICCG2 should be used since it runs up to four times faster and uses approximately 30% less storage. Similar methods in three dimensions are available in ICCG3 and ILUCG3. A general source, containing extensions and macros, which must be processed by a pre-compiler to obtain the standard FORTRAN source, is provided along with the standard FORTRAN source because it is believed to be more readable. The pre-compiler is not included, but pre-compilation may be performed by a text editor as described in the UCRL-88746 Preprint.« less
PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease.
Teich, Andrew F; Sakurai, Mikako; Patel, Mitesh; Holman, Cameron; Saeed, Faisal; Fiorito, Jole; Arancio, Ottavio
2016-03-01
Phosphodiesterase 5 (PDE5) is a critical component of the cGMP-PKG axis of cellular signaling in neurons, and inhibition of PDE5 has been shown to be therapeutic in a wide range of neurologic conditions in animal models. However, enthusiasm for PDE5 inhibitors in humans is limited by data suggesting that PDE5 may not exist in human neurons. Here, we first show that past attempts to quantify PDE5 mRNA were flawed due to the use of incorrect primers, and that when correct primers are used, PDE5 mRNA is detectable in human brain tissue. We then show that PDE5 protein exists in human brain by western blot and ELISA. Most importantly, we performed immunohistochemistry and demonstrate that PDE5 is present in human neurons. We hope that this work will trigger a renewed interest in the development of PDE5 inhibitors for neurologic disease. PMID:26967220
PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease
Teich, Andrew F.; Sakurai, Mikako; Patel, Mitesh; Holman, Cameron; Saeed, Faisal; Fiorito, Jole; Arancio, Ottavio
2016-01-01
Phosphodiesterase 5 (PDE5) is a critical component of the cGMP-PKG axis of cellular signaling in neurons, and inhibition of PDE5 has been shown to be therapeutic in a wide range of neurologic conditions in animal models. However, enthusiasm for PDE5 inhibitors in humans is limited by data suggesting that PDE5 may not exist in human neurons. Here, we first show that past attempts to quantify PDE5 mRNA were flawed due to the use of incorrect primers, and that when correct primers are used, PDE5 mRNA is detectable in human brain tissue. We then show that PDE5 protein exists in human brain by western blot and ELISA. Most importantly, we performed immunohistochemistry and demonstrate that PDE5 is present in human neurons. We hope that this work will trigger a renewed interest in the development of PDE5 inhibitors for neurologic disease. PMID:26967220
Zhang, Xiujun; Feng, Qing; Cote, Rick H.
2005-01-01
Purpose: Phosphodiesterase (PDE) inhibitors are important therapeutic agents, but their effects on photoreceptor PDE (PDE6) and photoreceptor cells are poorly understood. We characterized the potency and selectivity of various classes of PDE inhibitors on purified rod and cone PDE6 and on intact rod outer segments (ROS). Methods: The inhibition constant (KI) of isozyme-selective PDE inhibitors was determined for purified rod and cone PDE6. Perturbations of cGMP levels in isolated ROS suspensions by PDE inhibitors were quantitated by a cGMP enzyme-linked immunoassay. Results: Most PDE5-selective inhibitors are excellent PDE6 inhibitors. Vardenafil, a potent PDE5 inhibitor (KI = 0.2 nM), is the most potent PDE6 inhibitor tested (KI = 0.7 nM). Zaprinast is the only drug that inhibits PDE6 more potently than PDE5. PDE1-selective inhibitors were equally effective in inhibiting PDE6. In intact ROS, PDE inhibitors elevated cGMP levels but none fully inhibited PDE6. Their potency to elevate cGMP levels in ROS was much lower than their ability to inhibit the purified enzyme. Competition between PDE5/6-selective drugs and the inhibitory γ subunit for the active site of PDE6 is proposed to reduce the effectiveness of drugs at the enzyme active site. Conclusions: Several classes of PDE inhibitors equally well inhibit PDE6 as the PDE family to which they are targeted. In intact ROS, high PDE6 concentrations, binding of the γ subunit to the active site, and calcium feedback mechanisms attenuate the effectiveness of PDE inhibitors to inhibit PDE6 and disrupt the cGMP signaling pathway during visual transduction. PMID:16123402
Novel PDE4 Inhibitors Derived from Chinese Medicine Forsythia
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
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.
A new chemical tool for exploring the physiological function of the PDE2 isozyme.
Chambers, Robert J; Abrams, Kristin; Garceau, Norman Y; Kamath, Ajith V; Manley, Christopher M; Lilley, Susan C; Otte, Douglas A; Scott, Dennis O; Sheils, Alissa L; Tess, David A; Vellekoop, A Samuel; Zhang, Yan; Lam, Kelvin T
2006-01-15
Oxindole (2) is a potent and selective PDE2 inhibitor with a favorable ADME, physiochemical and pharmacokinetic profile to allow for use as a chemical tool in elucidating the physiological role of PDE2. PMID:16275071
Cherry, J A; Thompson, B E; Pho, V
2001-03-19
Cyclic AMP is hydrolyzed by members of at least eight classes of cyclic nucleotide phosphodiesterases (PDEs). Although it has been reported that cyclic AMP PDE activity in mammalian tissues can be inhibited by benzodiazepines, it has not been conclusively demonstrated that members of the class of cyclic AMP-specific, rolipram-inhibitable PDEs (PDE4s) are targets for these drugs. Moreover, no PDE4s expressed in mice have been characterized. To address these issues, we isolated two cDNAs representing homologues of PDE4A1 and PDE4B3 from a mouse brain library. After transient transfection in human embryonic kidney (HEK) 293 cells, the mouse PDEs hydrolyzed cyclic AMP with a low K(m) and were inhibited by rolipram; both are properties typical of other mammalian PDE4 enzymes. In addition, we found that diazepam inhibited cyclic AMP hydrolysis by the mouse PDE4 subtypes. Interestingly, PDE4B was significantly more sensitive to inhibition by both rolipram and diazepam than the PDE4A subtype. This is the first demonstration that recombinantly expressed PDE4s are inhibited by diazepam, and should facilitate future studies with mouse models of depression and anxiety. PMID:11267656
PDE5 inhibitors enhance celecoxib killing in multiple tumor types.
Booth, Laurence; Roberts, Jane L; Cruickshanks, Nichola; Tavallai, Seyedmehrad; Webb, Timothy; Samuel, Peter; Conley, Adam; Binion, Brittany; Young, Harold F; Poklepovic, Andrew; Spiegel, Sarah; Dent, Paul
2015-05-01
The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer. PMID:25303541
PDE3A mutations cause autosomal dominant hypertension with brachydactyly.
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. PMID:25961942
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.
PDE5 Inhibitors Enhance Celecoxib Killing in Multiple Tumor Types
BOOTH, LAURENCE; ROBERTS, JANE L.; CRUICKSHANKS, NICHOLA; TAVALLAI, SEYEDMEHRAD; WEBB, TIMOTHY; SAMUEL, PETER; CONLEY, ADAM; BINION, BRITTANY; YOUNG, HAROLD F.; POKLEPOVIC, ANDREW; SPIEGEL, SARAH; DENT, PAUL
2015-01-01
The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer. PMID:25303541
Student's Lab Assignments in PDE Course with MAPLE.
ERIC Educational Resources Information Center
Ponidi, B. Alhadi
Computer-aided software has been used intensively in many mathematics courses, especially in computational subjects, to solve initial value and boundary value problems in Partial Differential Equations (PDE). Many software packages were used in student lab assignments such as FORTRAN, PASCAL, MATLAB, MATHEMATICA, and MAPLE in order to accelerate…
NASA Technical Reports Server (NTRS)
Smith, Ralph C.
1994-01-01
A Galerkin method for systems of PDE's in circular geometries is presented with motivating problems being drawn from structural, acoustic, and structural acoustic applications. Depending upon the application under consideration, piecewise splines or Legendre polynomials are used when approximating the system dynamics with modifications included to incorporate the analytic solution decay near the coordinate singularity. This provides an efficient method which retains its accuracy throughout the circular domain without degradation at singularity. Because the problems under consideration are linear or weakly nonlinear with constant or piecewise constant coefficients, transform methods for the problems are not investigated. While the specific method is developed for the two dimensional wave equations on a circular domain and the equation of transverse motion for a thin circular plate, examples demonstrating the extension of the techniques to a fully coupled structural acoustic system are used to illustrate the flexibility of the method when approximating the dynamics of more complex systems.
BinMahfouz, Hawazen; Borthakur, Bibhusana; Yan, Dong; George, Tresa; Giembycz, Mark A; Newton, Robert
2015-01-01
Glucocorticoids, also known as corticosteroids, induce effector gene transcription as a part of their anti-inflammatory mechanisms of action. Such genomic effects can be significantly enhanced by long-acting β2-adrenoceptor agonists (LABAs) and may contribute to the clinical superiority of inhaled corticosteroid (ICS)/LABA combinations in asthma and chronic obstructive pulmonary disease (COPD) over ICSs alone. Using models of cAMP- and glucocorticoid-induced transcription in human bronchial epithelial BEAS-2B cells, we show that combining inhibitors of phosphodiesterase (PDE) 3 and PDE4 provides greater benefits compared with inhibiting either PDE alone. In respect to cAMP-dependent transcription, inhibitors of PDE3 (siguazodan, cilostazol) and PDE4 (rolipram, GSK256066, roflumilast N-oxide) each sensitized to the LABA, formoterol. This effect was magnified by dual PDE3 and PDE4 inhibition. Siguazodan plus rolipram was also more effective at inducing cAMP-dependent transcription than either inhibitor alone. Conversely, the concentration-response curve describing the enhancement of dexamethasone-induced, glucocorticoid response element-dependent transcription by formoterol was displaced to the left by PDE4, but not PDE3, inhibition. Overall, similar effects were described for bona fide genes, including RGS2, CD200, and CRISPLD2. Importantly, the combination of siguazodan plus rolipram prolonged the duration of gene expression induced by formoterol, dexamethasone, or dexamethasone plus formoterol. This was most apparent for RGS2, a bronchoprotective gene that may also reduce the proinflammatory effects of constrictor mediators. Collectively, these data provide a rationale for the use of PDE3 and PDE4 inhibitors in the treatment of COPD and asthma where they may enhance, sensitize, and prolong the effects of LABA/ICS combination therapies. PMID:25324049
Tumours with cancer stem cells: A PDE model.
Fasano, A; Mancini, A; Primicerio, M
2016-02-01
The role of cancer stem cells (CSC) in tumour growth has received increasing attention in the recent literature. Here we stem from an integro-differential system describing the evolution of a population of CSC and of ordinary (non-stem) tumour cells formulated and studied in a previous paper, and we investigate an approximation in which the system reduces to a pair of nonlinear coupled parabolic equation. We prove that the new system is well posed and we examine some general properties. Numerical simulations show more on the qualitative behaviour of the solutions, concerning in particular the so-called tumour paradox, according to which an increase of the mortality rate of ordinary (non-stem) tumour cells results asymptotically in a faster growth. PMID:26719124
Terascale Optimal PDE Simulations (TOPS) Center
Pothen, Alex
2006-08-23
This report covers the period from Oct. 2002 to Sep. 2004 when Old Dominion University (ODU) was the lead institution for the TOPS ISIC, until in Oct. 2004 Columbia University replaced ODU as the lead institution. The TOPS members from ODU focused on various aspects of the linear and nonlinear solver infrastructure required by the partial differential equations simulation codes, working directly with SciDAC teams from the Fusion Energy Sciences program: the Center for Extended agnetohydrodynamic Modeling (CEMM) at Princeton, and with the Center for Magnetic Reconnection Studies (CMRS) at University of New Hampshire. With CEMM we worked with their MHD simulation code, called M3D, which is semi-implicit, requiring linear solves but no onlinear solves. We contributed several improvements to their current semi-implicit code. Among these was the use of multilevel reconditioning, which provides optimal scaling. This was done through the multigrid preconditioner available in Hypre, another major solver package available in TOPS. We also provided them direct solver functionality for their linear solves since they may be required for more accurate solutions in some regimes. With the CMRS group, we implemented a fully implicit parallel magnetic reconnection simulation code, built on top of PETSc. Our first attempt was a Krylov linear iteration (GMRES because of the lack of symmetry), within each nonlinear (Newton) iteration, with optimal multilevel preconditioning, using the geometric multigrid preconditioner from PETSc. However, for reasons that we have not yet fully understood, the multigrid preconditioner fails early in the simulation, breaking the outer Newton iteration. Much better results were obtained after switching from optimal multilevel preconditioning to suboptimal one level preconditioning. Our current code, based on the additive Schwartz preconditioner from in PETSc, with ILU on subdomains, scales reasonably well, while matching the output of the original
The numerical performance of wavelets and reproducing kernels for PDE`s
Christon, M.A.; Roach, D.W.; Voth, T.E.
1998-08-01
The results presented here constitute a brief summary of an on-going multi-year effort to investigate hierarchical/wavelet bases for solving PDE`s and establish a rigorous foundation for these methods. A new, hierarchical, wavelet-Galerkin solution strategy based upon the Donovan-Geronimo-Hardin-Massopust (DGHM) compactly-supported multi-wavelet is presented for elliptic partial differential equations. This multi-scale wavelet-Galerkin method uses a wavelet transform to yield nearly mesh independent condition numbers for elliptic problems as opposed to the multi-scaling functions that yield condition numbers which increase as the square of the mesh size. In addition, the results of von Neumann analyses for the DGHM multi-wavelet element and the Reproducing Kernel Particle Method (RKPM) are presented for model hyperbolic partial differential equations. RKPM exhibits excellent dispersion characteristics using a consistent mass matrix with the proper choice of refinement parameter and mass matrix formulation. In comparison, the wavelet-Galerkin formulation using the DGHM element delivers a frequency response comparable to a Bubnov-Galerkin formulation with a quadratic element.
Fujishige, K; Kotera, J; Yuasa, K; Omori, K
2000-10-01
PDE10A is a cyclic nucleotide phosphodiesterase (PDE) exhibiting properties of a cAMP PDE and a cAMP-inhibited cGMP PDE. The transcripts are specifically expressed in the striatum. The human gene encoding PDE10A was cloned and investigated. The PDE10A gene spanned > 200 kb and contained 24 exons. The exon-intron organization of PDE10A was different from those of PDE5A and PDE6B, although these three PDEs include two GAF domains and have similar amino-acid sequences. The promoter sequence of PDE10A was highly GC-rich and did not contain a TATA motif and a CAAT box, suggesting it is a housekeeping gene. In Caenorhabditis elegans, the C32E12.2 gene encoding a probable PDE that is 48% identical to the human PDE10A protein showed similar exon organization to PDE10A but not PDE5A and PDE6B. This, together with the phylogenic tree analysis, suggested that the ancestral gene for PDE10A existed in a lower organism such as C. elegans. PMID:10998054
Estimating the magnitude of near-membrane PDE4 activity in living cells.
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. PMID:26201952
PDE Based Algorithms for Smooth Watersheds.
Hodneland, Erlend; Tai, Xue-Cheng; Kalisch, Henrik
2016-04-01
Watershed segmentation is useful for a number of image segmentation problems with a wide range of practical applications. Traditionally, the tracking of the immersion front is done by applying a fast sorting algorithm. In this work, we explore a continuous approach based on a geometric description of the immersion front which gives rise to a partial differential equation. The main advantage of using a partial differential equation to track the immersion front is that the method becomes versatile and may easily be stabilized by introducing regularization terms. Coupling the geometric approach with a proper "merging strategy" creates a robust algorithm which minimizes over- and under-segmentation even without predefined markers. Since reliable markers defined prior to segmentation can be difficult to construct automatically for various reasons, being able to treat marker-free situations is a major advantage of the proposed method over earlier watershed formulations. The motivation for the methods developed in this paper is taken from high-throughput screening of cells. A fully automated segmentation of single cells enables the extraction of cell properties from large data sets, which can provide substantial insight into a biological model system. Applying smoothing to the boundaries can improve the accuracy in many image analysis tasks requiring a precise delineation of the plasma membrane of the cell. The proposed segmentation method is applied to real images containing fluorescently labeled cells, and the experimental results show that our implementation is robust and reliable for a variety of challenging segmentation tasks. PMID:26625408
Schaefer, T L; Braun, A A; Amos-Kroohs, R M; Williams, M T; Ostertag, E; Vorhees, C V
2012-07-01
Phosphodiesterases (PDEs) are a superfamily of intracellular second messenger cyclic nucleotide hydrolyzing enzymes composed of 12 families. The Pde4 family has been implicated in depression and cognition, and PDE4 inhibitors have been evaluated as antidepressants and possible cognitive enhancers. Pde4d(-/-) mice show an antidepressant phenotype and learning enhancement on some tests, but not others as do mice treated with PDE4 inhibitors. Here, we report for the first time the behavioral phenotype of a new Pde4d knock-down (KD) rat model of PDE4D deficiency. Consistent with other data on PDE4D deficiency, Pde4d KD rats showed depression resistance in the Porsolt forced swim test and hyperreactivity of the acoustic startle response with no differential response on prepulse inhibition, suggesting no sensorimotor gating defect. Pde4d KD rats also exhibited a small exploratory activity reduction but no difference following habituation, and no enhanced spatial learning or reference memory in the Morris water maze. A selective improvement in route-based learning in the Cincinnati water maze was seen as well as enhanced contextual and cued fear conditioning and a more rapid rate of cued extinction from their higher freezing level that declined to wild-type (WT) levels only after ∼20 extinction trials. The rat model confirms Pde4d's role in depression but not in spatial learning or memory enhancement and shows for the first time higher fear conditioning and altered extinction compared with controls. The new model provides a tool by which to better understand the role of PDE4D in neuropsychiatric disorders and for the development of alternate treatment approaches. PMID:22487514
Mean field spin glasses treated with PDE techniques
NASA Astrophysics Data System (ADS)
Barra, Adriano; Del Ferraro, Gino; Tantari, Daniele
2013-07-01
Following an original idea of Guerra, in these notes we analyze the Sherrington-Kirkpatrick model from different perspectives, all sharing the underlying approach which consists in linking the resolution of the statistical mechanics of the model (e.g. solving for the free energy) to well-known partial differential equation (PDE) problems (in suitable spaces). The plan is then to solve the related PDE using techniques involved in their native field and lastly bringing back the solution in the proper statistical mechanics framework. Within this strand, after a streamlined test-case on the Curie-Weiss model to highlight the methods more than the physics behind, we solve the SK both at the replica symmetric and at the 1-RSB level, obtaining the correct expression for the free energy via an analogy to a Fourier equation and for the self-consistencies with an analogy to a Burger equation, whose shock wave develops exactly at critical noise level (triggering the phase transition). Our approach, beyond acting as a new alternative method (with respect to the standard routes) for tackling the complexity of spin glasses, links symmetries in PDE theory with constraints in statistical mechanics and, as a novel result from the theoretical physics perspective, we obtain a new class of polynomial identities (namely of Aizenman-Contucci type, but merged within the Guerra's broken replica measures), whose interest lies in understanding, via the recent Panchenko breakthroughs, how to force the overlap organization to the ultrametric tree predicted by Parisi.
Universal structure and universal equations (PDE) for unitary ensembles
NASA Astrophysics Data System (ADS)
Rumanov, Igor
2010-08-01
Random matrix ensembles with unitary invariance of measure (UE) are described in a unified way using a combination of Tracy-Widom (TW) and Adler-Shiota-van Moerbeke approaches to the derivation of partial differential equations (PDEs) for spectral gap probabilities. First, general three-term recurrence relations for UE restricted to subsets of real line, or, in other words, for functions in the resolvent kernel, are obtained. Using them, simple universal relations between all TW dependent variables and one-dimensional Toda lattice τ-functions are found. A universal system of PDE for UE is derived from previous relations, which leads also to a single independent PDE for spectral gap probability of various UE. Thus, orthogonal function bases and Toda lattice are seen at the core of correspondence of different approaches. Moreover, Toda-AKNS system provides a common structure of PDE for unitary ensembles. Interestingly, this structure can be seen in two very different forms: one arises from orthogonal function-Toda lattice considerations, while the other comes from Schlesinger equations for isomonodromic deformations and their relation to TW equations. The simple example of Gaussian matrices most neatly exposes this structure.
Diggle, Christine P; Sukoff Rizzo, Stacey J; Popiolek, Michael; Hinttala, Reetta; Schülke, Jan-Philip; Kurian, Manju A; Carr, Ian M; Markham, Alexander F; Bonthron, David T; Watson, Christopher; Sharif, Saghira Malik; Reinhart, Veronica; James, Larry C; Vanase-Frawley, Michelle A; Charych, Erik; Allen, Melanie; Harms, John; Schmidt, Christopher J; Ng, Joanne; Pysden, Karen; Strick, Christine; Vieira, Päivi; Mankinen, Katariina; Kokkonen, Hannaleena; Kallioinen, Matti; Sormunen, Raija; Rinne, Juha O; Johansson, Jarkko; Alakurtti, Kati; Huilaja, Laura; Hurskainen, Tiina; Tasanen, Kaisa; Anttila, Eija; Marques, Tiago Reis; Howes, Oliver; Politis, Marius; Fahiminiya, Somayyeh; Nguyen, Khanh Q; Majewski, Jacek; Uusimaa, Johanna; Sheridan, Eamonn; Brandon, Nicholas J
2016-04-01
Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species. PMID:27058446
Domain Organization and Conformational Plasticity of the G Protein Effector, PDE6*
Zhang, Zhixian; He, Feng; Constantine, Ryan; Baker, Matthew L.; Baehr, Wolfgang; Schmid, Michael F.; Wensel, Theodore G.; Agosto, Melina A.
2015-01-01
The cGMP phosphodiesterase of rod photoreceptor cells, PDE6, is the key effector enzyme in phototransduction. Two large catalytic subunits, PDE6α and -β, each contain one catalytic domain and two non-catalytic GAF domains, whereas two small inhibitory PDE6γ subunits allow tight regulation by the G protein transducin. The structure of holo-PDE6 in complex with the ROS-1 antibody Fab fragment was determined by cryo-electron microscopy. The ∼11 Å map revealed previously unseen features of PDE6, and each domain was readily fit with high resolution structures. A structure of PDE6 in complex with prenyl-binding protein (PrBP/δ) indicated the location of the PDE6 C-terminal prenylations. Reconstructions of complexes with Fab fragments bound to N or C termini of PDE6γ revealed that PDE6γ stretches from the catalytic domain at one end of the holoenzyme to the GAF-A domain at the other. Removal of PDE6γ caused dramatic structural rearrangements, which were reversed upon its restoration. PMID:25809480
PDE4D phosphorylation: A coincidence detector integrating multiple signaling pathways.
Mika, Delphine; Conti, Marco
2016-07-01
In Eukaryotes, more than 100 different phosphodiesterase (PDE) proteins serve to fine-tune cyclic nucleotide (cAMP and cGMP) signals and contribute to specificity of signaling. In mammals, PDEs are divided into 11 families, of which PDE4 represents the largest family. Four genes (pde4a, pde4b, pde4c and pde4d) encode for this class of enzymes in mammals and give rise to more than 20 variants. Within this family of genes, PDE4D was discovered on the basis of its regulatory properties and its induction by hormones and cAMP. PDE4D has often been used as the prototype PDE4 and large body of work has been generated on the biochemical, pharmacological, and physiological properties of this enzyme. This review covers the regulation of PDE4D by phosphorylation, the impact of this regulation in the context of the structure of this protein, and the functional consequences of this complex pattern of posttranslational modifications. PMID:26562185
Biochemical and behavioral effects of PDE10A inhibitors: Relationship to target site occupancy.
Li, Yu-Wen; Seager, Matthew A; Wojcik, Trevor; Heman, Karen; Molski, Thaddeus F; Fernandes, Alda; Langdon, Shaun; Pendri, Annapurna; Gerritz, Samuel; Tian, Yuan; Hong, Yang; Gallagher, Lizbeth; Merritt, James R; Zhang, Chongwu; Westphal, Ryan; Zaczek, Robert; Macor, John E; Bronson, Joanne J; Lodge, Nicholas J
2016-03-01
Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [(3)H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [(3)H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (KD) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [(3)H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident. PMID:26522433
Does phosphodiesterase 11A (PDE11A) hold promise as a future therapeutic target?
Kelly, Michy P
2015-01-01
Phosphodiesterase 11A (PDE11A) is the most recently discovered 3', 5'-cyclic nucleotide phosphodiesterase. By breaking down both cAMP and cGMP, PDE11A is a critical regulator of intracellular signaling. To date, PDE11A has been implicated to play a role in tumorigenesis, brain function, and inflammation. Here, we consolidate and, where necessary, reconcile the PDE11A literature to evaluate this enzyme as a potential therapeutic target. We compare the results and methodologies of numerous studies that report conflicting tissue expression profiles for PDE11A. We conclude that PDE11A expression is relatively restricted in the body, with reliable expression reported in tissues such as the brain (particularly the hippocampus), the prostate, and the adrenal gland. Each of the four PDE11A splice variants (PDE11A1-4) appears to exhibit a distinct tissue expression profile and has a unique N-terminal regulatory region, suggesting that each isoform could be individually targeted with a small molecule or biologic. Progress has been made in identifying a tool PDE11A inhibitor as well as an activator; however, the functional effects of these pharmacological tools remain to be determined. Importantly, PDE11A knockout mice do exist and appear healthy into late age, suggesting a potential safety window for targeting this enzyme. Considering the implication of PDE11A in disease-relevant biology, the potential to selectively target specific PDE11A variants, and the possibility of either activating or inhibiting the enzyme, we believe PDE11A holds promise as a potential future therapeutic target. PMID:25159071
Global attractors for a third order in time nonlinear dynamics
NASA Astrophysics Data System (ADS)
Caixeta, Arthur H.; Lasiecka, Irena; Cavalcanti, Valéria N. D.
2016-07-01
Long time behavior of a third order (in time) nonlinear PDE equation is considered. This type of equations arises in the context of nonlinear acoustics [12,20,22,24] where modeling accounts for a finite speed of propagation paradox, the latter results in hyperbolic nature of the dynamics. It will be proved that the underlying PDE generates a well-posed dynamical system which admits a global and finite dimensional attractor. The main difficulty associated with the problem studied is the lack of Lyapunov function along with the lack of compactness of trajectories, which fact prevents applicability of standard tools in the area of dynamical systems.
Michie, A M; Lobban, M; Müller, T; Harnett, M M; Houslay, M D
1996-02-01
The PDE2, cyclic GMP-stimulated, and the PDE4, cyclic AMP-specific enzymes provide the major, detectable cyclic AMP phosphodiesterase activities in murine thymocytes. In the absence of the cyclic GMP, PDE4 activity predominated (approximately 80% total) but in the presence of low (10 microM) cyclic GMP concentrations, PDE2 activity constituted the major PDE activity in thymocytes (approximately 80% total). The PDE4 selective inhibitor rolipram dose-dependently inhibited thymocyte PDE4 activity (IC50 approximately 65 nM). PDE2 was dose-dependently activated (EC50 approximately 1 microM) by cyclic GMP and inhibited by erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) (IC50 approximately 4 microM). EHNA was shown to serve as a selective inhibitor of PDE-2 activity as assessed from studies using separated PDE1, PDE2, PDE3 and PDE4 species from hepatocytes as well as human PDE2 and PDE4 enzymes. EHNA completely ablated the ability of cyclic GMP to activate PDE2 activity, whilst having a much smaller inhibitory effect on the unstimulated PDE2 activity. EHNA exhibited normal Michaelian kinetics of inhibition for the cyclic GMP-stimulated PDE2 activity with Hill plots near unity. Apparent negative co-operative effect were seen in the absence of cyclic GMP with Hill coefficients of approximately 0.3 for inhibition of PDE2 activity. Within 5 min of challenge of thymocytes with the lectin phytohaemagglutinin (PHA) there was a transient decrease (approximately 83%) in PDE-4 activity and in PDE2 activity (approximately 40%). Both anti-TCR antibodies also caused an initial reduction in the PDE4 activity which was followed by a sustained and profound increase in activity. In contrast to that observed with PHA, anti-TCR/CD3 antisera had little effect on PDE2 activity. It is suggested that, dependent upon the intracellular concentrations of cyclic GMP, thymocyte cyclic AMP metabolism can be expected to switch from being under the predominant control of PDE4 activity to that determined
Research in nonlinear structural and solid mechanics
NASA Technical Reports Server (NTRS)
Mccomb, H. G., Jr. (Compiler); Noor, A. K. (Compiler)
1980-01-01
Nonlinear analysis of building structures and numerical solution of nonlinear algebraic equations and Newton's method are discussed. Other topics include: nonlinear interaction problems; solution procedures for nonlinear problems; crash dynamics and advanced nonlinear applications; material characterization, contact problems, and inelastic response; and formulation aspects and special software for nonlinear analysis.
Van Gorder, Robert A
2015-05-01
The Hasimoto transformation between the classical LIA (local induction approximation, a model approximating the motion of a thin vortex filament) and the nonlinear Schrödinger equation (NLS) has proven very useful in the past, since it allows one to construct new solutions to the LIA once a solution to the NLS is known. In the present paper, the quantum form of the LIA (which includes mutual friction effects) is put into correspondence with a type of complex nonlinear dispersive partial differential equation (PDE) with cubic nonlinearity (similar in form to a Ginsburg-Landau equation, with additional nonlinear terms). Transforming the quantum LIA in such a way enables one to obtain quantum vortex filament solutions once solutions to this dispersive PDE are known. From our quantum Hasimoto transformation, we determine the form and behavior of Stokes waves, a standing one-soliton, traveling waves, and similarity solutions under normal and binormal friction effects. The quantum Hasimoto transformation is useful when normal fluid velocity is relatively weak, so for the case where the normal fluid velocity is dominant we resort to other approaches. We exhibit a number of solutions that exist only in the presence of the normal fluid velocity and mutual friction terms (which would therefore not exist in the limit taken to obtain the classical LIA, decaying into line filaments under such a limit), examples of which include normal fluid driven helices, stationary and propagating topological solitons, and a vortex ring whose radius varies inversely with the normal fluid magnitude. We show that, while chaos may not be impossible under the quantum LIA, it should not be expected to arise from traveling waves along quantum vortex filaments under the quantum LIA formulation. PMID:26066272
NASA Astrophysics Data System (ADS)
Van Gorder, Robert A.
2015-05-01
The Hasimoto transformation between the classical LIA (local induction approximation, a model approximating the motion of a thin vortex filament) and the nonlinear Schrödinger equation (NLS) has proven very useful in the past, since it allows one to construct new solutions to the LIA once a solution to the NLS is known. In the present paper, the quantum form of the LIA (which includes mutual friction effects) is put into correspondence with a type of complex nonlinear dispersive partial differential equation (PDE) with cubic nonlinearity (similar in form to a Ginsburg-Landau equation, with additional nonlinear terms). Transforming the quantum LIA in such a way enables one to obtain quantum vortex filament solutions once solutions to this dispersive PDE are known. From our quantum Hasimoto transformation, we determine the form and behavior of Stokes waves, a standing one-soliton, traveling waves, and similarity solutions under normal and binormal friction effects. The quantum Hasimoto transformation is useful when normal fluid velocity is relatively weak, so for the case where the normal fluid velocity is dominant we resort to other approaches. We exhibit a number of solutions that exist only in the presence of the normal fluid velocity and mutual friction terms (which would therefore not exist in the limit taken to obtain the classical LIA, decaying into line filaments under such a limit), examples of which include normal fluid driven helices, stationary and propagating topological solitons, and a vortex ring whose radius varies inversely with the normal fluid magnitude. We show that, while chaos may not be impossible under the quantum LIA, it should not be expected to arise from traveling waves along quantum vortex filaments under the quantum LIA formulation.
PDE4 in the human heart – major player or little helper?
Eschenhagen, Thomas
2013-01-01
PDEs restrict the positive inotropic effects of β-adrenoceptor stimulation by degrading cAMP. Hence, PDE inhibitors sensitize the heart to catecholamines and are therefore used as positive inotropes. On the downside, this is accompanied by exaggerated energy expenditure, cell death and arrhythmias. For many years, PDE3 was considered to be the major isoform responsible for the control of cardiac force and rhythm. However, recent work in gene-targeted mice and rodent cells has indicated that PDE4 is also involved. Furthermore, selective PDE4 inhibitors augment catecholamine-stimulated cAMP levels and induce arrhythmias in human atrial preparations, which suggests that PDE4 has a more prominent role in the human heart than anticipated, and that PDE4 inhibitors such as roflumilast may carry an arrhythmogenic risk. In this issue of the journal, a team of researchers from three laboratories report on the effect of PDE3 and PDE4 inhibitors on ventricular trabeculae from explanted human hearts. The key result is that the PDE4 inhibitor rolipram does not affect the positive inotropic effects of β1- or β2-adrenoceptor stimulation. Given that the ventricle rather than the atria is the critical region in terms of arrhythmogenic consequences, this is an important and reassuring finding. Linked Article This article is a commentary on the research paper by Molenaar et al., pp. 528–538 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12167 PMID:23489196
Beca, Sanja; Ahmad, Faiyaz; Shen, Weixing; Liu, Jie; Makary, Samy; Polidovitch, Nazari; Sun, Junhui; Hockman, Steven; Chung, Youn Wook; Movesian, Matthew; Murphy, Elizabeth; Manganiello, Vincent; Backx, Peter H.
2013-01-01
Rationale cAMP is an important regulator of myocardial function, and regulation of cAMP hydrolysis by cyclic nucleotide phosphodiesterases (PDEs) is a critical determinant of the amplitude, duration, and compartmentation of cAMP–mediated signaling. The role of different PDE isozymes, particularly PDE3A versus PDE3B, in the regulation of heart function remains unclear. Objective To determine the relative contribution of PDE3A versus PDE3B isozymes in the regulation of heart function and to dissect the molecular basis for this regulation. Methods and Results Compared to wild-type (WT) littermates, cardiac contractility and relaxation were enhanced in isolated hearts from PDE3A−/−, but not PDE3B−/−, mice. Furthermore, PDE3 inhibition had no effect on PDE3A−/− hearts but increased contractility in WT (as expected) and PDE3B−/− hearts to levels indistinguishable from PDE3A−/−. The enhanced contractility in PDE3A−/− hearts was associated with cAMP-dependent elevations in Ca2+ transient amplitudes and increased SR Ca2+ content, without changes in L-type Ca2+ currents (ICa,L) of cardiomyocytes, as well as with increased SR Ca2+-ATPase (SERCA2a) activity, SR Ca2+ uptake rates, and phospholamban (PLN) phosphorylation in SR fractions. Consistent with these observations, PDE3 activity was reduced ~8-fold in SR fractions from PDE3A−/− hearts. Co-immunoprecipitation experiments further revealed that PDE3A associates with both SERCA2a and PLN in a complex which also contains AKAP-18, PKA-RII and PP2A. Conclusion Our data support the conclusion that PDE3A is the primary PDE3 isozyme modulating basal contractility and SR Ca2+ content by regulating cAMP in microdomains containing macromolecular complexes of SERCA2a-PLN-PDE3A. PMID:23168336
Bortolini, Claudio; Pivato, Antonio; Bogialli, Sara; Pastore, Paolo
2015-08-01
A highly selective and robust method for simultaneous screening and confirmation of target and non-target phosphodiesterase type 5 (PDE-5) inhibitor analogues within a single chromatographic run in counterfeit herbal products was developed. The protocol, based on an easy and rapid extraction with a water/acetonitrile 1 % formic acid solution, followed by sonication and centrifugation, exploits an LC-diode array detector-quadrupole-time-of-flight (DAD-QTOF) system. The extraction method was optimized both at high concentrations and at trace levels. These two situations are typically encountered in pharmaceutical formulations and herbal food supplements. Carryover effects, never reported before and occurring mainly for vardenafil, were overcome using a polymer-based column. An in-house validation was carried out using five blanks of different bulk matrices spiked with seven standard analytes, namely yohimbine, sildenafil, vardenafil, tadalafil, homosildenafil, pseudovardenafil and hydroxyhomovardenafil. Reliable quantitation was possible using a conventional standard solution for all the pharmaceutical and herbal samples considered, as matrix effects were eliminated. Accuracy ranged from 80.9 to 108.1 % with overall relative standard deviation (RSD) <11 % (N = 15), measured at 1.0, 5.0 and 10.0 μg/g. Limits of detection (LODs) obtained ensured the determination of cross contaminations at nanogram per gram levels. A database with 82 PDE-5 inhibitor analogues was implemented for automatic non-target analysis. Among the 26 samples of dietary supplements and herbal remedies bulk marketed for erectile dysfunctions, three samples were found to be contaminated with both registered and unregistered synthetic PDE-5 inhibitors, i.e. yohimbine, sildenafil, dimethylsildenafil and thiodimethylsildenafil or thiomethisosildenafil. The occurrence of such contaminations, both at trace levels and at pharmaceutical dosage, indicates the illicit use of synthetic PDE-5 analogues
Simulation of Stochastic Processes by Coupled ODE-PDE
NASA Technical Reports Server (NTRS)
Zak, Michail
2008-01-01
A document discusses the emergence of randomness in solutions of coupled, fully deterministic ODE-PDE (ordinary differential equations-partial differential equations) due to failure of the Lipschitz condition as a new phenomenon. It is possible to exploit the special properties of ordinary differential equations (represented by an arbitrarily chosen, dynamical system) coupled with the corresponding Liouville equations (used to describe the evolution of initial uncertainties in terms of joint probability distribution) in order to simulate stochastic processes with the proscribed probability distributions. The important advantage of the proposed approach is that the simulation does not require a random-number generator.
Domain decomposition in time for PDE-constrained optimization
Barker, Andrew T.; Stoll, Martin
2015-08-28
Here, PDE-constrained optimization problems have a wide range of applications, but they lead to very large and ill-conditioned linear systems, especially if the problems are time dependent. In this paper we outline an approach for dealing with such problems by decomposing them in time and applying an additive Schwarz preconditioner in time, so that we can take advantage of parallel computers to deal with the very large linear systems. We then illustrate the performance of our method on a variety of problems.
Pyrazolopyridines as potent PDE4B inhibitors: 5-Heterocycle SAR
Mitchell, Charlotte J.; Ballantine, Stuart P.; Coe, Diane M.; Cook, Caroline M.; Delves, Christopher J.; Dowle, Mike D.; Edlin, Chris D.; Hamblin, J. Nicole; Holman, Stuart; Johnson, Martin R.; Jones, Paul S.; Keeling, Sue E.; Kranz, Michael; Lindvall, Mika; Lucas, Fiona S.; Neu, Margarete; Solanke, Yemisi E.; Somers, Don O.; Trivedi, Naimisha A.; Wiseman, Joanne O.
2012-05-03
Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-{alpha} production from isolated human peripheral blood mononuclear cells.
Jacobs, Nathan T.; Cortes, Daniel H.; Peloquin, John M.; Vresilovic, Edward J.; Elliott, Dawn M.
2014-01-01
Finite element (FE) models are advantageous in the study of intervertebral disc mechanics as the stress–strain distributions can be determined throughout the tissue and the applied loading and material properties can be controlled and modified. However, the complicated nature of the disc presents a challenge in developing an accurate and predictive disc model, which has led to limitations in FE geometry, material constitutive models and properties, and model validation. The objective of this study was to develop a new FE model of the intervertebral disc, to validate the model’s nonlinear and time-dependent responses without tuning or calibration, and to evaluate the effect of changes in nucleus pulposus (NP), cartilaginous endplate (CEP), and annulus fibrosus (AF) material properties on the disc mechanical response. The new FE disc model utilized an analytically-based geometry. The model was created from the mean shape of human L4/L5 discs, measured from high-resolution 3D MR images and averaged using signed distance functions. Structural hyperelastic constitutive models were used in conjunction with biphasic-swelling theory to obtain material properties from recent tissue tests in confined compression and uniaxial tension. The FE disc model predictions fit within the experimental range (mean ± 95% confidence interval) of the disc’s nonlinear response for compressive slow loading ramp, creep, and stress-relaxation simulations. Changes in NP and CEP properties affected the neutral-zone displacement but had little effect on the final stiffness during slow-ramp compression loading. These results highlight the need to validate FE models using the disc’s full nonlinear response in multiple loading scenarios. PMID:24998992
Jacobs, Nathan T; Cortes, Daniel H; Peloquin, John M; Vresilovic, Edward J; Elliott, Dawn M
2014-08-22
Finite element (FE) models are advantageous in the study of intervertebral disc mechanics as the stress-strain distributions can be determined throughout the tissue and the applied loading and material properties can be controlled and modified. However, the complicated nature of the disc presents a challenge in developing an accurate and predictive disc model, which has led to limitations in FE geometry, material constitutive models and properties, and model validation. The objective of this study was to develop a new FE model of the intervertebral disc, to validate the model's nonlinear and time-dependent responses without tuning or calibration, and to evaluate the effect of changes in nucleus pulposus (NP), cartilaginous endplate (CEP), and annulus fibrosus (AF) material properties on the disc mechanical response. The new FE disc model utilized an analytically-based geometry. The model was created from the mean shape of human L4/L5 discs, measured from high-resolution 3D MR images and averaged using signed distance functions. Structural hyperelastic constitutive models were used in conjunction with biphasic-swelling theory to obtain material properties from recent tissue tests in confined compression and uniaxial tension. The FE disc model predictions fit within the experimental range (mean ± 95% confidence interval) of the disc's nonlinear response for compressive slow loading ramp, creep, and stress-relaxation simulations. Changes in NP and CEP properties affected the neutral-zone displacement but had little effect on the final stiffness during slow-ramp compression loading. These results highlight the need to validate FE models using the disc's full nonlinear response in multiple loading scenarios. PMID:24998992
Shepherd, Malcolm; McSorley, Theresa; Olsen, Aileen E; Johnston, Lee Ann; Thomson, Neil C; Baillie, George S; Houslay, Miles D; Bolger, Graeme B
2003-01-01
We have isolated cDNAs encoding PDE4B4, a new cAMP-specific phosphodiesterase (PDE4) isoform with novel properties. The amino acid sequence of PDE4B4 demonstrates that it is encoded by the PDE4B gene, but that it differs from the previously isolated PDE4B1, PDE4B2 and PDE4B3 isoforms by the presence of a novel N-terminal region of 17 amino acids. PDE4B4 contains both of the upstream conserved region 1 (UCR1) and UCR2 regulatory units that are characteristic of 'long' PDE4 isoforms. RNase protection demonstrated that PDE4B4 mRNA is expressed preferentially in liver, skeletal muscle and various regions of the brain, which differs from the pattern of tissue distribution of the other known PDE4B long forms, PDE4B1 and PDE4B3. Expression of PDE4B4 cDNA in COS7 cells produced a protein of 85 kDa under denaturing conditions. Subcellular fractionation of recombinant, COS7-cell expressed PDE4B4 showed that the protein was localized within the cytosol, which was confirmed by confocal microscopic analysis of living COS7 cells transfected with a green fluorescent protein-PDE4B4 chimaera. PDE4B4 exhibited a K(m) for cAMP of 5.4 microM and a V(max), relative to that of the long PDE4B1 isoform, of 2.1. PDE4B4 was inhibited by the prototypical PDE4 inhibitor rolipram [4-[3-(cyclopentoxyl)-4-methoxyphenyl]-2-pyrrolidinone] with an IC(50) of 83 nM. Treatment of COS7 cells with forskolin, to elevate cAMP levels, produced activation of PDE4B4, which was associated with the phosphorylation of PDE4B4 on Ser-56 within UCR1. The unique tissue distribution and intracellular targeting of PDE4B4 suggests that this isoform may have a distinct functional role in regulating cAMP levels in specific cell types. PMID:12441002
Mesh Algorithms for PDE with Sieve I: Mesh Distribution
Knepley, Matthew G.; Karpeev, Dmitry A.
2009-01-01
We have developed a new programming framework, called Sieve, to support parallel numerical partial differential equation(s) (PDE) algorithms operating over distributed meshes. We have also developed a reference implementation of Sieve in C++ as a library of generic algorithms operating on distributed containers conforming to the Sieve interface. Sieve makes instances of the incidence relation, or arrows, the conceptual first-class objects represented in the containers. Further, generic algorithms acting on this arrow container are systematically used to provide natural geometric operations on the topology and also, through duality, on the data. Finally, coverings and duality are used to encode notmore » only individual meshes, but all types of hierarchies underlying PDE data structures, including multigrid and mesh partitions. In order to demonstrate the usefulness of the framework, we show how the mesh partition data can be represented and manipulated using the same fundamental mechanisms used to represent meshes. We present the complete description of an algorithm to encode a mesh partition and then distribute a mesh, which is independent of the mesh dimension, element shape, or embedding. Moreover, data associated with the mesh can be similarly distributed with exactly the same algorithm. The use of a high level of abstraction within the Sieve leads to several benefits in terms of code reuse, simplicity, and extensibility. We discuss these benefits and compare our approach to other existing mesh libraries.« less
Parallel PDE-Based Simulations Using the Common Component Architecture
McInnes, Lois C.; Allan, Benjamin A.; Armstrong, Robert; Benson, Steven J.; Bernholdt, David E.; Dahlgren, Tamara L.; Diachin, Lori; Krishnan, Manoj Kumar; Kohl, James A.; Larson, J. Walter; Lefantzi, Sophia; Nieplocha, Jarek; Norris, Boyana; Parker, Steven G.; Ray, Jaideep; Zhou, Shujia
2006-03-05
Summary. The complexity of parallel PDE-based simulations continues to increase as multimodel, multiphysics, and multi-institutional projects become widespread. A goal of componentbased software engineering in such large-scale simulations is to help manage this complexity by enabling better interoperability among various codes that have been independently developed by different groups. The Common Component Architecture (CCA) Forum is defining a component architecture specification to address the challenges of high-performance scientific computing. In addition, several execution frameworks, supporting infrastructure, and generalpurpose components are being developed. Furthermore, this group is collaborating with others in the high-performance computing community to design suites of domain-specific component interface specifications and underlying implementations. This chapter discusses recent work on leveraging these CCA efforts in parallel PDE-based simulations involving accelerator design, climate modeling, combustion, and accidental fires and explosions. We explain how component technology helps to address the different challenges posed by each of these applications, and we highlight how component interfaces built on existing parallel toolkits facilitate the reuse of software for parallel mesh manipulation, discretization, linear algebra, integration, optimization, and parallel data redistribution. We also present performance data to demonstrate the suitability of this approach, and we discuss strategies for applying component technologies to both new and existing applications.
PDE5 inhibitors protect against post-infarction heart failure.
Li, Na; Yuan, Yuan; Li, Shuang; Zeng, Cao; Yu, Wenjun; Shen, Mingzhi; Zhang, Rongqing; Li, Congye; Zhang, Yingmei; Wang, Haichang
2016-01-01
Heart failure (HF) is one of the main causes for cardiovascular morbidity and mortality. This study was designed to examine the effect of PDE-5 inhibition on cardiac geometry, function and apoptosis in post-infarct HF. Our data revealed that treatment of the PDE-5 inhibitor sildenafil, beginning 3 days after left anterior descending coronary artery ligation, attenuated LV remodeling, cardiac dysfunction, cardiomyocyte apoptosis and mitochondrial anomalies including ATP production, mitochondrial respiratory defects, decline of mitochondrial membrane potential (MMP) and compromised mitochondrial ultrastructure. Sildenafil partially ameliorated the downregulation of Sirt3 protein and acetylation of PGC-1alpha in peri-infarct myocardial regions. In cultured neonatal mouse ventricular myocytes subjected to hypoxia for 24 hrs, sildenafil suppressed apoptosis, promoted ATP production and elevated MMP, along with the increased Sirt3 protein expression and decreased PGC-1alpha acetylation. Interestingly, knock down of Sirt3 attenuated or nullified sildenafil-offered beneficial effects. Our findings demonstrated that sildenafil exerts its cardioprotective effect against post-infarction injury by improving mitochondrial ultrastructure and function via the Sirt3/PGC-1alpha pathway. This observation should shed some lights towards application of sildenafil in energy-related cardiovascular diseases. PMID:27100500
Keravis, Thérèse; Lugnier, Claire
2012-01-01
Cyclic nucleotide phosphodiesterases (PDEs) that specifically inactivate the intracellular messengers cAMP and cGMP in a compartmentalized manner represent an important enzyme class constituted by 11 gene-related families of isozymes (PDE1 to PDE11). Downstream receptors, PDEs play a major role in controlling the signalosome at various levels of phosphorylations and protein/protein interactions. Due to the multiplicity of isozymes, their various intracellular regulations and their different cellular and subcellular distributions, PDEs represent interesting targets in intracellular pathways. Therefore, the investigation of PDE isozyme alterations related to various pathologies and the design of specific PDE inhibitors might lead to the development of new specific therapeutic strategies in numerous pathologies. This manuscript (i) overviews the different PDEs including their endogenous regulations and their specific inhibitors; (ii) analyses the intracellular implications of PDEs in regulating signalling cascades in pathogenesis, exemplified by two diseases affecting cell cycle and proliferation; and (iii) discusses perspectives for future therapeutic developments. PMID:22014080
CELLULAR AND SUBCELLULAR LOCALIZATION OF PDE10A, A STRIATUM-ENRICHED PHOSPHODIESTERASE
XIE, Z.; ADAMOWICZ, W. O.; ELDRED, W. D.; JAKOWSKI, A. B.; KLEIMAN, R. J.; MORTON, D. G.; STEPHENSON, D. T.; STRICK, C. A.; WILLIAMS, R. D.; MENNITI, F. S.
2006-01-01
PDE10A is a recently identified phosphodiesterase that is highly expressed by the GABAergic medium spiny projection neurons of the mammalian striatum. Inhibition of PDE10A results in striatal activation and behavioral suppression, suggesting that PDE10A inhibitors represent a novel class of antipsychotic agents. In the present studies we further elucidate the localization of this enzyme in striatum of rat and cynomolgus monkey. We find by confocal microscopy that PDE10A-like immunoreactivity is excluded from each class of striatal interneuron. Thus, the enzyme is restricted to the medium spiny neurons. Subcellular fractionation indicates that PDE10A is primarily membrane bound. The protein is present in the synaptosomal fraction but is separated from the postsynaptic density upon solubilization with 0.4% Triton X-100. Immuno-electron microscopy of striatum confirms that PDE10A is most often associated with membranes in dendrites and spines. Immuno-gold particles are observed on the edge of the postsynaptic density but not within this structure. Our studies indicate that PDE10A is associated with post-synaptic membranes of the medium spiny neurons, suggesting that the specialized compartmentation of PDE10A enables the regulation of intracellular signaling from glutamatergic and dopaminergic inputs to these neurons. PMID:16483723
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…
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…
PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells
Roberts, Jane L; Booth, Laurence; Conley, Adam; Cruickshanks, Nichola; Malkin, Mark; Kukreja, Rakesh C; Grant, Steven; Poklepovic, Andrew; Dent, Paul
2014-01-01
We determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill medulloblastoma cells. In medulloblastoma cells PDE5 inhibitors interacted in a greater than additive fashion with vincristine/etoposide/cisplatin to cause cell death. Knockdown of PDE5 expression recapitulated the combination effects of PDE5 inhibitor drugs with chemotherapy drugs. Expression of dominant negative caspase 9 did not significantly inhibit chemotherapy lethality but did significantly reduce enhanced killing in combination with the PDE5 inhibitor sildenafil. Overexpression of BCL-XL and c-FLIP-s suppressed individual and combination drug toxicities. Knockdown of CD95 or FADD suppressed drug combination toxicity. Treatment with PDE5 inhibitors and chemotherapy drugs promoted autophagy which was maximal at ~12 h post-treatment, and in a cell type-dependent manner knockdown of Beclin1 or ATG5 either suppressed or enhanced drug combination lethality. PDE5 inhibitors enhanced the induction of chemotherapy-induced DNA damage in a nitric oxide synthase-dependent fashion. In conclusion, our data demonstrate that the combination of PDE5 inhibitors with standard of care chemotherapy agents for medulloblastoma represents a possible novel modality for future treatment of this disease. PMID:24651037
A novel thermoregulatory role for PDE10A in mouse and human adipocytes.
Hankir, Mohammed K; Kranz, Mathias; Gnad, Thorsten; Weiner, Juliane; Wagner, Sally; Deuther-Conrad, Winnie; Bronisch, Felix; Steinhoff, Karen; Luthardt, Julia; Klöting, Nora; Hesse, Swen; Seibyl, John P; Sabri, Osama; Heiker, John T; Blüher, Matthias; Pfeifer, Alexander; Brust, Peter; Fenske, Wiebke K
2016-01-01
Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small-animal PET/MRI and the novel radioligand [(18)F]-AQ28A, we found marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice. Pharmacological inactivation of PDE10A with the highly selective inhibitor MP-10 recruited BAT and potentiated thermogenesis in vivo In diet-induced obese mice, chronic administration of MP-10 caused weight loss associated with increased energy expenditure, browning of white adipose tissue, and improved insulin sensitivity. Analysis of human PET data further revealed marked levels of PDE10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Finally, the inhibition of PDE10A with MP-10 stimulated thermogenic gene expression in human brown adipocytes and induced browning of human white adipocytes. Collectively, our findings highlight a novel thermoregulatory role for PDE10A in mouse and human adipocytes and promote PDE10A inhibitors as promising candidates for the treatment of obesity and diabetes. PMID:27247380
Design and Microwave Assisted Synthesis of Coumarin Derivatives as PDE Inhibitors.
