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).
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)
Systematically improvable multiscale solver for correlated electron systems
NASA Astrophysics Data System (ADS)
Kananenka, Alexei A.; Gull, Emanuel; Zgid, Dominika
2015-03-01
The development of numerical methods capable of simulating realistic materials with strongly correlated electrons, with controllable errors, is a central challenge in quantum many-body physics. Here we describe a framework for a general multiscale method based on embedding a self-energy of a strongly correlated subsystem into a self-energy generated by a method able to treat large weakly correlated systems approximately. As an example, we present the embedding of an exact diagonalization self-energy into a self-energy generated from self-consistent second-order perturbation theory. Using a quantum impurity model, generated from a cluster dynamical mean field approximation to the two-dimensional Hubbard model, as a benchmark, we illustrate that our method allows us to obtain accurate results at a fraction of the cost of typical Monte Carlo calculations. We test the method in multiple regimes of interaction strengths and dopings of the model. The general embedding framework we present avoids difficulties such as double counting corrections, frequency-dependent interactions, or vertex functions. As it is solely formulated at the level of the single-particle Green's function, it provides a promising route for the simulation of realistic materials that are currently difficult to study with other methods.
Modeling and simulation of high dimensional stochastic multiscale PDE systems at the exascale
Zabaras, Nicolas J.
2016-11-08
Predictive Modeling of multiscale and Multiphysics systems requires accurate data driven characterization of the input uncertainties, and understanding of how they propagate across scales and alter the final solution. This project develops a rigorous mathematical framework and scalable uncertainty quantification algorithms to efficiently construct realistic low dimensional input models, and surrogate low complexity systems for the analysis, design, and control of physical systems represented by multiscale stochastic PDEs. The work can be applied to many areas including physical and biological processes, from climate modeling to systems biology.
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.
Parallel Algorithms for PDE Solvers
1988-07-15
This report lists all of the 39 scientific publications , these, technical reports and conference presentations supported by the grant AFOSR 84-0385. The principal focus of the results are in 1) The Collocation Method: New versions developed for parallel machines, new results on the convergence and new
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.
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.
A pseudo-compressible variational multiscale solver for turbulent incompressible flows
NASA Astrophysics Data System (ADS)
Yang, Liang; Badia, Santiago; Codina, Ramon
2016-12-01
In this work, we design an explicit time-stepping solver for the simulation of the incompressible turbulent flow through the combination of VMS methods and artificial compressibility. We evaluate the effect of the artificial compressibility on the accuracy of the explicit formulation for under-resolved LES simulations. A set of benchmarks have been solved, e.g., the 3D Taylor-Green vortex problem in turbulent regimes. The resulting method is proven to be an effective alternative to implicit methods in some application ranges (in terms of problem size and computational resources), providing comparable results with very low memory requirements. As an example, with the explicit approach, we are able to solve accurately the Taylor-Green vortex benchmark in a fine mesh with 512^3 cells on a 12 cores 64 GB ram machine.
A Localized Tau Method PDE Solver
NASA Technical Reports Server (NTRS)
Cottam, Russell
2002-01-01
In this paper we present a new form of the collocation method that allows one to find very accurate solutions to time marching problems without the unwelcome appearance of Gibb's phenomenon oscillations. The basic method is applicable to any partial differential equation whose solution is a continuous, albeit possibly rapidly varying function. Discontinuous functions are dealt with by replacing the function in a small neighborhood of the discontinuity with a spline that smoothly connects the function segments on either side of the discontinuity. This will be demonstrated when the solution to the inviscid Burgers equation is discussed.
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.
NASA Astrophysics Data System (ADS)
Prástaro, Agostino
1991-12-01
In this paper we present the formal quantization of PDE's [35-40] in categorial language. Formal quantization results as a canonical functor defined on the category of differential equations. Furthermore, a Dirac-quantization can be interpreted as a covering in the category of differential equations. A quantum (pre-)spectral measure is a functor that can be factorized by means of formal quantization and a (pre-)spectral measure. A relation between canonical Dirac- quantization and singular solutions of PDE's is given. It is also proved that the knowledge of Bäcklund correspondences, as well as the conservation laws, can aid the procedure of canonical quantization of PDE's. Physically interesting examples are considered. In particular, we give the canonical quantization of an anharmonic oscillator. A general theory of quantum tunneling effects in PDE's is given. In particular, quantum cobordism has been related with Leray-Serre spectral sequences of PDE's.
