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
Algebraic Multiscale Solver for Elastic Geomechanical Deformation
NASA Astrophysics Data System (ADS)
Castelletto, N.; Hajibeygi, H.; Tchelepi, H.
2015-12-01
Predicting the geomechanical response of geological formations to thermal, pressure, and mechanical loading is important in many engineering applications. The mathematical formulation that describes deformation of a reservoir coupled with flow and transport entails heterogeneous coefficients with a wide range of length scales. Such detailed heterogeneous descriptions of reservoir properties impose severe computational challenges for the study of realistic-scale (km) reservoirs. To deal with these challenges, we developed an Algebraic Multiscale Solver for ELastic geomechanical deformation (EL-AMS). Constructed on finite element fine-scale system, EL-AMS imposes a coarse-scale grid, which is a non-overlapping decomposition of the domain. Then, local (coarse) basis functions for the displacement vector are introduced. These basis functions honor the elastic properties of the local domains subject to the imposed local boundary conditions. The basis form the Restriction and Prolongation operators. These operators allow for the construction of accurate coarse-scale systems for the displacement. While the multiscale system is efficient for resolving low-frequency errors, coupling it with a fine-scale smoother, e.g., ILU(0), leads to an efficient iterative solver. Numerical results for several test cases illustrate that EL-AMS is quite efficient and applicable to simulate elastic deformation of large-scale heterogeneous reservoirs.
Multiscale Universal Interface: A concurrent framework for coupling heterogeneous solvers
Tang, Yu-Hang; Kudo, Shuhei; Bian, Xin; Li, Zhen; Karniadakis, George Em
2015-09-15
Graphical abstract: - Abstract: Concurrently coupled numerical simulations using heterogeneous solvers are powerful tools for modeling multiscale phenomena. However, major modifications to existing codes are often required to enable such simulations, posing significant difficulties in practice. In this paper we present a C++ library, i.e. the Multiscale Universal Interface (MUI), which is capable of facilitating the coupling effort for a wide range of multiscale simulations. The library adopts a header-only form with minimal external dependency and hence can be easily dropped into existing codes. A data sampler concept is introduced, combined with a hybrid dynamic/static typing mechanism, to create an easily customizable framework for solver-independent data interpretation. The library integrates MPI MPMD support and an asynchronous communication protocol to handle inter-solver information exchange irrespective of the solvers' own MPI awareness. Template metaprogramming is heavily employed to simultaneously improve runtime performance and code flexibility. We validated the library by solving three different multiscale problems, which also serve to demonstrate the flexibility of the framework in handling heterogeneous models and solvers. In the first example, a Couette flow was simulated using two concurrently coupled Smoothed Particle Hydrodynamics (SPH) simulations of different spatial resolutions. In the second example, we coupled the deterministic SPH method with the stochastic Dissipative Particle Dynamics (DPD) method to study the effect of surface grafting on the hydrodynamics properties on the surface. In the third example, we consider conjugate heat transfer between a solid domain and a fluid domain by coupling the particle-based energy-conserving DPD (eDPD) method with the Finite Element Method (FEM)
Multiscale Universal Interface: A concurrent framework for coupling heterogeneous solvers
NASA Astrophysics Data System (ADS)
Tang, Yu-Hang; Kudo, Shuhei; Bian, Xin; Li, Zhen; Karniadakis, George Em
2015-09-01
Concurrently coupled numerical simulations using heterogeneous solvers are powerful tools for modeling multiscale phenomena. However, major modifications to existing codes are often required to enable such simulations, posing significant difficulties in practice. In this paper we present a C++ library, i.e. the Multiscale Universal Interface (MUI), which is capable of facilitating the coupling effort for a wide range of multiscale simulations. The library adopts a header-only form with minimal external dependency and hence can be easily dropped into existing codes. A data sampler concept is introduced, combined with a hybrid dynamic/static typing mechanism, to create an easily customizable framework for solver-independent data interpretation. The library integrates MPI MPMD support and an asynchronous communication protocol to handle inter-solver information exchange irrespective of the solvers' own MPI awareness. Template metaprogramming is heavily employed to simultaneously improve runtime performance and code flexibility. We validated the library by solving three different multiscale problems, which also serve to demonstrate the flexibility of the framework in handling heterogeneous models and solvers. In the first example, a Couette flow was simulated using two concurrently coupled Smoothed Particle Hydrodynamics (SPH) simulations of different spatial resolutions. In the second example, we coupled the deterministic SPH method with the stochastic Dissipative Particle Dynamics (DPD) method to study the effect of surface grafting on the hydrodynamics properties on the surface. In the third example, we consider conjugate heat transfer between a solid domain and a fluid domain by coupling the particle-based energy-conserving DPD (eDPD) method with the Finite Element Method (FEM).
Bakhos, Tania; Saibaba, Arvind K.; Kitanidis, Peter K.
2015-10-15
We consider the problem of estimating parameters in large-scale weakly nonlinear inverse problems for which the underlying governing equations is a linear, time-dependent, parabolic partial differential equation. A major challenge in solving these inverse problems using Newton-type methods is the computational cost associated with solving the forward problem and with repeated construction of the Jacobian, which represents the sensitivity of the measurements to the unknown parameters. Forming the Jacobian can be prohibitively expensive because it requires repeated solutions of the forward and adjoint time-dependent parabolic partial differential equations corresponding to multiple sources and receivers. We propose an efficient method based on a Laplace transform-based exponential time integrator combined with a flexible Krylov subspace approach to solve the resulting shifted systems of equations efficiently. Our proposed solver speeds up the computation of the forward and adjoint problems, thus yielding significant speedup in total inversion time. We consider an application from Transient Hydraulic Tomography (THT), which is an imaging technique to estimate hydraulic parameters related to the subsurface from pressure measurements obtained by a series of pumping tests. The algorithms discussed are applied to a synthetic example taken from THT to demonstrate the resulting computational gains of this proposed method.
NASA Astrophysics Data System (ADS)
Cerroni, D.; Manservisi, S.; Pozzetti, G.
2015-11-01
In this work we investigate the potentialities of multi-scale engineering techniques to approach complex problems related to biomedical and biological fields. In particular we study the interaction between blood and blood vessel focusing on the presence of an aneurysm. The study of each component of the cardiovascular system is very difficult due to the fact that the movement of the fluid and solid is determined by the rest of system through dynamical boundary conditions. The use of multi-scale techniques allows us to investigate the effect of the whole loop on the aneurysm dynamic. A three-dimensional fluid-structure interaction model for the aneurysm is developed and coupled to a mono-dimensional one for the remaining part of the cardiovascular system, where a point zero-dimensional model for the heart is provided. In this manner it is possible to achieve rigorous and quantitative investigations of the cardiovascular disease without loosing the system dynamic. In order to study this biomedical problem we use a monolithic fluid-structure interaction (FSI) model where the fluid and solid equations are solved together. The use of a monolithic solver allows us to handle the convergence issues caused by large deformations. By using this monolithic approach different solid and fluid regions are treated as a single continuum and the interface conditions are automatically taken into account. In this way the iterative process characteristic of the commonly used segregated approach, it is not needed any more.
Min Yun, B; Aidun, Cyrus K; Yoganathan, Ajit P
2014-10-01
Bileaflet mechanical heart valves (BMHVs) are among the most popular prostheses to replace defective native valves. However, complex flow phenomena caused by the prosthesis are thought to induce serious thromboembolic complications. This study aims at employing a novel multiscale numerical method that models realistic sized suspended platelets for assessing blood damage potential in flow through BMHVs. A previously validated lattice-Boltzmann method (LBM) is used to simulate pulsatile flow through a 23 mm St. Jude Medical (SJM) Regent™ valve in the aortic position at very high spatiotemporal resolution with the presence of thousands of suspended platelets. Platelet damage is modeled for both the systolic and diastolic phases of the cardiac cycle. No platelets exceed activation thresholds for any of the simulations. Platelet damage is determined to be particularly high for suspended elements trapped in recirculation zones, which suggests a shift of focus in blood damage studies away from instantaneous flow fields and toward high flow mixing regions. In the diastolic phase, leakage flow through the b-datum gap is shown to cause highest damage to platelets. This multiscale numerical method may be used as a generic solver for evaluating blood damage in other cardiovascular flows and devices. PMID:25070372
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.
NASA Astrophysics Data System (ADS)
Vencels, Juris; Delzanno, Gian Luca; Manzini, Gianmarco; Markidis, Stefano; Peng, Ivy Bo; Roytershteyn, Vadim
2016-05-01
We present the design and implementation of a spectral code, called SpectralPlasmaSolver (SPS), for the solution of the multi-dimensional Vlasov-Maxwell equations. The method is based on a Hermite-Fourier decomposition of the particle distribution function. The code is written in Fortran and uses the PETSc library for solving the non-linear equations and preconditioning and the FFTW library for the convolutions. SPS is parallelized for shared- memory machines using OpenMP. As a verification example, we discuss simulations of the two-dimensional Orszag-Tang vortex problem and successfully compare them against a fully kinetic Particle-In-Cell simulation. An assessment of the performance of the code is presented, showing a significant improvement in the code running-time achieved by preconditioning, while strong scaling tests show a factor of 10 speed-up using 16 threads.
NASA Astrophysics Data System (ADS)
Ghattas, O.; Burstedde, C.; Stadler, G.; Wilcox, L. C.; Tu, T.; Issac, T.; Gurnis, M.; Alisic, L.; Tan, E.; Zhong, S.
2009-12-01
Many problems in solid earth geophysics are characterized by dynamics occurring on a wide range of length and time scales, placing the solution of the governing partial differential equations (PDEs) for such problems among the grand challenges of computational geophysics. One approach to overcoming the tyranny of scales is adaptive mesh refinement (AMR), which locally and dynamically adapts the mesh to resolve spatio-temporal scales and features of interest. For example, we are interested in modeling global mantle convection with nonlinear rheology and kilometer-scale resolution at faulted plate boundaries. Another problem of interest is modeling the dynamics of polar ice sheets with fine resolution in the vicinity of stick-slip transitions. Geophysical inverse problems characterized by a wide range of medium properties can also benefit from AMR as the earth model is updated. While AMR promises to help overcome the challenges inherent in modeling multiscale problems, the benefits are difficult to achieve in practice, particularly on petascale computers that are essential for frontier problems. Due to the complex dynamic data structures and communication patterns, and frequent data exchange and redistribution, scaling dynamic AMR to tens of thousands of processors has long been considered a challenge. Another difficulty is extending parallel AMR techniques to high-order-accurate, complex-geometry-conforming finite element methods that are favored for many classes of solid earth geophysical problems. Here, we present the ALPS (Adaptive Large-scale Parallel Simulations) framework for parallel adaptive solution of PDEs. ALPS includes the octor and p4est libraries for parallel dynamic mesh adaptivity on single-octree-based and forest-of-octree-based geometries, respectively, and the mangll library for arbitrary-order hexahedral continuous and discontinuous finite/spectral element discretizations on general multi-octree geometries. ALPS has been shown to scale well
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.
Energy Science and Technology Software Center (ESTSC)
2007-03-01
HPCCG is a simple PDE application and preconditioned conjugate gradient solver that solves a linear system on a beam-shaped domain. Although it does not address many performance issues present in real engineering applications, such as load imbalance and preconditioner scalability, it can serve as a first "sanity test" of new processor design choices, inter-connect network design choices and the scalability of a new computer system. Because it is self-contained, easy to compile and easily scaledmore » to 100s or 1000s of porcessors, it can be an attractive study code for computer system designers.« less
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.
A heterogeneous multiscale method for poroelasticity
NASA Astrophysics Data System (ADS)
Delgado, Paul M.
In this thesis, we develop and analyze a heterogeneous multiscale model for coupled fluid flow and solid deformation in porous media based on operator splitting and finite volume method. The splitting method results in two elliptic multiscale PDE's in the form of a reaction diffusion equation and a linear elasticity equation. We extend our previous multiscale method from 1D to higher dimensions and develop new approaches for the inclusion of mixed boundary conditions and source terms. We derive an error estimate for our multiscale method and analyze the stability of our splitting method. We also test the effectiveness of our method in the case of steady state linear poroelasticity.
New Multigrid Solver Advances in TOPS
Falgout, R D; Brannick, J; Brezina, M; Manteuffel, T; McCormick, S
2005-06-27
In this paper, we highlight new multigrid solver advances in the Terascale Optimal PDE Simulations (TOPS) project in the Scientific Discovery Through Advanced Computing (SciDAC) program. We discuss two new algebraic multigrid (AMG) developments in TOPS: the adaptive smoothed aggregation method ({alpha}SA) and a coarse-grid selection algorithm based on compatible relaxation (CR). The {alpha}SA method is showing promising results in initial studies for Quantum Chromodynamics (QCD) applications. The CR method has the potential to greatly improve the applicability of AMG.
Energy Science and Technology Software Center (ESTSC)
2004-03-01
Amesos is the Direct Sparse Solver Package in Trilinos. The goal of Amesos is to make AX=S as easy as it sounds, at least for direct methods. Amesos provides interfaces to a number of third party sparse direct solvers, including SuperLU, SuperLU MPI, DSCPACK, UMFPACK and KLU. Amesos provides a common object oriented interface to the best sparse direct solvers in the world. A sparse direct solver solves for x in Ax = b. wheremore » A is a matrix and x and b are vectors (or multi-vectors). A sparse direct solver flrst factors A into trinagular matrices L and U such that A = LU via gaussian elimination and then solves LU x = b. Switching amongst solvers in Amesos roquires a change to a single parameter. Yet, no solver needs to be linked it, unless it is used. All conversions between the matrices provided by the user and the format required by the underlying solver is performed by Amesos. As new sparse direct solvers are created, they will be incorporated into Amesos, allowing the user to simpty link with the new solver, change a single parameter in the calling sequence, and use the new solver. Amesos allows users to specify whether the matrix has changed. Amesos can be used anywhere that any sparse direct solver is needed.« less
Stanley, Vendall S.; Heroux, Michael A.; Hoekstra, Robert J.; Sala, Marzio
2004-03-01
Amesos is the Direct Sparse Solver Package in Trilinos. The goal of Amesos is to make AX=S as easy as it sounds, at least for direct methods. Amesos provides interfaces to a number of third party sparse direct solvers, including SuperLU, SuperLU MPI, DSCPACK, UMFPACK and KLU. Amesos provides a common object oriented interface to the best sparse direct solvers in the world. A sparse direct solver solves for x in Ax = b. where A is a matrix and x and b are vectors (or multi-vectors). A sparse direct solver flrst factors A into trinagular matrices L and U such that A = LU via gaussian elimination and then solves LU x = b. Switching amongst solvers in Amesos roquires a change to a single parameter. Yet, no solver needs to be linked it, unless it is used. All conversions between the matrices provided by the user and the format required by the underlying solver is performed by Amesos. As new sparse direct solvers are created, they will be incorporated into Amesos, allowing the user to simpty link with the new solver, change a single parameter in the calling sequence, and use the new solver. Amesos allows users to specify whether the matrix has changed. Amesos can be used anywhere that any sparse direct solver is needed.
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.
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.
Bordner, J.; Saied, F.
1996-12-31
GLab3D is an enhancement of an interactive environment (MGLab) for experimenting with iterative solvers and multigrid algorithms. It is implemented in MATLAB. The new version has built-in 3D elliptic pde`s and several iterative methods and preconditioners that were not available in the original version. A sparse direct solver option has also been included. The multigrid solvers have also been extended to 3D. The discretization and pde domains are restricted to standard finite differences on the unit square/cube. The power of this software studies in the fact that no programming is needed to solve, for example, the convection-diffusion equation in 3D with TFQMR and a customized V-cycle preconditioner, for a variety of problem sizes and mesh Reynolds, numbers. In addition to the graphical user interface, some sample drivers are included to show how experiments can be composed using the underlying suite of problems and solvers.
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
Multiscale Simulation Framework for Coupled Fluid Flow and Mechanical Deformation
Tchelepi, Hamdi
2014-11-14
A multiscale linear-solver framework for the pressure equation associated with flow in highly heterogeneous porous formations was developed. The multiscale based approach is cast in a general algebraic form, which facilitates integration of the new scalable linear solver in existing flow simulators. The Algebraic Multiscale Solver (AMS) is employed as a preconditioner within a multi-stage strategy. The formulations investigated include the standard MultiScale Finite-Element (MSFE) andMultiScale Finite-Volume (MSFV) methods. The local-stage solvers include incomplete factorization and the so-called Correction Functions (CF) associated with the MSFV approach. Extensive testing of AMS, as an iterative linear solver, indicate excellent convergence rates and computational scalability. AMS compares favorably with advanced Algebraic MultiGrid (AMG) solvers for highly detailed three-dimensional heterogeneous models. Moreover, AMS is expected to be especially beneficial in solving time-dependent problems of coupled multiphase flow and transport in large-scale subsurface formations.
Implementing Multiscale Fluid Simulations using Multiscale Universal Interface
NASA Astrophysics Data System (ADS)
Tang, Yu-Hang; Kudo, Shuhei; Bian, Xin; Li, Zhen; Karniadakis, George; Crunch Team
2015-11-01
The power of multiscale fluid simulations lies in its ability to recover a hierarchical levels of details by choreographing multiple solvers, thus extending the length and time scale accessible given a fixed amount of computing power. However, practical difficulties frequently arise when stitching together solvers which were not designed to be coupled, and would often result in tedious and unsustainable coding effort. The Multiscale Universal Interface (MUI) aims to solve this problem by exposing a small set of generalized programming interfaces that can be dropped into existing solvers with minimal intrusion. Three deployment cases will be given for demonstrating real-world applications of MUI. In the first case we used MUI to implement simulations of polymer-grafted surface in flow using Smoothed Particle Hydrodynamics/Dissipative Particle Dynamics (SPH/DPD) and state variable coupling. In the second case we constructed coupled DPD/Finite Element Method (FEM) simulation of conjugate heat transfer in heterogeneous coolant. In the third case we built hybrid DPD/molecular dynamics (MD) simulations by blending the forces on atoms at interface regions. Supported by the DOE Collaboratory on Mathematics for Mesoscopic Modeling of Materials (CM4) and AFOSR FA9550-12-1-0463. Computer hours at ORNL allocated through INCITE BIP118 and DD102.
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
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
Parallel Multigrid Equation Solver
Energy Science and Technology Software Center (ESTSC)
2001-09-07
Prometheus is a fully parallel multigrid equation solver for matrices that arise in unstructured grid finite element applications. It includes a geometric and an algebraic multigrid method and has solved problems of up to 76 mullion degrees of feedom, problems in linear elasticity on the ASCI blue pacific and ASCI red machines.
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
Adaptive kinetic-fluid solvers for heterogeneous computing architectures
NASA Astrophysics Data System (ADS)
Zabelok, Sergey; Arslanbekov, Robert; Kolobov, Vladimir
2015-12-01
We show feasibility and benefits of porting an adaptive multi-scale kinetic-fluid code to CPU-GPU systems. Challenges are due to the irregular data access for adaptive Cartesian mesh, vast difference of computational cost between kinetic and fluid cells, and desire to evenly load all CPUs and GPUs during grid adaptation and algorithm refinement. Our Unified Flow Solver (UFS) combines Adaptive Mesh Refinement (AMR) with automatic cell-by-cell selection of kinetic or fluid solvers based on continuum breakdown criteria. Using GPUs enables hybrid simulations of mixed rarefied-continuum flows with a million of Boltzmann cells each having a 24 × 24 × 24 velocity mesh. We describe the implementation of CUDA kernels for three modules in UFS: the direct Boltzmann solver using the discrete velocity method (DVM), the Direct Simulation Monte Carlo (DSMC) solver, and a mesoscopic solver based on the Lattice Boltzmann Method (LBM), all using adaptive Cartesian mesh. Double digit speedups on single GPU and good scaling for multi-GPUs have been demonstrated.
Kotulski, Joseph D.; Womble, David E.; Greenberg, David; Driessen, Brian
2004-03-01
PLIRIS is an object-oriented solver built on top of a previous matrix solver used in a number of application codes. Puns solves a linear system directly via LU factorization with partial pivoting. The user provides the linear system in terms of Epetra Objects including a matrix and right-hand-sides. The user can then factor the matrix and perform the forward and back solve at a later time or solve for multiple right-hand-sides at once. This package is used when dense matrices are obtained in the problem formulation. These dense matrices occur whenever boundary element techniques are chosen for the solution procedure. This has been used in electromagnetics for both static and frequency domain problems.
Energy Science and Technology Software Center (ESTSC)
2004-03-01
PLIRIS is an object-oriented solver built on top of a previous matrix solver used in a number of application codes. Puns solves a linear system directly via LU factorization with partial pivoting. The user provides the linear system in terms of Epetra Objects including a matrix and right-hand-sides. The user can then factor the matrix and perform the forward and back solve at a later time or solve for multiple right-hand-sides at once. This packagemore » is used when dense matrices are obtained in the problem formulation. These dense matrices occur whenever boundary element techniques are chosen for the solution procedure. This has been used in electromagnetics for both static and frequency domain problems.« less
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
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
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.
A novel high-order, entropy stable, 3D AMR MHD solver with guaranteed positive pressure
NASA Astrophysics Data System (ADS)
Derigs, Dominik; Winters, Andrew R.; Gassner, Gregor J.; Walch, Stefanie
2016-07-01
We describe a high-order numerical magnetohydrodynamics (MHD) solver built upon a novel non-linear entropy stable numerical flux function that supports eight travelling wave solutions. By construction the solver conserves mass, momentum, and energy and is entropy stable. The method is designed to treat the divergence-free constraint on the magnetic field in a similar fashion to a hyperbolic divergence cleaning technique. The solver described herein is especially well-suited for flows involving strong discontinuities. Furthermore, we present a new formulation to guarantee positivity of the pressure. We present the underlying theory and implementation of the new solver into the multi-physics, multi-scale adaptive mesh refinement (AMR) simulation code FLASH (http://flash.uchicago.edu)
A novel high-order, entropy stable, 3D AMR MHD solver with guaranteed positive pressure
NASA Astrophysics Data System (ADS)
Derigs, Dominik; Winters, Andrew R.; Gassner, Gregor J.; Walch, Stefanie
2016-07-01
We describe a high-order numerical magnetohydrodynamics (MHD) solver built upon a novel non-linear entropy stable numerical flux function that supports eight travelling wave solutions. By construction the solver conserves mass, momentum, and energy and is entropy stable. The method is designed to treat the divergence-free constraint on the magnetic field in a similar fashion to a hyperbolic divergence cleaning technique. The solver described herein is especially well-suited for flows involving strong discontinuities. Furthermore, we present a new formulation to guarantee positivity of the pressure. We present the underlying theory and implementation of the new solver into the multi-physics, multi-scale adaptive mesh refinement (AMR) simulation code FLASH (http://flash.uchicago.edu).
[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
Parallel tridiagonal equation solvers
NASA Technical Reports Server (NTRS)
Stone, H. S.
1974-01-01
Three parallel algorithms were compared for the direct solution of tridiagonal linear systems of equations. The algorithms are suitable for computers such as ILLIAC 4 and CDC STAR. For array computers similar to ILLIAC 4, cyclic odd-even reduction has the least operation count for highly structured sets of equations, and recursive doubling has the least count for relatively unstructured sets of equations. Since the difference in operation counts for these two algorithms is not substantial, their relative running times may be more related to overhead operations, which are not measured in this paper. The third algorithm, based on Buneman's Poisson solver, has more arithmetic operations than the others, and appears to be the least favorable. For pipeline computers similar to CDC STAR, cyclic odd-even reduction appears to be the most preferable algorithm for all cases.
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
Amesos2 Templated Direct Sparse Solver Package
Energy Science and Technology Software Center (ESTSC)
2011-05-24
Amesos2 is a templated direct sparse solver package. Amesos2 provides interfaces to direct sparse solvers, rather than providing native solver capabilities. Amesos2 is a derivative work of the Trilinos package Amesos.
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
Workload Characterization of CFD Applications Using Partial Differential Equation Solvers
NASA Technical Reports Server (NTRS)
Waheed, Abdul; Yan, Jerry; Saini, Subhash (Technical Monitor)
1998-01-01
Workload characterization is used for modeling and evaluating of computing systems at different levels of detail. We present workload characterization for a class of Computational Fluid Dynamics (CFD) applications that solve Partial Differential Equations (PDEs). This workload characterization focuses on three high performance computing platforms: SGI Origin2000, EBM SP-2, a cluster of Intel Pentium Pro bases PCs. We execute extensive measurement-based experiments on these platforms to gather statistics of system resource usage, which results in workload characterization. Our workload characterization approach yields a coarse-grain resource utilization behavior that is being applied for performance modeling and evaluation of distributed high performance metacomputing systems. In addition, this study enhances our understanding of interactions between PDE solver workloads and high performance computing platforms and is useful for tuning these applications.
X. Frank Xu
2010-03-30
Multiscale modeling of stochastic systems, or uncertainty quantization of multiscale modeling is becoming an emerging research frontier, with rapidly growing engineering applications in nanotechnology, biotechnology, advanced materials, and geo-systems, etc. While tremendous efforts have been devoted to either stochastic methods or multiscale methods, little combined work had been done on integration of multiscale and stochastic methods, and there was no method formally available to tackle multiscale problems involving uncertainties. By developing an innovative Multiscale Stochastic Finite Element Method (MSFEM), this research has made a ground-breaking contribution to the emerging field of Multiscale Stochastic Modeling (MSM) (Fig 1). The theory of MSFEM basically decomposes a boundary value problem of random microstructure into a slow scale deterministic problem and a fast scale stochastic one. The slow scale problem corresponds to common engineering modeling practices where fine-scale microstructure is approximated by certain effective constitutive constants, which can be solved by using standard numerical solvers. The fast scale problem evaluates fluctuations of local quantities due to random microstructure, which is important for scale-coupling systems and particularly those involving failure mechanisms. The Green-function-based fast-scale solver developed in this research overcomes the curse-of-dimensionality commonly met in conventional approaches, by proposing a random field-based orthogonal expansion approach. The MSFEM formulated in this project paves the way to deliver the first computational tool/software on uncertainty quantification of multiscale systems. The applications of MSFEM on engineering problems will directly enhance our modeling capability on materials science (composite materials, nanostructures), geophysics (porous media, earthquake), biological systems (biological tissues, bones, protein folding). Continuous development of MSFEM will
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
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.
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
NASA Technical Reports Server (NTRS)
Ilin, Andrew V.
2006-01-01
The Magnetic Field Solver computer program calculates the magnetic field generated by a group of collinear, cylindrical axisymmetric electromagnet coils. Given the current flowing in, and the number of turns, axial position, and axial and radial dimensions of each coil, the program calculates matrix coefficients for a finite-difference system of equations that approximates a two-dimensional partial differential equation for the magnetic potential contributed by the coil. The program iteratively solves these finite-difference equations by use of the modified incomplete Cholesky preconditioned-conjugate-gradient method. The total magnetic potential as a function of axial (z) and radial (r) position is then calculated as a sum of the magnetic potentials of the individual coils, using a high-accuracy interpolation scheme. Then the r and z components of the magnetic field as functions of r and z are calculated from the total magnetic potential by use of a high-accuracy finite-difference scheme. Notably, for the finite-difference calculations, the program generates nonuniform two-dimensional computational meshes from nonuniform one-dimensional meshes. Each mesh is generated in such a way as to minimize the numerical error for a benchmark one-dimensional magnetostatic problem.
Sherlock Holmes, Master Problem Solver.
ERIC Educational Resources Information Center
Ballew, Hunter
1994-01-01
Shows the connections between Sherlock Holmes's investigative methods and mathematical problem solving, including observations, characteristics of the problem solver, importance of data, questioning the obvious, learning from experience, learning from errors, and indirect proof. (MKR)
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.
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.
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)
Nejadmalayeri, Alireza
. The scalability and speedup studies of this powerful parallel PDE solver are performed on various architectures. Furthermore, Reynolds scaling of active spatial modes of both CVS and SCALES of linearly forced homogeneous turbulence at high Reynolds numbers is investigated for the first time. This computational complexity study, by demonstrating very promising slope for Reynolds scaling of SCALES even at constant level of fidelity for SGS dissipation, proves the argument that SCALES as a dynamically adaptive turbulence modeling technique, can offer a plethora of flexibilities in hierarchical multiscale space/time adaptive variable fidelity simulations of high Reynolds number turbulent flows.
Multiscale integration schemes for jump-diffusion systems
Givon, D.; Kevrekidis, I.G.
2008-12-09
We study a two-time-scale system of jump-diffusion stochastic differential equations. We analyze a class of multiscale integration methods for these systems, which, in the spirit of [1], consist of a hybridization between a standard solver for the slow components and short runs for the fast dynamics, which are used to estimate the effect that the fast components have on the slow ones. We obtain explicit bounds for the discrepancy between the results of the multiscale integration method and the slow components of the original system.
Domain decomposition solvers for PDEs : some basics, practical tools, and new developments.
Dohrmann, Clark R.
2010-11-01
The first part of this talk provides a basic introduction to the building blocks of domain decomposition solvers. Specific details are given for both the classical overlapping Schwarz (OS) algorithm and a recent iterative substructuring (IS) approach called balancing domain decomposition by constraints (BDDC). A more recent hybrid OS-IS approach is also described. The success of domain decomposition solvers depends critically on the coarse space. Similarities and differences between the coarse spaces for OS and BDDC approaches are discussed, along with how they can be obtained from discrete harmonic extensions. Connections are also made between coarse spaces and multiscale modeling approaches from computational mechanics. As a specific example, details are provided on constructing coarse spaces for incompressible fluid problems. The next part of the talk deals with a variety of implementation details for domain decomposition solvers. These include mesh partitioning options, local and global solver options, reducing the coarse space dimension, dealing with constraint equations, residual weighting to accelerate the convergence of OS methods, and recycling of Krylov spaces to efficiently solve problems with multiple right hand sides. Some potential bottlenecks and remedies for domain decomposition solvers are also discussed. The final part of the talk concerns some recent theoretical advances, new algorithms, and open questions in the analysis of domain decomposition solvers. The focus will be primarily on the work of the speaker and his colleagues on elasticity, fluid mechanics, problems in H(curl), and the analysis of subdomains with irregular boundaries.
MULTISCALE MATHEMATICS FOR BIOMASS CONVERSION TO RENEWABLE HYDROGEN
Vlachos, Dionisios; Plechac, Petr; Katsoulakis, Markos
2013-09-05
The overall objective of this project is to develop multiscale models for understanding and eventually designing complex processes for renewables. To the best of our knowledge, our work is the first attempt at modeling complex reacting systems, whose performance relies on underlying multiscale mathematics. Our specific application lies at the heart of biofuels initiatives of DOE and entails modeling of catalytic systems, to enable economic, environmentally benign, and efficient conversion of biomass into either hydrogen or valuable chemicals. Specific goals include: (i) Development of rigorous spatio-temporal coarse-grained kinetic Monte Carlo (KMC) mathematics and simulation for microscopic processes encountered in biomass transformation. (ii) Development of hybrid multiscale simulation that links stochastic simulation to a deterministic partial differential equation (PDE) model for an entire reactor. (iii) Development of hybrid multiscale simulation that links KMC simulation with quantum density functional theory (DFT) calculations. (iv) Development of parallelization of models of (i)-(iii) to take advantage of Petaflop computing and enable real world applications of complex, multiscale models. In this NCE period, we continued addressing these objectives and completed the proposed work. Main initiatives, key results, and activities are outlined.
AQUASOL: An efficient solver for the dipolar Poisson–Boltzmann–Langevin equation
Koehl, Patrice; Delarue, Marc
2010-01-01
The Poisson–Boltzmann (PB) formalism is among the most popular approaches to modeling the solvation of molecules. It assumes a continuum model for water, leading to a dielectric permittivity that only depends on position in space. In contrast, the dipolar Poisson–Boltzmann–Langevin (DPBL) formalism represents the solvent as a collection of orientable dipoles with nonuniform concentration; this leads to a nonlinear permittivity function that depends both on the position and on the local electric field at that position. The differences in the assumptions underlying these two models lead to significant differences in the equations they generate. The PB equation is a second order, elliptic, nonlinear partial differential equation (PDE). Its response coefficients correspond to the dielectric permittivity and are therefore constant within each subdomain of the system considered (i.e., inside and outside of the molecules considered). While the DPBL equation is also a second order, elliptic, nonlinear PDE, its response coefficients are nonlinear functions of the electrostatic potential. Many solvers have been developed for the PB equation; to our knowledge, none of these can be directly applied to the DPBL equation. The methods they use may adapt to the difference; their implementations however are PBE specific. We adapted the PBE solver originally developed by Holst and Saied [J. Comput. Chem. 16, 337 (1995)] to the problem of solving the DPBL equation. This solver uses a truncated Newton method with a multigrid preconditioner. Numerical evidences suggest that it converges for the DPBL equation and that the convergence is superlinear. It is found however to be slow and greedy in memory requirement for problems commonly encountered in computational biology and computational chemistry. To circumvent these problems, we propose two variants, a quasi-Newton solver based on a simplified, inexact Jacobian and an iterative self-consistent solver that is based directly on
AQUASOL: An efficient solver for the dipolar Poisson-Boltzmann-Langevin equation.
Koehl, Patrice; Delarue, Marc
2010-02-14
The Poisson-Boltzmann (PB) formalism is among the most popular approaches to modeling the solvation of molecules. It assumes a continuum model for water, leading to a dielectric permittivity that only depends on position in space. In contrast, the dipolar Poisson-Boltzmann-Langevin (DPBL) formalism represents the solvent as a collection of orientable dipoles with nonuniform concentration; this leads to a nonlinear permittivity function that depends both on the position and on the local electric field at that position. The differences in the assumptions underlying these two models lead to significant differences in the equations they generate. The PB equation is a second order, elliptic, nonlinear partial differential equation (PDE). Its response coefficients correspond to the dielectric permittivity and are therefore constant within each subdomain of the system considered (i.e., inside and outside of the molecules considered). While the DPBL equation is also a second order, elliptic, nonlinear PDE, its response coefficients are nonlinear functions of the electrostatic potential. Many solvers have been developed for the PB equation; to our knowledge, none of these can be directly applied to the DPBL equation. The methods they use may adapt to the difference; their implementations however are PBE specific. We adapted the PBE solver originally developed by Holst and Saied [J. Comput. Chem. 16, 337 (1995)] to the problem of solving the DPBL equation. This solver uses a truncated Newton method with a multigrid preconditioner. Numerical evidences suggest that it converges for the DPBL equation and that the convergence is superlinear. It is found however to be slow and greedy in memory requirement for problems commonly encountered in computational biology and computational chemistry. To circumvent these problems, we propose two variants, a quasi-Newton solver based on a simplified, inexact Jacobian and an iterative self-consistent solver that is based directly on the PBE
Scalable Parallel Algebraic Multigrid Solvers
Bank, R; Lu, S; Tong, C; Vassilevski, P
2005-03-23
The authors propose a parallel algebraic multilevel algorithm (AMG), which has the novel feature that the subproblem residing in each processor is defined over the entire partition domain, although the vast majority of unknowns for each subproblem are associated with the partition owned by the corresponding processor. This feature ensures that a global coarse description of the problem is contained within each of the subproblems. The advantages of this approach are that interprocessor communication is minimized in the solution process while an optimal order of convergence rate is preserved; and the speed of local subproblem solvers can be maximized using the best existing sequential algebraic solvers.