Kumbar, Mahadev N; Kamble, Ravindra R; Kamble, Atulkumar A; Salian, Sujith Raj; Kumari, Sandhya; Nair, Ramya; Kalthur, Guruprasad; Adiga, Satish Kumar; Prasad, D Jagadeesh
2016-01-01
Coumarins appended to benzimidazole through pyrazole are designed and synthesized using microwave irradiation. These compounds were analyzed for phosphodiesterase (PDE) inhibition indirectly by motility pattern in human spermatozoa. Some of the synthesized compounds, namely, 5d, 5e, 5f, 5g, 5h, and 5k, have exhibited potent inhibitory activity on PDE. PMID:26998358
Design and Microwave Assisted Synthesis of Coumarin Derivatives as PDE Inhibitors
Kumbar, Mahadev N.; Kamble, Ravindra R.; Kamble, Atulkumar A.; Salian, Sujith Raj; Kumari, Sandhya; Nair, Ramya; Kalthur, Guruprasad; Adiga, Satish Kumar; Prasad, D. Jagadeesh
2016-01-01
Coumarins appended to benzimidazole through pyrazole are designed and synthesized using microwave irradiation. These compounds were analyzed for phosphodiesterase (PDE) inhibition indirectly by motility pattern in human spermatozoa. Some of the synthesized compounds, namely, 5d, 5e, 5f, 5g, 5h, and 5k, have exhibited potent inhibitory activity on PDE. PMID:26998358
Takano, Akihiro; Stepanov, Vladimir; Nakao, Ryuji; Amini, Nahid; Gulyás, Balázs; Kimura, Haruhide; Halldin, Christer
2016-06-01
Because phosphodiesterase 10A (PDE10A) degrades both cyclic adenosine monophosphate and cyclic guanosine monophosphate and is distributed mainly in the striatum, PDE10A inhibitors have been considered to potentially be useful therapeutic agents for psychiatric and neurodegenerative diseases such as schizophrenia and Huntington's disease. We measured striatal PDE10A occupancy by TAK-063, a newly developed compound with high affinity and selectivity for PDE10A, using PET with [(11) C]T-773 in nonhuman primates. Two 123-min dynamic PET measurements were performed on three female rhesus monkeys, once at baseline and again after intravenous administration of different doses of TAK-063 (0.2-1.6 mg/kg). Total distribution volume (VT ) was calculated with a two-tissue compartment model using metabolite-corrected plasma input. Although the in vitro autoradiography did not show high specific binding to [(11) C]T-773 in the cerebellum, VT in the cerebellum decreased after TAK-063 treatment. The specific binding to PDE10A (VS ) was calculated as the difference of the VT between the target regions and the cerebellum. PDE10A occupancy was calculated as the percent change of VS . The average PDE10A occupancy of the caudate nucleus and putamen was 35.2% at 0.2 mg/kg and 83.2% at 1.6 mg/kg. In conclusion, this nonhuman primate PET study demonstrated that [(11) C]T-773 is useful to estimate the PDE10A occupancy by TAK-063 in the striatum although there is in vivo interaction of the uptake between [(11) C]T-773 and TAK-063 in the cerebellum. These results warrant further clinical occupancy study for TAK-063. Synapse 70:253-263, 2016. © 2016 Wiley Periodicals, Inc. PMID:26878349
Ahmed, Nermin S.; Gary, Bernard D.; Tinsley, Hethar N.; Piazza, Gary A.; Laufer, Stefan; Abadi, Ashraf H.
2016-01-01
Starting from tadalafil as a template, a series of functionalized tetrahydro-b-carboline derivatives have been prepared and identified as novel potent and selective PDE5 inhibitors. Replacing the 3,4-methylenedioxyphenyl at position 6 of tadalafil, together with elongation of the N2-methyl substituent and manipulation of the stereochemical aspects of the two chiral carbons led to the identification of compound XXI, a highly potent PDE5 inhibitor (IC50 = 3 nM). Compound XXI was also highly selective for PDE5 versus PDE3B, PDE4B, and PDE11A, with a selectivity index of 52 and 235 towards PDE5 rather than PDE11 with both cAMP and cGMP as substrate, respectively. PMID:21384413
KANEDA, Takeharu; KIDO, Yuuki; TAJIMA, Tsuyoshi; URAKAWA, Norimoto; SHIMIZU, Kazumasa
2014-01-01
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. PMID:25319411
NASA Astrophysics Data System (ADS)
Haven, Emmanuel
2005-11-01
Analytical solutions to the backward Kolmogorov PDE are very dependent on the functional form of b(y,t) and a(y,t). We suggest one solution technique for obtaining analytical solutions via the use of an adiabatic approximation to the Schrödinger PDE. This approximation takes the specific form of a so-called WKB (W D Wentzel [G. Wentzel, Eine Verallgemeinerung der Quantenbedingungen für die Zwecke der Wellenmechanik, Z. Phys. 38 (1926) 518-529], K D Kramers [H. Kramers, Wellenmechanik und halbzahlige Quantisierung, Z. Phys. 39 (1926) 828-840], B D Brillouin [L. Brillouin, La mécanique ondulatoire de Schrödinger: une méthode générale de résolution par approximations successives, C. R. Acad. Sci. 183 (1926) 24-26]) approximation. We provide for two examples, in financial option pricing, where we show how the proposed approximation could be of use.
PHLPP2 Downregulation Contributes to Lung Carcinogenesis Following B[a]P/B[a]PDE Exposure
Huang, Haishan; Pan, Xiaofu; Jin, Honglei; Li, Yang; Zhang, Lin; Yang, Caili; Liu, Pei; Liu, Ya; Chen, Lili; Li, Jingxia; Zhu, Junlan; Zeng, Xingruo; Fu, Kai; Chen, Guorong; Gao, Jimin; Huang, Chuanshu
2015-01-01
Purpose The carcinogenic capacity of B[a]P/B[a]PDE is supported by epidemiologic studies. However, the molecular mechanisms responsible for B[a]P/B[a]PDE-caused lung cancer have not been well investigated. We evaluated here the role of novel target PHLPP2 in lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure. Experimental Design We used the Western blotting, RT-PCR, [35S]methionine pulse and immunohistochemistry staining to determine PHLPP2 downregulation following B[a]P/B[a]PDE exposure. Both B[a]PDE-induced Beas-2B cell transformation model and B[a]P-caused mouse lung cancer model were used to elucidate the mechanisms leading to PHLPP2 downregulation and lung carcinogenesis. The important findings were also extended to in vivo human studies. Results We found that B[a]P/B[a]PDE exposure downregulated PHLPP2 expression in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The ectopic expression of PHLPP2 dramatically inhibited cell transformation upon B[a]PDE exposure. Mechanistic studies showed that miR-205 induction was crucial for inhibition of PHLPP2 protein translation by targeting PHLPP2-3′-UTR. Interestingly, PHLPP2 expression was inversely associated with tumor necrosis factor alpha (TNFα) expression, with low PHLPP2 and high TNFα expression in lung cancer tissues compared with the paired adjacent normal lung tissues. Additional studies revealed that PHLPP2 exhibited its antitumorigenic effect of B[a]P/B[a]PDE through the repression of inflammatory TNFα transcription. Conclusions Our studies not only first time identify PHLPP2 downregulation by lung carcinogen B[a]P/B[a]PDE, but also elucidate a novel molecular mechanisms underlying lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure. PMID:25977341
Mehraeen, Shahab; Jagannathan, Sarangapani
2011-11-01
In this paper, the direct neural dynamic programming technique is utilized to solve the Hamilton-Jacobi-Bellman equation forward-in-time for the decentralized near optimal regulation of a class of nonlinear interconnected discrete-time systems with unknown internal subsystem and interconnection dynamics, while the input gain matrix is considered known. Even though the unknown interconnection terms are considered weak and functions of the entire state vector, the decentralized control is attempted under the assumption that only the local state vector is measurable. The decentralized nearly optimal controller design for each subsystem consists of two neural networks (NNs), an action NN that is aimed to provide a nearly optimal control signal, and a critic NN which evaluates the performance of the overall system. All NN parameters are tuned online for both the NNs. By using Lyapunov techniques it is shown that all subsystems signals are uniformly ultimately bounded and that the synthesized subsystems inputs approach their corresponding nearly optimal control inputs with bounded error. Simulation results are included to show the effectiveness of the approach. PMID:21965197
Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory
Park, Alan J.; Tolentino, Rosa E.; Bruinenberg, Vibeke M.; Tudor, Jennifer C.; Lee, Yool; Hansen, Rolf T.; Guercio, Leonardo A.; Linton, Edward; Neves-Zaph, Susana R.; Meerlo, Peter; Baillie, George S.; Houslay, Miles D.
2016-01-01
Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo. Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. SIGNIFICANCE STATEMENT Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular
Therapeutic potential of PDE modulation in treating heart disease
Knight, Walter; Yan, Chen
2014-01-01
Altered cyclic nucleotide-mediated signaling plays a critical role in the development of cardiovascular pathology. By degrading cAMP/cGMP, the action of cyclic nucleotide PDEs is essential for controlling cyclic nucleotide-mediated signaling intensity, duration, and specificity. Altered expression, localization and action of PDEs have all been implicated in causing changes in cyclic nucleotide signaling in cardiovascular disease. Accordingly, pharmacological inhibition of PDEs has gained interest as a treatment strategy and as an area of drug development. While targeting of certain PDEs has the potential to ameliorate cardiovascular disease, inhibition of others might actually worsen it. This review will highlight recent research on the physiopathological role of cyclic nucleotide signaling, especially with regard to PDEs. While the physiological roles and biochemical properties of cardiovascular PDEs will be summarized, the primary emphasis will be pathological. Research into the potential benefits and hazards of PDE inhibition will also be discussed. PMID:24047267
On PDE solution in transient optimization of gas networks
NASA Astrophysics Data System (ADS)
Steinbach, Marc C.
2007-06-01
Operative planning in gas distribution networks leads to large-scale mixed-integer optimization problems involving a hyperbolic PDE defined on a graph. We consider the NLP obtained under prescribed combinatorial decisions--or as relaxation in a branch-and-bound framework, addressing in particular the KKT systems arising in primal-dual interior methods. We propose a custom solution algorithm using sparse projections locally in time, based on the KKT systems' structural properties in space as induced by the discretized gas flow equations in combination with the underlying network topology. The numerical efficiency and accuracy of the algorithm are investigated, and detailed computational comparisons with a previously developed control space method and with the multifrontal solver MA27 are provided.
Exome sequencing identifies PDE4D mutations in acrodysostosis.
Lee, Hane; Graham, John M; Rimoin, David L; Lachman, Ralph S; Krejci, Pavel; Tompson, Stuart W; Nelson, Stanley F; Krakow, Deborah; Cohn, Daniel H
2012-04-01
Acrodysostosis is a dominantly-inherited, multisystem disorder characterized by skeletal, endocrine, and neurological abnormalities. To identify the molecular basis of acrodysostosis, we performed exome sequencing on five genetically independent cases. Three different missense mutations in PDE4D, which encodes cyclic AMP (cAMP)-specific phosphodiesterase 4D, were found to be heterozygous in three of the cases. Two of the mutations were demonstrated to have occurred de novo, providing strong genetic evidence of causation. Two additional cases were heterozygous for de novo missense mutations in PRKAR1A, which encodes the cAMP-dependent regulatory subunit of protein kinase A and which has been recently reported to be the cause of a form of acrodysostosis resistant to multiple hormones. These findings demonstrate that acrodysostosis is genetically heterogeneous and underscore the exquisite sensitivity of many tissues to alterations in cAMP homeostasis. PMID:22464252
A regularizing iterative ensemble Kalman method for PDE-constrained inverse problems
NASA Astrophysics Data System (ADS)
Iglesias, Marco A.
2016-02-01
We introduce a derivative-free computational framework for approximating solutions to nonlinear PDE-constrained inverse problems. The general aim is to merge ideas from iterative regularization with ensemble Kalman methods from Bayesian inference to develop a derivative-free stable method easy to implement in applications where the PDE (forward) model is only accessible as a black box (e.g. with commercial software). The proposed regularizing ensemble Kalman method can be derived as an approximation of the regularizing Levenberg-Marquardt (LM) scheme (Hanke 1997 Inverse Problems 13 79-95) in which the derivative of the forward operator and its adjoint are replaced with empirical covariances from an ensemble of elements from the admissible space of solutions. The resulting ensemble method consists of an update formula that is applied to each ensemble member and that has a regularization parameter selected in a similar fashion to the one in the LM scheme. Moreover, an early termination of the scheme is proposed according to a discrepancy principle-type of criterion. The proposed method can be also viewed as a regularizing version of standard Kalman approaches which are often unstable unless ad hoc fixes, such as covariance localization, are implemented. The aim of this paper is to provide a detailed numerical investigation of the regularizing and convergence properties of the proposed regularizing ensemble Kalman scheme; the proof of these properties is an open problem. By means of numerical experiments, we investigate the conditions under which the proposed method inherits the regularizing properties of the LM scheme of (Hanke 1997 Inverse Problems 13 79-95) and is thus stable and suitable for its application in problems where the computation of the Fréchet derivative is not computationally feasible. More concretely, we study the effect of ensemble size, number of measurements, selection of initial ensemble and tunable parameters on the performance of the method
Identification of cancer cytotoxic modulators of PDE3A by predictive chemogenomics
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
Bradshaw, Nicholas J.; Ogawa, Fumiaki; Antolin-Fontes, Beatriz; Chubb, Jennifer E.; Carlyle, Becky C.; Christie, Sheila; Claessens, Antoine; Porteous, David J.; Millar, J. Kirsty
2008-12-26
Disrupted-In-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and other major mental illnesses. Its protein binding partners include the Nuclear Distribution Factor E Homologs (NDE1 and NDEL1), LIS1, and phosphodiesterases 4B and 4D (PDE4B and PDE4D). We demonstrate that NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. LIS1 and NDEL1 have been previously suggested to be synaptic, and we now demonstrate localisation of DISC1, NDE1, and PDE4B at synapses in cultured neurons. NDE1 is phosphorylated by cAMP-dependant Protein Kinase A (PKA), whose activity is, in turn, regulated by the cAMP hydrolysis activity of phosphodiesterases, including PDE4. We propose that DISC1 acts as an assembly scaffold for all of these proteins and that the NDE1/NDEL1/LIS1/dynein complex is modulated by cAMP levels via PKA and PDE4.
Three-dimensional reconstruction method on the PDE exhaust plume flow flame temperature field
NASA Astrophysics Data System (ADS)
Zhang, Zhimin; Wan, Xiong; Luo, Ningning; Li, Shujing
2010-10-01
Pulse detonation engine (referred to as PDE) has many advantage about simple structure, high efficiency thermal [1] cycling etc. In the future, it can be widely used in unmanned aircraft, target drone, luring the plane, the imaginary target, target missiles, long-range missiles and other military targets. However, because the exhaust flame of PDE is complicated [2], non-uniform temperature distribution and mutation in real time, its 3-D temperature distribution is difficult to be measured by normal way. As a result, PDE is used in the military project need to face many difficulties and challenges. In order to analyze and improve the working performance of PDE, deep research on the detonation combustion process is necessary. However, its performance characteristic which is in non-steady-state, as well as high temperature, high pressure, transient combustion characteristics put forward high demands about the flow field parameters measurement. In this paper, the PDE exhaust flames temperature field is reconstructed based on the theory of radiation thermometry [3] and Emission Spectral Tomography (referred to as EST) [4~6] which is one branch of Optical CT. It can monitor the detonation wave temperature distribution out of the exhaust flames at different moments, it also provides authentication for the numerical simulation which directs towards PDE work performance, and then it provides the basis for improving the structure of PDE.
Buijnsters, Peter; De Angelis, Meri; Langlois, Xavier; Rombouts, Frederik J R; Sanderson, Wendy; Tresadern, Gary; Ritchie, Alison; Trabanco, Andrés A; VanHoof, Greet; Roosbroeck, Yves Van; Andrés, José-Ignacio
2014-09-11
Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 μM. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive impairment and other central nervous system related disorders. PMID:25221665
2014-01-01
Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 μM. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive impairment and other central nervous system related disorders. PMID:25221665
Rare inactivating PDE11A variants associated with testicular germ cell tumors.
Pathak, Anand; Stewart, Douglas R; Faucz, Fabio R; Xekouki, Paraskevi; Bass, Sara; Vogt, Aurelie; Zhang, Xijun; Boland, Joseph; Yeager, Meredith; Loud, Jennifer T; Nathanson, Katherine L; McGlynn, Katherine A; Stratakis, Constantine A; Greene, Mark H; Mirabello, Lisa
2015-12-01
Germline inactivating mutations of isoform 4 of phosphodiesterase (PDE) 11A (coded by the PDE11A gene) have been associated with familial adrenocortical tumors and familial testicular cancer. Testicular tissue is unique in expressing all four isoforms of PDE11A. In a prior candidate gene study of 94 familial testicular germ cell tumor (TGCT) subjects, we identified a significant association between the presence of functionally abnormal variants in PDE11A and familial TGCT risk. To validate this novel observation, we sequenced the PDE11A coding region in 259 additional TGCT patients (both familial and sporadic) and 363 controls. We identified 55 PDE11A variants: 20 missense, four splice-site, two nonsense, seven synonymous, and 22 intronic. Ten missense variants were novel; nine occurred in transcript variant 4 and one in transcript variant 3. Five rare mutations (p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R) were present only in cases and were significantly more common in cases vs controls (P=0.0037). The latter two novel variants were functionally characterized and shown to be functionally inactivating, resulting in reduced PDE activity and increased cAMP levels. In further analysis of this cohort, we focused on white participants only to minimize confounding due to population stratification. This study builds upon our prior reports implicating PDE11A variants in familial TGCT, provides the first independent validation of those findings, extends that work to sporadic testicular cancer, demonstrates that these variants are uncommonly but reproducibly associated with TGCT, and refines our understanding regarding which specific inactivating PDE11A variants are most likely to be associated with TGCT risk. PMID:26459559
Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease.
Niccolini, Flavia; Haider, Salman; Reis Marques, Tiago; Muhlert, Nils; Tziortzi, Andri C; Searle, Graham E; Natesan, Sridhar; Piccini, Paola; Kapur, Shitij; Rabiner, Eugenii A; Gunn, Roger N; Tabrizi, Sarah J; Politis, Marios
2015-10-01
There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers. PMID:26198591
Egbert, Jeremy R; Uliasz, Tracy F; Shuhaibar, Leia C; Geerts, Andreas; Wunder, Frank; Kleiman, Robin J; Humphrey, John M; Lampe, Paul D; Artemyev, Nikolai O; Rybalkin, Sergei D; Beavo, Joseph A; Movsesian, Matthew A; Jaffe, Laurinda A
2016-05-01
The meiotic cell cycle of mammalian oocytes in preovulatory follicles is held in prophase arrest by diffusion of cGMP from the surrounding granulosa cells into the oocyte. Luteinizing hormone (LH) then releases meiotic arrest by lowering cGMP in the granulosa cells. The LH-induced reduction of cGMP is caused in part by a decrease in guanylyl cyclase activity, but the observation that the cGMP phosphodiesterase PDE5 is phosphorylated during LH signaling suggests that an increase in PDE5 activity could also contribute. To investigate this idea, we measured cGMP-hydrolytic activity in rat ovarian follicles. Basal activity was due primarily to PDE1A and PDE5, and LH increased PDE5 activity. The increase in PDE5 activity was accompanied by phosphorylation of PDE5 at serine 92, a protein kinase A/G consensus site. Both the phosphorylation and the increase in activity were promoted by elevating cAMP and opposed by inhibiting protein kinase A, supporting the hypothesis that LH activates PDE5 by stimulating its phosphorylation by protein kinase A. Inhibition of PDE5 activity partially suppressed LH-induced meiotic resumption as indicated by nuclear envelope breakdown, but inhibition of both PDE5 and PDE1 activities was needed to completely inhibit this response. These results show that activities of both PDE5 and PDE1 contribute to the LH-induced resumption of meiosis in rat oocytes, and that phosphorylation and activation of PDE5 is a regulatory mechanism. PMID:27009040
Convergence acceleration for time-independent first-order PDE using optimal PNB-approximations
Holmgren, S.; Branden, H.
1996-12-31
We consider solving time-independent (steady-state) flow problems in 2D or 3D governed by hyperbolic or {open_quotes}almost hyperbolic{close_quotes} systems of partial differential equations (PDE). Examples of such PDE are the Euler and the Navier-Stokes equations. The PDE is discretized using a finite difference or finite volume scheme with arbitrary order of accuracy. If the matrix B describes the discretized differential operator and u denotes the approximate solution, the discrete problem is given by a large system of equations.
Ochiana, Stefan O.; Bland, Nicholas D.; Settimo, Luca; Campbell, Robert K.; Pollastri, Michael P.
2014-01-01
Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and in Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). With this in mind, we recently reported the profiling of a range of human PDE inhibitors, showing that human PDE4 (hPDE4) inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK-256066, a potent inhibitor of hPDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure-activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of T. brucei cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported apo structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as anti-trypanosomal agents. PMID:25283372
Johnston, Lee Ann; Erdogan, Suat; Cheung, York Fong; Sullivan, Michael; Barber, Rachael; Lynch, Martin J; Baillie, George S; Van Heeke, Gino; Adams, David R; Huston, Elaine; Houslay, Miles D
2004-01-01
PDE4A7 is an isoform encoded by the human PDE4A cAMP-specific phosphodiesterase gene that fails to hydrolyse cAMP and whose transcripts are widely expressed. Removal of either the N- or C-terminal unique portions of PDE4A7 did not reconstitute catalytic activity, showing that they did not exert a chronic inhibitory effect. A chimera (Hyb2), formed by swapping the unique N-terminal portion of PDE4A7 with that of the active PDE4A4C form, was not catalytically active. However, one formed (Hyb1) by swapping the unique C-terminal portion of PDE4A7 with that common to all active PDE4 isoforms was catalytically active. Compared with the active PDE4A4B isoform, Hyb1 exhibited a similar K(m) value for cAMP and IC50 value for rolipram inhibition, but was less sensitive to inhibition by Ro-20-1724 and denbufylline, and considerably more sensitive to thermal denaturation. The unique C-terminal region of PDE4A7 was unable to support an active catalytic unit, whereas its unique N-terminal region can. The N-terminal portion of the PDE4 catalytic unit is essential for catalytic activity and can be supplied by either highly conserved sequence found in active PDE4 isoforms from all four PDE4 subfamilies or the unique N-terminal portion of PDE4A7. A discrete portion of the conserved C-terminal region in active PDE4A isoforms underpins their aberrant migration on SDS/PAGE. Unlike active PDE4A isoforms, PDE4A7 is exclusively localized to the P1 particulate fraction in cells. A region located within the C-terminal portion of active PDE4 isoforms prevents such exclusive targeting. Three functional regions in PDE4A isoforms are identified, which influence catalytic activity, subcellular targeting and conformational status. PMID:15025561
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.
Lobban, M; Shakur, Y; Beattie, J; Houslay, M D
1994-12-01
In order to detect the two splice variant forms of type-IVB cyclic AMP phosphodiesterase (PDE) activity, DPD (type-IVB1) and PDE-4 (type-IVB2), anti-peptide antisera were generated. One set ('DPD/PDE-4-common'), generated against a peptide sequence found at the common C-terminus of these two PDEs, detected both PDEs. A second set was PDE-4 specific, being directed against a peptide sequence found within the unique N-terminal region of PDE-4. In brain, DPD was found exclusively in the cytosol and PDE-4 exclusively associated with membranes. Both brain DPD and PDE-4 activities, isolated by immunoprecipitation, were cyclic AMP-specific (KmcyclicAMP: approximately 5 microM for DPD; approximately 4 microM for PDE-4) and were inhibited by low rolipram concentrations (K1rolipram approximately 1 microM for both). Transient expression of DPD in COS-1 cells allowed identification of an approx. 64 kDa species which co-migrated on SDS/PAGE with the immunoreactive species identified in both brain cytosol and membrane fractions using the DPD/PDE-4-common antisera. The subunit size observed for PDE-4 (approx. 64 kDa) in brain membranes was similar to that predicted from the cDNA sequence, but that observed for DPD was approx. 4 kDa greater. Type-IV, rolipram-inhibited PDE activity was found in all brain regions except the pituitary, where it formed between 30 and 70% of the PDE activity in membrane and cytosolic fractions when assayed with 1 microM cyclic AMP, PDE-4 formed 40-50% of the membrane type-IV activity in all brain regions save the midbrain (approx. 20%). DPD distribution was highly restricted to certain regions, providing approx. 35% of the type-IV cytosolic activity in hippocampus and 13-21% in cortex, hypothalamus and striatum with no presence in brain stem, cerebellum, midbrain and pituitary. The combined type-IVB PDE activities of DPD and PDE-4 contributed approx. 10% of the total PDE activity in most brain regions except for the pituitary (zero) and the mid
Phosphodiesterase 3B (PDE3B) regulates NLRP3 inflammasome in adipose tissue.
Ahmad, Faiyaz; Chung, Youn Wook; Tang, Yan; Hockman, Steven C; Liu, Shiwei; Khan, Yusuf; Huo, Kevin; Billings, Eric; Amar, Marcelo J; Remaley, Alan T; Manganiello, Vincent C
2016-01-01
Activation of inflammation in white adipose tissue (WAT), includes infiltration/expansion of WAT macrophages, contributes pathogenesis of obesity, insulin resistance, and metabolic syndrome. The inflammasome comprises an intracellular sensor (NLR), caspase-1 and the adaptor ASC. Inflammasome activation leads to maturation of caspase-1 and processing of IL1β, contributing to many metabolic disorders and directing adipocytes to a more insulin-resistant phenotype. Ablation of PDE3B in WAT prevents inflammasome activation by reducing expression of NLRP3, caspase-1, ASC, AIM2, TNFα, IL1β and proinflammatory genes. Following IP injection of lipopolysaccharide (LPS), serum levels of IL1β and TNFα were reduced in PDE3B(-/-)mice compared to WT. Activation of signaling cascades, which mediate inflammasome responses, were modulated in PDE3B(-/-)mice WAT, including smad, NFAT, NFkB, and MAP kinases. Moreover, expression of chemokine CCL2, MCP-1 and its receptor CCR2, which play an important role in macrophage chemotaxis, were reduced in WAT of PDE3B(-/-)mice. In addition, atherosclerotic plaque formation was significantly reduced in the aorta of apoE(-/-)/PDE3B(-/-)and LDL-R(-/-)/PDE3B(-/-)mice compared to apoE(-/-)and LDL-R(-/-)mice, respectively. Obesity-induced changes in serum-cholesterol were blocked in PDE3B(-/-)mice. Collectively, these data establish a role for PDE3B in modulating inflammatory response, which may contribute to a reduced inflammatory state in adipose tissue. PMID:27321128
Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype.
Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Jiao, Kangwei; Buena-Atienza, Elena; Sahaboglu, Ayse; Trifunović, Dragana; Balendran, Sukirthini; Koepfli, Tanja; Mühlfriedel, Regine; Schön, Christian; Biel, Martin; Heckmann, Angelique; Beck, Susanne C; Michalakis, Stylianos; Wissinger, Bernd; Seeliger, Mathias W; Paquet-Durand, François
2015-10-01
Mutations in the PDE6A gene can cause rod photoreceptors degeneration and the blinding disease retinitis pigmentosa (RP). While a number of pathogenic PDE6A mutations have been described, little is known about their impact on compound heterozygous situations and potential interactions of different disease-causing alleles. Here, we used a novel mouse model for the Pde6a R562W mutation in combination with an existing line carrying the V685M mutation to generate compound heterozygous Pde6a V685M/R562W animals, exactly homologous to a case of human RP. We compared the progression of photoreceptor degeneration in these compound heterozygous mice with the homozygous V685M and R562W mutants, and additionally with the D670G line that is known for a relatively mild phenotype. We investigated PDE6A expression, cyclic guanosine mono-phosphate accumulation, calpain and caspase activity, in vivo retinal function and morphology, as well as photoreceptor cell death and survival. This analysis confirms the severity of different Pde6a mutations and indicates that compound heterozygous mutants behave like intermediates of the respective homozygous situations. Specifically, the severity of the four different Pde6a situations may be categorized by the pace of photoreceptor degeneration: V685M (fastest) > V685M/R562W > R562W > D670G (slowest). While calpain activity was strongly increased in all four mutants, caspase activity was not. This points to the execution of non-apoptotic cell death and may lead to the identification of new targets for therapeutic interventions. For individual RP patients, our study may help to predict time-courses for Pde6a-related retinal degeneration and thereby facilitate the definition of a window-of-opportunity for clinical interventions. PMID:26188004
ADI Finite Difference Discretization of the Heston-Hull-White PDE
NASA Astrophysics Data System (ADS)
Haentjens, Tinne; Hout, Karel in't.
2010-09-01
This paper concerns the efficient numerical solution of the time-dependent, three-dimensional Heston-Hull-White PDE for the fair prices of European call options. The numerical solution method described in this paper consists of a finite difference discretization on non-uniform spatial grids followed by an Alternating Direction Implicit scheme for the time discretization and extends the method recently proved effective by In't Hout & Foulon (2010) for the simpler, two-dimensional Heston PDE.
Phosphodiesterase 3B (PDE3B) regulates NLRP3 inflammasome in adipose tissue
Ahmad, Faiyaz; Chung, Youn Wook; Tang, Yan; Hockman, Steven C.; Liu, Shiwei; Khan, Yusuf; Huo, Kevin; Billings, Eric; Amar, Marcelo J.; Remaley, Alan T.; Manganiello, Vincent C.
2016-01-01
Activation of inflammation in white adipose tissue (WAT), includes infiltration/expansion of WAT macrophages, contributes pathogenesis of obesity, insulin resistance, and metabolic syndrome. The inflammasome comprises an intracellular sensor (NLR), caspase-1 and the adaptor ASC. Inflammasome activation leads to maturation of caspase-1 and processing of IL1β, contributing to many metabolic disorders and directing adipocytes to a more insulin-resistant phenotype. Ablation of PDE3B in WAT prevents inflammasome activation by reducing expression of NLRP3, caspase-1, ASC, AIM2, TNFα, IL1β and proinflammatory genes. Following IP injection of lipopolysaccharide (LPS), serum levels of IL1β and TNFα were reduced in PDE3B−/−mice compared to WT. Activation of signaling cascades, which mediate inflammasome responses, were modulated in PDE3B−/−mice WAT, including smad, NFAT, NFkB, and MAP kinases. Moreover, expression of chemokine CCL2, MCP-1 and its receptor CCR2, which play an important role in macrophage chemotaxis, were reduced in WAT of PDE3B−/−mice. In addition, atherosclerotic plaque formation was significantly reduced in the aorta of apoE−/−/PDE3B−/−and LDL-R−/−/PDE3B−/−mice compared to apoE−/−and LDL-R−/−mice, respectively. Obesity-induced changes in serum-cholesterol were blocked in PDE3B−/−mice. Collectively, these data establish a role for PDE3B in modulating inflammatory response, which may contribute to a reduced inflammatory state in adipose tissue. PMID:27321128
Zhang, Xinhua; Zang, Ning; Wei, Yu; Yin, Jin; Teng, Ruobing; Seftel, Allen
2012-01-01
Testosterone (T) plays a permissive role in the development of benign prostatic hyperplasia (BPH), and phosphodiesterase 5 inhibitors (PDE5is) have been found to be effective for BPH and lower urinary tract symptoms (LUTS) in clinical trials. This study investigated the effect of T on smooth muscle (SM) contractile and regulatory signaling pathways, including PDE5 expression and functional activity in prostate in male rats (sham-operated, surgically castrated, and castrated with T supplementation). In vitro organ bath studies, real-time RT-PCR, Western blot analysis, and immunohistochemistry were performed. Castration heavily attenuated contractility, including sensitivity to phenylephrine with SM myosin immunostaining revealing a disrupted SM cell arrangement in the stroma. PDE5 was immunolocalized exclusively in the prostate stroma, and orchiectomy signficantly reduced PDE5 immunopositivity, mRNA, and protein expression, along with nNOS and ROKβ mRNA, whereas it increased eNOS plus α1a and α1b adrenoreceptor expression in castrated animals. The PDE5i zaprinast significantly increased prostate strip relaxation to the nitric oxide donor sodium nitroprusside (SNP) in control but not castrated rats. But SNP alone was more effective on castrated rats, comparable with sham treated with SNP plus zaprinast. T supplementation prevented or restored all above changes, including SNP and zaprinast in vitro responsiveness. In conclusion, our data show that T positively regulates PDE5 expression and functional activities in prostate, and T ablation not only suppresses prostate size but also reduces prostatic SM contractility, with several potential SM contraction/relaxation pathways implicated. Zaprinast findings strongly suggest a major role for PDE5/cGMP in this signaling cascade. PDE5 inhibition may represent a novel mechanism for treatment of BPH. PMID:22028410
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
Nonlinear optics at interfaces
Chen, C.K.
1980-12-01
Two aspects of surface nonlinear optics are explored in this thesis. The first part is a theoretical and experimental study of nonlinear intraction of surface plasmons and bulk photons at metal-dielectric interfaces. The second part is a demonstration and study of surface enhanced second harmonic generation at rough metal surfaces. A general formulation for nonlinear interaction of surface plasmons at metal-dielectric interfaces is presented and applied to both second and third order nonlinear processes. Experimental results for coherent second and third harmonic generation by surface plasmons and surface coherent antiStokes Raman spectroscopy (CARS) are shown to be in good agreement with the theory.
Zaprinast impairs spatial memory by increasing PDE5 expression in the rat hippocampus.
Giorgi, Mauro; Pompili, Assunta; Cardarelli, Silvia; Castelli, Valentina; Biagioni, Stefano; Sancesario, Giuseppe; Gasbarri, Antonella
2015-02-01
In this work, we report the effect of post-training intraperitoneal administration of zaprinast on rat memory retention in the Morris water maze task that revealed a significant memory impairment at the intermediate dose of 10mg/kg. Zaprinast is capable of inhibiting both striatal and hippocampal PDE activity but to a different extent which is probably due to the different PDE isoforms expressed in these areas. To assess the possible involvement of cyclic nucleotides in rat memory impairment, we compared the effects obtained 30 min after the zaprinast injection with respect to 24h after injection by measuring both cyclic nucleotide levels and PDE activity. As expected, 30 min after the zaprinast administration, we observed an increase of cyclic nucleotides, which returned to a basal level within 24h, with the exception of the hippocampal cGMP which was significantly decreased at the dose of 10mg/kg of zaprinast. This increase in the hippocampal region is the result of a cGMP-specific PDE5 induction, confirmed by sildenafil inhibition, in agreement with literature data that demonstrate transcriptional regulation of PDE5 by cAMP/cGMP intracellular levels. Our results highlight the possible rebound effect of PDE inhibitors. PMID:25281278
Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4
Cedervall, Peder; Aulabaugh, Ann; Geoghegan, Kieran F.; McLellan, Thomas J.
2015-01-01
Phosphodiesterase 4 (PDE4) is an essential contributor to intracellular signaling and an important drug target. The four members of this enzyme family (PDE4A to -D) are functional dimers in which each subunit contains two upstream conserved regions (UCR), UCR1 and -2, which precede the C-terminal catalytic domain. Alternative promoters, transcriptional start sites, and mRNA splicing lead to the existence of over 25 variants of PDE4, broadly classified as long, short, and supershort forms. We report the X-ray crystal structure of long form PDE4B containing UCR1, UCR2, and the catalytic domain, crystallized as a dimer in which a disulfide bond cross-links cysteines engineered into UCR2 and the catalytic domain. Biochemical and mass spectrometric analyses showed that the UCR2-catalytic domain interaction occurs in trans, and established that this interaction regulates the catalytic activity of PDE4. By elucidating the key structural determinants of dimerization, we show that only long forms of PDE4 can be regulated by this mechanism. The results also provide a structural basis for the long-standing observation of high- and low-affinity binding sites for the prototypic inhibitor rolipram. PMID:25775568
Data on the utilization of treatment modalities for ED in Taiwan in the era of PDE5 inhibitors.
Tsai, W-K; Jiann, B-P
2014-01-01
Oral PDE5 inhibitors, intracavernosal injection and penile implants are mainstay treatments for ED. Data on their utilization reflect economic aspects of ED, but are underreported. We report utilization data and user characteristics for these modalities in Taiwan between 1999 and 2011. Sales data on PDE5 inhibitors-sildenafil citrate, tadalafil and vardenafil and on alprostadil were retrieved from International Market Services Health, and on penile implants from the local importing company for them. Users' clinical characteristics were derived from one institution. Between 1999 and 2011, sales of PDE5 inhibitors increased 5.9-fold, whereas those of alprostadil and penile implants remained stable. Over 90% of PDE5 inhibitors were purchased in pharmacies without a prescription. Between 1999 and 2011, the number of patients who received PDE5 inhibitors (n=4715) exceeded those who underwent penile injection (n=333) and penile implantation (n=108). The mean age of patients with ED who first received PDE5 inhibitors tended to decrease over consecutive years. Discontinuation of treatment with PDE5 inhibitors or intracavernosal injection reached 90% within 3 years of treatment initiation. Our data on the increasing market for PDE5 inhibitors and the trend for first use of PDE5 inhibitors at younger ages highlight the growing burden of ED and the acceptance of PDE5 inhibitors as the primary treatment for ED. PMID:24451166
The geometry of weak solutions of certain integrable nonlinar PDE`s
Alder, M.S.; Camassa, R.; Holm, D.D.; Marsden, J.E.
1994-12-31
We investigate the geometry of new classes of soliton-like weak solutions for integrable nonlinear equations. One example is the class of peakons introduced by Camassa and Holm [1993] for their integrable shallow water equation. Alber, Camassa, Holm and Marsden [1994a] put this shallow water equation into the framework of complex integrable Hamiltonian systems on Riemann surfaces and use special limiting procedures to obtain new solutions such as quasiperiodic solutions, n-solitons, solitons with quasiperiodic background, billiard, and n-peakon solutions and complex angle representations for them. They also obtain explicit formulas for phase shifts of interacting soliton solutions using the method of asymptotic reduction of the corresponding angle representations. The method they use for the shallow water equation also leads to a link between one of the members of the Dym hierarchy and geodesic flow on N-dimensional quadrics. Amongst these geodesics, particularly interesting ones are the umbilic geodesics, which generate the class of umbilic soliton solutions. Umbilic solitons have the property that as the space variable x tends to infinity, the solution tends to a periodic wave, and as x tends to minus infinity, it tends to the same periodic wave with a phase shift. Elliptic billiards may be obtained from the problem of geodesics on quadrics by collapsing along the shortest semiaxis. The corresponding Hamiltonian billiard flows axe associated to new classes of solutions of equations in the Dym hierarchy. Such billiard type solutions have discontinuous spatial derivative and, thus, are weak solutions for this class of PDE`s.
Reliability of Complex Nonlinear Numerical Simulations
NASA Technical Reports Server (NTRS)
Yee, H. C.
2004-01-01
This work describes some of the procedure to ensure a higher level of confidence in the predictability and reliability (PAR) of numerical simulation of multiscale complex nonlinear problems. The focus is on relating PAR of numerical simulations with complex nonlinear phenomena of numerics. To isolate sources of numerical uncertainties, the possible discrepancy between the chosen partial differential equation (PDE) model and the real physics and/or experimental data is set aside. The discussion is restricted to how well numerical schemes can mimic the solution behavior of the underlying PDE model for finite time steps and grid spacings. The situation is complicated by the fact that the available theory for the understanding of nonlinear behavior of numerics is not at a stage to fully analyze the nonlinear Euler and Navier-Stokes equations. The discussion is based on the knowledge gained for nonlinear model problems with known analytical solutions to identify and explain the possible sources and remedies of numerical uncertainties in practical computations. Examples relevant to turbulent flow computations are included.
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.
Development of a series of novel carbon-11 labeled PDE10A inhibitors.
Stepanov, Vladimir; Miura, Shotaro; Takano, Akihiro; Amini, Nahid; Nakao, Ryuji; Hasui, Tomoaki; Nakashima, Kosuke; Taniguchi, Takahiko; Kimura, Haruhide; Kuroita, Takanobu; Halldin, Christer
2015-05-15
Phosphodiesterase 10A (PDE10A) is a member of the PDE family of enzymes that degrades cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our aim was to label a series of structurally related PDE10A inhibitors with carbon-11 and evaluate them as potential positron emission tomography (PET) radioligands for PDE10A using nonhuman primates. The series consisted of seven compounds based on the 3-(1H-pyrazol-5-yl)pyridazin-4(1H)-one backbone. These compounds were selected from the initial larger library based on a number of parameters such as affinity, selectivity for hPDE10A in in vitro tests, lipophilicity, and on the results of multidrug resistance protein 1 (MDR1)-LLCPK1 and the parallel artificial membrane permeability assays. Seven radioligands (KIT-1, 3, 5, 6, 7, 9, and 12) were radiolabeled with carbon-11 employing O-methylation on the hydroxyl moiety using [(11)C]methyl triflate. In vivo examination of each radioligand was performed using PET in rhesus monkeys; analysis of radiometabolites in plasma also was conducted using HPLC. All seven radioligands were labeled with high (>90%) incorporation of [(11)C]methyl triflate into their appropriate precursors and with high specific radioactivity. Carbon-11 labeled KIT-5 and KIT-6 showed high accumulation in the striatum, consistent with the known anatomical distribution of PDE10A in brain, accompanied by fast washout and high specific binding ratio. In particular [(11)C]KIT-6, named [(11)C]T-773, is a promising PET tool for further examination of PDE10A in human brain. PMID:25891816
A framework for the construction of preconditioners for systems of PDE
Holmgren, S.; Otto, K.
1994-12-31
The authors consider the solution of systems of partial differential equations (PDE) in 2D or 3D using preconditioned CG-like iterative methods. The PDE is discretized using a finite difference scheme with arbitrary order of accuracy. The arising sparse and highly structured system of equations is preconditioned using a discretization of a modified PDE, possibly exploiting a different discretization stencil. The preconditioner corresponds to a separable problem, and the discretization in one space direction is constructed so that the corresponding matrix is diagonalized by a unitary transformation. If this transformation is computable using a fast O(n log{sub 2} n) algorithm, the resulting preconditioner solve is of the same complexity. Also, since the preconditioner solves are based on a dimensional splitting, the intrinsic parallelism is good. Different choices of the unitary transformation are considered, e.g., the discrete Fourier transform, sine transform, and modified sine transform. The preconditioners fully exploit the structure of the original problem, and it is shown how to compute the parameters describing them subject to different optimality constraints. Some of these results recover results derived by e.g. R. Chan, T. Chan, and E. Tyrtyshnikov, but here they are stated in a {open_quotes}PDE context{close_quotes}. Numerical experiments where different preconditioners are exploited are presented. Primarily, high-order accurate discretizations for first-order PDE problems are studied, but also second-order derivatives are considered. The results indicate that utilizing preconditioners based on fast solvers for modified PDE problems yields good solution algorithms. These results extend previously derived theoretical and numerical results for second-order approximations for first-order PDE, exploiting preconditioners based on fast Fourier transforms.
PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer
Das, Anindita; Durrant, David; Salloum, Fadi N; Xi, Lei; Kukreja, Rakesh C
2015-01-01
The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and cancer benefits. Despite mixed results of these clinical trials, there is continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients. PMID:25444755
Zhang, Yang; Chong, Edwin K. P.; Hannig, Jan; Estep, Donald
2013-01-01
We inmore » troduce a continuum modeling method to approximate a class of large wireless networks by nonlinear partial differential equations (PDEs). This method is based on the convergence of a sequence of underlying Markov chains of the network indexed by N , the number of nodes in the network. As N goes to infinity, the sequence converges to a continuum limit, which is the solution of a certain nonlinear PDE. We first describe PDE models for networks with uniformly located nodes and then generalize to networks with nonuniformly located, and possibly mobile, nodes. Based on the PDE models, we develop a method to control the transmissions in nonuniform networks so that the continuum limit is invariant under perturbations in node locations. This enables the networks to maintain stable global characteristics in the presence of varying node locations.« less
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
Protein-protein interactions of PDE4 family members - Functions, interactions and therapeutic value.
Klussmann, Enno
2016-07-01
The second messenger cyclic adenosine monophosphate (cAMP) is ubiquitous and directs a plethora of functions in all cells. Although theoretically freely diffusible through the cell from the site of its synthesis it is not evenly distributed. It rather is shaped into gradients and these gradients are established by phospodiesterases (PDEs), the only enzymes that hydrolyse cAMP and thereby terminate cAMP signalling upstream of cAMP's effector systems. Miles D. Houslay has devoted most of his scientific life highly successfully to a particular family of PDEs, the PDE4 family. The family is encoded by four genes and gives rise to around 20 enzymes, all with different functions. M. Houslay has discovered many of these functions and realised early on that PDE4 family enzymes are attractive drug targets in a variety of human diseases, but not their catalytic activity as that is encoded in conserved domains in all family members. He postulated that targeting the intracellular location would provide the specificity that modern innovative drugs require to improve disease conditions with fewer side effects than conventional drugs. Due to the wealth of M. Houslay's work, this article can only summarize some of his discoveries and, therefore, focuses on protein-protein interactions of PDE4. The aim is to discuss functions of selected protein-protein interactions and peptide spot technology, which M. Houslay introduced into the PDE4 field for identifying interacting domains. The therapeutic potential of PDE4 interactions will also be discussed. PMID:26498857
Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis.
Lynch, Danielle C; Dyment, David A; Huang, Lijia; Nikkel, Sarah M; Lacombe, Didier; Campeau, Philippe M; Lee, Brendan; Bacino, Carlos A; Michaud, Jacques L; Bernier, Francois P; Parboosingh, Jillian S; Innes, A Micheil
2013-01-01
Acrodysostosis is characterized by nasal hypoplasia, peripheral dysostosis, variable short stature, and intellectual impairment. Recently, mutations in PRKAR1A were reported in patients with acrodysostosis and hormone resistance. Subsequently, mutations in a phosphodiesterase gene (PDE4D) were identified in seven sporadic cases. We sequenced PDE4D in seven acrodysostosis patients from five families. Missense mutations were identified in all cases. Families showed de novo inheritance except one family with three affected children whose father was subsequently found to have subtle features of acrodysostosis. There were no recurrent mutations. Short stature and endocrine resistance are rare in this series; however, cognitive involvement and obesity were frequent. This last finding is relevant given PDE4D is insulin responsive and potentially involved in lipolysis. PDE4D encodes a cyclic AMP regulator and places PDE4D-related acrodysostosis within the same family of diseases as pseudohypoparathyroidism, pseudopseudohypoparathyroidism, PRKAR1A-related acrodysostosis and brachydactyly-mental retardation syndrome; all characterized by cognitive impairment and short distal extremities. PMID:23033274
NASA Astrophysics Data System (ADS)
Dumbser, Michael; Balsara, Dinshaw S.
2016-01-01
In this paper a new, simple and universal formulation of the HLLEM Riemann solver (RS) is proposed that works for general conservative and non-conservative systems of hyperbolic equations. For non-conservative PDE, a path-conservative formulation of the HLLEM RS is presented for the first time in this paper. The HLLEM Riemann solver is built on top of a novel and very robust path-conservative HLL method. It thus naturally inherits the positivity properties and the entropy enforcement of the underlying HLL scheme. However, with just the slight additional cost of evaluating eigenvectors and eigenvalues of intermediate characteristic fields, we can represent linearly degenerate intermediate waves with a minimum of smearing. For conservative systems, our paper provides the easiest and most seamless path for taking a pre-existing HLL RS and quickly and effortlessly converting it to a RS that provides improved results, comparable with those of an HLLC, HLLD, Osher or Roe-type RS. This is done with minimal additional computational complexity, making our variant of the HLLEM RS also a very fast RS that can accurately represent linearly degenerate discontinuities. Our present HLLEM RS also transparently extends these advantages to non-conservative systems. For shallow water-type systems, the resulting method is proven to be well-balanced. Several test problems are presented for shallow water-type equations and two-phase flow models, as well as for gas dynamics with real equation of state, magnetohydrodynamics (MHD & RMHD), and nonlinear elasticity. Since our new formulation accommodates multiple intermediate waves and has a broader applicability than the original HLLEM method, it could alternatively be called the HLLI Riemann solver, where the "I" stands for the intermediate characteristic fields that can be accounted for.
Francis, S H; Morris, G Z; Corbin, J D
2008-01-01
Cyclic guanosine monophosphate (cGMP) in penile vascular smooth muscle cells (VSMC) plays a key role in promoting penile erection. Phosphodiesterase-5 (PDE5) in VSMC breaks down cGMP to counter this effect. Sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis), treatments for erectile dysfunction, inhibit PDE5 action. Many men with erectile dysfunction have improved erectile function after plasma inhibitor concentration falls below therapeutic levels. Maximum effect plus onset and duration of action of inhibitor determines its efficacy. The rate and extent of cellular drug accumulation and efflux of drug from smooth muscle cells plus persistence of drug effects in these cell impact these parameters. We propose possible molecular mechanisms that could account for prolonged action of PDE5 inhibitors including (1) persistence of biochemical effects after inhibitor is cleared from cells, and (2) retention of drug in VSMC beyond plasma clearance. PMID:18418391
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.
Ahmad, Faiyaz; Shen, Weixing; Vandeput, Fabrice; Szabo-Fresnais, Nicolas; Krall, Judith; Degerman, Eva; Goetz, Frank; Klussmann, Enno; Movsesian, Matthew; Manganiello, Vincent
2015-01-01
Cyclic nucleotide phosphodiesterase 3A (PDE3) regulates cAMP-mediated signaling in the heart, and PDE3 inhibitors augment contractility in patients with heart failure. Studies in mice showed that PDE3A, not PDE3B, is the subfamily responsible for these inotropic effects and that murine PDE3A1 associates with sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2), phospholamban (PLB), and AKAP18 in a multiprotein signalosome in human sarcoplasmic reticulum (SR). Immunohistochemical staining demonstrated that PDE3A co-localizes in Z-bands of human cardiac myocytes with desmin, SERCA2, PLB, and AKAP18. In human SR fractions, cAMP increased PLB phosphorylation and SERCA2 activity; this was potentiated by PDE3 inhibition but not by PDE4 inhibition. During gel filtration chromatography of solubilized SR membranes, PDE3 activity was recovered in distinct high molecular weight (HMW) and low molecular weight (LMW) peaks. HMW peaks contained PDE3A1 and PDE3A2, whereas LMW peaks contained PDE3A1, PDE3A2, and PDE3A3. Western blotting showed that endogenous HMW PDE3A1 was the principal PKA-phosphorylated isoform. Phosphorylation of endogenous PDE3A by rPKAc increased cAMP-hydrolytic activity, correlated with shift of PDE3A from LMW to HMW peaks, and increased co-immunoprecipitation of SERCA2, cav3, PKA regulatory subunit (PKARII), PP2A, and AKAP18 with PDE3A. In experiments with recombinant proteins, phosphorylation of recombinant human PDE3A isoforms by recombinant PKA catalytic subunit increased co-immunoprecipitation with rSERCA2 and rat rAKAP18 (recombinant AKAP18). Deletion of the recombinant human PDE3A1/PDE3A2 N terminus blocked interactions with recombinant SERCA2. Serine-to-alanine substitutions identified Ser-292/Ser-293, a site unique to human PDE3A1, as the principal site regulating its interaction with SERCA2. These results indicate that phosphorylation of human PDE3A1 at a PKA site in its unique N-terminal extension promotes its incorporation into SERCA2/AKAP18
Functional Analysis of a c-di-AMP-specific Phosphodiesterase MsPDE from Mycobacterium smegmatis
Tang, Qing; Luo, Yunchao; Zheng, Cao; Yin, Kang; Ali, Maria Kanwal; Li, Xinfeng; He, Jin
2015-01-01
Cyclic di‑AMP (c-di-AMP) is a second signaling molecule involved in the regulation of bacterial physiological processes and interaction between pathogen and host. However, the regulatory network mediated by c-di-AMP in Mycobacterium remains obscure. In M. smegmatis, a diadenylate cyclase (DAC) was reported recently, but there is still no investigation on c-di-AMP phosphodiesterase (PDE). Here, we provide a systematic study on signaling mechanism of c-di-AMP PDE in M. smegmatis. Based on our enzymatic analysis, MsPDE (MSMEG_2630), which contained a DHH-DHHA1 domain, displayed a 200-fold higher hydrolytic efficiency (kcat/Km) to c-di-AMP than to c-di-GMP. MsPDE was capable of converting c-di-AMP to pApA and AMP, and hydrolyzing pApA to AMP. Site-directed mutations in DHH and DHHA1 revealed that DHH domain was critical for the phosphodiesterase activity. To explore the regulatory role of c-di-AMP in vivo, we constructed the mspde mutant (Δmspde) and found that deficiency of MsPDE significantly enhanced intracellular C12-C20 fatty acid accumulation. Deficiency of DAC in many bacteria results in cell death. However, we acquired the M. smegmatis strain with DAC gene disrupted (ΔmsdisA) by homologous recombination approach. Deletion of msdisA reduced bacterial C12-C20 fatty acids production but scarcely affected bacterial survival. We also provided evidences that superfluous c-di-AMP in M. smegmatis could lead to abnormal colonial morphology. Collectively, our results indicate that MsPDE is a functional c-di-AMP-specific phosphodiesterase both in vitro and in vivo. Our study also expands the regulatory network mediated by c-di-AMP in M. smegmatis. PMID:26078723
Coupling vs decoupling approaches for PDE/ODE systems modeling intercellular signaling
NASA Astrophysics Data System (ADS)
Carraro, Thomas; Friedmann, Elfriede; Gerecht, Daniel
2016-06-01
We consider PDE/ODE systems for the simulation of intercellular signaling in multicellular environments. The intracellular processes for each cell described here by ODEs determine the long-time dynamics, but the PDE part dominates the solving effort. Thus, it is not clear if commonly used decoupling methods can outperform a coupling approach. Based on a sensitivity analysis, we present a systematic comparison between coupling and decoupling approaches for this class of problems and show numerical results. For biologically relevant configurations of the model, our quantitative study shows that a coupling approach performs much better than a decoupling one.