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.
Shulga, Dmytro; Morozov, Oleksii; Hunziker, Patrick
2016-12-19
Optical Diffusion Tomography (ODT) is a modern non-invasive medical imaging modality which requires mathematical modelling of near-infrared light propagation in tissue. Solving the ODT forward problem equation accurately and efficiently is crucial. Typically, the forward problem is represented by a Diffusion PDE and is solved using the Finite Element Method (FEM) on a mesh, which is often unstructured. Tensor B-spline signal processing has the attractive features of excellent interpolation and approximation properties, multiscale properties, fast algorithms and does not require meshing. This paper introduces Tensor B-spline methodology with arbitrary spline degree tailored to solve the ODT forward problem in an accurate and efficient manner. We show that our Tensor B-spline formulation induces efficient and highly parallelizable computational algorithms. Exploitation of B-spline properties for integration over irregular domains proved valuable. The Tensor B-spline solver was tested on standard problems and on synthetic medical data and compared to FEM, including state-ofthe art ODT forward solvers. Results show that 1) a significantly higher accuracy can be achieved with the same number of nodes, 2) fewer nodes are required to achieve a prespecified accuracy, 3) the algorithm converges in significantly fewer iterations to a given error. These findings support the value of Tensor Bspline methodology for high-performance ODT implementations. This may translate into advances in ODT imaging for biomedical research and clinical application.
A Space/Time Dynamically Adaptive Method for Multiscale Problems
NASA Astrophysics Data System (ADS)
Grenga, Temistocle; Zikoski, Zachary; Paolucci, Samuel; Valorani, Mauro
2011-11-01
Systems of partial differential equations (PDEs) describing problems that are multiscale in space and time are computationally very expensive to solve. In order to overcome the challenges related to both thin spatial layers and temporal stiffness we propose the use of a wavelet adaptive multilevel representation (WAMR) in space and an adaptive model reduction method (G-Scheme) in time. The multilevel structure of the algorithm provides a simple way to adapt computational refinements to local demands of the solution. High resolution computations are performed only in spatial regions where sharp transitions occur, while the G-Scheme is an explicit solver developed for stiff problems which is built upon a local decomposition of the dynamics in three subspaces involving slow, active and fast time scales. Only the modes in the active subspace are integrated numerically, the others are approximated asymptotically. Subsequently, the original problem not only becomes substantially smaller, but more importantly non-stiff. Combining the WAMR technique with the G-Scheme yields a time accurate solution of a prescribed accuracy with a much smaller number of space- time degrees of freedom. While the computational scheme can be used to solve a wide class of stiff PDE problems, we will illustrate its use in the solution of the Navier Stokes equations in reactive flows.
Kayık, Gülru; Tüzün, Nurcan Ş; Durdagi, Serdar
2017-12-01
The essential biological function of phosphodiesterase (PDE) type enzymes is to regulate the cytoplasmic levels of intracellular second messengers, 3',5'-cyclic guanosine monophosphate (cGMP) and/or 3',5'-cyclic adenosine monophosphate (cAMP). PDE targets have 11 isoenzymes. Of these enzymes, PDE5 has attracted a special attention over the years after its recognition as being the target enzyme in treating erectile dysfunction. Due to the amino acid sequence and the secondary structural similarity of PDE6 and PDE11 with the catalytic domain of PDE5, first-generation PDE5 inhibitors (i.e. sildenafil and vardenafil) are also competitive inhibitors of PDE6 and PDE11. Since the major challenge of designing novel PDE5 inhibitors is to decrease their cross-reactivity with PDE6 and PDE11, in this study, we attempt to identify potent tadalafil-like PDE5 inhibitors that have PDE5/PDE6 and PDE5/PDE11 selectivity. For this aim, the similarity-based virtual screening protocol is applied for the "clean drug-like subset of ZINC database" that contains more than 20 million small compounds. Moreover, molecular dynamics (MD) simulations of selected hits complexed with PDE5 and off-targets were performed in order to get insights for structural and dynamical behaviors of the selected molecules as selective PDE5 inhibitors. Since tadalafil blocks hERG1 K channels in concentration dependent manner, the cardiotoxicity prediction of the hit molecules was also tested. Results of this study can be useful for designing of novel, safe and selective PDE5 inhibitors.