General complex polynomial root solver
NASA Astrophysics Data System (ADS)
Skowron, J.; Gould, A.
2012-12-01
This general complex polynomial root solver, implemented in Fortran and further optimized for binary microlenses, uses a new algorithm to solve polynomial equations and is 1.6-3 times faster than the ZROOTS subroutine that is commercially available from Numerical Recipes, depending on application. The largest improvement, when compared to naive solvers, comes from a fail-safe procedure that permits skipping the majority of the calculations in the great majority of cases, without risking catastrophic failure in the few cases that these are actually required.
Self-correcting Multigrid Solver
Jerome L.V. Lewandowski
2004-06-29
A new multigrid algorithm based on the method of self-correction for the solution of elliptic problems is described. The method exploits information contained in the residual to dynamically modify the source term (right-hand side) of the elliptic problem. It is shown that the self-correcting solver is more efficient at damping the short wavelength modes of the algebraic error than its standard equivalent. When used in conjunction with a multigrid method, the resulting solver displays an improved convergence rate with no additional computational work.
Multiscale modeling of mucosal immune responses
2015-01-01
Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T cell differentiation and tissue level cell-cell interactions was developed to illustrate the capabilities, power and scope of ENISI MSM. Background Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Implementation Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. Conclusion We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut
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.
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
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
Multiscale Methods for Nuclear Reactor Analysis
NASA Astrophysics Data System (ADS)
Collins, Benjamin S.
The ability to accurately predict local pin powers in nuclear reactors is necessary to understand the mechanisms that cause fuel pin failure during steady state and transient operation. In the research presented here, methods are developed to improve the local solution using high order methods with boundary conditions from a low order global solution. Several different core configurations were tested to determine the improvement in the local pin powers compared to the standard techniques, that use diffusion theory and pin power reconstruction (PPR). Two different multiscale methods were developed and analyzed; the post-refinement multiscale method and the embedded multiscale method. The post-refinement multiscale methods use the global solution to determine boundary conditions for the local solution. The local solution is solved using either a fixed boundary source or an albedo boundary condition; this solution is "post-refinement" and thus has no impact on the global solution. The embedded multiscale method allows the local solver to change the global solution to provide an improved global and local solution. The post-refinement multiscale method is assessed using three core designs. When the local solution has more energy groups, the fixed source method has some difficulties near the interface: however the albedo method works well for all cases. In order to remedy the issue with boundary condition errors for the fixed source method, a buffer region is used to act as a filter, which decreases the sensitivity of the solution to the boundary condition. Both the albedo and fixed source methods benefit from the use of a buffer region. Unlike the post-refinement method, the embedded multiscale method alters the global solution. The ability to change the global solution allows for refinement in areas where the errors in the few group nodal diffusion are typically large. The embedded method is shown to improve the global solution when it is applied to a MOX/LEU assembly
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
NASA Astrophysics Data System (ADS)
Balsara, Dinshaw S.
2015-08-01
In this paper we build on our prior work on multidimensional Riemann solvers by detailing the construction of a three-dimensional HLL Riemann solver. As with the two-dimensional Riemann solver, this is accomplished by introducing a constant resolved state between the states being considered, which introduces sufficient dissipation for systems of conservation laws. Closed form expressions for the resolved fluxes are provided to facilitate numerical implementation. This is accomplished by introducing a novel derivation of the multidimensional Riemann solver. The novelty consists of integrating Lagrangian fluxes across moving surfaces. This makes the problem easier to visualize in three dimensions. (A video introduction to multidimensional Riemann solvers is available on http://www.nd.edu/~dbalsara/Numerical-PDE-Course A robust and efficient second order accurate numerical scheme for three dimensional Euler and MHD flows is presented. The scheme is built on the current three-dimensional Riemann solver and has been implemented in the author's RIEMANN code. We demonstrate that schemes that are based on the three-dimensional Riemann solver permit multidimensional discontinuities to propagate more isotropically on resolution-starved meshes. The number of zones updated per second by this scheme on a modern processor is shown to be cost competitive with schemes that are based on a one-dimensional Riemann solver. However, the present scheme permits larger timesteps in three dimensions because of its inclusion of genuinely three-dimensional effects in the flow. For MHD problems it is not necessary to double the dissipation when evaluating the edge-centered electric fields. Accuracy analysis for three-dimensional Euler and MHD problems shows that the scheme meets its design accuracy. Several stringent test problems involving Euler and MHD flows are also presented and the scheme is shown to perform robustly on all of them. For the very first time, we present the formulation and
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
A comparison of solver performance for complex gastric electrophysiology models.
Sathar, Shameer; Cheng, Leo K; Trew, Mark L
2015-08-01
Computational techniques for solving systems of equations arising in gastric electrophysiology have not been studied for efficient solution process. We present a computationally challenging problem of simulating gastric electrophysiology in anatomically realistic stomach geometries with multiple intracellular and extracellular domains. The multiscale nature of the problem and mesh resolution required to capture geometric and functional features necessitates efficient solution methods if the problem is to be tractable. In this study, we investigated and compared several parallel preconditioners for the linear systems arising from tetrahedral discretisation of electrically isotropic and anisotropic problems, with and without stimuli. The results showed that the isotropic problem was computationally less challenging than the anisotropic problem and that the application of extracellular stimuli increased workload considerably. Preconditioning based on block Jacobi and algebraic multigrid solvers were found to have the best overall solution times and least iteration counts, respectively. The algebraic multigrid preconditioner would be expected to perform better on large problems. PMID:26736543
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
Time-domain Raman analytical forward solvers.
Martelli, Fabrizio; Binzoni, Tiziano; Sekar, Sanathana Konugolu Venkata; Farina, Andrea; Cavalieri, Stefano; Pifferi, Antonio
2016-09-01
A set of time-domain analytical forward solvers for Raman signals detected from homogeneous diffusive media is presented. The time-domain solvers have been developed for two geometries: the parallelepiped and the finite cylinder. The potential presence of a background fluorescence emission, contaminating the Raman signal, has also been taken into account. All the solvers have been obtained as solutions of the time dependent diffusion equation. The validation of the solvers has been performed by means of comparisons with the results of "gold standard" Monte Carlo simulations. These forward solvers provide an accurate tool to explore the information content encoded in the time-resolved Raman measurements. PMID:27607645
Parallel multiscale simulations of a brain aneurysm
Grinberg, Leopold; Fedosov, Dmitry A.; Karniadakis, George Em
2013-07-01
Cardiovascular pathologies, such as a brain aneurysm, are affected by the global blood circulation as well as by the local microrheology. Hence, developing computational models for such cases requires the coupling of disparate spatial and temporal scales often governed by diverse mathematical descriptions, e.g., by partial differential equations (continuum) and ordinary differential equations for discrete particles (atomistic). However, interfacing atomistic-based with continuum-based domain discretizations is a challenging problem that requires both mathematical and computational advances. We present here a hybrid methodology that enabled us to perform the first multiscale simulations of platelet depositions on the wall of a brain aneurysm. The large scale flow features in the intracranial network are accurately resolved by using the high-order spectral element Navier–Stokes solver NεκTαr. The blood rheology inside the aneurysm is modeled using a coarse-grained stochastic molecular dynamics approach (the dissipative particle dynamics method) implemented in the parallel code LAMMPS. The continuum and atomistic domains overlap with interface conditions provided by effective forces computed adaptively to ensure continuity of states across the interface boundary. A two-way interaction is allowed with the time-evolving boundary of the (deposited) platelet clusters tracked by an immersed boundary method. The corresponding heterogeneous solvers (NεκTαr and LAMMPS) are linked together by a computational multilevel message passing interface that facilitates modularity and high parallel efficiency. Results of multiscale simulations of clot formation inside the aneurysm in a patient-specific arterial tree are presented. We also discuss the computational challenges involved and present scalability results of our coupled solver on up to 300 K computer processors. Validation of such coupled atomistic-continuum models is a main open issue that has to be addressed in
Parallel multiscale simulations of a brain aneurysm
NASA Astrophysics Data System (ADS)
Grinberg, Leopold; Fedosov, Dmitry A.; Karniadakis, George Em
2013-07-01
Cardiovascular pathologies, such as a brain aneurysm, are affected by the global blood circulation as well as by the local microrheology. Hence, developing computational models for such cases requires the coupling of disparate spatial and temporal scales often governed by diverse mathematical descriptions, e.g., by partial differential equations (continuum) and ordinary differential equations for discrete particles (atomistic). However, interfacing atomistic-based with continuum-based domain discretizations is a challenging problem that requires both mathematical and computational advances. We present here a hybrid methodology that enabled us to perform the first multiscale simulations of platelet depositions on the wall of a brain aneurysm. The large scale flow features in the intracranial network are accurately resolved by using the high-order spectral element Navier-Stokes solver NɛκTαr. The blood rheology inside the aneurysm is modeled using a coarse-grained stochastic molecular dynamics approach (the dissipative particle dynamics method) implemented in the parallel code LAMMPS. The continuum and atomistic domains overlap with interface conditions provided by effective forces computed adaptively to ensure continuity of states across the interface boundary. A two-way interaction is allowed with the time-evolving boundary of the (deposited) platelet clusters tracked by an immersed boundary method. The corresponding heterogeneous solvers (NɛκTαr and LAMMPS) are linked together by a computational multilevel message passing interface that facilitates modularity and high parallel efficiency. Results of multiscale simulations of clot formation inside the aneurysm in a patient-specific arterial tree are presented. We also discuss the computational challenges involved and present scalability results of our coupled solver on up to 300 K computer processors. Validation of such coupled atomistic-continuum models is a main open issue that has to be addressed in future
Parallel multiscale simulations of a brain aneurysm.
Grinberg, Leopold; Fedosov, Dmitry A; Karniadakis, George Em
2013-07-01
Cardiovascular pathologies, such as a brain aneurysm, are affected by the global blood circulation as well as by the local microrheology. Hence, developing computational models for such cases requires the coupling of disparate spatial and temporal scales often governed by diverse mathematical descriptions, e.g., by partial differential equations (continuum) and ordinary differential equations for discrete particles (atomistic). However, interfacing atomistic-based with continuum-based domain discretizations is a challenging problem that requires both mathematical and computational advances. We present here a hybrid methodology that enabled us to perform the first multi-scale simulations of platelet depositions on the wall of a brain aneurysm. The large scale flow features in the intracranial network are accurately resolved by using the high-order spectral element Navier-Stokes solver εκ αr . The blood rheology inside the aneurysm is modeled using a coarse-grained stochastic molecular dynamics approach (the dissipative particle dynamics method) implemented in the parallel code LAMMPS. The continuum and atomistic domains overlap with interface conditions provided by effective forces computed adaptively to ensure continuity of states across the interface boundary. A two-way interaction is allowed with the time-evolving boundary of the (deposited) platelet clusters tracked by an immersed boundary method. The corresponding heterogeneous solvers ( εκ αr and LAMMPS) are linked together by a computational multilevel message passing interface that facilitates modularity and high parallel efficiency. Results of multiscale simulations of clot formation inside the aneurysm in a patient-specific arterial tree are presented. We also discuss the computational challenges involved and present scalability results of our coupled solver on up to 300K computer processors. Validation of such coupled atomistic-continuum models is a main open issue that has to be addressed in future
A generalized gyrokinetic Poisson solver
Lin, Z.; Lee, W.W.
1995-03-01
A generalized gyrokinetic Poisson solver has been developed, which employs local operations in the configuration space to compute the polarization density response. The new technique is based on the actual physical process of gyrophase-averaging. It is useful for nonlocal simulations using general geometry equilibrium. Since it utilizes local operations rather than the global ones such as FFT, the new method is most amenable to massively parallel algorithms.
On unstructured grids and solvers
NASA Technical Reports Server (NTRS)
Barth, T. J.
1990-01-01
The fundamentals and the state-of-the-art technology for unstructured grids and solvers are highlighted. Algorithms and techniques pertinent to mesh generation are discussed. It is shown that grid generation and grid manipulation schemes rely on fast multidimensional searching. Flow solution techniques for the Euler equations, which can be derived from the integral form of the equations are discussed. Sample calculations are also provided.
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
Magnetospheric Multiscale (MMS) Orbit
This animation shows the orbits of Magnetospheric Multiscale (MMS) mission, a Solar-Terrestrial Probe mission comprising of four identically instrumented spacecraft that will study the Earth's magn...
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
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.
Finite Element Interface to Linear Solvers
Williams, Alan
2005-03-18
Sparse systems of linear equations arise in many engineering applications, including finite elements, finite volumes, and others. The solution of linear systems is often the most computationally intensive portion of the application. Depending on the complexity of problems addressed by the application, there may be no single solver capable of solving all of the linear systems that arise. This motivates the desire to switch an application from one solver librwy to another, depending on the problem being solved. The interfaces provided by solver libraries differ greatly, making it difficult to switch an application code from one library to another. The amount of library-specific code in an application Can be greatly reduced by having an abstraction layer between solver libraries and the application, putting a common "face" on various solver libraries. One such abstraction layer is the Finite Element Interface to Linear Solvers (EEl), which has seen significant use by finite element applications at Sandia National Laboratories and Lawrence Livermore National Laboratory.
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.
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…
Analysis Tools for CFD Multigrid Solvers
NASA Technical Reports Server (NTRS)
Mineck, Raymond E.; Thomas, James L.; Diskin, Boris
2004-01-01
Analysis tools are needed to guide the development and evaluate the performance of multigrid solvers for the fluid flow equations. Classical analysis tools, such as local mode analysis, often fail to accurately predict performance. Two-grid analysis tools, herein referred to as Idealized Coarse Grid and Idealized Relaxation iterations, have been developed and evaluated within a pilot multigrid solver. These new tools are applicable to general systems of equations and/or discretizations and point to problem areas within an existing multigrid solver. Idealized Relaxation and Idealized Coarse Grid are applied in developing textbook-efficient multigrid solvers for incompressible stagnation flow problems.
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
MACSYMA's symbolic ordinary differential equation solver
NASA Technical Reports Server (NTRS)
Golden, J. P.
1977-01-01
The MACSYMA's symbolic ordinary differential equation solver ODE2 is described. The code for this routine is delineated, which is of interest because it is written in top-level MACSYMA language, and may serve as a good example of programming in that language. Other symbolic ordinary differential equation solvers are mentioned.
KLU2 Direct Linear Solver Package
Energy Science and Technology Software Center (ESTSC)
2012-01-04
KLU2 is a direct sparse solver for solving unsymmetric linear systems. It is related to the existing KLU solver, (in Amesos package and also as a stand-alone package from University of Florida) but provides template support for scalar and ordinal types. It uses a left looking LU factorization method.
MUSIC: MUlti-Scale Initial Conditions
NASA Astrophysics Data System (ADS)
Hahn, Oliver; Abel, Tom
2013-11-01
MUSIC generates multi-scale initial conditions with multiple levels of refinements for cosmological ‘zoom-in’ simulations. The code uses an adaptive convolution of Gaussian white noise with a real-space transfer function kernel together with an adaptive multi-grid Poisson solver to generate displacements and velocities following first- (1LPT) or second-order Lagrangian perturbation theory (2LPT). MUSIC achieves rms relative errors of the order of 10-4 for displacements and velocities in the refinement region and thus improves in terms of errors by about two orders of magnitude over previous approaches. In addition, errors are localized at coarse-fine boundaries and do not suffer from Fourier space-induced interference ringing.
Improving Resource-Unaware SAT Solvers
NASA Astrophysics Data System (ADS)
Hölldobler, Steffen; Manthey, Norbert; Saptawijaya, Ari
The paper discusses cache utilization in state-of-the-art SAT solvers. The aim of the study is to show how a resource-unaware SAT solver can be improved by utilizing the cache sensibly. The analysis is performed on a CDCL-based SAT solver using a subset of the industrial SAT Competition 2009 benchmark. For the analysis, the total cycles, the resource stall cycles, the L2 cache hits and the L2 cache misses are traced using sample based profiling. Based on the analysis, several techniques - some of which have not been used in SAT solvers so far - are proposed resulting in a combined speedup up to 83% without affecting the search path of the solver. The average speedup on the benchmark is 60%. The new techniques are also applied to MiniSAT2.0 improving its runtime by 20% on average.
Belos Block Linear Solvers Package
Energy Science and Technology Software Center (ESTSC)
2004-03-01
Belos is an extensible and interoperable framework for large-scale, iterative methods for solving systems of linear equations with multiple right-hand sides. The motivation for this framework is to provide a generic interface to a collection of algorithms for solving large-scale linear systems. Belos is interoperable because both the matrix and vectors are considered to be opaque objects--only knowledge of the matrix and vectors via elementary operations is necessary. An implementation of Balos is accomplished viamore » the use of interfaces. One of the goals of Belos is to allow the user flexibility in specifying the data representation for the matrix and vectors and so leverage any existing software investment. The algorithms that will be included in package are Krylov-based linear solvers, like Block GMRES (Generalized Minimal RESidual) and Block CG (Conjugate-Gradient).« less
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
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
NASA Astrophysics Data System (ADS)
Balsara, Dinshaw S.; Vides, Jeaniffer; Gurski, Katharine; Nkonga, Boniface; Dumbser, Michael; Garain, Sudip; Audit, Edouard
2016-01-01
Just as the quality of a one-dimensional approximate Riemann solver is improved by the inclusion of internal sub-structure, the quality of a multidimensional Riemann solver is also similarly improved. Such multidimensional Riemann problems arise when multiple states come together at the vertex of a mesh. The interaction of the resulting one-dimensional Riemann problems gives rise to a strongly-interacting state. We wish to endow this strongly-interacting state with physically-motivated sub-structure. The self-similar formulation of Balsara [16] proves especially useful for this purpose. While that work is based on a Galerkin projection, in this paper we present an analogous self-similar formulation that is based on a different interpretation. In the present formulation, we interpret the shock jumps at the boundary of the strongly-interacting state quite literally. The enforcement of the shock jump conditions is done with a least squares projection (Vides, Nkonga and Audit [67]). With that interpretation, we again show that the multidimensional Riemann solver can be endowed with sub-structure. However, we find that the most efficient implementation arises when we use a flux vector splitting and a least squares projection. An alternative formulation that is based on the full characteristic matrices is also presented. The multidimensional Riemann solvers that are demonstrated here use one-dimensional HLLC Riemann solvers as building blocks. Several stringent test problems drawn from hydrodynamics and MHD are presented to show that the method works. Results from structured and unstructured meshes demonstrate the versatility of our method. The reader is also invited to watch a video introduction to multidimensional Riemann solvers on http://www.nd.edu/~dbalsara/Numerical-PDE-Course.
NASA Astrophysics Data System (ADS)
Bayona, V.; Flyer, N.; Lucas, G. M.; Baumgaertner, A. J. G.
2015-04-01
A numerical model based on Radial Basis Function-generated Finite Differences (RBF-FD) is developed for simulating the Global Electric Circuit (GEC) within the Earth's atmosphere, represented by a 3-D variable coefficient linear elliptic PDE in a spherically-shaped volume with the lower boundary being the Earth's topography and the upper boundary a sphere at 60 km. To our knowledge, this is (1) the first numerical model of the GEC to combine the Earth's topography with directly approximating the differential operators in 3-D space, and related to this (2) the first RBF-FD method to use irregular 3-D stencils for discretization to handle the topography. It benefits from the mesh-free nature of RBF-FD, which is especially suitable for modeling high-dimensional problems with irregular boundaries. The RBF-FD elliptic solver proposed here makes no limiting assumptions on the spatial variability of the coefficients in the PDE (i.e. the conductivity profile), the right hand side forcing term of the PDE (i.e. distribution of current sources) or the geometry of the lower boundary.
Macklin, Paul; Cristini, Vittorio
2013-01-01
Simulating cancer behavior across multiple biological scales in space and time, i.e., multiscale cancer modeling, is increasingly being recognized as a powerful tool to refine hypotheses, focus experiments, and enable more accurate predictions. A growing number of examples illustrate the value of this approach in providing quantitative insight on the initiation, progression, and treatment of cancer. In this review, we introduce the most recent and important multiscale cancer modeling works that have successfully established a mechanistic link between different biological scales. Biophysical, biochemical, and biomechanical factors are considered in these models. We also discuss innovative, cutting-edge modeling methods that are moving predictive multiscale cancer modeling toward clinical application. Furthermore, because the development of multiscale cancer models requires a new level of collaboration among scientists from a variety of fields such as biology, medicine, physics, mathematics, engineering, and computer science, an innovative Web-based infrastructure is needed to support this growing community. PMID:21529163
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
Multiscale Design of Advanced Materials based on Hybrid Ab Initio and Quasicontinuum Methods
Luskin, Mitchell
2014-03-12
This project united researchers from mathematics, chemistry, computer science, and engineering for the development of new multiscale methods for the design of materials. Our approach was highly interdisciplinary, but it had two unifying themes: first, we utilized modern mathematical ideas about change-of-scale and state-of-the-art numerical analysis to develop computational methods and codes to solve real multiscale problems of DOE interest; and, second, we took very seriously the need for quantum mechanics-based atomistic forces, and based our methods on fast solvers of chemically accurate methods.
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
GARDNER, P.R.
2006-04-01
Sudoku, also known as Number Place, is a logic-based placement puzzle. The aim of the puzzle is to enter a numerical digit from 1 through 9 in each cell of a 9 x 9 grid made up of 3 x 3 subgrids (called ''regions''), starting with various digits given in some cells (the ''givens''). Each row, column, and region must contain only one instance of each numeral. Completing the puzzle requires patience and logical ability. Although first published in a U.S. puzzle magazine in 1979, Sudoku initially caught on in Japan in 1986 and attained international popularity in 2005. Last fall, after noticing Sudoku puzzles in some newspapers and magazines, I attempted a few just to see how hard they were. Of course, the difficulties varied considerably. ''Obviously'' one could use Trial and Error but all the advice was to ''Use Logic''. Thinking to flex, and strengthen, those powers, I began to tackle the puzzles systematically. That is, when I discovered a new tactical rule, I would write it down, eventually generating a list of ten or so, with some having overlap. They served pretty well except for the more difficult puzzles, but even then I managed to develop an additional three rules that covered all of them until I hit the Oregonian puzzle shown. With all of my rules, I could not seem to solve that puzzle. Initially putting my failure down to rapid mental fatigue (being unable to hold a sufficient quantity of information in my mind at one time), I decided to write a program to implement my rules and see what I had failed to notice earlier. The solver, too, failed. That is, my rules were insufficient to solve that particular puzzle. I happened across a book written by a fellow who constructs such puzzles and who claimed that, sometimes, the only tactic left was trial and error. With a trial and error routine implemented, my solver successfully completed the Oregonian puzzle, and has successfully solved every puzzle submitted to it since.
ALPS - A LINEAR PROGRAM SOLVER
NASA Technical Reports Server (NTRS)
Viterna, L. A.
1994-01-01
Linear programming is a widely-used engineering and management tool. Scheduling, resource allocation, and production planning are all well-known applications of linear programs (LP's). Most LP's are too large to be solved by hand, so over the decades many computer codes for solving LP's have been developed. ALPS, A Linear Program Solver, is a full-featured LP analysis program. ALPS can solve plain linear programs as well as more complicated mixed integer and pure integer programs. ALPS also contains an efficient solution technique for pure binary (0-1 integer) programs. One of the many weaknesses of LP solvers is the lack of interaction with the user. ALPS is a menu-driven program with no special commands or keywords to learn. In addition, ALPS contains a full-screen editor to enter and maintain the LP formulation. These formulations can be written to and read from plain ASCII files for portability. For those less experienced in LP formulation, ALPS contains a problem "parser" which checks the formulation for errors. ALPS creates fully formatted, readable reports that can be sent to a printer or output file. ALPS is written entirely in IBM's APL2/PC product, Version 1.01. The APL2 workspace containing all the ALPS code can be run on any APL2/PC system (AT or 386). On a 32-bit system, this configuration can take advantage of all extended memory. The user can also examine and modify the ALPS code. The APL2 workspace has also been "packed" to be run on any DOS system (without APL2) as a stand-alone "EXE" file, but has limited memory capacity on a 640K system. A numeric coprocessor (80X87) is optional but recommended. The standard distribution medium for ALPS is a 5.25 inch 360K MS-DOS format diskette. IBM, IBM PC and IBM APL2 are registered trademarks of International Business Machines Corporation. MS-DOS is a registered trademark of Microsoft Corporation.
A multiscale two-point flux-approximation method
Møyner, Olav Lie, Knut-Andreas
2014-10-15
A large number of multiscale finite-volume methods have been developed over the past decade to compute conservative approximations to multiphase flow problems in heterogeneous porous media. In particular, several iterative and algebraic multiscale frameworks that seek to reduce the fine-scale residual towards machine precision have been presented. Common for all such methods is that they rely on a compatible primal–dual coarse partition, which makes it challenging to extend them to stratigraphic and unstructured grids. Herein, we propose a general idea for how one can formulate multiscale finite-volume methods using only a primal coarse partition. To this end, we use two key ingredients that are computed numerically: (i) elementary functions that correspond to flow solutions used in transmissibility upscaling, and (ii) partition-of-unity functions used to combine elementary functions into basis functions. We exemplify the idea by deriving a multiscale two-point flux-approximation (MsTPFA) method, which is robust with regards to strong heterogeneities in the permeability field and can easily handle general grids with unstructured fine- and coarse-scale connections. The method can easily be adapted to arbitrary levels of coarsening, and can be used both as a standalone solver and as a preconditioner. Several numerical experiments are presented to demonstrate that the MsTPFA method can be used to solve elliptic pressure problems on a wide variety of geological models in a robust and efficient manner.
Multiscale modeling and simulation of brain blood flow
NASA Astrophysics Data System (ADS)
Perdikaris, Paris; Grinberg, Leopold; Karniadakis, George Em
2016-02-01
The aim of this work is to present an overview of recent advances in multi-scale modeling of brain blood flow. In particular, we present some approaches that enable the in silico study of multi-scale and multi-physics phenomena in the cerebral vasculature. We discuss the formulation of continuum and atomistic modeling approaches, present a consistent framework for their concurrent coupling, and list some of the challenges that one needs to overcome in achieving a seamless and scalable integration of heterogeneous numerical solvers. The effectiveness of the proposed framework is demonstrated in a realistic case involving modeling the thrombus formation process taking place on the wall of a patient-specific cerebral aneurysm. This highlights the ability of multi-scale algorithms to resolve important biophysical processes that span several spatial and temporal scales, potentially yielding new insight into the key aspects of brain blood flow in health and disease. Finally, we discuss open questions in multi-scale modeling and emerging topics of future research.
A scalable 2-D parallel sparse solver
Kothari, S.C.; Mitra, S.
1995-12-01
Scalability beyond a small number of processors, typically 32 or less, is known to be a problem for existing parallel general sparse (PGS) direct solvers. This paper presents a parallel general sparse PGS direct solver for general sparse linear systems on distributed memory machines. The algorithm is based on the well-known sequential sparse algorithm Y12M. To achieve efficient parallelization, a 2-D scattered decomposition of the sparse matrix is used. The proposed algorithm is more scalable than existing parallel sparse direct solvers. Its scalability is evaluated on a 256 processor nCUBE2s machine using Boeing/Harwell benchmark matrices.
SIERRA framework version 4 : solver services.
Williams, Alan B.
2005-02-01
Several SIERRA applications make use of third-party libraries to solve systems of linear and nonlinear equations, and to solve eigenproblems. The classes and interfaces in the SIERRA framework that provide linear system assembly services and access to solver libraries are collectively referred to as solver services. This paper provides an overview of SIERRA's solver services including the design goals that drove the development, and relationships and interactions among the various classes. The process of assembling and manipulating linear systems will be described, as well as access to solution methods and other operations.
Euler solvers for transonic applications
NASA Technical Reports Server (NTRS)
Vanleer, Bram
1989-01-01
The 1980s may well be called the Euler era of applied aerodynamics. Computer codes based on discrete approximations of the Euler equations are now routinely used to obtain solutions of transonic flow problems in which the effects of entropy and vorticity production are significant. Such codes can even predict separation from a sharp edge, owing to the inclusion of artificial dissipation, intended to lend numerical stability to the calculation but at the same time enforcing the Kutta condition. One effect not correctly predictable by Euler codes is the separation from a smooth surface, and neither is viscous drag; for these some form of the Navier-Stokes equation is needed. It, therefore, comes as no surprise to observe that the Navier-Stokes has already begun before Euler solutions were fully exploited. Moreover, most numerical developments for the Euler equations are now constrained by the requirement that the techniques introduced, notably artificial dissipation, must not interfere with the new physics added when going from an Euler to a full Navier-Stokes approximation. In order to appreciate the contributions of Euler solvers to the understanding of transonic aerodynamics, it is useful to review the components of these computational tools. Space discretization, time- or pseudo-time marching and boundary procedures, the essential constituents are discussed. The subject of grid generation and grid adaptation to the solution are touched upon only where relevant. A list of unanswered questions and an outlook for the future are covered.
NASA Technical Reports Server (NTRS)
Ferencz, Donald C.; Viterna, Larry A.
1991-01-01
ALPS is a computer program which can be used to solve general linear program (optimization) problems. ALPS was designed for those who have minimal linear programming (LP) knowledge and features a menu-driven scheme to guide the user through the process of creating and solving LP formulations. Once created, the problems can be edited and stored in standard DOS ASCII files to provide portability to various word processors or even other linear programming packages. Unlike many math-oriented LP solvers, ALPS contains an LP parser that reads through the LP formulation and reports several types of errors to the user. ALPS provides a large amount of solution data which is often useful in problem solving. In addition to pure linear programs, ALPS can solve for integer, mixed integer, and binary type problems. Pure linear programs are solved with the revised simplex method. Integer or mixed integer programs are solved initially with the revised simplex, and the completed using the branch-and-bound technique. Binary programs are solved with the method of implicit enumeration. This manual describes how to use ALPS to create, edit, and solve linear programming problems. Instructions for installing ALPS on a PC compatible computer are included in the appendices along with a general introduction to linear programming. A programmers guide is also included for assistance in modifying and maintaining the program.
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
Parallelizing alternating direction implicit solver on GPUs
Technology Transfer Automated Retrieval System (TEKTRAN)
We present a parallel Alternating Direction Implicit (ADI) solver on GPUs. Our implementation significantly improves existing implementations in two aspects. First, we address the scalability issue of existing Parallel Cyclic Reduction (PCR) implementations by eliminating their hardware resource con...
Optimization of solver for gas flow modeling
NASA Astrophysics Data System (ADS)
Savichkin, D.; Dodulad, O.; Kloss, Yu
2014-05-01
The main purpose of the work is optimization of the solver for rarefied gas flow modeling based on the Boltzmann equation. Optimization method is based on SIMD extensions for ×86 processors. Computational code is profiled and manually optimized with SSE instructions. Heat flow, shock waves and Knudsen pump are modeled with optimized solver. Dependencies of computational time from mesh sizes and CPU capabilities are provided.
Community Multiscale Air Quality Model
The U.S. EPA developed the Community Multiscale Air Quality (CMAQ) system to apply a “one atmosphere” multiscale and multi-pollutant modeling approach based mainly on the “first principles” description of the atmosphere. The multiscale capability is supported by the governing di...
A parallel PCG solver for MODFLOW.
Dong, Yanhui; Li, Guomin
2009-01-01
In order to simulate large-scale ground water flow problems more efficiently with MODFLOW, the OpenMP programming paradigm was used to parallelize the preconditioned conjugate-gradient (PCG) solver with in this study. Incremental parallelization, the significant advantage supported by OpenMP on a shared-memory computer, made the solver transit to a parallel program smoothly one block of code at a time. The parallel PCG solver, suitable for both MODFLOW-2000 and MODFLOW-2005, is verified using an 8-processor computer. Both the impact of compilers and different model domain sizes were considered in the numerical experiments. Based on the timing results, execution times using the parallel PCG solver are typically about 1.40 to 5.31 times faster than those using the serial one. In addition, the simulation results are the exact same as the original PCG solver, because the majority of serial codes were not changed. It is worth noting that this parallelizing approach reduces cost in terms of software maintenance because only a single source PCG solver code needs to be maintained in the MODFLOW source tree. PMID:19563427
Finite Element Interface to Linear Solvers
Energy Science and Technology Software Center (ESTSC)
2005-03-18
Sparse systems of linear equations arise in many engineering applications, including finite elements, finite volumes, and others. The solution of linear systems is often the most computationally intensive portion of the application. Depending on the complexity of problems addressed by the application, there may be no single solver capable of solving all of the linear systems that arise. This motivates the desire to switch an application from one solver librwy to another, depending on themore » problem being solved. The interfaces provided by solver libraries differ greatly, making it difficult to switch an application code from one library to another. The amount of library-specific code in an application Can be greatly reduced by having an abstraction layer between solver libraries and the application, putting a common "face" on various solver libraries. One such abstraction layer is the Finite Element Interface to Linear Solvers (EEl), which has seen significant use by finite element applications at Sandia National Laboratories and Lawrence Livermore National Laboratory.« less
Adaptive multiscale model reduction with Generalized Multiscale Finite Element Methods
NASA Astrophysics Data System (ADS)
Chung, Eric; Efendiev, Yalchin; Hou, Thomas Y.
2016-09-01
In this paper, we discuss a general multiscale model reduction framework based on multiscale finite element methods. We give a brief overview of related multiscale methods. Due to page limitations, the overview focuses on a few related methods and is not intended to be comprehensive. We present a general adaptive multiscale model reduction framework, the Generalized Multiscale Finite Element Method. Besides the method's basic outline, we discuss some important ingredients needed for the method's success. We also discuss several applications. The proposed method allows performing local model reduction in the presence of high contrast and no scale separation.
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
PSPIKE: A Parallel Hybrid Sparse Linear System Solver
NASA Astrophysics Data System (ADS)
Manguoglu, Murat; Sameh, Ahmed H.; Schenk, Olaf
The availability of large-scale computing platforms comprised of tens of thousands of multicore processors motivates the need for the next generation of highly scalable sparse linear system solvers. These solvers must optimize parallel performance, processor (serial) performance, as well as memory requirements, while being robust across broad classes of applications and systems. In this paper, we present a new parallel solver that combines the desirable characteristics of direct methods (robustness) and effective iterative solvers (low computational cost), while alleviating their drawbacks (memory requirements, lack of robustness). Our proposed hybrid solver is based on the general sparse solver PARDISO, and the “Spike” family of hybrid solvers. The resulting algorithm, called PSPIKE, is as robust as direct solvers, more reliable than classical preconditioned Krylov subspace methods, and much more scalable than direct sparse solvers. We support our performance and parallel scalability claims using detailed experimental studies and comparison with direct solvers, as well as classical preconditioned Krylov methods.