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…
Ochiana, Stefan O; Bland, Nicholas D; Settimo, Luca; Campbell, Robert K; Pollastri, Michael P
2015-05-01
Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and Trypanosoma brucei, the causative agent of human African trypanosomiasis. With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK-256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure-activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of T. brucei cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported apo structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as antitrypanosomal agents. PMID:25283372
NASA Astrophysics Data System (ADS)
Dumbser, Michael; Peshkov, Ilya; Romenski, Evgeniy; Zanotti, Olindo
2016-06-01
This paper is concerned with the numerical solution of the unified first order hyperbolic formulation of continuum mechanics recently proposed by Peshkov and Romenski [110], further denoted as HPR model. In that framework, the viscous stresses are computed from the so-called distortion tensor A, which is one of the primary state variables in the proposed first order system. A very important key feature of the HPR model is its ability to describe at the same time the behavior of inviscid and viscous compressible Newtonian and non-Newtonian fluids with heat conduction, as well as the behavior of elastic and visco-plastic solids. Actually, the model treats viscous and inviscid fluids as generalized visco-plastic solids. This is achieved via a stiff source term that accounts for strain relaxation in the evolution equations of A. Also heat conduction is included via a first order hyperbolic system for the thermal impulse, from which the heat flux is computed. The governing PDE system is hyperbolic and fully consistent with the first and the second principle of thermodynamics. It is also fundamentally different from first order Maxwell-Cattaneo-type relaxation models based on extended irreversible thermodynamics. The HPR model represents therefore a novel and unified description of continuum mechanics, which applies at the same time to fluid mechanics and solid mechanics. In this paper, the direct connection between the HPR model and the classical hyperbolic-parabolic Navier-Stokes-Fourier theory is established for the first time via a formal asymptotic analysis in the stiff relaxation limit. From a numerical point of view, the governing partial differential equations are very challenging, since they form a large nonlinear hyperbolic PDE system that includes stiff source terms and non-conservative products. We apply the successful family of one-step ADER-WENO finite volume (FV) and ADER discontinuous Galerkin (DG) finite element schemes to the HPR model in the stiff
Brennenstuhl, Christina; Tanimoto, Naoyuki; Burkard, Markus; Wagner, Rebecca; Bolz, Sylvia; Trifunovic, Dragana; Kabagema-Bilan, Clement; Paquet-Durand, Francois; Beck, Susanne C; Huber, Gesine; Seeliger, Mathias W; Ruth, Peter; Wissinger, Bernd; Lukowski, Robert
2015-04-17
Phosphodiesterase-6 (PDE6) is a multisubunit enzyme that plays a key role in the visual transduction cascade in rod and cone photoreceptors. Each type of photoreceptor utilizes discrete catalytic and inhibitory PDE6 subunits to fulfill its physiological tasks, i.e. the degradation of cyclic guanosine-3',5'-monophosphate at specifically tuned rates and kinetics. Recently, the human PDE6H gene was identified as a novel locus for autosomal recessive (incomplete) color blindness. However, the three different classes of cones were not affected to the same extent. Short wave cone function was more preserved than middle and long wave cone function indicating that some basic regulation of the PDE6 multisubunit enzyme was maintained albeit by a unknown mechanism. To study normal and disease-related functions of cone Pde6h in vivo, we generated Pde6h knock-out (Pde6h(-/-)) mice. Expression of PDE6H in murine eyes was restricted to both outer segments and synaptic terminals of short and long/middle cone photoreceptors, whereas Pde6h(-/-) retinae remained PDE6H-negative. Combined in vivo assessment of retinal morphology with histomorphological analyses revealed a normal overall integrity of the retinal organization and an unaltered distribution of the different cone photoreceptor subtypes upon Pde6h ablation. In contrast to human patients, our electroretinographic examinations of Pde6h(-/-) mice suggest no defects in cone/rod-driven retinal signaling and therefore preserved visual functions. To this end, we were able to demonstrate the presence of rod PDE6G in cones indicating functional substitution of PDE6. The disparities between human and murine phenotypes caused by mutant Pde6h/PDE6H suggest species-to-species differences in the vulnerability of biochemical and neurosensory pathways of the visual signal transduction system. PMID:25739440
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
NASA Astrophysics Data System (ADS)
Schaa, R.; Gross, L.; du Plessis, J.
2016-04-01
We present a general finite-element solver, escript, tailored to solve geophysical forward and inverse modeling problems in terms of partial differential equations (PDEs) with suitable boundary conditions. Escript’s abstract interface allows geoscientists to focus on solving the actual problem without being experts in numerical modeling. General-purpose finite element solvers have found wide use especially in engineering fields and find increasing application in the geophysical disciplines as these offer a single interface to tackle different geophysical problems. These solvers are useful for data interpretation and for research, but can also be a useful tool in educational settings. This paper serves as an introduction into PDE-based modeling with escript where we demonstrate in detail how escript is used to solve two different forward modeling problems from applied geophysics (3D DC resistivity and 2D magnetotellurics). Based on these two different cases, other geophysical modeling work can easily be realized. The escript package is implemented as a Python library and allows the solution of coupled, linear or non-linear, time-dependent PDEs. Parallel execution for both shared and distributed memory architectures is supported and can be used without modifications to the scripts.
Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors.
Meegalla, Sanath K; Huang, Hui; Illig, Carl R; Parks, Daniel J; Chen, Jinsheng; Lee, Yu-Kai; Wilson, Kenneth J; Patel, Sharmila K; Cheung, Wing S; Lu, Tianbao; Kirchner, Thomas; Askari, Hossein B; Geisler, John; Patch, Raymond J; Gibbs, Alan C; Rady, Brian; Connelly, Margery; Player, Mark R
2016-09-01
Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo. PMID:27491708
LuchunYan; Liu, Jiemin; Qu, Chen; Gu, Xingye; Zhao, Xia
2015-01-01
In order to explore the odor interaction of binary odor mixtures, a series of odor intensity evaluation tests were performed using both individual components and binary mixtures of aldehydes. Based on the linear relation between the logarithm of odor activity value and odor intensity of individual substances, the relationship between concentrations of individual constituents and their joint odor intensity was investigated by employing a partial differential equation (PDE) model. The obtained results showed that the binary odor interaction was mainly influenced by the mixing ratio of two constituents, but not the concentration level of an odor sample. Besides, an extended PDE model was also proposed on the basis of the above experiments. Through a series of odor intensity matching tests for several different binary odor mixtures, the extended PDE model was proved effective at odor intensity prediction. Furthermore, odorants of the same chemical group and similar odor type exhibited similar characteristics in the binary odor interaction. The overall results suggested that the PDE model is a more interpretable way of demonstrating the odor interactions of binary odor mixtures. PMID:25635413
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
Synthesis and bioactivity of pyrazole and triazole derivatives as potential PDE4 inhibitors.
Li, Ya-Sheng; Tian, Hao; Zhao, Dong-Sheng; Hu, De-Kun; Liu, Xing-Yu; Jin, Hong-Wei; Song, Gao-Peng; Cui, Zi-Ning
2016-08-01
A series of pyrazole and triazole derivatives containing 5-phenyl-2-furan functionality were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Meanwhile, the activity of compounds containing 1,2,4-triazole (series II) was higher than that of pyrazole-attached derivatives (series I). The primary structure-activity relationship study and docking results showed that the 1,2,4-triazole moiety of compound IIk played a key role to form integral hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4. Compound IIk would be great promise as a hit compound for further study based on the preliminary structure-activity relationship and molecular modeling studies. PMID:27289320
PDE-based random-valued impulse noise removal based on new class of controlling functions.
Wu, Jian; Tang, Chen
2011-09-01
This paper is concerned with partial differential equation (PDE)-based image denoising for random-valued impulse noise. We introduce the notion of ENI (the abbreviation for "edge pixels, noisy pixels, and interior pixels") that denotes the number of homogeneous pixels in a local neighborhood and is significantly different for edge pixels, noisy pixels, and interior pixels. We redefine the controlling speed function and the controlling fidelity function to depend on ENI. According to our two controlling functions, the diffusion and fidelity process at edge pixels, noisy pixels, and interior pixels can be selectively carried out. Furthermore, a class of second-order improved and edge-preserving PDE denoising models is proposed based on the two new controlling functions in order to deal with random-valued impulse noise reliably. We demonstrate the performance of the proposed PDEs via application to five standard test images, corrupted by random-valued impulse noise with various noise levels and comparison with the related second-order PDE models and the other special filtering methods for random-valued impulse noise. Our two controlling functions are extended to automatically other PDE models. PMID:21435980
Association between PDE4D gene and ischemic stroke: recent advancements.
Das, Satrupa; Roy, Sitara; Munshi, Anjana
2016-07-01
Stroke is a severe complication and a leading cause of death worldwide and genetic studies among different ethnicities has provided the basis for involvement of phosphodiesterase 4D (PDE4D) gene in cerebrovascular diseases. Recent advancements have evaluated the role of this gene in stroke and these studies have provided a stronger support for the involvement of this gene in stroke development and few studies also suggest that it may influence outcome. Furthermore, case-control studies and meta-analysis studies have provided strong evidence for certain variants in PDE4D to predispose to stroke only among certain ethnicities. Thus, this review focuses on recent progress made in PDE4D gene research involving genetic, molecular and pharmacological aspect. A strong conclusion has emerged that clearly indicates a pivotal role played by this gene in ischemic stroke globally. Studies have also noticeably highlighted that PDE4D gene/pathway can be a suitable drug target for managing stroke; however, a more comprehensive research is still required to understand the molecular and cellular intricacies this gene plays in stroke development, progression and its outcome. PMID:26004910
Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies.
Hu, Essa; Chen, Ning; Kunz, Roxanne K; Hwang, Dah-Ren; Michelsen, Klaus; Davis, Carl; Ma, Ji; Shi, Jianxia; Lester-Zeiner, Dianna; Hungate, Randall; Treanor, James; Chen, Hang; Allen, Jennifer R
2016-07-14
We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding potential (BPND) in NHP than our previously reported tracer 1, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washout rate in vivo. Five candidates (2-6) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines (2, 3) and one keto-benzimidazole (5) exhibited PDE10A target specificity and brain uptake comparable to or better than 1 in the in vivo LC-MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [(18)F]-5 produced a significantly improved BPND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies. PMID:27437084
AB233. PDE5-Is for erectile dysfunction in patients with multiple sclerosis
Yang, Xingliang; Yuan, Jiuhong
2016-01-01
Objective Male patients with multiple sclerosis commonly suffered sexual dysfunction. Phosphodiesterase five inhibitors are efficacious and widely used for erectile dysfunction in general population and even post-TURPT patients. However, whether PDE5-Is is effective for MS-associated ED is still unclear. Methods PubMed, ISI Web of Science and Google Scholar were searched and relevant studies were evaluated for the efficacy and safety of PDE5-Is on MS-associated ED. Results Sildenafil and tadalafil were used for the treatment of MS-associated ED in reported trials. In Safarinejad trial, sildenafil was slightly better than placebo regarding improved erections, successful penetration and successful sexual attempts. For side-effects, patients in sildenafil group showed significantly high proportion and the main AE was headache. In Fowler and Lombardi trials, sildenafil and tadalafil were used for treatment of MS-associated ED respectively. Both trials showed that PDE5-Is could improve erection or quality of life for patients and his partners. Although adverse events reported in two trials, no patient discontinued because of AEs. Conclusions PDE5-Is seems to be an effective for those MS-associated ED patients. However, the detail mechanism and long-term efficacy is still unknown.
Exome Sequencing Identifies PDE4D Mutations as Another Cause of Acrodysostosis
Michot, Caroline; Le Goff, Carine; Goldenberg, Alice; Abhyankar, Avinash; Klein, Céline; Kinning, Esther; Guerrot, Anne-Marie; Flahaut, Philippe; Duncombe, Alice; Baujat, Genevieve; Lyonnet, Stanislas; Thalassinos, Caroline; Nitschke, Patrick; Casanova, Jean-Laurent; Le Merrer, Martine; Munnich, Arnold; Cormier-Daire, Valérie
2012-01-01
Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368∗]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368∗] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis. PMID:22464250
Phosphodiesterase (PDE) inhibitors in the treatment of lower urinary tract dysfunction
Ückert, Stefan; Oelke, Matthias
2011-01-01
Several disorders of the human upper and lower urinary tract, such as urinary stone disease, lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and detrusor overactivity, can be therapeutically addressed by influencing the function of the smooth musculature of the ureter, prostate or urinary bladder, respectively. In order to ensure a drug effect without significant adverse events, a certain degree of tissue selectivity is mandatory. The treatment of said conditions aims to focus on orally available drugs acting via intracellular signalling pathways. Specifically, the cyclic nucleotide monophosphate cyclic GMP represents an important mediator in the control of the outflow region (bladder, urethra). The use of phosphodiesterase (PDE) inhibitors, such as sildenafil, tadalafil, vardenafil, avanafil or udenafil, known to restrain the degradation of the second messenger cyclic GMP, offers great opportunities in the treatment of lower urinary tract dysfunction. PDE inhibitors are regarded as efficacious, have a rapid onset of action and favourable effect-to-side-effect ratio. The role of PDE5 inhibitors in the treatment of BPH/LUTS and the overactive bladder has already been addressed in randomized, double-blind, placebo-controlled trials, as well as preliminary open-label studies enrolling either several hundreds or only 20 patients. The purpose of this review is to focus on the potential use and clinical significance of PDE inhibitors in the treatment of storage and voiding dysfunctions of the lower urinary tract. The strategy of modulating the activity of PDE isoenzymes might represent a novel approach in patients with lower urinary tract dysfunction (LUTD). PMID:21745238
Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis.
Michot, Caroline; Le Goff, Carine; Goldenberg, Alice; Abhyankar, Avinash; Klein, Céline; Kinning, Esther; Guerrot, Anne-Marie; Flahaut, Philippe; Duncombe, Alice; Baujat, Genevieve; Lyonnet, Stanislas; Thalassinos, Caroline; Nitschke, Patrick; Casanova, Jean-Laurent; Le Merrer, Martine; Munnich, Arnold; Cormier-Daire, Valérie
2012-04-01
Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368*]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368(∗)] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis. PMID:22464250
The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses.
Vanmierlo, Tim; Creemers, Pim; Akkerman, Sven; van Duinen, Marlies; Sambeth, Anke; De Vry, Jochen; Uz, Tolga; Blokland, Arjan; Prickaerts, Jos
2016-04-15
Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram. PMID:26794595
De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions.
Mencacci, Niccolò E; Kamsteeg, Erik-Jan; Nakashima, Kosuke; R'Bibo, Lea; Lynch, David S; Balint, Bettina; Willemsen, Michèl A A P; Adams, Matthew E; Wiethoff, Sarah; Suzuki, Kazunori; Davies, Ceri H; Ng, Joanne; Meyer, Esther; Veneziano, Liana; Giunti, Paola; Hughes, Deborah; Raymond, F Lucy; Carecchio, Miryam; Zorzi, Giovanna; Nardocci, Nardo; Barzaghi, Chiara; Garavaglia, Barbara; Salpietro, Vincenzo; Hardy, John; Pittman, Alan M; Houlden, Henry; Kurian, Manju A; Kimura, Haruhide; Vissers, Lisenka E L M; Wood, Nicholas W; Bhatia, Kailash P
2016-04-01
Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders. PMID:27058447
Suvarna, Neesha U; O'Donnell, James M
2002-07-01
Stimulation of N-methyl-D-aspartate (NMDA) receptors on neurons activates both cAMP and cGMP signaling pathways. Experiments were carried out to determine which phosphodiesterase (PDE) families are involved in the hydrolysis of the cyclic nucleotides formed via this mechanism, using primary neuronal cultures prepared from rat cerebral cortex and hippocampus. The nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) potentiated the ability of NMDA to increase cAMP and cGMP. However, among the family-selective inhibitors, only the PDE4 inhibitor rolipram enhanced the ability of NMDA to increase cAMP in the neurons. In contrast, only the PDE2 inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) enhanced the ability of NMDA to increase cGMP. Neither adenosine nor an adenosine deaminase inhibitor mimicked the effect of EHNA; this suggests that EHNA's inhibition of PDE2, not its effects on adenosine metabolism, mediates its effects on NMDA-stimulated cGMP concentrations. The PDE inhibitor-augmented effects of NMDA on cAMP and cGMP formation were antagonized by 5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate (MK-801), verifying NMDA receptor mediation. In contrast, only NMDA-mediated cGMP formation was affected by altering either nitric oxide signaling or guanylyl cyclase; this suggests that NMDA-induced changes in cAMP are not secondary to altered cGMP concentrations. Overall, the present findings indicate that cAMP and cGMP formed in neurons as a result of NMDA receptor stimulation are hydrolyzed by PDE4 and PDE2, respectively. Selective inhibitors of the two PDE families will differentially affect the functional consequences of activation of these two signaling pathways by NMDA receptor stimulation. PMID:12065724
Preventing Blow up by Convective Terms in Dissipative PDE's
NASA Astrophysics Data System (ADS)
Bilgin, Bilgesu; Kalantarov, Varga; Zelik, Sergey
2016-06-01
We study the impact of the convective terms on the global solvability or finite time blow up of solutions of dissipative PDEs. We consider the model examples of 1D Burger's type equations, convective Cahn-Hilliard equation, generalized Kuramoto-Sivashinsky equation and KdV type equations. The following common scenario is established: adding sufficiently strong (in comparison with the destabilizing nonlinearity) convective terms to equation prevents the solutions from blowing up in a finite time and makes the considered system globally well-posed and dissipative and for weak enough convective terms the finite time blow up may occur similar to the case, when the equation does not involve convective term. This kind of result has been previously known for the case of Burger's type equations and has been strongly based on maximum principle. In contrast to this, our results are based on the weighted energy estimates which do not require the maximum principle for the considered problem.
Reeuwijk, N M; Venhuis, B J; de Kaste, D; Hoogenboom, L A P; Rietjens, I M C M; Martena, M J
2013-01-01
Herbal food supplements, claiming to enhance sexual potency, may contain deliberately added active pharmacological ingredients (APIs) that can be used for the treatment of erectile dysfunction (ED). The aim of this study was to determine whether herbal food supplements on the Dutch market indeed contain APIs that inhibit phosphodiesterase type 5 (PDE-5) inhibitors, such as sildenafil and analogous PDE-5 inhibitors. Herbal food supplements intended to enhance sexual potency (n = 71), and two soft drinks, were sampled from 2003 up to and including 2012. In 23 herbal supplements, nine different PDE-5 inhibitors were identified; in a few cases (n = 3), more than one inhibitor was indentified. The presence of these APIs was however not stated on the label. The concentrations of PDE-5 inhibitors per dose unit were analysed. Furthermore, the potential pharmacologically active properties of the detected PDE-5 inhibitors were estimated by using data from the scientific and patent literature regarding (1) in vitro PDE-5 activity, (2) reported effective doses of registered drugs with PDE-5 inhibitor activity and (3) similarity to other structural analogues. It was concluded that 18 of the 23 herbal food supplements, when used as recommended, would have significant pharmacological effects due to added APIs. Adequate use of existing regulation and control measures seems necessary to protect consumers against the adverse effects of these products. PMID:24261938
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
Rowther, Farjana B; Wei, Weinbin; Dawson, Timothy P; Ashton, Katherine; Singh, Anushree; Madiesse-Timchou, Mylene P; Thomas, D G T; Darling, John L; Warr, Tracy
2016-03-01
Cyclic nucleotides (cAMP & cGMP) are critical intracellular second messengers involved in the transduction of a diverse array of stimuli and their catabolism is mediated by phosphodiesterases (PDEs). We previously detected focal genomic amplification of PDE1C in >90 glioblastoma multiforme (GBM) cells suggesting a potential as a novel therapeutic target in these cells. In this report, we show that genomic gain of PDE1C was associated with increased expression in low passage GBM-derived cell cultures. We demonstrate that PDE1C is essential in driving cell proliferation, migration and invasion in GBM cultures since silencing of this gene significantly mitigates these functions. We also define the mechanistic basis of this functional effect through whole genome expression analysis by identifying down-stream gene effectors of PDE1C which are involved in cell cycle and cell adhesion regulation. In addition, we also demonstrate that Vinpocetine, a general PDE1 inhibitor, can also attenuate proliferation with no effect on invasion/migration. Up-regulation of at least one of this gene set (IL8, CXCL2, FOSB, NFE2L3, SUB1, SORBS2, WNT5A, and MMP1) in TCGA GBM cohorts is associated with worse outcome and PDE1C silencing down-regulated their expression, thus also indicating potential to influence patient survival. Therefore we conclude that proliferation, migration, and invasion of GBM cells could also be regulated downstream of PDE1C. PMID:25620587
Gobejishvili, Leila; Barve, Shirish; Breitkopf-Heinlein, Katja; Li, Yan; Zhang, JingWen; Avila, Diana V; Dooley, Steven; McClain, Craig J
2013-10-01
Anti-inflammatory and antifibrotic effects of the broad spectrum phosphodiesterase (PDE) inhibitor pentoxifylline have suggested an important role for cyclic nucleotides in the pathogenesis of hepatic fibrosis; however, studies examining the role of specific PDEs are lacking. Endotoxemia and Toll-like receptor 4 (TLR4)-mediated inflammatory and profibrotic signaling play a major role in the development of hepatic fibrosis. Because cAMP-specific PDE4 critically regulates lipopolysaccharide (LPS)-TLR4-induced inflammatory cytokine expression, its pathogenic role in bile duct ligation-induced hepatic injury and fibrogenesis in Sprague-Dawley rats was examined. Initiation of cholestatic liver injury and fibrosis was accompanied by a significant induction of PDE4A, B, and D expression and activity. Treatment with the PDE4-specific inhibitor rolipram significantly decreased liver PDE4 activity, hepatic inflammatory and profibrotic cytokine expression, injury, and fibrosis. At the cellular level, in relevance to endotoxemia and inflammatory cytokine production, PDE4B was observed to play a major regulatory role in the LPS-inducible tumor necrosis factor (TNF) production by isolated Kupffer cells. Moreover, PDE4 expression was also involved in the in vitro activation and transdifferentiation of isolated hepatic stellate cells (HSCs). Particularly, PDE4A, B, and D upregulation preceded induction of the HSC activation marker α-smooth muscle actin (α-SMA). In vitro treatment of HSCs with rolipram effectively attenuated α-SMA, collagen expression, and accompanying morphologic changes. Overall, these data strongly suggest that upregulation of PDE4 expression during cholestatic liver injury plays a potential pathogenic role in the development of inflammation, injury, and fibrosis. PMID:23887098
Soler, Fernando; Fernández-Belda, Francisco; Pérez-Schindler, Joaquín; Handschin, Christoph; Fuente, Teodomiro; Hernandez-Cascales, Jesús
2015-09-01
The important regulator of cardiac function, cAMP, is hydrolyzed by different cyclic nucleotide phosphodiesterases (PDEs), whose expression and activity are not uniform throughout the heart. Of these enzymes, PDE2 shapes β1 adrenoceptor-dependent cardiac cAMP signaling, both in the right and left ventricular myocardium, but its role in regulating β2 adrenoceptor-mediated responses is less well known. Our aim was to investigate possible differences in PDE2 transcription and activity between right (RV) and left (LV) rat ventricular myocardium, as well as its role in regulating β2 adrenoceptor effects. The free walls of the RV and the LV were obtained from Sprague-Dawley rat hearts. Relative mRNA for PDE2 (quantified by qPCR) and PDE2 activity (evaluated by a colorimetric procedure and using the PDE2 inhibitor EHNA) were determined in RV and LV. Also, β2 adrenoceptor-mediated effects (β2-adrenoceptor agonist salbutamol + β1 adrenoceptor antagonist CGP-20712A) on contractility and cAMP concentrations, in the absence or presence of EHNA, were studied in the RV and LV. PDE2 transcript levels were less abundant in RV than in LV and the contribution of PDE2 to the total PDE activity was around 25% lower in the microsomal fraction of the RV compared with the LV. β2 adrenoceptor activation increased inotropy and cAMP levels in the LV when measured in the presence of EHNA, but no such effects were observed in the RV, either in the presence or absence of EHNA. These results indicate interventricular differences in PDE2 transcript and activity levels, which may distinctly regulate β2 adrenoceptor-mediated contractility and cAMP concentrations in the RV and in the LV of the rat heart. PMID:25432985
Houslay, Miles D; Adams, David R
2003-01-01
cAMP is a second messenger that controls many key cellular functions. The only way to inactivate cAMP is to degrade it through the action of cAMP phosphodiesterases (PDEs). PDEs are thus poised to play a key regulatory role. PDE4 cAMP-specific phosphodiesterases appear to have specific functions with selective inhibitors serving as potent anti-inflammatory agents. The recent elucidation of the structure of the PDE4 catalytic unit allows for molecular insight into the mode of catalysis as well as substrate and inhibitor selectivity. The four PDE4 genes encode over 16 isoforms, each of which is characterized by a unique N-terminal region. PDE4 isoforms play a pivotal role in controlling functionally and spatially distinct pools of cAMP by virtue of their unique intracellular targeting. Targeting occurs by association with proteins, such as arrestins, SRC family tyrosyl kinases, A-kinase anchoring proteins ('AKAPs') and receptor for activated C kinase 1 ('RACK1'), and, in the case of isoform PDE4A1, by a specific interaction (TAPAS-1) with phosphatidic acid. PDE4 isoforms are 'designed' to be regulated by extracellular-signal-related protein kinase (ERK), which binds to anchor sites on the PDE4 catalytic domain that it phosphorylates. The upstream conserved region 1 (UCR1) and 2 (UCR2) modules that abut the PDE4 catalytic unit confer regulatory functions by orchestrating the functional outcome of phosphorylation by cAMP-dependent protein kinase ('PKA') and ERK. PDE4 enzymes stand at a crossroads that allows them to integrate various signalling pathways with that of cAMP in spatially distinct compartments. PMID:12444918
MacMullen, C M; Vick, K; Pacifico, R; Fallahi-Sichani, M; Davis, R L
2016-01-01
Bipolar disorder is a highly heritable neuropsychiatric disorder affecting nearly 2.5% of the population. Prior genetic studies identified a panel of common and rare single-nucleotide polymorphisms associated with the disease that map to the first intron of the PDE10A gene. RNA sequencing of striatal brain tissue from bipolar and healthy control subjects identified a novel transcript of PDE10A, named PDE10A19, that codes for a PDE10A isoform with a unique N terminus. Genomic sequences that can encode the novel N terminus were conserved in other primates but not rodents. The RNA transcript was expressed at equal or greater levels in the human striatum compared with the two annotated transcripts, PDE10A1 and PDE10A2. The PDE10A19 transcript was detected in polysomal fractions; western blotting experiments confirmed that the RNA transcript is translated into protein. Immunocytochemistry studies using transfected mouse striatal and cortical neurons demonstrated that the PDE10A19 protein distributes to the cytosol, like PDE10A1, and unlike PDE10A2, which is associated with plasma membranes. Immunoprecipitation and immunocytochemical experiments revealed that the PDE10A19 isoform interacts physically with PDE10A2 and, when expressed at elevated levels, interferes with the plasma membrane localization of PDE10A2. These studies illustrate the complexity of PDE10A gene expression in the human brain and highlight the need to unravel the gene's complex and complete coding capabilities along with its transcriptional and translational regulation to guide the development of therapeutic agents that target the protein for the treatment of neuropsychiatric illness. PMID:26905414
MacMullen, C M; Vick, K; Pacifico, R; Fallahi-Sichani, M; Davis, R L
2016-01-01
Bipolar disorder is a highly heritable neuropsychiatric disorder affecting nearly 2.5% of the population. Prior genetic studies identified a panel of common and rare single-nucleotide polymorphisms associated with the disease that map to the first intron of the PDE10A gene. RNA sequencing of striatal brain tissue from bipolar and healthy control subjects identified a novel transcript of PDE10A, named PDE10A19, that codes for a PDE10A isoform with a unique N terminus. Genomic sequences that can encode the novel N terminus were conserved in other primates but not rodents. The RNA transcript was expressed at equal or greater levels in the human striatum compared with the two annotated transcripts, PDE10A1 and PDE10A2. The PDE10A19 transcript was detected in polysomal fractions; western blotting experiments confirmed that the RNA transcript is translated into protein. Immunocytochemistry studies using transfected mouse striatal and cortical neurons demonstrated that the PDE10A19 protein distributes to the cytosol, like PDE10A1, and unlike PDE10A2, which is associated with plasma membranes. Immunoprecipitation and immunocytochemical experiments revealed that the PDE10A19 isoform interacts physically with PDE10A2 and, when expressed at elevated levels, interferes with the plasma membrane localization of PDE10A2. These studies illustrate the complexity of PDE10A gene expression in the human brain and highlight the need to unravel the gene's complex and complete coding capabilities along with its transcriptional and translational regulation to guide the development of therapeutic agents that target the protein for the treatment of neuropsychiatric illness. PMID:26905414
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
Algorithmic Perspectives on Problem Formulations in MDO
NASA Technical Reports Server (NTRS)
Alexandrov, Natalia M.; Lewis, Robert Michael
2000-01-01
This work is concerned with an approach to formulating the multidisciplinary optimization (MDO) problem that reflects an algorithmic perspective on MDO problem solution. The algorithmic perspective focuses on formulating the problem in light of the abilities and inabilities of optimization algorithms, so that the resulting nonlinear programming problem can be solved reliably and efficiently by conventional optimization techniques. We propose a modular approach to formulating MDO problems that takes advantage of the problem structure, maximizes the autonomy of implementation, and allows for multiple easily interchangeable problem statements to be used depending on the available resources and the characteristics of the application problem.
Yoshikawa, Masato; Hitaka, Takenori; Hasui, Tomoaki; Fushimi, Makoto; Kunitomo, Jun; Kokubo, Hironori; Oki, Hideyuki; Nakashima, Kosuke; Taniguchi, Takahiko
2016-08-15
Utilizing structure-based drug design techniques, we designed and synthesized phosphodiesterase 10A (PDE10A) inhibitors based on pyridazin-4(1H)-one. These compounds can interact with Tyr683 in the PDE10A selectivity pocket. Pyridazin-4(1H)-one derivative 1 was linked with a benzimidazole group through an alkyl spacer to interact with the OH of Tyr683 and fill the PDE10A selectivity pocket. After optimizing the linker length, we identified 1-(cyclopropylmethyl)-5-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (16f) as having highly potent PDE10A inhibitory activity (IC50=0.76nM) and perfect selectivity against other PDEs (>13,000-fold, IC50=>10,000nM). The crystal structure of 16f bound to PDE10A revealed that the benzimidazole moiety was located deep within the PDE10A selectivity pocket and interacted with Tyr683. Additionally, a bidentate interaction existed between the 5-alkoxypyridazin-4(1H)-one moiety and the conserved Gln716 present in all PDEs. PMID:27301679
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
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. 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.
Toward Interoperable Mesh, Geometry and Field Components for PDE Simulation Development
Chand, K K; Diachin, L F; Li, X; Ollivier-Gooch, C; Seol, E S; Shephard, M; Tautges, T; Trease, H
2005-07-11
Mesh-based PDE simulation codes are becoming increasingly sophisticated and rely on advanced meshing and discretization tools. Unfortunately, it is still difficult to interchange or interoperate tools developed by different communities to experiment with various technologies or to develop new capabilities. To address these difficulties, we have developed component interfaces designed to support the information flow of mesh-based PDE simulations. We describe this information flow and discuss typical roles and services provided by the geometry, mesh, and field components of the simulation. Based on this delineation for the roles of each component, we give a high-level description of the abstract data model and set of interfaces developed by the Department of Energy's Interoperable Tools for Advanced Petascale Simulation (ITAPS) center. These common interfaces are critical to our interoperability goal, and we give examples of several services based upon these interfaces including mesh adaptation and mesh improvement.
PDE-constrained multispectral imaging of tissue chromophores with the equation of radiative transfer
Kim, Hyun Keol; Flexman, Molly; Yamashiro, Darrell J.; Kandel, Jessica J.; Hielscher, Andreas H.
2010-01-01
We introduce a transport-theory-based PDE-constrained multispectral model for direct imaging of the spatial distributions of chromophores concentrations in biological tissue. The method solves the forward problem (boundary radiance at each wavelength) and the inverse problem (spatial distribution of chromophores concentrations), in an all-at-once manner in the framework of a reduced Hessian sequential quadratic programming method. To illustrate the code’s performance, we present numerical and experimental studies involving tumor bearing mice. It is shown that the PDE-constrained multispectral method accelerates the reconstruction process by up to 15 times compared to unconstrained reconstruction algorithms and provides more accurate results as compared to the so-called two-step approach to multi-wavelength imaging. PMID:21258511
Investigation of Thrust Augmentation and Acoustic Performance by Ejectors on PDE
NASA Astrophysics Data System (ADS)
Xu, Gui-yang; Weng, Chun-sheng; Li, Ning; Huang, Xiao-long
2016-04-01
Thrust augmentation and acoustic performance of a Pulse Detonation Engine (PDE) with ejector system is experimentally investigated. For these tests the LEjector/DEjector is varied from 1.18 to 4 and the axial placement of the ejector relative to the PDE exhaust is varied from an x/DPDE of -3 to 3. Results from the tests show that the optimum LEjector/DEjector based on thrust augmentation and Overall Sound Pressure Level (OASPL) is found to be 2.61. The divergent ejector performed the best based on thrust augmentation, while the reduction effect for OASPL and Peak Sound Pressure Level (PSPL) at 60° is most prominent for the convergent ejector. The optimum axial position based on thrust augmentation is determined to be x/DPDE = 2, while, x/DPDE = 0 based on OASPL and PSPL.
The estimation of material and patch parameters in a PDE-based circular plate model
NASA Technical Reports Server (NTRS)
Banks, H. T.; Smith, Ralph C.; Brown, D. E.; Metcalf, Vern L.; Silcox, R. J.
1995-01-01
The estimation of material and patch parameters for a system involving a circular plate, to which piezoceramic patches are bonded, is considered. A partial differential equation (PDE) model for the thin circular plate is used with the passive and active contributions form the patches included in the internal and external bending moments. This model contains piecewise constant parameters describing the density, flexural rigidity, Poisson ratio, and Kelvin-Voigt damping for the system as well as patch constants and a coefficient for viscous air damping. Examples demonstrating the estimation of these parameters with experimental acceleration data and a variety of inputs to the experimental plate are presented. By using a physically-derived PDE model to describe the system, parameter sets consistent across experiments are obtained, even when phenomena such as damping due to electric circuits affect the system dynamics.
Optimality conditions for the numerical solution of optimization problems with PDE constraints :
Aguilo Valentin, Miguel Alejandro; Ridzal, Denis
2014-03-01
A theoretical framework for the numerical solution of partial di erential equation (PDE) constrained optimization problems is presented in this report. This theoretical framework embodies the fundamental infrastructure required to e ciently implement and solve this class of problems. Detail derivations of the optimality conditions required to accurately solve several parameter identi cation and optimal control problems are also provided in this report. This will allow the reader to further understand how the theoretical abstraction presented in this report translates to the application.
Portegies, J M; Fick, R H J; Sanguinetti, G R; Meesters, S P L; Girard, G; Duits, R
2015-01-01
We propose two strategies to improve the quality of tractography results computed from diffusion weighted magnetic resonance imaging (DW-MRI) data. Both methods are based on the same PDE framework, defined in the coupled space of positions and orientations, associated with a stochastic process describing the enhancement of elongated structures while preserving crossing structures. In the first method we use the enhancement PDE for contextual regularization of a fiber orientation distribution (FOD) that is obtained on individual voxels from high angular resolution diffusion imaging (HARDI) data via constrained spherical deconvolution (CSD). Thereby we improve the FOD as input for subsequent tractography. Secondly, we introduce the fiber to bundle coherence (FBC), a measure for quantification of fiber alignment. The FBC is computed from a tractography result using the same PDE framework and provides a criterion for removing the spurious fibers. We validate the proposed combination of CSD and enhancement on phantom data and on human data, acquired with different scanning protocols. On the phantom data we find that PDE enhancements improve both local metrics and global metrics of tractography results, compared to CSD without enhancements. On the human data we show that the enhancements allow for a better reconstruction of crossing fiber bundles and they reduce the variability of the tractography output with respect to the acquisition parameters. Finally, we show that both the enhancement of the FODs and the use of the FBC measure on the tractography improve the stability with respect to different stochastic realizations of probabilistic tractography. This is shown in a clinical application: the reconstruction of the optic radiation for epilepsy surgery planning. PMID:26465600
Portegies, J. M.; Fick, R. H. J.; Sanguinetti, G. R.; Meesters, S. P. L.; Girard, G.; Duits, R.
2015-01-01
We propose two strategies to improve the quality of tractography results computed from diffusion weighted magnetic resonance imaging (DW-MRI) data. Both methods are based on the same PDE framework, defined in the coupled space of positions and orientations, associated with a stochastic process describing the enhancement of elongated structures while preserving crossing structures. In the first method we use the enhancement PDE for contextual regularization of a fiber orientation distribution (FOD) that is obtained on individual voxels from high angular resolution diffusion imaging (HARDI) data via constrained spherical deconvolution (CSD). Thereby we improve the FOD as input for subsequent tractography. Secondly, we introduce the fiber to bundle coherence (FBC), a measure for quantification of fiber alignment. The FBC is computed from a tractography result using the same PDE framework and provides a criterion for removing the spurious fibers. We validate the proposed combination of CSD and enhancement on phantom data and on human data, acquired with different scanning protocols. On the phantom data we find that PDE enhancements improve both local metrics and global metrics of tractography results, compared to CSD without enhancements. On the human data we show that the enhancements allow for a better reconstruction of crossing fiber bundles and they reduce the variability of the tractography output with respect to the acquisition parameters. Finally, we show that both the enhancement of the FODs and the use of the FBC measure on the tractography improve the stability with respect to different stochastic realizations of probabilistic tractography. This is shown in a clinical application: the reconstruction of the optic radiation for epilepsy surgery planning. PMID:26465600
``Once Nonlinear, Always Nonlinear''
NASA Astrophysics Data System (ADS)
Blackstock, David T.
2006-05-01
The phrase "Once nonlinear, always nonlinear" is attributed to David F. Pernet. In the 1970s he noticed that nonlinearly generated higher harmonic components (both tones and noise) don't decay as small signals, no matter how far the wave propagates. Despite being out of step with the then widespread notion that small-signal behavior is restored in "old age," Pernet's view is supported by the Burgers-equation solutions of the early 1960s. For a plane wave from a sinusoidally vibrating source in a thermoviscous fluid, the old-age decay of the nth harmonic is e-nαx, not e-n2αx (small-signal expectation), where α is the absorption coefficient at the fundamental frequency f and x is propagation distance. Moreover, for spherical waves (r the distance) the harmonic diminishes as e-nαx/rn, not e-n2αx/r. While not new, these results have special application to aircraft noise propagation, since the large propagation distances of interest imply old age. The virtual source model may be used to explain the "anomalous" decay rates. In old age most of the nth harmonic sound comes from virtual sources close to the receiver. Their strength is proportional to the nth power of the local fundamental amplitude, and that sets the decay law for the nth harmonic.
Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa
Danciger, M.; Blaney, J.; Gao, Y.Q.; Zhao, D.Y.
1995-11-01
We have studied 24 small families with presumed autosomal recessive inheritance of retinitis pigmentosa by a combination of haplotype analysis and exon screening. Initial analysis of the families was made with a dinucleotide repeat polymorphism adjacent to the gene for rod cGMP-phosphodiesterase (PDE6B). This was followed by denaturing gradient gel electrophoresis (DGGE) and single-strand conformation polymorphism electrophoresis (SSCPE) of the 22 exons and a portion of the 5{prime} untranslated region of the PDE6B gene in the probands of each family in which the PDE6B locus could not be ruled out from segregating with disease. Two probands were found with compound heterozygous mutations: Gly576Asp and His620(1-bp del) mutations were present in one proband, and a Lys706X null mutation and an AG to AT splice acceptor site mutation in intron 2 were present in the other. Only the affecteds of each of the two families carried both corresponding mutations. 29 refs., 3 figs., 1 tab.
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.
Wang, Li; Burmeister, Brian T.; Johnson, Keven R.; Baillie, George S.; Karginov, Andrei V.; Skidgel, Randal A.; O’Bryan, John P.; Carnegie, Graeme K.
2015-01-01
Hypertrophy increases the risk of heart failure and arrhythmia. Prevention or reversal of the maladaptive hypertrophic phenotype has thus been proposed to treat heart failure. Chronic β-adrenergic receptor (β-AR) stimulation induces cardiomyocyte hypertrophy by elevating 3′, 5′-cyclic adenosine monophosphate (cAMP) levels and activating downstream effectors such protein kinase A (PKA). Conversely, hydrolysis of cAMP by phosphodiesterases (PDEs) spatiotemporally restricts cAMP signaling. Here, we demonstrate that PDE4, but not PDE3, is critical in regulating cardiomyocyte hypertrophy, and may represent a potential target for preventing maladaptive hypertrophy. We identify a sequence within the upstream conserved region 1 of PDE4D, termed UCR1C, as a novel activator of PDE4 long isoforms. UCR1C activates PDE4 in complex with A-Kinase anchoring protein (AKAP)-Lbc resulting in decreased PKA signaling facilitated by AKAP-Lbc. Expression of UCR1C in cardiomyocytes inhibits hypertrophy in response to chronic β-AR stimulation. This effect is partially due to inhibition of nuclear PKA activity, which decreases phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In conclusion, PDE4 activation by UCR1C attenuates cardiomyocyte hypertrophy by specifically inhibiting nuclear PKA activity. PMID:25683917
Linear stability analysis for travelling waves of second order in time PDE's
NASA Astrophysics Data System (ADS)
Stanislavova, Milena; Stefanov, Atanas
2012-09-01
We study travelling waves φc of second order in time PDE's u_{tt}+{ L} u+N(u)=0 . The linear stability analysis for these models is reduced to the question of the stability of quadratic pencils in the form \\lambda^2Id+2c\\lambda \\partial_x+{ H}_c , where { H}_c=c^2 \\partial_{xx}+{ L}+N'(\\varphi_c) . If { H}_c is a self-adjoint operator, with a simple negative eigenvalue and a simple eigenvalue at zero, then we completely characterize the linear stability of φc. More precisely, we introduce an explicitly computable index \\omega^*({ H}_c)\\in (0, \\infty] , so that the wave φc is stable if and only if |c|\\geq \\omega^*({ H}_c) . The results are applicable both in the periodic case and in the whole line case. The method of proof involves a delicate analysis of a function { G} , associated with { H} , whose positive zeros are exactly the positive (unstable) eigenvalues of the pencil \\lambda^2Id+2c\\lambda \\partial_x+{ H} . We would like to emphasize that the function { G} is not the Evans function for the problem, but rather a new object that we define herein, which fits the situation rather well. As an application, we consider three classical models—the ‘good’ Boussinesq equation, the Klein-Gordon-Zakharov (KGZ) system and the fourth order beam equation. In the whole line case, for the Boussinesq case and the KGZ system (and as a direct application of the main results), we compute explicitly the set of speeds which give rise to linearly stable travelling waves (and for all powers of p in the case of Boussinesq). This result is new for the KGZ system, while it generalizes the results of Alexander et al (2012, personal communication) and Alexander and Sachs (1995 Nonlinear World 2 471-507), which apply to the case p = 2. For the beam equation, we provide an implicit formula (depending only on the function \\|\\varphi_c'\\|_{L^2}) , which works for all p and for both the periodic and the whole line cases. Our results complement (and exactly match
Thomae, David; Morley, Thomas J; Lee, Hsiaoju S; Barret, Olivier; Constantinescu, Cristian; Papin, Caroline; Baldwin, Ronald M; Tamagnan, Gilles D; Alagille, David
2016-05-15
Phosphodiesterase (PDE) 4 is the most prevalent PDE in the central nervous system (CNS) and catalyzes hydrolysis of intracellular cAMP, a secondary messenger. By therapeutic inhibition of PDE4, intracellular cAMP levels can be stabilized, and the symptoms of psychiatric and neurodegenerative disorders including depression, memory loss and Parkinson's disease can be ameliorated. Radiotracers targeting PDE4 can be used to study PDE4 density and function, and evaluate new PDE4 therapeutics, in vivo in a non-invasive way, as has been shown using the carbon-11 labeled PDE4 inhibitor R-(-)-rolipram. Herein we describe a small series of rolipram analogs that contain fluoro- or iodo-substituents that could be used as fluorine-18 PET or iodine-123 SPECT PDE4 radiotracers. This series was evaluated with an in vitro binding assay and a 4-(fluoromethyl) derivative of rolipram, MNI-617, was identified, with a five-fold increase in affinity for PDE4 (Kd = 0.26 nM) over R-(-)-rolipram (Kd = 1.6 nM). A deutero-analogue d2 -[(18) F]MNI-617 was radiolabeled and produced in 23% yield with high (>5 Ci/µmol) specific activity and evaluated in non-human primate, where it rapidly entered the brain, with SUVs between 4 and 5, and with a distribution pattern consistent with that of PDE4. PMID:27006107
NASA Technical Reports Server (NTRS)
Abarbanel, Saul; Gottlieb, David; Carpenter, Mark H.
1994-01-01
It has been previously shown that the temporal integration of hyperbolic partial differential equations (PDE's) may, because of boundary conditions, lead to deterioration of accuracy of the solution. A procedure for removal of this error in the linear case has been established previously. In the present paper we consider hyperbolic (PDE's) (linear and non-linear) whose boundary treatment is done via the SAT-procedure. A methodology is present for recovery of the full order of accuracy, and has been applied to the case of a 4th order explicit finite difference scheme.
Jeon, Kye-Im; Jono, Hirofumi; Miller, Clint L.; Cai, Yujun; Lim, Soyeon; Liu, Xuan; Gao, Pingjin; Abe, Jun-Ichi; Li, Jian-Dong; Yan, Chen
2010-01-01
The phenotypic change of vascular smooth muscle cells (VSMCs), from a “contractile” phenotype to “synthetic” phenotype, is crucial for pathogenic vascular remodeling in vascular diseases such as atherosclerosis and restenosis. Ca2+-calmodulin stimulated phosphodiesterase 1 (PDE1) isozymes, including PDE1A and PDE1C, play integral roles in regulating the proliferation of synthetic VSMCs. However, the underlying molecular mechanism(s) remain unknown. In this study, we explore the role and mechanism of PDE1 isoforms in regulating β-catenin/TCF signaling in VSMCs, a pathway important for vascular remodeling through promoting VSMC growth and survival. We found that inhibition of PDE1 activity markedly attenuated β-catenin/TCF signaling by down-regulating β-catenin protein. The effect of PDE1 inhibition on β-catenin protein reduction is exerted via promoting GSK3β activation, β-catenin phosphorylation, and subsequent β-catenin protein degradation. Moreover, PDE1 inhibition specifically upregulated phosphatase PP2A B56γ subunit gene expression, which is responsible for the effects of PDE1 inhibition on GSK3β and β-catenin/TCF signaling. Further more, the effect of PDE1 inhibition on β-catenin was specifically mediated by PDE1A but not PDE1C isozyme. Interestingly, in synthetic VSMCs PP2A B56γ, phospho-GSK3β, and phospho-β-catenin were all found in the nucleus, suggesting that PDE1A regulates nuclear β-catenin protein stability through the nuclear PP2A-GSK3β-β-catenin signaling axis. Taken together these findings provide direct evidence for the first time that PP2A B56γ is a critical mediator for PDE1A in the regulation of β-catenin signaling in proliferating VSMCs. PMID:21078118
Cox, Christopher D; Hostetler, Eric D; Flores, Broc A; Evelhoch, Jeffrey L; Fan, Hong; Gantert, Liza; Holahan, Marie; Eng, Waisi; Joshi, Aniket; McGaughey, Georgia; Meng, Xiangjun; Purcell, Mona; Raheem, Izzat T; Riffel, Kerry; Yan, Youwei; Renger, John J; Smith, Sean M; Coleman, Paul J
2015-11-01
Phosphodiesterase 10A (PDE10A) inhibition has recently been identified as a potential mechanism to treat multiple symptoms that manifest in schizophrenia. In order to facilitate preclinical development and support key proof-of-concept clinical trials of novel PDE10A inhibitors, it is critical to discover positron emission tomography (PET) tracers that enable plasma concentration/PDE10A occupancy relationships to be established across species with structurally diverse PDE10A inhibitors. In this Letter, we describe how a high-throughput screening hit was optimized to provide [(11)C]MK-8193 (8j), a PET tracer that supports the determination of plasma concentration/PDE10A occupancy relationships for structurally diverse series of PDE10A inhibitors in both rat and rhesus monkey. PMID:26077491
NASA Astrophysics Data System (ADS)
Grayver, Alexander V.; Kuvshinov, Alexey V.
2016-05-01
This paper presents a methodology to sample equivalence domain (ED) in nonlinear partial differential equation (PDE)-constrained inverse problems. For this purpose, we first applied state-of-the-art stochastic optimization algorithm called Covariance Matrix Adaptation Evolution Strategy (CMAES) to identify low-misfit regions of the model space. These regions were then randomly sampled to create an ensemble of equivalent models and quantify uncertainty. CMAES is aimed at exploring model space globally and is robust on very ill-conditioned problems. We show that the number of iterations required to converge grows at a moderate rate with respect to number of unknowns and the algorithm is embarrassingly parallel. We formulated the problem by using the generalized Gaussian distribution. This enabled us to seamlessly use arbitrary norms for residual and regularization terms. We show that various regularization norms facilitate studying different classes of equivalent solutions. We further show how performance of the standard Metropolis-Hastings Markov chain Monte Carlo algorithm can be substantially improved by using information CMAES provides. This methodology was tested by using individual and joint inversions of magneotelluric, controlled-source electromagnetic (EM) and global EM induction data.
NASA Astrophysics Data System (ADS)
Grayver, Alexander V.; Kuvshinov, Alexey V.
2016-02-01
This paper presents a methodology to sample equivalence domain (ED) in non-linear PDE-constrained inverse problems. For this purpose, we first applied state-of-the-art stochastic optimization algorithm called Covariance Matrix Adaptation Evolution Strategy (CMAES) to identify low misfit regions of the model space. These regions were then randomly sampled to create an ensemble of equivalent models and quantify uncertainty. CMAES is aimed at exploring model space globally and is robust on very ill-conditioned problems. We show that the number of iterations required to converge grows at a moderate rate with respect to number of unknowns and the algorithm is embarrassingly parallel. We formulated the problem by using the generalized Gaussian distribution. This enabled us to seamlessly use arbitrary norms for residual and regularization terms. We show that various regularization norms facilitate studying different classes of equivalent solutions. We further show how performance of the standard Metropolis-Hastings Markov chain Monte Carlo (MCMC) algorithm can be substantially improved by using information CMAES provides. This methodology was tested by using individual and joint inversions of Magneotelluric, Controlled-source Electromagnetic (EM) and Global EM induction data.
Polito, Marina; Guiot, Elvire; Gangarossa, Giuseppe; Longueville, Sophie; Doulazmi, Mohamed; Valjent, Emmanuel; Hervé, Denis; Girault, Jean-Antoine; Paupardin-Tritsch, Danièle; Castro, Liliana R. V.
2015-01-01
Abstract Type 10A phosphodiesterase (PDE10A) is highly expressed in the striatum, in striatonigral and striatopallidal medium-sized spiny neurons (MSNs), which express D1 and D2 dopamine receptors, respectively. PDE10A inhibitors have pharmacological and behavioral effects suggesting an antipsychotic profile, but the cellular bases of these effects are unclear. We analyzed the effects of PDE10A inhibition in vivo by immunohistochemistry, and imaged cAMP, cAMP-dependent protein kinase A (PKA), and cGMP signals with biosensors in mouse brain slices. PDE10A inhibition in mouse striatal slices produced a steady-state increase in intracellular cAMP concentration in D1 and D2 MSNs, demonstrating that PDE10A regulates basal cAMP levels. Surprisingly, the PKA-dependent AKAR3 phosphorylation signal was strong in D2 MSNs, whereas D1 MSNs remained unresponsive. This effect was also observed in adult mice in vivo since PDE10A inhibition increased phospho-histone H3 immunoreactivity selectively in D2 MSNs in the dorsomedial striatum. The PKA-dependent effects in D2 MSNs were prevented in brain slices and in vivo by mutation of the PKA-regulated phosphorylation site of 32 kDa dopamine- and cAMP-regulated phosphoprotein (DARPP-32), which is required for protein phosphatase-1 inhibition. These data highlight differences in the integration of the cAMP signal in D1 and D2 MSNs, resulting from stronger inhibition of protein phosphatase-1 by DARPP-32 in D2 MSNs than in D1 MSNs. This study shows that PDE10A inhibitors share with antipsychotic medications the property of activating preferentially PKA-dependent signaling in D2 MSNs. PMID:26465004
Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis
Sandner, Peter; Tinel, Hanna; Affaitati, Giannapia; Costantini, Raffaele; Giamberardino, Maria Adele
2015-01-01
Urinary colics from calculosis are frequent and intense forms of pain whose current pharmacological treatment remains unsatisfactory. New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO) / cyclic guanosine monophosphate (cGMP) / phosphodiesterase type 5 (PDE5) system may contribute to ureteral motility influencing stone expulsion. We investigated if PDE5 inhibitors and sGC stimulators influence ureteral contractility, pain behaviour and stone expulsion in a rat model of ureteral calculosis. We investigated: a)the sex-specific PDE5 distribution in the rat ureter; b)the functional in vitro effects of vardenafil and sildenafil (PDE5 inhibitors) and BAY41-2272 (sGC stimulator) on induced ureteral contractility in rats and c)the in vivo effectiveness of vardenafil and BAY41-2272, alone and combined with ketoprofen, vs hyoscine-N-butylbromide alone or combined with ketoprofen, on behavioural pain indicators and stone expulsion in rats with artificial calculosis in one ureter. PDE5 was abundantly expressed in male and female rats’ ureter. In vitro, both vardenafil and BAY41-2272 significantly relaxed pre-contracted ureteral strips. In vivo, all compounds significantly reduced number and global duration of “ureteral crises” and post-stone lumbar muscle hyperalgesia in calculosis rats. The highest level of reduction of the pain behaviour was observed with BAY41-2272 among all spasmolytics administered alone, and with the combination of ketoprofen with BAY41-2272. The percentage of stone expulsion was maximal in the ketoprofen+BAY41-2272 group. The NO/cGMP/PDE5 pathway is involved in the regulation of ureteral contractility and pain behaviour in urinary calculosis. PDE5 inhibitors and sGC stimulators could become a potent new option for treatment of urinary colic pain. PMID:26509272
Polito, Marina; Guiot, Elvire; Gangarossa, Giuseppe; Longueville, Sophie; Doulazmi, Mohamed; Valjent, Emmanuel; Hervé, Denis; Girault, Jean-Antoine; Paupardin-Tritsch, Danièle; Castro, Liliana R V; Vincent, Pierre
2015-01-01
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
Thompson, B E; Freking, F; Pho, V; Schlinger, B A; Cherry, J A
2000-11-10
Songbirds are important animal models for studying neural mechanisms underlying learning and memory. While evidence has emerged that cAMP plays a significant role in invertebrate and mammalian learning, little is known about the role of cAMP pathways in regulating neuronal function in birds. With the goal of identifying important components of this pathway, we report the first cloning of a cAMP-specific, Type IV phosphodiesterase (PDE4) in a non-mammalian vertebrate. A combination of PCR analysis and cDNA library screening was used to show that homologs of the four known mammalian PDE4 genes also exist in zebra finch. A full-length cDNA representing the zebra finch homolog of PDE4B1 was isolated from a telencephalic library. Expression of this cDNA in human embryonic kidney 293 (HEK) cells yielded an enzyme that hydrolyzed cAMP with a low K(m) and was inhibited by micromolar concentrations of rolipram; these properties are typical of all known mammalian PDE4s. In brain, northern blots revealed transcripts of 3.6 and 4.4 kb in adults, but only the 3.6 kb transcript in juveniles, suggesting that PDE4 expression is developmentally regulated. In situ hybridization of tissue sections demonstrated that PDE4 message was distributed widely throughout the adult zebra finch brain, including regions controlling the learning of songs and the acquisition of spatial memories. These data suggest that PDE4 enzymes may influence a variety of brain functions in these birds and play a role in learning. PMID:11072099
Hajjhussein, Hassan; Suvarna, Neesha U.; Gremillion, Carmen; Judson Chandler, L.; O’Donnell, James M.