PDE11A negatively regulates lithium responsivity
Pathak, G.; Agostino, M.J.; Bishara, K.; Capell, W.R.; Fisher, J.L.; Hegde, S.; Ibrahim, B.A.; Pilarzyk, Kaitlyn; Sabin, C.; Tuczkewycz, Taras; Wilson, Steven; Kelly, M.P.
2016-01-01
Lithium responsivity in patients with bipolar disorder has been genetically associated with Phosphodiesterase 11A (PDE11A), and lithium decreases PDE11A mRNA in IPSC-derived hippocampal neurons originating from lithium responsive patients. PDE11 is an enzyme uniquely enriched in the hippocampus that breaks down cAMP and cGMP. Here, we determined if decreasing PDE11A expression is sufficient to increase lithium responsivity in mice. In dorsal hippocampus (DHIPP) and ventral hippocampus (VHIPP), lithium-responsive C57BL/6J and 129S6/SvEvTac mice show decreased PDE11A4 protein expression relative to lithium-unresponsive BALB/cJ mice. In VHIPP, C57BL/6J mice also show differences in PDE11A4 compartmentalization relative to BALB/cJ mice. In contrast, neither PDE2A nor PDE10A expression differ among the strains. The compartment-specific differences in PDE11A4 protein expression are explained by a coding SNP at amino acid 499, which falls within the GAF-B homodimerization domain. Relative to the BALB/cJ 499T, the C57BL/6J 499A decreases PDE11A4 homodimerization, which removes PDE11A4 from the membrane. Consistent with the observation that lower PDE11A4 expression correlates with better lithium responsiveness, we found that Pde11a KO mice given 0.4% lithium chow for 3+ weeks exhibit greater lithium responsivity relative to WT littermates in tail suspension, an antidepressant predictive assay, and amphetamine hyperlocomotion, an anti-manic predictive assay. Reduced PDE11A4 expression may represent a lithium-sensitive pathophysiology, because both C57BL/6J and Pde11a KO mice show increased expression of the pro-inflammatory cytokine IL-6 relative to BALB/cJ and PDE11A WT mice, respectively. Our finding that PDE11A4 negatively regulates lithium responsivity in mice suggests that the PDE11A SNPs identified in patients may be functionally relevant. PMID:27646265
Evaluation of PDE5 and PDE9 expression in benign and malignant breast tumors.
Karami-Tehrani, Fatemeh; Moeinifard, Marzieh; Aghaei, Mahmoud; Atri, Morteza
2012-08-01
Phosphodiesterases 5 and 9 (PDE5, PDE9) are enzymes responsible for regulating second messenger signaling by hydrolyzing 3',5' cyclic guanosine monophosphate (cGMP). PDE isoforms are deregulated in some types of human cancer. The present study was carried out to evaluate the expression of phosphodiesterase isoenzymes, PDE5 and PDE9, in benign and malignant breast tumors. The expression levels of PDE5 and PDE9 were assayed in malignant and benign breast tumors and corresponding normal breast tissues using quantitative real-time RT-PCR. Moreover, the correlation between PDE5, PDE9 relative expression and clinicopathological characteristics were analyzed. The relative expressions of PDE5 and PDE9 in malignant tumors were significantly higher than those of respective normal breast tissues and benign tumors (5.5-fold, p <0.001 and 6-fold, p <0.001, respectively). Furthermore, a significant positive correlation was found between PDE5 and PDE9 overexpression and tumor grade, stage, and lymph node involvement. However, a negative correlation was observed with age. Based on the present results, it is concluded that assessment of PDE5 and PDE9 expression may be useful in the differential diagnosis of benign and malignant breast disease and successful treatment of breast cancer. To the best of our knowledge, this is the first study to show that PDE5 and PDE9 expression levels are higher in malignant breast tumors than those of normal and benign breast tissue. Copyright © 2012 IMSS. Published by Elsevier Inc. All rights reserved.