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.
NASA Astrophysics Data System (ADS)
Mena, Andres; Ferrero, Jose M.; Rodriguez Matas, Jose F.
2015-11-01
Solving the electric activity of the heart possess a big challenge, not only because of the structural complexities inherent to the heart tissue, but also because of the complex electric behaviour of the cardiac cells. The multi-scale nature of the electrophysiology problem makes difficult its numerical solution, requiring temporal and spatial resolutions of 0.1 ms and 0.2 mm respectively for accurate simulations, leading to models with millions degrees of freedom that need to be solved for thousand time steps. Solution of this problem requires the use of algorithms with higher level of parallelism in multi-core platforms. In this regard the newer programmable graphic processing units (GPU) has become a valid alternative due to their tremendous computational horsepower. This paper presents results obtained with a novel electrophysiology simulation software entirely developed in Compute Unified Device Architecture (CUDA). The software implements fully explicit and semi-implicit solvers for the monodomain model, using operator splitting. Performance is compared with classical multi-core MPI based solvers operating on dedicated high-performance computer clusters. Results obtained with the GPU based solver show enormous potential for this technology with accelerations over 50 × for three-dimensional problems.
NASA Astrophysics Data System (ADS)
Kevlahan, N. N.; Vasilyev, O. V.; Yuen, D. A.
2003-12-01
An adaptive multilevel wavelet collocation method for solving multi-dimensional elliptic problems with localized structures is developed. The method is based on the general class of multi-dimensional second generation wavelets and is an extension of the dynamically adaptive second generation wavelet collocation method for evolution problems. Wavelet decomposition is used for grid adaptation and interpolation, while O(N) hierarchical finite difference scheme, which takes advantage of wavelet multilevel decomposition, is used for derivative calculations. The multilevel structure of the wavelet approximation provides a natural way to obtain the solution on a near optimal grid. In order to accelerate the convergence of the iterative solver, an iterative procedure analogous to the multigrid algorithm is developed. For the problems with slowly varying viscosity simple diagonal preconditioning works. For problems with large laterally varying viscosity contrasts either direct solver on shared-memory machines or multilevel iterative solver with incomplete LU preconditioner may be used. The method is demonstrated for the solution of a number of two-dimensional elliptic test problems with both constant and spatially varying viscosity with multiscale character.
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
NASA Astrophysics Data System (ADS)
Bhattacharjee, Satyaki; Matouš, Karel
2016-05-01
A new manifold-based reduced order model for nonlinear problems in multiscale modeling of heterogeneous hyperelastic materials is presented. The model relies on a global geometric framework for nonlinear dimensionality reduction (Isomap), and the macroscopic loading parameters are linked to the reduced space using a Neural Network. The proposed model provides both homogenization and localization of the multiscale solution in the context of computational homogenization. To construct the manifold, we perform a number of large three-dimensional simulations of a statistically representative unit cell using a parallel finite strain finite element solver. The manifold-based reduced order model is verified using common principles from the machine-learning community. Both homogenization and localization of the multiscale solution are demonstrated on a large three-dimensional example and the local microscopic fields as well as the homogenized macroscopic potential are obtained with acceptable engineering accuracy.
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
New iterative solvers for the NAG Libraries
Salvini, S.; Shaw, G.
1996-12-31
The purpose of this paper is to introduce the work which has been carried out at NAG Ltd to update the iterative solvers for sparse systems of linear equations, both symmetric and unsymmetric, in the NAG Fortran 77 Library. Our current plans to extend this work and include it in our other numerical libraries in our range are also briefly mentioned. We have added to the Library the new Chapter F11, entirely dedicated to sparse linear algebra. At Mark 17, the F11 Chapter includes sparse iterative solvers, preconditioners, utilities and black-box routines for sparse symmetric (both positive-definite and indefinite) linear systems. Mark 18 will add solvers, preconditioners, utilities and black-boxes for sparse unsymmetric systems: the development of these has already been completed.
Using SPARK as a Solver for Modelica
Wetter, Michael; Wetter, Michael; Haves, Philip; Moshier, Michael A.; Sowell, Edward F.
2008-06-30
Modelica is an object-oriented acausal modeling language that is well positioned to become a de-facto standard for expressing models of complex physical systems. To simulate a model expressed in Modelica, it needs to be translated into executable code. For generating run-time efficient code, such a translation needs to employ algebraic formula manipulations. As the SPARK solver has been shown to be competitive for generating such code but currently cannot be used with the Modelica language, we report in this paper how SPARK's symbolic and numerical algorithms can be implemented in OpenModelica, an open-source implementation of a Modelica modeling and simulation environment. We also report benchmark results that show that for our air flow network simulation benchmark, the SPARK solver is competitive with Dymola, which is believed to provide the best solver for Modelica.
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.
Machné, Rainer; Finney, Andrew; Müller, Stefan; Lu, James; Widder, Stefanie; Flamm, Christoph
2006-06-01
The SBML ODE Solver Library (SOSlib) is a programming library for symbolic and numerical analysis of chemical reaction network models encoded in the Systems Biology Markup Language (SBML). It is written in ISO C and distributed under the open source LGPL license. The package employs libSBML structures for formula representation and associated functions to construct a system of ordinary differential equations, their Jacobian matrix and other derivatives. SUNDIALS' CVODES is incorporated for numerical integration and sensitivity analysis. Preliminary benchmarking results give a rough overview on the behavior of different tools and are discussed in the Supplementary Material. The native application program interface provides fine-grained interfaces to all internal data structures, symbolic operations and numerical routines, enabling the construction of very efficient analytic applications and hybrid or multi-scale solvers with interfaces to SBML and non SBML data sources. Optional modules based on XMGrace and Graphviz allow quick inspection of structure and dynamics. PMID:16527832
Steady potential solver for unsteady aerodynamic analyses
NASA Technical Reports Server (NTRS)
Hoyniak, Dan
1994-01-01
Development of a steady flow solver for use with LINFLO was the objective of this report. The solver must be compatible with LINFLO, be composed of composite mesh, and have transonic capability. The approaches used were: (1) steady flow potential equations written in nonconservative form; (2) Newton's Method; (3) implicit, least-squares, interpolation method to obtain finite difference equations; and (4) matrix inversion routines from LINFLO. This report was given during the NASA LeRC Workshop on Forced Response in Turbomachinery in August of 1993.
Multigrid in energy preconditioner for Krylov solvers
Slaybaugh, R.N.; Evans, T.M.; Davidson, G.G.; Wilson, P.P.H.
2013-06-01
We have added a new multigrid in energy (MGE) preconditioner to the Denovo discrete-ordinates radiation transport code. This preconditioner takes advantage of a new multilevel parallel decomposition. A multigroup Krylov subspace iterative solver that is decomposed in energy as well as space-angle forms the backbone of the transport solves in Denovo. The space-angle-energy decomposition facilitates scaling to hundreds of thousands of cores. The multigrid in energy preconditioner scales well in the energy dimension and significantly reduces the number of Krylov iterations required for convergence. This preconditioner is well-suited for use with advanced eigenvalue solvers such as Rayleigh Quotient Iteration and Arnoldi.
ODE System Solver W. Krylov Iteration & Rootfinding
Hindmarsh, Alan C.
1991-09-09
LSODKR is a new initial value ODE solver for stiff and nonstiff systems. It is a variant of the LSODPK and LSODE solvers, intended mainly for large stiff systems. The main differences between LSODKR and LSODE are the following: (a) for stiff systems, LSODKR uses a corrector iteration composed of Newton iteration and one of four preconditioned Krylov subspace iteration methods. The user must supply routines for the preconditioning operations, (b) Within the corrector iteration, LSODKR does automatic switching between functional (fixpoint) iteration and modified Newton iteration, (c) LSODKR includes the ability to find roots of given functions of the solution during the integration.
ODE System Solver W. Krylov Iteration & Rootfinding
Energy Science and Technology Software Center (ESTSC)
1991-09-09
LSODKR is a new initial value ODE solver for stiff and nonstiff systems. It is a variant of the LSODPK and LSODE solvers, intended mainly for large stiff systems. The main differences between LSODKR and LSODE are the following: (a) for stiff systems, LSODKR uses a corrector iteration composed of Newton iteration and one of four preconditioned Krylov subspace iteration methods. The user must supply routines for the preconditioning operations, (b) Within the corrector iteration,more » LSODKR does automatic switching between functional (fixpoint) iteration and modified Newton iteration, (c) LSODKR includes the ability to find roots of given functions of the solution during the integration.« less
Wave Speeds, Riemann Solvers and Artificial Viscosity
Rider, W.J.
1999-07-18
A common perspective on the numerical solution of the equation Euler equations for shock physics is examined. The common viewpoint is based upon the selection of nonlinear wavespeeds upon which the dissipation (implicit or explicit) is founded. This perspective shows commonality between Riemann solver based method (i.e. Godunov-type) and artificial viscosity (i.e. von Neumann-Richtmyer). As an example we derive an improved nonlinear viscous stabilization of a Richtmyer-Lax-Wendroff method. Additionally, we will define a form of classical artificial viscosity based upon the HLL Riemann solver.
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
NASA Astrophysics Data System (ADS)
Cusini, Matteo; Lukyanov, Alexander A.; Natvig, Jostein; Hajibeygi, Hadi
2015-10-01
We develop the first multiscale method for fully implicit (FIM) simulations of multiphase flow in porous media, namely CPR-MS method. Built on the FIM Jacobian matrix, the pressure system is obtained by employing a Constrained Pressure Residual (CPR) operator. Multiscale Finite Element (MSFE) and Finite Volume (MSFV) methods are then formulated algebraically to obtain efficient and accurate solutions of this pressure equation. The multiscale prediction stage (first-stage) is coupled with a corrector stage (second-stage) employed on the full system residual. The converged solution is enhanced through outer GMRES iterations preconditioned by these first and second stage operators. While the second-stage FIM stage is solved using a classical iterative solver, the multiscale stage is investigated in full detail. Several choices for fine-scale pre- and post-smoothing along with different choices of coarse-scale solvers are considered for a range of heterogeneous three-dimensional cases with capillarity and three-phase systems. The CPR-MS method is the first of its kind, and extends the applicability of the so-far developed multiscale methods (both MSFE and MSFV) to displacements with strong coupling terms.
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
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.
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
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).
Multiscale geometric modeling of macromolecules I: Cartesian representation
NASA Astrophysics Data System (ADS)
Xia, Kelin; Feng, Xin; Chen, Zhan; Tong, Yiying; Wei, Guo-Wei
2014-01-01
This paper focuses on the geometric modeling and computational algorithm development of biomolecular structures from two data sources: Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) in the Eulerian (or Cartesian) representation. Molecular surface (MS) contains non-smooth geometric singularities, such as cusps, tips and self-intersecting facets, which often lead to computational instabilities in molecular simulations, and violate the physical principle of surface free energy minimization. Variational multiscale surface definitions are proposed based on geometric flows and solvation analysis of biomolecular systems. Our approach leads to geometric and potential driven Laplace-Beltrami flows for biomolecular surface evolution and formation. The resulting surfaces are free of geometric singularities and minimize the total free energy of the biomolecular system. High order partial differential equation (PDE)-based nonlinear filters are employed for EMDB data processing. We show the efficacy of this approach in feature-preserving noise reduction. After the construction of protein multiresolution surfaces, we explore the analysis and characterization of surface morphology by using a variety of curvature definitions. Apart from the classical Gaussian curvature and mean curvature, maximum curvature, minimum curvature, shape index, and curvedness are also applied to macromolecular surface analysis for the first time. Our curvature analysis is uniquely coupled to the analysis of electrostatic surface potential, which is a by-product of our variational multiscale solvation models. As an expository investigation, we particularly emphasize the numerical algorithms and computational protocols for practical applications of the above multiscale geometric models. Such information may otherwise be scattered over the vast literature on this topic. Based on the curvature and electrostatic analysis from our multiresolution surfaces, we introduce a new concept, the
Multiscale geometric modeling of macromolecules I: Cartesian representation
Xia, Kelin; Feng, Xin; Chen, Zhan; Tong, Yiying; Wei, Guo-Wei
2014-01-15
This paper focuses on the geometric modeling and computational algorithm development of biomolecular structures from two data sources: Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) in the Eulerian (or Cartesian) representation. Molecular surface (MS) contains non-smooth geometric singularities, such as cusps, tips and self-intersecting facets, which often lead to computational instabilities in molecular simulations, and violate the physical principle of surface free energy minimization. Variational multiscale surface definitions are proposed based on geometric flows and solvation analysis of biomolecular systems. Our approach leads to geometric and potential driven Laplace–Beltrami flows for biomolecular surface evolution and formation. The resulting surfaces are free of geometric singularities and minimize the total free energy of the biomolecular system. High order partial differential equation (PDE)-based nonlinear filters are employed for EMDB data processing. We show the efficacy of this approach in feature-preserving noise reduction. After the construction of protein multiresolution surfaces, we explore the analysis and characterization of surface morphology by using a variety of curvature definitions. Apart from the classical Gaussian curvature and mean curvature, maximum curvature, minimum curvature, shape index, and curvedness are also applied to macromolecular surface analysis for the first time. Our curvature analysis is uniquely coupled to the analysis of electrostatic surface potential, which is a by-product of our variational multiscale solvation models. As an expository investigation, we particularly emphasize the numerical algorithms and computational protocols for practical applications of the above multiscale geometric models. Such information may otherwise be scattered over the vast literature on this topic. Based on the curvature and electrostatic analysis from our multiresolution surfaces, we introduce a new concept, the
Multiscale geometric modeling of macromolecules I: Cartesian representation
Xia, Kelin; Feng, Xin; Chen, Zhan; Tong, Yiying; Wei, Guo Wei
2013-01-01
This paper focuses on the geometric modeling and computational algorithm development of biomolecular structures from two data sources: Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) in the Eulerian (or Cartesian) representation. Molecular surface (MS) contains non-smooth geometric singularities, such as cusps, tips and self-intersecting facets, which often lead to computational instabilities in molecular simulations, and violate the physical principle of surface free energy minimization. Variational multiscale surface definitions are proposed based on geometric flows and solvation analysis of biomolecular systems. Our approach leads to geometric and potential driven Laplace-Beltrami flows for biomolecular surface evolution and formation. The resulting surfaces are free of geometric singularities and minimize the total free energy of the biomolecular system. High order partial differential equation (PDE)-based nonlinear filters are employed for EMDB data processing. We show the efficacy of this approach in feature-preserving noise reduction. After the construction of protein multiresolution surfaces, we explore the analysis and characterization of surface morphology by using a variety of curvature definitions. Apart from the classical Gaussian curvature and mean curvature, maximum curvature, minimum curvature, shape index, and curvedness are also applied to macromolecular surface analysis for the first time. Our curvature analysis is uniquely coupled to the analysis of electrostatic surface potential, which is a by-product of our variational multiscale solvation models. As an expository investigation, we particularly emphasize the numerical algorithms and computational protocols for practical applications of the above multiscale geometric models. Such information may otherwise be scattered over the vast literature on this topic. Based on the curvature and electrostatic analysis from our multiresolution surfaces, we introduce a new concept, the
Multiscale geometric modeling of macromolecules I: Cartesian representation.
Xia, Kelin; Feng, Xin; Chen, Zhan; Tong, Yiying; Wei, Guo Wei
2014-01-01
This paper focuses on the geometric modeling and computational algorithm development of biomolecular structures from two data sources: Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) in the Eulerian (or Cartesian) representation. Molecular surface (MS) contains non-smooth geometric singularities, such as cusps, tips and self-intersecting facets, which often lead to computational instabilities in molecular simulations, and violate the physical principle of surface free energy minimization. Variational multiscale surface definitions are proposed based on geometric flows and solvation analysis of biomolecular systems. Our approach leads to geometric and potential driven Laplace-Beltrami flows for biomolecular surface evolution and formation. The resulting surfaces are free of geometric singularities and minimize the total free energy of the biomolecular system. High order partial differential equation (PDE)-based nonlinear filters are employed for EMDB data processing. We show the efficacy of this approach in feature-preserving noise reduction. After the construction of protein multiresolution surfaces, we explore the analysis and characterization of surface morphology by using a variety of curvature definitions. Apart from the classical Gaussian curvature and mean curvature, maximum curvature, minimum curvature, shape index, and curvedness are also applied to macromolecular surface analysis for the first time. Our curvature analysis is uniquely coupled to the analysis of electrostatic surface potential, which is a by-product of our variational multiscale solvation models. As an expository investigation, we particularly emphasize the numerical algorithms and computational protocols for practical applications of the above multiscale geometric models. Such information may otherwise be scattered over the vast literature on this topic. Based on the curvature and electrostatic analysis from our multiresolution surfaces, we introduce a new concept, the
NASA Astrophysics Data System (ADS)
Bayona, V.; Flyer, N.; Lucas, G. M.; Baumgaertner, A. J. G.
2015-10-01
A numerical model based on radial basis function-generated finite differences (RBF-FD) is developed for simulating the global electric circuit (GEC) within the Earth's atmosphere, represented by a 3-D variable coefficient linear elliptic partial differential equation (PDE) in a spherically shaped volume with the lower boundary being the Earth's topography and the upper boundary a sphere at 60 km. To our knowledge, this is (1) the first numerical model of the GEC to combine the Earth's topography with directly approximating the differential operators in 3-D space and, related to this, (2) the first RBF-FD method to use irregular 3-D stencils for discretization to handle the topography. It benefits from the mesh-free nature of RBF-FD, which is especially suitable for modeling high-dimensional problems with irregular boundaries. The RBF-FD elliptic solver proposed here makes no limiting assumptions on the spatial variability of the coefficients in the PDE (i.e., the conductivity profile), the right hand side forcing term of the PDE (i.e., distribution of current sources) or the geometry of the lower boundary.
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.
Multiscale Fluctuation Analysis Revisited
NASA Astrophysics Data System (ADS)
Struzik, Zbigniew R.; Kiyono, Ken; Yamamoto, Yoshiharu
2007-07-01
Ubiquitous non-Gaussianity of the probability density of (time-series) fluctuations in many real world phenomena has been known and modelled extensively in recent years. Similarly, the analysis of (multi)scaling properties of (fluctuations in) complex systems has become a standard way of addressing unknown complexity. Yet the combined analysis and modelling of multiscale behaviour of probability density — multiscale PDF analysis — has only recently been proposed for the analysis of time series arising in complex systems, such as the cardiac neuro-regulatory system, financial markets or hydrodynamic turbulence. This relatively new technique has helped significantly to expand the previously obtained insights into the phenomena addressed. In particular, it has helped to identify a novel class of scale invariant behaviour of the multiscale PDF in healthy heart rate regulation during daily activity and in a market system undergoing crash dynamics. This kind of invariance reflects invariance of the system under renormalisation and resembles behaviour at criticality of a system undergoing continuous phase transition — indeed in both phenomena, such phase transition behaviour has been revealed. While the precise mechanism underlying invariance of the PDF under system renormalisation of both systems discussed is not to date understood, there is an intimate link between the non-Gaussian PDF characteristics and the persistent invariant correlation structure emerging between fluctuations across scale and time.
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
Multiscale Modeling of Cavitating Bubbly Flows
NASA Astrophysics Data System (ADS)
Ma, J.; Hsiao, C.-T.; Chahine, G. L.
2013-03-01
Modeling of cavitating bubbly flows is challenging due to the wide range of characteristic lengths of the physics at play: from micrometers (e.g., bubble nuclei radius) to meters (e.g., propeller diameter or sheet cavity length). To address this, we present here a multiscale approach which integrates a Discrete Bubble Model for dispersed microbubbles and a level set N-S solver for macro cavities, along with a mesoscale transition model to bridge the two. This approach was implemented in 3DYNAFScopyright and used to simulate sheet-to-cloud cavitation over a hydrofoil. The hybrid model captures well the full cavitation process starting from free field nuclei and nucleation from solid surfaces. In low pressure region of the foil small nuclei are seen to grow large and eventually merge to form a large scale sheet cavity. A reentrant jet forms under the cavity, travels upstream, and breaks it, resulting in a bubble cloud of a large amount of microbubbles as the broken pockets shrink and travel downstream. This is in good agreement with experimental observations based of sheet lengths and frequency of lift force oscillation. DOE-SBIR, ONR (monitored by Dr. Ki-Han Kim)
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
Verifying a Local Generic Solver in Coq
NASA Astrophysics Data System (ADS)
Hofmann, Martin; Karbyshev, Aleksandr; Seidl, Helmut
Fixpoint engines are the core components of program analysis tools and compilers. If these tools are to be trusted, special attention should be paid also to the correctness of such solvers. In this paper we consider the local generic fixpoint solver RLD which can be applied to constraint systems {x}sqsupseteq fx,{x}in V, over some lattice {D} where the right-hand sides f x are given as arbitrary functions implemented in some specification language. The verification of this algorithm is challenging, because it uses higher-order functions and relies on side effects to track variable dependences as they are encountered dynamically during fixpoint iterations. Here, we present a correctness proof of this algorithm which has been formalized by means of the interactive proof assistant Coq.
Aleph Field Solver Challenge Problem Results Summary.
Hooper, Russell; Moore, Stan Gerald
2015-01-01
Aleph models continuum electrostatic and steady and transient thermal fields using a finite-element method. Much work has gone into expanding the core solver capability to support enriched mod- eling consisting of multiple interacting fields, special boundary conditions and two-way interfacial coupling with particles modeled using Aleph's complementary particle-in-cell capability. This report provides quantitative evidence for correct implementation of Aleph's field solver via order- of-convergence assessments on a collection of problems of increasing complexity. It is intended to provide Aleph with a pedigree and to establish a basis for confidence in results for more challeng- ing problems important to Sandia's mission that Aleph was specifically designed to address.
Srinath Vadlamani; Scott Kruger; Travis Austin
2008-06-19
Extended magnetohydrodynamic (MHD) codes are used to model the large, slow-growing instabilities that are projected to limit the performance of International Thermonuclear Experimental Reactor (ITER). The multiscale nature of the extended MHD equations requires an implicit approach. The current linear solvers needed for the implicit algorithm scale poorly because the resultant matrices are so ill-conditioned. A new solver is needed, especially one that scales to the petascale. The most successful scalable parallel processor solvers to date are multigrid solvers. Applying multigrid techniques to a set of equations whose fundamental modes are dispersive waves is a promising solution to CEMM problems. For the Phase 1, we implemented multigrid preconditioners from the HYPRE project of the Center for Applied Scientific Computing at LLNL via PETSc of the DOE SciDAC TOPS for the real matrix systems of the extended MHD code NIMROD which is a one of the primary modeling codes of the OFES-funded Center for Extended Magnetohydrodynamic Modeling (CEMM) SciDAC. We implemented the multigrid solvers on the fusion test problem that allows for real matrix systems with success, and in the process learned about the details of NIMROD data structures and the difficulties of inverting NIMROD operators. The further success of this project will allow for efficient usage of future petascale computers at the National Leadership Facilities: Oak Ridge National Laboratory, Argonne National Laboratory, and National Energy Research Scientific Computing Center. The project will be a collaborative effort between computational plasma physicists and applied mathematicians at Tech-X Corporation, applied mathematicians Front Range Scientific Computations, Inc. (who are collaborators on the HYPRE project), and other computational plasma physicists involved with the CEMM project.
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
Domain decomposition for the SPN solver MINOS
Jamelot, Erell; Baudron, Anne-Marie; Lautard, Jean-Jacques
2012-07-01
In this article we present a domain decomposition method for the mixed SPN equations, discretized with Raviart-Thomas-Nedelec finite elements. This domain decomposition is based on the iterative Schwarz algorithm with Robin interface conditions to handle communications. After having described this method, we give details on how to optimize the convergence. Finally, we give some numerical results computed in a realistic 3D domain. The computations are done with the MINOS solver of the APOLLO3 (R) code. (authors)
A perspective on unstructured grid flow solvers
NASA Technical Reports Server (NTRS)
Venkatakrishnan, V.
1995-01-01
This survey paper assesses the status of compressible Euler and Navier-Stokes solvers on unstructured grids. Different spatial and temporal discretization options for steady and unsteady flows are discussed. The integration of these components into an overall framework to solve practical problems is addressed. Issues such as grid adaptation, higher order methods, hybrid discretizations and parallel computing are briefly discussed. Finally, some outstanding issues and future research directions are presented.
Perfectly matched multiscale simulations
NASA Astrophysics Data System (ADS)
Liu, Xiaohu
In this dissertation, the Perfectly Matched Multiscale Simulations (PMMS), a method of discrete-to-continuum multiscale scale computation is studied, revised and extended. In particular, the role of the Perfectly Matched Layer (PML) in PMMS is carefully studied. We show that instead of following the PML theory of continuum, the PML equations of motion in PMMS can be derived by stretching the inter-atomic equilibrium distance. As a result, the displacement solution in the PML region has the desired spatial damping property. It is also shown that the dispersion relationship in the PML region is different from the one in the original lattice. And a reflection coefficient is computed. We also incorporate the local Quasicontinuum (QC) theory with the cohesive Finite Element (FE) method to form a cohesive QC scheme which can deal with arbitrary discontinuities. This idea is built into the PMMS method to simulate a moving screw dislocation. The second part of the dissertation is to extend PMMS to finite temperature. A multiscale thermodynamics is proposed based on the idea of distributed coarse scale thermostats. Each coarse scale node is viewed as a thermostat and has part of atoms associated with it. The atomic motion at the fine scale level is governed by the Nose-Hoover dynamics. At the coarse scale, the expression of a coarse-grained Helmholtz free energy is derived and coupled thermo-mechanical equations are formulated based on it. With the proposed framework, the finite-temperature PMMS method is capable of simulating problems with drastic temperature change. Several numerical examples are computed to validate the method.
Multiscale methods for nanoengineering
NASA Astrophysics Data System (ADS)
Jolley, Kenny
This project is presented in two sections. Two different multiscale models are developed in order to increase the computational speed of two well known atomistic algorithms, Molecular Dynamics (MD) and Kinetic Monte Carlo (KMC). In Section I, the MD method is introduced. Following this, a multiscale method of linking an MD simulation of heat conduction to a finite element (FE) simulation is presented. The method is simple to implement into a conventional MD code and is independent of the atomistic model employed. This bridge between the FE and MD simulations works by ensuring that energy is conserved across the FE/MD boundary. The multiscale simulation allows for the investigation of large systems which are beyond the range of MD. The method is tested extensively in the steady state and transient regimes, and is shown to agree with well with large scale MD and FE simulations. Furthermore, the method removes the artificial boundary effects due to the thermostats and hence allows exact temperatures and temperature gradients to be imposed on to an MD simulation. This allows for better study of temperature gradients on crystal defects etc.. In Section II, the KMC method is introduced. A continuum model for the KMC method is presented and compared to the standard KMC model of surface diffusion. This method replaces the many discrete back and forth atom jumps performed by a standard KMC algorithm with a single flux that can evolve in time. Elastic strain is then incorporated into both algorithms and used to simulate atom deposition upon a substrate by Molecular Beam Epitaxy. Quantum dot formation due to a mismatch in the lattice spacing between a substrate and a deposited film is readily observed in both models. Furthermore, by depositing alternating layers of substrate and deposit, self-organised quantum dot super-lattices are observed in both models..
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
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
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
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.
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
MILAMIN 2 - Fast MATLAB FEM solver
NASA Astrophysics Data System (ADS)
Dabrowski, Marcin; Krotkiewski, Marcin; Schmid, Daniel W.
2013-04-01
MILAMIN is a free and efficient MATLAB-based two-dimensional FEM solver utilizing unstructured meshes [Dabrowski et al., G-cubed (2008)]. The code consists of steady-state thermal diffusion and incompressible Stokes flow solvers implemented in approximately 200 lines of native MATLAB code. The brevity makes the code easily customizable. An important quality of MILAMIN is speed - it can handle millions of nodes within minutes on one CPU core of a standard desktop computer, and is faster than many commercial solutions. The new MILAMIN 2 allows three-dimensional modeling. It is designed as a set of functional modules that can be used as building blocks for efficient FEM simulations using MATLAB. The utilities are largely implemented as native MATLAB functions. For performance critical parts we use MUTILS - a suite of compiled MEX functions optimized for shared memory multi-core computers. The most important features of MILAMIN 2 are: 1. Modular approach to defining, tracking, and discretizing the geometry of the model 2. Interfaces to external mesh generators (e.g., Triangle, Fade2d, T3D) and mesh utilities (e.g., element type conversion, fast point location, boundary extraction) 3. Efficient computation of the stiffness matrix for a wide range of element types, anisotropic materials and three-dimensional problems 4. Fast global matrix assembly using a dedicated MEX function 5. Automatic integration rules 6. Flexible prescription (spatial, temporal, and field functions) and efficient application of Dirichlet, Neuman, and periodic boundary conditions 7. Treatment of transient and non-linear problems 8. Various iterative and multi-level solution strategies 9. Post-processing tools (e.g., numerical integration) 10. Visualization primitives using MATLAB, and VTK export functions We provide a large number of examples that show how to implement a custom FEM solver using the MILAMIN 2 framework. The examples are MATLAB scripts of increasing complexity that address a given
Vencels, Juris; Delzanno, Gian Luca; Johnson, Alec; Peng, Ivy Bo; Laure, Erwin; Markidis, Stefano
2015-06-01
A spectral method for kinetic plasma simulations based on the expansion of the velocity distribution function in a variable number of Hermite polynomials is presented. The method is based on a set of non-linear equations that is solved to determine the coefficients of the Hermite expansion satisfying the Vlasov and Poisson equations. In this paper, we first show that this technique combines the fluid and kinetic approaches into one framework. Second, we present an adaptive strategy to increase and decrease the number of Hermite functions dynamically during the simulation. The technique is applied to the Landau damping and two-stream instabilitymore » test problems. Performance results show 21% and 47% saving of total simulation time in the Landau and two-stream instability test cases, respectively.« less
Vencels, Juris; Delzanno, Gian Luca; Johnson, Alec; Peng, Ivy Bo; Laure, Erwin; Markidis, Stefano
2015-06-01
A spectral method for kinetic plasma simulations based on the expansion of the velocity distribution function in a variable number of Hermite polynomials is presented. The method is based on a set of non-linear equations that is solved to determine the coefficients of the Hermite expansion satisfying the Vlasov and Poisson equations. In this paper, we first show that this technique combines the fluid and kinetic approaches into one framework. Second, we present an adaptive strategy to increase and decrease the number of Hermite functions dynamically during the simulation. The technique is applied to the Landau damping and two-stream instability test problems. Performance results show 21% and 47% saving of total simulation time in the Landau and two-stream instability test cases, respectively.
Multiscale modeling of chalcogenides
NASA Astrophysics Data System (ADS)
Mauro, John C.
Chalcogenide glasses exhibit unique properties applicable to a wide range of fields, including electrical and optical switching and the transmission of infrared radiation. In this thesis, we adopt a hierarchical multiscale modeling approach to investigate the fundamental physics of chalcogenide systems. Our multiscale modeling begins in Part I at the quantum mechanical level, where we use the highly accurate Moller-Plesset perturbation technique to derive interaction potentials for elemental and heterogeneous chalcogenide systems. The resulting potentials consist of two-, three-, and effective four-body terms. In Part II, we use these ab initio potentials in classical Monte Carlo simulations to investigate the structure of chalcogenide glasses. We discuss our simulation results in relation to the Phillips model of topological constraints, which predicts critical behavior in chalcogenide systems as a function of average coordination number. Finally, in Part III we address the issue of glass transition range behavior. After reviewing previous models of the glass transition, we derive a new model based on nonequilibrium statistical mechanics and an energy landscape formalism. The new model requires as input a description of inherent structure energies and the transition energies between these structures. To address this issue, we derive an eigenvector-following technique for mapping a multidimensional potential energy landscape. This technique is then extended for application to enthalpy landscapes. Our model will enable the first-ever calculation of glass transition behavior based on only ab initio physics.
MULTISCALE PHENOMENA IN MATERIALS
A. BISHOP
2000-09-01
This project developed and supported a technology base in nonequilibrium phenomena underpinning fundamental issues in condensed matter and materials science, and applied this technology to selected problems. In this way the increasingly sophisticated synthesis and characterization available for classes of complex electronic and structural materials provided a testbed for nonlinear science, while nonlinear and nonequilibrium techniques helped advance our understanding of the scientific principles underlying the control of material microstructure, their evolution, fundamental to macroscopic functionalities. The project focused on overlapping areas of emerging thrusts and programs in the Los Alamos materials community for which nonlinear and nonequilibrium approaches will have decisive roles and where productive teamwork among elements of modeling, simulations, synthesis, characterization and applications could be anticipated--particularly multiscale and nonequilibrium phenomena, and complex matter in and between fields of soft, hard and biomimetic materials. Principal topics were: (i) Complex organic and inorganic electronic materials, including hard, soft and biomimetic materials, self-assembly processes and photophysics; (ii) Microstructure and evolution in multiscale and hierarchical materials, including dynamic fracture and friction, dislocation and large-scale deformation, metastability, and inhomogeneity; and (iii) Equilibrium and nonequilibrium phases and phase transformations, emphasizing competing interactions, frustration, landscapes, glassy and stochastic dynamics, and energy focusing.
Multiscale Cloud System Modeling
NASA Technical Reports Server (NTRS)
Tao, Wei-Kuo; Moncrieff, Mitchell W.
2009-01-01
The central theme of this paper is to describe how cloud system resolving models (CRMs) of grid spacing approximately 1 km have been applied to various important problems in atmospheric science across a wide range of spatial and temporal scales and how these applications relate to other modeling approaches. A long-standing problem concerns the representation of organized precipitating convective cloud systems in weather and climate models. Since CRMs resolve the mesoscale to large scales of motion (i.e., 10 km to global) they explicitly address the cloud system problem. By explicitly representing organized convection, CRMs bypass restrictive assumptions associated with convective parameterization such as the scale gap between cumulus and large-scale motion. Dynamical models provide insight into the physical mechanisms involved with scale interaction and convective organization. Multiscale CRMs simulate convective cloud systems in computational domains up to global and have been applied in place of contemporary convective parameterizations in global models. Multiscale CRMs pose a new challenge for model validation, which is met in an integrated approach involving CRMs, operational prediction systems, observational measurements, and dynamical models in a new international project: the Year of Tropical Convection, which has an emphasis on organized tropical convection and its global effects.
Multiscale reactive molecular dynamics
NASA Astrophysics Data System (ADS)
Knight, Chris; Lindberg, Gerrick E.; Voth, Gregory A.