2007-01-01
NMDA receptor-induced cAMP and cGMP are selectively hydrolyzed by PDE4 and PDE2, respectively, in rat primary cerebral cortical and hippocampal cultures. Because cAMP levels regulate the expression of PDE4 in rat primary cortical cultures, we examined the manner in which NMDA receptor activity regulates the age-dependent increase in the expression of PDE4A observed in vivo and in vitro. Inhibiting the activity of NR2B subunit with ifenprodil blocked NMDA receptor-induced cGMP synthesis and increased NMDA receptor-induced cAMP levels in a manner that reduced PDE4 activity. Therefore, NR1/NR2B receptor-induced cGMP signaling is involved in an acute cross-talk regulation of NR1/NR2A receptor-induced cAMP levels, mediated by PDE4. Chronic inhibition of NMDA receptor activity with MK-801 reduced PDE4A1 and PDE4A5 expression and activity in a time-dependent manner; this effect was reversed by adding the PKA activator dbr-cAMP. Inhibiting GABA receptors with bicuculline increased NMDA receptor-induced cAMP synthesis and PDE4A expression in cultures treated between DIV 16 and DIV 21 but not in cultures treated between DIV 8 and DIV 13. This effect was due to a high tone of NMDA receptor-induced cGMP in younger cultures, which negatively regulated the expression of PDE4A by a PKG-mediated process. The present results are consistent with behavioral data showing that both PDE4 and PDE2 are involved in NMDA receptor-mediated memory processes. PMID:17407767
Marx, Degenhard; Tassabehji, Mahmoud; Heer, Sabine; Hüttenbrink, K-B; Szelenyi, Istvan
2002-01-01
The aim of this study was to investigate the role of the inhibitors of different PDE isoenzymes (PDE 1-5) on the production of two pro-inflammatory cytokines - tumor necrosis factor alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Two in vitro models were used to compare the antiinflammatory properties of PDE inhibitors with that of glucocorticoids. The effect on TNF release from diluted human blood following lipopolysaccharide (LPS from Salmonella abortus equi) stimulation as well as the GM-CSF and TNF release from human nasal polyp cells following allergic stimulation were investigated. Both models proofed to be well suited for the characterisation of the antiinflammatory properties of new chemical entities. In diluted human blood and dispersed human nasal polyp cells the induced TNF release was most potently suppressed by selective PDE4 inhibitors. Amrinone and milrinone, selective PDE3 inhibitors, suppressed TNF secretion to a lesser extent. The effects of theophylline (unspecific PDE inhibitor), vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor) and the PDE5 inhibitors zaprinast and E 4021 were weak. In human blood, the tested glucocorticoids beclomethasone, dexamethasone and fluticasone inhibited the LPS induced TNF release potently in a concentration dependent manner, whereas in dispersed human nasal polyp cells, the effect of the glucocorticoids on allergically induced TNF release, with the exception of dexamethasone, was much less pronounced. Glucocorticoids were the most potent inhibitors of GM-CSF release and the effect correlates well with the affinity to the glucocorticoid receptor. The selective PDE 4 inhibitors, and to a certain extent the PDE3 inhibitors amrinone and milrinone, reduced the GM-CSF release in a concentration dependent manner. In all investigations selective PDE4 inhibitors reduced TNF release to a much higher degree (4-10 fold) than GM-CSF release. PMID:11969359
Schafer, Peter H; Truzzi, Francesca; Parton, Anastasia; Wu, Lei; Kosek, Jolanta; Zhang, Ling-Hua; Horan, Gerald; Saltari, Annalisa; Quadri, Marika; Lotti, Roberta; Marconi, Alessandra; Pincelli, Carlo
2016-07-01
Phosphodiesterases 4 (PDE4) act as proinflammatory enzymes via degradation of cAMP, whereas PDE4 inhibitors play an anti-inflammatory role in vitro and in vivo. In particular, apremilast has been recently approved for the treatment of psoriasis and psoriatic arthritis. However, little is known on the expression pattern of PDE4 in psoriasis. We report that PDE4B and PDE4D mRNA are overexpressed in peripheral blood mononuclear cells (PBMC) from psoriasis, as compared with normal controls, while apremilast reduces PBMC production of a number of pro-inflammatory cytokines and increases the levels of anti-inflammatory mediators. PDE4 expression is up-regulated in psoriatic dermis as compared with normal skin, with particular regard to fibroblasts. This is confirmed in vitro, where both dermal fibroblasts (DF) and, to a greater extent, myofibroblasts (DM) express all PDE4 isoforms at the mRNA and protein level. Because PDE4 interacts with the nerve growth factor (NGF) receptor CD271 in lung fibroblasts, we evaluated the relationship and function of PDE4 and CD271 in normal human skin fibroblasts. All PDE4 isoforms co-immunoprecipitate with CD271 in DM, while apremilast inhibits apoptosis induced by β-amyloid, a CD271 ligand, in DM. Furthermore, apremilast significantly reduces NGF- and transforming growth factor-β1 (TGF-β1)-induced fibroblast migration, and inhibits DF differentiation into DM mediated by NGF or TGF-β1. Finally, in DM, apremilast significantly reduces cAMP degradation induced by treatment with β-amyloid. Taken together, these results indicate that PDE4 play an important role in psoriasis. In addition, the study reveals that the PDE4/CD271 complex could be important in modulating fibroblast functions. PMID:26806620
Nonlinear control in fusion reactors
NASA Astrophysics Data System (ADS)
Schuster, Eugenio
There is consensus in the fusion reactor community that active control will be one of the key enabling technologies. With further advancements in reduced-order fusion modeling, advances in control systems for fusion will continue, including vertical and shape control, kinetic and current profile control, MHD (magnetohydrodynamic) stabilization and plasma transport reduction. This dissertation addresses different control problems in tokamaks using as common denominator a nonlinear control approach. Contributions are made in the areas of kinetic control, magnetic control, and MHD flow control. In the area of kinetic control, we approach the problem of nonlinear control of burn instability in fission reactors, where a lumped-parameter nonlinear model involving approximate conservation equations for the energy and the densities of the species is used to synthesize a nonlinear feedback controller (backstepping, feedback linearization, passivity and input to state stability) for stabilizing the thermally unstable burn condition of a fusion reactor. In addition, the problem of control of kinetic profiles in non-burning plasmas, where a set of nonlinear partial differential equations (PDE's) describing approximately the dynamics of the density and energy was considered as the plant model used to synthesize a boundary controller (infinite-dimensional nonlinear backstepping) whose goal was the control of the density and energy spatial distributions, is also considered. In the area of magnetic control, the problem of plasma vertical position stabilization and shape control under actuation saturation in the DIII-D Tokamak at General Atomics is approached. In this case, modifications of the nominal control loops (nonlinear anti-windup augmentation) are proposed to ensure stability of the plant and good behavior of the nominal controller under the presence of voltage saturation in the coils that are used to vertically position and shape the plasma inside the tokamak. In the area
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
Feed Formulation and Manufacture
Technology Transfer Automated Retrieval System (TEKTRAN)
This chapter provides information on feed formulation and manufacture. To formulate and manufacture high quality fish feeds, including tilapia feeds, one should have knowledge of nutrient requirements, nutrient composition, digestibility, and availability of feed ingredients; impacts of manufacturin...
Bolger, Graeme B.; Dunlop, Allan J.; Meng, Dong; Day, Jon P.; Klussmann, Enno; Baillie, George S.; Adams, David R.; Houslay, Miles D.
2015-01-01
PDE4 family cAMP phosphodiesterases play a pivotal role in determining compartmentalised cAMP signalling through targeted cAMP breakdown. Expressing the widely found PDE4D5 isoform, as both bait and prey in a yeast 2-hybrid system, we demonstrated interaction consistent with the notion that long PDE4 isoforms form dimers. Four potential dimerization sites were uncovered using a scanning peptide array approach, where a recombinant purified PDE4D5 fusion protein was used to probe a 25-mer library of overlapping peptides covering the entire PDE4D5 sequence. Key residues involved in PDE4D5 dimerization were defined using a site-directed mutagenesis programme directed by an alanine scanning peptide array approach. Critical residues stabilising PDE4D5 dimerization were defined within the regulatory UCR1 region found in long, but not short, PDE4 isoforms, namely the Arg173, Asn174 and Asn175 (DD1) cluster. Disruption of the DD1 cluster was not sufficient, in itself, to destabilise PDE4D5 homodimers. Instead, disruption of an additional interface, located on the PDE4 catalytic unit, was also required to convert PDE4D5 into a monomeric form. This second dimerization site on the conserved PDE4 catalytic unit is dependent upon a critical ion pair interaction. This involves Asp463 and Arg499 in PDE4D5, which interact in a trans fashion involving the two PDE4D5 molecules participating in the homodimer. PDE4 long isoforms adopt a dimeric state in living cells that is underpinned by two key contributory interactions, one involving the UCR modules and one involving an interface on the core catalytic domain. We propose that short forms do not adopt a dimeric configuration because, in the absence of the UCR1 module, residual engagement of the remaining core catalytic domain interface provides insufficient free energy to drive dimerization. The functioning of PDE4 long and short forms is thus poised to be inherently distinct due to this difference in quaternary structure. PMID
Penmatsa, Himabindu; Zhang, Weiqiang; Yarlagadda, Sunitha; Li, Chunying; Conoley, Veronica G.; Yue, Junming; Bahouth, Suleiman W.; Buddington, Randal K.; Zhang, Guangping; Nelson, Deborah J.; Sonecha, Monal D.; Manganiello, Vincent; Wine, Jeffrey J.
2010-01-01
Formation of multiple-protein macromolecular complexes at specialized subcellular microdomains increases the specificity and efficiency of signaling in cells. In this study, we demonstrate that phosphodiesterase type 3A (PDE3A) physically and functionally interacts with cystic fibrosis transmembrane conductance regulator (CFTR) channel. PDE3A inhibition generates compartmentalized cyclic adenosine 3′,5′-monophosphate (cAMP), which further clusters PDE3A and CFTR into microdomains at the plasma membrane and potentiates CFTR channel function. Actin skeleton disruption reduces PDE3A–CFTR interaction and segregates PDE3A from its interacting partners, thus compromising the integrity of the CFTR-PDE3A–containing macromolecular complex. Consequently, compartmentalized cAMP signaling is lost. PDE3A inhibition no longer activates CFTR channel function in a compartmentalized manner. The physiological relevance of PDE3A–CFTR interaction was investigated using pig trachea submucosal gland secretion model. Our data show that PDE3A inhibition augments CFTR-dependent submucosal gland secretion and actin skeleton disruption decreases secretion. PMID:20089840
Punzalan, Florencio Rusty; Kunieda, Yoshitoshi; Amano, Akira
2015-01-01
Clinical and experimental studies involving human hearts can have certain limitations. Methods such as computer simulations can be an important alternative or supplemental tool. Physiological simulation at the tissue or organ level typically involves the handling of partial differential equations (PDEs). Boundary conditions and distributed parameters, such as those used in pharmacokinetics simulation, add to the complexity of the PDE solution. These factors can tailor PDE solutions and their corresponding program code to specific problems. Boundary condition and parameter changes in the customized code are usually prone to errors and time-consuming. We propose a general approach for handling PDEs and boundary conditions in computational models using a replacement scheme for discretization. This study is an extension of a program generator that we introduced in a previous publication. The program generator can generate code for multi-cell simulations of cardiac electrophysiology. Improvements to the system allow it to handle simultaneous equations in the biological function model as well as implicit PDE numerical schemes. The replacement scheme involves substituting all partial differential terms with numerical solution equations. Once the model and boundary equations are discretized with the numerical solution scheme, instances of the equations are generated to undergo dependency analysis. The result of the dependency analysis is then used to generate the program code. The resulting program code are in Java or C programming language. To validate the automatic handling of boundary conditions in the program code generator, we generated simulation code using the FHN, Luo-Rudy 1, and Hund-Rudy cell models and run cell-to-cell coupling and action potential propagation simulations. One of the simulations is based on a published experiment and simulation results are compared with the experimental data. We conclude that the proposed program code generator can be used to
Punzalan, Florencio Rusty; Kunieda, Yoshitoshi; Amano, Akira
2015-01-01
Clinical and experimental studies involving human hearts can have certain limitations. Methods such as computer simulations can be an important alternative or supplemental tool. Physiological simulation at the tissue or organ level typically involves the handling of partial differential equations (PDEs). Boundary conditions and distributed parameters, such as those used in pharmacokinetics simulation, add to the complexity of the PDE solution. These factors can tailor PDE solutions and their corresponding program code to specific problems. Boundary condition and parameter changes in the customized code are usually prone to errors and time-consuming. We propose a general approach for handling PDEs and boundary conditions in computational models using a replacement scheme for discretization. This study is an extension of a program generator that we introduced in a previous publication. The program generator can generate code for multi-cell simulations of cardiac electrophysiology. Improvements to the system allow it to handle simultaneous equations in the biological function model as well as implicit PDE numerical schemes. The replacement scheme involves substituting all partial differential terms with numerical solution equations. Once the model and boundary equations are discretized with the numerical solution scheme, instances of the equations are generated to undergo dependency analysis. The result of the dependency analysis is then used to generate the program code. The resulting program code are in Java or C programming language. To validate the automatic handling of boundary conditions in the program code generator, we generated simulation code using the FHN, Luo-Rudy 1, and Hund-Rudy cell models and run cell-to-cell coupling and action potential propagation simulations. One of the simulations is based on a published experiment and simulation results are compared with the experimental data. We conclude that the proposed program code generator can be used to
Patel, Dhavalkumar Narendrabhai; Li, Lin; Kee, Chee-Leong; Ge, Xiaowei; Low, Min-Yong; Koh, Hwee-Ling
2014-01-01
The popularity of phosphodiesterase type 5 (PDE-5) enzyme inhibitors for the treatment of erectile dysfunction has led to the increase in prevalence of illicit sexual performance enhancement products. PDE-5 inhibitors, namely sildenafil, tadalafil and vardenafil, and their unapproved designer analogues are being increasingly used as adulterants in the herbal products and health supplements marketed for sexual performance enhancement. To date, more than 50 unapproved analogues of prescription PDE-5 inhibitors were found as adulterants in the literature. To avoid detection of such adulteration by standard screening protocols, the perpetrators of such illegal products are investing time and resources to synthesize exotic analogues and devise novel means for adulteration. A comprehensive review of conventional and advance analytical techniques to detect and characterize the adulterants is presented. The rapid identification and structural elucidation of unknown analogues as adulterants is greatly enhanced by the wide myriad of analytical techniques employed, including high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), liquid chromatography mass-spectrometry (LC-MS), nuclear magnetic resonance (NMR) spectroscopy, vibrational spectroscopy, liquid chromatography-Fourier transform ion cyclotron resonance-mass spectrometry (LC-FT-ICR-MS), liquid chromatograph-hybrid triple quadrupole linear ion trap mass spectrometer with information dependent acquisition, ultra high performance liquid chromatography-time of flight-mass spectrometry (UHPLC-TOF-MS), ion mobility spectroscopy (IMS) and immunoassay methods. The many challenges in detecting and characterizing such adulterants, and the need for concerted effort to curb adulteration in order to safe guard public safety and interest are discussed. PMID:23721687
Yang, Shao-Hua; Bi, Xiao-Jun; Xie, Yan; Li, Cong; Zhang, Sheng-Li; Zhang, Qin; Sun, Dong-Xiao
2015-01-01
Phosphodiesterase9A (PDE9A) is a cyclic guanosine monophosphate (cGMP)-specific enzyme widely expressed among the tissues, which is important in activating cGMP-dependent signaling pathways. In our previous genome-wide association study, a single nucleotide polymorphism (SNP) (BTA-55340-no-rsb) located in the intron 14 of PDE9A, was found to be significantly associated with protein yield. In addition, we found that PDE9A was highly expressed in mammary gland by analyzing its mRNA expression in different tissues. The objectives of this study were to identify genetic polymorphisms of PDE9A and to determine the effects of these variants on milk production traits in dairy cattle. DNA sequencing identified 11 single nucleotide polymorphisms (SNPs) and six SNPs in 5′ regulatory region were genotyped to test for the subsequent association analyses. After Bonferroni correction for multiple testing, all these identified SNPs were statistically significant for one or more milk production traits (p < 0.0001~0.0077). Interestingly, haplotype-based association analysis revealed similar effects on milk production traits (p < 0.01). In follow-up RNA expression analyses, two SNPs (c.-1376 G>A, c.-724 A>G) were involved in the regulation of gene expression. Consequently, our findings provide confirmatory evidences for associations of PDE9A variants with milk production traits and these identified SNPs may serve as genetic markers to accelerate Chinese Holstein breeding program. PMID:26556348
Yang, Shao-Hua; Bi, Xiao-Jun; Xie, Yan; Li, Cong; Zhang, Sheng-Li; Zhang, Qin; Sun, Dong-Xiao
2015-01-01
Phosphodiesterase9A (PDE9A) is a cyclic guanosine monophosphate (cGMP)-specific enzyme widely expressed among the tissues, which is important in activating cGMP-dependent signaling pathways. In our previous genome-wide association study, a single nucleotide polymorphism (SNP) (BTA-55340-no-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. PMID:26556348
Liu, Jianrong; Wenzel, Barbara; Dukic-Stefanovic, Sladjana; Teodoro, Rodrigo; Ludwig, Friedrich-Alexander; Deuther-Conrad, Winnie; Schröder, Susann; Chezal, Jean-Michel; Moreau, Emmanuel; Brust, Peter; Maisonial-Besset, Aurélie
2016-01-01
Phosphodiesterases (PDEs) are enzymes that play a major role in cell signalling by hydrolysing the secondary messengers cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) throughout the body and brain. Altered cyclic nucleotide-mediated signalling has been associated with a wide array of disorders, including neurodegenerative disorders. Recently, PDE5 has been shown to be involved in neurodegenerative disorders such as Alzheimer’s disease, but its precise role has not been elucidated yet. To visualize and quantify the expression of this enzyme in brain, we developed a radiotracer for specific PET imaging of PDE5. A quinoline-based lead compound has been structurally modified resulting in the fluoroethoxymethyl derivative ICF24027 with high inhibitory activity towards PDE5 (IC50 = 1.86 nM). Radiolabelling with fluorine-18 was performed by a one-step nucleophilic substitution reaction using a tosylate precursor (RCY(EOB) = 12.9% ± 1.8%; RCP > 99%; SA(EOS) = 70–126 GBq/μmol). In vitro autoradiographic studies of [18F]ICF24027 on different mouse tissue as well as on porcine brain slices demonstrated a moderate specific binding to PDE5. In vivo studies in mice revealed that [18F]ICF24027 was metabolized under formation of brain penetrable radiometabolites making the radiotracer unsuitable for PET imaging of PDE5 in brain. PMID:27110797
Prediction of meteor shower associated with Comet 122P/de Vico
NASA Astrophysics Data System (ADS)
Tomko, Dusan; Neslusan, Lubos
2013-01-01
We model, for a far past, a theoretical stream associated with Comet 122P/de Vico and follow its dynamical evolution until present. Selecting the modeled particles approaching the Earth's orbit at the present, we predict the characteristics of a potential meteor shower and try to identify these particles with the meteors in three databases (photo, radar, and video). Our overall prediction is, however, negative because only the particles released from the comet nucleus before approximately 37 000 years ago are found to evolve into a collision course with the Earth and, therefore, form a possible shower. Meteoroids are known to survive a much shorter time in interplanetary space, unfortunately.
A discontinuous Galerkin method for two-dimensional PDE models of Asian options
NASA Astrophysics Data System (ADS)
Hozman, J.; Tichý, T.; Cvejnová, D.
2016-06-01
In our previous research we have focused on the problem of plain vanilla option valuation using discontinuous Galerkin method for numerical PDE solution. Here we extend a simple one-dimensional problem into two-dimensional one and design a scheme for valuation of Asian options, i.e. options with payoff depending on the average of prices collected over prespecified horizon. The algorithm is based on the approach combining the advantages of the finite element methods together with the piecewise polynomial generally discontinuous approximations. Finally, an illustrative example using DAX option market data is provided.
Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity.
Schafer, P H; Parton, A; Capone, L; Cedzik, D; Brady, H; Evans, J F; Man, H-W; Muller, G W; Stirling, D I; Chopra, R
2014-09-01
Apremilast, an oral small molecule inhibitor of phosphodiesterase 4 (PDE4), is in development for chronic inflammatory disorders, and has shown efficacy in psoriasis, psoriatic arthropathies, and Behçet's syndrome. In March 2014, the US Food and Drug Administration approved apremilast for the treatment of adult patients with active psoriatic arthritis. The properties of apremilast were evaluated to determine its specificity, effects on intracellular signaling, gene and protein expression, and in vivo pharmacology using models of innate and adaptive immunity. Apremilast inhibited PDE4 isoforms from all four sub-families (A1A, B1, B2, C1, and D2), with IC50 values in the range of 10 to 100 nM. Apremilast did not significantly inhibit other PDEs, kinases, enzymes, or receptors. While both apremilast and thalidomide share a phthalimide ring structure, apremilast lacks the glutarimide ring and thus fails to bind to cereblon, the target of thalidomide action. In monocytes and T cells, apremilast elevated intracellular cAMP and induced phosphorylation of the protein kinase A substrates CREB and activating transcription factor-1 while inhibiting NF-κB transcriptional activity, resulting in both up- and down-regulation of several genes induced via TLR4. Apremilast reduced interferon-α production by plasmacytoid dendritic cells and inhibited T-cell cytokine production, but had little effect on B-cell immunoglobulin secretion. In a transgenic T-cell and B-cell transfer murine model, apremilast (5mg/kg/day p.o.) did not affect clonal expansion of either T or B cells and had little or no effect on their expression of activation markers. The effect of apremilast on innate immunity was tested in the ferret lung neutrophilia model, which allows monitoring of the known PDE4 inhibitor gastrointestinal side effects (nausea and vomiting). Apremilast significantly inhibited lung neutrophilia at 1mg/kg, but did not induce significant emetic reflexes at doses <30 mg/kg. Overall, the
Carnosic acid slows photoreceptor degeneration in the Pde6brd10 mouse model of retinitis pigmentosa
Kang, Kai; Tarchick, Matthew J.; Yu, Xiaoshan; Beight, Craig; Bu, Ping; Yu, Minzhong
2016-01-01
The photoreceptor cell death associated with the various genetic forms of retinitis pigmentosa (RP) is currently untreatable and leads to partial or complete vision loss. Carnosic acid (CA) upregulates endogenous antioxidant enzymes and has proven neuroprotective in studies of neurodegenerative models affecting the brain. In this study, we examined the potential effect of CA on photoreceptor death in the Pde6brd10 mouse model of RP. Our data shows that CA provided morphological and functional preservation of photoreceptors. CA appears to exert its neuroprotective effects through inhibition of oxidative stress and endoplasmic reticulum stress. PMID:26961159
A homotopy analysis method for the option pricing PDE in illiquid markets
NASA Astrophysics Data System (ADS)
E-Khatib, Youssef
2012-09-01
One of the shortcomings of the Black and Scholes model on option pricing is the assumption that trading the underlying asset does not affect the underlying asset price. This can happen in perfectly liquid markets and it is evidently not viable in markets with imperfect liquidity (illiquid markets). It is well-known that markets with imperfect liquidity are more realistic. Thus, the presence of price impact while studying options is very important. This paper investigates a solution for the option pricing PDE in illiquid markets using the homotopy analysis method.
Lagrangian formulation of the one-dimensional Vlasov equation. [in plasma physics
NASA Technical Reports Server (NTRS)
Lewak, G. J.
1974-01-01
A new formulation of the one-dimensional Vlasov equation is derived which is analogous to the Kalman-transformed cold-plasma equations. The equations are shown to yield nonsecular, nonlinear approximations to a source or boundary-value problem. It is suggested that the formulation may have other applications in nonlinear plasma theory.
Stationary nonlinear Alfven waves and solitons
NASA Technical Reports Server (NTRS)
Hada, T.; Kennel, C. F.; Buti, B.
1989-01-01
Stationary solutions of the derivative nonlinear Schroedinger equation are discussed and classified by using a pseudopotential formulation. The solutions consist of a rich family of nonlinear Alfven waves and solitons with parallel and oblique propagation directions. Expressions for the envelope and the phase of nonlinear waves with periodic envelope modulation, and 'hyperbolic' and 'algebraic' solitons are given. The propagation angle for the slightly modulated elliptic, periodic waves and for oblique solitons is evaluated.
Avila, Diana V; Barker, David F; Zhang, JingWen; McClain, Craig J; Barve, Shirish; Gobejishvili, Leila
2016-09-01
Alcohol-induced hepatic steatosis is a significant risk factor for progressive liver disease. Cyclic adenosine monophosphate (cAMP) signalling has been shown to significantly regulate lipid metabolism; however, the role of altered cAMP homeostasis in alcohol-mediated hepatic steatosis has never been studied. Our previous work demonstrated that increased expression of hepatic phosphodiesterase 4 (Pde4), which specifically hydrolyses and decreases cAMP levels, plays a pathogenic role in the development of liver inflammation/injury. The aim of this study was to examine the role of PDE4 in alcohol-induced hepatic steatosis. C57BL/6 wild-type and Pde4b knockout (Pde4b(-/-) ) mice were pair-fed control or ethanol liquid diets. One group of wild-type mice received rolipram, a PDE4-specific inhibitor, during alcohol feeding. We demonstrate for the first time that an early increase in PDE4 enzyme expression and a resultant decrease in hepatic cAMP levels are associated with the significant reduction in carnitine palmitoyltransferase 1A (Cpt1a) expression. Notably, alcohol-fed (AF) Pde4b(-/-) mice and AF wild-type mice treated with rolipram had significantly lower hepatic free fatty acid content compared with AF wild-type mice. Importantly, PDE4 inhibition in alcohol-fed mice prevented the decrease in hepatic Cpt1a expression via the Pparα/Sirt1/Pgc1α pathway. These results demonstrate that the alcohol- induced increase in hepatic Pde4, specifically Pde4b expression, and compromised cAMP signalling predispose the liver to impaired fatty acid oxidation and the development of steatosis. Moreover, these data also suggest that hepatic PDE4 may be a clinically relevant therapeutic target for the treatment of alcohol-induced hepatic steatosis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27287961
Computational Contact Formulations for Soft Body Adhesion
NASA Astrophysics Data System (ADS)
Sauer, Roger A.
This article gives an overview of adhesive contact for soft bodies and focuses on a general computational framework that is suitable for treating a large class of adhesion problems. The contact formulation is based on a non-linear continuum approach that is capable of describing bodies down to length scales of several nanometers. Several finite element formulations are presented, that introduce various approximations in order to increase the computational efficiency. The approaches are illustrated by several examples throughout the text. These include carbon nanotube interaction, adhesion of spheres, nanoindentation, thin film peeling, gecko adhesion and self-cleaning surface mechanisms.
Bernard, Jamie J; Lou, You-Rong; Peng, Qing-Yun; Li, Tao; Lu, Yao-Ping
2014-01-01
Our previous studies demonstrated that the topical application of caffeine is a potent inhibitor of UVB-induced carcinogenesis and selectively increases apoptosis in tumors but not in non-tumor areas of the epidermis in mice that are at a high risk for developing skin cancer. While this effect is mainly through a p53 independent pathway, the mechanism by which caffeine inhibits skin tumor formation has not been fully elucidated. Since caffeine is a non-specific phosphodiesterase inhibitor, we investigated the effects of several PDE inhibitors on the formation of sunburn cells in mouse skin after an acute exposure to ultraviolet light B (UVB). The topical application of a PDE2 inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA hydrochloride), stimulated epidermal apoptosis compared to control (P<0.01) and to a greater extent than caffeine whereas a PDE4 inhibitor attenuated the epidermal apoptosis compared to control (P<0.01). Since PDE2 hydrolyzes cyclic nucleotides, mainly cGMP, the effects of EHNA hydrochloride on epidermal apoptosis following UVB exposure may be mediated, in part, by increased cGMP signaling. Data demonstrated that the topical application of dibutyryl cGMP stimulated epidermal apoptosis (P<0.01) following an acute exposure to UVB. Treating UVB-pretreated mice topically with 3.1 µmole or 0.8 µmole of EHNA hydrochloride attenuated tumor formation to a greater extent than treating with 6.2 µmole caffeine when these compounds were applied once a day, five days a week for 18 weeks. These observations suggest a novel role for PDE2 in UVB-induced tumorigenesis and that PDE2 inhibitors that mediate cGMP signaling may be useful for the prevention and treatment of skin cancer. PMID:25330380
Korhonen, Riku; Hömmö, Tuija; Keränen, Tiina; Laavola, Mirka; Hämäläinen, Mari; Vuolteenaho, Katriina; Lehtimäki, Lauri; Kankaanranta, Hannu; Moilanen, Eeva
2013-01-01
Background and Purpose 3′,5′-Cyclic nucleotide PDE4 is expressed in several inflammatory and immune cells, and PDE4 catalyses the hydrolysis of cAMP to 5′AMP, down-regulating cAMP signalling in cells. MAPK phosphatase-1 (MKP-1) is an endogenous p38 MAPK signalling suppressor and limits inflammatory gene expression and inflammation. In the present study, we investigated the effect of a PDE4 inhibitor rolipram on MKP-1 expression and whether MKP-1 is involved in the anti-inflammatory effects of rolipram. Experimental Approach The effect of rolipram on TNF production was investigated in J774 mouse macrophage cell line and in primary mouse peritoneal macrophages (PM) from wild-type (WT) and MKP-1(–/–) mice. We also investigated the effect of rolipram on carrageenan-induced paw inflammation in WT and MKP-1(–/–) mice. Key Results MKP-1 expression was enhanced by rolipram, by a non-selective PDE inhibitor IBMX and by a cAMP analogue 8-Br-cAMP in J774 cells and in PM. Enhanced MKP-1 mRNA expression by rolipram was reversed by a PKA inhibitor. Rolipram, IBMX and 8-Br-cAMP also inhibited TNF production in activated macrophages. Accordingly, rolipram inhibited TNF production in PMs from WT mice but, interestingly, not in PMs from MKP-1(–/–) mice. Furthermore, rolipram attenuated carrageenan-induced paw inflammation in WT but not in MKP-1(–/–) mice. Conclusions and Implications PDE4 inhibitor rolipram was found to enhance the expression of MKP-1, and MKP-1 mediated, at least partly, the anti-inflammatory effects of PDE4 inhibition. The results suggest that compounds that enhance MKP-1 expression and/or MKP-1 activity hold potential as novel anti-inflammatory drugs. PMID:23849041
Bernard, Jamie J.; Lou, You-Rong; Peng, Qing-Yun; Li, Tao; Lu, Yao-Ping
2014-01-01
Our previous studies demonstrated that the topical application of caffeine is a potent inhibitor of UVB-induced carcinogenesis and selectively increases apoptosis in tumors but not in non-tumor areas of the epidermis in mice that are at a high risk for developing skin cancer. While this effect is mainly through a p53 independent pathway, the mechanism by which caffeine inhibits skin tumor formation has not been fully elucidated. Since caffeine is a non-specific phosphodiesterase inhibitor, we investigated the effects of several PDE inhibitors on the formation of sunburn cells in mouse skin after an acute exposure to ultraviolet light B (UVB). The topical application of a PDE2 inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA hydrochloride), stimulated epidermal apoptosis compared to control (P<0.01) and to a greater extent than caffeine whereas a PDE4 inhibitor attenuated the epidermal apoptosis compared to control (P<0.01). Since PDE2 hydrolyzes cyclic nucleotides, mainly cGMP, the effects of EHNA hydrochloride on epidermal apoptosis following UVB exposure may be mediated, in part, by increased cGMP signaling. Data demonstrated that the topical application of dibutyryl cGMP stimulated epidermal apoptosis (P<0.01) following an acute exposure to UVB. Treating UVB-pretreated mice topically with 3.1 µmole or 0.8 µmole of EHNA hydrochloride attenuated tumor formation to a greater extent than treating with 6.2 µmole caffeine when these compounds were applied once a day, five days a week for 18 weeks. These observations suggest a novel role for PDE2 in UVB-induced tumorigenesis and that PDE2 inhibitors that mediate cGMP signaling may be useful for the prevention and treatment of skin cancer. PMID:25330380
Denoising of brain MRI images using modified PDE based on pixel similarity
NASA Astrophysics Data System (ADS)
Jin, Renchao; Song, Enmin; Zhang, Lijuan; Min, Zhifang; Xu, Xiangyang; Huang, Chih-Cheng
2008-03-01
Although various image denoising methods such as PDE-based algorithms have made remarkable progress in the past years, the trade-off between noise reduction and edge preservation is still an interesting and difficult problem in the field of image processing and analysis. A new image denoising algorithm, using a modified PDE model based on pixel similarity, is proposed to deal with the problem. The pixel similarity measures the similarity between two pixels. Then the neighboring consistency of the center pixel can be calculated. Informally, if a pixel is not consistent enough with its surrounding pixels, it can be considered as a noise, but an extremely strong inconsistency suggests an edge. The pixel similarity is a probability measure, its value is between 0 and 1. According to the neighboring consistency of the pixel, a diffusion control factor can be determined by a simple thresholding rule. The factor is combined into the primary partial differential equation as an adjusting factor for controlling the speed of diffusion for different type of pixels. An evaluation of the proposed algorithm on the simulated brain MRI images was carried out. The initial experimental results showed that the new algorithm can smooth the MRI images better while keeping the edges better and achieve higher peak signal to noise ratio (PSNR) comparing with several existing denoising algorithms.
A Novel Access to Arylated and Heteroarylated Beta-Carboline Based PDE5 Inhibitors
Ahmed, Nermin S.; Gary, Bernard D.; Piazza, Gary A.; Tinsley, Heather N.; Laufer, Stefan; Abadi, Ashraf H.
2016-01-01
Starting from a previously reported lead compound GR30040X (a hydantoin tetrahydro-β-carboline derivative with a 4- pyridinyl ring at C- 5), a series of structurally related tetrahydro-β-carboline derivatives were prepared. The tet-rahydro-β-carboline skeleton was fused either to a hydantoin or to a piperazindione ring, the pendant aryl group attached to C-5 or C-6 was changed to a 3, 4-dimethoxyphenyl or a 3-pyridinyl ring; different N-substituents on the terminal ring were introduced, a straight chain ethyl group, a branched tert. butyl and P-chlorophenyl group rather than n-butyl group of the lead compound. All four possible diastereomers of target tetrahydro-β-carboline derivatives were prepared, separated by column chromatography and the significance of these stereochemical manipulations was studied. Synthesized compounds were evaluated for their inhibitory effect versus PDE5. Seven hits were obtained with appreciable inhibitory activity versus PDE5 with IC50s 0.14 - 4.99 μM. PMID:21054274
PDE5 Inhibitors Enhance Tumor Permeability and Efficacy of Chemotherapy in a Rat Brain Tumor Model
Black, Keith L.; Yin, Dali; Ong, John M.; Hu, Jinwei; Konda, Bindu M.; Wang, Xiao; Ko, MinHee K.; Bayan, Jennifer-Ann; Sacapano, Manuel R.; Espinoza, Andreas; Morris-Irvin, Dwain K; Shu, Yan
2008-01-01
The blood-brain tumor barrier (BTB) significantly limits delivery of therapeutic concentrations of chemotherapy to brain tumors. A novel approach to selectively increase drug delivery is pharmacologic modulation of signaling molecules that regulate BTB permeability, such as those in cGMP signaling. Here we show that oral administration of sildenafil (Viagra) and vardenafil (Levitra), inhibitors of cGMP-specific PDE5, selectively increased tumor capillary permeability in 9L gliosarcoma-bearing rats with no significant increase in normal brain capillaries. Tumor-bearing rats treated with the chemotherapy agent, adriamycin, in combination with vardenafil survived significantly longer than rats treated with adriamycin alone. The selective increase in tumor capillary permeability appears to be mediated by a selective increase in tumor cGMP levels and increased vesicular transport through tumor capillaries, and could be attenuated by iberiotoxin, a selective inhibitor for calcium-dependent potassium (KCa) channels, that are effectors in cGMP signaling. The effect by sildenafil could be further increased by simultaneously using another BTB “opener”, bradykinin. Collectively, this data demonstrates that oral administration of PDE5 inhibitors selectively increases BTB permeability and enhance anti-tumor efficacy for a chemotherapeutic agent. These findings have significant implications for improving delivery of anti-tumor agents to brain tumors. PMID:18674521
A Cell-based PDE4 Assay in 1536-well Plate format for High Throughput Screening
Titus, Steven A.; Li, Xiao; Southall, Noel; Lu, Jianming; Inglese, James; Brasch, Michael; Austin, Christopher P.; Zheng, Wei
2009-01-01
The cyclic nucleotide phosphodiesterases (PDEs) are intracellular enzymes that catalyze the hydrolysis of 3', 5'-cyclic nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), to their corresponding 5'-nucleotide monophosphates. These enzymes play an important role in controlling cellular concentrations of cyclic nucleotides and thus regulate a variety of cellular signaling events. PDEs are emerging as drug targets for several diseases including asthma, cardiovascular disease, ADHD, Parkinson’s disease, and Alzheimer’s disease. Though biochemical assays with purified recombinant PDE enzymes and cAMP or cGMP substrate are commonly used for compound screening, cell-based assays would provide a better assessment of compound activity in a more physiological context. Here we report the development and validation of a new cell-based PDE4 assay using a constitutively active GPCR as a driving force for cAMP production and a cyclic nucleotide gated (CNG) cation channel as a biosensor in 1536-well plates. PMID:18591513
Effective viscosity of bacterial suspensions: a three-dimensional PDE model with stochastic torque.
Haines, B. M.; Aranson, I. S.; Berlyand, L.; Karpeev, D. A.
2012-01-01
We present a PDE model for dilute suspensions of swimming bacteria in a three-dimensional Stokesian fluid. This model is used to calculate the statistically-stationary bulk deviatoric stress and effective viscosity of the suspension from the microscopic details of the interaction of an elongated body with the background flow. A bacterium is modeled as an impenetrable prolate spheroid with self-propulsion provided by a point force, which appears in the model as an inhomogeneous delta function in the PDE. The bacterium is also subject to a stochastic torque in order to model tumbling (random reorientation). Due to a bacterium's asymmetric shape, interactions with prescribed generic planar background flows, such as a pure straining or planar shear flow, cause the bacterium to preferentially align in certain directions. Due to the stochastic torque, the steady-state distribution of orientations is unique for a given background flow. Under this distribution of orientations, self-propulsion produces a reduction in the effective viscosity. For sufficiently weak background flows, the effect of self-propulsion on the effective viscosity dominates all other contributions, leading to an effective viscosity of the suspension that is lower than the viscosity of the ambient fluid. This is in qualitative agreement with recent experiments on suspensions of Bacillus subtilis.
Inhibition of PDE5 Restores Depressed Baroreflex Sensitivity in Renovascular Hypertensive Rats
Cavalcanti, Clênia de Oliveira; Alves, Rafael R.; de Oliveira, Alessandro L.; Cruz, Josiane de Campos; de França-Silva, Maria do Socorro; Braga, Valdir de Andrade; Balarini, Camille de Moura
2016-01-01
Renal artery stenosis is frequently associated with resistant hypertension, which is defined as failure to normalize blood pressure (BP) even when combined drugs are used. Inhibition of PDE5 by sildenafil has been shown to increase endothelial function and decrease blood pressure in experimental models. However, no available study evaluated the baroreflex sensitivity nor autonomic balance in renovascular hypertensive rats treated with sildenafil. In a translational medicine perspective, our hypothesis is that sildenafil could improve autonomic imbalance and baroreflex sensitivity, contributing to lower blood pressure. Renovascular hypertensive 2-kidney-1-clip (2K1C) and sham rats were treated with sildenafil (45 mg/Kg/day) during 7 days. At the end of treatment, BP and heart rate (HR) were recorded in conscious rats after a 24-h-recovery period. Spontaneous and drug-induced baroreflex sensitivity and autonomic tone were evaluated; in addition, lipid peroxidation was measured in plasma samples. Treatment was efficient in increasing both spontaneous and induced baroreflex sensitivity in treated hypertensive animals. Inhibition of PDE5 was also capable of ameliorating autonomic imbalance in 2K1C rats and decreasing systemic oxidative stress. Taken together, these beneficial effects resulted in significant reductions in BP without affecting HR. We suggest that sildenafil could be considered as a promising alternative to treat resistant hypertension. PMID:26858657
A PDE approach for quantifying and visualizing tumor progression and regression
NASA Astrophysics Data System (ADS)
Sintay, Benjamin J.; Bourland, J. Daniel
2009-02-01
Quantification of changes in tumor shape and size allows physicians the ability to determine the effectiveness of various treatment options, adapt treatment, predict outcome, and map potential problem sites. Conventional methods are often based on metrics such as volume, diameter, or maximum cross sectional area. This work seeks to improve the visualization and analysis of tumor changes by simultaneously analyzing changes in the entire tumor volume. This method utilizes an elliptic partial differential equation (PDE) to provide a roadmap of boundary displacement that does not suffer from the discontinuities associated with other measures such as Euclidean distance. Streamline pathways defined by Laplace's equation (a commonly used PDE) are used to track tumor progression and regression at the tumor boundary. Laplace's equation is particularly useful because it provides a smooth, continuous solution that can be evaluated with sub-pixel precision on variable grid sizes. Several metrics are demonstrated including maximum, average, and total regression and progression. This method provides many advantages over conventional means of quantifying change in tumor shape because it is observer independent, stable for highly unusual geometries, and provides an analysis of the entire three-dimensional tumor volume.
Luo, Biao; Wu, Huai-Ning; Li, Han-Xiong
2015-04-01
Highly dissipative nonlinear partial differential equations (PDEs) are widely employed to describe the system dynamics of industrial spatially distributed processes (SDPs). In this paper, we consider the optimal control problem of the general highly dissipative SDPs, and propose an adaptive optimal control approach based on neuro-dynamic programming (NDP). Initially, Karhunen-Loève decomposition is employed to compute empirical eigenfunctions (EEFs) of the SDP based on the method of snapshots. These EEFs together with singular perturbation technique are then used to obtain a finite-dimensional slow subsystem of ordinary differential equations that accurately describes the dominant dynamics of the PDE system. Subsequently, the optimal control problem is reformulated on the basis of the slow subsystem, which is further converted to solve a Hamilton-Jacobi-Bellman (HJB) equation. HJB equation is a nonlinear PDE that has proven to be impossible to solve analytically. Thus, an adaptive optimal control method is developed via NDP that solves the HJB equation online using neural network (NN) for approximating the value function; and an online NN weight tuning law is proposed without requiring an initial stabilizing control policy. Moreover, by involving the NN estimation error, we prove that the original closed-loop PDE system with the adaptive optimal control policy is semiglobally uniformly ultimately bounded. Finally, the developed method is tested on a nonlinear diffusion-convection-reaction process and applied to a temperature cooling fin of high-speed aerospace vehicle, and the achieved results show its effectiveness. PMID:25794375
On the dynamics of approximating schemes for dissipative nonlinear equations
NASA Technical Reports Server (NTRS)
Jones, Donald A.
1993-01-01
Since one can rarely write down the analytical solutions to nonlinear dissipative partial differential equations (PDE's), it is important to understand whether, and in what sense, the behavior of approximating schemes to these equations reflects the true dynamics of the original equations. Further, because standard error estimates between approximations of the true solutions coming from spectral methods - finite difference or finite element schemes, for example - and the exact solutions grow exponentially in time, this analysis provides little value in understanding the infinite time behavior of a given approximating scheme. The notion of the global attractor has been useful in quantifying the infinite time behavior of dissipative PDEs, such as the Navier-Stokes equations. Loosely speaking, the global attractor is all that remains of a sufficiently large bounded set in phase space mapped infinitely forward in time under the evolution of the PDE. Though the attractor has been shown to have some nice properties - it is compact, connected, and finite dimensional, for example - it is in general quite complicated. Nevertheless, the global attractor gives a way to understand how the infinite time behavior of approximating schemes such as the ones coming from a finite difference, finite element, or spectral method relates to that of the original PDE. Indeed, one can often show that such approximations also have a global attractor. We therefore only need to understand how the structure of the attractor for the PDE behaves under approximation. This is by no means a trivial task. Several interesting results have been obtained in this direction. However, we will not go into the details. We mention here that approximations generally lose information about the system no matter how accurate they are. There are examples that show certain parts of the attractor may be lost by arbitrary small perturbations of the original equations.
De Young, L; Yu, D; Freeman, D; Brock, G B
2003-10-01
Phosphodiesterase (PDE) inhibitors represent an important advance in the treatment of erectile dysfunction (ED). In spite of widespread use and generally good efficacy, as a class they remain ineffective in 15-57% of men. Specific cohorts of patients with severe vascular or neurogenic basis to their ED, such as diabetic men or those who have undergone radical pelvic surgery, demonstrate lower response rates with PDE inhibition treatment. We believe that circulating levels of nitric oxide (NO) may be enhanced through delivery of adequate concentrations of free oxygen radical scavenger molecules such as vitamin E. Higher levels of NO, theoretically, should produce increased penile blood flow with the potential for a synergistic effect when combined with a PDE5 inhibitor. With this hypothesis in mind, 20 adult male Sprague-Dawley streptozotocin-induced (60 mg/kg i.p.) diabetic rats were divided into four therapeutic groups (n=5). Group I--control animals received peanut oil, group II--vitamin E 20 IU/day, group III--sildenafil 5 mg/kg/day and group IV--vitamin E 20 IU/day plus sildenafil 5 mg/kg/day, by oral gavage daily for 3 weeks. Erectile function was assessed as a rise in intracavernous pressure following cavernous nerve electrostimulation. Penile tissue was harvested to determine the changes in tissue morphology including neuronal nitric oxide synthase, smooth muscle alpha-actin and endothelial cell integrity. PDE5 protein content and activity were measured. Significant increases in intracavernous pressure were measured in the animals receiving combined vitamin E plus sildenafil treatment. Immunohistochemical staining showed increases of neuronal nitric oxide synthase, endothelial cell and smooth muscle cell staining. Western blot analysis did not show significant differences of PDE5 protein between the groups. However, higher PDE5 activity was measured in the sildenafil group and lower activity of PDE5 was recorded in the cohort receiving vitamin E with
Dresner, L.
1987-08-01
Problems of technological interest can very often be described by partial differential equations (PDEs) with one dependent and two independent variables (call them c, z, and t, respectively). Many such PDEs are invariant to one-parameter families of one-parameter affine groups. Similarity solutions are solutions of the PDE that are invariant to one group of the family. The great utility of similarity solutions is that they may be calculated by solving an ODE rather than a PDE and are thus much more easily accessible than other solutions. The form of the principal ODE depends, of course, on the form of the PDE, but it can be proved quite generally that the principal ODE is itself invarient to the one-parameter affine group or associated group. because of the invariance of the principal ODE to the associated group, the dependence on the boundary and initial conditions of certain special values of the function y(x), e.g., y(O), y(infinity), y(O), ets., may be predicted a priori without solving the principal ODE. The nonlinear PDE of heat transport in superfluid He-II, is used as an illustration of these ideas in this review.
The nonlinear dynamics of the Oklo natural reactor
Bilanovic, Z.; Harms, A.A.
1985-11-01
An analysis of the Oklo natural reactor, a self-sustaining and self-regulating critical assembly that existed some 2 billion years ago in Gabon, Africa, is presented. Nonlinear continuous dif ferential and nonlinear discrete iterative formulations are established and selected parameter characterizations identified. Conceivable power oscillations are calculated and discussed. Some implications of nonlinear mappings for nuclear simulation are suggested.
PREFACE Integrability and nonlinear phenomena Integrability and nonlinear phenomena
NASA Astrophysics Data System (ADS)
Gómez-Ullate, David; Lombardo, Sara; Mañas, Manuel; Mazzocco, Marta; Nijhoff, Frank; Sommacal, Matteo
2010-10-01
according to the standards of the journal. The selection of papers in this issue aims to bring together recent developments and findings, even though it consists of only a fraction of the impressive developments in recent years which have affected a broad range of fields, including the theory of special functions, quantum integrable systems, numerical analysis, cellular automata, representations of quantum groups, symmetries of difference equations, discrete geometry, among others. The special issue begins with four review papers: Integrable models in nonlinear optics and soliton solutions Degasperis [1] reviews integrable models in nonlinear optics. He presents a number of approximate models which are integrable and illustrates the links between the mathematical and applicative aspects of the theory of integrable dynamical systems. In particular he discusses the recent impact of boomeronic-type wave equations on applications arising in the context of the resonant interaction of three waves. Hamiltonian PDEs: deformations, integrability, solutions Dubrovin [2] presents classification results for systems of nonlinear Hamiltonian partial differential equations (PDEs) in one spatial dimension. In particular he uses a perturbative approach to the theory of integrability of these systems and discusses their solutions. He conjectures universality of the critical behaviour for the solutions, where the notion of universality refers to asymptotic independence of the structure of solutions (at the point of gradient catastrophe) from the choice of generic initial data as well as from the choice of a generic PDE. KP solitons in shallow water Kodama [3] presents a survey of recent studies on soliton solutions of the Kadomtsev-Petviashvili (KP) equation. A large variety of exact soliton solutions of the KP equation are presented and classified. The study includes numerical analysis of the stability of the found solution as well as numerical simulations of the initial value problems which
Peters, Arne
2016-01-01
The enduring stages of entomopathogenic nematodes of the genera Steinernema and Heterorhabditis are infective juveniles, which require a high humidity and sufficient ventilation for survival. Formulations must account for these requirements. Nematodes may be formulated inside the insects in which they reproduced or they need to be cleaned and mixed with a suitable binder to maintain humidity but allowing for gas exchange. Another method for formulation is the encapsulation in beads of Ca-alginate. Generic procedures for these formulation techniques are described. PMID:27565496
Psychiatrists' use of formulation
Hughes, Patricia M.
2016-01-01
Both psychologists and psychiatrists are trained to write formulations of their patients' illnesses, with some differences in how they do this. Psychologists focus on psychological understanding, while psychiatrists' formulation brings together aetiology, functioning and a management plan. Mohtashemi et al's study records how some psychiatrists understand formulation and its usefulness. Time pressure was an important barrier to making a full formulation, and some believed the medical role of the psychiatrist was a priority. The study illustrates some of the challenges facing psychiatrists working in the NHS in terms of maintaining high clinical standards and a holistic approach to patient care. PMID:27512593
BELSHER JD; MEINERT FL
2009-12-07
This document presents the differences between two HLW glass formulation models (GFM): The 1996 GFM and 2009 GFM. A glass formulation model is a collection of glass property correlations and associated limits, as well as model validity and solubility constraints; it uses the pretreated HLW feed composition to predict the amount and composition of glass forming additives necessary to produce acceptable HLW glass. The 2009 GFM presented in this report was constructed as a nonlinear optimization calculation based on updated glass property data and solubility limits described in PNNL-18501 (2009). Key mission drivers such as the total mass of HLW glass and waste oxide loading are compared between the two glass formulation models. In addition, a sensitivity study was performed within the 2009 GFM to determine the effect of relaxing various constraints on the predicted mass of the HLW glass.
Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi
Susuki-Miyata, Seiko; Miyata, Masanori; Lee, Byung-Cheol; Xu, Haidong; Kai, Hirofumi; Yan, Chen; Li, Jian-Dong
2015-01-01
Phosphodiesterase 4B (PDE4B) plays a key role in regulating inflammation. Roflumilast, a phosphodiesterase (PDE)4-selective inhibitor, has recently been approved for treating severe chronic obstructive pulmonary disease (COPD) patients with exacerbation. However, there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of PDE4B up-regulation, which could be counterproductive for suppressing inflammation. Thus, understanding how PDE4B is up-regulated in the context of the complex pathogenesis and medications of COPD may help improve the efficacy and possibly ameliorate the tolerance of roflumilast. Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae (NTHi), a major bacterial cause of COPD exacerbation, to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo. Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners. We also found that protein kinase A catalytic subunit β (PKA-Cβ) and nuclear factor-κB (NF-κB) p65 subunit were required for the synergistic induction of PDE4B2. PKA-Cβ phosphorylates p65 in a cAMP-dependent manner. Moreover, Ser276 of p65 is critical for mediating the PKA-Cβ–induced p65 phosphorylation and the synergistic induction of PDE4B2. Collectively, our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of PDE4 inhibitor. PMID:25831493
Vettel, C; Lämmle, S; Ewens, S; Cervirgen, C; Emons, J; Ongherth, A; Dewenter, M; Lindner, D; Westermann, D; Nikolaev, V O; Lutz, S; Zimmermann, W H; El-Armouche, A
2014-04-15
Recent studies suggest that the signal molecules cAMP and cGMP have antifibrotic effects by negatively regulating pathways associated with fibroblast to myofibroblast (MyoCF) conversion. The phosphodiesterase 2 (PDE2) has the unique property to be stimulated by cGMP, which leads to a remarkable increase in cAMP hydrolysis and thus mediates a negative cross-talk between both pathways. PDE2 has been recently investigated in cardiomyocytes; here we specifically addressed its role in fibroblast conversion and cardiac fibrosis. PDE2 is abundantly expressed in both neonatal rat cardiac fibroblasts (CFs) and cardiomyocytes. The overexpression of PDE2 in CFs strongly reduced basal and isoprenaline-induced cAMP synthesis, and this decrease was sufficient to induce MyoCF conversion even in the absence of exogenous profibrotic stimuli. Functional stress-strain experiments with fibroblast-derived engineered connective tissue (ECT) demonstrated higher stiffness in ECTs overexpressing PDE2. In regard to cGMP, neither basal nor atrial natriuretic peptide-induced cGMP levels were affected by PDE2, whereas the response to nitric oxide donor sodium nitroprusside was slightly but significantly reduced. Interestingly, despite persistently depressed cAMP levels, both cGMP-elevating stimuli were able to completely prevent the PDE2-induced MyoCF phenotype, arguing for a double-tracked mechanism. In conclusion, PDE2 accelerates CF to MyoCF conversion, which leads to greater stiffness in ECTs. Atrial natriuretic peptide- and sodium nitroprusside-mediated cGMP synthesis completely reverses PDE2-induced fibroblast conversion. Thus PDE2 may augment cardiac remodeling, but this effect can also be overcome by enhanced cGMP. The redundant role of cAMP and cGMP as antifibrotic meditators may be viewed as a protective mechanism in heart failure. PMID:24531807
Ginting, Victor
2014-03-15
it was demonstrated that a posteriori analyses in general and in particular one that uses adjoint methods can accurately and efficiently compute numerical error estimates and sensitivity for critical Quantities of Interest (QoIs) that depend on a large number of parameters. Activities include: analysis and implementation of several time integration techniques for solving system of ODEs as typically obtained from spatial discretization of PDE systems; multirate integration methods for ordinary differential equations; formulation and analysis of an iterative multi-discretization Galerkin finite element method for multi-scale reaction-diffusion equations; investigation of an inexpensive postprocessing technique to estimate the error of finite element solution of the second-order quasi-linear elliptic problems measured in some global metrics; investigation of an application of the residual-based a posteriori error estimates to symmetric interior penalty discontinuous Galerkin method for solving a class of second order quasi-linear elliptic problems; a posteriori analysis of explicit time integrations for system of linear ordinary differential equations; derivation of accurate a posteriori goal oriented error estimates for a user-defined quantity of interest for two classes of first and second order IMEX schemes for advection-diffusion-reaction problems; Postprocessing finite element solution; and A Bayesian Framework for Uncertain Quantification of Porous Media Flows.
NASA Astrophysics Data System (ADS)
Bui-Thanh, T.; Girolami, M.
2014-11-01
We consider the Riemann manifold Hamiltonian Monte Carlo (RMHMC) method for solving statistical inverse problems governed by partial differential equations (PDEs). The Bayesian framework is employed to cast the inverse problem into the task of statistical inference whose solution is the posterior distribution in infinite dimensional parameter space conditional upon observation data and Gaussian prior measure. We discretize both the likelihood and the prior using the H1-conforming finite element method together with a matrix transfer technique. The power of the RMHMC method is that it exploits the geometric structure induced by the PDE constraints of the underlying inverse problem. Consequently, each RMHMC posterior sample is almost uncorrelated/independent from the others providing statistically efficient Markov chain simulation. However this statistical efficiency comes at a computational cost. This motivates us to consider computationally more efficient strategies for RMHMC. At the heart of our construction is the fact that for Gaussian error structures the Fisher information matrix coincides with the Gauss-Newton Hessian. We exploit this fact in considering a computationally simplified RMHMC method combining state-of-the-art adjoint techniques and the superiority of the RMHMC method. Specifically, we first form the Gauss-Newton Hessian at the maximum a posteriori point and then use it as a fixed constant metric tensor throughout RMHMC simulation. This eliminates the need for the computationally costly differential geometric Christoffel symbols, which in turn greatly reduces computational effort at a corresponding loss of sampling efficiency. We further reduce the cost of forming the Fisher information matrix by using a low rank approximation via a randomized singular value decomposition technique. This is efficient since a small number of Hessian-vector products are required. The Hessian-vector product in turn requires only two extra PDE solves using the adjoint
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
Active site coupling in PDE:PKA complexes promotes resetting of mammalian cAMP signaling.
Krishnamurthy, Srinath; Moorthy, Balakrishnan Shenbaga; Xin Xiang, Lim; Xin Shan, Lim; Bharatham, Kavitha; Tulsian, Nikhil Kumar; Mihalek, Ivana; Anand, Ganesh S
2014-09-16
Cyclic 3'5' adenosine monophosphate (cAMP)-dependent-protein kinase (PKA) signaling is a fundamental regulatory pathway for mediating cellular responses to hormonal stimuli. The pathway is activated by high-affinity association of cAMP with the regulatory subunit of PKA and signal termination is achieved upon cAMP dissociation from PKA. Although steps in the activation phase are well understood, little is known on how signal termination/resetting occurs. Due to the high affinity of cAMP to PKA (KD ∼ low nM), bound cAMP does not readily dissociate from PKA, thus begging the question of how tightly bound cAMP is released from PKA to reset its signaling state to respond to subsequent stimuli. It has been recently shown that phosphodiesterases (PDEs) can catalyze dissociation of bound cAMP and thereby play an active role in cAMP signal desensitization/termination. This is achieved through direct interactions with the regulatory subunit of PKA, thereby facilitating cAMP dissociation and hydrolysis. In this study, we have mapped direct interactions between a specific cyclic nucleotide phosphodiesterase (PDE8A) and a PKA regulatory subunit (RIα isoform) in mammalian cAMP signaling, by a combination of amide hydrogen/deuterium exchange mass spectrometry, peptide array, and computational docking. The interaction interface of the PDE8A:RIα complex, probed by peptide array and hydrogen/deuterium exchange mass spectrometry, brings together regions spanning the phosphodiesterase active site and cAMP-binding sites of RIα. Computational docking combined with amide hydrogen/deuterium exchange mass spectrometry provided a model for parallel dissociation of bound cAMP from the two tandem cAMP-binding domains of RIα. Active site coupling suggests a role for substrate channeling in the PDE-dependent dissociation and hydrolysis of cAMP bound to PKA. This is the first instance, to our knowledge, of PDEs directly interacting with a cAMP-receptor protein in a mammalian system, and
NASA Astrophysics Data System (ADS)
Skerget, P.; Brebbia, C. A.
In many practical applications of boundary elements, the potential problems may be nonlinear. The use of Kirchoff's transform provides an approach to convert a nonlinear material problem into a linear one. A description of several different shape functions to define the conductivity is presented. Attention is given to the type of integral equations which are obtained if the Kirchoff's transform is applied for nonlinear material in the presence of mixed boundary conditions. The integral formulation for nonlinear radiation boundary conditions with and without potential dependent conductivity is also considered. For steady heat conduction problems with constant conductivity a boundary integral equation relating boundary values for temperatures (or potentials) and its normal derivatives over the boundary can be obtained. Applications which concern the solution of steady state conduction problems are investigated. The problems are related to a hollow cylinder, a nuclear reactor pressure vessel, and an industrial furnace.
PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity.
Fansa, Eyad Kalawy; Kösling, Stefanie Kristine; Zent, Eldar; Wittinghofer, Alfred; Ismail, Shehab
2016-01-01
The phosphodiesterase 6 delta subunit (PDE6δ) shuttles several farnesylated cargos between membranes. The cargo sorting mechanism between cilia and other compartments is not understood. Here we show using the inositol polyphosphate 5'-phosphatase E (INPP5E) and the GTP-binding protein (Rheb) that cargo sorting depends on the affinity towards PDE6δ and the specificity of cargo release. High-affinity cargo is exclusively released by the ciliary transport regulator Arl3, while low-affinity cargo is released by Arl3 and its non-ciliary homologue Arl2. Structures of PDE6δ/cargo complexes reveal the molecular basis of the sorting signal which depends on the residues at the -1 and -3 positions relative to farnesylated cysteine. Structure-guided mutation allows the generation of a low-affinity INPP5E mutant which loses exclusive ciliary localization. We postulate that the affinity to PDE6δ and the release by Arl2/3 in addition to a retention signal are the determinants for cargo sorting and enrichment at its destination. PMID:27063844
Brooks, Michael D.; Jackson, Erin; Warrington, Nicole M.; Luo, Jingqin; Forys, Jason T.; Taylor, Sara; Mao, Diane D.; Leonard, Jeffrey R.; Kim, Albert H.; Piwnica-Worms, David
2014-01-01
Cell-cell interactions between tumor cells and constituents of their microenvironment are critical determinants of tumor tissue biology and therapeutic responses. Interactions between glioblastoma (GBM) cells and endothelial cells (ECs) establish a purported cancer stem cell niche. We hypothesized that genes regulated by these interactions would be important, particularly as therapeutic targets. Using a computational approach, we deconvoluted expression data from a mixed physical co-culture of GBM cells and ECs and identified a previously undescribed upregulation of the cAMP specific phosphodiesterase PDE7B in GBM cells in response to direct contact with ECs. We further found that elevated PDE7B expression occurs in most GBM cases and has a negative effect on survival. PDE7B overexpression resulted in the expansion of a stem-like cell subpopulation in vitro and increased tumor growth and aggressiveness in an in vivo intracranial GBM model. Collectively these studies illustrate a novel approach for studying cell-cell interactions and identifying new therapeutic targets like PDE7B in GBM. PMID:25203500
LI, QING; SHU, YAN
2013-01-01
Purpose Previous research has led to the recognition of a cGMP signaling pathway governing drug transport. This study is to investigate whether inhibitors of phosphodiesterase type 5 (PDE5), which increase intracellular cGMP levels, modulate the cytotoxicity and uptake of anti-cancer drugs in cancer cells. Methods The experiments were conducted with and without PDE5 inhibitors: dipyridamole, vardenafil, and/or sildenafil. The cytotoxicity of doxorubicin, cisplatin and oxaliplatin was determined in multiple cancer cell lines derived from different tissues. The cellular uptake of structurally diverse compounds was further examined in lung cancer cells with and without various endocytotic inhibitors. The tumor accumulation and the anti-tumor effect of trastuzumab were examined in a lung cancer xenograft mouse model. Results Dipyridamole could modulate the cytotoxicity of doxorubicin, cisplatin, and oxaliplatin in cancer cells. Particularly, PDE5 inhibitors increased cellular uptake of structurally diverse compounds into lung cancer cells both in vitro and in vivo. The effect of vardenafil on drug uptake could be blocked by endocytotic inhibitors. The growth of lung cancer xenograft in nude mice was significantly suppressed by addition of vardenafil to trastuzumab treatment. Conclusion PDE5 inhibitors may increase the efficacy of anti-cancer drugs by increasing endocytosis-mediated cellular drug uptake, and thus serve as adjuvant therapy for certain cancers such as lung cancer. PMID:23884568
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.
Insulin inhibits human erythrocyte cAMP accumulation and ATP release: role of PDE3 and PI3K
Hanson, Madelyn S.; Stephenson, Alan H.; Bowles, Elizabeth A.; Sprague, Randy S.
2010-01-01
In non – erythroid cells, insulin stimulates a signal transduction pathway that results in the activation of phosphoinositide 3 – kinase (PI3K) and phosphorylation of phosphodiesterase 3 (PDE3). Erythrocytes possess insulin receptors, PI3K, and PDE3B. These cells release ATP via a signaling pathway that requires activation of the G protein, Gi, as well as increases in cAMP. Although insulin inhibits ATP release from human erythrocytes in response to Gi activation with mastoparan 7 (Mas 7), no effect on cAMP was described. Here, we investigated the hypothesis that insulin activates PDE3 in human erythrocytes via a PI3K – mediated mechanism resulting in cAMP hydrolysis and inhibition of ATP release. We show that insulin attenuates Mas 7 – induced increases in cAMP and that selective inhibitors of PDE3 (cilostazol) or PI3K (LY294002) rescue this effect of insulin. In addition, we demonstrated that both cilostazol and LY294002 prevent insulin – induced attenuation of Mas 7 – induced ATP release. These results provide support for the hypothesis that insulin activates PDE3 in erythrocytes via a PI3K – dependent mechanism. Once activated, PDE3 limits Mas 7 – induced increases in intracellular cAMP. This effect of insulin leads, ultimately, to decreased ATP release in response to Mas 7. Since the activation of Gi is required for reduced O2 tension – induced ATP release from erythrocytes, and insulin has been shown to inhibit that release, these results suggest a novel mechanism by which supraphysiological levels of plasma insulin, such as those reported in humans with prediabetes, could inhibit ATP release from erythrocytes. Erythrocyte – derived ATP has been shown to participate in the matching of O2 supply with demand in skeletal muscle. Thus, pathological increases in circulating insulin could, via activation of PDE3, inhibit ATP release from erythrocytes depriving the peripheral circulation of a mechanism that regulates delivery of O2 to meet tissue
A Nonlinear Physics-Based Optimal Control Method for Magnetostrictive Actuators
NASA Technical Reports Server (NTRS)
Smith, Ralph C.
1998-01-01
This paper addresses the development of a nonlinear optimal control methodology for magnetostrictive actuators. At moderate to high drive levels, the output from these actuators is highly nonlinear and contains significant magnetic and magnetomechanical hysteresis. These dynamics must be accommodated by models and control laws to utilize the full capabilities of the actuators. A characterization based upon ferromagnetic mean field theory provides a model which accurately quantifies both transient and steady state actuator dynamics under a variety of operating conditions. The control method consists of a linear perturbation feedback law used in combination with an optimal open loop nonlinear control. The nonlinear control incorporates the hysteresis and nonlinearities inherent to the transducer and can be computed offline. The feedback control is constructed through linearization of the perturbed system about the optimal system and is efficient for online implementation. As demonstrated through numerical examples, the combined hybrid control is robust and can be readily implemented in linear PDE-based structural models.
PREFACE Integrability and nonlinear phenomena Integrability and nonlinear phenomena
NASA Astrophysics Data System (ADS)
Gómez-Ullate, David; Lombardo, Sara; Mañas, Manuel; Mazzocco, Marta; Nijhoff, Frank; Sommacal, Matteo
2010-10-01
according to the standards of the journal. The selection of papers in this issue aims to bring together recent developments and findings, even though it consists of only a fraction of the impressive developments in recent years which have affected a broad range of fields, including the theory of special functions, quantum integrable systems, numerical analysis, cellular automata, representations of quantum groups, symmetries of difference equations, discrete geometry, among others. The special issue begins with four review papers: Integrable models in nonlinear optics and soliton solutions Degasperis [1] reviews integrable models in nonlinear optics. He presents a number of approximate models which are integrable and illustrates the links between the mathematical and applicative aspects of the theory of integrable dynamical systems. In particular he discusses the recent impact of boomeronic-type wave equations on applications arising in the context of the resonant interaction of three waves. Hamiltonian PDEs: deformations, integrability, solutions Dubrovin [2] presents classification results for systems of nonlinear Hamiltonian partial differential equations (PDEs) in one spatial dimension. In particular he uses a perturbative approach to the theory of integrability of these systems and discusses their solutions. He conjectures universality of the critical behaviour for the solutions, where the notion of universality refers to asymptotic independence of the structure of solutions (at the point of gradient catastrophe) from the choice of generic initial data as well as from the choice of a generic PDE. KP solitons in shallow water Kodama [3] presents a survey of recent studies on soliton solutions of the Kadomtsev-Petviashvili (KP) equation. A large variety of exact soliton solutions of the KP equation are presented and classified. The study includes numerical analysis of the stability of the found solution as well as numerical simulations of the initial value problems which
Prediction of evolution of meteor shower associated with comet 122P/de Vico
NASA Astrophysics Data System (ADS)
Tomko, D.
2014-04-01
We deal with a theoretical meteoroid stream of the comet 122P/de Vico. For five perihelion passages in the distant past, we model a theoretical stream and follow its dynamical evolution until the present. We predict the characteristics of potential a meteor shower approaching the Earth's orbit and we make also the identification of the particles of the predicted shower with the real meteors in three databases (photo, radar, and video). Our overall prediction is, however, negative because only the particles released from the comet nucleus before approximately 37 000 years are found to evolve into a collision course with the Earth and, therefore, form a possible shower. Many meteoroids do not survive such a long time in interplanetary space.
NASA Astrophysics Data System (ADS)
Tang, Chen; Zhang, Junjiang; Sun, Chen; Su, Yonggang; Su, Kai Leung
2015-05-01
Nuclear graphite has been widely used as moderating and reflecting materials. However, due to severe neutron irradiation under high temperature, nuclear graphite is prone to deteriorate, resulting in massive microscopic flaws and even cracks under large stress in the later period of its service life. It is indispensable, therefore, to understand the fracture behavior of nuclear graphite to provide reference to structural integrity and safety analysis of nuclear graphite members in reactors. In this paper, we investigated the fracture expansion in nuclear graphite based on PDE image processing methods. We used the second-order oriented partial differential equations filtering model (SOOPDE) to denoise speckle noise, then used the oriented gradient vector fields for to obtain skeletons. The full-field displacement of fractured nuclear graphite and the location of the crack tip were lastly measured under various loading conditions.
Solid state of a new PDE-5 inhibitor DA-8159: characterization, dissolution, transformation.
Ryu, Ji Yoon; Sohn, Young-Taek
2012-05-01
The polymorphic forms of a new PDE-5 inhibitor DA-8159 were prepared and characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and thermogravimetric analysis (TG). Two crystal forms and one amorphous form of DA-8159 have been isolated by recrystallization and characterized by DSC, TG and PXRD. From the TG data it was confirmed that two crystal forms are neither solvates nor hydrates. The PXRD patterns of the two crystal forms were different. In the dissolution studies in simulated intestinal fluid at 37 ± 0.5°C, the solubility decreased in the order of amorphous form > Form 1 > Form 2. After storage of 60 days, Form 1 was transformed to Form 2. Form 2 was not transformed. The amorphous form was transformed to Form 2 at 52% R.H. and 95% R.H., but it did not transform at 0% R.H. PMID:22644853
Experimental confirmation of a PDE-based approach to design of feedback controls
NASA Technical Reports Server (NTRS)
Banks, H. T.; Smith, Ralph C.; Brown, D. E.; Silcox, R. J.; Metcalf, Vern L.
1995-01-01
Issues regarding the experimental implementation of partial differential equation based controllers are discussed in this work. While the motivating application involves the reduction of vibration levels for a circular plate through excitation of surface-mounted piezoceramic patches, the general techniques described here will extend to a variety of applications. The initial step is the development of a PDE model which accurately captures the physics of the underlying process. This model is then discretized to yield a vector-valued initial value problem. Optimal control theory is used to determine continuous-time voltages to the patches, and the approximations needed to facilitate discrete time implementation are addressed. Finally, experimental results demonstrating the control of both transient and steady state vibrations through these techniques are presented.
Ribaudo, Giovanni; Pagano, Mario Angelo; Pavan, Valeria; Redaelli, Marco; Zorzan, Maira; Pezzani, Raffaele; Mucignat-Caretta, Carla; Vendrame, Tiziano; Bova, Sergio; Zagotto, Giuseppe
2015-09-01
Natural (iso)flavonoids have been recently reported to inhibit cyclic nucleotide phosphodiesterases (PDEs) and induce vasorelaxation, albeit the results described in the literature are discordant. The cGMP-selective isoform PDE-5A, in particular, represents the target of sildenafil and its analogues in the treatment of erectile dysfunction (ED) and pulmonary hypertension by promoting relaxation in vascular smooth muscle through the activation of the NO/cGMP pathway. We undertook this study to verify if osajin and pomiferin, two natural prenylated isoflavones and major constituents of Maclura pomifera extracts previously investigated for their anticancer, antibacterial and antidiabetic properties, show inhibitory activity on PDE-5A. These two isoflavones were isolated from the plant extracts and then synthetically modified to obtain a set of semi-synthetic derivatives with slight and focused modifications on the natural scaffold. The compounds were at first screened against PDE-5A in vitro and, based on the encouraging results, further tested for their relaxant effect on isolated rat artery rings. Computational docking studies were also carried out to explore the mode of interaction with the target protein. The obtained data were compared to the behaviour of the well-known PDE-5A inhibitor sildenafil. Our results demonstrate that semi-synthetic derivatives of osajin and pomiferin show an inhibitory effect on the isolated enzyme that, for some of the compounds, is accompanied by a vasorelaxant activity. Based on our findings, we propose the here described isoflavones as potential lead compounds for the development, starting from natural scaffolds, of a new class of PDE-5A inhibitors with vasorelaxant properties. PMID:26136059
Audits of radiopharmaceutical formulations.
Castronovo, F P
1992-03-01
A procedure for auditing radiopharmaceutical formulations is described. To meet FDA guidelines regarding the quality of radiopharmaceuticals, institutional radioactive drug research committees perform audits when such drugs are formulated away from an institutional pharmacy. All principal investigators who formulate drugs outside institutional pharmacies must pass these audits before they can obtain a radiopharmaceutical investigation permit. The audit team meets with the individual who performs the formulation at the site of drug preparation to verify that drug formulations meet identity, strength, quality, and purity standards; are uniform and reproducible; and are sterile and pyrogen free. This team must contain an expert knowledgeable in the preparation of radioactive drugs; a radiopharmacist is the most qualified person for this role. Problems that have been identified by audits include lack of sterility and apyrogenicity testing, formulations that are open to the laboratory environment, failure to use pharmaceutical-grade chemicals, inadequate quality control methods or records, inadequate training of the person preparing the drug, and improper unit dose preparation. Investigational radiopharmaceutical formulations, including nonradiolabeled drugs, must be audited before they are administered to humans. A properly trained pharmacist should be a member of the audit team. PMID:1598931
Inversion of geothermal heat flux in a thermomechanically coupled nonlinear Stokes ice sheet model
NASA Astrophysics Data System (ADS)
Zhu, Hongyu; Petra, Noemi; Stadler, Georg; Isaac, Tobin; Hughes, Thomas J. R.; Ghattas, Omar
2016-07-01
We address the inverse problem of inferring the basal geothermal heat flux from surface velocity observations using a steady-state thermomechanically coupled nonlinear Stokes ice flow model. This is a challenging inverse problem since the map from basal heat flux to surface velocity observables is indirect: the heat flux is a boundary condition for the thermal advection-diffusion equation, which couples to the nonlinear Stokes ice flow equations; together they determine the surface ice flow velocity. This multiphysics inverse problem is formulated as a nonlinear least-squares optimization problem with a cost functional that includes the data misfit between surface velocity observations and model predictions. A Tikhonov regularization term is added to render the problem well posed. We derive adjoint-based gradient and Hessian expressions for the resulting partial differential equation (PDE)-constrained optimization problem and propose an inexact Newton method for its solution. As a consequence of the Petrov-Galerkin discretization of the energy equation, we show that discretization and differentiation do not commute; that is, the order in which we discretize the cost functional and differentiate it affects the correctness of the gradient. Using two- and three-dimensional model problems, we study the prospects for and limitations of the inference of the geothermal heat flux field from surface velocity observations. The results show that the reconstruction improves as the noise level in the observations decreases and that short-wavelength variations in the geothermal heat flux are difficult to recover. We analyze the ill-posedness of the inverse problem as a function of the number of observations by examining the spectrum of the Hessian of the cost functional. Motivated by the popularity of operator-split or staggered solvers for forward multiphysics problems - i.e., those that drop two-way coupling terms to yield a one-way coupled forward Jacobian - we study the
Reactive decontamination formulation
Giletto, Anthony; White, William; Cisar, Alan J.; Hitchens, G. Duncan; Fyffe, James
2003-05-27
The present invention provides a universal decontamination formulation and method for detoxifying chemical warfare agents (CWA's) and biological warfare agents (BWA's) without producing any toxic by-products, as well as, decontaminating surfaces that have come into contact with these agents. The formulation includes a sorbent material or gel, a peroxide source, a peroxide activator, and a compound containing a mixture of KHSO.sub.5, KHSO.sub.4 and K.sub.2 SO.sub.4. The formulation is self-decontaminating and once dried can easily be wiped from the surface being decontaminated. A method for decontaminating a surface exposed to chemical or biological agents is also disclosed.
Formulation techniques for nanofluids.
Rivera-Solorio, Carlos I; Payán-Rodríguez, Luis A; García-Cuéllar, Alejandro J; Ramón-Raygoza, E D; L Cadena-de-la-Peña, Natalia; Medina-Carreón, David
2013-11-01
Fluids with suspended nanoparticles, commonly known as nanofluids, may be formulated to improve the thermal performance of industrial heat transfer systems and applications. Nanofluids may show enhanced thermal and electrical properties such as thermal conductivity, viscosity, heat transfer coefficient, dielectric strength, etc. However, stability problems may arise as nanoparticles usually have the tendency to agglomerate and sediment producing deterioration in the increment of these properties. In this review, we discuss patents that report advances in the formulation of nanofluids including: production methods, selection of components (nanoparticles, base fluid and surfactants), their chemical compositions and morphologies, and characterization techniques. Finally, current and future directions in the development of nanofluid formulation are discussed. PMID:24330043
Li, Nan; Chen, Xi; Zhu, Bing; Ramírez-Alcántara, Verónica; Canzoneri, Joshua C.; Lee, Kevin; Sigler, Sara; Gary, Bernard; Li, Yonghe; Zhang, Wei; Moyer, Mary P.; Salter, E. Alan; Wierzbicki, Andrzej; Keeton, Adam B.; Piazza, Gary A.
2015-01-01
Previous studies suggest the anti-inflammatory drug, sulindac inhibits tumorigenesis by a COX independent mechanism involving cGMP PDE inhibition. Here we report that the cGMP PDE isozymes, PDE5 and 10, are elevated in colon tumor cells compared with normal colonocytes, and that inhibitors and siRNAs can selectively suppress colon tumor cell growth. Combined treatment with inhibitors or dual knockdown suppresses tumor cell growth to a greater extent than inhibition from either isozyme alone. A novel sulindac derivative, ADT-094 was designed to lack COX-1/-2 inhibitory activity but have improved potency to inhibit PDE5 and 10. ADT-094 displayed >500 fold higher potency to inhibit colon tumor cell growth compared with sulindac by activating cGMP/PKG signaling to suppress proliferation and induce apoptosis. Combined inhibition of PDE5 and 10 by treatment with ADT-094, PDE isozyme-selective inhibitors, or by siRNA knockdown also suppresses β-catenin, TCF transcriptional activity, and the levels of downstream targets, cyclin D1 and survivin. These results suggest that dual inhibition of PDE5 and 10 represents novel strategy for developing potent and selective anticancer drugs. PMID:26299804
Ning, Chen; Wen, Jiaming; Zhang, Yujin; Dai, Yingbo; Wang, Wei; Zhang, Weiru; Qi, Lin; Grenz, Almut; Eltzschig, Holger K.; Blackburn, Michael R.; Kellems, Rodney E.; Xia, Yang
2014-01-01
Priapism is featured with prolonged and painful penile erection and is prevalent among males with sickle cell disease (SCD). The disorder is a dangerous urological and hematological emergency since it is associated with ischemic tissue damage and erectile disability. Here we report that phosphodiesterase-5 (PDE5) gene expression and PDE activity is significantly reduced in penile tissues of two independent priapic models: SCD mice and adenosine deaminase (ADA)-deficient mice. Moreover, using ADA enzyme therapy to reduce adenosine or a specific antagonist to block A2B adenosine receptor (ADORA2B) signaling, we successfully attenuated priapism in both ADA−/− and SCD mice by restoring penile PDE5 gene expression to normal levels. This finding led us to further discover that excess adenosine signaling via ADORA2B activation directly reduces PDE5 gene expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. Overall, we reveal that excess adenosine-mediated ADORA2B signaling underlies reduced penile PDE activity by decreasing PDE5 gene expression in a HIF-1α-dependent manner and provide new insight for the pathogenesis of priapism and novel therapies for the disease.—Ning, C., Wen, J., Zhang, Y., Dai, Y., Wang, W., Zhang, W., Qi, L., Grenz, A., Eltzschig, H. K., Blackburn, M. R., Kellems, R. E., Xia, Y. Excess adenosine A2B receptor signaling contributes to priapism through HIF-1α mediated reduction of PDE5 gene expression. PMID:24614760
Edge detection by nonlinear dynamics
Wong, Yiu-fai
1994-07-01
We demonstrate how the formulation of a nonlinear scale-space filter can be used for edge detection and junction analysis. By casting edge-preserving filtering in terms of maximizing information content subject to an average cost function, the computed cost at each pixel location becomes a local measure of edgeness. This computation depends on a single scale parameter and the given image data. Unlike previous approaches which require careful tuning of the filter kernels for various types of edges, our scheme is general enough to be able to handle different edges, such as lines, step-edges, corners and junctions. Anisotropy in the data is handled automatically by the nonlinear dynamics.
Hunter, Roger W.; MacKintosh, Carol; Hers, Ingeborg
2009-01-01
The elevation of [cAMP]i is an important mechanism of platelet inhibition and is regulated by the opposing activity of adenylyl cyclase and phosphodiesterase (PDE). In this study, we demonstrate that a variety of platelet agonists, including thrombin, significantly enhance the activity of PDE3A in a phosphorylation-dependent manner. Stimulation of platelets with the PAR-1 agonist SFLLRN resulted in rapid and transient phosphorylation of PDE3A on Ser312, Ser428, Ser438, Ser465, and Ser492, in parallel with the PKC (protein kinase C) substrate, pleckstrin. Furthermore, phosphorylation and activation of PDE3A required the activation of PKC, but not of PI3K/PKB, mTOR/p70S6K, or ERK/RSK. Activation of PKC by phorbol esters also resulted in phosphorylation of the same PDE3A sites in a PKC-dependent, PKB-independent manner. This was further supported by the finding that IGF-1, which strongly activates PI3K/PKB, but not PKC, did not regulate PDE3A. Platelet activation also led to a PKC-dependent association between PDE3A and 14-3-3 proteins. In contrast, cAMP-elevating agents such as PGE1 and forskolin-induced phosphorylation of Ser312 and increased PDE3A activity, but did not stimulate 14-3-3 binding. Finally, complete antagonism of PGE1-evoked cAMP accumulation by thrombin required both Gi and PKC activation. Together, these results demonstrate that platelet activation stimulates PKC-dependent phosphorylation of PDE3A on Ser312, Ser428, Ser438, Ser465, and Ser492 leading to a subsequent increase in cAMP hydrolysis and 14-3-3 binding. PMID:19261611
NASA Astrophysics Data System (ADS)
Kramer, Sean; Bollt, Erik M.
2013-09-01
Given multiple images that describe chaotic reaction-diffusion dynamics, parameters of a partial differential equation (PDE) model are estimated using autosynchronization, where parameters are controlled by synchronization of the model to the observed data. A two-component system of predator-prey reaction-diffusion PDEs is used with spatially dependent parameters to benchmark the methods described. Applications to modeling the ecological habitat of marine plankton blooms by nonlinear data assimilation through remote sensing are discussed.
2015-01-01
A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12. PMID:25815146
Rombouts, Frederik J R; Tresadern, Gary; Buijnsters, Peter; Langlois, Xavier; Tovar, Fulgencio; Steinbrecher, Thomas B; Vanhoof, Greet; Somers, Marijke; Andrés, José-Ignacio; Trabanco, Andrés A
2015-03-12
A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12. PMID:25815146
Kaname, Tadashi; Ki, Chang-Seok; Niikawa, Norio; Baillie, George S; Day, Jonathan P; Yamamura, Ken-Ichi; Ohta, Tohru; Nishimura, Gen; Mastuura, Nobuo; Kim, Ok-Hwa; Sohn, Young Bae; Kim, Hyun Woo; Cho, Sung Yoon; Ko, Ah-Ra; Lee, Jin Young; Kim, Hyun Wook; Ryu, Sung Ho; Rhee, Hwanseok; Yang, Kap-Seok; Joo, Keehyoung; Lee, Jooyoung; Kim, Chi Hwa; Cho, Kwang-Hyun; Kim, Dongsan; Yanagi, Kumiko; Naritomi, Kenji; Yoshiura, Ko-Ichiro; Kondoh, Tatsuro; Nii, Eiji; Tonoki, Hidefumi; Houslay, Miles D; Jin, Dong-Kyu
2014-11-01
Acrodysostosis without hormone resistance is a rare skeletal disorder characterized by brachydactyly, nasal hypoplasia, mental retardation and occasionally developmental delay. Recently, loss-of-function mutations in the gene encoding cAMP-hydrolyzing phosphodiesterase-4D (PDE4D) have been reported to cause this rare condition but the pathomechanism has not been fully elucidated. To understand the pathogenetic mechanism of PDE4D mutations, we conducted 3D modeling studies to predict changes in the binding efficacy of cAMP to the catalytic pocket in PDE4D mutants. Our results indicated diminished enzyme activity in the two mutants we analyzed (Gly673Asp and Ile678Thr; based on PDE4D4 residue numbering). Ectopic expression of PDE4D mutants in HEK293 cells demonstrated this reduction in activity, which was identified by increased cAMP levels. However, the cells from an acrodysostosis patient showed low cAMP accumulation, which resulted in a decrease in the phosphorylated cAMP Response Element-Binding Protein (pCREB)/CREB ratio. The reason for this discrepancy was due to a compensatory increase in expression levels of PDE4A and PDE4B isoforms, which accounted for the paradoxical decrease in cAMP levels in the patient cells expressing mutant isoforms with a lowered PDE4D activity. Skeletal radiographs of 10-week-old knockout (KO) rats showed that the distal part of the forelimb was shorter than in wild-type (WT) rats and that all the metacarpals and phalanges were also shorter in KO, as the name acrodysostosis implies. Like the G-protein α-stimulatory subunit and PRKAR1A, PDE4D critically regulates the cAMP signal transduction pathway and influences bone formation in a way that activity-compromising PDE4D mutations can result in skeletal dysplasia. We propose that specific inhibitory PDE4D mutations can lead to the molecular pathology of acrodysostosis without hormone resistance but that the pathological phenotype may well be dependent on an over-compensatory induction
Forward model nonlinearity versus inverse model nonlinearity
Mehl, S.
2007-01-01
The issue of concern is the impact of forward model nonlinearity on the nonlinearity of the inverse model. The question posed is, "Does increased nonlinearity in the head solution (forward model) always result in increased nonlinearity in the inverse solution (estimation of hydraulic conductivity)?" It is shown that the two nonlinearities are separate, and it is not universally true that increased forward model nonlinearity increases inverse model nonlinearity. ?? 2007 National Ground Water Association.
Schaal, Sandra Marie; Garg, Maneesh Sen; Ghosh, Mousumi; Lovera, Lilie; Lopez, Michael; Patel, Monal; Louro, Jack; Patel, Samik; Tuesta, Luis; Chan, Wai-Man; Pearse, Damien Daniel
2012-01-01
The extent of damage following spinal cord injury (SCI) can be reduced by various neuroprotective regimens that include maintaining levels of cyclic adenosine monophosphate (cyclic AMP), via administration of the phosphodiesterase 4 (PDE4) inhibitor Rolipram. The current study sought to determine the optimal neuroprotective dose, route and therapeutic window for Rolipram following contusive SCI in rat as well as its prominent PDE target and putative mechanism of protection. Rolipram or vehicle control (10% ethanol) was given subcutaneously (s.c.) daily for 2 wk post-injury (PI) after which the preservation of oligodendrocytes, neurons and central myelinated axons was stereologically assessed. Doses of 0.1 mg/kg to 1.0 mg/kg (given at 1 h PI) increased neuronal survival; 0.5 mg to 1.0 mg/kg protected oligodendrocytes and 1.0 mg/kg produced optimal preservation of central myelinated axons. Ethanol also demonstrated significant neuronal and oligo-protection; though the preservation provided was significantly less than Rolipram. Subsequent use of this optimal Rolipram dose, 1.0 mg/kg, via different routes (i.v., s.c. or oral, 1 h PI), demonstrated that i.v. administration produced the most significant and consistent cyto- and axo- protection, although all routes were effective. Examination of the therapeutic window for i.v. Rolipram (1.0 mg/kg), when initiated between 1 and 48 h after SCI, revealed maximal neuroprotection at 2 h post-SCI, although the protective efficacy of Rolipram could still be observed when administration was delayed for up to 48 h PI. Importantly, use of the optimal Rolipram regimen significantly improved locomotor function after SCI as measured by the BBB score. Lastly we show SCI-induced changes in PDE4A, B and D expression and phosphorylation as well as cytokine expression and immune cell infiltration. We demonstrate that Rolipram abrogates SCI-induced PDE4B1 and PDE4A5 production, PDE4A5 phosphorylation, MCP-1 expression and immune cell
Khan, Shahid Y.; Ali, Shahbaz; Naeem, Muhammad Asif; Khan, Shaheen N.; Husnain, Tayyab; Butt, Nadeem H.; Qazi, Zaheeruddin A.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Hejtmancik, J. Fielding
2015-01-01
Purpose This study was conducted to localize and identify causal mutations associated with autosomal recessive retinitis pigmentosa (RP) in consanguineous familial cases of Pakistani origin. Methods Ophthalmic examinations that included funduscopy and electroretinography (ERG) were performed to confirm the affectation status. Blood samples were collected from all participating individuals, and genomic DNA was extracted. A genome-wide scan was performed, and two-point logarithm of odds (LOD) scores were calculated. Sanger sequencing was performed to identify the causative variants. Subsequently, we performed whole exome sequencing to rule out the possibility of a second causal variant within the linkage interval. Sequence conservation was performed with alignment analyses of PDE6A orthologs, and in silico splicing analysis was completed with Human Splicing Finder version 2.4.1. Results A large multigenerational consanguineous family diagnosed with early-onset RP was ascertained. An ophthalmic clinical examination consisting of fundus photography and electroretinography confirmed the diagnosis of RP. A genome-wide scan was performed, and suggestive two-point LOD scores were observed with markers on chromosome 5q. Haplotype analyses identified the region; however, the region did not segregate with the disease phenotype in the family. Subsequently, we performed a second genome-wide scan that excluded the entire genome except the chromosome 5q region harboring PDE6A. Next-generation whole exome sequencing identified a splice acceptor site mutation in intron 16: c.2028–1G>A, which was completely conserved in PDE6A orthologs and was absent in ethnically matched 350 control chromosomes, the 1000 Genomes database, and the NHLBI Exome Sequencing Project. Subsequently, we investigated our entire cohort of RP familial cases and identified a second family who harbored a splice acceptor site mutation in intron 10: c.1408–2A>G. In silico analysis suggested that these
Wellposedness of the boundary value formulation of a fixed strike Asian option
NASA Astrophysics Data System (ADS)
Hugger, Jens
2006-01-01
This work is the follow up to [J. Hugger, Numerical Mathematics and Advanced Applications--Enumath 2001, Springer, Italy, 2003] where a partial differential equation equivalent to the stochastic formulation for a fixed strike Asian option was derived.In the present work the differential equation is complemented with boundary value conditions that are derived from financial conditions.With the complete boundary value formulation thus recovered, wellposedness of the problem is adressed. It turns out that the problem takes the form of a degenerated parabolic boundary value problem with a second-order, linear, time-dependent PDE with non-negative characteristic form. Apart from the degeneracy in the PDE, also the boundary conditions (derived from the financial understanding) are "the wrong ones" or at least are non-standard. There are conditions on boundaries where none are expected to be needed bacause of the degeneracy and there are boundaries where conditions are expected to be needed but none can be found.
NASA Astrophysics Data System (ADS)
SjöBerg, Daniel
2003-04-01
We investigate the propagation of electromagnetic waves in a cylindrical waveguide with an arbitrary cross section filled with a nonlinear material. The electromagnetic field is expanded in the usual eigenmodes of the waveguide, and the coupling between the modes is quantified. We derive the wave equations governing each mode with special emphasis on the situation with a dominant TE mode. The result is a strictly hyperbolic system of nonlinear partial differential equations for the dominating mode, whereas the minor modes satisfy hyperbolic systems of linear, nonstationary, and partial differential equations. A growth estimate is given for the minor modes.
Nonlinear feedback control of multiple robot arms
NASA Technical Reports Server (NTRS)
Tarn, T. J.; Yun, X.; Bejczy, A. K.
1987-01-01
Multiple coordinated robot arms are modeled by considering the arms: (1) as closed kinematic chains, and (2) as a force constrained mechanical system working on the same object simultaneously. In both formulations a new dynamic control method is discussed. It is based on a feedback linearization and simultaneous output decoupling technique. Applying a nonlinear feedback and a nonlinear coordinate transformation, the complicated model of the multiple robot arms in either formulation is converted into a linear and output decoupled system. The linear system control theory and optimal control theory are used to design robust controllers in the task space. The first formulation has the advantage of automatically handling the coordination and load distribution among the robot arms. In the second formulation, by choosing a general output equation, researchers can superimpose the position and velocity error feedback with the force-torque error feedback in the task space simultaneously.
NASA Astrophysics Data System (ADS)
Papadopoulos, Vissarion; Kalogeris, Ioannis
2016-05-01
The present paper proposes a Galerkin finite element projection scheme for the solution of the partial differential equations (pde's) involved in the probability density evolution method, for the linear and nonlinear static analysis of stochastic systems. According to the principle of preservation of probability, the probability density evolution of a stochastic system is expressed by its corresponding Fokker-Planck (FP) stochastic partial differential equation. Direct integration of the FP equation is feasible only for simple systems with a small number of degrees of freedom, due to analytical and/or numerical intractability. However, rewriting the FP equation conditioned to the random event description, a generalized density evolution equation (GDEE) can be obtained, which can be reduced to a one dimensional pde. Two Galerkin finite element method schemes are proposed for the numerical solution of the resulting pde's, namely a time-marching discontinuous Galerkin scheme and the StreamlineUpwind/Petrov Galerkin (SUPG) scheme. In addition, a reformulation of the classical GDEE is proposed, which implements the principle of probability preservation in space instead of time, making this approach suitable for the stochastic analysis of finite element systems. The advantages of the FE Galerkin methods and in particular the SUPG over finite difference schemes, like the modified Lax-Wendroff, which is the most frequently used method for the solution of the GDEE, are illustrated with numerical examples and explored further.
Kim, Bo-Hyung; Lim, Hyeong-Seok; Chung, Jae-Yong; Kim, Jung-Ryul; Lim, Kyoung Soo; Sohn, Dong-Ryul; Cho, Joo-Youn; Yu, Kyung-Sang; Shin, Sang-Goo; Paick, Jae-Seung; Jang, In-Jin
2008-01-01
AIM To evaluate the safety, tolerability and pharmacokinetics (PK) of udenafil, a novel phosphodiesterase type 5 inhibitor. METHODS A double-blind, randomized, placebo-controlled, dose-rising, parallel-group, single- and multiple-dose study was conducted in healthy Korean subjects. The subjects were allocated to single-dose groups of 25, 50, 100, 200 or 300 mg (eight subjects in each dose group, including two placebos), or to multiple-dose groups of 100 or 200 mg (once-daily dosing for 7 days; nine subjects in each dose group, including three placebos). Serial samples of blood and urine were collected after oral administration and the drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Safety and tolerability were evaluated by monitoring clinical laboratory parameters and adverse events. RESULTS Udenafil reached peak plasma concentrations at 0.8–1.3 h, and then declined mono-exponentially with a terminal half-life of 7.3–12.1 h in the single-dose study. The area under the time–concentration curves (AUC) and maximum plasma concentrations (Cmax) increased supraproportionally with increasing dose in the single-dose study. During multiple dosing, a steady state was reached at 5 days and little accumulation occurred after repeated dosing for 7 days. Udenafil was generally well tolerated in these healthy subjects, and no serious adverse events occurred. CONCLUSIONS Udenafil was safe and well tolerated in healthy volunteers. The AUC and Cmax of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The phosphodiesterase (PDE) type 5 inhibitor is a widely used agent that facilitates penile erection. Udenafil is newly developed as a PDE-5 inhibitor. WHAT THIS STUDY ADDS This is the first study to determine the safety, tolerability and pharmacokinetics of udenafil in
NASA Technical Reports Server (NTRS)
Mickens, Ronald E.
1996-01-01
A large class of physical phenomena can be modeled by evolution and wave type Partial Differential Equations (PDE). Few of these equations have known explicit exact solutions. Finite-difference techniques are a popular method for constructing discrete representations of these equations for the purpose of numerical integration. However, the solutions to the difference equations often contain so called numerical instabilities; these are solutions to the difference equations that do not correspond to any solution of the PDE's. For explicit schemes, the elimination of this behavior requires functional relations to exist between the time and space steps-sizes. We show that such functional relations can be obtained for certain PDE's by use of a positivity condition. The PDE's studied are the Burgers, Fisher, and linearized Euler equations.
Beaumont, Vahri; Park, Larry; Rassoulpour, Arash; Dijkman, Ulrike; Heikkinen, Taneli; Lehtimaki, Kimmo; Kontkanen, Outi; Al Nackkash, Rand; Bates, Gillian P.; Gleyzes, Melanie; Steidl, Esther; Ramboz, Sylvie; Murphy, Carol; Beconi, Maria G.; Dominguez, Celia; Munoz-Sanjuan, Ignacio
2014-01-01
Huntington’s disease is a neurodegenerative disorder caused by mutations in the CAG tract of huntingtin. Several studies in HD cellular and rodent systems have identified disturbances in cyclic nucleotide signaling, which might be relevant to pathogenesis and therapeutic intervention. To investigate whether selective phosphodiesterase (PDE) inhibitors can improve some aspects of disease pathogenesis in HD models, we have systematically evaluated the effects of a variety of cAMP and cGMP selective PDE inhibitors in various HD models. Here we present the lack of effect in a variety of endpoints of the PDE subtype selective inhibitor SCH-51866, a PDE1/5 inhibitor, in the R6/2 mouse model of HD, after chronic oral dosing. PMID:24558637
Ahmed, Nermin S.; Ali, Amal H.; El-Nashar, Shreen M.; Gary, Bernard D.; Fajardo, Alexandra M.; Tinsley, Heather N.; Piazza, Gary A.; Negri, Matthias; Abadi, Ashraf H.
2016-01-01
By studying the co-crystal information of interactions between PDE5 and its inhibitors, forty new tetrahydro-β-carbolines based-analogues were synthesized, and tested for their PDE5 inhibition. Some compounds were as active as tadalafil in inhibiting PDE5 and of better selectivity profile particularly versus PDE11A, the nature of the terminal ring and its nitrogen substituent are the main determinants of selectivity. Ensemble docking confirmed the role of H-loop closed conformer in activity versus its occluded and open forms. Conformational studies showed the effect of bulkiness of the terminal ring N-alkyl substituent on the formation of stable enzyme ligands conformers. The difference in potencies of hydantoin and piperazinedione analogues, together with the necessity of C-5/C-6 R-absolute configuration has been revealed through molecular docking. PMID:23117589
Lythgoe, Casey; McVary, Kevin T
2013-12-01
The relationship between lower urinary tract symptoms secondary to BPH and ED has recently been the subject of significant research due to the prevalence of both conditions concomitantly existing in older men. Many large-scale studies have demonstrated an association between erectile dysfunction and lower urinary tract symptoms. Although the mechanisms underlying the relationship between LUTS and ED are not fully elucidated, several theories are currently proposed in literature: the nitric oxide/cGMP pathway, RhoA/Rho-kinase signaling, pelvic atherosclerosis associated with chronic hypoxia, and autonomic adrenergic hyperactivity. The mechanisms by which these pathways affect the bladder, prostate, pelvic vasculature and spinal cord are also the subject of current research. In this chapter, we examine the randomized, placebo-controlled trials that have evaluated the use of PDE-5Is in LUTS, as well as randomized, controlled trials (RCTs) researching combination PDE-5Is and alpha blockers. PMID:24136683
Computer aided nonlinear electrical networks analysis
NASA Technical Reports Server (NTRS)
Slapnicar, P.
1977-01-01
Techniques used in simulating an electrical circuit with nonlinear elements for use in computer-aided circuit analysis programs are described. Elements of the circuit include capacitors, resistors, inductors, transistors, diodes, and voltage and current sources (constant or time varying). Simulation features are discussed for dc, ac, and/or transient circuit analysis. Calculations are based on the model approach of formulating the circuit equations. A particular solution of transient analysis for nonlinear storage elements is described.
Nonlinear transient analysis via energy minimization
NASA Technical Reports Server (NTRS)
Kamat, M. P.; Knight, N. F., Jr.
1978-01-01
The formulation basis for nonlinear transient analysis of finite element models of structures using energy minimization is provided. Geometric and material nonlinearities are included. The development is restricted to simple one and two dimensional finite elements which are regarded as being the basic elements for modeling full aircraft-like structures under crash conditions. The results indicate the effectiveness of the technique as a viable tool for this purpose.
2012-01-01
Background We previously established a three-dimensional (3-D) colonic crypt model using HKe3 cells which are human colorectal cancer (CRC) HCT116 cells with a disruption in oncogenic KRAS, and revealed the crucial roles of oncogenic KRAS both in inhibition of apoptosis and in disruption of cell polarity; however, the molecular mechanism of KRAS-induced these 3-D specific biological changes remains to be elucidated. Results Among the genes that were upregulated by oncogenic KRAS in this model, we focused on the phosphodiesterase 4B (PDE4B) of which expression levels were found to be higher in clinical tumor samples from CRC patients in comparison to those from healthy control in the public datasets of gene expression analysis. PDE4B2 was specifically overexpressed among other PDE4 isoforms, and re-expression of oncogenic KRAS in HKe3 cells resulted in PDE4B overexpression. Furthermore, the inhibition of PDE4 catalytic activity using rolipram reverted the disorganization of HCT116 cells into the normal physiologic state of the epithelial cell polarity by inducing the apical assembly of ZO-1 (a tight junction marker) and E-cadherin (an adherens junction marker) and by increasing the activity of caspase-3 (an apoptosis marker) in luminal cavities. Notably, rolipram reduced the AKT phosphorylation, which is known to be associated with the disruption of luminal cavity formation and CRC development. Similar results were also obtained using PDE4B2-shRNAs. In addition, increased expression of PDE4B mRNA was found to be correlated with relapsed CRC in a public datasets of gene expression analysis. Conclusions These results collectively suggested that PDE4B is upregulated by oncogenic KRAS, and also that the inhibition of PDE4 catalytic activity can induce both epithelial cell polarity and luminal apoptosis in CRC, thus highlighting the utility of our 3-D culture (3 DC) model for the KRAS-induced development of CRC in 3-D microenvironment. Indeed, using this model, we
Wang, Wei
2015-01-01
It is well recognized that protein product development is far more challenging than that for small-molecule drugs. The major challenges include inherent sensitivity to different types of stresses during the drug product manufacturing process, high rate of physical and chemical degradation during long-term storage, and enhanced aggregation and/or viscosity at high protein concentrations. In the past decade, many novel formulation concepts and technologies have been or are being developed to address these product development challenges for proteins. These concepts and technologies include use of uncommon/combination of formulation stabilizers, conjugation or fusion with potential stabilizers, site-specific mutagenesis, and preparation of nontraditional types of dosage forms—semiaqueous solutions, nonfreeze-dried solid formulations, suspensions, and other emerging concepts. No one technology appears to be mature, ideal, and/or adequate to address all the challenges. These gaps will likely remain in the foreseeable future and need significant efforts for ultimate resolution. PMID:25858529
Granulated decontamination formulations
Tucker, Mark D.
2007-10-02
A decontamination formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a sorbent additive, and water. A highly adsorbent sorbent additive (e.g., amorphous silica, sorbitol, mannitol, etc.) is used to "dry out" one or more liquid ingredients into a dry, free-flowing powder that has an extended shelf life, and is more convenient to handle and mix in the field.
Wilson, Lindsay S; Elbatarny, Hisham S; Crawley, Scott W; Bennett, Brian M; Maurice, Donald H
2008-09-01
It is generally accepted that nitric oxide (NO) donors, such as sodium nitroprusside (SNP), or phosphodiesterase 5 (PDE5) inhibitors, including sildenafil, each impact human platelet function. Although a strong correlation exists between the actions of NO donors in platelets and their impact on cGMP, agents such as sildenafil act without increasing global intra-platelet cGMP levels. This study was undertaken to identify how PDE5 inhibitors might act without increasing cGMP. Our data identify PDE5 as an integral component of a protein kinase G1beta (PKG1beta)-containing signaling complex, reported previously to coordinate cGMP-mediated inhibition of inositol-1, 4, 5-trisphosphate receptor type 1 (IP(3)R1)-mediated Ca(2+)-release. PKG1beta and PDE5 did not interact in subcellular fractions devoid of IP(3)R1 and were not recruited to IP(3)R1-enriched membranes in response to cGMP-elevating agents. Activation of platelet PKG promoted phosphorylation and activation of the PDE5 fraction tethered to the IP(3)R1-PKG complex, an effect not observed for the nontethered PDE5. Based on these findings, we elaborate a model in which PKG selectively activates PDE5 within a defined microdomain in platelets and propose that this mechanism allows spatial and temporal regulation of cGMP signaling in these cells. Recent reports indicate that sildenafil might prove useful in limiting in-stent thrombosis and the thrombotic events associated with the acute coronary syndromes (ACS), situations poorly regulated with currently available therapeutics. We submit that our findings may define a molecular mechanism by which PDE5 inhibition can differentially impact selected cellular functions of platelets, and perhaps of other cell types. PMID:18757735
Ørstavik, Øivind; Manfra, Ornella; Andressen, Kjetil Wessel; Andersen, Geir Øystein; Skomedal, Tor; Osnes, Jan-Bjørn; Levy, Finn Olav; Krobert, Kurt Allen
2015-01-01
Aims We recently published that the positive inotropic response (PIR) to levosimendan can be fully accounted for by phosphodiesterase (PDE) inhibition in both failing human heart and normal rat heart. To determine if the PIR of the active metabolite OR-1896, an important mediator of the long-term clinical effects of levosimendan, also results from PDE3 inhibition, we compared the effects of OR-1896, a representative Ca2+ sensitizer EMD57033 (EMD), levosimendan and other PDE inhibitors. Methods Contractile force was measured in rat ventricular strips. PDE assay was conducted on rat ventricular homogenate. cAMP was measured using RII_epac FRET-based sensors. Results OR-1896 evoked a maximum PIR of 33±10% above basal at 1 μM. This response was amplified in the presence of the PDE4 inhibitor rolipram (89±14%) and absent in the presence of the PDE3 inhibitors cilostamide (0.5±5.3%) or milrinone (3.2±4.4%). The PIR was accompanied by a lusitropic response, and both were reversed by muscarinic receptor stimulation with carbachol and absent in the presence of β-AR blockade with timolol. OR-1896 inhibited PDE activity and increased cAMP levels at concentrations giving PIRs. OR-1896 did not sensitize the concentration-response relationship to extracellular Ca2+. Levosimendan, OR-1896 and EMD all increased the sensitivity to β-AR stimulation. The combination of either EMD and levosimendan or EMD and OR-1896 further sensitized the response, indicating at least two different mechanisms responsible for the sensitization. Only EMD sensitized the α1-AR response. Conclusion The observed PIR to OR-1896 in rat ventricular strips is mediated through PDE3 inhibition, enhancing cAMP-mediated effects. These results further reinforce our previous finding that Ca2+ sensitization does not play a significant role in the inotropic (and lusitropic) effect of levosimendan, nor of its main metabolite OR-1896. PMID:25738589
DISC1–ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1
Soda, T; Frank, C; Ishizuka, K; Baccarella, A; Park, Y-U; Flood, Z; Park, S K; Sawa, A; Tsai, L-H
2013-01-01
Disrupted-In-Schizophrenia 1 (DISC1), a risk factor for major mental illnesses, has been studied extensively in the context of neurodevelopment. However, the role of DISC1 in neuronal signaling, particularly in conjunction with intracellular cascades that occur in response to dopamine, a neurotransmitter implicated in numerous psychiatric disorders, remains elusive. Previous data suggest that DISC1 interacts with numerous proteins that impact neuronal function, including activating transcription factor 4 (ATF4). In this study, we identify a novel DISC1 and ATF4 binding region in the genomic locus of phosphodiesterase 4D (PDE4D), a gene implicated in psychiatric disorders. We found that the loss of function of either DISC1 or ATF4 increases PDE4D9 transcription, and that the association of DISC1 with the PDE4D9 locus requires ATF4. We also show that PDE4D9 is increased by D1-type dopamine receptor dopaminergic stimulation. We demonstrate that the mechanism for this increase is due to DISC1 dissociation from the PDE4D locus in mouse brain. We further characterize the interaction of DISC1 with ATF4 to show that it is regulated via protein kinase A-mediated phosphorylation of DISC1 serine-58. Our results suggest that the release of DISC1-mediated transcriptional repression of PDE4D9 acts as feedback inhibition to regulate dopaminergic signaling. Furthermore, as DISC1 loss-of-function leads to a specific increase in PDE4D9, PDE4D9 itself may represent an attractive target for therapeutic approaches in psychiatric disorders. PMID:23587879
Tinsley, Heather N.; Gary, Bernard D.; Keeton, Adam B.; Zhang, Wei; Abadi, Ashraf H.; Reynolds, Robert C.; Piazza, Gary A.