2012-12-01
Many processes important to chemistry, materials science, and biology cannot be described without considering electronic and nuclear-level dynamics and their coupling to slower, cooperative motions of the system. These inherently multiscale problems require computationally efficient and accurate methods to converge statistical properties. In this paper, a method is presented that uses data directly from condensed phase ab initio simulations to develop reactive molecular dynamics models that do not require predefined empirical functions. Instead, the interactions used in the reactive model are expressed as linear combinations of interpolating functions that are optimized by using a linear least-squares algorithm. One notable benefit of the procedure outlined here is the capability to minimize the number of parameters requiring nonlinear optimization. The method presented can be generally applied to multiscale problems and is demonstrated by generating reactive models for the hydrated excess proton and hydroxide ion based directly on condensed phase ab initio molecular dynamics simulations. The resulting models faithfully reproduce the water-ion structural properties and diffusion constants from the ab initio simulations. Additionally, the free energy profiles for proton transfer, which is sensitive to the structural diffusion of both ions in water, are reproduced. The high fidelity of these models to ab initio simulations will permit accurate modeling of general chemical reactions in condensed phase systems with computational efficiency orders of magnitudes greater than currently possible with ab initio simulation methods, thus facilitating a proper statistical sampling of the coupling to slow, large-scale motions of the system.
Multiscale reactive molecular dynamics
Knight, Chris; Lindberg, Gerrick E.; Voth, Gregory A.
2012-01-01
Many processes important to chemistry, materials science, and biology cannot be described without considering electronic and nuclear-level dynamics and their coupling to slower, cooperative motions of the system. These inherently multiscale problems require computationally efficient and accurate methods to converge statistical properties. In this paper, a method is presented that uses data directly from condensed phase ab initio simulations to develop reactive molecular dynamics models that do not require predefined empirical functions. Instead, the interactions used in the reactive model are expressed as linear combinations of interpolating functions that are optimized by using a linear least-squares algorithm. One notable benefit of the procedure outlined here is the capability to minimize the number of parameters requiring nonlinear optimization. The method presented can be generally applied to multiscale problems and is demonstrated by generating reactive models for the hydrated excess proton and hydroxide ion based directly on condensed phase ab initio molecular dynamics simulations. The resulting models faithfully reproduce the water-ion structural properties and diffusion constants from the ab initio simulations. Additionally, the free energy profiles for proton transfer, which is sensitive to the structural diffusion of both ions in water, are reproduced. The high fidelity of these models to ab initio simulations will permit accurate modeling of general chemical reactions in condensed phase systems with computational efficiency orders of magnitudes greater than currently possible with ab initio simulation methods, thus facilitating a proper statistical sampling of the coupling to slow, large-scale motions of the system. PMID:23249062
Multiscale simulation of ideal mixtures using smoothed dissipative particle dynamics.
Petsev, Nikolai D; Leal, L Gary; Shell, M Scott
2016-02-28
Smoothed dissipative particle dynamics (SDPD) [P. Español and M. Revenga, Phys. Rev. E 67, 026705 (2003)] is a thermodynamically consistent particle-based continuum hydrodynamics solver that features scale-dependent thermal fluctuations. We obtain a new formulation of this stochastic method for ideal two-component mixtures through a discretization of the advection-diffusion equation with thermal noise in the concentration field. The resulting multicomponent approach is consistent with the interpretation of the SDPD particles as moving volumes of fluid and reproduces the correct fluctuations and diffusion dynamics. Subsequently, we provide a general multiscale multicomponent SDPD framework for simulations of molecularly miscible systems spanning length scales from nanometers to the non-fluctuating continuum limit. This approach reproduces appropriate equilibrium properties and is validated with simulation of simple one-dimensional diffusion across multiple length scales. PMID:26931689
Multiscale simulation of ideal mixtures using smoothed dissipative particle dynamics
NASA Astrophysics Data System (ADS)
Petsev, Nikolai D.; Leal, L. Gary; Shell, M. Scott
2016-02-01
Smoothed dissipative particle dynamics (SDPD) [P. Español and M. Revenga, Phys. Rev. E 67, 026705 (2003)] is a thermodynamically consistent particle-based continuum hydrodynamics solver that features scale-dependent thermal fluctuations. We obtain a new formulation of this stochastic method for ideal two-component mixtures through a discretization of the advection-diffusion equation with thermal noise in the concentration field. The resulting multicomponent approach is consistent with the interpretation of the SDPD particles as moving volumes of fluid and reproduces the correct fluctuations and diffusion dynamics. Subsequently, we provide a general multiscale multicomponent SDPD framework for simulations of molecularly miscible systems spanning length scales from nanometers to the non-fluctuating continuum limit. This approach reproduces appropriate equilibrium properties and is validated with simulation of simple one-dimensional diffusion across multiple length scales.
Approximate Riemann solvers for the Godunov SPH (GSPH)
NASA Astrophysics Data System (ADS)
Puri, Kunal; Ramachandran, Prabhu
2014-08-01
The Godunov Smoothed Particle Hydrodynamics (GSPH) method is coupled with non-iterative, approximate Riemann solvers for solutions to the compressible Euler equations. The use of approximate solvers avoids the expensive solution of the non-linear Riemann problem for every interacting particle pair, as required by GSPH. In addition, we establish an equivalence between the dissipative terms of GSPH and the signal based SPH artificial viscosity, under the restriction of a class of approximate Riemann solvers. This equivalence is used to explain the anomalous “wall heating” experienced by GSPH and we provide some suggestions to overcome it. Numerical tests in one and two dimensions are used to validate the proposed Riemann solvers. A general SPH pairing instability is observed for two-dimensional problems when using unequal mass particles. In general, Ducowicz Roe's and HLLC approximate Riemann solvers are found to be suitable replacements for the iterative Riemann solver in the original GSPH scheme.
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
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
Performance of distributed multiscale simulations
Borgdorff, J.; Ben Belgacem, M.; Bona-Casas, C.; Fazendeiro, L.; Groen, D.; Hoenen, O.; Mizeranschi, A.; Suter, J. L.; Coster, D.; Coveney, P. V.; Dubitzky, W.; Hoekstra, A. G.; Strand, P.; Chopard, B.
2014-01-01
Multiscale simulations model phenomena across natural scales using monolithic or component-based code, running on local or distributed resources. In this work, we investigate the performance of distributed multiscale computing of component-based models, guided by six multiscale applications with different characteristics and from several disciplines. Three modes of distributed multiscale computing are identified: supplementing local dependencies with large-scale resources, load distribution over multiple resources, and load balancing of small- and large-scale resources. We find that the first mode has the apparent benefit of increasing simulation speed, and the second mode can increase simulation speed if local resources are limited. Depending on resource reservation and model coupling topology, the third mode may result in a reduction of resource consumption. PMID:24982258
Robust parallel iterative solvers for linear and least-squares problems, Final Technical Report
Saad, Yousef
2014-01-16
The primary goal of this project is to study and develop robust iterative methods for solving linear systems of equations and least squares systems. The focus of the Minnesota team is on algorithms development, robustness issues, and on tests and validation of the methods on realistic problems. 1. The project begun with an investigation on how to practically update a preconditioner obtained from an ILU-type factorization, when the coefficient matrix changes. 2. We investigated strategies to improve robustness in parallel preconditioners in a specific case of a PDE with discontinuous coefficients. 3. We explored ways to adapt standard preconditioners for solving linear systems arising from the Helmholtz equation. These are often difficult linear systems to solve by iterative methods. 4. We have also worked on purely theoretical issues related to the analysis of Krylov subspace methods for linear systems. 5. We developed an effective strategy for performing ILU factorizations for the case when the matrix is highly indefinite. The strategy uses shifting in some optimal way. The method was extended to the solution of Helmholtz equations by using complex shifts, yielding very good results in many cases. 6. We addressed the difficult problem of preconditioning sparse systems of equations on GPUs. 7. A by-product of the above work is a software package consisting of an iterative solver library for GPUs based on CUDA. This was made publicly available. It was the first such library that offers complete iterative solvers for GPUs. 8. We considered another form of ILU which blends coarsening techniques from Multigrid with algebraic multilevel methods. 9. We have released a new version on our parallel solver - called pARMS [new version is version 3]. As part of this we have tested the code in complex settings - including the solution of Maxwell and Helmholtz equations and for a problem of crystal growth.10. As an application of polynomial preconditioning we considered the
DPS--a computerised diagnostic problem solver.
Bartos, P; Gyárfas, F; Popper, M
1982-01-01
The paper contains a short description of the DPS system which is a computerized diagnostic problem solver. The system is under development of the Research Institute of Medical Bionics in Bratislava, Czechoslovakia. Its underlying philosophy yields from viewing the diagnostic process as process of cognitive problem solving. The implementation of the system is based on the methods of Artificial Intelligence and utilisation of production systems and frame theory should be noted in this context. Finally a list of program modules and their characterisation is presented. PMID:6811229
Updates to the NEQAIR Radiation Solver
NASA Technical Reports Server (NTRS)
Cruden, Brett A.; Brandis, Aaron M.
2014-01-01
The NEQAIR code is one of the original heritage solvers for radiative heating prediction in aerothermal environments, and is still used today for mission design purposes. This paper discusses the implementation of the first major revision to the NEQAIR code in the last five years, NEQAIR v14.0. The most notable features of NEQAIR v14.0 are the parallelization of the radiation computation, reducing runtimes by about 30×, and the inclusion of mid-wave CO2 infrared radiation.
Input-output-controlled nonlinear equation solvers
NASA Technical Reports Server (NTRS)
Padovan, Joseph
1988-01-01
To upgrade the efficiency and stability of the successive substitution (SS) and Newton-Raphson (NR) schemes, the concept of input-output-controlled solvers (IOCS) is introduced. By employing the formal properties of the constrained version of the SS and NR schemes, the IOCS algorithm can handle indefiniteness of the system Jacobian, can maintain iterate monotonicity, and provide for separate control of load incrementation and iterate excursions, as well as having other features. To illustrate the algorithmic properties, the results for several benchmark examples are presented. These define the associated numerical efficiency and stability of the IOCS.
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.
The Magnetospheric Multiscale Constellation
NASA Astrophysics Data System (ADS)
Tooley, C. R.; Black, R. K.; Robertson, B. P.; Stone, J. M.; Pope, S. E.; Davis, G. T.
2016-03-01
The Magnetospheric Multiscale (MMS) mission is the fourth mission of the Solar Terrestrial Probe (STP) program of the National Aeronautics and Space Administration (NASA). The MMS mission was launched on March 12, 2015. The MMS mission consists of four identically instrumented spin-stabilized observatories which are flown in formation to perform the first definitive study of magnetic reconnection in space. The MMS mission was presented with numerous technical challenges, including the simultaneous construction and launch of four identical large spacecraft with 100 instruments total, stringent electromagnetic cleanliness requirements, closed-loop precision maneuvering and pointing of spinning flexible spacecraft, on-board GPS based orbit determination far above the GPS constellation, and a flight dynamics design that enables formation flying with separation distances as small as 10 km. This paper describes the overall mission design and presents an overview of the design, testing, and early on-orbit operation of the spacecraft systems and instrument suite.
MULTISCALE THERMOHYDROLOGIC MODEL
T.A. Buscheck
2001-12-21
The purpose of the Multiscale Thermohydrologic Model (MSTHM) is to describe the thermohydrologic evolution of the near-field environment (NFE) and engineered barrier system (EBS) throughout the potential high-level nuclear waste repository at Yucca Mountain for a particular engineering design (CRWMS M&O 2000c). The process-level model will provide thermohydrologic (TH) information and data (such as in-drift temperature, relative humidity, liquid saturation, etc.) for use in other technical products. This data is provided throughout the entire repository area as a function of time. The MSTHM couples the Smeared-heat-source Drift-scale Thermal-conduction (SDT), Line-average-heat-source Drift-scale Thermohydrologic (LDTH), Discrete-heat-source Drift-scale Thermal-conduction (DDT), and Smeared-heat-source Mountain-scale Thermal-conduction (SMT) submodels such that the flow of water and water vapor through partially-saturated fractured rock is considered. The MSTHM accounts for 3-D drift-scale and mountain-scale heat flow, repository-scale variability of stratigraphy and infiltration flux, and waste package (WP)-to-WP variability in heat output from WPs. All submodels use the nonisothermal unsaturated-saturated flow and transport (NUFT) simulation code. The MSTHM is implemented in several data-processing steps. The four major steps are: (1) submodel input-file preparation, (2) execution of the four submodel families with the use of the NUFT code, (3) execution of the multiscale thermohydrologic abstraction code (MSTHAC), and (4) binning and post-processing (i.e., graphics preparation) of the output from MSTHAC. Section 6 describes the MSTHM in detail. The objectives of this Analyses and Model Report (AMR) are to investigate near field (NF) and EBS thermohydrologic environments throughout the repository area at various evolution periods, and to provide TH data that may be used in other process model reports.
On the relationship between ODE solvers and iterative solvers for linear equations
Lorber, A.; Joubert, W.; Carey, G.F.
1994-12-31
The connection between the solution of linear systems of equations by both iterative methods and explicit time stepping techniques is investigated. Based on the similarities, a suite of Runge-Kutta time integration schemes with extended stability domains are developed using Chebyshev iteration polynomials. These Runge-Kutta schemes are applied to linear and non-linear systems arising from the numerical solution of PDE`s containing either physical or artificial transient terms. Specifically, the solutions of model linear convection and convection-diffusion equations are presented, as well as the solution of a representative non-linear Navier-Stokes fluid flow problem. Included are results of parallel computations.
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
Comparison of electromagnetic solvers for antennas mounted on vehicles
NASA Astrophysics Data System (ADS)
Mocker, M. S. L.; Hipp, S.; Spinnler, F.; Tazi, H.; Eibert, T. F.
2015-11-01
An electromagnetic solver comparison for various use cases of antennas mounted on vehicles is presented. For this purpose, several modeling approaches, called transient, frequency and integral solver, including the features fast resonant method and autoregressive filter, offered by CST MWS, are investigated. The solvers and methods are compared for a roof antenna itself, a simplified vehicle, a roof including a panorama window and a combination of antenna and vehicle. With these examples, the influence of different materials, data formats and parameters such as size and complexity are investigated. Also, the necessary configurations for the mesh and the solvers are described.
Frequency-domain elastic full-waveform multiscale inversion method based on dual-level parallelism
NASA Astrophysics Data System (ADS)
Li, Yuan-Yuan; Li, Zhen-Chun; Zhang, Kai; Zhang, Xuan
2015-12-01
The complexity of an elastic wavefield increases the nonlinearity of inversion. To some extent, multiscale inversion decreases the nonlinearity of inversion and prevents it from falling into local extremes. A multiscale strategy based on the simultaneous use of frequency groups and layer stripping method based on damped wave field improves the stability of inversion. A dual-level parallel algorithm is then used to decrease the computational cost and improve practicability. The seismic wave modeling of a single frequency and inversion in a frequency group are computed in parallel by multiple nodes based on multifrontal massively parallel sparse direct solver and MPI. Numerical tests using an overthrust model show that the proposed inversion algorithm can effectively improve the stability and accuracy of inversion by selecting the appropriate inversion frequency and damping factor in lowfrequency seismic data.
Sen, Oishik; Davis, Sean; Jacobs, Gustaaf; Udaykumar, H.S.
2015-08-01
The effectiveness of several metamodeling techniques, viz. the Polynomial Stochastic Collocation method, Adaptive Stochastic Collocation method, a Radial Basis Function Neural Network, a Kriging Method and a Dynamic Kriging Method is evaluated. This is done with the express purpose of using metamodels to bridge scales between micro- and macro-scale models in a multi-scale multimaterial simulation. The rate of convergence of the error when used to reconstruct hypersurfaces of known functions is studied. For sufficiently large number of training points, Stochastic Collocation methods generally converge faster than the other metamodeling techniques, while the DKG method converges faster when the number of input points is less than 100 in a two-dimensional parameter space. Because the input points correspond to computationally expensive micro/meso-scale computations, the DKG is favored for bridging scales in a multi-scale solver.
A multiphysics and multiscale software environment for modeling astrophysical systems
NASA Astrophysics Data System (ADS)
Portegies Zwart, Simon; McMillan, Steve; Harfst, Stefan; Groen, Derek; Fujii, Michiko; Nualláin, Breanndán Ó.; Glebbeek, Evert; Heggie, Douglas; Lombardi, James; Hut, Piet; Angelou, Vangelis; Banerjee, Sambaran; Belkus, Houria; Fragos, Tassos; Fregeau, John; Gaburov, Evghenii; Izzard, Rob; Jurić, Mario; Justham, Stephen; Sottoriva, Andrea; Teuben, Peter; van Bever, Joris; Yaron, Ofer; Zemp, Marcel
2009-05-01
We present MUSE, a software framework for combining existing computational tools for different astrophysical domains into a single multiphysics, multiscale application. MUSE facilitates the coupling of existing codes written in different languages by providing inter-language tools and by specifying an interface between each module and the framework that represents a balance between generality and computational efficiency. This approach allows scientists to use combinations of codes to solve highly coupled problems without the need to write new codes for other domains or significantly alter their existing codes. MUSE currently incorporates the domains of stellar dynamics, stellar evolution and stellar hydrodynamics for studying generalized stellar systems. We have now reached a "Noah's Ark" milestone, with (at least) two available numerical solvers for each domain. MUSE can treat multiscale and multiphysics systems in which the time- and size-scales are well separated, like simulating the evolution of planetary systems, small stellar associations, dense stellar clusters, galaxies and galactic nuclei. In this paper we describe three examples calculated using MUSE: the merger of two galaxies, the merger of two evolving stars, and a hybrid N-body simulation. In addition, we demonstrate an implementation of MUSE on a distributed computer which may also include special-purpose hardware, such as GRAPEs or GPUs, to accelerate computations. The current MUSE code base is publicly available as open source at http://muse.li.
Atomistic hybrid DSMC/NEMD method for nonequilibrium multiscale simulations
Gu Kai; Watkins, Charles B. Koplik, Joel
2010-03-01
A multiscale hybrid method for coupling the direct simulation Monte Carlo (DSMC) method to the nonequilibrium molecular dynamics (NEMD) method is introduced. The method addresses Knudsen layer type gas flows within a few mean free paths of an interface or about an object with dimensions of the order of a few mean free paths. It employs the NEMD method to resolve nanoscale phenomena closest to the interface along with coupled DSMC simulation of the remainder of the Knudsen layer. The hybrid DSMC/NEMD method is a particle based algorithm without a buffer zone. It incorporates a new, modified generalized soft sphere (MGSS) molecular collision model to improve the poor computational efficiency of the traditional generalized soft sphere GSS model and to achieve DSMC compatibility with Lennard-Jones NEMD molecular interactions. An equilibrium gas, a Fourier thermal flow, and an oscillatory Couette flow, are simulated to validate the method. The method shows good agreement with Maxwell-Boltzmann theory for the equilibrium system, Chapman-Enskog theory for Fourier flow, and pure DSMC simulations for oscillatory Couette flow. Speedup in CPU time of the hybrid solver is benchmarked against a pure NEMD solver baseline for different system sizes and solver domain partitions. Finally, the hybrid method is applied to investigate interaction of argon gas with solid surface molecules in a parametric study of the influence of wetting effects and solid molecular mass on energy transfer and thermal accommodation coefficients. It is determined that wetting effect strength and solid molecular mass have a significant impact on the energy transfer between gas and solid phases and thermal accommodation coefficient.
On code verification of RANS solvers
NASA Astrophysics Data System (ADS)
Eça, L.; Klaij, C. M.; Vaz, G.; Hoekstra, M.; Pereira, F. S.
2016-04-01
This article discusses Code Verification of Reynolds-Averaged Navier Stokes (RANS) solvers that rely on face based finite volume discretizations for volumes of arbitrary shape. The study includes test cases with known analytical solutions (generated with the method of manufactured solutions) corresponding to laminar and turbulent flow, with the latter using eddy-viscosity turbulence models. The procedure to perform Code Verification based on grid refinement studies is discussed and the requirements for its correct application are illustrated in a simple one-dimensional problem. It is shown that geometrically similar grids are recommended for proper Code Verification and so the data should not have scatter making the use of least square fits unnecessary. Results show that it may be advantageous to determine the extrapolated error to cell size/time step zero instead of assuming that it is zero, especially when it is hard to determine the asymptotic order of grid convergence. In the RANS examples, several of the features of the ReFRESCO solver are checked including the effects of the available turbulence models in the convergence properties of the code. It is shown that it is required to account for non-orthogonality effects in the discretization of the diffusion terms and that the turbulence quantities transport equations can deteriorate the order of grid convergence of mean flow quantities.
Using the scalable nonlinear equations solvers package
Gropp, W.D.; McInnes, L.C.; Smith, B.F.
1995-02-01
SNES (Scalable Nonlinear Equations Solvers) is a software package for the numerical solution of large-scale systems of nonlinear equations on both uniprocessors and parallel architectures. SNES also contains a component for the solution of unconstrained minimization problems, called SUMS (Scalable Unconstrained Minimization Solvers). Newton-like methods, which are known for their efficiency and robustness, constitute the core of the package. As part of the multilevel PETSc library, SNES incorporates many features and options from other parts of PETSc. In keeping with the spirit of the PETSc library, the nonlinear solution routines are data-structure-neutral, making them flexible and easily extensible. This users guide contains a detailed description of uniprocessor usage of SNES, with some added comments regarding multiprocessor usage. At this time the parallel version is undergoing refinement and extension, as we work toward a common interface for the uniprocessor and parallel cases. Thus, forthcoming versions of the software will contain additional features, and changes to parallel interface may result at any time. The new parallel version will employ the MPI (Message Passing Interface) standard for interprocessor communication. Since most of these details will be hidden, users will need to perform only minimal message-passing programming.
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
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.
Multiscale full waveform inversion
NASA Astrophysics Data System (ADS)
Fichtner, Andreas; Trampert, Jeannot; Cupillard, Paul; Saygin, Erdinc; Taymaz, Tuncay; Capdeville, Yann; Villaseñor, Antonio
2013-07-01
We develop and apply a full waveform inversion method that incorporates seismic data on a wide range of spatio-temporal scales, thereby constraining the details of both crustal and upper-mantle structure. This is intended to further our understanding of crust-mantle interactions that shape the nature of plate tectonics, and to be a step towards improved tomographic models of strongly scale-dependent earth properties, such as attenuation and anisotropy. The inversion for detailed regional earth structure consistently embedded within a large-scale model requires locally refined numerical meshes that allow us to (1) model regional wave propagation at high frequencies, and (2) capture the inferred fine-scale heterogeneities. The smallest local grid spacing sets the upper bound of the largest possible time step used to iteratively advance the seismic wave field. This limitation leads to extreme computational costs in the presence of fine-scale structure, and it inhibits the construction of full waveform tomographic models that describe earth structure on multiple scales. To reduce computational requirements to a feasible level, we design a multigrid approach based on the decomposition of a multiscale earth model with widely varying grid spacings into a family of single-scale models where the grid spacing is approximately uniform. Each of the single-scale models contains a tractable number of grid points, which ensures computational efficiency. The multi-to-single-scale decomposition is the foundation of iterative, gradient-based optimization schemes that simultaneously and consistently invert data on all scales for one multi-scale model. We demonstrate the applicability of our method in a full waveform inversion for Eurasia, with a special focus on Anatolia where coverage is particularly dense. Continental-scale structure is constrained by complete seismic waveforms in the 30-200 s period range. In addition to the well-known structural elements of the Eurasian mantle
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
jShyLU Scalable Hybrid Preconditioner and Solver
Energy Science and Technology Software Center (ESTSC)
2012-09-11
ShyLU is numerical software to solve sparse linear systems of equations. ShyLU uses a hybrid direct-iterative Schur complement method, and may be used either as a preconditioner or as a solver. ShyLU is parallel and optimized for a single compute Solver node. ShyLU will be a package in the Trilinos software framework.
Experiences with linear solvers for oil reservoir simulation problems
Joubert, W.; Janardhan, R.; Biswas, D.; Carey, G.
1996-12-31
This talk will focus on practical experiences with iterative linear solver algorithms used in conjunction with Amoco Production Company`s Falcon oil reservoir simulation code. The goal of this study is to determine the best linear solver algorithms for these types of problems. The results of numerical experiments will be presented.
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.
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.
Shape reanalysis and sensitivities utilizing preconditioned iterative boundary solvers
NASA Technical Reports Server (NTRS)
Guru Prasad, K.; Kane, J. H.
1992-01-01
The computational advantages associated with the utilization of preconditined iterative equation solvers are quantified for the reanalysis of perturbed shapes using continuum structural boundary element analysis (BEA). Both single- and multi-zone three-dimensional problems are examined. Significant reductions in computer time are obtained by making use of previously computed solution vectors and preconditioners in subsequent analyses. The effectiveness of this technique is demonstrated for the computation of shape response sensitivities required in shape optimization. Computer times and accuracies achieved using the preconditioned iterative solvers are compared with those obtained via direct solvers and implicit differentiation of the boundary integral equations. It is concluded that this approach employing preconditioned iterative equation solvers in reanalysis and sensitivity analysis can be competitive with if not superior to those involving direct solvers.
A multigrid fluid pressure solver handling separating solid boundary conditions.
Chentanez, Nuttapong; Müller-Fischer, Matthias
2012-08-01
We present a multigrid method for solving the linear complementarity problem (LCP) resulting from discretizing the Poisson equation subject to separating solid boundary conditions in an Eulerian liquid simulation’s pressure projection step. The method requires only a few small changes to a multigrid solver for linear systems. Our generalized solver is fast enough to handle 3D liquid simulations with separating boundary conditions in practical domain sizes. Previous methods could only handle relatively small 2D domains in reasonable time, because they used expensive quadratic programming (QP) solvers. We demonstrate our technique in several practical scenarios, including nonaxis-aligned containers and moving solids in which the omission of separating boundary conditions results in disturbing artifacts of liquid sticking to solids. Our measurements show, that the convergence rate of our LCP solver is close to that of a standard multigrid solver. PMID:22411885
A real-time impurity solver for DMFT
NASA Astrophysics Data System (ADS)
Kim, Hyungwon; Aron, Camille; Han, Jong E.; Kotliar, Gabriel
Dynamical mean-field theory (DMFT) offers a non-perturbative approach to problems with strongly correlated electrons. The method heavily relies on the ability to numerically solve an auxiliary Anderson-type impurity problem. While powerful Matsubara-frequency solvers have been developed over the past two decades to tackle equilibrium situations, the status of real-time impurity solvers that could compete with Matsubara-frequency solvers and be readily generalizable to non-equilibrium situations is still premature. We present a real-time solver which is based on a quantum Master equation description of the dissipative dynamics of the impurity and its exact diagonalization. As a benchmark, we illustrate the strengths of our solver in the context of the equilibrium Mott-insulator transition of the one-band Hubbard model and compare it with iterative perturbation theory (IPT) method. Finally, we discuss its direct application to a nonequilibrium situation.
Linear iterative solvers for implicit ODE methods
NASA Technical Reports Server (NTRS)
Saylor, Paul E.; Skeel, Robert D.
1990-01-01
The numerical solution of stiff initial value problems, which lead to the problem of solving large systems of mildly nonlinear equations are considered. For many problems derived from engineering and science, a solution is possible only with methods derived from iterative linear equation solvers. A common approach to solving the nonlinear equations is to employ an approximate solution obtained from an explicit method. The error is examined to determine how it is distributed among the stiff and non-stiff components, which bears on the choice of an iterative method. The conclusion is that error is (roughly) uniformly distributed, a fact that suggests the Chebyshev method (and the accompanying Manteuffel adaptive parameter algorithm). This method is described, also commenting on Richardson's method and its advantages for large problems. Richardson's method and the Chebyshev method with the Mantueffel algorithm are applied to the solution of the nonlinear equations by Newton's method.
Scalable Adaptive Multilevel Solvers for Multiphysics Problems
Xu, Jinchao
2014-12-01
In this project, we investigated adaptive, parallel, and multilevel methods for numerical modeling of various real-world applications, including Magnetohydrodynamics (MHD), complex fluids, Electromagnetism, Navier-Stokes equations, and reservoir simulation. First, we have designed improved mathematical models and numerical discretizaitons for viscoelastic fluids and MHD. Second, we have derived new a posteriori error estimators and extended the applicability of adaptivity to various problems. Third, we have developed multilevel solvers for solving scalar partial differential equations (PDEs) as well as coupled systems of PDEs, especially on unstructured grids. Moreover, we have integrated the study between adaptive method and multilevel methods, and made significant efforts and advances in adaptive multilevel methods of the multi-physics problems.
Optimising a parallel conjugate gradient solver
Field, M.R.
1996-12-31
This work arises from the introduction of a parallel iterative solver to a large structural analysis finite element code. The code is called FEX and it was developed at Hitachi`s Mechanical Engineering Laboratory. The FEX package can deal with a large range of structural analysis problems using a large number of finite element techniques. FEX can solve either stress or thermal analysis problems of a range of different types from plane stress to a full three-dimensional model. These problems can consist of a number of different materials which can be modelled by a range of material models. The structure being modelled can have the load applied at either a point or a surface, or by a pressure, a centrifugal force or just gravity. Alternatively a thermal load can be applied with a given initial temperature. The displacement of the structure can be constrained by having a fixed boundary or by prescribing the displacement at a boundary.
Parallel hyperbolic PDE simulation on clusters: Cell versus GPU
NASA Astrophysics Data System (ADS)
Rostrup, Scott; De Sterck, Hans
2010-12-01
:http://cpc.cs.qub.ac.uk/summaries/AEGY_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GPL v3 No. of lines in distributed program, including test data, etc.: 59 168 No. of bytes in distributed program, including test data, etc.: 453 409 Distribution format: tar.gz Programming language: C, CUDA Computer: Parallel Computing Clusters. Individual compute nodes may consist of x86 CPU, Cell processor, or x86 CPU with attached NVIDIA GPU accelerator. Operating system: Linux Has the code been vectorised or parallelized?: Yes. Tested on 1-128 x86 CPU cores, 1-32 Cell Processors, and 1-32 NVIDIA GPUs. RAM: Tested on Problems requiring up to 4 GB per compute node. Classification: 12 External routines: MPI, CUDA, IBM Cell SDK Nature of problem: MPI-parallel simulation of Shallow Water equations using high-resolution 2D hyperbolic equation solver on regular Cartesian grids for x86 CPU, Cell Processor, and NVIDIA GPU using CUDA. Solution method: SWsolver provides 3 implementations of a high-resolution 2D Shallow Water equation solver on regular Cartesian grids, for CPU, Cell Processor, and NVIDIA GPU. Each implementation uses MPI to divide work across a parallel computing cluster. Additional comments: Sub-program numdiff is used for the test run.
General purpose nonlinear system solver based on Newton-Krylov method.
Energy Science and Technology Software Center (ESTSC)
2013-12-01
KINSOL is part of a software family called SUNDIALS: SUite of Nonlinear and Differential/Algebraic equation Solvers [1]. KINSOL is a general-purpose nonlinear system solver based on Newton-Krylov and fixed-point solver technologies [2].
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…
The Magnetospheric Multiscale Magnetometers
NASA Astrophysics Data System (ADS)
Russell, C. T.; Anderson, B. J.; Baumjohann, W.; Bromund, K. R.; Dearborn, D.; Fischer, D.; Le, G.; Leinweber, H. K.; Leneman, D.; Magnes, W.; Means, J. D.; Moldwin, M. B.; Nakamura, R.; Pierce, D.; Plaschke, F.; Rowe, K. M.; Slavin, J. A.; Strangeway, R. J.; Torbert, R.; Hagen, C.; Jernej, I.; Valavanoglou, A.; Richter, I.
2016-03-01
The success of the Magnetospheric Multiscale mission depends on the accurate measurement of the magnetic field on all four spacecraft. To ensure this success, two independently designed and built fluxgate magnetometers were developed, avoiding single-point failures. The magnetometers were dubbed the digital fluxgate (DFG), which uses an ASIC implementation and was supplied by the Space Research Institute of the Austrian Academy of Sciences and the analogue magnetometer (AFG) with a more traditional circuit board design supplied by the University of California, Los Angeles. A stringent magnetic cleanliness program was executed under the supervision of the Johns Hopkins University's Applied Physics Laboratory. To achieve mission objectives, the calibration determined on the ground will be refined in space to ensure all eight magnetometers are precisely inter-calibrated. Near real-time data plays a key role in the transmission of high-resolution observations stored on board so rapid processing of the low-resolution data is required. This article describes these instruments, the magnetic cleanliness program, and the instrument pre-launch calibrations, the planned in-flight calibration program, and the information flow that provides the data on the rapid time scale needed for mission success.
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
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
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.
Multiscale Thermohydrologic Model
T. Buscheck
2004-10-12
The purpose of the multiscale thermohydrologic model (MSTHM) is to predict the possible range of thermal-hydrologic conditions, resulting from uncertainty and variability, in the repository emplacement drifts, including the invert, and in the adjoining host rock for the repository at Yucca Mountain. Thus, the goal is to predict the range of possible thermal-hydrologic conditions across the repository; this is quite different from predicting a single expected thermal-hydrologic response. The MSTHM calculates the following thermal-hydrologic parameters: temperature, relative humidity, liquid-phase saturation, evaporation rate, air-mass fraction, gas-phase pressure, capillary pressure, and liquid- and gas-phase fluxes (Table 1-1). These thermal-hydrologic parameters are required to support ''Total System Performance Assessment (TSPA) Model/Analysis for the License Application'' (BSC 2004 [DIRS 168504]). The thermal-hydrologic parameters are determined as a function of position along each of the emplacement drifts and as a function of waste package type. These parameters are determined at various reference locations within the emplacement drifts, including the waste package and drip-shield surfaces and in the invert. The parameters are also determined at various defined locations in the adjoining host rock. The MSTHM uses data obtained from the data tracking numbers (DTNs) listed in Table 4.1-1. The majority of those DTNs were generated from the following analyses and model reports: (1) ''UZ Flow Model and Submodels'' (BSC 2004 [DIRS 169861]); (2) ''Development of Numerical Grids for UZ Flow and Transport Modeling'' (BSC 2004); (3) ''Calibrated Properties Model'' (BSC 2004 [DIRS 169857]); (4) ''Thermal Conductivity of the Potential Repository Horizon'' (BSC 2004 [DIRS 169854]); (5) ''Thermal Conductivity of the Non-Repository Lithostratigraphic Layers'' (BSC 2004 [DIRS 170033]); (6) ''Ventilation Model and Analysis Report'' (BSC 2004 [DIRS 169862]); (7) ''Heat Capacity
Comparison of open-source linear programming solvers.