2009-01-01
Sulindac displays promising antineoplastic activity, but toxicities from cyclooxygenase (COX) inhibition limit its use for chemoprevention. Previous reports suggest that its anticancer properties may be attributed to a COX-independent mechanism, although alternative targets have not been well defined. Here we show that sulindac sulfide (SS) induces apoptosis and inhibits the growth of human breast tumor cells with IC50 values of 60-85 μM. Within the same concentration range, SS inhibited cGMP hydrolysis in tumor cell lysates, but did not affect cAMP hydrolysis. SS did not induce apoptosis of normal human mammary epithelial cells (HMEC), nor did it inhibit PDE activity in HMEC lysates. SS increased intracellular cGMP levels and activated protein kinase G in breast tumor cells, but not HMEC. The guanylyl cyclase (GC) activator, NOR-3, and cGMP PDE inhibitors, trequinsin and MY5445, displayed similar growth inhibitory activity as SS, but the adenylyl cyclase activator, forskolin, and other PDE inhibitors had no effect. Moreover, GC activation increased the sensitivity of tumor cells to SS, while GC inhibition reduced sensitivity. By comparing PDE isozyme profiles in breast tumor cells with HMEC and determining the sensitivity of recombinant PDE isozymes to SS, PDE5 was found to be overexpressed in breast tumor cells and selectively inhibited by SS. The mechanism of SS binding to the catalytic domain of PDE5 was revealed by molecular modeling. These data suggest that PDE5 inhibition is responsible for the breast tumor cell growth inhibitory and apoptosis inducing activity of SS and may contribute to the chemopreventive properties of sulindac. PMID:19996273
Zhang, Liyun; Xiang, Lue; Liu, Yiwen; Venkatraman, Prahatha; Chong, Leelyn; Cho, Jin; Bonilla, Sylvia; Jin, Zi-Bing; Pang, Chi Pui; Ko, Kam Ming; Ma, Ping; Zhang, Mingzhi; Leung, Yuk Fai
2016-01-01
Retinal degeneration is often progressive. This feature has provided a therapeutic window for intervention that may extend functional vision in patients. Even though this approach is feasible, few promising drug candidates are available. The scarcity of new drugs has motivated research to discover novel compounds through different sources. One such example is Schisandrin B (SchB), an active component isolated from the five-flavor fruit (Fructus Schisandrae) that is postulated in traditional Chinese medicines to exert prophylactic visual benefit. This SchB benefit was investigated in this study in pde6cw59, a zebrafish retinal-degeneration model. In this model, the pde6c gene (phosphodiesterase 6C, cGMP-specific, cone, alpha prime) carried a mutation which caused cone degeneration. This altered the local environment and caused the bystander rods to degenerate too. To test SchB on the pde6cw59 mutants, a treatment concentration was first determined that would not cause morphological defects, and would initiate known physiological response. Then, the mutants were treated with the optimized SchB concentration before the appearance of retinal degeneration at 3 days postfertilization (dpf). The light sensation of animals was evaluated at 6 dpf by the visual motor response (VMR), a visual startle that could be initiated by drastic light onset and offset. The results show that the VMR of pde6cw59 mutants towards light onset was enhanced by the SchB treatment, and that the initial phase of the enhancement was primarily mediated through the mutants' eyes. Further immunostaining analysis indicates that the treatment specifically reduced the size of the abnormally large rods. These observations implicate an interesting hypothesis: that the morphologically-improved rods drive the observed VMR enhancement. Together, these investigations have identified a possible visual benefit of SchB on retinal degeneration, a benefit that can potentially be further developed to extend
Zhang, Liyun; Xiang, Lue; Liu, Yiwen; Venkatraman, Prahatha; Chong, Leelyn; Cho, Jin; Bonilla, Sylvia; Jin, Zi-Bing; Pang, Chi Pui; Ko, Kam Ming; Ma, Ping
2016-01-01
Retinal degeneration is often progressive. This feature has provided a therapeutic window for intervention that may extend functional vision in patients. Even though this approach is feasible, few promising drug candidates are available. The scarcity of new drugs has motivated research to discover novel compounds through different sources. One such example is Schisandrin B (SchB), an active component isolated from the five-flavor fruit (Fructus Schisandrae) that is postulated in traditional Chinese medicines to exert prophylactic visual benefit. This SchB benefit was investigated in this study in pde6cw59, a zebrafish retinal-degeneration model. In this model, the pde6c gene (phosphodiesterase 6C, cGMP-specific, cone, alpha prime) carried a mutation which caused cone degeneration. This altered the local environment and caused the bystander rods to degenerate too. To test SchB on the pde6cw59 mutants, a treatment concentration was first determined that would not cause morphological defects, and would initiate known physiological response. Then, the mutants were treated with the optimized SchB concentration before the appearance of retinal degeneration at 3 days postfertilization (dpf). The light sensation of animals was evaluated at 6 dpf by the visual motor response (VMR), a visual startle that could be initiated by drastic light onset and offset. The results show that the VMR of pde6cw59 mutants towards light onset was enhanced by the SchB treatment, and that the initial phase of the enhancement was primarily mediated through the mutants’ eyes. Further immunostaining analysis indicates that the treatment specifically reduced the size of the abnormally large rods. These observations implicate an interesting hypothesis: that the morphologically-improved rods drive the observed VMR enhancement. Together, these investigations have identified a possible visual benefit of SchB on retinal degeneration, a benefit that can potentially be further developed to extend
An analytical formulation for phase noise in MEMS oscillators.
Agrawal, Deepak; Seshia, Ashwin
2014-12-01
In recent years, there has been much interest in the design of low-noise MEMS oscillators. This paper presents a new analytical formulation for noise in a MEMS oscillator encompassing essential resonator and amplifier nonlinearities. The analytical expression for oscillator noise is derived by solving a second-order nonlinear stochastic differential equation. This approach is applied to noise modeling of an electrostatically addressed MEMS resonator-based square-wave oscillator in which the resonator and oscillator circuit nonlinearities are integrated into a single modeling framework. By considering the resulting amplitude and phase relations, we derive additional noise terms resulting from resonator nonlinearities. The phase diffusion of an oscillator is studied and the phase diffusion coefficient is proposed as a metric for noise optimization. The proposed nonlinear phase noise model provides analytical insight into the underlying physics and a pathway toward the design optimization for low-noise MEMS oscillators. PMID:25474770
A conservation law formulation of nonlinear elasticity in general relativity
NASA Astrophysics Data System (ADS)
Gundlach, Carsten; Hawke, Ian; Erickson, Stephanie J.
2012-01-01
We present a practical framework for ideal hyperelasticity in numerical relativity. For this purpose, we recast the formalism of Carter and Quintana as a set of Eulerian conservation laws in an arbitrary 3+1 split of spacetime. The resulting equations are presented as an extension of the standard Valencia formalism for a perfect fluid, with additional terms in the stress-energy tensor, plus a set of kinematic conservation laws that evolve a configuration gradient ψAi. We prove that the equations can be made symmetric hyperbolic by suitable constraint additions, at least in a neighbourhood of the unsheared state. We discuss the Newtonian limit of our formalism and its relation to a second formalism also used in Newtonian elasticity. We validate our framework by numerically solving a set of Riemann problems in Minkowski spacetime, as well as Newtonian ones from the literature.
In vitro and in vivo metabolism of CHF 6001, a selective phosphodiesterase (PDE4) inhibitor.
Cenacchi, Valentina; Battaglia, Rosangela; Cinato, Flavio; Riccardi, Benedetta; Spinabelli, Daniele; Brogin, Giandomenico; Puccini, Paola; Pezzetta, Daniele
2015-01-01
1. The metabolism of CHF 6001, a novel PDE4 inhibitor, was determined in vitro in mouse, rat, dog, monkey and human microsomes and hepatocytes and in vivo in plasma, urine, feces and bile of rats after intravenous and intratracheal administration. 2. The behavior of CHF 6001 in microsomes and hepatocytes changed across species. CYP3A4/5 isoenzymes were identified to be the primary enzymes responsible for the metabolism of CHF 6001 in human liver microsomes. 3. In the rat, CHF 6001 was found extensively metabolized in urine, feces and bile, but not in plasma, where CHF 6001 was the main compound present. The metabolite profiles were different in the four biological matrices from both qualitative and quantitative point of view. 4. CHF 6001 was metabolized through hydrolysis with the formation of the alcohol CHF 5956, loss of a chlorine atom, loss of the N-oxide, hydroxylation, loss of the cyclopropylmethyl group in the alcohol moiety, conjugation with glucuronic acid, glutathione and cysteine-glycine. 5. The major metabolite present in the bile was isolated and characterized by nuclear magnetic resonance analysis. It derived from CHF 6001 through contraction of the pyridine-N-oxide ring to N-hydroxy pyrrole and conjugation with glucuronic acid. PMID:25733029
AAV-mediated Gene Therapy Halts Retinal Degeneration in PDE6β-deficient Dogs.
Pichard, Virginie; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Hulin, Philippe; Tshilenge, Kizito-Tshitoko; Biget, Marine; Ameline, Baptiste; Deschamps, Jack-Yves; Weber, Michel; Le Meur, Guylène; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne
2016-05-01
We previously reported that subretinal injection of AAV2/5 RK.cpde6β allowed long-term preservation of photoreceptor function and vision in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency. The present study builds on these earlier findings to provide a detailed assessment of the long-term effects of gene therapy on the spatiotemporal pattern of retinal degeneration in rcd1 dogs treated at 20 days of age. We analyzed the density distribution of the retinal layers and of particular photoreceptor cells in 3.5-year-old treated and untreated rcd1 dogs. Whereas no rods were observed outside the bleb or in untreated eyes, gene transfer halted rod degeneration in all vector-exposed regions. Moreover, while gene therapy resulted in the preservation of cones, glial cells and both the inner nuclear and ganglion cell layers, no cells remained in vector-unexposed retinas, except in the visual streak. Finally, the retinal structure of treated 3.5-year-old rcd1 dogs was identical to that of unaffected 4-month-old rcd1 dogs, indicating near complete preservation. Our findings indicate that gene therapy arrests the degenerative process even if intervention is initiated after the onset of photoreceptor degeneration, and point to significant potential of this therapeutic approach in future clinical trials. PMID:26857842
Instantaneous stroke volume by PDE during and after constant LBNP (-50 torr)
NASA Technical Reports Server (NTRS)
1980-01-01
Six male subjects were exposed to -50 torr lower body negative pressure (LBNP) for 10 min while stroke volume was recorded beat by beat at regular intervals before, during and after release of LBNP. Stroke volume was calculated from the systolic velocity integral in the ascending aorta by pulsed Doppler echocardiography (PDE) and the cross sectional area of the vessel by M mode echocardiography. Changes in leg volume were recorded continuously and blood pressure was taken every minute. Stroke volume dropped by 51% of the control in the first 33 sec of LBNP and continued to decline slowly to -62% toward the end. Heart rate increased by 15% in the first 10 sec and was 22% above control at the end of exposure. The resulting cardiac output closely followed the course of stroke volume (-47% at 33 sec, -53% at 8 min) showing that the modest increase in heart rate did little to offset the drop in stroke volume. Leg volume increased markedly within the first 10 sec with a more gradual rise reaching +3.5% at the end. Upon sudden release of LBNP, leg volume dropped significantly during the first 3 sec simultaneously with an increase in stroke volume followed by a substantial decline in heart rate below the baseline.
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.
Mixed formulation for frictionless contact problems
NASA Technical Reports Server (NTRS)
Noor, Ahmed K.; Kim, Kyun O.
1989-01-01
Simple mixed finite element models and a computational precedure are presented for the solution of frictionless contact problems. The analytical formulation is based on a form of Reissner's large rotation theory of the structure with the effects of transverse shear deformation included. The contact conditions are incorporated into the formulation by using a perturbed Lagrangian approach with the fundamental unknowns consisting of the internal forces (stress resultants), the generalized displacements, and the Lagrange multipliers associated with the contact conditions. The element characteristic array are obtained by using a modified form of the two-field Hellinger-Reissner mixed variational principle. The internal forces and the Lagrange multipliers are allowed to be discontinuous at interelement boundaries. The Newton-Raphson iterative scheme is used for the solution of the nonlinear algebraic equations, and the determination of the contact area and the contact pressures.
Hamiltonian Formulation for Wave-Current Interactions in Stratified Rotational Flows
NASA Astrophysics Data System (ADS)
Constantin, A.; Ivanov, R. I.; Martin, C.-I.
2016-09-01
We show that the Hamiltonian framework permits an elegant formulation of the nonlinear governing equations for the coupling between internal and surface waves in stratified water flows with piecewise constant vorticity.
Formulation and Application of the Generalized Multilevel Facets Model
ERIC Educational Resources Information Center
Wang, Wen-Chung; Liu, Chih-Yu
2007-01-01
In this study, the authors develop a generalized multilevel facets model, which is not only a multilevel and two-parameter generalization of the facets model, but also a multilevel and facet generalization of the generalized partial credit model. Because the new model is formulated within a framework of nonlinear mixed models, no efforts are…
Parallelized solvers for heat conduction formulations
NASA Technical Reports Server (NTRS)
Padovan, Joe; Kwang, Abel
1991-01-01
Based on multilevel partitioning, this paper develops a structural parallelizable solution methodology that enables a significant reduction in computational effort and memory requirements for very large scale linear and nonlinear steady and transient thermal (heat conduction) models. Due to the generality of the formulation of the scheme, both finite element and finite difference simulations can be treated. Diverse model topologies can thus be handled, including both simply and multiply connected (branched/perforated) geometries. To verify the methodology, analytical and numerical benchmark trends are verified in both sequential and parallel computer environments.
Michie, A M; Rena, G; Harnett, M M; Houslay, M D
1998-01-01
We have previously shown that the major cAMP phosphodiesterase (PDE) isoforms present in murine thymocytes are the cGMP-stimulated PDE activity (PDE-2) and the cAMP-specific PDE activity (PDE-4), and that these isoforms are differentially regulated following ligation of the TCR (Michie, A.M., Lobban, M. D., Mueller, T., Harnett, M. M., and Houslay, M.D. [1996] Cell. Signalling 8, 97-110). We show here that the anti-CD3-stimulated elevation in PDE-4 activity in murine thymocytes is dependent on protein tyrosine kinase and protein kinase C (PKC)-mediated signals as the TCR-coupled increase in PDE-4 activity can be abrogated by both the tyrosine kinase inhibitor, genistein, and the PKC selective inhibitors chelerythrine and staurosporine. Moreover, the PKC-activating phorbol ester, phorbol-12-myristate, 13-acetate (PMA) caused an increase in PDE-4 activity, similar to that observed in cells challenged with anti-CD3 monoclonal antibodies and which was not additive with cochallenge using anti-CD3 antibodies. Both the PMA- and the anti-CD3 antibody-mediated increases in PDE-4 activity were blocked by treatment with either cycloheximide or actinomycin D. Despite the upregulation of PDE-4 activity consequent to TCR ligation, intracellular cAMP levels increased on challenge of thymocytes with anti-CD3 antibody, indicating that adenylate cyclase activity was also increased by TCR ligation. It is suggested that the anti-CD3-mediated increase in PDE-4 activity was owing to a rapid PKC-dependent induction of PDE-4 activity following crosslinking of the TCR complex. This identifies "crosstalk" occurring between the PKA and PKC signaling pathways initiated by ligation of the antigen receptor in murine thymocytes. That both adenylate cyclase and PDE-4 activities were increased may indicate the presence of compartmentalized cAMP responses present in these cells. PMID:9515165
Lane, M E; Hadgraft, J; Oliveira, G; Vieira, R; Mohammed, D; Hirata, K
2012-12-01
To be efficacious and to satisfy the requirements for claim substantiation, a cosmetic formulation must achieve effective targeting of an active in the skin. Although the basic principles governing the skin permeation and disposition of molecules have been known for many years, attention has been far less focused on the role of the vehicle, particularly at cosmetically relevant doses. In this article, we discuss the necessity to understand the fate of the formulation components as well as the active once applied onto skin. Recent data confirm that the residence time of the formulation constituents can have a profound impact on the fate of the active. Approaches to identify the ideal vehicle for skin delivery are considered critically, specifically the recent work on 'formulating for efficacy' (FFE) by the late Johann Wiechers. Essentially, FFE aims to match the active with the optimal vehicle for skin delivery based on matching polarity/solubility values of the trinity of skin, active and vehicle. The emerging importance of techniques that provide insight to how the vehicle distributes in and on skin is highlighted. PMID:22882873
Payloads minimum EIRP formulations
NASA Technical Reports Server (NTRS)
1980-01-01
The effective isotropic radiated power (EIRP) of the payloads is formulated. The EIRP consists of three components; EIRP = P sub T + G sub T + L sub TX, where P sub T is the transmitter total RF output power, G sub T is the transmitting antenna gain, and L sub TX is all transmitter circuit losses.
Technology Transfer Automated Retrieval System (TEKTRAN)
Formulation development is one of many steps required for commercialization of biological pesticides and holds the promise to bridge the gap between production of the active agent and use by consumers. A biological pesticide begins with discovery of an agent capable of controlling a pest. Active a...
Xiao, Heng-Jun; Yan, Weixin; Chen, Jun; Gao, Xin; Zhuan, Li; Wang, Tao; Yang, Jun; Liu, Ji-Hong
2016-01-01
Objective To investigate the expression of PDE5 in ex vivo differentiation of gene-modified BM-MSCs using the lentiviral vector containing silencing target gene PDE5 of shRNA. Methods SD rat bone marrow-derived MSCs were separated, cultured and purified in vitro by Percoll density gradient centrifugation combined with adherent culture. The third passage rat BM-MSCs were obtained, and were identified by cell surface markers with flow cytometry (FCM). The lentiviral vector carrying silencing target gene PDE5 of shRNA was constructed and then transfected into the third passage rat BM-MSCs. The gene-modified rat BM-MSCs were induced to differentiate into smooth muscle-like cells exposed to VEGF and b-FGF media in vitro. The proliferative ability of these cells was tested by cell counting kit 8 (CCK-8). Smooth muscle-like cells differentiation was assessed by immunofluorescence and then subjected to immunocytochemistry for specific markers of α-smooth muscle actin (α-SMA). Real-time quantitative PCR, immunohistochemical staining and Western blot analysis for PDE5 gene expression in differentiated smooth muscle-like cells were carried out. Results After the conducted lentiviral vector containing PDE5-shRNA was transfected into rat BM-MSCs, the expression of EGFP was detected at 24 h and it became the strongest at 72 h, which FCM showed the transfection efficiency was 91.3% at this time. The EGFP expression rates of rat BM-MSCs transfected with PDE5-shRNA at 3 d, 7 d, 14 d after transduction were 91.3%, 86.1%, and 82.7%, respectively. There was still visible green fluorescence at 28 d after transfection. The gene-modified rat BM-MSCs with PDE5-shRNA were successfully induced to differentiate into smooth muscle-like cells. Transduction of the lentiviral vector PDE5-shRNA into rat BM-MSCs led to down-regulation of PDE5. The expression of PDE5 was reduced 67.2% by PDE5-shRNA compared with the control lentiviral vector. The proliferative property of rat BM-MSCs did not
cGMP decreases surface NKCC2 levels in the thick ascending limb: role of phosphodiesterase 2 (PDE2)
Ares, Gustavo R.; Caceres, Paulo; Alvarez-Leefmans, Francisco J.; Ortiz, Pablo A.
2008-01-01
NaCl absorption in the medullary thick ascending limb of the loop of Henle (THAL) is mediated by the apical Na/K/2Cl cotransporter (NKCC2). Hormones that increase cGMP, such as nitric oxide (NO) and natriuretic peptides, decrease NaCl absorption by the THAL. However, the mechanism by which cGMP decreases NaCl absorption in THALs is not known. We hypothesized that cGMP decreases surface NKCC2 levels in the THAL. We used surface biotinylation to measure surface NKCC2 levels in rat THAL suspensions. We tested the effect of the membrane-permeant cGMP analog dibutyryl-cGMP (db-cGMP) on surface NKCC2 levels. Incubating THALs with db-cGMP for 20 min decreased surface NKCC2 levels in a concentration-dependent manner (basal = 100%; db-cGMP 100 μM = 77 ± 7%; 500 μM = 54 ± 10% and 1,000 μM = 61 ± 8%). A different cGMP analog 8-bromo-cGMP (8-Br-cGMP) also decreased surface NKCC2 levels by 25%, (basal = 100%; 8-Br-cGMP = 75 ± 5%). Incubation of isolated, perfused THALs with db-cGMP decreased apical surface NKCC2 labeling levels as measured by immunofluorescence and confocal microscopy. cGMP-stimulated phosphodiesterase 2 (PDE2) mediates the inhibitory effect of NO on NaCl absorption by THALs. Thus we examined the role of PDE2 and found that PDE2 inhibitors blocked the effect of db-cGMP on surface NKCC2. Also, a nonstimulatory concentration of db-cAMP blocked the cGMP-induced decrease in surface NKCC2. Finally, db-cGMP inhibited THAL net Cl absorption by 48 ± 4%, and this effect was completely blocked by PDE2 inhibition. We conclude that cGMP decreases NKCC2 levels in the apical membrane of THALs and that this effect is mediated by PDE2. This is an important mechanism by which cGMP inhibits NaCl absorption by the THAL. PMID:18684888
Feng, Yanguo; Cheng, Dejun; Zhang, Chaofeng; Li, Yuchun; Zhang, Zhiying; Wang, Juan; Shi, Yuzhong
2016-01-01
Background The PDE4B single nucleotide polymorphisms (SNPs) have been reported to be associated with schizophrenia risk. However, current findings are ambiguous or even conflicting. To better facilitate the understanding the genetic role played by PDE4B in susceptibility to schizophrenia, we collected currently available data and conducted this meta-analysis. Methods A comprehensive electronic literature searching of PubMed, Embase, Web of Science and Cochrane Library was performed. The association between PDE4B SNPs and schizophrenia was evaluated by odds ratios (ORs) and 95% confidence intervals (CIs) under allelic, dominant and recessive genetic models. The random effects model was utilized when high between-study heterogeneity (I2 > 50%) existed, otherwise the fixed effects model was used. Results Five studies comprising 2376 schizophrenia patients and 3093 controls were finally included for meta-analysis. The rs1040716 was statistically significantly associated with schizophrenia risk in Asian and Caucasian populations under dominant model (OR = 0.87, 95% CI: 0.76–0.99, P = 0.04). The rs2180335 was significantly related with schizophrenia risk in Asian populations under allelic (OR = 0.82, 95% CI: 0.72–0.93, P = 0.003) and dominant (OR = 0.75, 95% CI: 0.64–0.88, P < 0.001) models. A significant association was also observed between rs4320761 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.75–1.00, P = 0.048). In addition, a strong association tendency was found between rs6588190 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.76–1.00, P = 0.055). Conclusion This meta-analysis suggests that PDE4B SNPs are genetically associated with susceptibility to schizophrenia. However, due to limited sample size, more large-scale, multi-racial association studies are needed to further clarify the genetic association between various PDE4B variants and schizophrenia. PMID:26756575
Surface effect on the nonlinear forced vibration of cantilevered nanobeams
NASA Astrophysics Data System (ADS)
Dai, H. L.; Zhao, D. M.; Zou, J. J.; Wang, L.
2016-06-01
The nonlinear forced vibration behavior of a cantilevered nanobeam is investigated in this paper, essentially considering the effect due to the surface elastic layer. The governing equation of motion for the nano-cantilever is derived, with consideration of the geometrical nonlinearity and the effects of additional flexural rigidity and residual stress of the surface layer. Then, the nonlinear partial differential equation (PDE) is discretized into a set of nonlinear ordinary differential equations (ODEs) by means of the Galerkin's technique. It is observed that surface effects on the natural frequency of the nanobeam is of significance, especially for the case when the aspect ratio of the nanobeam is large. The nonlinear resonant dynamics of the nanobeam system is evaluated by varying the excitation frequency around the fundamental resonance, showing that the nanobeam would display hardening-type behavior and hence the frequency-response curves bend to the right in the presence of positive residual surface stress. However, with the negative residual surface stress, this hardening-type behavior can be shifted to a softening-type one which becomes even more evident with increase of the aspect ratio parameter. It is also demonstrated that the combined effects of the residual stress and aspect ratio on the maximum amplitude of the nanobeam may be pronounced.
Development of solution techniques for nonlinear structural analysis
NASA Technical Reports Server (NTRS)
Vos, R. G.; Andrews, J. S.
1974-01-01
Nonlinear structural solution methods in the current research literature are classified according to order of the solution scheme, and it is shown that the analytical tools for these methods are uniformly derivable by perturbation techniques. A new perturbation formulation is developed for treating an arbitrary nonlinear material, in terms of a finite-difference generated stress-strain expansion. Nonlinear geometric effects are included in an explicit manner by appropriate definition of an applicable strain tensor. A new finite-element pilot computer program PANES (Program for Analysis of Nonlinear Equilibrium and Stability) is presented for treatment of problems involving material and geometric nonlinearities, as well as certain forms on nonconservative loading.
NASA Technical Reports Server (NTRS)
Simon, M. K.
1980-01-01
A technique is presented for generating phase plane plots on a digital computer which circumvents the difficulties associated with more traditional methods of numerical solving nonlinear differential equations. In particular, the nonlinear differential equation of operation is formulated.
Equivalence of Dirac formulations
NASA Astrophysics Data System (ADS)
Joyce, William P.; Martin, Jeremy G.
2002-06-01
We construct general Dirac theories in both ⊗ ℓ(3, 1) and ⊗ ℓ(1, 3) using a first order left acting Dirac operator. Any two such theories are equivalent provided they have the same dimension. We also show that every 16- or 8-dimensional real Dirac theory in ℓ(3, 1) is equivalent to some (complex) Dirac theory in ⊗ ℓ(1, 3). As an immediate consequence of this we have that the Hestenes and original Dirac formulations are equivalent.
Nonlinear quantum optical properties of graphene
NASA Astrophysics Data System (ADS)
Semnani, Behrooz; Hamed Majedi, Amir; Safavi-Naeini, Safieddin
2016-03-01
We present a semiclassical theory of the linear and nonlinear optical response of graphene. The emphasis is placed on the nonlinear optical response of graphene from the standpoint of the underlying chiral symmetry. The Bloch quasiparticles in the low-energy limit around the degeneracy points are dominantly chiral. It is shown that this chiral behavior in conjunction with scale invariance in graphene around the Dirac points results in the strong nonlinear optical response. Explicit expressions for the linear and nonlinear conductivity tensors are derived based on semiconductor Bloch equations (SBEs). The linear terms agree with the result of Kubo formulation. The three main additive mechanisms contribute in the nonlinear optical response of graphene: pure intraband, pure interband and the interplay between them. For each contribution, an explicit response function is derived. The Kerr-type nonlinearity of graphene is then numerically studied and it is demonstrated that the nonlinear refractive index of graphene can be tuned and enhanced by applying a gate voltage. It is also discussed that a strong Kerr nonlinearity can be achieved in a gated graphene monolayer. However, this nonlinearity is accompanied with a significant amount of absorption loss.
Liposomal formulations for inhalation.
Cipolla, David; Gonda, Igor; Chan, Hak-Kim
2013-08-01
No marketed inhaled products currently use sustained release formulations such as liposomes to enhance drug disposition in the lung, but that may soon change. This review focuses on the interaction between liposomal formulations and the inhalation technology used to deliver them as aerosols. There have been a number of dated reviews evaluating nebulization of liposomes. While the information they shared is still accurate, this paper incorporates data from more recent publications to review the factors that affect aerosol performance. Recent reviews have comprehensively covered the development of dry powder liposomes for aerosolization and only the key aspects of those technologies will be summarized. There are now at least two inhaled liposomal products in late-stage clinical development: ARIKACE(®) (Insmed, NJ, USA), a liposomal amikacin, and Pulmaquin™ (Aradigm Corp., CA, USA), a liposomal ciprofloxacin, both of which treat a variety of patient populations with lung infections. This review also highlights the safety of inhaled liposomes and summarizes the clinical experience with liposomal formulations for pulmonary application. PMID:23919478
Yuen, P.S.T.; Walseth, T.F.; Panter, S.S.; Sundby, S.R.; Graeff, R.M.; Goldberg, N.D.
1987-05-01
cGMP binding proteins in toad ROS were identified by direct photoaffinity labeling (PAL) with /sup 32/P-cGMP and quantified by retention of complexes on nitrocellulose filters. By PAL, high affinity sites were present on the ..cap alpha.. and ..beta.. subunits of the cGMP-specific phosphodiesterase (PDE) which have MW/sub app/ of 94 and 90 kDa. A doublet was deduced from its photolabeling properties to represent PDE/sub ..gamma../ photocrosslinked with PDE/sub ..cap alpha../ or PDE/sub ..beta../, respectively. cGMP prebound to these high affinity sites was released by light-activated G-protein or its ..cap alpha.. subunit complexed with GTP..gamma..S; this inhibition of cGMP binding to PDE did not result from decreased cGMP availability due to enhanced hydrolysis. A low affinity cGMP binding component identified by PAL is tightly associated with ROS membranes. Apparent ATP/light-dependent stimulation of cGMP binding was shown to result from light activated cGMP hydrolysis in conjunction with ATP-promoted conversion of GMP to GDP/GTP and increased GDP/GTP binding. These findings coincide with a model for light-related regulation of cGMP binding and metabolism predicted from intact and cellfree kinetic measurements: in the dark state the cGMP hydrolic rate is constrained by the availability of cGMP because of its binding to high affinity sites on PDE. Light activated G-protein releases cGMP from these sites and allows for its redistribution to lower affinity sites represented by PDE catalytic site(s) and possible cGMP-dependent membrane cation channels.
Meyers, John A.; Taverna, Josephine; Chaves, Jorge; Makkinje, Anthony; Lerner, Adam
2009-01-01
Purpose Type 4 cAMP phosphodiesterase (PDE4) inhibitors, compounds that activate cAMP-mediated signaling by inhibiting cAMP catabolism, potentiate glucocorticoid-mediated apoptosis in chronic lymphocytic leukemia (CLL) cells but the mechanism by which this occurs is unknown. In this study, we sought to address whether PDE4 inhibitors alter expression of glucocorticoid receptor (GRα) in CLL cells. Experimental Design CLL cells or normal hematopoietic cells were treated with PDE4 inhibitors followed by analysis of GRα transcript and protein by real-time PCR and Western analysis. Results PDE4 inhibitors up-regulate glucocorticoid receptor transcript levels in CLL cells but not normal circulating T cells, B cells, monocytes or neutrophils. As GRα transcript half-life does not vary in CLL cells treated with the prototypic PDE4 inhibitor rolipram, the four-fold increase in GRα mRNA levels observed within four hours of rolipram treatment appears to result from an increase in transcription. Rolipram treatment increases levels of transcripts derived from the 1A3 promoter to a greater extent than the 1B promoter. Treatment of CLL cells with cilomilast and roflumilast, two PDE4 inhibitors previously studied in clinical trials also augments GRα transcript levels and glucocorticoid-mediated apoptosis. Washout studies demonstrate that simultaneous treatment with both drug classes irreversibly augments apoptosis over the same time frame that glucocorticoid receptor up-regulation occurs. While treatment of CLL cells with glucocorticoids reduces basal GRα transcript levels in a dose-related manner, co-treatment with rolipram maintained GRα transcript levels above baseline. Conclusion Our results suggest that PDE4 inhibitors may sensitize CLL cells to glucocorticoid-induced apoptosis by augmenting GRα expression. PMID:17699872
ERIC Educational Resources Information Center
Natesan, Prathiba; Limbers, Christine; Varni, James W.
2010-01-01
The present study presents the formulation of graded response models in the multilevel framework (as nonlinear mixed models) and demonstrates their use in estimating item parameters and investigating the group-level effects for specific covariates using Bayesian estimation. The graded response multilevel model (GRMM) combines the formulation of…
Micosoft Excel Sensitivity Analysis for Linear and Stochastic Program Feed Formulation
Technology Transfer Automated Retrieval System (TEKTRAN)
Sensitivity analysis is a part of mathematical programming solutions and is used in making nutritional and economic decisions for a given feed formulation problem. The terms, shadow price and reduced cost, are familiar linear program (LP) terms to feed formulators. Because of the nonlinear nature of...
A comparison of two formulations of the fin efficiency for straight fins
NASA Astrophysics Data System (ADS)
Momoniat, Ebrahim
2012-04-01
A formulation of the fin efficiency based on Newton's law of cooling is compared with a formulation based on a ratio of heat transferred from the fin surface to the surrounding fluid to the heat conducted through the base. The first formulation requires that the solution of the nonlinear fin equations for constant heat transfer coefficient and constant thermal conductivity is known, whilst the second formulation of the fin efficiency requires only that a first integral of the model equation is known. This paper shows the first formulation of the fin efficiency contains approximation errors as only power series and approximate solutions to the nonlinear fin equations have been determined. The second formulation of the fin efficiency is exact when the first integrals can be determined.
How to characterize the nonlinear amplifier?
NASA Technical Reports Server (NTRS)
Kallistratova, Dmitri Kouznetsov; Cotera, Carlos Flores
1994-01-01
The conception of the amplification of the coherent field is formulated. The definition of the coefficient of the amplification as the relation between the mean value of the field at the output to the value at the input and the definition of the noise as the difference between the number of photons in the output mode and square of the modulus of the mean value of the output amplitude are considered. Using a simple example it is shown that by these definitions the noise of the nonlinear amplifier may be less than the noise of the ideal linear amplifier of the same amplification coefficient. Proposals to search another definition of basic parameters of the nonlinear amplifiers are discussed. This definition should enable us to formulate the universal fundamental lower limit of the noise which should be valid for linear quantum amplifiers as for nonlinear ones.
Méhats, C; Tanguy, G; Paris, B; Robert, B; Pernin, N; Ferré, F; Leroy, M J
2000-02-01
The inhibitory impacts of RP 73401, a phosphodiesterase type 4 (PDE4) selective inhibitor of the second generation, versus rolipram, the prototypal PDE4 inhibitor, were evaluated and compared on cAMP phosphodiesterase (PDE) activity and contractility of the myometrium in nonpregnant and pregnant women. In enzymatic studies, RP 73401 and rolipram inhibited the cAMP PDE activity with significantly greater maximal efficiency in the myometrium of pregnant compared with nonpregnant women (75 versus 55%; P <.05). Although myometrial PDE4 presented a single class of interaction with RP 73401 [pD(2) (-log [IC(50)]) = -8.2], it exhibited at least two classes of interaction with rolipram (pD(2) = -8.2 and -5.6). In the myometrium of pregnant versus nonpregnant women, rolipram is significantly more efficacious in the concentration range >0.01 to 100 microM (P <.01), whereas no difference was observed for the concentration range <0.01 microM. In contractility studies, RP 73401 was equally effective in relaxing myometrial strips from both nonpregnant and pregnant women (pD(2) = -8.8). Conversely, the ability of rolipram to inhibit contractions of the myometrium in pregnant women was significantly lower (pD(2) = -7.2) compared with that in nonpregnant women (pD(2) = -8.2; P <.01). Concomitantly, in the myometrium of pregnant women, a rise in immunoreactive PDE4B2 signal was detected, whereas the PDE4D3 signal was less intense. These results demonstrate that parallel to an accumulation of PDE4B2 isoform, a modification in the ratio of PDE4 conformers HPDE4 and LPDE4 (conformer that binds rolipram with high and low affinity, respectively) occurs in the myometrium of near-term pregnant women with an increase of LPDE4 functionally implicated in the contractile process. Such modifications provide a strong rationale to propose LPDE4 as potential pharmacologic targets for the design of new tocolytic treatments. PMID:10640323
Nonlinear mechanical behavior of thermoplastic matrix materials for advanced composites
NASA Technical Reports Server (NTRS)
Arenz, R. J.; Landel, R. F.
1989-01-01
Two recent theories of nonlinear mechanical response are quantitatively compared and related to experimental data. Computer techniques are formulated to handle the numerical integration and iterative procedures needed to solve the associated sets of coupled nonlinear differential equations. Problems encountered during these formulations are discussed and some open questions described. Bearing in mind these cautions, the consequences of changing parameters that appear in the formulations on the resulting engineering properties are discussed. Hence, engineering approaches to the analysis of thermoplastic matrix material can be suggested.
Formulations of entomopathogens as bioinsecticides
Technology Transfer Automated Retrieval System (TEKTRAN)
Developing a proper formulation is a necessary component for commercialization of entomopathogenic microbes as biological insecticides. The objective of this chapter is to present broad-ranging information about formulations to foster research toward developing commercial microbial-based insecticide...
Bardhan, Jaydeep P.; Altman, Michael D.
2009-01-01
We present a partial-differential-equation (PDE)-constrained approach for optimizing a molecule’s electrostatic interactions with a target molecule. The approach, which we call reverse-Schur co-optimization, can be more than two orders of magnitude faster than the traditional approach to electrostatic optimization. The efficiency of the co-optimization approach may enhance the value of electrostatic optimization for ligand-design efforts–in such projects, it is often desirable to screen many candidate ligands for their viability, and the optimization of electrostatic interactions can improve ligand binding affinity and specificity. The theoretical basis for electrostatic optimization derives from linear-response theory, most commonly continuum models, and simple assumptions about molecular binding processes. Although the theory has been used successfully to study a wide variety of molecular binding events, its implications have not yet been fully explored, in part due to the computational expense associated with the optimization. The co-optimization algorithm achieves improved performance by solving the optimization and electrostatic simulation problems simultaneously, and is applicable to both unconstrained and constrained optimization problems. Reverse-Schur co-optimization resembles other well-known techniques for solving optimization problems with PDE constraints. Model problems as well as realistic examples validate the reverse-Schur method, and demonstrate that our technique and alternative PDE-constrained methods scale very favorably compared to the standard approach. Regularization, which ordinarily requires an explicit representation of the objective function, can be included using an approximate Hessian calculated using the new BIBEE/P (boundary-integral-based electrostatics estimation by preconditioning) method. PMID:23055839
Formal descriptions for formulation.
This, Hervé
2007-11-01
Two formalisms used to describe the physical microstructure and the organization of formulated products are given. The first, called "complex disperse systems formalism" (CDS formalism) is useful for the description of the physical nature of disperse matter. The second, called "non periodical organizational space formalism" (NPOS formalism) has the same operators as the CDS formalism, but different elements; it is useful to describe the arrangement of any objects in space. Both formalisms can be viewed as the same, applied to different orders of magnitude for spatial size. PMID:17875375
On shallow water waves in a medium with time-dependent dispersion and nonlinearity coefficients.
Abdel-Gawad, Hamdy I; Osman, Mohamed
2015-07-01
In this paper, we studied the progression of shallow water waves relevant to the variable coefficient Korteweg-de Vries (vcKdV) equation. We investigated two kinds of cases: when the dispersion and nonlinearity coefficients are proportional, and when they are not linearly dependent. In the first case, it was shown that the progressive waves have some geometric structures as in the case of KdV equation with constant coefficients but the waves travel with time dependent speed. In the second case, the wave structure is maintained when the nonlinearity balances the dispersion. Otherwise, water waves collapse. The objectives of the study are to find a wide class of exact solutions by using the extended unified method and to present a new algorithm for treating the coupled nonlinear PDE's. PMID:26199750
NASA Astrophysics Data System (ADS)
Lou, Sen-yue
1998-05-01
To study a nonlinear partial differential equation (PDE), the Painleve expansion developed by Weiss, Tabor and Carnevale (WTC) is one of the most powerful methods. In this paper, using any singular manifold, the expansion series in the usual Painleve analysis is shown to be resummable in some different ways. A simple nonstandard truncated expansion with a quite universal reduction function is used for many nonlinear integrable and nonintegrable PDEs such as the Burgers, Korteweg de-Vries (KdV), Kadomtsev-Petviashvli (KP), Caudrey-Dodd-Gibbon-Sawada-Kortera (CDGSK), Nonlinear Schrödinger (NLS), Davey-Stewartson (DS), Broer-Kaup (BK), KdV-Burgers (KdVB), λf4 , sine-Gordon (sG) etc.
Venneri, Mary Anna; Giannetta, Elisa; Panio, Giuseppe; De Gaetano, Rita; Gianfrilli, Daniele; Pofi, Riccardo; Masciarelli, Silvia; Fazi, Francesco; Pellegrini, Manuela; Lenzi, Andrea; Naro, Fabio; Isidori, Andrea M.
2015-01-01
Diabetes mellitus is characterized by changes in endothelial cells that alter monocyte recruitment, increase classic (M1-type) tissue macrophage infiltration and lead to self-sustained inflammation. Our and other groups recently showed that chronic inhibition of phosphodiesterase-5 (PDE5i) affects circulating cytokine levels in patients with diabetes; whether PDE5i also affects circulating monocytes and tissue inflammatory cell infiltration remains to be established. Using murine streptozotocin (STZ)-induced diabetes and in human vitro cell-cell adhesion models we show that chronic hyperglycemia induces changes in myeloid and endothelial cells that alter monocyte recruitment and lead to self-sustained inflammation. Continuous PDE5i with sildenafil (SILD) expanded tissue anti-inflammatory TIE2-expressing monocytes (TEMs), which are known to limit inflammation and promote tissue repair. Specifically, SILD: 1) normalizes the frequency of circulating pro-inflammatory monocytes triggered by hyperglycemia (53.7 ± 7.9% of CD11b+Gr-1+ cells in STZ vs. 30.4 ± 8.3% in STZ+SILD and 27.1 ± 1.6% in CTRL, P<0.01); 2) prevents STZ-induced tissue inflammatory infiltration (4-fold increase in F4/80+ macrophages in diabetic vs. control mice) by increasing renal and heart anti-inflammatory TEMs (30.9 ± 3.6% in STZ+SILD vs. 6.9 ± 2.7% in STZ, P <0.01, and 11.6 ± 2.9% in CTRL mice); 3) reduces vascular inflammatory proteins (iNOS, COX2, VCAM-1) promoting tissue protection; 4) lowers monocyte adhesion to human endothelial cells in vitro through the TIE2 receptor. All these changes occurred independently from changes of glycemic status. In summary, we demonstrate that circulating renal and cardiac TEMs are defective in chronic hyperglycemia and that SILD normalizes their levels by facilitating the shift from classic (M1-like) to alternative (M2-like)/TEM macrophage polarization. Restoration of tissue TEMs with PDE5i could represent an additional pharmacological tool to prevent end
Woodrow, Michael D; Ballantine, Stuart P; Barker, Michael D; Clarke, Beth J; Dawson, John; Dean, Tony W; Delves, Christopher J; Evans, Brian; Gough, Sharon L; Guntrip, Steven B; Holman, Stuart; Holmes, Duncan S; Kranz, Michael; Lindvaal, Mika K; Lucas, Fiona S; Neu, Margarete; Ranshaw, Lisa E; Solanke, Yemisi E; Somers, Don O; Ward, Peter; Wiseman, Joanne O
2009-09-01
Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-alpha from isolated human peripheral blood mononuclear cells with a pIC(50) of 11.1. GSK256066 also has a suitable profile for inhaled dosing. PMID:19656678
Multilevel algorithms for nonlinear optimization
NASA Technical Reports Server (NTRS)
Alexandrov, Natalia; Dennis, J. E., Jr.
1994-01-01
Multidisciplinary design optimization (MDO) gives rise to nonlinear optimization problems characterized by a large number of constraints that naturally occur in blocks. We propose a class of multilevel optimization methods motivated by the structure and number of constraints and by the expense of the derivative computations for MDO. The algorithms are an extension to the nonlinear programming problem of the successful class of local Brown-Brent algorithms for nonlinear equations. Our extensions allow the user to partition constraints into arbitrary blocks to fit the application, and they separately process each block and the objective function, restricted to certain subspaces. The methods use trust regions as a globalization strategy, and they have been shown to be globally convergent under reasonable assumptions. The multilevel algorithms can be applied to all classes of MDO formulations. Multilevel algorithms for solving nonlinear systems of equations are a special case of the multilevel optimization methods. In this case, they can be viewed as a trust-region globalization of the Brown-Brent class.
A general formulation for compositional reservoir simulation
Rodriguez, F.; Guzman, J.; Galindo-Nava, A.
1994-12-31
In this paper the authors present a general formulation to solve the non-linear difference equations that arise in compositional reservoir simulation. The general approach here presented is based on newton`s method and provides a systematic approach to generate several formulations to solve the compositional problem, each possessing a different degree of implicitness and stability characteristics. The Fully-Implicit method is at the higher end of the implicitness spectrum while the IMPECS method, implicit in pressure-explicit in composition and saturation, is at the lower end. They show that all methods may be obtained as particular cases of the fully-implicit method. Regarding the matrix problem, all methods have a similar matrix structure; the composition of the Jacobian matrix is however unique in each case, being in some instances amenable to reductions for optimal solution of the matrix problem. Based on this, a different approach to derive IMPECS type methods is proposed; in this case, the whole set of 2nc + 6 equations, that apply in each gridblock, is reduced to a single pressure equation through matrix reduction operations; this provides a more stable numerical scheme, compared to other published IMPCS methods, in which the subset of thermodynamic equilibrium equations is arbitrarily decoupled form the set of gridblock equations to perform such reduction. The authors discuss how the general formulation here presented can be used to formulate and construct an adaptive-implicit compositional simulators. They also present results on the numerical performance of FI, IMPSEC and IMPECS methods on some test problems.
Suzuki, Kazunori; Harada, Akina; Suzuki, Hirobumi; Miyamoto, Maki; Kimura, Haruhide
2016-08-01
Phosphodiesterase 10A (PDE10A) inhibitors are expected to be novel drugs for schizophrenia through activation of both direct and indirect pathway medium spiny neurons. However, excess activation of the direct pathway by a dopamine D1 receptor agonist SKF82958 canceled antipsychotic-like effects of a dopamine D2 receptor antagonist haloperidol in methamphetamine (METH)-induced hyperactivity in rats. Thus, balanced activation of these pathways may be critical for PDE10A inhibitors. Current antipsychotics and the novel PDE10A inhibitor TAK-063, but not the selective PDE10A inhibitor MP-10, produced dose-dependent antipsychotic-like effects in METH-induced hyperactivity and prepulse inhibition in rodents. TAK-063 and MP-10 activated the indirect pathway to a similar extent; however, MP-10 caused greater activation of the direct pathway than did TAK-063. Interestingly, the off-rate of TAK-063 from PDE10A in rat brain sections was faster than that of MP-10, and a slower off-rate PDE10A inhibitor with TAK-063-like chemical structure showed an MP-10-like pharmacological profile. In general, faster off-rate enzyme inhibitors are more sensitive than slower off-rate inhibitors to binding inhibition by enzyme substrates. As expected, TAK-063 was more sensitive than MP-10 to binding inhibition by cyclic nucleotides. Moreover, an immunohistochemistry study suggested that cyclic adenosine monophosphate levels in the direct pathway were higher than those in the indirect pathway. These data can explain why TAK-063 showed partial activation of the direct pathway compared with MP-10. The findings presented here suggest that TAK-063's antipsychotic-like efficacy may be attributable to its unique pharmacological properties, resulting in balanced activation of the direct and indirect striatal pathways. PMID:26849714
Nyberg, Michael; Piil, Peter; Egelund, Jon; Sprague, Randy S; Mortensen, Stefan P; Hellsten, Ylva
2015-12-01
Aging is associated with an altered regulation of blood flow to contracting skeletal muscle; however, the precise mechanisms remain unclear. We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not young human subjects. Here we examined whether this effect of PDE5 inhibition was related to an improved ability to blunt α-adrenergic vasoconstriction (functional sympatholysis) and/or improved efficacy of local vasodilator pathways. A group of young (23 ± 1 yr) and a group of older (72 ± 1 yr) male subjects performed knee-extensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. During both conditions, exercise was performed without and with arterial tyramine infusion to evoke endogenous norepinephrine release and consequently stimulation of α1- and α2-adrenergic receptors. The level of the sympatholytic compound ATP was measured in venous plasma by use of the microdialysis technique. Sildenafil increased (P < 0.05) vascular conductance during exercise in the older group, but tyramine infusion reduced (P < 0.05) this effect by 38 ± 9%. Similarly, tyramine reduced (P < 0.05) the vasodilation induced by arterial infusion of a nitric oxide (NO) donor by 54 ± 9% in the older group, and this effect was not altered by sildenafil. Venous plasma [ATP] did not change with PDE5 inhibition in the older subjects during exercise. Collectively, PDE5 inhibition in older humans was not associated with an improved ability for functional sympatholysis. An improved efficacy of the NO system may be one mechanism underlying the effect of PDE5 inhibition on exercise hyperemia in aging. PMID:26432842
Nanoliposomal Dry Powder Formulations
Patel, Gaurang; Chougule, Mahavir; Singh, Mandip; Misra, Ambikanandan
2013-01-01
Liposomal dry powder formulations (DPFs) have proven their superiority over conventional DPFs due to favorably improved pharmacokinetics and pharmacodynamics of entrapped drugs, and thus, reduced local and systemic toxicities. Nanoliposomal DPFs (NLDPFs) provide stable, high aerosolization efficiency to deep lung, prolonged drug release, slow systemic dilution, and avoid macrophage uptake of encapsulated drug by carrier-based delivery of nano-range liposomes. This chapter describes methods of preparation of nanoliposomes (NLs) and NLDPFs, using various techniques, and their characterization with respect to size distribution, flow behavior, in vitro drug release profile, lung deposition, cellular uptake and cytotoxicity, and in vivo pharmacokinetics and pharmacodynamics. Some examples have been detailed for better understanding of the methods of preparation and evaluation of NLDPFs by investigators. PMID:19903555
New Nonlinear Multigrid Analysis
NASA Technical Reports Server (NTRS)
Xie, Dexuan
1996-01-01
The nonlinear multigrid is an efficient algorithm for solving the system of nonlinear equations arising from the numerical discretization of nonlinear elliptic boundary problems. In this paper, we present a new nonlinear multigrid analysis as an extension of the linear multigrid theory presented by Bramble. In particular, we prove the convergence of the nonlinear V-cycle method for a class of mildly nonlinear second order elliptic boundary value problems which do not have full elliptic regularity.
Nonlinear drainage of some non-Newtonian free films
NASA Astrophysics Data System (ADS)
Tabakova, S.
2015-10-01
In the present work we apply the generalized lubrication approach (including inertial, viscous, capillary and van-der-Waals forces) to study the dynamics of a free thin film of a non-Newtonian fluid, whose viscosity is described by the Power law and Carreau models. For planar films with fully mobile surfaces, this approach leads to a system of two nonlinear PDE for the film thickness and lateral velocity. This system is solved numerically in the case of laterally bounded free films. The calculations of the film shape and velocity are presented using data of some real liquids: blood and aqueous solution of 0.5% hydroxyethylcellulose. It is shown that the Power law model predicts a very different viscosity to the Carreau model viscosity, although that the film profiles are not very different for all film wetting angles.
Liu, Lei; Li, Jian; Zhang, Yan; Zhang, Shenghui; Ye, Jianqin; Wen, Zhichao; Ding, Jianping; Kunapuli, Satya P; Luo, Xinping; Ding, Zhongren
2014-10-01
Salviae miltiorrhiza (Danshen) has been used for thousands of years in China and some other Asian countries to treat atherothrombotic diseases. Salvianolate which consists of three water-soluble ingredients purified from Salviae miltiorrhiza, has been approved by Chinese SFDA to treat coronary artery disease. So far, there is no evidence clearly showing the clinical efficiency of salvianolate and the underlying mechanism. This study is to evaluate the effects of salvianolate on platelets in patients with acute coronary syndrome and explore the underlying mechanism. We evaluated the effects of salvianolate on platelets in patients with acute coronary syndrome by measuring ADP-induced PAC-1 binding and P-selectin expression on platelets. Salvianolate significantly potentiated the antiplatelet effects of standard dual antiplatelet therapy. We also investigated the antiplatelet effects of salvianolatic acid B (Sal-B), the major component which composes 85% of salvianolate. Sal-B inhibits human platelet activation induced by multiple agonists in vitro by inhibiting phosphodiesterase (PDE) and antagonizing P2Y12 receptor. For the first time, we show the antiplatelet efficiency of salvianolate in ACS patients undergoing treatment with clopidogrel plus aspirin, and demonstrate that Sal-B, the major component of salvianolate inhibits human platelet activation via PDE inhibition and P2Y12 antagonism which may account for the clinical antiplatelet effects of salvianolate. Our results suggest that Sal-B may substitute salvianolate for clinical use. PMID:25077998
cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function.
Jaumann, Mirko; Dettling, Juliane; Gubelt, Martin; Zimmermann, Ulrike; Gerling, Andrea; Paquet-Durand, François; Feil, Susanne; Wolpert, Stephan; Franz, Christoph; Varakina, Ksenya; Xiong, Hao; Brandt, Niels; Kuhn, Stephanie; Geisler, Hyun-Soon; Rohbock, Karin; Ruth, Peter; Schlossmann, Jens; Hütter, Joachim; Sandner, Peter; Feil, Robert; Engel, Jutta; Knipper, Marlies; Rüttiger, Lukas
2012-02-01
Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL. PMID:22270721
Cole, Joanne B; Manyama, Mange; Kimwaga, Emmanuel; Mathayo, Joshua; Larson, Jacinda R; Liberton, Denise K; Lukowiak, Ken; Ferrara, Tracey M; Riccardi, Sheri L; Li, Mao; Mio, Washington; Prochazkova, Michaela; Williams, Trevor; Li, Hong; Jones, Kenneth L; Klein, Ophir D; Santorico, Stephanie A; Hallgrimsson, Benedikt; Spritz, Richard A
2016-08-01
The human face is a complex assemblage of highly variable yet clearly heritable anatomic structures that together make each of us unique, distinguishable, and recognizable. Relatively little is known about the genetic underpinnings of normal human facial variation. To address this, we carried out a large genomewide association study and two independent replication studies of Bantu African children and adolescents from Mwanza, Tanzania, a region that is both genetically and environmentally relatively homogeneous. We tested for genetic association of facial shape and size phenotypes derived from 3D imaging and automated landmarking of standard facial morphometric points. SNPs within genes SCHIP1 and PDE8A were associated with measures of facial size in both the GWAS and replication cohorts and passed a stringent genomewide significance threshold adjusted for multiple testing of 34 correlated traits. For both SCHIP1 and PDE8A, we demonstrated clear expression in the developing mouse face by both whole-mount in situ hybridization and RNA-seq, supporting their involvement in facial morphogenesis. Ten additional loci demonstrated suggestive association with various measures of facial shape. Our findings, which differ from those in previous studies of European-derived whites, augment understanding of the genetic basis of normal facial development, and provide insights relevant to both human disease and forensics. PMID:27560698
Guo, Li; Xu, Yan; Xu, Zhengfu; Jiang, Jingfeng
2015-10-01
Obtaining accurate ultrasonically estimated displacements along both axial (parallel to the acoustic beam) and lateral (perpendicular to the beam) directions is an important task for various clinical elastography applications (e.g., modulus reconstruction and temperature imaging). In this study, a partial differential equation (PDE)-based regularization algorithm was proposed to enhance motion tracking accuracy. More specifically, the proposed PDE-based algorithm, utilizing two-dimensional (2D) displacement estimates from a conventional elastography system, attempted to iteratively reduce noise contained in the original displacement estimates by mathematical regularization. In this study, tissue incompressibility was the physical constraint used by the above-mentioned mathematical regularization. This proposed algorithm was tested using computer-simulated data, a tissue-mimicking phantom, and in vivo breast lesion data. Computer simulation results demonstrated that the method significantly improved the accuracy of lateral tracking (e.g., a factor of 17 at 0.5% compression). From in vivo breast lesion data investigated, we have found that, as compared with the conventional method, higher quality axial and lateral strain images (e.g., at least 78% improvements among the estimated contrast-to-noise ratios of lateral strain images) were obtained. Our initial results demonstrated that this conceptually and computationally simple method could be useful for improving the image quality of ultrasound elastography with current clinical equipment as a post-processing tool. PMID:25452434
Tripuraneni, Naga Srinivas; Azam, Mohammed Afzal
2016-04-01
Pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulation studies have been performed, to explore the putative binding modes of 2-phenylpyrimidine series as PDE4B selective inhibitors. A five point pharmacophore model was developed using 87 molecules having pIC50 ranging from 8.52 to 5.07. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2)=0.918), cross validation coefficient (Q(2)=0.852), and F value (175) at 4 component PLS factor. The external validation indicated that our QSAR model possessed high predictive power (R(2)=0.70). The generated model was further validated by enrichment studies using the decoy test. To evaluate the effectiveness of docking protocol in flexible docking, we have selected crystallographic bound compound to validate our docking procedure as evident from root mean square deviation. A 10ns molecular dynamics simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Further, similar orientation was observed between the superposition of the conformations of 85 after MD simulation and best XP-docking pose; MD simulation and 3D-QSAR pose; best XP-docking and 3D-QSAR poses. Outcomes of the present study provide insight in designing novel molecules with better PDE4B selective inhibitory activity. PMID:26804643
Manyama, Mange; Kimwaga, Emmanuel; Mathayo, Joshua; Larson, Jacinda R.; Liberton, Denise K.; Lukowiak, Ken; Riccardi, Sheri L.; Li, Mao; Williams, Trevor; Li, Hong; Jones, Kenneth L.; Klein, Ophir D.; Santorico, Stephanie A.; Hallgrimsson, Benedikt; Spritz, Richard A.
2016-01-01
The human face is a complex assemblage of highly variable yet clearly heritable anatomic structures that together make each of us unique, distinguishable, and recognizable. Relatively little is known about the genetic underpinnings of normal human facial variation. To address this, we carried out a large genomewide association study and two independent replication studies of Bantu African children and adolescents from Mwanza, Tanzania, a region that is both genetically and environmentally relatively homogeneous. We tested for genetic association of facial shape and size phenotypes derived from 3D imaging and automated landmarking of standard facial morphometric points. SNPs within genes SCHIP1 and PDE8A were associated with measures of facial size in both the GWAS and replication cohorts and passed a stringent genomewide significance threshold adjusted for multiple testing of 34 correlated traits. For both SCHIP1 and PDE8A, we demonstrated clear expression in the developing mouse face by both whole-mount in situ hybridization and RNA-seq, supporting their involvement in facial morphogenesis. Ten additional loci demonstrated suggestive association with various measures of facial shape. Our findings, which differ from those in previous studies of European-derived whites, augment understanding of the genetic basis of normal facial development, and provide insights relevant to both human disease and forensics. PMID:27560698
Electromagnetic nonlinear gyrokinetics with polarization drift
Duthoit, F.-X.; Hahm, T. S.; Wang, Lu
2014-08-15
A set of new nonlinear electromagnetic gyrokinetic Vlasov equation with polarization drift and gyrokinetic Maxwell equations is systematically derived by using the Lie-transform perturbation method in toroidal geometry. For the first time, we recover the drift-kinetic expression for parallel acceleration [R. M. Kulsrud, in Basic Plasma Physics, edited by A. A. Galeev and R. N. Sudan (North-Holland, Amsterdam, 1983)] from the nonlinear gyrokinetic equations, thereby bridging a gap between the two formulations. This formalism should be useful in addressing nonlinear ion Compton scattering of intermediate-mode-number toroidal Alfvén eigenmodes for which the polarization current nonlinearity [T. S. Hahm and L. Chen, Phys. Rev. Lett. 74, 266 (1995)] and the usual finite Larmor radius effects should compete.
Nonlinear modeling of MEMS piezoelectric energy harvesters
NASA Astrophysics Data System (ADS)
Wang, Y. C.; Huang, T. W.; Shu, Y. C.; Lin, S. C.; Wu, W. J.
2016-04-01
This article presents the modeling of nonlinear response of micro piezoelectric energy harvesters under amplified base excitation. The micro transducer is a composite cantilever beam made of the PZT thick film deposited on the stainless-steel substrate. The model is developed based on the Euler-Bernoulli beam theory considering geometric and inertia nonlinearities, and the reduced formulation is derived based on the Hamiltonian variational principle. The harmonic balance method is used to simulate the nonlinear frequency response under various magnitudes of excitation and electric loads. The hardening type of nonlinearity is predicted and is found to be in good agreement with experiment. However, the softening response is also observed in different samples fabricated under different conditions. Such disagreement is under investigation.
Electromagnetic nonlinear gyrokinetics with polarization drift
NASA Astrophysics Data System (ADS)
Duthoit, F.-X.; Hahm, T. S.; Wang, Lu
2014-08-01
A set of new nonlinear electromagnetic gyrokinetic Vlasov equation with polarization drift and gyrokinetic Maxwell equations is systematically derived by using the Lie-transform perturbation method in toroidal geometry. For the first time, we recover the drift-kinetic expression for parallel acceleration [R. M. Kulsrud, in Basic Plasma Physics, edited by A. A. Galeev and R. N. Sudan (North-Holland, Amsterdam, 1983)] from the nonlinear gyrokinetic equations, thereby bridging a gap between the two formulations. This formalism should be useful in addressing nonlinear ion Compton scattering of intermediate-mode-number toroidal Alfvén eigenmodes for which the polarization current nonlinearity [T. S. Hahm and L. Chen, Phys. Rev. Lett. 74, 266 (1995)] and the usual finite Larmor radius effects should compete.
Martin, Tamara P; Hortigon-Vinagre, Maria P; Findlay, Jane E; Elliott, Christina; Currie, Susan; Baillie, George S
2014-01-01
Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20-phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20-PDE4D interaction leads to attenuation of pathological cardiac remodelling. PMID:25426411
Chang, Bo; Grau, Tanja; Dangel, Susann; Hurd, Ron; Jurklies, Bernhard; Sener, E. Cumhur; Andreasson, Sten; Dollfus, Helene; Baumann, Britta; Bolz, Sylvia; Artemyev, Nikolai; Kohl, Susanne; Heckenlively, John; Wissinger, Bernd
2009-01-01
Retinal cone photoreceptors mediate fine visual acuity, daylight vision, and color vision. Congenital hereditary conditions in which there is a lack of cone function in humans cause achromatopsia, an autosomal recessive trait, characterized by low vision, photophobia, and lack of color discrimination. Herein we report the identification of mutations in the PDE6C gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase as a cause of autosomal recessive achromatopsia. Moreover, we show that the spontaneous mouse mutant cpfl1 that features a lack of cone function and rapid degeneration of the cone photoreceptors represents a homologous mouse model for PDE6C associated achromatopsia. PMID:19887631
Mäkelä, J T A; Korhonen, R K
2016-06-14
Modern fibril-reinforced computational models of articular cartilage can include inhomogeneous tissue composition and structure, and nonlinear mechanical behavior of collagen, proteoglycans and fluid. These models can capture well experimental single step creep and stress-relaxation tests or measurements under small strains in unconfined and confined compression. Yet, it is known that in indentation, especially at high strain velocities, cartilage can express highly nonlinear response. Different fibril reinforced poroelastic and poroviscoelastic models were used to assess measured highly nonlinear stress-relaxation response of rabbit articular cartilage in indentation. Experimentally measured depth-dependent volume fractions of different tissue constituents and their mechanical nonlinearities were taken into account in the models. In particular, the collagen fibril network was modeled using eight separate models that implemented five different constitutive equations to describe the nonlinearity. These consisted of linear elastic, nonlinear viscoelastic and multiple nonlinear elastic representations. The model incorporating the most nonlinearly increasing Young׳s modulus of collagen fibrils as a function of strain captured best the experimental data. Relative difference between the model and experiment was ~3%. Surprisingly, the difference in the peak forces between the experiment and the model with viscoelastic collagen fibrils was almost 20%. Implementation of the measured volume fractions did not improve the ability of the model to capture the measured mechanical data. These results suggest that a highly nonlinear formulation for collagen fibrils is needed to replicate multi-step stress-relaxation response of rabbit articular cartilage in indentation with high strain rates. PMID:27130474
[Nonlinear magnetohydrodynamics
Not Available
1994-01-01
Resistive MHD equilibrium, even for small resistivity, differs greatly from ideal equilibrium, as do the dynamical consequences of its instabilities. The requirement, imposed by Faraday`s law, that time independent magnetic fields imply curl-free electric fields, greatly restricts the electric fields allowed inside a finite-resistivity plasma. If there is no flow and the implications of the Ohm`s law are taken into account (and they need not be, for ideal equilibria), the electric field must equal the resistivity times the current density. The vanishing of the divergence of the current density then provides a partial differential equation which, together with boundary conditions, uniquely determines the scalar potential, the electric field, and the current density, for any given resistivity profile. The situation parallels closely that of driven shear flows in hydrodynamics, in that while dissipative steady states are somewhat more complex than ideal ones, there are vastly fewer of them to consider. Seen in this light, the vast majority of ideal MHD equilibria are just irrelevant, incapable of being set up in the first place. The steady state whose stability thresholds and nonlinear behavior needs to be investigated ceases to be an arbitrary ad hoc exercise dependent upon the whim of the investigator, but is determined by boundary conditions and choice of resistivity profile.
Nonrecursive formulations of multibody dynamics and concurrent multiprocessing
NASA Technical Reports Server (NTRS)
Kurdila, Andrew J.; Menon, Ramesh
1993-01-01
Since the late 1980's, research in recursive formulations of multibody dynamics has flourished. Historically, much of this research can be traced to applications of low dimensionality in mechanism and vehicle dynamics. Indeed, there is little doubt that recursive order N methods are the method of choice for this class of systems. This approach has the advantage that a minimal number of coordinates are utilized, parallelism can be induced for certain system topologies, and the method is of order N computational cost for systems of N rigid bodies. Despite the fact that many authors have dismissed redundant coordinate formulations as being of order N(exp 3), and hence less attractive than recursive formulations, we present recent research that demonstrates that at least three distinct classes of redundant, nonrecursive multibody formulations consistently achieve order N computational cost for systems of rigid and/or flexible bodies. These formulations are as follows: (1) the preconditioned range space formulation; (2) penalty methods; and (3) augmented Lagrangian methods for nonlinear multibody dynamics. The first method can be traced to its foundation in equality constrained quadratic optimization, while the last two methods have been studied extensively in the context of coercive variational boundary value problems in computational mechanics. Until recently, however, they have not been investigated in the context of multibody simulation, and present theoretical questions unique to nonlinear dynamics. All of these nonrecursive methods have additional advantages with respect to recursive order N methods: (1) the formalisms retain the highly desirable order N computational cost; (2) the techniques are amenable to concurrent simulation strategies; (3) the approaches do not depend upon system topology to induce concurrency; and (4) the methods can be derived to balance the computational load automatically on concurrent multiprocessors. In addition to the presentation of
McPhee, I; Pooley, L; Lobban, M; Bolger, G; Houslay, M D
1995-09-15
COS-7 cells were transfected with a plasmid encoding a putative splice variant of PDE4A cyclic AMP-specific phosphodiesterase, RPDE-6 (RNPDE4A5). This led to the expression of a novel, cyclic AMP-specific, rolipram-inhibited phosphodiesterase activity. In such transfected cells a novel approximately 109 kDa species was recognized by anti-peptide sera raised against a dodecapeptide whose sequence is found at the extreme C-terminus of both RPDE-6 and another PDE4A splice variant. RD1 (RNPDE4A1A). RPDE-6 activity and immunoreactivity was found distributed between both pellet (approximately 25%) and cytosol (approximately 75%) fractions of transfected COS-7 cells. Soluble and pellet RPDE-6 activities exhibited similar low Km values for cyclic AMP (approximately 2.4 microM) and were both inhibited by low concentrations of rolipram, with IC50 values for the soluble activity being lower (approximately 0.16 microM) than for the pellet activity (approximately 1.2 microM). Pellet RPDE-6 was resistant to release by either high NaCl concentrations or the detergent Triton X-100. Probing brain homogenates with the anti-(C-terminal peptide) sera identified two immunoreactive species, namely an approximately 79 kDa species reflecting RD1 and an approximately 109 kDa species that co-migrated with the immunoreactive species seen in COS cells transfected to express RPDE-6. The approximately 109 kDa species was found distributed between both the low-speed (P1) and high-speed (P2) pellet fractions as well as the cytosol fractions derived from both brain and RPDE-6-transfected COS cells. In contrast, RD1 was found exclusively in the P2 fraction. Phosphodiesterase (PDE) activity immuno-precipitated by these antisera from brain cytosol had the characteristics of COS cell-expressed RPDE-6 with KmcyclicAMP approximately 3.7 microM and IC50rolipram approximately 0.12 microM. The distribution of PDE activity immunoprecipitated from the cytosol of various brain regions paralleled that seen for
Plutonium Immobilization Project Baseline Formulation
Ebbinghaus, B.
1999-02-01
A key milestone for the Immobilization Project (AOP Milestone 3.2a) in Fiscal Year 1998 (FY98) is the definition of the baseline composition or formulation for the plutonium ceramic form. The baseline formulation for the plutonium ceramic product must be finalized before the repository- and plant-related process specifications can be determined. The baseline formulation that is currently specified is given in Table 1.1. In addition to the baseline formulation specification, this report provides specifications for two alternative formulations, related compositional specifications (e.g., precursor compositions and mixing recipes), and other preliminary form and process specifications that are linked to the baseline formulation. The preliminary specifications, when finalized, are not expected to vary tremendously from the preliminary values given.
Explosive Formulation Code Naming SOP
Martz, H. E.
2014-09-19
The purpose of this SOP is to provide a procedure for giving individual HME formulations code names. A code name for an individual HME formulation consists of an explosive family code, given by the classified guide, followed by a dash, -, and a number. If the formulation requires preparation such as packing or aging, these add additional groups of symbols to the X-ray specimen name.
Geometrically nonlinear behavior of piezoelectric laminated plates
NASA Astrophysics Data System (ADS)
Rabinovitch, Oded
2005-08-01
The geometrically nonlinear behavior of piezo-laminated plates actuated with isotropic or anisotropic piezoelectric layers is analytically investigated. The analytical model is derived using the variational principle of virtual work along with the lamination and plate theories, the von Karman large displacement and moderate rotation kinematic relations, and the anisotropic piezoelectric constitutive laws. A solution strategy that combines the approach of the method of lines, the advantages of the finite element concept, and the variational formulation is developed. This approach yields a set of nonlinear ordinary differential equations with nonlinear boundary conditions, which are solved using the multiple-shooting method. Convergence and verification of the model are examined through comparison with linear and nonlinear results of other approximation methods. The nonlinear response of two active plate structures is investigated numerically. The first plate is actuated in bending using monolithic piezoceramic layers and the second one is actuated in twist using macro-fiber composites. The results quantitatively reveal the complicated in-plane stress state associated with the piezoelectric actuation and the geometrically nonlinear coupling of the in-plane and out-of-plane responses of the plate. The influence of the nonlinear effects ranges from significant stiffening in certain combinations of electrical loads and boundary conditions to amplifications of the induced deflections in others. The paper closes with a summary and conclusions.
Mathematical programming formulations for satellite synthesis
NASA Technical Reports Server (NTRS)
Bhasin, Puneet; Reilly, Charles H.
1987-01-01
The problem of satellite synthesis can be described as optimally allotting locations and sometimes frequencies and polarizations, to communication satellites so that interference from unwanted satellite signals does not exceed a specified threshold. In this report, mathematical programming models and optimization methods are used to solve satellite synthesis problems. A nonlinear programming formulation which is solved using Zoutendijk's method and a gradient search method is described. Nine mixed integer programming models are considered. Results of computer runs with these nine models and five geographically compatible scenarios are presented and evaluated. A heuristic solution procedure is also used to solve two of the models studied. Heuristic solutions to three large synthesis problems are presented. The results of our analysis show that the heuristic performs very well, both in terms of solution quality and solution time, on the two models to which it was applied. It is concluded that the heuristic procedure is the best of the methods considered for solving satellite synthesis problems.
Baseline LAW Glass Formulation Testing
Kruger, Albert A.; Mooers, Cavin; Bazemore, Gina; Pegg, Ian L.; Hight, Kenneth; Lai, Shan Tao; Buechele, Andrew; Rielley, Elizabeth; Gan, Hao; Muller, Isabelle S.; Cecil, Richard
2013-06-13
The major objective of the baseline glass formulation work was to develop and select glass formulations that are compliant with contractual and processing requirements for each of the LAW waste streams. Other objectives of the work included preparation and characterization of glasses with respect to the properties of interest, optimization of sulfate loading in the glasses, evaluation of ability to achieve waste loading limits, testing to demonstrate compatibility of glass melts with melter materials of construction, development of glass formulations to support ILAW qualification activities, and identification of glass formulation issues with respect to contract specifications and processing requirements.
Böttcher, R; Henderson, D J P; Dulla, K; van Strijp, D; Waanders, L F; Tevz, G; Lehman, M L; Merkle, D; van Leenders, G J L H; Baillie, G S; Jenster, G; Houslay, M D; Hoffmann, R
2015-01-01
Background: There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples. Methods: About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold >3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample. Results: We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC). Conclusions: We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression. PMID:26575822
NASA Astrophysics Data System (ADS)
Su, Tao; Zhang, Tianhua; Xie, Shishun; Yan, Jun; Wu, Yinuo; Li, Xingshu; Huang, Ling; Luo, Hai-Bin
2016-02-01
Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer’s disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ1-42 aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu2+-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.
Chen, Jun-Jiang; Sun, Yue-Li; Tiwari, Amit K; Xiao, Zhi-Jie; Sodani, Kamlesh; Yang, Dong-Hua; Vispute, Saraubh G; Jiang, Wen-Qi; Chen, Si-Dong; Chen, Zhe-Sheng
2012-08-01
Phosphodiesterase type 5 (PDE5) inhibitors are widely used in the treatment of male erectile dysfunction and pulmonary hypertension. Recently, several groups have evaluated the ability of PDE5 inhibitors for their anticancer activities. Previously, we had shown that sildenafil, vardenafil and tadalafil could reverse P-glycoprotein (ATP-binding cassette B1)-mediated MDR. In the present study, we determined whether these PDE5 inhibitors have the potential to reverse multidrug resistance protein 7 (MRP7; ATP-binding cassette C10)-mediated MDR. We found that sildenafil and vardenafil dose-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine, while tadalafil had only a minimal effect. Accumulation and efflux experiments demonstrated that sildenafil and vardenafil increased the intracellular accumulation of [(3)H]-paclitaxel by inhibiting the efflux of [(3 H]-paclitaxel in HEK/MRP7 cells. In addition, immunoblot and immunofluorescence analyses indicated that no significant alterations of MRP7 protein expression and localization in plasma membranes were found after treatment with sildenafil, vardenafil or tadalafil. These results demonstrate that sildenafil and vardenafil reverse MRP7-mediated a MDR through inhibition of the drug efflux function of MRP7. Our findings indicate a potentially novel use of PDE5 inhibitors as an adjuvant chemotherapeutic agent in clinical practice. PMID:22578167
cGMP-PDE3-cAMP signal pathway involved in the inhibitory effect of CNP on gastric motility in rat.
Cai, Ying-Lan; Sun, Qian; Huang, Xu; Jiang, Jing-Zhi; Zhang, Mo-Han; Piao, Li-Hua; Jin, Zheng; Xu, Wen-Xie
2013-01-10
In the present study, we investigated the mechanism of C-type natriuretic peptide (CNP)-induced inhibitory effect on spontaneous contraction of gastric antral smooth muscle to clarify CNP-NPR-B/pGC-cGMP downstream signal transduction pathway using organ bath and ELISA methods in rat. CNP significantly reduced the amplitude of the spontaneous contraction and increased the contents of cGMP and cAMP in the gastric antral smooth muscle tissue. In the presence of IBMX, a non-selective phosphodiesterase (PDE) inhibitor, the inhibitory effect of CNP on spontaneous contraction was significantly suppressed; however, the production of cGMP but not cAMP was still increased by CNP. EHNA, a PDE2 inhibitor, did not affect both CNP-induced inhibition of the contraction and CNP-induced increase of cGMP and cAMP generations in gastric smooth muscle tissue, while milrinone, a PDE3 inhibitor, similar to IBMX, attenuated the CNP-induced inhibitory effect on spontaneous contraction and increased the content of cGMP but not cAMP. The results suggest that cGMP-PDE3-cAMP signal pathway is also involved in the CNP-induced inhibition of gastric motility in rat. PMID:23186653
Gesztelyi, R; Zsuga, J; Hajdú, P; Szabó, J Zs; Cseppento, A; Szentmiklósi, A J
2003-12-01
The significance of PDE2 on the atrial inotropy was studied in eu- and hyperthyroidism. The contractile force was measured and negative inotropic capacity of N6-cyclopentyladenosine (CPA) was determined on left atria isolated from 8-day thyroxine- or solvent-treated guinea pigs, in the presence or absence of EHNA (adenosine deaminase and PDE2 inhibitor) or NBTI (nucleoside transporter inhibitor). EHNA was administered to inhibit PDE2, while NBTI was used to model the accumulation of endogenous adenosine. The reduction of the contractile force caused by EHNA was smaller in the thyroxine-treated atria than in the solvent-treated samples. Contrary, NBTI induced a decrease in the contractile force without significant difference between the two groups. In addition, EHNA enhanced the efficiency of CPA in thyroxine-treated atria and did not affect it in solvent-treated samples, while the response to CPA was decreased by NBTI in all atria, especially in hyperthyroidism. On the basis of greater retention of the contractile force and sustained/enhanced responsiveness to CPA in the presence of EHNA we conclude that PDE2's inhibition has a significant positive inotropic effect in guinea pig atria and this effect is proven to be augmented in hyperthyroidism. PMID:15113122
PKA and PDE4D3 anchoring to AKAP9 provides distinct regulation of cAMP signals at the centrosome
Terrin, Anna; Monterisi, Stefania; Stangherlin, Alessandra; Zoccarato, Anna; Koschinski, Andreas; Surdo, Nicoletta C.; Mongillo, Marco; Sawa, Akira; Jordanides, Niove E.; Mountford, Joanne C.
2012-01-01
Previous work has shown that the protein kinase A (PKA)–regulated phosphodiesterase (PDE) 4D3 binds to A kinase–anchoring proteins (AKAPs). One such protein, AKAP9, localizes to the centrosome. In this paper, we investigate whether a PKA–PDE4D3–AKAP9 complex can generate spatial compartmentalization of cyclic adenosine monophosphate (cAMP) signaling at the centrosome. Real-time imaging of fluorescence resonance energy transfer reporters shows that centrosomal PDE4D3 modulated a dynamic microdomain within which cAMP concentration selectively changed over the cell cycle. AKAP9-anchored, centrosomal PKA showed a reduced activation threshold as a consequence of increased autophosphorylation of its regulatory subunit at S114. Finally, disruption of the centrosomal cAMP microdomain by local displacement of PDE4D3 impaired cell cycle progression as a result of accumulation of cells in prophase. Our findings describe a novel mechanism of PKA activity regulation that relies on binding to AKAPs and consequent modulation of the enzyme activation threshold rather than on overall changes in cAMP levels. Further, we provide for the first time direct evidence that control of cell cycle progression relies on unique regulation of centrosomal cAMP/PKA signals. PMID:22908311
Pedurupillay, Christeen Ramane J; Landsend, Erlend Christoffer Sommer; Vigeland, Magnus Dehli; Ansar, Muhammad; Frengen, Eirik; Misceo, Doriana; Strømme, Petter
2016-01-01
We report on two brothers with visual impairment, and non-syndromic alopecia in the elder proband. The parents were first-degree Pakistani cousins. Whole exome sequencing of the elder brother and parents, followed by Sanger sequencing of all four family members, led to the identification of the variants responsible for the two phenotypes. One variant was a homozygous nonsense variant in the inhibitory subunit of the cone-specific cGMP phosphodiesterase gene, PDE6H:c.35C>G (p.Ser12*). PDE6H is expressed in the cones of the retina, which are involved in perception of color vision. This is the second report of a homozygous PDE6H:c.35C>G variant causing incomplete achromatopsia (OMIM 610024), thus strongly supporting the hypothesis that loss-of-function variants in PDE6H cause this visual deficiency phenotype. The second variant was a homozygous missense substitution in the lysophosphatidic acid receptor 6, LPAR6:c.188A>T (p.Asp63Val). LPAR6 acts as a G-protein-coupled receptor involved in hair growth. Biallelic loss-of-function variants in LPAR6 cause hypotrichosis type 8 (OMIM 278150), with or without woolly hair, a form of non-syndromic alopecia. Biallelic LPAR6:c.188A>T was previously described in five families from Pakistan. PMID:27472364
Su, Tao; Zhang, Tianhua; Xie, Shishun; Yan, Jun; Wu, Yinuo; Li, Xingshu; Huang, Ling; Luo, Hai-Bin
2016-01-01
Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer’s disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ1-42 aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu2+-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD. PMID:26911795
Pedurupillay, Christeen Ramane J.; Landsend, Erlend Christoffer Sommer; Vigeland, Magnus Dehli; Ansar, Muhammad; Frengen, Eirik; Misceo, Doriana; Strømme, Petter
2016-01-01
We report on two brothers with visual impairment, and non-syndromic alopecia in the elder proband. The parents were first-degree Pakistani cousins. Whole exome sequencing of the elder brother and parents, followed by Sanger sequencing of all four family members, led to the identification of the variants responsible for the two phenotypes. One variant was a homozygous nonsense variant in the inhibitory subunit of the cone-specific cGMP phosphodiesterase gene, PDE6H:c.35C>G (p.Ser12*). PDE6H is expressed in the cones of the retina, which are involved in perception of color vision. This is the second report of a homozygous PDE6H:c.35C>G variant causing incomplete achromatopsia (OMIM 610024), thus strongly supporting the hypothesis that loss-of-function variants in PDE6H cause this visual deficiency phenotype. The second variant was a homozygous missense substitution in the lysophosphatidic acid receptor 6, LPAR6:c.188A>T (p.Asp63Val). LPAR6 acts as a G-protein-coupled receptor involved in hair growth. Biallelic loss-of-function variants in LPAR6 cause hypotrichosis type 8 (OMIM 278150), with or without woolly hair, a form of non-syndromic alopecia. Biallelic LPAR6:c.188A>T was previously described in five families from Pakistan. PMID:27472364
Saltstone Clean Cap Formulation
Langton, C
2005-04-22
The current operation strategy for using Saltstone Vault 4 to receive 0.2 Ci/gallon salt solution waste involves pouring a clean grout layer over the radioactive grout prior to initiating pour into another cell. This will minimize the radiating surface area and reduce the dose rate at the vault and surrounding area. The Clean Cap will be used to shield about four feet of Saltstone poured into a Z-Area vault cell prior to moving to another cell. The minimum thickness of the Clean Cap layer will be determined by the cesium concentration and resulting dose levels and it is expected to be about one foot thick based on current calculations for 0.1 Ci Saltstone that is produced in the Saltstone process by stabilization of 0.2 Ci salt solution. This report documents experiments performed to identify a formulation for the Clean Cap. Thermal transient calculations, adiabatic temperature rise measurements, pour height, time between pour calculations and shielding calculations were beyond the scope and time limitations of this study. However, data required for shielding calculations (composition and specific gravity) are provided for shielding calculations. The approach used to design a Clean Cap formulation was to produce a slurry from the reference premix (10/45/45 weight percent cement/slag/fly ash) and domestic water that resembled as closely as possible the properties of the Saltstone slurry. In addition, options were investigated that may offer advantages such as less bleed water and less heat generation. The options with less bleed water required addition of dispersants. The options with lower heat contained more fly ash and less slag. A mix containing 10/45/45 weight percent cement/slag/fly ash with a water to premix ratio of 0.60 is recommended for the Clean Cap. Although this mix may generate more than 3 volume percent standing water (bleed water), it has rheological, mixing and flow properties that are similar to previously processed Saltstone. The recommended
Marcantoni, A; Carabelli, V; Vandael, D H; Comunanza, V; Carbone, E
2009-03-01
We studied the effects of the cAMP-hydrolyzing enzyme phosphodiesterase type-4 (PDE4) on the L-type Ca(2+) channels (LTCCs) and Ca(2+)-dependent secretion in mouse chromaffin cells (MCCs). The selective PDE4 inhibitor rolipram (3 microM) had a specific potentiating action on Ca(2+) currents of MCCs (40% increase within 3 min). A similar effect was produced by the selective beta(1)-AR agonist denopamine (1 microM) and by the unselective PDEs inhibitor IBMX (100 microM). Rolipram and denopamine actions were selective for LTCCs, and the Ca(2+) current increase remained unchanged if the two compounds were applied simultaneously. This suggests that at rest, LTCCs in MCCs are down-regulated by the low levels of cAMP determined by PDE4 activity and that LTCCs can be up-regulated by either inhibiting PDE4 or activating beta(1)-AR. No other PDEs are likely involved in this specific action. PDE4 inhibition had also a marked effect on the spontaneous firing of resting MCCs and catecholamine secretion. Rolipram up-regulated the LTCCs contributing to the "pace-maker" current underlying action potential (AP) discharges and accelerated the firing rate, with no significant effects on AP waveform. Acceleration of AP firing was also induced by the LTCC-agonist Bay K (1 microM), while nifedipine (3 microM) reduced the firing frequency, suggesting that LTCCs and intracellular cAMP play a key role in setting the pace-maker current regulating MCCs excitability. Rolipram increased also the size of the ready-releasable pool and the quantal content of secretory vesicles without affecting their probability of release. Thus, rolipram acts on MCCs by up-regulating both exocytosis and AP firings. These two processes are effectively down-regulated by PDE4 at rest and can dramatically increase the quantity of released catecholamines when PDE4 is inhibited and/or cAMP is raised. PMID:18779976
Operator Formulation of Classical Mechanics.
ERIC Educational Resources Information Center
Cohn, Jack
1980-01-01
Discusses the construction of an operator formulation of classical mechanics which is directly concerned with wave packets in configuration space and is more similar to that of convential quantum theory than other extant operator formulations of classical mechanics. (Author/HM)
Biopsychosocial Formulation: Recognizing Educational Shortcomings
ERIC Educational Resources Information Center
McClain, Tina; O'Sullivan, Patricia S.; Clardy, James A.
2004-01-01
Objective: Since Engel introduced the biopsychosocial model, it has been extensively examined. The authors expect psychiatrists to formulate cases using the biopsychosocial model. However, resident psychiatrists' ability to generate formulations using this model has received little attention. Methods: The authors evaluated resident biopsychosocial…
NASA Technical Reports Server (NTRS)
Banks, H. T.; Brown, D. E.; Metcalf, Vern L.; Silcox, R. J.; Smith, Ralph C.; Wang, Yun
1994-01-01
A problem of continued interest concerns the control of vibrations in a flexible structure and the related problem of reducing structure-borne noise in structural acoustic systems. In both cases, piezoceramic patches bonded to the structures have been successfully used as control actuators. Through the application of a controlling voltage, the patches can be used to reduce structural vibrations which in turn lead to methods for reducing structure-borne noise. A PDE-based methodology for modeling, estimating physical parameters, and implementing a feedback control scheme for problems of this type is discussed. While the illustrating example is a circular plate, the methodology is sufficiently general so as to be applicable in a variety of structural and structural acoustic systems.
The dynamics of p53 in single cells: physiologically based ODE and reaction-diffusion PDE models
NASA Astrophysics Data System (ADS)
Eliaš, Ján; Dimitrio, Luna; Clairambault, Jean; Natalini, Roberto
2014-08-01
The intracellular signalling network of the p53 protein plays important roles in genome protection and the control of cell cycle phase transitions. Recently observed oscillatory behaviour in single cells under stress conditions has inspired several research groups to simulate and study the dynamics of the protein with the aim of gaining a proper understanding of the physiological meanings of the oscillations. We propose compartmental ODE and PDE models of p53 activation and regulation in single cells following DNA damage and we show that the p53 oscillations can be retrieved by plainly involving p53-Mdm2 and ATM-p53-Wip1 negative feedbacks, which are sufficient for oscillations experimentally, with no further need to introduce any delays into the protein responses and without considering additional positive feedback.
Parallel Allostery by cAMP and PDE Coordinates Activation and Termination Phases in cAMP Signaling.
Krishnamurthy, Srinath; Tulsian, Nikhil Kumar; Chandramohan, Arun; Anand, Ganesh S
2015-09-15
The second messenger molecule cAMP regulates the activation phase of the cAMP signaling pathway through high-affinity interactions with the cytosolic cAMP receptor, the protein kinase A regulatory subunit (PKAR). Phosphodiesterases (PDEs) are enzymes responsible for catalyzing hydrolysis of cAMP to 5' AMP. It was recently shown that PDEs interact with PKAR to initiate the termination phase of the cAMP signaling pathway. While the steps in the activation phase are well understood, steps in the termination pathway are unknown. Specifically, the binding and allosteric networks that regulate the dynamic interplay between PKAR, PDE, and cAMP are unclear. In this study, PKAR and PDE from Dictyostelium discoideum (RD and RegA, respectively) were used as a model system to monitor complex formation in the presence and absence of cAMP. Amide hydrogen/deuterium exchange mass spectrometry was used to monitor slow conformational transitions in RD, using disordered regions as conformational probes. Our results reveal that RD regulates its interactions with cAMP and RegA at distinct loci by undergoing slow conformational transitions between two metastable states. In the presence of cAMP, RD and RegA form a stable ternary complex, while in the absence of cAMP they maintain transient interactions. RegA and cAMP each bind at orthogonal sites on RD with resultant contrasting effects on its dynamics through parallel allosteric relays at multiple important loci. RD thus serves as an integrative node in cAMP termination by coordinating multiple allosteric relays and governing the output signal response. PMID:26276689
Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy
Petit, Lolita; Lhériteau, Elsa; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Guihal, Caroline; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne
2012-01-01
Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment. PMID:22828504
Tanaka, Saori; Tanaka, Rina; Harada, Saeko; Kohda, Yuka; Matsumura, Hitoshi; Shimamoto, Chikao; Sawabe, Yukinori; Marunaka, Yoshinori; Kuwabara, Hiroko; Takahashi, Yuko; Ito, Shigenori; Nakahari, Takashi
2013-05-01
In antral mucous cells, acetylcholine (ACh, 1 μM) activates Ca(2+)-regulated exocytosis, consisting of an initial peak that declines rapidly (initial transient phase) followed by a second slower decline (late phase) lasting during ACh stimulation. The addition of 8-bromo-cGMP (8-BrcGMP) enhanced the initial phase, which was inhibited by the protein kinase G (PKG) inhibitor guanosine 3',5'-cyclic monophosphorothoiate, β-phenyl-1,N(2)-etheno-8-bromo, Rp-isomer, sodium salt (Rp-8-BrPETcGMPS, 100 nM). However, Rp-8-BrPETcGMPS produced a delayed, but transient, increase in the exocytotic frequency during the late phase that was abolished by a protein kinase A (PKA) inhibitor (PKI-amide), suggesting that Rp-8-BrPETcGMPS accumulates cAMP. The cGMP-dependent phosphodiesterase 2 (PDE2), which degrades cAMP, may exist in antral mucous cells. The PDE2 inhibitor BAY-60-7550 (250 nM) mimicked the effect of Rp-8-BrPETcGMPS on ACh-stimulated exocytosis. Measurement of the cGMP and cAMP contents in antral mucosae revealed that ACh stimulates the accumulation of cGMP and that BAY-60-7550 accumulates cAMP similarly to Rp-8-BrPETcGMPS during ACh stimulation. Analyses of Western blot and immunohistochemistry demonstrated that PDE2A exists in antral mucous cells. In conclusion, Rp-8-BrPETcGMPS accumulates cAMP by inhibiting PDE2 in ACh-stimulated antral mucous cells, leading to the delayed, but transient, increase in the frequency of Ca(2+)-regulated exocytosis. PDE2 may prevent antral mucous cells from excessive mucin secretion caused by the cAMP accumulation. PMID:23449671
Tripuraneni, Naga Srinivas; Azam, Mohammed Afzal
2015-11-01
Phosphodiesterases 4 enzyme is an attractive target for the design of anti-inflammatory and bronchodilator agents. In the present study pharmacophore and atom based 3D-QSAR studies were carried out for pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues. A five point pharmacophore model was developed using 52 molecules having pIC50 values ranging from 9.959 to 3.939. The best predictive pharmacophoric hypothesis AHHRR.3 was characterized by survival score (2.944), cross validated (r(2) = 0.8147), regression coefficient (R(2) = 0.9545) and Fisher ratio (F =173) with 4 component PLS factor. Results explained that one hydrogen bond acceptor, two aromatic rings and two hydrophobic groups are crucial for the PDE4 inhibition. The docking studies of all selected inhibitors in the active site of PDE4 showed crucial hydrogen bond interactions with Asp392, Asn395 Tyr233, and Gln443 residues. The pharmacophoric features R15 and R16 exhibited π-π stacking with His234, Phe414, and Phe446 residues. The generated model was further validated by carrying out the decoy test. The binding free energies of these inhibitors in the catalytic domain of 1XMU were calculated by the molecular mechanics/generalized Born surface area VSGB 2.0 method. The results of molecular dynamics simulation confirmed the extra precision docking-predicted priority for binding sites, the accuracy of docking, and the reliability of active conformations. Pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues in this study showed lower binding affinity toward PDE3A in comparison to PDE4. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity. Graphical Abstract Pyrozolo[1,5-a]pyridines/4,4-dimethylpyrazolones. PMID:26499496
Variational approach to stochastic nonlinear problems
Phythian, R.; Curtis, W.D.
1986-03-01
A variational principle is formulated which enables the mean value and higher moments of the solution of a stochastic nonlinear differential equation to be expressed as stationary values of certain quantities. Approximations are generated by using suitable trial functions in this variational principle and some of these are investigated numerically for the case of a Bernoulli oscillator driven by white noise. Comparison with exact data available for this system show that the variational approach to such problems can be quite effective.
Entropy-Based Approach To Nonlinear Stability
NASA Technical Reports Server (NTRS)
Merriam, Marshal L.
1991-01-01
NASA technical memorandum suggests schemes for numerical solution of differential equations of flow made more accurate and robust by invoking second law of thermodynamics. Proposes instead of using artificial viscosity to suppress such unphysical solutions as spurious numerical oscillations and nonlinear instabilities, one should formulate equations so that rate of production of entropy within each cell of computational grid be nonnegative, as required by second law.
NASA Astrophysics Data System (ADS)
Lauterborn, Werner; Kurz, Thomas; Akhatov, Iskander
At high sound intensities or long propagation distances at
Charlie, Nicole K; Thomure, Angela M; Schade, Michael A; Miller, Kenneth G
2006-05-01
Forward genetic screens for mutations that rescue the paralysis of ric-8 (Synembryn) reduction-of-function mutations frequently reveal mutations that cause hyperactivation of one or more components of the G alpha(s) pathway. Here, we report that one of these mutations strongly reduces the function of the Dunce cAMP phosphodiesterase PDE-4 by disrupting a conserved active site residue. Loss of function and neural overexpression of PDE-4 have profound and opposite effects on locomotion rate, but drug-response assays suggest that loss of PDE-4 function does not affect steady-state acetylcholine release or reception. Our genetic analysis suggests that PDE-4 regulates both G alpha(s)-dependent and G alpha(s)-independent cAMP pools in the neurons controlling locomotion rate. By immunostaining, PDE-4 is strongly expressed throughout the nervous system, where it localizes to small regions at the outside boundaries of synaptic vesicle clusters as well as intersynaptic regions. The synaptic subregions containing PDE-4 are distinct from those containing active zones, as indicated by costaining with an antibody against the long form of UNC-13. This highly focal subsynaptic localization suggests that PDE-4 may exert its effects by spatially regulating intrasynaptic cAMP pools. PMID:16624912
MGGHAT: Elliptic PDE software with adaptive refinement, multigrid and high order finite elements
NASA Technical Reports Server (NTRS)
Mitchell, William F.
1993-01-01
MGGHAT (MultiGrid Galerkin Hierarchical Adaptive Triangles) is a program for the solution of linear second order elliptic partial differential equations in two dimensional polygonal domains. This program is now available for public use. It is a finite element method with linear, quadratic or cubic elements over triangles. The adaptive refinement via newest vertex bisection and the multigrid iteration are both based on a hierarchical basis formulation. Visualization is available at run time through an X Window display, and a posteriori through output files that can be used as GNUPLOT input. In this paper, we describe the methods used by MGGHAT, define the problem domain for which it is appropriate, illustrate use of the program, show numerical and graphical examples, and explain how to obtain the software.
Naval fuel saltstone formulation change
Harley, J.P. Jr.; Langton, C.A.
1987-10-19
Laboratory results support a formulation change for Naval Fuels saltstone from a cement-only waste form to a cement and Class F fly ash waste form. The recommended base formulation is waste, concentrated to a SpG of 1.35, mixed with a 1:1 ratio of Type 1 Portland cement and class F fly ash to achieve a water to cementitious materials (includes fly ash) ratio of 0.4. Due to variations in waste water chemistry, permit modifications should specify formulation ranges such that saltstone physical and chemical properties are enhanced. Operations should be based on pretesting each waste batch and adjusting the base formulation within specified ranges (ie. Draft DPSOL 247 WW-0312, ``Saltcrete Formulation Testing for Rapid Set and Excess Water.``) EP toxicity and TCLP tests are included and show comparable results for both cement-only and cement/fly ash waste forms. Heat generation due to hydration, a current problem with the cementonly formulation, is significantly reduced in the cement/fly ash mixture. In addition to the improved physical characteristics of the cement/fly ash formulation, savings of approximately 33% in raw materials cost may be obtained due to the substitution of the lower cost fly ash for cement in the Naval Fuels waste solidification process.
Naval fuel saltstone formulation change
Harley, J.P. Jr. and Co., Aiken, SC . Savannah River Plant); Langton, C.A. )
1987-10-19
Laboratory results support a formulation change for Naval Fuels saltstone from a cement-only waste form to a cement and Class F fly ash waste form. The recommended base formulation is waste, concentrated to a SpG of 1.35, mixed with a 1:1 ratio of Type 1 Portland cement and class F fly ash to achieve a water to cementitious materials (includes fly ash) ratio of 0.4. Due to variations in waste water chemistry, permit modifications should specify formulation ranges such that saltstone physical and chemical properties are enhanced. Operations should be based on pretesting each waste batch and adjusting the base formulation within specified ranges (ie. Draft DPSOL 247 WW-0312, Saltcrete Formulation Testing for Rapid Set and Excess Water.'') EP toxicity and TCLP tests are included and show comparable results for both cement-only and cement/fly ash waste forms. Heat generation due to hydration, a current problem with the cementonly formulation, is significantly reduced in the cement/fly ash mixture. In addition to the improved physical characteristics of the cement/fly ash formulation, savings of approximately 33% in raw materials cost may be obtained due to the substitution of the lower cost fly ash for cement in the Naval Fuels waste solidification process.
Novel Formulations for Antimicrobial Peptides
Carmona-Ribeiro, Ana Maria; Carrasco, Letícia Dias de Melo
2014-01-01
Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. This review discusses how novel formulations may improve the therapeutic index of antimicrobial peptides by protecting their activity and improving their bioavailability. The diversity of novel formulations using lipids, liposomes, nanoparticles, polymers, micelles, etc., within the limits of nanotechnology may also provide novel applications going beyond antimicrobial chemotherapy. PMID:25302615
Stochastic differential equations for non-linear hydrodynamics
NASA Astrophysics Data System (ADS)
Español, Pep
1998-02-01
We formulate the stochastic differential equations for non-linear hydrodynamic fluctuations. The equations incorporate the random forces through a random stres tensor and random heat flux as in the Landau and Lifshitz theory. However, the equations are non-linear and the random forces are non-Gaussian. We provide explicit expressions for these random quantities in terms of the well-defined increments of the Wienner process.
Nonlinear theory of a plasma Cherenkov maser
Choi, J.S.; Heo, E.G.; Choi, D.I.
1995-12-31
The nonlinear saturation state in a plasma Cherenkov maser (PCM) propagating the intense relativistic electron beam through a circular waveguide partially filled with a dense annular plasma, is analyzed from the nonlinear formulation based on the cold fluid-Maxwell equations. We obtain the nonlinear efficiency and the final operation frequency under consideration of the effects of the beam current, the beam energy and the slow wave structure. We show that the saturation mechanism of a PCM instablity is a close correspondence in that of the relativistic two stream instability by the coherent trapping of electrons in a single most-ustable wave. And the optimal conditions in PCM operation are also obtained from performing our nonliear analysis together with computer simulations.
Parallel computation of three-dimensional nonlinear magnetostatic problems.
Levine, D.; Gropp, W.; Forsman, K.; Kettunen, L.; Mathematics and Computer Science; Tampere Univ. of Tech.
1999-02-01
We describe a general-purpose parallel electromagnetic code for computing accurate solutions to large computationally demanding, 3D, nonlinear magnetostatic problems. The code, CORAL, is based on a volume integral equation formulation. Using an IBM SP parallel computer and iterative solution methods, we successfully solved the dense linear systems inherent in such formulations. A key component of our work was the use of the PETSc library, which provides parallel portability and access to the latest linear algebra solution technology.
Elwasif, Wael R; Foley, Samantha S; Bernholdt, David E; Berry, Lee A; Samaddar, D.; Newman, David E; Sanchez, R.
2011-01-01
Parareal is a novel algorithm that allows the solution of time-dependent systems of differential or partial differential equations (PDE) to be parallelized in the temporal domain. Parareal-based implementations of PDE problems can take advantage of this parallelism to significantly reduce the time to solution for a simulation (though at an increased total cost) while making effective use of the much larger processor counts available on current high-end systems. In this paper, we present a dynamic, dependency-driven version of the parareal algorithm which breaks the final sequential bottleneck remaining in the original formulation, making it amenable to a "many-task" treatment. We further improve the cost and execution time of the algorithm by introducing a moving window for time slices, which avoids the execution of tasks which contribute little to the final global solution. We describe how this approach has been realized in the Integrated Plasma Simulator (IPS), a framework for coupled multiphysics simulations, and examine the trade-offs among time-to-solution, total cost, and resource utilization efficiency as a function of the compute resources applied to the problem.
Simple formulation of magnetoplasmadynamic acceleration
Sasoh, A. )
1994-03-01
A simple formulation of magnetoplasmadynamic acceleration has been made based on energy conservation relations and a generalized Ohm's law. An exhaust velocity is expressed using three characteristic parameters: (1) a dimensionless characteristic velocity [ital [tilde U
Nonlinear Hysteretic Torsional Waves.
Cabaret, J; Béquin, P; Theocharis, G; Andreev, V; Gusev, V E; Tournat, V
2015-07-31
We theoretically study and experimentally report the propagation of nonlinear hysteretic torsional pulses in a vertical granular chain made of cm-scale, self-hanged magnetic beads. As predicted by contact mechanics, the torsional coupling between two beads is found to be nonlinear hysteretic. This results in a nonlinear pulse distortion essentially different from the distortion predicted by classical nonlinearities and in a complex dynamic response depending on the history of the wave particle angular velocity. Both are consistent with the predictions of purely hysteretic nonlinear elasticity and the Preisach-Mayergoyz hysteresis model, providing the opportunity to study the phenomenon of nonlinear dynamic hysteresis in the absence of other types of material nonlinearities. The proposed configuration reveals a plethora of interesting phenomena including giant amplitude-dependent attenuation, short-term memory, as well as dispersive properties. Thus, it could find interesting applications in nonlinear wave control devices such as strong amplitude-dependent filters. PMID:26274421
Nonlinear Hysteretic Torsional Waves
NASA Astrophysics Data System (ADS)
Cabaret, J.; Béquin, P.; Theocharis, G.; Andreev, V.; Gusev, V. E.; Tournat, V.
2015-07-01
We theoretically study and experimentally report the propagation of nonlinear hysteretic torsional pulses in a vertical granular chain made of cm-scale, self-hanged magnetic beads. As predicted by contact mechanics, the torsional coupling between two beads is found to be nonlinear hysteretic. This results in a nonlinear pulse distortion essentially different from the distortion predicted by classical nonlinearities and in a complex dynamic response depending on the history of the wave particle angular velocity. Both are consistent with the predictions of purely hysteretic nonlinear elasticity and the Preisach-Mayergoyz hysteresis model, providing the opportunity to study the phenomenon of nonlinear dynamic hysteresis in the absence of other types of material nonlinearities. The proposed configuration reveals a plethora of interesting phenomena including giant amplitude-dependent attenuation, short-term memory, as well as dispersive properties. Thus, it could find interesting applications in nonlinear wave control devices such as strong amplitude-dependent filters.
Formulation Optimization of Arecoline Patches
Wu, Pao-Chu; Tsai, Pi-Ju; Lin, Shin-Chen; Huang, Yaw-Bin
2014-01-01
The response surface methodology (RSM) including polynomial equations has been used to design an optimal patch formulation with appropriate adhesion and flux. The patch formulations were composed of different polymers, including Eudragit RS 100 (ERS), Eudragit RL 100 (ERL) and polyvinylpyrrolidone K30 (PVP), plasticizers (PEG 400), and drug. In addition, using terpenes as enhancers could increase the flux of the drug. Menthol showed the highest enhancement effect on the flux of arecoline. PMID:24707220
Dynamic analysis of nonlinear rotor-housing systems
NASA Technical Reports Server (NTRS)
Noah, Sherif T.
1988-01-01
Nonlinear analysis methods are developed which will enable the reliable prediction of the dynamic behavior of the space shuttle main engine (SSME) turbopumps in the presence of bearing clearances and other local nonlinearities. A computationally efficient convolution method, based on discretized Duhamel and transition matrix integral formulations, is developed for the transient analysis. In the formulation, the coupling forces due to the nonlinearities are treated as external forces acting on the coupled subsystems. Iteration is utilized to determine their magnitudes at each time increment. The method is applied to a nonlinear generic model of the high pressure oxygen turbopump (HPOTP). As compared to the fourth order Runge-Kutta numerical integration methods, the convolution approach proved to be more accurate and more highly efficient. For determining the nonlinear, steady-state periodic responses, an incremental harmonic balance method was also developed. The method was successfully used to determine dominantly harmonic and subharmonic responses fo the HPOTP generic model with bearing clearances. A reduction method similar to the impedance formulation utilized with linear systems is used to reduce the housing-rotor models to their coordinates at the bearing clearances. Recommendations are included for further development of the method, for extending the analysis to aperiodic and chaotic regimes and for conducting critical parameteric studies of the nonlinear response of the current SSME turbopumps.
Neonates need tailored drug formulations
Allegaert, Karel
2013-01-01
Drugs are very strong tools used to improve outcome in neonates. Despite this fact and in contrast to tailored perfusion equipment, incubators or ventilators for neonates, we still commonly use drug formulations initially developed for adults. We would like to make the point that drug formulations given to neonates need to be tailored for this age group. Besides the obvious need to search for active compounds that take the pathophysiology of the newborn into account, this includes the dosage and formulation. The dosage or concentration should facilitate the administration of low amounts and be flexible since clearance is lower in neonates with additional extensive between-individual variability. Formulations need to be tailored for dosage variability in the low ranges and also to the clinical characteristics of neonates. A specific focus of interest during neonatal drug development therefore is a need to quantify and limit excipient exposure based on the available knowledge of their safety or toxicity. Until such tailored vials and formulations become available, compounding practices for drug formulations in neonates should be evaluated to guarantee the correct dosing, product stability and safety. PMID:25254168
Lee, Dong I.; Vahebi, Susan; Tocchetti, Carlo Gabriele; Barouch, Lili A.; Solaro, R. John; Takimoto, Eiki
2010-01-01
Phosphodiesterase type 5A (PDE5A) inhibitors acutely suppress beta-adrenergic receptor (β-AR) stimulation in left ventricular myocytes and hearts. This modulation requires cyclic GMP synthesis via nitric oxide synthase (NOS)-NO stimulation, but upstream and downstream mechanisms remain un-defined. To determine this, adult cardiac myocytes from genetically engineered mice and controls were studied by video microscopy to assess sarcomere shortening (SS) and fura2-AM fluorescence to measure calcium transients (CaT). Enhanced SS from isoproterenol (ISO, 10 nM) was suppressed ≥50% by the PDE5A inhibitor sildenafil (SIL, 1 µM), without altering CaT. This regulation was unaltered despite co-inhibition of either the cGMP-stimulated cAMP-esterase PDE2 (Bay 60-7550), or cGMP-inhibited cAMP-esterase PDE3 (cilostamide). Thus, the SIL response could not be ascribed to cGMP interaction with alternative PDEs. However, genetic deletion (or pharmacologic blockade) of β3-ARs, which couple to NOS signaling, fully prevented SIL modulation of ISO-stimulated SS. Importantly, both PDE5A protein expression and activity were similar in β3-AR knockout (β3-AR−/−) myocytes as in controls. Downstream, cGMP stimulates protein kinase G (PKG), and we found contractile modulation by SIL required PKG activation and enhanced TnI phosphorylation at S23, S24. Myocytes expressing the slow skeletal TnI isoform which lacks these sites displayed no modulation of ISO responses by SIL. Non-equilibrium isoelectric focusing gel electrophoresis showed SIL increased TnI phosphorylation above that from concomitant ISO in control but not β3-AR−/− myocytes. These data support a cascade involving β3-AR stimulation, and subsequent PKG-dependent TnI S23, S24 phosphorylation as primary factors underlying the capacity of acute PDE5A inhibition to blunt myocardial β-adrenergic stimulation. PMID:20107996
Solitary waves and chaotic twisting in a PDE model of Faraday resonance
NASA Astrophysics Data System (ADS)
Decent, S. P.