Gearhart, Jared Lee; Adair, Kristin Lynn; Durfee, Justin D.; Jones, Katherine A.; Martin, Nathaniel; Detry, Richard Joseph
2013-10-01
When developing linear programming models, issues such as budget limitations, customer requirements, or licensing may preclude the use of commercial linear programming solvers. In such cases, one option is to use an open-source linear programming solver. A survey of linear programming tools was conducted to identify potential open-source solvers. From this survey, four open-source solvers were tested using a collection of linear programming test problems and the results were compared to IBM ILOG CPLEX Optimizer (CPLEX) [1], an industry standard. The solvers considered were: COIN-OR Linear Programming (CLP) [2], [3], GNU Linear Programming Kit (GLPK) [4], lp_solve [5] and Modular In-core Nonlinear Optimization System (MINOS) [6]. As no open-source solver outperforms CPLEX, this study demonstrates the power of commercial linear programming software. CLP was found to be the top performing open-source solver considered in terms of capability and speed. GLPK also performed well but cannot match the speed of CLP or CPLEX. lp_solve and MINOS were considerably slower and encountered issues when solving several test problems.
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
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).
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.
Multi-GPU kinetic solvers using MPI and CUDA
NASA Astrophysics Data System (ADS)
Zabelok, Sergey; Arslanbekov, Robert; Kolobov, Vladimir
2014-12-01
This paper describes recent progress towards porting a Unified Flow Solver (UFS) to heterogeneous parallel computing. The main challenge of porting UFS to graphics processing units (GPUs) comes from the dynamically adapted mesh, which causes irregular data access. We describe the implementation of CUDA kernels for three modules in UFS: the direct Boltzmann solver using discrete velocity method (DVM), the DSMC module, and the Lattice Boltzmann Method (LBM) solver, all using octree Cartesian mesh with adaptive Mesh Refinement (AMR). Double digit speedup on single GPU and good scaling for multi-GPU has been demonstrated.
A non-conforming 3D spherical harmonic transport solver
Van Criekingen, S.
2006-07-01
A new 3D transport solver for the time-independent Boltzmann transport equation has been developed. This solver is based on the second-order even-parity form of the transport equation. The angular discretization is performed through the expansion of the angular neutron flux in spherical harmonics (PN method). The novelty of this solver is the use of non-conforming finite elements for the spatial discretization. Such elements lead to a discontinuous flux approximation. This interface continuity requirement relaxation property is shared with mixed-dual formulations such as the ones based on Raviart-Thomas finite elements. Encouraging numerical results are presented. (authors)
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
Multi-Scale Infrastructure Assessment
The U.S. Environmental Protection Agency’s (EPA) multi-scale infrastructure assessment project supports both water resource adaptation to climate change and the rehabilitation of the nation’s aging water infrastructure by providing tools, scientific data and information to progra...
Elliptic Solvers for Adaptive Mesh Refinement Grids
Quinlan, D.J.; Dendy, J.E., Jr.; Shapira, Y.
1999-06-03
We are developing multigrid methods that will efficiently solve elliptic problems with anisotropic and discontinuous coefficients on adaptive grids. The final product will be a library that provides for the simplified solution of such problems. This library will directly benefit the efforts of other Laboratory groups. The focus of this work is research on serial and parallel elliptic algorithms and the inclusion of our black-box multigrid techniques into this new setting. The approach applies the Los Alamos object-oriented class libraries that greatly simplify the development of serial and parallel adaptive mesh refinement applications. In the final year of this LDRD, we focused on putting the software together; in particular we completed the final AMR++ library, we wrote tutorials and manuals, and we built example applications. We implemented the Fast Adaptive Composite Grid method as the principal elliptic solver. We presented results at the Overset Grid Conference and other more AMR specific conferences. We worked on optimization of serial and parallel performance and published several papers on the details of this work. Performance remains an important issue and is the subject of continuing research work.
Advanced Multigrid Solvers for Fluid Dynamics
NASA Technical Reports Server (NTRS)
Brandt, Achi
1999-01-01
The main objective of this project has been to support the development of multigrid techniques in computational fluid dynamics that can achieve "textbook multigrid efficiency" (TME), which is several orders of magnitude faster than current industrial CFD solvers. Toward that goal we have assembled a detailed table which lists every foreseen kind of computational difficulty for achieving it, together with the possible ways for resolving the difficulty, their current state of development, and references. We have developed several codes to test and demonstrate, in the framework of simple model problems, several approaches for overcoming the most important of the listed difficulties that had not been resolved before. In particular, TME has been demonstrated for incompressible flows on one hand, and for near-sonic flows on the other hand. General approaches were advanced for the relaxation of stagnation points and boundary conditions under various situations. Also, new algebraic multigrid techniques were formed for treating unstructured grid formulations. More details on all these are given below.
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
NASA Technical Reports Server (NTRS)
Raju, Manthena S.
1998-01-01
Sprays occur in a wide variety of industrial and power applications and in the processing of materials. A liquid spray is a phase flow with a gas as the continuous phase and a liquid as the dispersed phase (in the form of droplets or ligaments). Interactions between the two phases, which are coupled through exchanges of mass, momentum, and energy, can occur in different ways at different times and locations involving various thermal, mass, and fluid dynamic factors. An understanding of the flow, combustion, and thermal properties of a rapidly vaporizing spray requires careful modeling of the rate-controlling processes associated with the spray's turbulent transport, mixing, chemical kinetics, evaporation, and spreading rates, as well as other phenomena. In an attempt to advance the state-of-the-art in multidimensional numerical methods, we at the NASA Lewis Research Center extended our previous work on sprays to unstructured grids and parallel computing. LSPRAY, which was developed by M.S. Raju of Nyma, Inc., is designed to be massively parallel and could easily be coupled with any existing gas-phase flow and/or Monte Carlo probability density function (PDF) solver. The LSPRAY solver accommodates the use of an unstructured mesh with mixed triangular, quadrilateral, and/or tetrahedral elements in the gas-phase solvers. It is used specifically for fuel sprays within gas turbine combustors, but it has many other uses. The spray model used in LSPRAY provided favorable results when applied to stratified-charge rotary combustion (Wankel) engines and several other confined and unconfined spray flames. The source code will be available with the National Combustion Code (NCC) as a complete package.
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
Handling Vacuum Regions in a Hybrid Plasma Solver
NASA Astrophysics Data System (ADS)
Holmström, M.
2013-04-01
In a hybrid plasma solver (particle ions, fluid mass-less electrons) regions of vacuum, or very low charge density, can cause problems since the evaluation of the electric field involves division by charge density. This causes large electric fields in low density regions that can lead to numerical instabilities. Here we propose a self consistent handling of vacuum regions for hybrid solvers. Vacuum regions can be considered having infinite resistivity, and in this limit Faraday's law approaches a magnetic diffusion equation. We describe an algorithm that solves such a diffusion equation in regions with charge density below a threshold value. We also present an implementation of this algorithm in a hybrid plasma solver, and an application to the interaction between the Moon and the solar wind. We also discuss the implementation of hyperresistivity for smoothing the electric field in a PIC solver.
Parallel iterative solvers and preconditioners using approximate hierarchical methods
Grama, A.; Kumar, V.; Sameh, A.
1996-12-31
In this paper, we report results of the performance, convergence, and accuracy of a parallel GMRES solver for Boundary Element Methods. The solver uses a hierarchical approximate matrix-vector product based on a hybrid Barnes-Hut / Fast Multipole Method. We study the impact of various accuracy parameters on the convergence and show that with minimal loss in accuracy, our solver yields significant speedups. We demonstrate the excellent parallel efficiency and scalability of our solver. The combined speedups from approximation and parallelism represent an improvement of several orders in solution time. We also develop fast and paralellizable preconditioners for this problem. We report on the performance of an inner-outer scheme and a preconditioner based on truncated Green`s function. Experimental results on a 256 processor Cray T3D are presented.
NASA Astrophysics Data System (ADS)
Angelidis, Dionysios; Sotiropoulos, Fotis
2015-11-01
The geometrical details of wind turbines determine the structure of the turbulence in the near and far wake and should be taken in account when performing high fidelity calculations. Multi-resolution simulations coupled with an immersed boundary method constitutes a powerful framework for high-fidelity calculations past wind farms located over complex terrains. We develop a 3D Immersed-Boundary Adaptive Mesh Refinement flow solver (IB-AMR) which enables turbine-resolving LES of wind turbines. The idea of using a hybrid staggered/non-staggered grid layout adopted in the Curvilinear Immersed Boundary Method (CURVIB) has been successfully incorporated on unstructured meshes and the fractional step method has been employed. The overall performance and robustness of the second order accurate, parallel, unstructured solver is evaluated by comparing the numerical simulations against conforming grid calculations and experimental measurements of laminar and turbulent flows over complex geometries. We also present turbine-resolving multi-scale LES considering all the details affecting the induced flow field; including the geometry of the tower, the nacelle and especially the rotor blades of a wind tunnel scale turbine. This material is based upon work supported by the Department of Energy under Award Number DE-EE0005482 and the Sandia National Laboratories.
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
An advanced implicit solver for MHD
NASA Astrophysics Data System (ADS)
Udrea, Bogdan
A new implicit algorithm has been developed for the solution of the time-dependent, viscous and resistive single fluid magnetohydrodynamic (MHD) equations. The algorithm is based on an approximate Riemann solver for the hyperbolic fluxes and central differencing applied on a staggered grid for the parabolic fluxes. The algorithm employs a locally aligned coordinate system that allows the solution to the Riemann problems to be solved in a natural direction, normal to cell interfaces. The result is an original scheme that is robust and reduces the complexity of the flux formulas. The evaluation of the parabolic fluxes is also implemented using a locally aligned coordinate system, this time on the staggered grid. The implicit formulation employed by WARP3 is a two level scheme that was applied for the first time to the single fluid MHD model. The flux Jacobians that appear in the implicit scheme are evaluated numerically. The linear system that results from the implicit discretization is solved using a robust symmetric Gauss-Seidel method. The code has an explicit mode capability so that implementation and test of new algorithms or new physics can be performed in this simpler mode. Last but not least the code was designed and written to run on parallel computers so that complex, high resolution runs can be per formed in hours rather than days. The code has been benchmarked against analytical and experimental gas dynamics and MHD results. The benchmarks consisted of one-dimensional Riemann problems and diffusion dominated problems, two-dimensional supersonic flow over a wedge, axisymmetric magnetoplasmadynamic (MPD) thruster simulation and three-dimensional supersonic flow over intersecting wedges and spheromak stability simulation. The code has been proven to be robust and the results of the simulations showed excellent agreement with analytical and experimental results. Parallel performance studies showed that the code performs as expected when run on parallel
Benchmarking transport solvers for fracture flow problems
NASA Astrophysics Data System (ADS)
Olkiewicz, Piotr; Dabrowski, Marcin
2015-04-01
Fracture flow may dominate in rocks with low porosity and it can accompany both industrial and natural processes. Typical examples of such processes are natural flows in crystalline rocks and industrial flows in geothermal systems or hydraulic fracturing. Fracture flow provides an important mechanism for transporting mass and energy. For example, geothermal energy is primarily transported by the flow of the heated water or steam rather than by the thermal diffusion. The geometry of the fracture network and the distribution of the mean apertures of individual fractures are the key parameters with regard to the fracture network transmissivity. Transport in fractures can occur through the combination of advection and diffusion processes like in the case of dissolved chemical components. The local distribution of the fracture aperture may play an important role for both flow and transport processes. In this work, we benchmark various numerical solvers for flow and transport processes in a single fracture in 2D and 3D. Fracture aperture distributions are generated by a number of synthetic methods. We examine a single-phase flow of an incompressible viscous Newtonian fluid in the low Reynolds number limit. Periodic boundary conditions are used and a pressure difference is imposed in the background. The velocity field is primarly found using the Stokes equations. We systematically compare the obtained velocity field to the results obtained by solving the Reynolds equation. This allows us to examine the impact of the aperture distribution on the permeability of the medium and the local velocity distribution for two different mathematical descriptions of the fracture flow. Furthermore, we analyse the impact of aperture distribution on the front characteristics such as the standard deviation and the fractal dimension for systems in 2D and 3D.
A robust multilevel simultaneous eigenvalue solver
NASA Technical Reports Server (NTRS)
Costiner, Sorin; Taasan, Shlomo
1993-01-01
Multilevel (ML) algorithms for eigenvalue problems are often faced with several types of difficulties such as: the mixing of approximated eigenvectors by the solution process, the approximation of incomplete clusters of eigenvectors, the poor representation of solution on coarse levels, and the existence of close or equal eigenvalues. Algorithms that do not treat appropriately these difficulties usually fail, or their performance degrades when facing them. These issues motivated the development of a robust adaptive ML algorithm which treats these difficulties, for the calculation of a few eigenvectors and their corresponding eigenvalues. The main techniques used in the new algorithm include: the adaptive completion and separation of the relevant clusters on different levels, the simultaneous treatment of solutions within each cluster, and the robustness tests which monitor the algorithm's efficiency and convergence. The eigenvectors' separation efficiency is based on a new ML projection technique generalizing the Rayleigh Ritz projection, combined with a technique, the backrotations. These separation techniques, when combined with an FMG formulation, in many cases lead to algorithms of O(qN) complexity, for q eigenvectors of size N on the finest level. Previously developed ML algorithms are less focused on the mentioned difficulties. Moreover, algorithms which employ fine level separation techniques are of O(q(sub 2)N) complexity and usually do not overcome all these difficulties. Computational examples are presented where Schrodinger type eigenvalue problems in 2-D and 3-D, having equal and closely clustered eigenvalues, are solved with the efficiency of the Poisson multigrid solver. A second order approximation is obtained in O(qN) work, where the total computational work is equivalent to only a few fine level relaxations per eigenvector.
MULTISCALE THERMOHYDROLOGIC MODEL
T. Buscheck
2005-07-07
The intended purpose of the multiscale thermohydrologic model (MSTHM) is to predict the possible range of thermal-hydrologic conditions, resulting from uncertainty and variability, in the repository emplacement drifts, including the invert, and in the adjoining host rock for the repository at Yucca Mountain. The goal of the MSTHM is to predict a reasonable range of possible thermal-hydrologic conditions within the emplacement drift. To be reasonable, this range includes the influence of waste-package-to-waste-package heat output variability relevant to the license application design, as well as the influence of uncertainty and variability in the geologic and hydrologic conditions relevant to predicting the thermal-hydrologic response in emplacement drifts. This goal is quite different from the goal of a model to predict a single expected thermal-hydrologic response. As a result, the development and validation of the MSTHM and the associated analyses using this model are focused on the goal of predicting a reasonable range of thermal-hydrologic conditions resulting from parametric uncertainty and waste-package-to-waste-package heat-output variability. Thermal-hydrologic conditions within emplacement drifts depend primarily on thermal-hydrologic conditions in the host rock at the drift wall and on the temperature difference between the drift wall and the drip-shield and waste-package surfaces. Thus, the ability to predict a reasonable range of relevant in-drift MSTHM output parameters (e.g., temperature and relative humidity) is based on valid predictions of thermal-hydrologic processes in the host rock, as well as valid predictions of heat-transfer processes between the drift wall and the drip-shield and waste-package surfaces. Because the invert contains crushed gravel derived from the host rock, the invert is, in effect, an extension of the host rock, with thermal and hydrologic properties that have been modified by virtue of the crushing (and the resulting
The Magnetospheric Multiscale Mission
NASA Astrophysics Data System (ADS)
Burch, James
Magnetospheric Multiscale (MMS), a NASA four-spacecraft mission scheduled for launch in November 2014, will investigate magnetic reconnection in the boundary regions of the Earth’s magnetosphere, particularly along its dayside boundary with the solar wind and the neutral sheet in the magnetic tail. Among the important questions about reconnection that will be addressed are the following: Under what conditions can magnetic-field energy be converted to plasma energy by the annihilation of magnetic field through reconnection? How does reconnection vary with time, and what factors influence its temporal behavior? What microscale processes are responsible for reconnection? What determines the rate of reconnection? In order to accomplish its goals the MMS spacecraft must probe both those regions in which the magnetic fields are very nearly antiparallel and regions where a significant guide field exists. From previous missions we know the approximate speeds with which reconnection layers move through space to be from tens to hundreds of km/s. For electron skin depths of 5 to 10 km, the full 3D electron population (10 eV to above 20 keV) has to be sampled at rates greater than 10/s. The MMS Fast-Plasma Instrument (FPI) will sample electrons at greater than 30/s. Because the ion skin depth is larger, FPI will make full ion measurements at rates of greater than 6/s. 3D E-field measurements will be made by MMS once every ms. MMS will use an Active Spacecraft Potential Control device (ASPOC), which emits indium ions to neutralize the photoelectron current and keep the spacecraft from charging to more than +4 V. Because ion dynamics in Hall reconnection depend sensitively on ion mass, MMS includes a new-generation Hot Plasma Composition Analyzer (HPCA) that corrects problems with high proton fluxes that have prevented accurate ion-composition measurements near the dayside magnetospheric boundary. Finally, Energetic Particle Detector (EPD) measurements of electrons and
A Comparative Study of Randomized Constraint Solvers for Random-Symbolic Testing
NASA Technical Reports Server (NTRS)
Takaki, Mitsuo; Cavalcanti, Diego; Gheyi, Rohit; Iyoda, Juliano; dAmorim, Marcelo; Prudencio, Ricardo
2009-01-01
The complexity of constraints is a major obstacle for constraint-based software verification. Automatic constraint solvers are fundamentally incomplete: input constraints often build on some undecidable theory or some theory the solver does not support. This paper proposes and evaluates several randomized solvers to address this issue. We compare the effectiveness of a symbolic solver (CVC3), a random solver, three hybrid solvers (i.e., mix of random and symbolic), and two heuristic search solvers. We evaluate the solvers on two benchmarks: one consisting of manually generated constraints and another generated with a concolic execution of 8 subjects. In addition to fully decidable constraints, the benchmarks include constraints with non-linear integer arithmetic, integer modulo and division, bitwise arithmetic, and floating-point arithmetic. As expected symbolic solving (in particular, CVC3) subsumes the other solvers for the concolic execution of subjects that only generate decidable constraints. For the remaining subjects the solvers are complementary.
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
Hybrid Numerical Methods for Multiscale Simulations of Subsurface Biogeochemical Processes
Scheibe, Timothy D.; Tartakovsky, Alexandre M.; Tartakovsky, Daniel M.; Redden, George D.; Meakin, Paul
2007-08-01
Many subsurface flow and transport problems of importance today involve coupled non-linear flow, transport, and reaction in media exhibiting complex heterogeneity. In particular, problems involving biological mediation of reactions fall into this class of problems. Recent experimental research has revealed important details about the physical, chemical, and biological mechanisms involved in these processes at a variety of scales ranging from molecular to laboratory scales. However, it has not been practical or possible to translate detailed knowledge at small scales into reliable predictions of field-scale phenomena important for environmental management applications. A large assortment of numerical simulation tools have been developed, each with its own characteristic scale including molecular (e.g., molecular dynamics), microbial (e.g., cellular automata or particle individual-based models), pore (e.g., lattice-Boltzmann, pore network models, and discrete particle methods such as smoothed particle hydrodynamics) and continuum scales (e.g., traditional partial differential equations solved by finite difference or finite element methods). While many problems can be effectively addressed by one of these models at a single scale, some problems may require explicit integration of models across multiple scales. We are developing a hybrid multi-scale subsurface reactive transport modeling framework that integrates models with diverse representations of physics, chemistry and biology at different scales (sub-pore, pore and continuum). The modeling framework is being designed to take advantage of advanced computational technologies including parallel code components using the Common Component Architecture, parallel solvers, gridding, data and workflow management, and visualization. This paper describes the specific methods/codes being used at each scale, techniques used to directly and adaptively couple across model scales, and preliminary results of application to a
Foundations for a multiscale collaborative Earth model
NASA Astrophysics Data System (ADS)
Afanasiev, Michael; Peter, Daniel; Sager, Korbinian; Simutė, Saulė; Ermert, Laura; Krischer, Lion; Fichtner, Andreas
2016-01-01
We present a computational framework for the assimilation of local to global seismic data into a consistent model describing Earth structure on all seismically accessible scales. This Collaborative Seismic Earth Model (CSEM) is designed to meet the following requirements: (i) Flexible geometric parametrization, capable of capturing topography and bathymetry, as well as all aspects of potentially resolvable structure, including small-scale heterogeneities and deformations of internal discontinuities. (ii) Independence of any particular wave equation solver, in order to enable the combination of inversion techniques suitable for different types of seismic data. (iii) Physical parametrization that allows for full anisotropy and for variations in attenuation and density. While not all of these parameters are always resolvable, the assimilation of data that constrain any parameter subset should be possible. (iv) Ability to accommodate successive refinements through the incorporation of updates on any scale as new data or inversion techniques become available. (v) Enable collaborative Earth model construction. The structure of the initial CSEM is represented on a variable-resolution tetrahedral mesh. It is assembled from a long-wavelength 3-D global model into which several regional-scale tomographies are embedded. We illustrate the CSEM workflow of successive updating with two examples from Japan and the Western Mediterranean, where we constrain smaller scale structure using full-waveform inversion. Furthermore, we demonstrate the ability of the CSEM to act as a vehicle for the combination of different tomographic techniques with a joint full-waveform and traveltime ray tomography of Europe. This combination broadens the exploitable frequency range of the individual techniques, thereby improving resolution. We perform two iterations of a whole-Earth full-waveform inversion using a long-period reference data set from 225 globally recorded earthquakes. At this early stage
Quantitative analysis of numerical solvers for oscillatory biomolecular system models
Quo, Chang F; Wang, May D
2008-01-01
Background This article provides guidelines for selecting optimal numerical solvers for biomolecular system models. Because various parameters of the same system could have drastically different ranges from 10-15 to 1010, the ODEs can be stiff and ill-conditioned, resulting in non-unique, non-existing, or non-reproducible modeling solutions. Previous studies have not examined in depth how to best select numerical solvers for biomolecular system models, which makes it difficult to experimentally validate the modeling results. To address this problem, we have chosen one of the well-known stiff initial value problems with limit cycle behavior as a test-bed system model. Solving this model, we have illustrated that different answers may result from different numerical solvers. We use MATLAB numerical solvers because they are optimized and widely used by the modeling community. We have also conducted a systematic study of numerical solver performances by using qualitative and quantitative measures such as convergence, accuracy, and computational cost (i.e. in terms of function evaluation, partial derivative, LU decomposition, and "take-off" points). The results show that the modeling solutions can be drastically different using different numerical solvers. Thus, it is important to intelligently select numerical solvers when solving biomolecular system models. Results The classic Belousov-Zhabotinskii (BZ) reaction is described by the Oregonator model and is used as a case study. We report two guidelines in selecting optimal numerical solver(s) for stiff, complex oscillatory systems: (i) for problems with unknown parameters, ode45 is the optimal choice regardless of the relative error tolerance; (ii) for known stiff problems, both ode113 and ode15s are good choices under strict relative tolerance conditions. Conclusions For any given biomolecular model, by building a library of numerical solvers with quantitative performance assessment metric, we show that it is possible
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
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.
Euler/Navier-Stokes Solvers Applied to Ducted Fan Configurations
NASA Technical Reports Server (NTRS)
Keith, Theo G., Jr.; Srivastava, Rakesh
1997-01-01
Due to noise considerations, ultra high bypass ducted fans have become a more viable design. These ducted fans typically consist of a rotor stage containing a wide chord fan and a stator stage. One of the concerns for this design is the classical flutter that keeps occurring in various unducted fan blade designs. These flutter are catastrophic and are to be avoided in the flight envelope of the engine. Some numerical investigations by Williams, Cho and Dalton, have suggested that a duct around a propeller makes it more unstable. This needs to be further investigated. In order to design an engine to safely perform a set of desired tasks, accurate information of the stresses on the blade during the entire cycle of blade motion is required. This requirement in turn demands that accurate knowledge of steady and unsteady blade loading be available. Aerodynamic solvers based on unsteady three-dimensional analysis will provide accurate and fast solutions and are best suited for aeroelastic analysis. The Euler solvers capture significant physics of the flowfield and are reasonably fast. An aerodynamic solver Ref. based on Euler equations had been developed under a separate grant from NASA Lewis in the past. Under the current grant, this solver has been modified to calculate the aeroelastic characteristics of unducted and ducted rotors. Even though, the aeroelastic solver based on three-dimensional Euler equations is computationally efficient, it is still very expensive to investigate the effects of multiple stages on the aeroelastic characteristics. In order to investigate the effects of multiple stages, a two-dimensional multi stage aeroelastic solver was also developed under this task, in collaboration with Dr. T. S. R. Reddy of the University of Toledo. Both of these solvers were applied to several test cases and validated against experimental data, where available.
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
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)
Balsara, Dinshaw S.; Kim, Jinho
2016-05-01
The relativistic magnetohydrodynamics (RMHD) set of equations has recently seen an increased use in astrophysical computations. Even so, RMHD codes remain fragile. The reconstruction can sometimes yield superluminal velocities in certain parts of the mesh. The current generation of RMHD codes does not have any particularly good strategy for avoiding such an unphysical situation. In this paper we present a reconstruction strategy that overcomes this problem by making a single conservative to primitive transformation per cell followed by higher order WENO reconstruction on a carefully chosen set of primitives that guarantee subluminal reconstruction of the flow variables. For temporal evolution via a predictor step we also present second, third and fourth order accurate ADER methods that keep the velocity subluminal during the predictor step. The methods presented here are very general and should apply to other PDE systems where physical realizability is most easily asserted in the primitive variables. The RMHD system also requires the magnetic field to be evolved in a divergence-free fashion. In the treatment of classical numerical MHD the analogous issue has seen much recent progress with the advent of multidimensional Riemann solvers. By developing multidimensional Riemann solvers for RMHD, we show that similar advances extend to RMHD. As a result, the face-centered magnetic fields can be evolved much more accurately using the edge-centered electric fields in the corrector step. Those edge-centered electric fields come from a multidimensional Riemann solver for RMHD which we present in this paper. The overall update results in a one-step, fully conservative scheme that is suited for AMR. In this paper we also develop several new test problems for RMHD. We show that RMHD vortices can be designed that propagate on the computational mesh as self-preserving structures. These RMHD vortex test problems provide a means to do truly multidimensional accuracy testing for
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
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
Differential Geometry Based Multiscale Models
Wei, Guo-Wei
2010-01-01
Large chemical and biological systems such as fuel cells, ion channels, molecular motors, and viruses are of great importance to the scientific community and public health. Typically, these complex systems in conjunction with their aquatic environment pose a fabulous challenge to theoretical description, simulation, and prediction. In this work, we propose a differential geometry based multiscale paradigm to model complex macromolecular systems, and to put macroscopic and microscopic descriptions on an equal footing. In our approach, the differential geometry theory of surfaces and geometric measure theory are employed as a natural means to couple the macroscopic continuum mechanical description of the aquatic environment with the microscopic discrete atom-istic description of the macromolecule. Multiscale free energy functionals, or multiscale action functionals are constructed as a unified framework to derive the governing equations for the dynamics of different scales and different descriptions. Two types of aqueous macromolecular complexes, ones that are near equilibrium and others that are far from equilibrium, are considered in our formulations. We show that generalized Navier–Stokes equations for the fluid dynamics, generalized Poisson equations or generalized Poisson–Boltzmann equations for electrostatic interactions, and Newton's equation for the molecular dynamics can be derived by the least action principle. These equations are coupled through the continuum-discrete interface whose dynamics is governed by potential driven geometric flows. Comparison is given to classical descriptions of the fluid and electrostatic interactions without geometric flow based micro-macro interfaces. The detailed balance of forces is emphasized in the present work. We further extend the proposed multiscale paradigm to micro-macro analysis of electrohydrodynamics, electrophoresis, fuel cells, and ion channels. We derive generalized Poisson–Nernst–Planck equations that
Performance Models for the Spike Banded Linear System Solver
Manguoglu, Murat; Saied, Faisal; Sameh, Ahmed; Grama, Ananth
2011-01-01
With availability of large-scale parallel platforms comprised of tens-of-thousands of processors and beyond, there is significant impetus for the development of scalable parallel sparse linear system solvers and preconditioners. An integral part of this design process is the development of performance models capable of predicting performance and providing accurate cost models for the solvers and preconditioners. There has been some work in the past on characterizing performance of the iterative solvers themselves. In this paper, we investigate the problem of characterizing performance and scalability of banded preconditioners. Recent work has demonstrated the superior convergence properties and robustness of banded preconditioners,more » compared to state-of-the-art ILU family of preconditioners as well as algebraic multigrid preconditioners. Furthermore, when used in conjunction with efficient banded solvers, banded preconditioners are capable of significantly faster time-to-solution. Our banded solver, the Truncated Spike algorithm is specifically designed for parallel performance and tolerance to deep memory hierarchies. Its regular structure is also highly amenable to accurate performance characterization. Using these characteristics, we derive the following results in this paper: (i) we develop parallel formulations of the Truncated Spike solver, (ii) we develop a highly accurate pseudo-analytical parallel performance model for our solver, (iii) we show excellent predication capabilities of our model – based on which we argue the high scalability of our solver. Our pseudo-analytical performance model is based on analytical performance characterization of each phase of our solver. These analytical models are then parameterized using actual runtime information on target platforms. An important consequence of our performance models is that they reveal underlying performance bottlenecks in both serial and parallel formulations. All of our results are validated
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
The novel high-performance 3-D MT inverse solver
NASA Astrophysics Data System (ADS)
Kruglyakov, Mikhail; Geraskin, Alexey; Kuvshinov, Alexey
2016-04-01
We present novel, robust, scalable, and fast 3-D magnetotelluric (MT) inverse solver. The solver is written in multi-language paradigm to make it as efficient, readable and maintainable as possible. Separation of concerns and single responsibility concepts go through implementation of the solver. As a forward modelling engine a modern scalable solver extrEMe, based on contracting integral equation approach, is used. Iterative gradient-type (quasi-Newton) optimization scheme is invoked to search for (regularized) inverse problem solution, and adjoint source approach is used to calculate efficiently the gradient of the misfit. The inverse solver is able to deal with highly detailed and contrasting models, allows for working (separately or jointly) with any type of MT responses, and supports massive parallelization. Moreover, different parallelization strategies implemented in the code allow optimal usage of available computational resources for a given problem statement. To parameterize an inverse domain the so-called mask parameterization is implemented, which means that one can merge any subset of forward modelling cells in order to account for (usually) irregular distribution of observation sites. We report results of 3-D numerical experiments aimed at analysing the robustness, performance and scalability of the code. In particular, our computational experiments carried out at different platforms ranging from modern laptops to HPC Piz Daint (6th supercomputer in the world) demonstrate practically linear scalability of the code up to thousands of nodes.
Performance of Nonlinear Finite-Difference Poisson-Boltzmann Solvers.
Cai, Qin; Hsieh, Meng-Juei; Wang, Jun; Luo, Ray
2010-01-12
We implemented and optimized seven finite-difference solvers for the full nonlinear Poisson-Boltzmann equation in biomolecular applications, including four relaxation methods, one conjugate gradient method, and two inexact Newton methods. The performance of the seven solvers was extensively evaluated with a large number of nucleic acids and proteins. Worth noting is the inexact Newton method in our analysis. We investigated the role of linear solvers in its performance by incorporating the incomplete Cholesky conjugate gradient and the geometric multigrid into its inner linear loop. We tailored and optimized both linear solvers for faster convergence rate. In addition, we explored strategies to optimize the successive over-relaxation method to reduce its convergence failures without too much sacrifice in its convergence rate. Specifically we attempted to adaptively change the relaxation parameter and to utilize the damping strategy from the inexact Newton method to improve the successive over-relaxation method. Our analysis shows that the nonlinear methods accompanied with a functional-assisted strategy, such as the conjugate gradient method and the inexact Newton method, can guarantee convergence in the tested molecules. Especially the inexact Newton method exhibits impressive performance when it is combined with highly efficient linear solvers that are tailored for its special requirement. PMID:24723843
NASA Technical Reports Server (NTRS)
Ricks, Trenton M.; Lacy, Thomas E., Jr.; Bednarcyk, Brett A.; Arnold, Steven M.; Hutchins, John W.
2014-01-01
A multiscale modeling methodology was developed for continuous fiber composites that incorporates a statistical distribution of fiber strengths into coupled multiscale micromechanics/finite element (FE) analyses. A modified two-parameter Weibull cumulative distribution function, which accounts for the effect of fiber length on the probability of failure, was used to characterize the statistical distribution of fiber strengths. A parametric study using the NASA Micromechanics Analysis Code with the Generalized Method of Cells (MAC/GMC) was performed to assess the effect of variable fiber strengths on local composite failure within a repeating unit cell (RUC) and subsequent global failure. The NASA code FEAMAC and the ABAQUS finite element solver were used to analyze the progressive failure of a unidirectional SCS-6/TIMETAL 21S metal matrix composite tensile dogbone specimen at 650 degC. Multiscale progressive failure analyses were performed to quantify the effect of spatially varying fiber strengths on the RUC-averaged and global stress-strain responses and failure. The ultimate composite strengths and distribution of failure locations (predominately within the gage section) reasonably matched the experimentally observed failure behavior. The predicted composite failure behavior suggests that use of macroscale models that exploit global geometric symmetries are inappropriate for cases where the actual distribution of local fiber strengths displays no such symmetries. This issue has not received much attention in the literature. Moreover, the model discretization at a specific length scale can have a profound effect on the computational costs associated with multiscale simulations.models that yield accurate yet tractable results.
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
Data Assimilation and Propagation of Uncertainty in Multiscale Cardiovascular Simulation
NASA Astrophysics Data System (ADS)
Schiavazzi, Daniele; Marsden, Alison
2015-11-01
Cardiovascular modeling is the application of computational tools to predict hemodynamics. State-of-the-art techniques couple a 3D incompressible Navier-Stokes solver with a boundary circulation model and can predict local and peripheral hemodynamics, analyze the post-operative performance of surgical designs and complement clinical data collection minimizing invasive and risky measurement practices. The ability of these tools to make useful predictions is directly related to their accuracy in representing measured physiologies. Tuning of model parameters is therefore a topic of paramount importance and should include clinical data uncertainty, revealing how this uncertainty will affect the predictions. We propose a fully Bayesian, multi-level approach to data assimilation of uncertain clinical data in multiscale circulation models. To reduce the computational cost, we use a stable, condensed approximation of the 3D model build by linear sparse regression of the pressure/flow rate relationship at the outlets. Finally, we consider the problem of non-invasively propagating the uncertainty in model parameters to the resulting hemodynamics and compare Monte Carlo simulation with Stochastic Collocation approaches based on Polynomial or Multi-resolution Chaos expansions.
A Multiphysics and Multiscale Software Environment for Modeling Astrophysical Systems
NASA Astrophysics Data System (ADS)
Portegies Zwart, Simon; McMillan, Steve; O'Nualláin, Breanndán; Heggie, Douglas; Lombardi, James; Hut, Piet; Banerjee, Sambaran; Belkus, Houria; Fragos, Tassos; Fregeau, John; Fuji, Michiko; Gaburov, Evghenii; Glebbeek, Evert; Groen, Derek; Harfst, Stefan; Izzard, Rob; Jurić, Mario; Justham, Stephen; Teuben, Peter; van Bever, Joris; Yaron, Ofer; Zemp, Marcel
We present MUSE, a software framework for tying together existing computational tools for different astrophysical domains into a single multiphysics, multiscale workload. MUSE facilitates the coupling of existing codes written in different languages by providing inter-language tools and by specifying an interface between each module and the framework that represents a balance between generality and computational efficiency. This approach allows scientists to use combinations of codes to solve highly-coupled problems without the need to write new codes for other domains or significantly alter their existing codes. MUSE currently incorporates the domains of stellar dynamics, stellar evolution and stellar hydrodynamics for a generalized stellar systems workload. MUSE has now reached a "Noah's Ark" milestone, with two available numerical solvers for each domain. MUSE can treat small stellar associations, galaxies and everything in between, including planetary systems, dense stellar clusters and galactic nuclei. Here we demonstrate an examples calculated with MUSE: the merger of two galaxies. In addition we demonstrate the working of MUSE on a distributed computer. The current MUSE code base is publicly available as open source at http://muse.li.
General Equation Set Solver for Compressible and Incompressible Turbomachinery Flows
NASA Technical Reports Server (NTRS)
Sondak, Douglas L.; Dorney, Daniel J.
2002-01-01
Turbomachines for propulsion applications operate with many different working fluids and flow conditions. The flow may be incompressible, such as in the liquid hydrogen pump in a rocket engine, or supersonic, such as in the turbine which may drive the hydrogen pump. Separate codes have traditionally been used for incompressible and compressible flow solvers. The General Equation Set (GES) method can be used to solve both incompressible and compressible flows, and it is not restricted to perfect gases, as are many compressible-flow turbomachinery solvers. An unsteady GES turbomachinery flow solver has been developed and applied to both air and water flows through turbines. It has been shown to be an excellent alternative to maintaining two separate codes.
Two Solvers for Tractable Temporal Constraints with Preferences
NASA Technical Reports Server (NTRS)
Rossi, F.; Khatib,L.; Morris, P.; Morris, R.; Clancy, Daniel (Technical Monitor)
2002-01-01
A number of reasoning problems involving the manipulation of temporal information can naturally be viewed as implicitly inducing an ordering of potential local decisions involving time on the basis of preferences. Soft temporal constraints problems allow to describe in a natural way scenarios where events happen over time and preferences are associated to event distances and durations. In general, solving soft temporal problems require exponential time in the worst case, but there are interesting subclasses of problems which are polynomially solvable. We describe two solvers based on two different approaches for solving the same tractable subclass. For each solver we present the theoretical results it stands on, a description of the algorithm and some experimental results. The random generator used to build the problems on which tests are performed is also described. Finally, we compare the two solvers highlighting the tradeoff between performance and representational power.
A multiple right hand side iterative solver for history matching
Killough, J.E.; Sharma, Y.; Dupuy, A.; Bissell, R.; Wallis, J.
1995-12-31
History matching of oil and gas reservoirs can be accelerated by directly calculating the gradients of observed quantities (e.g., well pressure) with respect to the adjustable reserve parameters (e.g., permeability). This leads to a set of linear equations which add a significant overhead to the full simulation run without gradients. Direct Gauss elimination solvers can be used to address this problem by performing the factorization of the matrix only once and then reusing the factor matrix for the solution of the multiple right hand sides. This is a limited technique, however. Experience has shown that problems with greater than few thousand cells may not be practical for direct solvers because of computation time and memory limitations. This paper discusses the implementation of a multiple right hand side iterative linear equation solver (MRHS) for a system of adjoint equations to significantly enhance the performance of a gradient simulator.
Gpu Implementation of a Viscous Flow Solver on Unstructured Grids
NASA Astrophysics Data System (ADS)
Xu, Tianhao; Chen, Long
2016-06-01
Graphics processing units have gained popularities in scientific computing over past several years due to their outstanding parallel computing capability. Computational fluid dynamics applications involve large amounts of calculations, therefore a latest GPU card is preferable of which the peak computing performance and memory bandwidth are much better than a contemporary high-end CPU. We herein focus on the detailed implementation of our GPU targeting Reynolds-averaged Navier-Stokes equations solver based on finite-volume method. The solver employs a vertex-centered scheme on unstructured grids for the sake of being capable of handling complex topologies. Multiple optimizations are carried out to improve the memory accessing performance and kernel utilization. Both steady and unsteady flow simulation cases are carried out using explicit Runge-Kutta scheme. The solver with GPU acceleration in this paper is demonstrated to have competitive advantages over the CPU targeting one.
The Adaptive Multi-scale Simulation Infrastructure
Tobin, William R.
2015-09-01
The Adaptive Multi-scale Simulation Infrastructure (AMSI) is a set of libraries and tools developed to support the development, implementation, and execution of general multimodel simulations. Using a minimal set of simulation meta-data AMSI allows for minimally intrusive work to adapt existent single-scale simulations for use in multi-scale simulations. Support for dynamic runtime operations such as single- and multi-scale adaptive properties is a key focus of AMSI. Particular focus has been spent on the development on scale-sensitive load balancing operations to allow single-scale simulations incorporated into a multi-scale simulation using AMSI to use standard load-balancing operations without affecting the integrity of the overall multi-scale simulation.
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
Fast Euler solver for transonic airfoils. I - Theory. II - Applications
NASA Technical Reports Server (NTRS)
Dadone, Andrea; Moretti, Gino
1988-01-01
Equations written in terms of generalized Riemann variables are presently integrated by inverting six bidiagonal matrices and two tridiagonal matrices, using an implicit Euler solver that is based on the lambda-formulation. The solution is found on a C-grid whose boundaries are very close to the airfoil. The fast solver is then applied to the computation of several flowfields on a NACA 0012 airfoil at various Mach number and alpha values, yielding results that are primarily concerned with transonic flows. The effects of grid fineness and boundary distances are analyzed; the code is found to be robust and accurate, as well as fast.
Numerical System Solver Developed for the National Cycle Program
NASA Technical Reports Server (NTRS)
Binder, Michael P.
1999-01-01
As part of the National Cycle Program (NCP), a powerful new numerical solver has been developed to support the simulation of aeropropulsion systems. This software uses a hierarchical object-oriented design. It can provide steady-state and time-dependent solutions to nonlinear and even discontinuous problems typically encountered when aircraft and spacecraft propulsion systems are simulated. It also can handle constrained solutions, in which one or more factors may limit the behavior of the engine system. Timedependent simulation capabilities include adaptive time-stepping and synchronization with digital control elements. The NCP solver is playing an important role in making the NCP a flexible, powerful, and reliable simulation package.
Peridynamic Multiscale Finite Element Methods
Costa, Timothy; Bond, Stephen D.; Littlewood, David John; Moore, Stan Gerald
2015-12-01
The problem of computing quantum-accurate design-scale solutions to mechanics problems is rich with applications and serves as the background to modern multiscale science research. The prob- lem can be broken into component problems comprised of communicating across adjacent scales, which when strung together create a pipeline for information to travel from quantum scales to design scales. Traditionally, this involves connections between a) quantum electronic structure calculations and molecular dynamics and between b) molecular dynamics and local partial differ- ential equation models at the design scale. The second step, b), is particularly challenging since the appropriate scales of molecular dynamic and local partial differential equation models do not overlap. The peridynamic model for continuum mechanics provides an advantage in this endeavor, as the basic equations of peridynamics are valid at a wide range of scales limiting from the classical partial differential equation models valid at the design scale to the scale of molecular dynamics. In this work we focus on the development of multiscale finite element methods for the peridynamic model, in an effort to create a mathematically consistent channel for microscale information to travel from the upper limits of the molecular dynamics scale to the design scale. In particular, we first develop a Nonlocal Multiscale Finite Element Method which solves the peridynamic model at multiple scales to include microscale information at the coarse-scale. We then consider a method that solves a fine-scale peridynamic model to build element-support basis functions for a coarse- scale local partial differential equation model, called the Mixed Locality Multiscale Finite Element Method. Given decades of research and development into finite element codes for the local partial differential equation models of continuum mechanics there is a strong desire to couple local and nonlocal models to leverage the speed and state of the
Fluid simulations with atomistic resolution: a hybrid multiscale method with field-wise coupling
Borg, Matthew K.; Lockerby, Duncan A.; Reese, Jason M.
2013-12-15
We present a new hybrid method for simulating dense fluid systems that exhibit multiscale behaviour, in particular, systems in which a Navier–Stokes model may not be valid in parts of the computational domain. We apply molecular dynamics as a local microscopic refinement for correcting the Navier–Stokes constitutive approximation in the bulk of the domain, as well as providing a direct measurement of velocity slip at bounding surfaces. Our hybrid approach differs from existing techniques, such as the heterogeneous multiscale method (HMM), in some fundamental respects. In our method, the individual molecular solvers, which provide information to the macro model, are not coupled with the continuum grid at nodes (i.e. point-wise coupling), instead coupling occurs over distributed heterogeneous fields (here referred to as field-wise coupling). This affords two major advantages. Whereas point-wise coupled HMM is limited to regions of flow that are highly scale-separated in all spatial directions (i.e. where the state of non-equilibrium in the fluid can be adequately described by a single strain tensor and temperature gradient vector), our field-wise coupled HMM has no such limitations and so can be applied to flows with arbitrarily-varying degrees of scale separation (e.g. flow from a large reservoir into a nano-channel). The second major advantage is that the position of molecular elements does not need to be collocated with nodes of the continuum grid, which means that the resolution of the microscopic correction can be adjusted independently of the resolution of the continuum model. This in turn means the computational cost and accuracy of the molecular correction can be independently controlled and optimised. The macroscopic constraints on the individual molecular solvers are artificial body-force distributions, used in conjunction with standard periodicity. We test our hybrid method on the Poiseuille flow problem for both Newtonian (Lennard-Jones) and non
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
Multiscale hierarchical support vector clustering
NASA Astrophysics Data System (ADS)
Hansen, Michael Saas; Holm, David Alberg; Sjöstrand, Karl; Ley, Carsten Dan; Rowland, Ian John; Larsen, Rasmus
2008-03-01
Clustering is the preferred choice of method in many applications, and support vector clustering (SVC) has proven efficient for clustering noisy and high-dimensional data sets. A method for multiscale support vector clustering is demonstrated, using the recently emerged method for fast calculation of the entire regularization path of the support vector domain description. The method is illustrated on artificially generated examples, and applied for detecting blood vessels from high resolution time series of magnetic resonance imaging data. The obtained results are robust while the need for parameter estimation is reduced, compared to support vector clustering.
Energy Science and Technology Software Center (ESTSC)
2009-08-01
The code to be released is a new addition to the LAMMPS molecular dynamics code. LAMMPS is developed and maintained by Sandia, is publicly available, and is used widely by both natioanl laboratories and academics. The new addition to be released enables LAMMPS to perform molecular dynamics simulations of shock waves using the Multi-scale Shock Simulation Technique (MSST) which we have developed and has been previously published. This technique enables molecular dynamics simulations of shockmore » waves in materials for orders of magnitude longer timescales than the direct, commonly employed approach.« less
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
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
Towards a Multiscale Approach to Cybersecurity Modeling
Hogan, Emilie A.; Hui, Peter SY; Choudhury, Sutanay; Halappanavar, Mahantesh; Oler, Kiri J.; Joslyn, Cliff A.
2013-11-12
We propose a multiscale approach to modeling cyber networks, with the goal of capturing a view of the network and overall situational awareness with respect to a few key properties--- connectivity, distance, and centrality--- for a system under an active attack. We focus on theoretical and algorithmic foundations of multiscale graphs, coming from an algorithmic perspective, with the goal of modeling cyber system defense as a specific use case scenario. We first define a notion of \\emph{multiscale} graphs, in contrast with their well-studied single-scale counterparts. We develop multiscale analogs of paths and distance metrics. As a simple, motivating example of a common metric, we present a multiscale analog of the all-pairs shortest-path problem, along with a multiscale analog of a well-known algorithm which solves it. From a cyber defense perspective, this metric might be used to model the distance from an attacker's position in the network to a sensitive machine. In addition, we investigate probabilistic models of connectivity. These models exploit the hierarchy to quantify the likelihood that sensitive targets might be reachable from compromised nodes. We believe that our novel multiscale approach to modeling cyber-physical systems will advance several aspects of cyber defense, specifically allowing for a more efficient and agile approach to defending these systems.
Multiscale analysis of neural spike trains.
Ramezan, Reza; Marriott, Paul; Chenouri, Shojaeddin
2014-01-30
This paper studies the multiscale analysis of neural spike trains, through both graphical and Poisson process approaches. We introduce the interspike interval plot, which simultaneously visualizes characteristics of neural spiking activity at different time scales. Using an inhomogeneous Poisson process framework, we discuss multiscale estimates of the intensity functions of spike trains. We also introduce the windowing effect for two multiscale methods. Using quasi-likelihood, we develop bootstrap confidence intervals for the multiscale intensity function. We provide a cross-validation scheme, to choose the tuning parameters, and study its unbiasedness. Studying the relationship between the spike rate and the stimulus signal, we observe that adjusting for the first spike latency is important in cross-validation. We show, through examples, that the correlation between spike trains and spike count variability can be multiscale phenomena. Furthermore, we address the modeling of the periodicity of the spike trains caused by a stimulus signal or by brain rhythms. Within the multiscale framework, we introduce intensity functions for spike trains with multiplicative and additive periodic components. Analyzing a dataset from the retinogeniculate synapse, we compare the fit of these models with the Bayesian adaptive regression splines method and discuss the limitations of the methodology. Computational efficiency, which is usually a challenge in the analysis of spike trains, is one of the highlights of these new models. In an example, we show that the reconstruction quality of a complex intensity function demonstrates the ability of the multiscale methodology to crack the neural code. PMID:23996238
Assessment of Linear Finite-Difference Poisson-Boltzmann Solvers
Wang, Jun; Luo, Ray
2009-01-01
CPU time and memory usage are two vital issues that any numerical solvers for the Poisson-Boltzmann equation have to face in biomolecular applications. In this study we systematically analyzed the CPU time and memory usage of five commonly used finite-difference solvers with a large and diversified set of biomolecular structures. Our comparative analysis shows that modified incomplete Cholesky conjugate gradient and geometric multigrid are the most efficient in the diversified test set. For the two efficient solvers, our test shows that their CPU times increase approximately linearly with the numbers of grids. Their CPU times also increase almost linearly with the negative logarithm of the convergence criterion at very similar rate. Our comparison further shows that geometric multigrid performs better in the large set of tested biomolecules. However, modified incomplete Cholesky conjugate gradient is superior to geometric multigrid in molecular dynamics simulations of tested molecules. We also investigated other significant components in numerical solutions of the Poisson-Boltzmann equation. It turns out that the time-limiting step is the free boundary condition setup for the linear systems for the selected proteins if the electrostatic focusing is not used. Thus, development of future numerical solvers for the Poisson-Boltzmann equation should balance all aspects of the numerical procedures in realistic biomolecular applications. PMID:20063271
Navier-Stokes Solvers and Generalizations for Reacting Flow Problems
Elman, Howard C
2013-01-27
This is an overview of our accomplishments during the final term of this grant (1 September 2008 -- 30 June 2012). These fall mainly into three categories: fast algorithms for linear eigenvalue problems; solution algorithms and modeling methods for partial differential equations with uncertain coefficients; and preconditioning methods and solvers for models of computational fluid dynamics (CFD).
Assessment of linear finite-difference Poisson-Boltzmann solvers.
Wang, Jun; Luo, Ray
2010-06-01
CPU time and memory usage are two vital issues that any numerical solvers for the Poisson-Boltzmann equation have to face in biomolecular applications. In this study, we systematically analyzed the CPU time and memory usage of five commonly used finite-difference solvers with a large and diversified set of biomolecular structures. Our comparative analysis shows that modified incomplete Cholesky conjugate gradient and geometric multigrid are the most efficient in the diversified test set. For the two efficient solvers, our test shows that their CPU times increase approximately linearly with the numbers of grids. Their CPU times also increase almost linearly with the negative logarithm of the convergence criterion at very similar rate. Our comparison further shows that geometric multigrid performs better in the large set of tested biomolecules. However, modified incomplete Cholesky conjugate gradient is superior to geometric multigrid in molecular dynamics simulations of tested molecules. We also investigated other significant components in numerical solutions of the Poisson-Boltzmann equation. It turns out that the time-limiting step is the free boundary condition setup for the linear systems for the selected proteins if the electrostatic focusing is not used. Thus, development of future numerical solvers for the Poisson-Boltzmann equation should balance all aspects of the numerical procedures in realistic biomolecular applications. PMID:20063271
Advances in computational fluid dynamics solvers for modern computing environments
NASA Astrophysics Data System (ADS)
Hertenstein, Daniel; Humphrey, John R.; Paolini, Aaron L.; Kelmelis, Eric J.
2013-05-01
EM Photonics has been investigating the application of massively multicore processors to a key problem area: Computational Fluid Dynamics (CFD). While the capabilities of CFD solvers have continually increased and improved to support features such as moving bodies and adjoint-based mesh adaptation, the software architecture has often lagged behind. This has led to poor scaling as core counts reach the tens of thousands. In the modern High Performance Computing (HPC) world, clusters with hundreds of thousands of cores are becoming the standard. In addition, accelerator devices such as NVIDIA GPUs and Intel Xeon Phi are being installed in many new systems. It is important for CFD solvers to take advantage of the new hardware as the computations involved are well suited for the massively multicore architecture. In our work, we demonstrate that new features in NVIDIA GPUs are able to empower existing CFD solvers by example using AVUS, a CFD solver developed by the Air Force Research Labratory (AFRL) and the Volcanic Ash Advisory Center (VAAC). The effort has resulted in increased performance and scalability without sacrificing accuracy. There are many well-known codes in the CFD space that can benefit from this work, such as FUN3D, OVERFLOW, and TetrUSS. Such codes are widely used in the commercial, government, and defense sectors.
Coordinate Projection-based Solver for ODE with Invariants
Serban, Radu
2008-04-08
CPODES is a general purpose (serial and parallel) solver for systems of ordinary differential equation (ODE) with invariants. It implements a coordinate projection approach using different types of projection (orthogonal or oblique) and one of several methods for the decompositon of the Jacobian of the invariant equations.
Intellectual Abilities That Discriminate Good and Poor Problem Solvers.
ERIC Educational Resources Information Center
Meyer, Ruth Ann
1981-01-01
This study compared good and poor fourth-grade problem solvers on a battery of 19 "reference" tests for verbal, induction, numerical, word fluency, memory, perceptual speed, and simple visualization abilities. Results suggest verbal, numerical, and especially induction abilities are important to successful mathematical problem solving. (MP)
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
Modeling Complex Biological Flows in Multi-Scale Systems using the APDEC Framework
Trebotich, D
2006-06-24
We have developed advanced numerical algorithms to model biological fluids in multiscale flow environments using the software framework developed under the SciDAC APDEC ISIC. The foundation of our computational effort is an approach for modeling DNA-laden fluids as ''bead-rod'' polymers whose dynamics are fully coupled to an incompressible viscous solvent. The method is capable of modeling short range forces and interactions between particles using soft potentials and rigid constraints. Our methods are based on higher-order finite difference methods in complex geometry with adaptivity, leveraging algorithms and solvers in the APDEC Framework. Our Cartesian grid embedded boundary approach to incompressible viscous flow in irregular geometries has also been interfaced to a fast and accurate level-sets method within the APDEC Framework for extracting surfaces from volume renderings of medical image data and used to simulate cardio-vascular and pulmonary flows in critical anatomies.
Griebel, M. E-mail: ruettgers@ins.uni-bonn.de; Rüttgers, A. E-mail: ruettgers@ins.uni-bonn.de
2014-05-15
The multiscale FENE model is applied to a 3D square-square contraction flow problem. For this purpose, the stochastic Brownian configuration field method (BCF) has been coupled with our fully parallelized three-dimensional Navier-Stokes solver NaSt3DGPF. The robustness of the BCF method enables the numerical simulation of high Deborah number flows for which most macroscopic methods suffer from stability issues. The results of our simulations are compared with that of experimental measurements from literature and show a very good agreement. In particular, flow phenomena such as a strong vortex enhancement, streamline divergence and a flow inversion for highly elastic flows are reproduced. Due to their computational complexity, our simulations require massively parallel computations. Using a domain decomposition approach with MPI, the implementation achieves excellent scale-up results for up to 128 processors.
Multi-scale Godunov-type method for cell-centered discrete Lagrangian hydrodynamics
NASA Astrophysics Data System (ADS)
Maire, Pierre-Henri; Nkonga, Boniface
2009-02-01
This work presents a multi-dimensional cell-centered unstructured finite volume scheme for the solution of multimaterial compressible fluid flows written in the Lagrangian formalism. This formulation is considered in the Arbitrary-Lagrangian-Eulerian (ALE) framework with the constraint that the mesh velocity and the fluid velocity coincide. The link between the vertex velocity and the fluid motion is obtained by a formulation of the momentum conservation on a class of multi-scale encased volumes around mesh vertices. The vertex velocity is derived with a nodal Riemann solver constructed in such a way that the mesh motion and the face fluxes are compatible. Finally, the resulting scheme conserves both momentum and total energy and, it satisfies a semi-discrete entropy inequality. The numerical results obtained for some classical 2D and 3D hydrodynamic test cases show the robustness and the accuracy of the proposed algorithm.
NASA Technical Reports Server (NTRS)
Ricks, Trenton M.; Lacy, Thomas E., Jr.; Pineda, Evan J.; Bednarcyk, Brett A.; Arnold, Steven M.
2013-01-01
A multiscale modeling methodology, which incorporates a statistical distribution of fiber strengths into coupled micromechanics/ finite element analyses, is applied to unidirectional polymer matrix composites (PMCs) to analyze the effect of mesh discretization both at the micro- and macroscales on the predicted ultimate tensile (UTS) strength and failure behavior. The NASA code FEAMAC and the ABAQUS finite element solver were used to analyze the progressive failure of a PMC tensile specimen that initiates at the repeating unit cell (RUC) level. Three different finite element mesh densities were employed and each coupled with an appropriate RUC. Multiple simulations were performed in order to assess the effect of a statistical distribution of fiber strengths on the bulk composite failure and predicted strength. The coupled effects of both the micro- and macroscale discretizations were found to have a noticeable effect on the predicted UTS and computational efficiency of the simulations.
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.
Decision Engines for Software Analysis Using Satisfiability Modulo Theories Solvers
NASA Technical Reports Server (NTRS)
Bjorner, Nikolaj
2010-01-01
The area of software analysis, testing and verification is now undergoing a revolution thanks to the use of automated and scalable support for logical methods. A well-recognized premise is that at the core of software analysis engines is invariably a component using logical formulas for describing states and transformations between system states. The process of using this information for discovering and checking program properties (including such important properties as safety and security) amounts to automatic theorem proving. In particular, theorem provers that directly support common software constructs offer a compelling basis. Such provers are commonly called satisfiability modulo theories (SMT) solvers. Z3 is a state-of-the-art SMT solver. It is developed at Microsoft Research. It can be used to check the satisfiability of logical formulas over one or more theories such as arithmetic, bit-vectors, lists, records and arrays. The talk describes some of the technology behind modern SMT solvers, including the solver Z3. Z3 is currently mainly targeted at solving problems that arise in software analysis and verification. It has been applied to various contexts, such as systems for dynamic symbolic simulation (Pex, SAGE, Vigilante), for program verification and extended static checking (Spec#/Boggie, VCC, HAVOC), for software model checking (Yogi, SLAM), model-based design (FORMULA), security protocol code (F7), program run-time analysis and invariant generation (VS3). We will describe how it integrates support for a variety of theories that arise naturally in the context of the applications. There are several new promising avenues and the talk will touch on some of these and the challenges related to SMT solvers. Proceedings
Migration of vectorized iterative solvers to distributed memory architectures
Pommerell, C.; Ruehl, R.
1994-12-31
Both necessity and opportunity motivate the use of high-performance computers for iterative linear solvers. Necessity results from the size of the problems being solved-smaller problems are often better handled by direct methods. Opportunity arises from the formulation of the iterative methods in terms of simple linear algebra operations, even if this {open_quote}natural{close_quotes} parallelism is not easy to exploit in irregularly structured sparse matrices and with good preconditioners. As a result, high-performance implementations of iterative solvers have attracted a lot of interest in recent years. Most efforts are geared to vectorize or parallelize the dominating operation-structured or unstructured sparse matrix-vector multiplication, or to increase locality and parallelism by reformulating the algorithm-reducing global synchronization in inner products or local data exchange in preconditioners. Target architectures for iterative solvers currently include mostly vector supercomputers and architectures with one or few optimized (e.g., super-scalar and/or super-pipelined RISC) processors and hierarchical memory systems. More recently, parallel computers with physically distributed memory and a better price/performance ratio have been offered by vendors as a very interesting alternative to vector supercomputers. However, programming comfort on such distributed memory parallel processors (DMPPs) still lags behind. Here the authors are concerned with iterative solvers and their changing computing environment. In particular, they are considering migration from traditional vector supercomputers to DMPPs. Application requirements force one to use flexible and portable libraries. They want to extend the portability of iterative solvers rather than reimplementing everything for each new machine, or even for each new architecture.
Efficient three-dimensional Poisson solvers in open rectangular conducting pipe
NASA Astrophysics Data System (ADS)
Qiang, Ji
2016-06-01
Three-dimensional (3D) Poisson solver plays an important role in the study of space-charge effects on charged particle beam dynamics in particle accelerators. In this paper, we propose three new 3D Poisson solvers for a charged particle beam in an open rectangular conducting pipe. These three solvers include a spectral integrated Green function (IGF) solver, a 3D spectral solver, and a 3D integrated Green function solver. These solvers effectively handle the longitudinal open boundary condition using a finite computational domain that contains the beam itself. This saves the computational cost of using an extra larger longitudinal domain in order to set up an appropriate finite boundary condition. Using an integrated Green function also avoids the need to resolve rapid variation of the Green function inside the beam. The numerical operational cost of the spectral IGF solver and the 3D IGF solver scales as O(N log(N)) , where N is the number of grid points. The cost of the 3D spectral solver scales as O(Nn N) , where Nn is the maximum longitudinal mode number. We compare these three solvers using several numerical examples and discuss the advantageous regime of each solver in the physical application.
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
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
A framework for multi-scale modelling
Chopard, B.; Borgdorff, Joris; Hoekstra, A. G.
2014-01-01
We review a methodology to design, implement and execute multi-scale and multi-science numerical simulations. We identify important ingredients of multi-scale modelling and give a precise definition of them. Our framework assumes that a multi-scale model can be formulated in terms of a collection of coupled single-scale submodels. With concepts such as the scale separation map, the generic submodel execution loop (SEL) and the coupling templates, one can define a multi-scale modelling language which is a bridge between the application design and the computer implementation. Our approach has been successfully applied to an increasing number of applications from different fields of science and technology. PMID:24982249
On multiscale entropy analysis for physiological data
NASA Astrophysics Data System (ADS)
Thuraisingham, Ranjit A.; Gottwald, Georg A.
2006-07-01
We perform an analysis of cardiac data using multiscale entropy as proposed in Costa et al. [Multiscale entropy analysis of complex physiological time series, Phys. Rev. Lett. 89 (2002) 068102]. We reproduce the signatures of the multiscale entropy for the three cases of young healthy hearts, atrial fibrillation and congestive heart failure. We show that one has to be cautious how to interpret these signatures in terms of the underlying dynamics. In particular, we show that different dynamical systems can exhibit the same signatures depending on the sampling time, and that similar systems may have different signatures depending on the time scales involved. Besides the total amount of data we identify the sampling time, the correlation time and the period of possible nonlinear oscillations as important time scales which have to be involved in a detailed analysis of the signatures of multiscale entropies. We illustrate our ideas with the Lorenz equation as a simple deterministic chaotic system.
Collaborating for Multi-Scale Chemical Science
William H. Green
2006-07-14
Advanced model reduction methods were developed and integrated into the CMCS multiscale chemical science simulation software. The new technologies were used to simulate HCCI engines and burner flames with exceptional fidelity.
Multiscale modelling in immunology: a review.
Cappuccio, Antonio; Tieri, Paolo; Castiglione, Filippo
2016-05-01
One of the greatest challenges in biomedicine is to get a unified view of observations made from the molecular up to the organism scale. Towards this goal, multiscale models have been highly instrumental in contexts such as the cardiovascular field, angiogenesis, neurosciences and tumour biology. More recently, such models are becoming an increasingly important resource to address immunological questions as well. Systematic mining of the literature in multiscale modelling led us to identify three main fields of immunological applications: host-virus interactions, inflammatory diseases and their treatment and development of multiscale simulation platforms for immunological research and for educational purposes. Here, we review the current developments in these directions, which illustrate that multiscale models can consistently integrate immunological data generated at several scales, and can be used to describe and optimize therapeutic treatments of complex immune diseases. PMID:25810307
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.
NASA Astrophysics Data System (ADS)
Ulz, Manfred H.
2015-01-01
Multiscale models are designed to handle problems with different length scales and time scales in a suitable and efficient manner. Such problems include inelastic deformation or failure of materials. In particular, hierarchical multiscale methods are computationally powerful as no direct coupling between the scales is given. This paper proposes a hierarchical two-scale setting appropriate for isothermal quasi-static problems: a macroscale treated by continuum mechanics and the finite element method and a microscale modelled by a canonical ensemble of statistical mechanics solved with molecular dynamics. This model will be implemented into the framework of the heterogeneous multiscale method. The focus is laid on an efficient coupling of the macro- and micro-solvers. An iterative solution algorithm presents the macroscopic solver, which invokes for each iteration an atomistic computation. As the microscopic computation is considered to be very time consuming, two optimisation strategies are proposed. Firstly, the macroscopic solver is chosen to reduce the number of required iterations to a minimum. Secondly, the number of time steps used for the time average on the microscale will be increased with each iteration. As a result, the molecular dynamics cell will be allowed to reach its state of thermodynamic equilibrium only in the last macroscopic iteration step. In the preceding iteration steps, the molecular dynamics cell will reach a state close to equilibrium by using considerably fewer microscopic time steps. This adapted number of microsteps will result in an accelerated algorithm (aFE-MD-HMM) obtaining the same accuracy of results at significantly reduced computational cost. Numerical examples demonstrate the performance of the proposed scheme.
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
Multiscale Theory of Dislocation Climb
NASA Astrophysics Data System (ADS)
Geslin, Pierre-Antoine; Appolaire, Benoît; Finel, Alphonse
2015-12-01
Dislocation climb is a ubiquitous mechanism playing a major role in the plastic deformation of crystals at high temperature. We propose a multiscale approach to model quantitatively this mechanism at mesoscopic length and time scales. First, we analyze climb at a nanoscopic scale and derive an analytical expression of the climb rate of a jogged dislocation. Next, we deduce from this expression the activation energy of the process, bringing valuable insights to experimental studies. Finally, we show how to rigorously upscale the climb rate to a mesoscopic phase-field model of dislocation climb. This upscaling procedure opens the way to large scale simulations where climb processes are quantitatively reproduced even though the mesoscopic length scale of the simulation is orders of magnitude larger than the atomic one.
Multiscale Theory of Dislocation Climb.
Geslin, Pierre-Antoine; Appolaire, Benoît; Finel, Alphonse
2015-12-31
Dislocation climb is a ubiquitous mechanism playing a major role in the plastic deformation of crystals at high temperature. We propose a multiscale approach to model quantitatively this mechanism at mesoscopic length and time scales. First, we analyze climb at a nanoscopic scale and derive an analytical expression of the climb rate of a jogged dislocation. Next, we deduce from this expression the activation energy of the process, bringing valuable insights to experimental studies. Finally, we show how to rigorously upscale the climb rate to a mesoscopic phase-field model of dislocation climb. This upscaling procedure opens the way to large scale simulations where climb processes are quantitatively reproduced even though the mesoscopic length scale of the simulation is orders of magnitude larger than the atomic one. PMID:26765003
Multiscale Representation of Genomic Signals
Knijnenburg, Theo A.; Ramsey, Stephen A.; Berman, Benjamin P.; Kennedy, Kathleen A.; Smit, Arian F.A.; Wessels, Lodewyk F.A.; Laird, Peter W.; Aderem, Alan; Shmulevich, Ilya
2014-01-01
Genomic information is encoded on a wide range of distance scales, ranging from tens of base pairs to megabases. We developed a multiscale framework to analyze and visualize the information content of genomic signals. Different types of signals, such as GC content or DNA methylation, are characterized by distinct patterns of signal enrichment or depletion across scales spanning several orders of magnitude. These patterns are associated with a variety of genomic annotations, including genes, nuclear lamina associated domains, and repeat elements. By integrating the information across all scales, as compared to using any single scale, we demonstrate improved prediction of gene expression from Polymerase II chromatin immunoprecipitation sequencing (ChIP-seq) measurements and we observed that gene expression differences in colorectal cancer are not most strongly related to gene body methylation, but rather to methylation patterns that extend beyond the single-gene scale. PMID:24727652
Multiscale dynamics in relaxor ferroelectrics
NASA Astrophysics Data System (ADS)
Toulouse, Jean; Cai, L.; Pattnaik, R. K.; Boatner, L. A.
2014-01-01
The multiscale dynamics of complex oxides is illustrated by pairs of mechanical resonances that are excited in the relaxor ferroelectric K1-xLixTaO3 (KLT). These macroscopic resonances are shown to originate in the collective dynamics of piezoelectric polar nanodomains (PNDs) interacting with the surrounding lattice. Their characteristic Fano lineshapes and rapid evolution with temperature reveal the coherent interplay between the piezoelectric oscillations and orientational relaxations of the PNDs at higher temperature and the contribution of heterophase oscillations near the phase transition. A theoretical model is presented, that describes the evolution of the resonances over the entire temperature range. Similar resonances are observed in other relaxors and must therefore be a common characteristics of these systems.
[Multiscale entropy analysis of electrocardiogram].
Wang, Jun; Ning, Xinbao; Li, Jin; Ma, Qianli; Xu, Yinlin; Bian, Chunhua
2007-10-01
Using the algorithm proposed by Costa M, et al., we studied the multiscale entropy (MSE) of electrocardiogram. The sample entropy (SampEn) of the healthy subjects was found to be higher than that of the subjects with coronary heart disease or myocardial infarction. The healthy subjects' complexity was found to be the highest. The SampEn of the subjects with coronary heart disease was noted to be only slightly higher than that of the subjects with myocardial infarction. These findings show that the complexity of the subjects with coronary heart disease or myocardial infarction is distinctly lower than the complexity of the healthy ones, and the subjects suffereing from coronary heart disease are liable to the onset of myocardial infarction. PMID:18027679
MULTISCALE MODELING OF POLYMER NANOCOMPOSITES
Maiti, A
2007-07-16
Polymer Nanocomposites are an important class of nanomaterials with potential applications including but not limited to structural and cushion materials, electromagnetic and heat shields, conducting plastics, sensors, and catalysts for various chemical and bio processes. Success in most such applications hinges on molecular-level control of structure and assembly, and a deep understanding of how the overall morphology of various components and the interfaces between them affect the composite properties at the macroscale. The length and time-scales associated with such assemblies are prohibitively large for a full atomistic modeling. Instead we adopt a multiscale methodology in which atomic-level interactions between different components of a composite are incorporated into a coarse-grained simulation of the mesoscale morphology, which is then represented on a numerical grid and the macroscopic properties computed using a finite-elements method.