1997-08-01
Standing solitary waves and twisting waves which result from parametric excitation in a narrow rectangular water tank are discussed. We derive a generalized Schrödinger equation, extending the Lagrangian method of Miles [J. Fluid Mech. 148 (1984) 451]. The effects of damping and forcing terms third-order in the wave amplitude, and also the fifth-order conservative frequency shift are investigated. In particular, it is found that constant-phase stationary solitary waves no longer exist when cubic damping and cubic forcing are non-zero: in this case a non-constant phase stationary solution is found which results in a modification of the shape of the standing solitary wave. We also find that non-zero cubic damping can, in some circumstances, give rise to a time-modulated solitary wave and/or coexistent solitary wave solutions. It is also demonstrated that these nonlinear terms greatly effect mode competition between twisting waves, and can cause the twisting waves to evolve chaotically.
40 CFR 152.43 - Alternate formulations.
Code of Federal Regulations, 2011 CFR
2011-07-01
... PESTICIDE REGISTRATION AND CLASSIFICATION PROCEDURES Registration Procedures § 152.43 Alternate formulations... label text of the alternate formulation product must be identical to that of the basic formulation....
40 CFR 152.43 - Alternate formulations.
Code of Federal Regulations, 2010 CFR
2010-07-01
... PESTICIDE REGISTRATION AND CLASSIFICATION PROCEDURES Registration Procedures § 152.43 Alternate formulations... label text of the alternate formulation product must be identical to that of the basic formulation....
Generic element formulation for modelling bolted lap joints
NASA Astrophysics Data System (ADS)
Ahmadian, Hamid; Jalali, Hassan
2007-07-01
Joints have significant effects on the dynamic response of the assembled structures due to existence of two non-linear mechanisms in their interface, namely slipping and slapping. These mechanisms affect the structural response by adding considerable damping into the structure and lowering the natural frequencies due to the stiffness softening. Neglecting these effects in modelling of joints produces errors in predictions of the structure responses. In this paper, a non-linear generic element formulation is developed for modelling bolted lap joints. The generic element is formed by satisfying all conditions that are known for a joint interface and hence providing a non-linear parametric formulation for the families of allowable joint models. Dynamic response of the developed model for the assembled structure including the generic joint interface element is obtained using the incremental harmonic balance (IHB) method. The generic parameters of the joint are identified by minimising the difference between the model response obtained from IHB method and the observed behaviour of the structure. The procedure is demonstrated by modelling an actual structure containing a single lap bolted joint in the middle. The frequency responses of the structure around the first two resonance frequencies are measured by exciting the structure using a sinusoidal force at each individual frequency. The measured responses are compared with the predictions of the model containing a parametric generic joint element. The parameters of the joint interface model are successfully identified by minimising the difference between the measured responses and the model predictions.
Nonlinear Transient Problems Using Structure Compatible Heat Transfer Code
NASA Technical Reports Server (NTRS)
Hou, Gene
2000-01-01
The report documents the recent effort to enhance a transient linear heat transfer code so as to solve nonlinear problems. The linear heat transfer code was originally developed by Dr. Kim Bey of NASA Largely and called the Structure-Compatible Heat Transfer (SCHT) code. The report includes four parts. The first part outlines the formulation of the heat transfer problem of concern. The second and the third parts give detailed procedures to construct the nonlinear finite element equations and the required Jacobian matrices for the nonlinear iterative method, Newton-Raphson method. The final part summarizes the results of the numerical experiments on the newly enhanced SCHT code.
Nonlinear analysis of axisymmetrix layered pressure vessels; Part 1: theory
Blandford, G.E.; Tauchert, T.R.; Leigh, D.C. )
1989-05-01
A finite element formulation for the nonlinear heat conduction and thermoelastic analyses of orthotropic, axisymmetric layered pressure vessels is presented. Nonlinearities include temperature-dependent material properties and stress-dependent layer interface conditions. Solution of the nonlinear heat conduction equations is iteratively obtained using a modified Newton-Raphson scheme. Direct iteration between heat conduction and stress analyses is employed when stress-dependent interface thermal resistance is considered. A modified time integration scheme to reduce oscillatory noise is introduced, and the stability and accuracy of the time integration scheme are discussed.
Linear and nonlinear dynamic analysis of redundant load path bearingless rotor systems
NASA Technical Reports Server (NTRS)
Murthy, V. R.; Shultz, Louis A.
1994-01-01
The goal of this research is to develop the transfer matrix method to treat nonlinear autonomous boundary value problems with multiple branches. The application is the complete nonlinear aeroelastic analysis of multiple-branched rotor blades. Once the development is complete, it can be incorporated into the existing transfer matrix analyses. There are several difficulties to be overcome in reaching this objective. The conventional transfer matrix method is limited in that it is applicable only to linear branch chain-like structures, but consideration of multiple branch modeling is important for bearingless rotors. Also, hingeless and bearingless rotor blade dynamic characteristics (particularly their aeroelasticity problems) are inherently nonlinear. The nonlinear equations of motion and the multiple-branched boundary value problem are treated together using a direct transfer matrix method. First, the formulation is applied to a nonlinear single-branch blade to validate the nonlinear portion of the formulation. The nonlinear system of equations is iteratively solved using a form of Newton-Raphson iteration scheme developed for differential equations of continuous systems. The formulation is then applied to determine the nonlinear steady state trim and aeroelastic stability of a rotor blade in hover with two branches at the root. A comprehensive computer program is developed and is used to obtain numerical results for the (1) free vibration, (2) nonlinearly deformed steady state, (3) free vibration about the nonlinearly deformed steady state, and (4) aeroelastic stability tasks. The numerical results obtained by the present method agree with results from other methods.
NASA Astrophysics Data System (ADS)
Volders, K.
2012-09-01
This paper concerns the numerical solution of the Black-Scholes PDE with a Neumann boundary condition on the right boundary. We consider finite difference schemes for the semi-discretization, which leads to a system of ODEs with corresponding matrix M. In this paper stability bounds for exp(tM) (t ≥ 0) are proved. A scaled version of the Euclidean norm, denoted by ‖ ṡ ‖H is considered. The advection and diffusion term of the PDE are analyzed separately. It turns out that the Neumann boundary condition leads to a growth of ‖exp(tM)‖H with the number of grid points m for the pure advection problem.
Rao, Raja Mohan; Luther, Bethala Jawahar; Rani, Chekuri Sharmila; Suresh, Namburi; Kapavarapu, Ravikumar; Parsa, Kishore V L; Rao, Mandava V Basaveswara; Pal, Manojit
2014-02-15
A number of 2H-1,3-benzoxazin-4(3H)-one derivatives containing indole or benzofuran moieties were synthesized by using Pd/C-Cu mediated coupling-cyclization strategy as a key step. The o-iodoanilides or o-iodophenol were coupled with 3-{2-(prop-2-ynyloxy)ethyl}-2H-benzo[e][1,3]oxazin-4(3H)-one using 10%Pd/C-CuI-PPh3 as a catalyst system and Et3N as a base to give the target compounds. All the synthesized compounds were tested for their PDE4B inhibitory potential in vitro using a cell based cAMP reporter assay. Some of them showed fold increase of the cAMP level when tested at 30 μM. A representative compound showed encouraging PDE4B inhibitory properties that were supported by its docking results. PMID:24440301
An adaptive nonlinear solution scheme for reservoir simulation
Lett, G.S.
1996-12-31
Numerical reservoir simulation involves solving large, nonlinear systems of PDE with strongly discontinuous coefficients. Because of the large demands on computer memory and CPU, most users must perform simulations on very coarse grids. The average properties of the fluids and rocks must be estimated on these grids. These coarse grid {open_quotes}effective{close_quotes} properties are costly to determine, and risky to use, since their optimal values depend on the fluid flow being simulated. Thus, they must be found by trial-and-error techniques, and the more coarse the grid, the poorer the results. This paper describes a numerical reservoir simulator which accepts fine scale properties and automatically generates multiple levels of coarse grid rock and fluid properties. The fine grid properties and the coarse grid simulation results are used to estimate discretization errors with multilevel error expansions. These expansions are local, and identify areas requiring local grid refinement. These refinements are added adoptively by the simulator, and the resulting composite grid equations are solved by a nonlinear Fast Adaptive Composite (FAC) Grid method, with a damped Newton algorithm being used on each local grid. The nonsymmetric linear system of equations resulting from Newton`s method are in turn solved by a preconditioned Conjugate Gradients-like algorithm. The scheme is demonstrated by performing fine and coarse grid simulations of several multiphase reservoirs from around the world.
Formulation of the aeroelastic stability and response problem of coupled rotor/support systems
NASA Technical Reports Server (NTRS)
Warmbrodt, W.; Friedmann, P.
1979-01-01
The consistent formulation of the governing nonlinear equations of motion for a coupled rotor/support system is presented. Rotor/support coupling is clearly documented by enforcing dynamic equilibrium between the rotor and the moving flexible support. The nonlinear periodic coefficient equations of motion are applicable to both coupled rotor/fuselage aeroelastic problems of helicopters in hover or forward flight and coupled rotor/tower dynamics of a large horizontal axis wind turbine (HAWT). Finally, the equations of motion are used to study the influence of flexible supports and nonlinear terms on rotor aeroelastic stability and response of a large two-bladed HAWT.
Nonlinear stability analysis, energy exchange and solitons on vortex cores
NASA Astrophysics Data System (ADS)
Eftekhari, Kamran
1999-10-01
The subject of this dissertation is to develop reliable analytical and numerical methods for the study of the nonlinear stability of a class of slender, incompressible axisymmetric swirling flows. We desire to understanding early nonlinear evolution and possibly gain insight into phenomena such as solitary waves observed on vortex filaments and strongly nonlinear phenomena like vortex breakdown. We use an extension of the method used by Leibovich & Ma [1982] for the development of the equations, which differs in some significant aspects from the formulation of the aforementioned authors. We find, in agreement with Leibovich & Ma [1982], that the complex envelope amplitude of weakly nonlinear asymmetric waves is governed by the cubically nonlinear Schrodinger equation (NLS), however our form for coefficients differs from those of Leibovich & Ma [1982]. Most significantly, our formulation includes an axisymmetric disturbance component at second order (a full order lower than Leibovich & Ma) and thus permits energy exchange between asymmetric and axisymmetric disturbance components. The resulting equations also explicitly demonstrate the possibility of singular points where the group (not phase) velocity of linear disturbance equals the local axial flow velocity (group-velocity critical layer in our terminology) and where the NLS coefficients blow up, thus providing a wavenumber selection mechanism for the weakly nonlinear evolution. After implementation of numerical algorithm, our goal is to investigate the effects of weak nonlinearities on the stability of axisymmetric columnar flows. The analysis is applied to several model vortical flows, namely the Q-vortex and the Batchelor [1964] trailing line vortex.
Ehrman, L A; Williams, M T; Schaefer, T L; Gudelsky, G A; Reed, T M; Fienberg, A A; Greengard, P; Vorhees, C V
2006-10-01
Mice lacking phosphodiesterase 1B (PDE1B) exhibit an exaggerated locomotor response to D-methamphetamine and increased in vitro phosphorylation of DARPP32 (dopamine- and cAMP-regulated phosphoprotein, M r 32 kDa) at Thr34 in striatal brain slices treated with the D1 receptor agonist, SKF81297. These results indicated a possible regulatory role for PDE1B in pathways involving DARPP32. Here, we generated PDE1B x DARPP32 double-knockout (double-KO) mice to test the role of PDE1B in DARPP32-dependent pathways in vivo. Analysis of the response to d-methamphetamine on locomotor activity showed that the hyperactivity experienced by PDE1B mutant mice was blocked in PDE1B-/- x DARPP32-/- double-KO mice, consistent with participation of PDE1B and DARPP32 in the same pathway. Further behavioral testing in the elevated zero-maze revealed that DARPP32-/- mice showed a less anxious phenotype that was nullified in double-mutant mice. In contrast, in the Morris water maze, double-KO mice showed deficits in spatial reversal learning not observed in either single mutant compared with wild-type mice. The data suggest a role for PDE1B in locomotor responses to psychostimulants through modulation of DARPP32-dependent pathways; however, this modulation does not necessarily impact other behaviors, such as anxiety or learning. Instead, the phenotype of double-KOs observed in these latter tasks may be mediated through independent pathways. PMID:17010100
Pooley, L; Shakur, Y; Rena, G; Houslay, M D
1997-01-01
Cells of two human follicular thyroid carcinoma cell lines (FTC133, FTC236) were stably transfected with a cDNA encoding the PDE4A cAMP-specific phosphodiesterase (PDE) splice variant RD1 (RNPDE4A1A) so as to generate the cloned cell lines, FTC133A and FTC236A. This allowed the expression of a novel rolipram-inhibited cAMP-specific PDE activity in these cells. Unlike the parent cell lines in which Ca2+/calmodulin caused a profound activation (approx. 3-4-fold) of homogenate PDE activity, no such stimulation was evident in the RD1-expressing cell lines, indicating loss of PDE1 activity. Reverse transcriptase-PCR analysis indicated that this was due to the down-regulation of the PDE1C isoform. The novel PDE4 activity in transfected cells was located exclusively in the membrane fraction, as was immunoreactive RD1. Low concentrations of the detergent Triton X-100, but not high NaCl concentrations, allowed RD1 to be solubilized. Laser scanning confocal immunofluorescence analyses identified RD1 immunoreactivity in a discrete perinuclear region of these RD1-expressing transfected cell lines. A similar pattern of labelling was observed using the antiserum Tex1, which specifically identified the Golgi apparatus. Treatment of FTC133A cells with the Golgi-perturbing agents monensin and brefeldin A led to a similar redistribution of immunoreactive species detected using both the Tex1 and anti-RD1 antisera. It is suggested that the PDE4A splice variant RD1 contains a membrane-association signal which allows the targeted expression of RD1 within the Golgi complex of these human follicular thyroid carcinoma cell lines. PMID:9003417
An approach to probabilistic finite element analysis using a mixed-iterative formulation
NASA Technical Reports Server (NTRS)
Dias, J. B.; Nakazawa, S.
1988-01-01
An efficient algorithm for computing the response sensitivity of finite element problems based on a mixed-iterative formulation is proposed. This method does not involve explicit differentiation of the tangent stiffness array and can be used with formulations for which a consistent tangent stiffness is not readily available. The method has been successfully applied to probabilistic finite element analysis of problems using the proposed mixed formulation, and this exercise has provided valuable insights regarding the extension of the method to a more general class of problems to include material and geometric nonlinearities.
Jiao, K; Sahaboglu, A; Zrenner, E; Ueffing, M; Ekström, P A R; Paquet-Durand, F
2016-01-01
Retinitis pigmentosa (RP), an inherited blinding disease, is caused by a variety of different mutations that affect retinal photoreceptor function and survival. So far there is neither effective treatment nor cure. We have previously shown that poly(ADP-ribose)polymerase (PARP) acts as a common and critical denominator of cell death in photoreceptors, qualifying it as a potential target for future therapeutic intervention. A significant fraction of RP-causing mutations affect the genes for the rod photoreceptor phosphodiesterase 6A (PDE6A) subunit, but it is not known whether they all engage the same death pathway. Analysing three homozygous point mutations (Pde6a R562W, D670G, and V685M) and one compound heterozygous Pde6aV685M/R562W mutation in mouse models that match human RP patients, we demonstrate excessive activation of PARP, which correlated in time with the progression of photoreceptor degeneration. The causal involvement of PARP activity in the neurodegenerative process was confirmed in organotypic retinal explant cultures treated with the PARP-selective inhibitor PJ34, using different treatment time-points and durations. Remarkably, the neuroprotective efficacy of PARP inhibition correlated inversely with the strength of the genetically induced insult, with the D670G mutant showing the best treatment effects. Our results highlight PARP as a target for neuroprotective interventions in RP caused by PDE6A mutations and are a first attempt towards personalized, genotype-matched therapy development for RP. In addition, for each of the different mutant situations, our work identifies windows of opportunity for an optimal treatment regimen for further in vivo experimentation and possibly clinical studies. PMID:27551530
Turko, I V; Francis, S H; Corbin, J D
1998-01-01
cGMP-binding phosphodiesterases contain two homologous allosteric cGMP-binding sites (sites a and b) that are arranged in tandem; they constitute a superfamily of mammalian cyclic nucleotide receptors distinct from the cyclic nucleotide-dependent protein kinases/cation channels family. The functional role of each of these two sites in the phosphodiesterases is not known. The cGMP-binding sites of one of these phosphodiesterases, the cGMP-binding cGMP-specific phosphodiesterase (cGB-PDE, PDE5), have been analysed by using site-directed mutagenesis. Mutations that affect cGMP binding to either one or both allosteric sites do not influence cGMP hydrolysis in the catalytic site under the conditions used. However, compared with wild-type enzyme, the D289A, D478A and D289A/D478A mutants, which are defective in cGMP binding to either site a or site b, or both allosteric sites, require much higher cGMP concentrations for the allosteric stimulation of phosphorylation by the catalytic subunit of cAMP-dependent protein kinase. The cGMP effect is on the cGB-PDE rather than on the catalytic subunit of the protein kinase because the latter enzyme does not require cGMP for activity. The D289N mutant, which has higher binding affinity for cGMP than does the wild-type enzyme, is phosphorylated at lower concentrations of cGMP than is the wild-type enzyme. It is concluded that cGMP binding to the allosteric sites of cGB-PDE does not directly affect catalysis, but binding to both of these sites regulates phosphorylation of this enzyme. PMID:9445376
Nikiforuk, Agnieszka; Potasiewicz, Agnieszka; Rafa, Dominik; Drescher, Karla; Bespalov, Anton; Popik, Piotr
2016-06-01
Inhibitors of phosphodiesterase 10A (PDE10A) represent a novel class of potential antipsychotic compounds. These principles increase the level of cAMP and cGMP in the medium spiny neurons of the striatum and resemble the neurochemical consequences of dopamine D2 receptor inhibition and dopamine D1 receptor stimulation. Cognitive dysfunctions, including an impaired ability to shift perceptual attentional set, are core features of schizophrenia. In the present study, we investigated the involvement of D1 receptors in the procognitive action of the PDE10A inhibitor using the attentional set-shifting task in rats. The performance of the rats in the extradimensional shift stage of the attentional set-shifting task was taken as an index of cognitive flexibility. We first assessed the effects of the D1 agonist in otherwise untreated animals and in animals pretreated with the D1 receptor antagonist. We then investigated the procognitive effects of the PDE10A inhibitor, MP-10, in otherwise untreated animals and in animals pretreated with the D1 receptor antagonist. The dopamine D1 receptor antagonist SCH-23390 produced cognitive impairment at the dose of 0.0125 mg/kg, but not at 0.0063 mg/kg. The D1 receptor agonist, SKF-81,297, produced a procognitive effect that was abolished by 0.0063 mg/kg of SCH-23390. The compound MP-10 produced a procognitive effect at the dose of 0.3 mg/kg, but not at 0.1 mg/kg. Rat pretreatment with 0.0063 mg/kg of SCH-23390 did not block the procognitive effect of 0.3 mg/kg of MP-10. The present study demonstrates that the blockade of dopamine D1 receptors is unlikely to affect the procognitive effects of PDE10A inhibition. PMID:26580130
Nonlinear theory of unstable fluid mixing driven by shock wave
NASA Astrophysics Data System (ADS)
Zhang, Qiang; Sohn, Sung-Ik
1997-04-01
A shock driven material interface between two fluids of different density is unstable. This instability is known as Richtmyer-Meshkov (RM) instability. In this paper, we present a quantitative nonlinear theory of compressible Richtmyer-Meshkov instability in two dimensions. Our nonlinear theory contains no free parameter and provides analytical predictions for the overall growth rate, as well as the growth rates of the bubble and spike, from early to later times for fluids of all density ratios. The theory also includes a general formulation of perturbative nonlinear solutions for incompressible fluids (evaluated explicitly through the fourth order). Our theory shows that the RM unstable system goes through a transition from a compressible and linear one at early times to a nonlinear and incompressible one at later times. Our theoretical predictions are in excellent agreement with the results of full numerical simulations from linear to nonlinear regimes.
Optimization approaches to nonlinear model predictive control
Biegler, L.T. . Dept. of Chemical Engineering); Rawlings, J.B. . Dept. of Chemical Engineering)
1991-01-01
With the development of sophisticated methods for nonlinear programming and powerful computer hardware, it now becomes useful and efficient to formulate and solve nonlinear process control problems through on-line optimization methods. This paper explores and reviews control techniques based on repeated solution of nonlinear programming (NLP) problems. Here several advantages present themselves. These include minimization of readily quantifiable objectives, coordinated and accurate handling of process nonlinearities and interactions, and systematic ways of dealing with process constraints. We motivate this NLP-based approach with small nonlinear examples and present a basic algorithm for optimization-based process control. As can be seen this approach is a straightforward extension of popular model-predictive controllers (MPCs) that are used for linear systems. The statement of the basic algorithm raises a number of questions regarding stability and robustness of the method, efficiency of the control calculations, incorporation of feedback into the controller and reliable ways of handling process constraints. Each of these will be treated through analysis and/or modification of the basic algorithm. To highlight and support this discussion, several examples are presented and key results are examined and further developed. 74 refs., 11 figs.
Nonlinear analysis of helix traveling wave tubes
Freund, H.P.; Zaidman, E.G.; Vanderplaats, N.R.; Kodis, M.A.
1994-12-31
A nonlinear formulation of the interaction in a helix traveling wave tube (TWT) is presented. The formulation is intended to treat a wide class of helix TWTs including both emission-gated and multi-tone operation. The essential feature of each of these configurations is that multiple waves must be included in the formulation. As a result, a fully time-dependent analysis is required. The numerical procedure for this in a helix TWT is complicated by the fact that the radial profile of the field varies with frequency. This contrasts, for example, with the case of a smooth bore waveguide in which the radial profile for each TE{sub ln} or TM{sub ln} mode is invariant in frequency. Because of this, a complete self-consistent particle-in-cell (PIC) formulation must be three-dimensional. In order to circumvent the computational expense of a 3D PIC formulation, the authors adopt an approach in which the electromagnetic field is represented as a superposition of azimuthally symmetric modes in a vacuum sheath helix. The specific electron distributions are chosen to model either a continuous beam for the multi-tone TWT and a pulsed beam for the emission-gated TWT. Numerical results of the simulation for examples of interest to an emission-gated TWT experiment at NRL will be presented.
Decontamination formulation with sorbent additive
Tucker; Mark D. , Comstock; Robert H.
2007-10-16
A decontamination formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a bleaching activator, a sorbent additive, and water. The highly adsorbent, water-soluble sorbent additive (e.g., sorbitol or mannitol) is used to "dry out" one or more liquid ingredients, such as the liquid bleaching activator (e.g., propylene glycol diacetate or glycerol diacetate) and convert the activator into a dry, free-flowing powder that has an extended shelf life, and is more convenient to handle and mix in the field.
Mokrý, J; Urbanová, A; Medvedová, I; Kertys, M; Mikolka, P; Kosutová, P; Mokrá, D
2016-01-01
Phosphodiesterases (PDEs) are enzymes involved in the degradation of cAMP and cGMP. Selective PDE4 inhibitors (e.g., roflumilast) are effective in therapy of chronic obstructive pulmonary disease associated with neutrophil inflammation. The aim of this study was to evaluate the effects of a selective PDE4 inhibitor, YM976, on citric acid-induced cough, in vivo and in vitro airway smooth muscle reactivity to histamine, and on inflammatory mediators in ovalbumin-sensitized guinea pigs, with experimentally induced eosinophil inflammation. The YM976 was administered intraperitoneally at a dose of 1.0 mg/kg once daily for 7 days. Sensitization with ovalbumin led to a significant increase in the number of coughs, and in vivo and in vitro airway reactivity. Also, increased plasma levels of IL-4, IL-5, and PAF were observed, with a significant increase in the differential count of eosinophils in both blood and bronchoalveolar lavage fluid. The YM976 suppressed the number of coughs, the airway reactivity in tracheal tissue strips, and the IL-4 level. The findings indicate that PDE4 inhibition by YM976 exerts antitussive and anti-inflammatory effects in guinea pigs with ovalbumin-induced eosinophilic inflammation. PMID:27130219
Polito, Marina; Klarenbeek, Jeffrey; Jalink, Kees; Paupardin-Tritsch, Danièle; Vincent, Pierre; Castro, Liliana R.V.
2013-01-01
The NO-cGMP signaling plays an important role in the regulation of striatal function although the mechanisms of action of cGMP specifically in medium spiny neurons (MSNs) remain unclear. Using genetically encoded fluorescent biosensors, including a novel Epac-based sensor (EPAC-SH150) with increased sensitivity for cAMP, we analyze the cGMP response to NO and whether it affected cAMP/PKA signaling in MSNs. The Cygnet2 sensor for cGMP reported large responses to NO donors in both striatonigral and striatopallidal MSNs, this cGMP signal was controlled partially by PDE2. At the level of cAMP brief forskolin stimulations produced transient cAMP signals which differed between D1 and D2 MSNs. NO inhibited these cAMP transients through cGMP-dependent PDE2 activation, an effect that was translated and magnified downstream of cAMP, at the level of PKA. PDE2 thus appears as a critical effector of NO which modulates the post-synaptic response of MSNs to dopaminergic transmission. PMID:24302895
Bayesian Analysis of Structural Equation Models with Nonlinear Covariates and Latent Variables
ERIC Educational Resources Information Center
Song, Xin-Yuan; Lee, Sik-Yum
2006-01-01
In this article, we formulate a nonlinear structural equation model (SEM) that can accommodate covariates in the measurement equation and nonlinear terms of covariates and exogenous latent variables in the structural equation. The covariates can come from continuous or discrete distributions. A Bayesian approach is developed to analyze the…
Carney, J Aidan; Gaillard, Rolf C; Bertherat, Jérôme; Stratakis, Constantine A
2010-04-01
We present the pathologic findings in the adrenal glands of 4 patients, aged 10 to 38 years, with Cushing syndrome and germline inactivating mutations of the gene PDE11A4 that encodes phosphodiesterase11A4. The gene is expressed in the adrenal cortex and catalyses the hydrolysis of cyclic adenosine monophosphate and cyclic guanosine monophosphate. Two of the patients were mother and daughter; the third had no affected relative; the fourth patient inherited the mutation from her father. Three of the group, including the mother and daughter, had the same pathology, primary pigmented nodular adrenocortical disease, a disorder known to be caused by inactivating mutations of the PRKAR1A gene. In these cases, the adrenal glands were small and the pathologic change was deep in the cortex in which numerous pigmented micronodules developed. In the remaining patient, the glands were slightly enlarged primarily owing to a diffuse hyperplasia of the superficial cortex that extended into the epi-adrenal fat. PMID:20351491
A nonlinear strategy for sensor based vehicle path control
NASA Technical Reports Server (NTRS)
Mayr, R.
1994-01-01
A method of transverse control which makes use of nonlinear formulations is presented. The strategy is utilized to stabilize a vehicle. The vehicle is autonomously guided and takes its control inputs from an optical sensing system. Additionally, the velocity of the vehicle is dictated by a longitudinal controller, which is also discussed.
NASA Technical Reports Server (NTRS)
1976-01-01
The development of two new shell finite elements for applications to large deflection problems is considered. The elements in question are doubly curved and of triangular and quadrilateral planform. They are restricted to small strains of elastic materials, and can accommodate large rotations. The elements described, which are based on relatively simple linear elements, make use of a new displacement function approach specifically designed for strongly nonlinear problems. The displacement function development for nonlinear applications is based on certain beam element formulations, and the strain-displacement equations are of a shallow shell type. Additional terms were included in these equations in an attempt to avoid the large errors characteristic of shallow shell elements in certain types of problems. An incremental nonlinear solution procedure specifically adopted to the element formulation was developed. The solution procedure is of combined incremental and total Lagrangian type, and uses a new updating scheme. A computer program was written to evaluate the developed formulations. This program can accommodate small element groups in arbitrary arrangements. Two simple programs were successfully solved. The results indicate that this new type of element has definite promise and should be a fruitful area for further research.
Variational formulation of a moment problem quantization method
NASA Astrophysics Data System (ADS)
Handy, Carlos R.; Maweu, John; Atterberry, Leticia Soto
1996-03-01
The eigenvalue moment method (EMM) has proven to be an effective technique for generating converging lower and upper bounds to the bosonic ground state energy of singular, strongly coupled, quantum systems. Application of EMM theory requires an appropriate linearization of the highly nonlinear Hankel-Hadamard (HH) moment determinant constraints for the (n+1)×(n+1) Hankel matrices Mn[u]≡M̂n0+∑i=1msM̂niu i), dependent on the missing moment variables {u(i)}≡u. We propose an alternate variational formulation utilizing the functions Det(Mn+1[u])/Det(Mn[u]), which we prove to be locally convex over the missing moment subset satisfying the HH positivity conditions Det(Mν[u])≳0, for ν≤n. Additional features of this variational formulation facilitate its application to important problems such as the octic, sextic, and quartic anharmonic oscillators.
Non-linear dynamic analysis of ancient masonry structures by 3D rigid block models
NASA Astrophysics Data System (ADS)
Orduña, Agustin; Ayala, A. Gustavo
2015-12-01
This work presents a formulation for non-linear dynamic analysis of unreinforced masonry structures using rigid block models. This procedure is akin to the distinct element family of methods, nevertheless, we assume that small displacements occur and, therefore, the formulation does not involve the search for new contacts between blocks. This proposal is also related to the rigid element method, although, in this case we use full three-dimensional models and a more robust interface formulation.
Boundary formulations for shape sensitivity of temperature dependent conductivity problems
NASA Technical Reports Server (NTRS)
Kane, James H.; Wang, Hua
1992-01-01
Used in concert with the Kirchhoff transformation, implicit differentiation of the discretized boundary integral equations governing the conduction of heat in solids with temperature dependent thermal conductivity is shown to generate an accurate and economical approach for computation of shape sensitivities. For problems with specified temperature and heat flux boundary conditions, a linear problem results for both the analysis and sensitivity analysis. In problems with either convection or radiation boundary conditions, a nonlinear problem is generated. Several iterative strategies are presented for the solution of the resulting sets of nonlinear equations and the computational performances examined in detail. Multizone analysis and zone condensation strategies are demonstrated to provide substantive computational economies in this process for models with either localized nonlinear boundary conditions or regions of geometric insensitivity to design variables. A series of nonlinear example problems is presented that have closed form solutions. Exact analytical expressions for the shape sensitivities associated with these problems are developed and these are compared with the sensitivities computed using the boundary element formulation.
A new Lagrangian formulation for laser-plasma interactions
Brizard, A.J. |
1998-04-01
A new Lagrangian structure for cold relativistic plasma electrodynamics is presented. This new formulation uses the fluid velocity {bold v} instead of the canonical-momentum Clebsch potential {psi} [X. L. Chen and R. N. Sudan, Phys. Fluids B {bold 5}, 1336 (1993)]. As a simple application, it is used to derive (through the Noether method) new {ital exact} conservation laws associated with nonlinear laser wake-field equations in the multi-dimensional quasi-static approximation. {copyright} {ital 1998 American Institute of Physics.}
Renormalization of stochastic lattice models: basic formulation.
Haselwandter, Christoph A; Vvedensky, Dimitri D
2007-10-01
We describe a general method for the multiscale analysis of stochastic lattice models. Beginning with a lattice Langevin formulation of site fluctuations, we derive stochastic partial differential equations by regularizing the transition rules of the model. Subsequent coarse graining is accomplished by calculating renormalization-group (RG) trajectories from initial conditions determined by the regularized atomistic models. The RG trajectories correspond to hierarchies of continuum equations describing lattice models over expanding length and time scales. These continuum equations retain a quantitative connection over different scales, as well as to the underlying atomistic dynamics. This provides a systematic method for the derivation of continuum equations from the transition rules of lattice models for any length and time scales. As an illustration we consider the one-dimensional (1D) Wolf-Villain (WV) model [Europhys. Lett. 13, 389 (1990)]. The RG analysis of this model, which we develop in detail, is generic and can be applied to a wide range of conservative lattice models. The RG trajectory of the 1D WV model shows a complex crossover sequence of linear and nonlinear stochastic differential equations, which is in excellent agreement with kinetic Monte Carlo simulations of this model. We conclude by discussing possible applications of the multiscale method described here to other nonequilibrium systems. PMID:17994944
Nonlinear rotordynamics analysis
NASA Technical Reports Server (NTRS)
Day, W. B.
1985-01-01
The special nonlinearities of the Jeffcott equations in rotordynamics are examined. The immediate application of this analysis is directed toward understanding the excessive vibrations recorded in the LOX pump of the SSME during hot firing ground testing. Deadband, side force and rubbing are three possible sources of inducing nonlinearity in the Jeffcott equations. The present analysis initially reduces these problems to the same mathematical description. A special frequency, named the nonlinear natural frequency is defined and used to develop the solutions of the nonlinear Jeffcott equations as asympotic expansions. This nonlinear natural frequency which is the ratio of the cross-stiffness and the damping, plays a major role in determining response frequencies. Numerical solutions are included for comparison with the analysis. Also, nonlinear frequency-response tables are made for a typical range of values.
ERIC Educational Resources Information Center
Rogers, Gregory M.; Reinecke, Mark A.; Curry, John F.
2005-01-01
For the Treatment for Adolescents With Depression Study (TADS), a cognitive-behavioral therapy (CBT) manual was developed with the aim of balancing standardization and flexibility. In this article, we describe the manual's case formulation procedures, which served as one major mechanism of flexibility in TADS CBT. We first describe the essential…
TERATOLOGY OF A ZINEB FORMULATION
The purpose of the present study was to evaluate the teratogenic potential of a zineb formulation. An initial toxicity study indicated that oral doses of 1,000 or 2,000 mg/kg/day adversely affected the weight gain of nonpregnant rats but not nonpregnant mice. In the teratology st...
On-line robust nonlinear state estimators for nonlinear bioprocess systems
NASA Astrophysics Data System (ADS)
Iratni, A.; Katebi, R.; Mostefai, M.
2012-04-01
This paper presents the design of a new robust nonlinear estimator for estimation of states of nonlinear systems. Two approaches are considered based on the state-dependent Riccati equation formulation and the technique of H-infinity control design. The proposed method differs from other well-known state estimators, because not only nonlinear dynamics but also the robustness is taken into account. The proposed method is implemented and tested on a biological wastewater system. The simulation study compares the Extended Kalman Estimator ( EKE), the State-Dependent Riccati Estimator ( SDRE), and the Extended H-infinity Estimator ( EHE) with a new proposed State Dependent H-infinity Estimator ( SDHE). The results are compared for different weather conditions, i.e. dry, rain and storm, showing a superior performance of the proposed method.
Stationary nonlinear Airy beams
Lotti, A.; Faccio, D.; Couairon, A.; Papazoglou, D. G.; Panagiotopoulos, P.; Tzortzakis, S.; Abdollahpour, D.
2011-08-15
We demonstrate the existence of an additional class of stationary accelerating Airy wave forms that exist in the presence of third-order (Kerr) nonlinearity and nonlinear losses. Numerical simulations and experiments, in agreement with the analytical model, highlight how these stationary solutions sustain the nonlinear evolution of Airy beams. The generic nature of the Airy solution allows extension of these results to other settings, and a variety of applications are suggested.
Nonlinear modes of clarinet-like musical instruments
NASA Astrophysics Data System (ADS)
Noreland, Daniel; Bellizzi, Sergio; Vergez, Christophe; Bouc, Robert
2009-07-01
The concept of nonlinear modes is applied in order to analyze the behavior of a model of woodwind reed instruments. Using a modal expansion of the impedance of the instrument, and by projecting the equation for the acoustic pressure on the normal modes of the air column, a system of second-order ordinary differential equations is obtained. The equations are coupled through the nonlinear relation describing the volume flow of air through the reed channel in response to the pressure difference across the reed. The system is treated using an amplitude-phase formulation for nonlinear modes, where the frequency and damping functions, as well as the invariant manifolds in the phase space, are unknowns to be determined. The formulation gives, without explicit integration of the underlying ordinary differential equation, access to the transient, the limit cycle, its period and stability. The process is illustrated for a model reduced to three normal modes of the air column.
Nonlinear predictive energy management of residential buildings with photovoltaics & batteries
NASA Astrophysics Data System (ADS)
Sun, Chao; Sun, Fengchun; Moura, Scott J.
2016-09-01
This paper studies a nonlinear predictive energy management strategy for a residential building with a rooftop photovoltaic (PV) system and second-life lithium-ion battery energy storage. A key novelty of this manuscript is closing the gap between building energy management formulations, advanced load forecasting techniques, and nonlinear battery/PV models. Additionally, we focus on the fundamental trade-off between lithium-ion battery aging and economic performance in energy management. The energy management problem is formulated as a model predictive controller (MPC). Simulation results demonstrate that the proposed control scheme achieves 96%-98% of the optimal performance given perfect forecasts over a long-term horizon. Moreover, the rate of battery capacity loss can be reduced by 25% with negligible losses in economic performance, through an appropriate cost function formulation.
Organic nonlinear optical materials
NASA Technical Reports Server (NTRS)
Umegaki, S.
1987-01-01
Recently, it became clear that organic compounds with delocalized pi electrons show a great nonlinear optical response. Especially, secondary nonlinear optical constants of more than 2 digits were often seen in the molecular level compared to the existing inorganic crystals such as LiNbO3. The crystallization was continuously tried. Organic nonlinear optical crystals have a new future as materials for use in the applied physics such as photomodulation, optical frequency transformation, opto-bistabilization, and phase conjugation optics. Organic nonlinear optical materials, e.g., urea, O2NC6H4NH2, I, II, are reviewed with 50 references.
Baillie, George S; Adams, David R; Bhari, Narinder; Houslay, Thomas M; Vadrevu, Suryakiran; Meng, Dong; Li, Xiang; Dunlop, Allan; Milligan, Graeme; Bolger, Graeme B; Klussmann, Enno; Houslay, Miles D
2007-05-15
Beta2-ARs (beta2-adrenoceptors) become desensitized rapidly upon recruitment of cytosolic beta-arrestin. PDE4D5 (family 4 cAMP-specific phosphodiesterase, subfamily D, isoform 5) can be recruited in complex with beta-arrestin, whereupon it regulates PKA (cAMP-dependent protein kinase) phosphorylation of the beta2-AR. In the present study, we have used novel technology, employing a library of overlapping peptides (25-mers) immobilized on cellulose membranes that scan the entire sequence of beta-arrestin 2, to define the interaction sites on beta-arrestin 2 for binding of PDE4D5 and the cognate long isoform, PDE4D3. We have identified a binding site in the beta-arrestin 2 N-domain for the common PDE4D catalytic unit and two regions in the beta-arrestin 2 C-domain that confer specificity for PDE4D5 binding. Alanine-scanning peptide array analysis of the N-domain binding region identified severely reduced interaction with PDE4D5 upon R26A substitution, and reduced interaction upon either K18A or T20A substitution. Similar analysis of the beta-arrestin 2 C-domain identified Arg286 and Asp291, together with the Leu215-His220 region, as being important for binding PDE4D5, but not PDE4D3. Transfection with wild-type beta-arrestin 2 profoundly decreased isoprenaline-stimulated PKA phosphorylation of the beta2-AR in MEFs (mouse embryo fibroblasts) lacking both beta-arrestin 1 and beta-arrestin 2. This effect was negated using either the R26A or the R286A mutant form of beta-arrestin 2 or a mutant with substitution of an alanine cassette for Leu215-His220, which showed little or no PDE4D5 binding, but was still recruited to the beta2-AR upon isoprenaline challenge. These data show that the interaction of PDE4D5 with both the N- and C-domains of beta-arrestin 2 are essential for beta2-AR regulation. PMID:17288540
Dodge-Kafka, Kimberly L.; Bauman, Andrea; Mayer, Nicole; Henson, Edward; Heredia, Lorena; Ahn, Jung; McAvoy, Thomas; Nairn, Angus C.; Kapiloff, Michael S.
2010-01-01
The concentration of the second messenger cAMP is tightly controlled in cells by the activity of phosphodiesterases. We have previously described how the protein kinase A-anchoring protein mAKAP serves as a scaffold for the cAMP-dependent protein kinase PKA and the cAMP-specific phosphodiesterase PDE4D3 in cardiac myocytes. PKA and PDE4D3 constitute a negative feedback loop whereby PKA-catalyzed phosphorylation and activation of PDE4D3 attenuate local cAMP levels. We now show that protein phosphatase 2A (PP2A) associated with mAKAP complexes is responsible for reversing the activation of PDE4D3 by catalyzing the dephosphorylation of PDE4D3 serine residue 54. Mapping studies reveal that a C-terminal mAKAP domain (residues 2085–2319) binds PP2A. Binding to mAKAP is required for PP2A function, such that deletion of the C-terminal domain enhances both base-line and forskolin-stimulated PDE4D3 activity. Interestingly, PP2A holoenzyme associated with mAKAP complexes in the heart contains the PP2A targeting subunit B56δ. Like PDE4D3, B56δ is a PKA substrate, and PKA phosphorylation of mAKAP-bound B56δ enhances phosphatase activity 2-fold in the complex. Accordingly, expression of a B56δ mutant that cannot be phosphorylated by PKA results in increased PDE4D3 phosphorylation. Taken together, our findings demonstrate that PP2A associated with mAKAP complexes promotes PDE4D3 dephosphorylation, serving both to inhibit PDE4D3 in unstimulated cells and also to mediate a cAMP-induced positive feedback loop following adenylyl cyclase activation and B56δ phosphorylation. In general, PKA·PP2A·mAKAP complexes exemplify how protein kinases and phosphatases may participate in molecular signaling complexes to dynamically regulate localized intracellular signaling. PMID:20106966
Dodge-Kafka, Kimberly L; Bauman, Andrea; Mayer, Nicole; Henson, Edward; Heredia, Lorena; Ahn, Jung; McAvoy, Thomas; Nairn, Angus C; Kapiloff, Michael S
2010-04-01
The concentration of the second messenger cAMP is tightly controlled in cells by the activity of phosphodiesterases. We have previously described how the protein kinase A-anchoring protein mAKAP serves as a scaffold for the cAMP-dependent protein kinase PKA and the cAMP-specific phosphodiesterase PDE4D3 in cardiac myocytes. PKA and PDE4D3 constitute a negative feedback loop whereby PKA-catalyzed phosphorylation and activation of PDE4D3 attenuate local cAMP levels. We now show that protein phosphatase 2A (PP2A) associated with mAKAP complexes is responsible for reversing the activation of PDE4D3 by catalyzing the dephosphorylation of PDE4D3 serine residue 54. Mapping studies reveal that a C-terminal mAKAP domain (residues 2085-2319) binds PP2A. Binding to mAKAP is required for PP2A function, such that deletion of the C-terminal domain enhances both base-line and forskolin-stimulated PDE4D3 activity. Interestingly, PP2A holoenzyme associated with mAKAP complexes in the heart contains the PP2A targeting subunit B56delta. Like PDE4D3, B56delta is a PKA substrate, and PKA phosphorylation of mAKAP-bound B56delta enhances phosphatase activity 2-fold in the complex. Accordingly, expression of a B56delta mutant that cannot be phosphorylated by PKA results in increased PDE4D3 phosphorylation. Taken together, our findings demonstrate that PP2A associated with mAKAP complexes promotes PDE4D3 dephosphorylation, serving both to inhibit PDE4D3 in unstimulated cells and also to mediate a cAMP-induced positive feedback loop following adenylyl cyclase activation and B56delta phosphorylation. In general, PKA.PP2A.mAKAP complexes exemplify how protein kinases and phosphatases may participate in molecular signaling complexes to dynamically regulate localized intracellular signaling. PMID:20106966
NASA Astrophysics Data System (ADS)
Norman, M. R.
2013-12-01
Differential Transforms (DTs), a core component of so-called "automatic" or "algorithmic" differentiation, offer significant flexibility and efficiency to any numerical method. The i-th and j-th DT, U(i,j), of a function, u(x,y), is simply U(i,j)=1/(i!j!)*∂(i+j)u/∂xi∂yj. Being a term in the Taylor series of u(x,y) makes the reverse transform trivial. This relation also computes initial DTs from known spatial derivatives. What is novel about DTs is how they simplify a complex PDE system, transforming most arithmetic, trigonometric, and other operators into simple recurrence relations in derivative space. This allows one to simply and quickly compute analytical derivatives of highly complex and non-linear functions. Consider a pseudo-conservation law system, u(x)t+f(u,x)x=s(u,x), for instance. The fluxes and source terms could be (and often are) highly complex, non-linear functions of the state vector and independent variables. Regardless of the spatial discretization (variational / finite-element, weak / finite-volume, or strong / finite-difference), one nearly always must resort to tensored quadrature to evaluate face fluxes and body source terms, and this treatment is expensive. However, if one uses DTs to analytically compute spatial derivatives of the flux and source terms, given spatial derivatives of u, then the fluxes and source terms are directly expanded as polynomials, allowing for significantly cheaper, quadrature-free integration, sampling, and differentiation with a single dot product. Besides being simpler, this also allows flexibility for Galerkin methods in particular to analytically and cheaply compute body integrals, which are often approximated inexactly with quadrature. Computing Nth-order DTs in D dimensions is of O(D2*N) complexity, and whether for transport or non-linear compressible Euler equations, they are cheaper to compute and integrate analytically than quadrature. Further, because time-dependent PDE systems relate spatial
Nonlinear Propagation of Infrasound from Large Explosions
NASA Astrophysics Data System (ADS)
de Groot-Hedlin, Catherine
2015-04-01
Atmospheric explosions release immense quantities of infrasound energy that can be detected at receivers located from hundreds to thousands of kilometers from the origin. This has led to the deployment of a global 60-station network of micro-barometer arrays to aid in nuclear explosion monitoring. Current methods of estimating the radiated source energy from remote recordings of infrasound signals use simplified empirical source-yield relations that account for stratospheric winds along the source-receiver path. These formulations apply only to direct and stratospherically ducted arrivals. More recently, considerable progress has been made in applying numerical modeling techniques to develop more accurate source-yield formulations for realistic sound and wind speed profiles. However, these methods assume linear infrasound propagation along the travel path even though nonlinear effects - which arise when the amplitude of the acoustic pressure perturbation is a finite fraction of the ambient atmospheric pressure - are known to significantly alter infrasound frequencies, velocities and amplitudes, and thus can affect derived source yield estimates. For realistic atmospheric profiles, nonlinearity can be significant both in the vicinity of a large explosive source as well as at much greater distances. Within the stratosphere, nonlinearity may arise at caustics created by ducting; in the thermosphere, nonlinearity may arise due to very low ambient pressures at high altitudes. In this study, the effects of nonlinearity on infrasound signal amplitudes and frequencies are simulated using a nonlinear finite difference, time-domain (FDTD) method. The key features that allow for accurate and efficient nonlinear synthesis of infrasound propagation through realistic media are that 1) it includes for atmospheric viscosity, and 2) the environmental models are constrained to have axial symmetry, yielding solutions relevant to a point source in a fully 3D model with rotational
Goldstein, Orly; Mezey, Jason G.; Schweitzer, Peter A.; Boyko, Adam R.; Gao, Chuan; Bustamante, Carlos D.; Jordan, Julie Ann; Aguirre, Gustavo D.; Acland, Gregory M.
2013-01-01
Purpose. To identify the causative mutations in two early-onset canine retinal degenerations, crd1 and crd2, segregating in the American Staffordshire terrier and the Pit Bull Terrier breeds, respectively. Methods. Retinal morphology of crd1- and crd2-affected dogs was evaluated by light microscopy. DNA was extracted from affected and related unaffected controls. Association analysis was undertaken using the Illumina Canine SNP array and PLINK (crd1 study), or the Affymetrix Version 2 Canine array, the “MAGIC” genotype algorithm, and Fisher's Exact test for association (crd2 study). Positional candidate genes were evaluated for each disease. Results. Structural photoreceptor abnormalities were observed in crd1-affected dogs as young as 11-weeks old. Rod and cone inner segment (IS) and outer segments (OS) were abnormal in size, shape, and number. In crd2-affected dogs, rod and cone IS and OS were abnormal as early as 3 weeks of age, progressing with age to severe loss of the OS, and thinning of the outer nuclear layer (ONL) by 12 weeks of age. Genome-wide association study (GWAS) identified association at the telomeric end of CFA3 in crd1-affected dogs and on CFA33 in crd2-affected dogs. Candidate gene evaluation identified a three bases deletion in exon 21 of PDE6B in crd1-affected dogs, and a cytosine insertion in exon 10 of IQCB1 in crd2-affected dogs. Conclusions. Identification of the mutations responsible for these two early-onset retinal degenerations provides new large animal models for comparative disease studies and evaluation of potential therapeutic approaches for the homologous human diseases. PMID:24045995
Newton, Robert
2015-01-01
Inhaled glucocorticoids acting via the glucocorticoid receptor are a mainstay treatment option for individuals with asthma. There is a consensus that the remedial actions of inhaled glucocorticoids are due to their ability to suppress inflammation by modulating gene expression. While inhaled glucocorticoids are generally effective in asthma, there are subjects with moderate-to-severe disease in whom inhaled glucocorticoids fail to provide adequate control. For these individuals, asthma guidelines recommend that a long-acting β2-adrenoceptor agonist (LABA) be administered concurrently with an inhaled glucocorticoid. This so-called “combination therapy” is often effective and clinically superior to the inhaled glucocorticoid alone, irrespective of dose. LABAs, and another class of drug known as phosphodiesterase 4 (PDE4) inhibitors, may also enhance the efficacy of inhaled glucocorticoids in chronic obstructive pulmonary disease (COPD). In both conditions, these drugs are believed to work by elevating the concentration of cyclic adenosine-3',5'-monophosphate (cAMP) in target cells and tissues. Despite the success of inhaled glucocorticoid/LABA combination therapy, it remains unclear how an increase in cAMP enhances the clinical efficacy of an inhaled glucocorticoid. In this report, we provide a state-of-the-art appraisal, including unresolved and controversial issues, of how cAMP-elevating drugs and inhaled glucocorticoids interact at a molecular level to deliver enhanced anti-inflammatory benefit over inhaled glucocorticoid monotherapy. We also speculate on ways to further exploit this desirable interaction. Critical discussion of how these two drug classes regulate gene transcription, often in a synergistic manner, is a particular focus. Indeed, because interplay between glucocorticoid receptor and cAMP signaling pathways may contribute to the superiority of inhaled glucocorticoid/LABA combination therapy, understanding this interaction may provide a logical
Friction and nonlinear dynamics
NASA Astrophysics Data System (ADS)
Manini, N.; Braun, O. M.; Tosatti, E.; Guerra, R.; Vanossi, A.
2016-07-01
The nonlinear dynamics associated with sliding friction forms a broad interdisciplinary research field that involves complex dynamical processes and patterns covering a broad range of time and length scales. Progress in experimental techniques and computational resources has stimulated the development of more refined and accurate mathematical and numerical models, capable of capturing many of the essentially nonlinear phenomena involved in friction.
Friction and nonlinear dynamics.
Manini, N; Braun, O M; Tosatti, E; Guerra, R; Vanossi, A
2016-07-27
The nonlinear dynamics associated with sliding friction forms a broad interdisciplinary research field that involves complex dynamical processes and patterns covering a broad range of time and length scales. Progress in experimental techniques and computational resources has stimulated the development of more refined and accurate mathematical and numerical models, capable of capturing many of the essentially nonlinear phenomena involved in friction. PMID:27249652
Nonlinear Optics and Applications
NASA Technical Reports Server (NTRS)
Abdeldayem, Hossin A. (Editor); Frazier, Donald O. (Editor)
2007-01-01
Nonlinear optics is the result of laser beam interaction with materials and started with the advent of lasers in the early 1960s. The field is growing daily and plays a major role in emerging photonic technology. Nonlinear optics play a major role in many of the optical applications such as optical signal processing, optical computers, ultrafast switches, ultra-short pulsed lasers, sensors, laser amplifiers, and many others. This special review volume on Nonlinear Optics and Applications is intended for those who want to be aware of the most recent technology. This book presents a survey of the recent advances of nonlinear optical applications. Emphasis will be on novel devices and materials, switching technology, optical computing, and important experimental results. Recent developments in topics which are of historical interest to researchers, and in the same time of potential use in the fields of all-optical communication and computing technologies, are also included. Additionally, a few new related topics which might provoke discussion are presented. The book includes chapters on nonlinear optics and applications; the nonlinear Schrodinger and associated equations that model spatio-temporal propagation; the supercontinuum light source; wideband ultrashort pulse fiber laser sources; lattice fabrication as well as their linear and nonlinear light guiding properties; the second-order EO effect (Pockels), the third-order (Kerr) and thermo-optical effects in optical waveguides and their applications in optical communication; and, the effect of magnetic field and its role in nonlinear optics, among other chapters.
Nonlinear Elasticity in a Deforming Ambient Space
NASA Astrophysics Data System (ADS)
Yavari, Arash; Ozakin, Arkadas; Sadik, Souhayl
2016-07-01
In this paper, we formulate a nonlinear elasticity theory in which the ambient space is evolving. For a continuum moving in an evolving ambient space, we model time dependency of the metric by a time-dependent embedding of the ambient space in a larger manifold with a fixed background metric. We derive both the tangential and the normal governing equations. We then reduce the standard energy balance written in the larger ambient space to that in the evolving ambient space. We consider quasi-static deformations of the ambient space and show that a quasi-static deformation of the ambient space results in stresses, in general. We linearize the nonlinear theory about a reference motion and show that variation of the spatial metric corresponds to an effective field of body forces.