Propagation in multiscale random media
NASA Astrophysics Data System (ADS)
Balk, Alexander M.
2003-10-01
Many studies consider media with microstructure, which has variations on some microscale, while the macroproperties are under investigation. Sometimes the medium has several microscales, all of them being much smaller than the macroscale. Sometimes the variations on the macroscale are also included, which are taken into account by some procedures, like WKB or geometric optics. What if the medium has variations on all scales from microscale to macroscale? This situation occurs in several practical problems. The talk is about such situations, in particular, passive tracer in a random velocity field, wave propagation in a random medium, Schrödinger equation with random potential. To treat such problems we have developed the statistical near-identity transformation. We find anomalous attenuation of the pulse propagating in a multiscale medium.
A concurrent multiscale micromorphic molecular dynamics
Li, Shaofan Tong, Qi
2015-04-21
In this work, we have derived a multiscale micromorphic molecular dynamics (MMMD) from first principle to extend the (Andersen)-Parrinello-Rahman molecular dynamics to mesoscale and continuum scale. The multiscale micromorphic molecular dynamics is a con-current three-scale dynamics that couples a fine scale molecular dynamics, a mesoscale micromorphic dynamics, and a macroscale nonlocal particle dynamics together. By choosing proper statistical closure conditions, we have shown that the original Andersen-Parrinello-Rahman molecular dynamics is the homogeneous and equilibrium case of the proposed multiscale micromorphic molecular dynamics. In specific, we have shown that the Andersen-Parrinello-Rahman molecular dynamics can be rigorously formulated and justified from first principle, and its general inhomogeneous case, i.e., the three scale con-current multiscale micromorphic molecular dynamics can take into account of macroscale continuum mechanics boundary condition without the limitation of atomistic boundary condition or periodic boundary conditions. The discovered multiscale scale structure and the corresponding multiscale dynamics reveal a seamless transition from atomistic scale to continuum scale and the intrinsic coupling mechanism among them based on first principle formulation.
Multiscale simulation of DC corona discharge and ozone generation from nanostructures
NASA Astrophysics Data System (ADS)
Wang, Pengxiang
simulation of corona discharges from nanostructures, a one-dimensional (1-D) multiscale model is used due to the prohibitive computational expense associated with two-dimensional (2-D) modeling. Near the nanoscale discharge electrode surface, a kinetic model based on PIC-MCC is used due to a relatively large Knudsen number in this region. Far away from the nanoscale discharge electrode, a continuum model is used since the Knudsen number is very small there. The multiscale modeling results are compared with experimental data. The quantitative agreement in positive discharges and qualitative agreement in negative discharges validate the modeling approach. The mechanism of sustaining the discharge process from nanostructures is revealed and is found to be different from that of discharge from micro- or macro-sized electrodes. Finally, the corona plasma model is combined with a plasma chemistry model and a transport model to predict the ozone production from the nanoscale corona. The dependence of ozone production on the applied potential and air velocity is studied. The electric field distribution in a 2-D multiscale domain (from nanoscale to microscale) is predicted by solving the Poisson's equation using a finite difference scheme. The discretized linear equations are solved using a multigrid method under the framework of PETSc on a paralleled supercomputer. Although the Poisson solver is able to resolve the multiscale field, the prohibitively long computation time limits the use of a 2-D solver in the current PIC-MCC scheme.
NASA Astrophysics Data System (ADS)
Zahid Husain, Syed; Girard, Claude
2016-04-01
High resolution forecasting at the sub-kilometer scale with the Global Environmental Multiscale (GEM) atmospheric model leads to a number of challenges. The three-dimensional elliptic problem resulting from vertical discretization imposes severe restrictions on the vertical resolution and the time-step size in order to maintain vertical separability that permits the use of a direct solver. Although iterative solvers do not depend on vertical separability, readjusting the contributions of the nonhydrostatic pressure perturbation is found to circumvent the separability issue for the direct solver. In addition to the vertical-separability problem, at sub-kilometer resolutions the model currently exhibits strong instability particularly over complex orography where the model may encounter mountains with steep slopes. Off-centered averaging in the semi-Lagrangian scheme as well as the explicit high order numerical diffusion scheme - available within the GEM model to control high wave number noise - are found to be inadequate in addressing this strong orography-induced instability. Increasing the level of off-centering for the equations attributable to the non-hydrostatic aspects of the atmospheric flow is found to improve model stability during preliminary tests. Furthermore, as the existing hyperdiffusion schemes in GEM does not conserve angular momentum a new Smagorinsky-type diffusion scheme is currently being developed that will be compatible with the conservation laws. The improved diffusion scheme coupled with the modified off-centering of the non-hydrostatic equations is expected to have a more meaningful impact on the orgography-induced instability. Pertinent results will be presented at the conference.
Elliptic Solvers with Adaptive Mesh Refinement on Complex Geometries
Phillip, B.
2000-07-24
Adaptive Mesh Refinement (AMR) is a numerical technique for locally tailoring the resolution computational grids. Multilevel algorithms for solving elliptic problems on adaptive grids include the Fast Adaptive Composite grid method (FAC) and its parallel variants (AFAC and AFACx). Theory that confirms the independence of the convergence rates of FAC and AFAC on the number of refinement levels exists under certain ellipticity and approximation property conditions. Similar theory needs to be developed for AFACx. The effectiveness of multigrid-based elliptic solvers such as FAC, AFAC, and AFACx on adaptively refined overlapping grids is not clearly understood. Finally, a non-trivial eye model problem will be solved by combining the power of using overlapping grids for complex moving geometries, AMR, and multilevel elliptic solvers.
An Upwind Solver for the National Combustion Code
NASA Technical Reports Server (NTRS)
Sockol, Peter M.
2011-01-01
An upwind solver is presented for the unstructured grid National Combustion Code (NCC). The compressible Navier-Stokes equations with time-derivative preconditioning and preconditioned flux-difference splitting of the inviscid terms are used. First order derivatives are computed on cell faces and used to evaluate the shear stresses and heat fluxes. A new flux limiter uses these same first order derivatives in the evaluation of left and right states used in the flux-difference splitting. The k-epsilon turbulence equations are solved with the same second-order method. The new solver has been installed in a recent version of NCC and the resulting code has been tested successfully in 2D on two laminar cases with known solutions and one turbulent case with experimental data.
CASTRO: A NEW COMPRESSIBLE ASTROPHYSICAL SOLVER. II. GRAY RADIATION HYDRODYNAMICS
Zhang, W.; Almgren, A.; Bell, J.; Howell, L.; Burrows, A.
2011-10-01
We describe the development of a flux-limited gray radiation solver for the compressible astrophysics code, CASTRO. CASTRO uses an Eulerian grid with block-structured adaptive mesh refinement based on a nested hierarchy of logically rectangular variable-sized grids with simultaneous refinement in both space and time. The gray radiation solver is based on a mixed-frame formulation of radiation hydrodynamics. In our approach, the system is split into two parts, one part that couples the radiation and fluid in a hyperbolic subsystem, and another parabolic part that evolves radiation diffusion and source-sink terms. The hyperbolic subsystem is solved explicitly with a high-order Godunov scheme, whereas the parabolic part is solved implicitly with a first-order backward Euler method.
Parallel Auxiliary Space AMG Solver for $H(div)$ Problems
Kolev, Tzanio V.; Vassilevski, Panayot S.
2012-12-18
We present a family of scalable preconditioners for matrices arising in the discretization of $H(div)$ problems using the lowest order Raviart--Thomas finite elements. Our approach belongs to the class of “auxiliary space''--based methods and requires only the finite element stiffness matrix plus some minimal additional discretization information about the topology and orientation of mesh entities. Also, we provide a detailed algebraic description of the theory, parallel implementation, and different variants of this parallel auxiliary space divergence solver (ADS) and discuss its relations to the Hiptmair--Xu (HX) auxiliary space decomposition of $H(div)$ [SIAM J. Numer. Anal., 45 (2007), pp. 2483--2509] and to the auxiliary space Maxwell solver AMS [J. Comput. Math., 27 (2009), pp. 604--623]. Finally, an extensive set of numerical experiments demonstrates the robustness and scalability of our implementation on large-scale $H(div)$ problems with large jumps in the material coefficients.
Verification and Validation Studies for the LAVA CFD Solver
NASA Technical Reports Server (NTRS)
Moini-Yekta, Shayan; Barad, Michael F; Sozer, Emre; Brehm, Christoph; Housman, Jeffrey A.; Kiris, Cetin C.
2013-01-01
The verification and validation of the Launch Ascent and Vehicle Aerodynamics (LAVA) computational fluid dynamics (CFD) solver is presented. A modern strategy for verification and validation is described incorporating verification tests, validation benchmarks, continuous integration and version control methods for automated testing in a collaborative development environment. The purpose of the approach is to integrate the verification and validation process into the development of the solver and improve productivity. This paper uses the Method of Manufactured Solutions (MMS) for the verification of 2D Euler equations, 3D Navier-Stokes equations as well as turbulence models. A method for systematic refinement of unstructured grids is also presented. Verification using inviscid vortex propagation and flow over a flat plate is highlighted. Simulation results using laminar and turbulent flow past a NACA 0012 airfoil and ONERA M6 wing are validated against experimental and numerical data.
A spectral Poisson solver for kinetic plasma simulation
NASA Astrophysics Data System (ADS)
Szeremley, Daniel; Obberath, Jens; Brinkmann, Ralf
2011-10-01
Plasma resonance spectroscopy is a well established plasma diagnostic method, realized in several designs. One of these designs is the multipole resonance probe (MRP). In its idealized - geometrically simplified - version it consists of two dielectrically shielded, hemispherical electrodes to which an RF signal is applied. A numerical tool is under development which is capable of simulating the dynamics of the plasma surrounding the MRP in electrostatic approximation. In this contribution we concentrate on the specialized Poisson solver for that tool. The plasma is represented by an ensemble of point charges. By expanding both the charge density and the potential into spherical harmonics, a largely analytical solution of the Poisson problem can be employed. For a practical implementation, the expansion must be appropriately truncated. With this spectral solver we are able to efficiently solve the Poisson equation in a kinetic plasma simulation without the need of introducing a spatial discretization.
Benchmarking ICRF Full-wave Solvers for ITER
R. V. Budny, L. Berry, R. Bilato, P. Bonoli, M. Brambilla, R. J. Dumont, A. Fukuyama, R. Harvey, E. F. Jaeger, K. Indireshkumar, E. Lerche, D. McCune, C. K. Phillips, V. Vdovin, J. Wright, and members of the ITPA-IOS
2011-01-06
Abstract Benchmarking of full-wave solvers for ICRF simulations is performed using plasma profiles and equilibria obtained from integrated self-consistent modeling predictions of four ITER plasmas. One is for a high performance baseline (5.3 T, 15 MA) DT H-mode. The others are for half-field, half-current plasmas of interest for the pre-activation phase with bulk plasma ion species being either hydrogen or He4. The predicted profiles are used by six full-wave solver groups to simulate the ICRF electromagnetic fields and heating, and by three of these groups to simulate the current-drive. Approximate agreement is achieved for the predicted heating power for the DT and He4 cases. Factor of two disagreements are found for the cases with second harmonic He3 heating in bulk H cases. Approximate agreement is achieved simulating the ICRF current drive.
A functional implementation of the Jacobi eigen-solver
Boehm, A.P.W.; Hiromoto, R.E.
1993-02-01
In this paper, we describe the systematic development of two implementations of the Jacobi eigen-solver and give performance results for the MIT/Motorola Monsoon dataflow machine. Our study is carried out using MINT, the MIT Monsoon simulator. The design of these implementations follows from the mathematics of the Jacobi method, and not from a translation of an existing sequential code. The functional semantics with respect to array updates, which cause excessive array copying, has lead us to a new implementation of a parallel ``group-rotations`` algorithm first described by Sameh. Our version of this algorithm requires 0(n{sup 3}) operations, whereas Sameh`s original version requires 0(n{sup 4}) operations. The implementations are programmed in the language Id, and although Id has non-functional features, we have restricted the development of our eigen-solvers to the functional sub-set of the language.
A functional implementation of the Jacobi eigen-solver
Boehm, A.P.W. . Dept. of Computer Science); Hiromoto, R.E. )
1993-01-01
In this paper, we describe the systematic development of two implementations of the Jacobi eigen-solver and give performance results for the MIT/Motorola Monsoon dataflow machine. Our study is carried out using MINT, the MIT Monsoon simulator. The design of these implementations follows from the mathematics of the Jacobi method, and not from a translation of an existing sequential code. The functional semantics with respect to array updates, which cause excessive array copying, has lead us to a new implementation of a parallel group-rotations'' algorithm first described by Sameh. Our version of this algorithm requires 0(n[sup 3]) operations, whereas Sameh's original version requires 0(n[sup 4]) operations. The implementations are programmed in the language Id, and although Id has non-functional features, we have restricted the development of our eigen-solvers to the functional sub-set of the language.
LDRD report : parallel repartitioning for optimal solver performance.
Heaphy, Robert; Devine, Karen Dragon; Preis, Robert; Hendrickson, Bruce Alan; Heroux, Michael Allen; Boman, Erik Gunnar
2004-02-01
We have developed infrastructure, utilities and partitioning methods to improve data partitioning in linear solvers and preconditioners. Our efforts included incorporation of data repartitioning capabilities from the Zoltan toolkit into the Trilinos solver framework, (allowing dynamic repartitioning of Trilinos matrices); implementation of efficient distributed data directories and unstructured communication utilities in Zoltan and Trilinos; development of a new multi-constraint geometric partitioning algorithm (which can generate one decomposition that is good with respect to multiple criteria); and research into hypergraph partitioning algorithms (which provide up to 56% reduction of communication volume compared to graph partitioning for a number of emerging applications). This report includes descriptions of the infrastructure and algorithms developed, along with results demonstrating the effectiveness of our approaches.
On improving linear solver performance: a block variant of GMRES
Baker, A H; Dennis, J M; Jessup, E R
2004-05-10
The increasing gap between processor performance and memory access time warrants the re-examination of data movement in iterative linear solver algorithms. For this reason, we explore and establish the feasibility of modifying a standard iterative linear solver algorithm in a manner that reduces the movement of data through memory. In particular, we present an alternative to the restarted GMRES algorithm for solving a single right-hand side linear system Ax = b based on solving the block linear system AX = B. Algorithm performance, i.e. time to solution, is improved by using the matrix A in operations on groups of vectors. Experimental results demonstrate the importance of implementation choices on data movement as well as the effectiveness of the new method on a variety of problems from different application areas.
A Nonlinear Modal Aeroelastic Solver for FUN3D
NASA Technical Reports Server (NTRS)
Goldman, Benjamin D.; Bartels, Robert E.; Biedron, Robert T.; Scott, Robert C.
2016-01-01
A nonlinear structural solver has been implemented internally within the NASA FUN3D computational fluid dynamics code, allowing for some new aeroelastic capabilities. Using a modal representation of the structure, a set of differential or differential-algebraic equations are derived for general thin structures with geometric nonlinearities. ODEPACK and LAPACK routines are linked with FUN3D, and the nonlinear equations are solved at each CFD time step. The existing predictor-corrector method is retained, whereby the structural solution is updated after mesh deformation. The nonlinear solver is validated using a test case for a flexible aeroshell at transonic, supersonic, and hypersonic flow conditions. Agreement with linear theory is seen for the static aeroelastic solutions at relatively low dynamic pressures, but structural nonlinearities limit deformation amplitudes at high dynamic pressures. No flutter was found at any of the tested trajectory points, though LCO may be possible in the transonic regime.
Scalable Out-of-Core Solvers on Xeon Phi Cluster
D'Azevedo, Ed F; Chan, Ki Shing; Su, Shiquan; Wong, Kwai
2015-01-01
This paper documents the implementation of a distributive out-of-core (OOC) solver for performing LU and Cholesky factorizations of a large dense matrix on clusters of many-core programmable co-processors. The out-of- core algorithm combines both the left-looking and right-looking schemes aimed to minimize the movement of data between the CPU host and the co-processor, optimizing data locality as well as computing throughput. The OOC solver is built to align with the format of the ScaLAPACK software library, making it readily portable to any existing codes using ScaLAPACK. A runtime analysis conducted on Beacon (an Intel Xeon plus Intel Xeon Phi cluster which composed of 48 nodes of multi-core CPU and MIC) at the Na- tional Institute for Computational Sciences is presented. Comparison of the performance on the Intel Xeon Phi and GPU clusters are also provided.
Brittle Solvers: Lessons and insights into effective solvers for visco-plasticity in geodynamics
NASA Astrophysics Data System (ADS)
Spiegelman, M. W.; May, D.; Wilson, C. R.
2014-12-01
Plasticity/Fracture and rock failure are essential ingredients in geodynamic models as terrestrial rocks do not possess an infinite yield strength. Numerous physical mechanisms have been proposed to limit the strength of rocks, including low temperature plasticity and brittle fracture. While ductile and creep behavior of rocks at depth is largely accepted, the constitutive relations associated with brittle failure, or shear localisation, are more controversial. Nevertheless, there are really only a few macroscopic constitutive laws for visco-plasticity that are regularly used in geodynamics models. Independent of derivation, all of these can be cast as simple effective viscosities which act as stress limiters with different choices for yield surfaces; the most common being a von Mises (constant yield stress) or Drucker-Prager (pressure dependent yield-stress) criterion. The choice of plasticity model, however, can have significant consequences for the degree of non-linearity in a problem and the choice and efficiency of non-linear solvers. Here we describe a series of simplified 2 and 3-D model problems to elucidate several issues associated with obtaining accurate description and solution of visco-plastic problems. We demonstrate that1) Picard/Successive substitution schemes for solution of the non-linear problems can often stall at large values of the non-linear residual, thus producing spurious solutions2) Combined Picard/Newton schemes can be effective for a range of plasticity models, however, they can produce serious convergence problems for strongly pressure dependent plasticity models such as Drucker-Prager.3) Nevertheless, full Drucker-Prager may not be the plasticity model of choice for strong materials as the dynamic pressures produced in these layers can develop pathological behavior with Drucker-Prager, leading to stress strengthening rather than stress weakening behavior.4) In general, for any incompressible Stoke's problem, it is highly advisable to
A chemical reaction network solver for the astrophysics code NIRVANA
NASA Astrophysics Data System (ADS)
Ziegler, U.
2016-02-01
Context. Chemistry often plays an important role in astrophysical gases. It regulates thermal properties by changing species abundances and via ionization processes. This way, time-dependent cooling mechanisms and other chemistry-related energy sources can have a profound influence on the dynamical evolution of an astrophysical system. Modeling those effects with the underlying chemical kinetics in realistic magneto-gasdynamical simulations provide the basis for a better link to observations. Aims: The present work describes the implementation of a chemical reaction network solver into the magneto-gasdynamical code NIRVANA. For this purpose a multispecies structure is installed, and a new module for evolving the rate equations of chemical kinetics is developed and coupled to the dynamical part of the code. A small chemical network for a hydrogen-helium plasma was constructed including associated thermal processes which is used in test problems. Methods: Evolving a chemical network within time-dependent simulations requires the additional solution of a set of coupled advection-reaction equations for species and gas temperature. Second-order Strang-splitting is used to separate the advection part from the reaction part. The ordinary differential equation (ODE) system representing the reaction part is solved with a fourth-order generalized Runge-Kutta method applicable for stiff systems inherent to astrochemistry. Results: A series of tests was performed in order to check the correctness of numerical and technical implementation. Tests include well-known stiff ODE problems from the mathematical literature in order to confirm accuracy properties of the solver used as well as problems combining gasdynamics and chemistry. Overall, very satisfactory results are achieved. Conclusions: The NIRVANA code is now ready to handle astrochemical processes in time-dependent simulations. An easy-to-use interface allows implementation of complex networks including thermal processes
Scaling Algebraic Multigrid Solvers: On the Road to Exascale
Baker, A H; Falgout, R D; Gamblin, T; Kolev, T; Schulz, M; Yang, U M
2010-12-12
Algebraic Multigrid (AMG) solvers are an essential component of many large-scale scientific simulation codes. Their continued numerical scalability and efficient implementation is critical for preparing these codes for exascale. Our experiences on modern multi-core machines show that significant challenges must be addressed for AMG to perform well on such machines. We discuss our experiences and describe the techniques we have used to overcome scalability challenges for AMG on hybrid architectures in preparation for exascale.
Boltzmann Solver with Adaptive Mesh in Velocity Space
Kolobov, Vladimir I.; Arslanbekov, Robert R.; Frolova, Anna A.
2011-05-20
We describe the implementation of direct Boltzmann solver with Adaptive Mesh in Velocity Space (AMVS) using quad/octree data structure. The benefits of the AMVS technique are demonstrated for the charged particle transport in weakly ionized plasmas where the collision integral is linear. We also describe the implementation of AMVS for the nonlinear Boltzmann collision integral. Test computations demonstrate both advantages and deficiencies of the current method for calculations of narrow-kernel distributions.
A contribution to the great Riemann solver debate
NASA Technical Reports Server (NTRS)
Quirk, James J.
1992-01-01
The aims of this paper are threefold: to increase the level of awareness within the shock capturing community to the fact that many Godunov-type methods contain subtle flaws that can cause spurious solutions to be computed; to identify one mechanism that might thwart attempts to produce very high resolution simulations; and to proffer a simple strategy for overcoming the specific failings of individual Riemann solvers.
An automatic ordering method for incomplete factorization iterative solvers
Forsyth, P.A.; Tang, W.P. . Dept. of Computer Science); D'Azevedo, E.F.D. )
1991-01-01
The minimum discarded fill (MDF) ordering strategy for incomplete factorization iterative solvers is developed. MDF ordering is demonstrated for several model son-symmetric problems, as well as a water-flooding simulation which uses an unstructured grid. The model problems show a three to five fold decrease in the number of iterations compared to natural orderings. Greater than twofold improvement was observed for the waterflooding simulation. 26 refs., 7 figs., 3 tabs.
Menu-Driven Solver Of Linear-Programming Problems
NASA Technical Reports Server (NTRS)
Viterna, L. A.; Ferencz, D.
1992-01-01
Program assists inexperienced user in formulating linear-programming problems. A Linear Program Solver (ALPS) computer program is full-featured LP analysis program. Solves plain linear-programming problems as well as more-complicated mixed-integer and pure-integer programs. Also contains efficient technique for solution of purely binary linear-programming problems. Written entirely in IBM's APL2/PC software, Version 1.01. Packed program contains licensed material, property of IBM (copyright 1988, all rights reserved).
Wagner, Gregory John; Collis, Samuel Scott; Templeton, Jeremy Alan; Lehoucq, Richard B.; Parks, Michael L.; Jones, Reese E.; Silling, Stewart Andrew; Scovazzi, Guglielmo; Bochev, Pavel B.
2007-10-01
This report is a collection of documents written as part of the Laboratory Directed Research and Development (LDRD) project A Mathematical Framework for Multiscale Science and Engineering: The Variational Multiscale Method and Interscale Transfer Operators. We present developments in two categories of multiscale mathematics and analysis. The first, continuum-to-continuum (CtC) multiscale, includes problems that allow application of the same continuum model at all scales with the primary barrier to simulation being computing resources. The second, atomistic-to-continuum (AtC) multiscale, represents applications where detailed physics at the atomistic or molecular level must be simulated to resolve the small scales, but the effect on and coupling to the continuum level is frequently unclear.
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
NITSOL: A Newton iterative solver for nonlinear systems
Pernice, M.; Walker, H.F.
1996-12-31
Newton iterative methods, also known as truncated Newton methods, are implementations of Newton`s method in which the linear systems that characterize Newton steps are solved approximately using iterative linear algebra methods. Here, we outline a well-developed Newton iterative algorithm together with a Fortran implementation called NITSOL. The basic algorithm is an inexact Newton method globalized by backtracking, in which each initial trial step is determined by applying an iterative linear solver until an inexact Newton criterion is satisfied. In the implementation, the user can specify inexact Newton criteria in several ways and select an iterative linear solver from among several popular {open_quotes}transpose-free{close_quotes} Krylov subspace methods. Jacobian-vector products used by the Krylov solver can be either evaluated analytically with a user-supplied routine or approximated using finite differences of function values. A flexible interface permits a wide variety of preconditioning strategies and allows the user to define a preconditioner and optionally update it periodically. We give details of these and other features and demonstrate the performance of the implementation on a representative set of test problems.
Transonic Drag Prediction Using an Unstructured Multigrid Solver
NASA Technical Reports Server (NTRS)
Mavriplis, D. J.; Levy, David W.
2001-01-01
This paper summarizes the results obtained with the NSU-3D unstructured multigrid solver for the AIAA Drag Prediction Workshop held in Anaheim, CA, June 2001. The test case for the workshop consists of a wing-body configuration at transonic flow conditions. Flow analyses for a complete test matrix of lift coefficient values and Mach numbers at a constant Reynolds number are performed, thus producing a set of drag polars and drag rise curves which are compared with experimental data. Results were obtained independently by both authors using an identical baseline grid and different refined grids. Most cases were run in parallel on commodity cluster-type machines while the largest cases were run on an SGI Origin machine using 128 processors. The objective of this paper is to study the accuracy of the subject unstructured grid solver for predicting drag in the transonic cruise regime, to assess the efficiency of the method in terms of convergence, cpu time, and memory, and to determine the effects of grid resolution on this predictive ability and its computational efficiency. A good predictive ability is demonstrated over a wide range of conditions, although accuracy was found to degrade for cases at higher Mach numbers and lift values where increasing amounts of flow separation occur. The ability to rapidly compute large numbers of cases at varying flow conditions using an unstructured solver on inexpensive clusters of commodity computers is also demonstrated.
A Survey of Solver-Related Geometry and Meshing Issues
NASA Technical Reports Server (NTRS)
Masters, James; Daniel, Derick; Gudenkauf, Jared; Hine, David; Sideroff, Chris
2016-01-01
There is a concern in the computational fluid dynamics community that mesh generation is a significant bottleneck in the CFD workflow. This is one of several papers that will help set the stage for a moderated panel discussion addressing this issue. Although certain general "rules of thumb" and a priori mesh metrics can be used to ensure that some base level of mesh quality is achieved, inadequate consideration is often given to the type of solver or particular flow regime on which the mesh will be utilized. This paper explores how an analyst may want to think differently about a mesh based on considerations such as if a flow is compressible vs. incompressible or hypersonic vs. subsonic or if the solver is node-centered vs. cell-centered. This paper is a high-level investigation intended to provide general insight into how considering the nature of the solver or flow when performing mesh generation has the potential to increase the accuracy and/or robustness of the solution and drive the mesh generation process to a state where it is no longer a hindrance to the analysis process.
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
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
Multi-Scale Initial Conditions For Cosmological Simulations
Hahn, Oliver; Abel, Tom; /KIPAC, Menlo Park /ZAH, Heidelberg /HITS, Heidelberg
2011-11-04
We discuss a new algorithm to generate multi-scale initial conditions with multiple levels of refinements for cosmological 'zoom-in' simulations. The method uses an adaptive convolution of Gaussian white noise with a real-space transfer function kernel together with an adaptive multi-grid Poisson solver to generate displacements and velocities following first- (1LPT) or second-order Lagrangian perturbation theory (2LPT). The new algorithm achieves rms relative errors of the order of 10{sup -4} for displacements and velocities in the refinement region and thus improves in terms of errors by about two orders of magnitude over previous approaches. In addition, errors are localized at coarse-fine boundaries and do not suffer from Fourier-space-induced interference ringing. An optional hybrid multi-grid and Fast Fourier Transform (FFT) based scheme is introduced which has identical Fourier-space behaviour as traditional approaches. Using a suite of re-simulations of a galaxy cluster halo our real-space-based approach is found to reproduce correlation functions, density profiles, key halo properties and subhalo abundances with per cent level accuracy. Finally, we generalize our approach for two-component baryon and dark-matter simulations and demonstrate that the power spectrum evolution is in excellent agreement with linear perturbation theory. For initial baryon density fields, it is suggested to use the local Lagrangian approximation in order to generate a density field for mesh-based codes that is consistent with the Lagrangian perturbation theory instead of the current practice of using the Eulerian linearly scaled densities.
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.
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
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
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.
Fisher, A. C.; Bailey, D. S.; Kaiser, T. B.; Eder, D. C.; Gunney, B. T. N.; Masters, N. D.; Koniges, A. E.; Anderson, R. W.
2015-02-01
Here, we present a novel method for the solution of the diffusion equation on a composite AMR mesh. This approach is suitable for including diffusion based physics modules to hydrocodes that support ALE and AMR capabilities. To illustrate, we proffer our implementations of diffusion based radiation transport and heat conduction in a hydrocode called ALE-AMR. Numerical experiments conducted with the diffusion solver and associated physics packages yield 2nd order convergence in the L_{2} norm.
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
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 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.
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
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.
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
Multiscale Modeling of Hematologic Disorders
Fedosov, Dmitry A.; Pivkin, Igor; Pan, Wenxiao; Dao, Ming; Caswell, Bruce; Karniadakis, George E.
2012-01-28
Parasitic infectious diseases and other hereditary hematologic disorders are often associated with major changes in the shape and viscoelastic properties of red blood cells (RBCs). Such changes can disrupt blood flow and even brain perfusion, as in the case of cerebral malaria. Modeling of these hematologic disorders requires a seamless multiscale approach, where blood cells and blood flow in the entire arterial tree are represented accurately using physiologically consistent parameters. In this chapter, we present a computational methodology based on dissipative particle dynamics (DPD) which models RBCs as well as whole blood in health and disease. DPD is a Lagrangian method that can be derived from systematic coarse-graining of molecular dynamics but can scale efficiently up to small arteries and can also be used to model RBCs down to spectrin level. To this end, we present two complementary mathematical models for RBCs and describe a systematic procedure on extracting the relevant input parameters from optical tweezers and microfluidic experiments for single RBCs. We then use these validated RBC models to predict the behavior of whole healthy blood and compare with experimental results. The same procedure is applied to modeling malaria, and results for infected single RBCs and whole blood are presented.
A Multiscale Bidirectional Coupling Framework
Kabilan, Senthil; Kuprat, Andrew P.; Hlastala, Michael P.; Corley, Richard A.; Einstein, Daniel R.
2011-12-01
The lung is geometrically articulated across multiple scales from the trachea to the alveoli. A major computational challenge is to tightly link ODEs that describe lower scales to 3D finite element or finite volume models of airway mechanics using iterative communication between scales. In this study, we developed a novel multiscale computational framework for bidirectionally coupling 3D CFD models and systems of lower order ODEs. To validate the coupling framework, a four and eight generation Weibel lung model was constructed. For the coupled CFD-ODE simulations, the lung models were truncated at different generations and a RL circuit represented the truncated portion. The flow characteristics from the coupled models were compared to untruncated full 3D CFD models at peak inhalation and peak exhalation. Results showed that at no time or simulation was the difference in mass flux and/or pressure at a given location between uncoupled and coupled models was greater than 2.43%. The flow characteristics at prime locations for the coupled models showed good agreement to uncoupled models. Remarkably, due to reuse of the Krylov subspace, the cost of the ODE coupling is not much greater than uncoupled full 3D-CFD computations with simple prescribed pressure values at the outlets.
MULTISCALE DISCRETIZATION OF SHAPE CONTOURS
Prasad, L.; Rao, R.
2000-09-01
We present an efficient multi-scale scheme to adaptively approximate the continuous (or densely sampled) contour of a planar shape at varying resolutions. The notion of shape is intimately related to the notion of contour, and the efficient representation of the contour of a shape is vital to a computational understanding of the shape. Any polygonal approximation of a planar smooth curve is equivalent to a piecewise constant approximation of the parameterized X and Y coordinate functions of a discrete point set obtained by densely sampling the curve. Using the Haar wavelet transform for the piecewise approximation yields a hierarchical scheme in which the size of the approximating point set is traded off against the morphological accuracy of the approximation. Our algorithm compresses the representation of the initial shape contour to a sparse sequence of points in the plane defining the vertices of the shape's polygonal approximation. Furthermore, it is possible to control the overall resolution of the approximation by a single, scale-independent parameter.
Multiscale structure of sheet nacre.
Rousseau, Marthe; Lopez, Evelyne; Stempflé, Philippe; Brendlé, Marcel; Franke, Loïc; Guette, Alain; Naslain, Roger; Bourrat, Xavier
2005-11-01
This work was conducted on Pinctada maxima nacre (mother of pearl) in order to understand its multiscale ordering and the role of the organic matrix in its structure. Intermittent-contact atomic force microscopy with phase detection imaging reveals a nanostructure within the tablet. A continuous organic framework divides each tablet into nanograins. Their shape is supposed to be flat with a mean extension of 45nm. TEM performed in the darkfield mode evidences that at least part of the intracrystalline matrix is crystallized and responds like a 'single crystal'. The tablet is a 'hybrid composite'. The organic matrix is continuous. The mineral phase is thus finely divided still behaving as a single crystal. It is proposed that each tablet results from the coherent aggregation of nanograins keeping strictly the same crystallographic orientation thanks to a hetero-epitaxy mechanism. Finally, high-resolution TEM performed on bridges from one tablet to the next, in the overlying row, did not permit to evidence a mineral lattice but crystallized organic bridges. The same organic bridges were evidenced by SEM in the interlaminar sequence. PMID:15907339
Multiscale modelling of evolving foams
NASA Astrophysics Data System (ADS)
Saye, R. I.; Sethian, J. A.
2016-06-01
We present a set of multi-scale interlinked algorithms to model the dynamics of evolving foams. These algorithms couple the key effects of macroscopic bubble rearrangement, thin film drainage, and membrane rupture. For each of the mechanisms, we construct consistent and accurate algorithms, and couple them together to work across the wide range of space and time scales that occur in foam dynamics. These algorithms include second order finite difference projection methods for computing incompressible fluid flow on the macroscale, second order finite element methods to solve thin film drainage equations in the lamellae and Plateau borders, multiphase Voronoi Implicit Interface Methods to track interconnected membrane boundaries and capture topological changes, and Lagrangian particle methods for conservative liquid redistribution during rearrangement and rupture. We derive a full set of numerical approximations that are coupled via interface jump conditions and flux boundary conditions, and show convergence for the individual mechanisms. We demonstrate our approach by computing a variety of foam dynamics, including coupled evolution of three-dimensional bubble clusters attached to an anchored membrane and collapse of a foam cluster.
Multiscale simulation of erythrocyte membranes
NASA Astrophysics Data System (ADS)
Peng, Zhangli; Asaro, Robert J.; Zhu, Qiang
2010-03-01
To quantitatively predict the mechanical response and mechanically induced remodeling of red blood cells, we developed a multiscale method to correlate distributions of internal stress with overall cell deformation. This method consists of three models at different length scales: in the complete cell level the membrane is modeled as two distinct layers of continuum shells using finite element method (Level III), in which the skeleton-bilayer interactions are depicted as a slide in the lateral (i.e., in-plane) direction (caused by the mobility of the skeleton-bilayer pinning points) and a normal contact force; the constitutive laws of the inner layer (the protein skeleton) are obtained from a molecular-based model (Level II); the mechanical properties of the spectrin (Sp, a key component of the skeleton), including its folding/unfolding reactions, are obtained with a stress-strain model (Level I). Model verification is achieved through comparisons with existing numerical and experimental studies in terms of the resting shape of the cell as well as cell deformations induced by micropipettes and optical tweezers. Detailed distributions of the interaction force between the lipid bilayer and the skeleton that may cause their dissociation and lead to phenomena such as vesiculation are predicted. Specifically, our model predicts correlation between the occurrence of Sp unfolding and increase in the mechanical load upon individual skeleton-bilayer pinning points. Finally a simulation of the necking process after skeleton-bilayer dissociation, a precursor of vesiculation, is conducted.
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
NASA Astrophysics Data System (ADS)
Crivellini, A.; D'Alessandro, V.; Di Benedetto, D.; Montelpare, S.; Ricci, R.
2014-04-01
This work is devoted to the Computational Fluid-Dynamics (CFD) simulation of laminar separation bubble (LSB) on low Reynolds number operating airfoils. This phenomenon is of large interest in several fields, such as wind energy, and it is characterised by slow recirculating flow at an almost constant pressure. Presently Reynolds Averaged Navier-Stokes (RANS) methods, due to their limited computational requests, are the more efficient and feasible CFD simulation tool for complex engineering applications involving LSBs. However adopting RANS methods for LSB prediction is very challenging since widely used models assume a fully turbulent regime. For this reason several transitional models for RANS equations based on further Partial Differential Equations (PDE) have been recently introduced in literature. Nevertheless in some cases they show questionable results. In this work RANS equations and the standard Spalart-Allmaras (SA) turbulence model are used to deal with LSB problems obtaining promising results. This innovative result is related to: (i) a particular behaviour of the SA equation; (ii) a particular implementation of SA equation; (iii) the use of a high-order discontinuous Galerkin (DG) solver. The effectiveness of the proposed approach is tested on different airfoils at several angles of attack and Reynolds numbers. Numerical results were verified with both experimental measurements performed at the open circuit subsonic wind tunnel of Università Politecnica delle Marche (UNIVPM) and literature data.
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
Multiscale Modeling of Plastic Bonded Explosives
NASA Astrophysics Data System (ADS)
Smith, Grant; Bedrov, Dmitry; Borodin, Oleg
2007-06-01
We have developed a multiscale modeling paradigm for the prediction of the viscoelastic properties, equation of state and yielding behavior of plastic bonded explosives (PBXs). In our multiscale modeling approach the components of the explosive (e.g., energetic material, metal and binder) are explicitly resolved and the material point method (MPM) is utilized to predict the response of the composite material to loading (isentropic, shock, etc.). This data are then utilized to develop equation-of-state and constitutive models for the PBX. The properties of the components are determined either from atomistic simulations or are taken from the literature. Force fields for the atomistic simulations in turn have been developed based upon high-level electronic structure calculations of model compounds and molecular complexes. Hence, our multiscale simulation approach systematically bridges length scales from atomistic to macroscopic. Applications of this approach to PBX-9501 and other PBXs will be considered.
Multiscale Computational Models of Complex Biological Systems
Walpole, Joseph; Papin, Jason A.; Peirce, Shayn M.
2014-01-01
Integration of data across spatial, temporal, and functional scales is a primary focus of biomedical engineering efforts. The advent of powerful computing platforms, coupled with quantitative data from high-throughput experimental platforms, has allowed multiscale modeling to expand as a means to more comprehensively investigate biological phenomena in experimentally relevant ways. This review aims to highlight recently published multiscale models of biological systems while using their successes to propose the best practices for future model development. We demonstrate that coupling continuous and discrete systems best captures biological information across spatial scales by selecting modeling techniques that are suited to the task. Further, we suggest how to best leverage these multiscale models to gain insight into biological systems using quantitative, biomedical engineering methods to analyze data in non-intuitive ways. These topics are discussed with a focus on the future of the field, the current challenges encountered, and opportunities yet to be realized. PMID:23642247
Multiscale stochastic approach for phase screens synthesis.
Beghi, Alessandro; Cenedese, Angelo; Masiero, Andrea
2011-07-20
Simulating the turbulence effect on ground telescope observations is of fundamental importance for the design and test of suitable control algorithms for adaptive optics systems. In this paper we propose a multiscale approach for efficiently synthesizing turbulent phases at very high resolution. First, the turbulence is simulated at low resolution, taking advantage of a previously developed method for generating phase screens [J. Opt. Soc. Am. A 25, 515 (2008)]. Then, high-resolution phase screens are obtained as the output of a multiscale linear stochastic system. The multiscale approach significantly improves the computational efficiency of turbulence simulation with respect to recently developed methods [Opt. Express 14, 988 (2006)] [J. Opt. Soc. Am. A 25, 515 (2008)] [J. Opt. Soc. Am. A 25, 463 (2008)]. Furthermore, the proposed procedure ensures good accuracy in reproducing the statistical characteristics of the turbulent phase. PMID:21772400
The Center for Multiscale Plasma Dynamics
Kevrekidis, Yannis G
2015-01-20
This final report describes research performed in Princeton University, led by Professor Yannis G. Kevrekidis, over a period of six years (August 1, 2014 to July 31, 2010, including a one-year, no-cost extension) as part of the Center for Multiscale Plasma Dynamics led by the University of Maryland. The work resulted in the development and implementation of several multiscale algorithms based on the equation-free approach pioneered by the PI, including its applications in plasma dynamics problems. These algoriithms include coarse projective integration and coarse stability/bifurcation computations. In the later stages of the work, new links were made between this multiscale, coarse-graining approach and advances in data mining/machine learning algorithms.
A multiscale modeling approach to adhesive contact
NASA Astrophysics Data System (ADS)
Fan, KangQi; Wang, WeiDong; Zhu, YingMin; Zhang, XiuYan
2011-09-01
In order to model the adhesive contact across different length scales, a multiscale approach is developed and used to study the adhesive contact behaviors between a rigid cylinder and an elastic face-centered cubic (FCC) substrate. The approach combines an atomistic treatment of the interfacial region with an elastic mechanics method description of the continuum region. The two regions are connected by a coupling region where nodes of the continuum region are refined to atoms of the atomistic region. Moreover, the elastic constants of FCC crystals are obtained directly from the Lennard-Jones potential to describe the elastic response characteristics of the continuum region, which ensures the consistency of material proprieties between atomistic and continuum regions. The multiscale approach is examined by comparing it with the pure MD simulation, and the results indicate that the multiscale modeling approach agrees well with the MD method in studying the adhesive contact behaviors.
Application of Aeroelastic Solvers Based on Navier Stokes Equations
NASA Technical Reports Server (NTRS)
Keith, Theo G., Jr.; Srivastava, Rakesh
2001-01-01
The propulsion element of the NASA Advanced Subsonic Technology (AST) initiative is directed towards increasing the overall efficiency of current aircraft engines. This effort requires an increase in the efficiency of various components, such as fans, compressors, turbines etc. Improvement in engine efficiency can be accomplished through the use of lighter materials, larger diameter fans and/or higher-pressure ratio compressors. However, each of these has the potential to result in aeroelastic problems such as flutter or forced response. To address the aeroelastic problems, the Structural Dynamics Branch of NASA Glenn has been involved in the development of numerical capabilities for analyzing the aeroelastic stability characteristics and forced response of wide chord fans, multi-stage compressors and turbines. In order to design an engine to safely perform a set of desired tasks, accurate information of the stresses on the blade during the entire cycle of blade motion is required. This requirement in turn demands that accurate knowledge of steady and unsteady blade loading is available. To obtain the steady and unsteady aerodynamic forces for the complex flows around the engine components, for the flow regimes encountered by the rotor, an advanced compressible Navier-Stokes solver is required. A finite volume based Navier-Stokes solver has been developed at Mississippi State University (MSU) for solving the flow field around multistage rotors. The focus of the current research effort, under NASA Cooperative Agreement NCC3- 596 was on developing an aeroelastic analysis code (entitled TURBO-AE) based on the Navier-Stokes solver developed by MSU. The TURBO-AE code has been developed for flutter analysis of turbomachine components and delivered to NASA and its industry partners. The code has been verified. validated and is being applied by NASA Glenn and by aircraft engine manufacturers to analyze the aeroelastic stability characteristics of modem fans, compressors
Code Verification of the HIGRAD Computational Fluid Dynamics Solver
Van Buren, Kendra L.; Canfield, Jesse M.; Hemez, Francois M.; Sauer, Jeremy A.
2012-05-04
The purpose of this report is to outline code and solution verification activities applied to HIGRAD, a Computational Fluid Dynamics (CFD) solver of the compressible Navier-Stokes equations developed at the Los Alamos National Laboratory, and used to simulate various phenomena such as the propagation of wildfires and atmospheric hydrodynamics. Code verification efforts, as described in this report, are an important first step to establish the credibility of numerical simulations. They provide evidence that the mathematical formulation is properly implemented without significant mistakes that would adversely impact the application of interest. Highly accurate analytical solutions are derived for four code verification test problems that exercise different aspects of the code. These test problems are referred to as: (i) the quiet start, (ii) the passive advection, (iii) the passive diffusion, and (iv) the piston-like problem. These problems are simulated using HIGRAD with different levels of mesh discretization and the numerical solutions are compared to their analytical counterparts. In addition, the rates of convergence are estimated to verify the numerical performance of the solver. The first three test problems produce numerical approximations as expected. The fourth test problem (piston-like) indicates the extent to which the code is able to simulate a 'mild' discontinuity, which is a condition that would typically be better handled by a Lagrangian formulation. The current investigation concludes that the numerical implementation of the solver performs as expected. The quality of solutions is sufficient to provide credible simulations of fluid flows around wind turbines. The main caveat associated to these findings is the low coverage provided by these four problems, and somewhat limited verification activities. A more comprehensive evaluation of HIGRAD may be beneficial for future studies.
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
Algorithms for parallel flow solvers on message passing architectures
NASA Technical Reports Server (NTRS)
Vanderwijngaart, Rob F.
1995-01-01
The purpose of this project has been to identify and test suitable technologies for implementation of fluid flow solvers -- possibly coupled with structures and heat equation solvers -- on MIMD parallel computers. In the course of this investigation much attention has been paid to efficient domain decomposition strategies for ADI-type algorithms. Multi-partitioning derives its efficiency from the assignment of several blocks of grid points to each processor in the parallel computer. A coarse-grain parallelism is obtained, and a near-perfect load balance results. In uni-partitioning every processor receives responsibility for exactly one block of grid points instead of several. This necessitates fine-grain pipelined program execution in order to obtain a reasonable load balance. Although fine-grain parallelism is less desirable on many systems, especially high-latency networks of workstations, uni-partition methods are still in wide use in production codes for flow problems. Consequently, it remains important to achieve good efficiency with this technique that has essentially been superseded by multi-partitioning for parallel ADI-type algorithms. Another reason for the concentration on improving the performance of pipeline methods is their applicability in other types of flow solver kernels with stronger implied data dependence. Analytical expressions can be derived for the size of the dynamic load imbalance incurred in traditional pipelines. From these it can be determined what is the optimal first-processor retardation that leads to the shortest total completion time for the pipeline process. Theoretical predictions of pipeline performance with and without optimization match experimental observations on the iPSC/860 very well. Analysis of pipeline performance also highlights the effect of uncareful grid partitioning in flow solvers that employ pipeline algorithms. If grid blocks at boundaries are not at least as large in the wall-normal direction as those
A Simple Quantum Integro-Differential Solver (SQuIDS)
NASA Astrophysics Data System (ADS)
Argüelles Delgado, Carlos A.; Salvado, Jordi; Weaver, Christopher N.
2015-11-01
Simple Quantum Integro-Differential Solver (SQuIDS) is a C++ code designed to solve semi-analytically the evolution of a set of density matrices and scalar functions. This is done efficiently by expressing all operators in an SU(N) basis. SQuIDS provides a base class from which users can derive new classes to include new non-trivial terms from the right hand sides of density matrix equations. The code was designed in the context of solving neutrino oscillation problems, but can be applied to any problem that involves solving the quantum evolution of a collection of particles with Hilbert space of dimension up to six.
Object-Oriented Design for Sparse Direct Solvers
NASA Technical Reports Server (NTRS)
Dobrian, Florin; Kumfert, Gary; Pothen, Alex
1999-01-01
We discuss the object-oriented design of a software package for solving sparse, symmetric systems of equations (positive definite and indefinite) by direct methods. At the highest layers, we decouple data structure classes from algorithmic classes for flexibility. We describe the important structural and algorithmic classes in our design, and discuss the trade-offs we made for high performance. The kernels at the lower layers were optimized by hand. Our results show no performance loss from our object-oriented design, while providing flexibility, case of use, and extensibility over solvers using procedural design.
FDIPS: Finite Difference Iterative Potential-field Solver
NASA Astrophysics Data System (ADS)
Toth, Gabor; van der Holst, Bartholomeus; Huang, Zhenguang
2016-06-01
FDIPS is a finite difference iterative potential-field solver that can generate the 3D potential magnetic field solution based on a magnetogram. It is offered as an alternative to the spherical harmonics approach, as when the number of spherical harmonics is increased, using the raw magnetogram data given on a grid that is uniform in the sine of the latitude coordinate can result in inaccurate and unreliable results, especially in the polar regions close to the Sun. FDIPS is written in Fortran 90 and uses the MPI library for parallel execution.
Hierarchically Parallelized Constrained Nonlinear Solvers with Automated Substructuring
NASA Technical Reports Server (NTRS)
Padovan, Joe; Kwang, Abel
1994-01-01
This paper develops a parallelizable multilevel multiple constrained nonlinear equation solver. The substructuring process is automated to yield appropriately balanced partitioning of each succeeding level. Due to the generality of the procedure,_sequential, as well as partially and fully parallel environments can be handled. This includes both single and multiprocessor assignment per individual partition. Several benchmark examples are presented. These illustrate the robustness of the procedure as well as its capability to yield significant reductions in memory utilization and calculational effort due both to updating and inversion.
Preconditioned CG-solvers and finite element grids
Bauer, R.; Selberherr, S.
1994-12-31
To extract parasitic capacitances in wiring structures of integrated circuits the authors developed the two- and three-dimensional finite element program SCAP (Smart Capacitance Analysis Program). The program computes the task of the electrostatic field from a solution of Poisson`s equation via finite elements and calculates the energies from which the capacitance matrix is extracted. The unknown potential vector, which has for three-dimensional applications 5000-50000 unknowns, is computed by a ICCG solver. Currently three- and six-node triangular, four- and ten-node tetrahedronal elements are supported.
Reformulation of the Fourier-Bessel steady state mode solver
NASA Astrophysics Data System (ADS)
Gauthier, Robert C.
2016-09-01
The Fourier-Bessel resonator state mode solver is reformulated using Maxwell's field coupled curl equations. The matrix generating expressions are greatly simplified as well as a reduction in the number of pre-computed tables making the technique simpler to implement on a desktop computer. The reformulation maintains the theoretical equivalence of the permittivity and permeability and as such structures containing both electric and magnetic properties can be examined. Computation examples are presented for a surface nanoscale axial photonic resonator and hybrid { ε , μ } quasi-crystal resonator.
High Energy Boundary Conditions for a Cartesian Mesh Euler Solver
NASA Technical Reports Server (NTRS)
Pandya, Shishir A.; Murman, Scott M.; Aftosmis, Michael J.
2004-01-01
Inlets and exhaust nozzles are often omitted or fared over in aerodynamic simulations of aircraft due to the complexities involving in the modeling of engine details such as complex geometry and flow physics. However, the assumption is often improper as inlet or plume flows have a substantial effect on vehicle aerodynamics. A tool for specifying inlet and exhaust plume conditions through the use of high-energy boundary conditions in an established inviscid flow solver is presented. The effects of the plume on the flow fields near the inlet and plume are discussed.
A fast solver for the Ornstein-Zernike equations
NASA Astrophysics Data System (ADS)
Kelley, C. T.; Pettitt, B. Montgomery
2004-07-01
In this paper, we report on the design and analysis of a multilevel method for the solution of the Ornstein-Zernike Equations and related systems of integro-algebraic equations. Our approach is based on an extension of the Atkinson-Brakhage method, with Newton-GMRES used as the coarse mesh solver. We report on several numerical experiments to illustrate the effectiveness of the method. The problems chosen are related to simple short ranged fluids with continuous potentials. Speedups over traditional methods for a given accuracy are reported. The new multilevel method is roughly six times faster than Newton-GMRES and 40 times faster than Picard.
Performance issues for iterative solvers in device simulation
NASA Technical Reports Server (NTRS)
Fan, Qing; Forsyth, P. A.; Mcmacken, J. R. F.; Tang, Wei-Pai
1994-01-01
Due to memory limitations, iterative methods have become the method of choice for large scale semiconductor device simulation. However, it is well known that these methods still suffer from reliability problems. The linear systems which appear in numerical simulation of semiconductor devices are notoriously ill-conditioned. In order to produce robust algorithms for practical problems, careful attention must be given to many implementation issues. This paper concentrates on strategies for developing robust preconditioners. In addition, effective data structures and convergence check issues are also discussed. These algorithms are compared with a standard direct sparse matrix solver on a variety of problems.
Evaluating point-based POMDP solvers on multicore machines.
Shani, Guy
2010-08-01
Recent scaling up of partially observable Markov decision process solvers toward realistic applications is largely due to point-based methods which quickly provide approximate solutions for midsized problems. New multicore machines offer an opportunity to scale up to larger domains. These machines support parallel execution and can speed up existing algorithms considerably. In this paper, we evaluate several ways in which point-based algorithms can be adapted to parallel computing. We overview the challenges and opportunities and present experimental results, providing evidence to the usability of our suggestions. PMID:19914897
Multiscale Modeling of Ceramic Matrix Composites
NASA Technical Reports Server (NTRS)
Bednarcyk, Brett A.; Mital, Subodh K.; Pineda, Evan J.; Arnold, Steven M.
2015-01-01
Results of multiscale modeling simulations of the nonlinear response of SiC/SiC ceramic matrix composites are reported, wherein the microstructure of the ceramic matrix is captured. This micro scale architecture, which contains free Si material as well as the SiC ceramic, is responsible for residual stresses that play an important role in the subsequent thermo-mechanical behavior of the SiC/SiC composite. Using the novel Multiscale Generalized Method of Cells recursive micromechanics theory, the microstructure of the matrix, as well as the microstructure of the composite (fiber and matrix) can be captured.
Multiscale Modeling of Cortical Neural Networks
NASA Astrophysics Data System (ADS)
Torben-Nielsen, Benjamin; Stiefel, Klaus M.
2009-09-01
In this study, we describe efforts at modeling the electrophysiological dynamics of cortical networks in a multi-scale manner. Specifically, we describe the implementation of a network model composed of simple single-compartmental neuron models, in which a single complex multi-compartmental model of a pyramidal neuron is embedded. The network is capable of generating Δ (2 Hz, observed during deep sleep states) and γ (40 Hz, observed during wakefulness) oscillations, which are then imposed onto the multi-compartmental model, thus providing realistic, dynamic boundary conditions. We furthermore discuss the challenges and chances involved in multi-scale modeling of neural function.
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
Multiply scaled constrained nonlinear equation solvers. [for nonlinear heat conduction problems
NASA Technical Reports Server (NTRS)
Padovan, Joe; Krishna, Lala
1986-01-01
To improve the numerical stability of nonlinear equation solvers, a partitioned multiply scaled constraint scheme is developed. This scheme enables hierarchical levels of control for nonlinear equation solvers. To complement the procedure, partitioned convergence checks are established along with self-adaptive partitioning schemes. Overall, such procedures greatly enhance the numerical stability of the original solvers. To demonstrate and motivate the development of the scheme, the problem of nonlinear heat conduction is considered. In this context the main emphasis is given to successive substitution-type schemes. To verify the improved numerical characteristics associated with partitioned multiply scaled solvers, results are presented for several benchmark examples.
A GPU-accelerated flow solver for incompressible two-phase fluid flows
NASA Astrophysics Data System (ADS)
Codyer, Stephen; Raessi, Mehdi; Khanna, Gaurav
2011-11-01
We present a numerical solver for incompressible, immiscible, two-phase fluid flows that is accelerated by using Graphics Processing Units (GPUs). The Navier-Stokes equations are solved by the projection method, which involves solving a pressure Poisson problem at each time step. A second-order discretization of the Poisson problem leads to a sparse matrix with five and seven diagonals for two- and three-dimensional simulations, respectively. Running a serial linear algebra solver on a single CPU can take 50-99.9% of the total simulation time to solve the above system for pressure. To remove this bottleneck, we utilized the large parallelization capabilities of GPUs; we developed a linear algebra solver based on the conjugate gradient iterative method (CGIM) by using CUDA 4.0 libraries and compared its performance with CUSP, an open-source, GPU library for linear algebra. Compared to running the CGIM solver on a single CPU core, for a 2D case, our GPU solver yields speedups of up to 88x in solver time and 81x overall time on a single GPU card. In 3D cases, the speedups are up to 81x (solver) and 15x (overall). Speedup is faster at higher grid resolutions and our GPU solver outperforms CUSP. Current work examines the acceleration versus a parallel CGIM CPU solver.
NASA Astrophysics Data System (ADS)
Pelanti, Marica; Bouchut, François; Mangeney, Anne
2011-02-01
We present a Riemann solver derived by a relaxation technique for classical single-phase shallow flow equations and for a two-phase shallow flow model describing a mixture of solid granular material and fluid. Our primary interest is the numerical approximation of this two-phase solid/fluid model, whose complexity poses numerical difficulties that cannot be efficiently addressed by existing solvers. In particular, we are concerned with ensuring a robust treatment of dry bed states. The relaxation system used by the proposed solver is formulated by introducing auxiliary variables that replace the momenta in the spatial gradients of the original model systems. The resulting relaxation solver is related to Roe solver in that its Riemann solution for the flow height and relaxation variables is formally computed as Roe's Riemann solution. The relaxation solver has the advantage of a certain degree of freedom in the specification of the wave structure through the choice of the relaxation parameters. This flexibility can be exploited to handle robustly vacuum states, which is a well known difficulty of standard Roe's method, while maintaining Roe's low diffusivity. For the single-phase model positivity of flow height is rigorously preserved. For the two-phase model positivity of volume fractions in general is not ensured, and a suitable restriction on the CFL number might be needed. Nonetheless, numerical experiments suggest that the proposed two-phase flow solver efficiently models wet/dry fronts and vacuum formation for a large range of flow conditions. As a corollary of our study, we show that for single-phase shallow flow equations the relaxation solver is formally equivalent to the VFRoe solver with conservative variables of Gallouët and Masella [T. Gallouët, J.-M. Masella, Un schéma de Godunov approché C.R. Acad. Sci. Paris, Série I, 323 (1996) 77-84]. The relaxation interpretation allows establishing positivity conditions for this VFRoe method.
Fast solver for systems of axisymmetric ring vortices
NASA Astrophysics Data System (ADS)
Strickland, James H.; Amos, Donald E.
1992-03-01
A method that is capable of efficient calculation of the axisymmetric flowfield produced by a large system of ring vortices is presented in this paper. The system of ring vortices can, in turn, be used to model body surfaces and wakes in incompressible unsteady axisymmetric flowfields. This method takes advantage of source-point and field-point series expansion, which enables one to make calculations for interactions between groups of vortices that are in well-separated spatial domains rather than having to consider interactions between every pair of vortices. A FORTRAN computer code, RSOLV, has been written to execute the fast solution technique. For 100 vortices in the field, there is virtually no CPU time savings with the fast solver. For 10,000 vortices in the flow, the fast solver obtains solutions in about 1-3 percent of the time required for the direct solution technique. Formulas for the self-induced velocity of discretized regions of the flowfield have been developed. Use of these formulas allows correct convection of discretized patches of vorticity in the flowfiled.
CASTRO: A NEW COMPRESSIBLE ASTROPHYSICAL SOLVER. III. MULTIGROUP RADIATION HYDRODYNAMICS
Zhang, W.; Almgren, A.; Bell, J.; Howell, L.; Burrows, A.; Dolence, J.
2013-01-15
We present a formulation for multigroup radiation hydrodynamics that is correct to order O(v/c) using the comoving-frame approach and the flux-limited diffusion approximation. We describe a numerical algorithm for solving the system, implemented in the compressible astrophysics code, CASTRO. CASTRO uses a Eulerian grid with block-structured adaptive mesh refinement based on a nested hierarchy of logically rectangular variable-sized grids with simultaneous refinement in both space and time. In our multigroup radiation solver, the system is split into three parts: one part that couples the radiation and fluid in a hyperbolic subsystem, another part that advects the radiation in frequency space, and a parabolic part that evolves radiation diffusion and source-sink terms. The hyperbolic subsystem and the frequency space advection are solved explicitly with high-order Godunov schemes, whereas the parabolic part is solved implicitly with a first-order backward Euler method. Our multigroup radiation solver works for both neutrino and photon radiation.
An efficient chemical kinetics solver using high dimensional model representation
Shorter, J.A.; Ip, P.C.; Rabitz, H.A.
1999-09-09
A high dimensional model representation (HDMR) technique is introduced to capture the input-output behavior of chemical kinetic models. The HDMR expresses the output chemical species concentrations as a rapidly convergent hierarchical correlated function expansion in the input variables. In this paper, the input variables are taken as the species concentrations at time t{sub i} and the output is the concentrations at time t{sub i} + {delta}, where {delta} can be much larger than conventional integration time steps. A specially designed set of model runs is performed to determine the correlated functions making up the HDMR. The resultant HDMR can be used to (1) identify the key input variables acting independently or cooperatively on the output, and (2) create a high speed fully equivalent operational model (FEOM) serving to replace the original kinetic model and its differential equation solver. A demonstration of the HDMR technique is presented for stratospheric chemical kinetics. The FEOM proved to give accurate and stable chemical concentrations out to long times of many years. In addition, the FEOM was found to be orders of magnitude faster than a conventional stiff equation solver. This computational acceleration should have significance in many chemical kinetic applications.
Using computer algebra and SMT solvers in algebraic biology
NASA Astrophysics Data System (ADS)
Pineda Osorio, Mateo
2014-05-01
Biologic processes are represented as Boolean networks, in a discrete time. The dynamics within these networks are approached with the help of SMT Solvers and the use of computer algebra. Software such as Maple and Z3 was used in this case. The number of stationary states for each network was calculated. The network studied here corresponds to the immune system under the effects of drastic mood changes. Mood is considered as a Boolean variable that affects the entire dynamics of the immune system, changing the Boolean satisfiability and the number of stationary states of the immune network. Results obtained show Z3's great potential as a SMT Solver. Some of these results were verified in Maple, even though it showed not to be as suitable for the problem approach. The solving code was constructed using Z3-Python and Z3-SMT-LiB. Results obtained are important in biology systems and are expected to help in the design of immune therapies. As a future line of research, more complex Boolean network representations of the immune system as well as the whole psychological apparatus are suggested.
Matrix decomposition graphics processing unit solver for Poisson image editing
NASA Astrophysics Data System (ADS)
Lei, Zhao; Wei, Li
2012-10-01
In recent years, gradient-domain methods have been widely discussed in the image processing field, including seamless cloning and image stitching. These algorithms are commonly carried out by solving a large sparse linear system: the Poisson equation. However, solving the Poisson equation is a computational and memory intensive task which makes it not suitable for real-time image editing. A new matrix decomposition graphics processing unit (GPU) solver (MDGS) is proposed to settle the problem. A matrix decomposition method is used to distribute the work among GPU threads, so that MDGS will take full advantage of the computing power of current GPUs. Additionally, MDGS is a hybrid solver (combines both the direct and iterative techniques) and has two-level architecture. These enable MDGS to generate identical solutions with those of the common Poisson methods and achieve high convergence rate in most cases. This approach is advantageous in terms of parallelizability, enabling real-time image processing, low memory-taken and extensive applications.
Agglomeration Multigrid for an Unstructured-Grid Flow Solver
NASA Technical Reports Server (NTRS)
Frink, Neal; Pandya, Mohagna J.
2004-01-01
An agglomeration multigrid scheme has been implemented into the sequential version of the NASA code USM3Dns, tetrahedral cell-centered finite volume Euler/Navier-Stokes flow solver. Efficiency and robustness of the multigrid-enhanced flow solver have been assessed for three configurations assuming an inviscid flow and one configuration assuming a viscous fully turbulent flow. The inviscid studies include a transonic flow over the ONERA M6 wing and a generic business jet with flow-through nacelles and a low subsonic flow over a high-lift trapezoidal wing. The viscous case includes a fully turbulent flow over the RAE 2822 rectangular wing. The multigrid solutions converged with 12%-33% of the Central Processing Unit (CPU) time required by the solutions obtained without multigrid. For all of the inviscid cases, multigrid in conjunction with an explicit time-stepping scheme performed the best with regard to the run time memory and CPU time requirements. However, for the viscous case multigrid had to be used with an implicit backward Euler time-stepping scheme that increased the run time memory requirement by 22% as compared to the run made without multigrid.
Adaptively truncated Hilbert spaces for Hamiltonian-based impurity solvers
NASA Astrophysics Data System (ADS)
Go, Ara; Millis, Andrew
We investigate truncations of the exponentially large Hilbert space in the exact diagonalization (ED) as an impurity solver for the dynamical mean-field theory (DMFT). A key issue is to maintain the high degree of numerical accuracy required in the construction of Greens functions. We test various truncation schemes with similar number of Slater determinants in both Hilbert spaces for the ground state and a particle- or a hole-excited state, and show that the excited states play an important role in accurate computation as well as the ground state. Appropriate truncation for both spaces enables us to compute the accurate self-energy of the impurity Hamiltonian with up to eight correlated orbitals hybridized with a sufficient number of bath orbitals to obtain converged solutions of the self-consistent equation in the DMFT, which is not solvable by the original ED. Application to spin-orbit coupled multi-orbital models and the one-dimensional Hubbard model and comparison to results from exact diagonalization and the configuration interaction based impurity solvers demonstrate the power of the method. This work was supported by the US Department of Energy under Grants No. DE-FG02-04ER46169 and DE-SC0006613.
Assessent of elliptic solvers for the pressure Poisson equation
NASA Astrophysics Data System (ADS)
Strodtbeck, J. P.; Polly, J. B.; McDonough, J. M.
2008-11-01
It is well known that as much as 80% of the total arithmetic needed for a solution of the incompressible Navier--Stokes equations can be expended for solving the pressure Poisson equation, and this has long been one of the prime motivations for study of elliptic solvers. In recent years various Krylov-subspace methods have begun to receive wide use because of their rapid convergence rates and automatic generation of iteration parameters. However, it is actually total floating-point arithmetic operations that must be of concern when selecting a solver for CFD, and not simply required number of iterations. In the present study we recast speed of convergence for typical CFD pressure Poisson problems in terms of CPU time spent on floating-point arithmetic and demonstrate that in many cases simple successive-overrelaxation (SOR) methods are as effective as some of the popular Krylov-subspace techniques such as BiCGStab(l) provided optimal SOR iteration parameters are employed; furthermore, SOR procedures require significantly less memory. We then describe some techniques for automatically predicting optimal SOR parameters.
CASTRO: A New Compressible Astrophysical Solver. III. Multigroup Radiation Hydrodynamics
NASA Astrophysics Data System (ADS)
Zhang, W.; Howell, L.; Almgren, A.; Burrows, A.; Dolence, J.; Bell, J.
2013-01-01
We present a formulation for multigroup radiation hydrodynamics that is correct to order O(v/c) using the comoving-frame approach and the flux-limited diffusion approximation. We describe a numerical algorithm for solving the system, implemented in the compressible astrophysics code, CASTRO. CASTRO uses a Eulerian grid with block-structured adaptive mesh refinement based on a nested hierarchy of logically rectangular variable-sized grids with simultaneous refinement in both space and time. In our multigroup radiation solver, the system is split into three parts: one part that couples the radiation and fluid in a hyperbolic subsystem, another part that advects the radiation in frequency space, and a parabolic part that evolves radiation diffusion and source-sink terms. The hyperbolic subsystem and the frequency space advection are solved explicitly with high-order Godunov schemes, whereas the parabolic part is solved implicitly with a first-order backward Euler method. Our multigroup radiation solver works for both neutrino and photon radiation.
User documentation for PVODE, an ODE solver for parallel computers
Hindmarsh, A.C., LLNL
1998-05-01
PVODE is a general purpose ordinary differential equation (ODE) solver for stiff and nonstiff ODES It is based on CVODE [5] [6], which is written in ANSI- standard C PVODE uses MPI (Message-Passing Interface) [8] and a revised version of the vector module in CVODE to achieve parallelism and portability PVODE is intended for the SPMD (Single Program Multiple Data) environment with distributed memory, in which all vectors are identically distributed across processors In particular, the vector module is designed to help the user assign a contiguous segment of a given vector to each of the processors for parallel computation The idea is for each processor to solve a certain fixed subset of the ODES To better understand PVODE, we first need to understand CVODE and its historical background The ODE solver CVODE, which was written by Cohen and Hindmarsh, combines features of two earlier Fortran codes, VODE [l] and VODPK [3] Those two codes were written by Brown, Byrne, and Hindmarsh. Both use variable-coefficient multi-step integration methods, and address both stiff and nonstiff systems (Stiffness is defined as the presence of one or more very small damping time constants ) VODE uses direct linear algebraic techniques to solve the underlying banded or dense linear systems of equations in conjunction with a modified Newton method in the stiff ODE case On the other hand, VODPK uses a preconditioned Krylov iterative method [2] to solve the underlying linear system User-supplied preconditioners directly address the dominant source of stiffness Consequently, CVODE implements both the direct and iterative methods Currently, with regard to the nonlinear and linear system solution, PVODE has three method options available. functional iteration, Newton iteration with a diagonal approximate Jacobian, and Newton iteration with the iterative method SPGMR (Scaled Preconditioned Generalized Minimal Residual method) Both CVODE and PVODE are written in such a way that other linear
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