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.
SOLVCON: An Unstructured PDE Framework
2011-10-01
object-oriented (like C++ or Java), and functional (like Lisp or Scheme ). Realize high-level construct: type registries, plug-ins, etc. Python is... schemes and calculate the Jacobian and fluxes SOLVCON has built in support for Euler and linear solvers. New physics can be added by creating new
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.
Structure -activity relationships of PDE5 inhibitors.
Eros, D; Szántai-Kis, Cs; Kiss, R; Kéri, Gy; Hegymegi-Barakonyi, B; Kövesdi, I; Orfi, L
2008-01-01
cGMP has a short-term effect on smooth muscle tone and a longer-term effect on responses to chronic drug treatment or proliferative signals. cGMP-Phosphodiesterase type 5 (PDE5) hydrolizes cGMP, and the result is smooth muscle contraction. PDE5 is a relatively novel therapeutic target of various diseases, such as erectile dysfunction and pulmonary hypertension. The most intensively examined and marketed PDE5 inhibitor was sildenafil (Viagra) but recently vardenafil (Levitra) and tadalafil (Cialis) were launched with beneficial ADME parameters and PDE5 selectivity. The increasing interest in PDE5 inhibition made it reasonable to collect the available inhibitory data from the scientific literature and set up a structure-activity relationship study. Chemical structures of 438 compounds and their cGMP-PDE5 inhibitory data (IC50) were collected from recently published articles. In this paper physiology, regulation and inhibition of PDE5 (and briefly other PDE-s) are discussed and inhibitors are tabulated by the core structures. Finally, a general QSAR model built from these data is presented. All data used in the QSAR study were summarized in a Supplement (for description please see the online version of the article).
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.
Parallel Multigrid Equation Solver
Adams, Mark
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.
8-Methoxyquinolines as PDE4 inhibitors.
Billah, Motasim; Buckley, George M; Cooper, Nicola; Dyke, Hazel J; Egan, Robert; Ganguly, Ashit; Gowers, Lewis; Haughan, Alan F; Kendall, Hannah J; Lowe, Christopher; Minnicozzi, Michael; Montana, John G; Oxford, Janet; Peake, Joanna C; Picken, C Louise; Piwinski, John J; Naylor, Robert; Sabin, Verity; Shih, Neng-Yang; Warneck, Julie B H
2002-06-17
The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).
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
Biomolecular surface construction by PDE transform
Zheng, Qiong; Yang, Siyang; Wei, Guo-Wei
2011-01-01
This work proposes a new framework for the surface generation based on the partial differential equation (PDE) transform. The PDE transform has recently been introduced as a general approach for the mode decomposition of images, signals, and data. It relies on the use of arbitrarily high order PDEs to achieve the time-frequency localization, control the spectral distribution, and regulate the spatial resolution. The present work provides a new variational derivation of high order PDE transforms. The fast Fourier transform is utilized to accomplish the PDE transform so as to avoid stringent stability constraints in solving high order PDEs. As a consequence, the time integration of high order PDEs can be done efficiently with the fast Fourier transform. The present approach is validated with a variety of test examples in two and three-dimensional settings. We explore the impact of the PDE transform parameters, such as the PDE order and propagation time, on the quality of resulting surfaces. Additionally, we utilize a set of 10 proteins to compare the computational efficiency of the present surface generation method and the MSMS approach in Cartesian meshes. Moreover, we analyze the present method by examining some benchmark indicators of biomolecular surface, i.e., surface area, surface enclosed volume, solvation free energy and surface electrostatic potential. A test set of 13 protein molecules is used in the present investigation. The electrostatic analysis is carried out via the Poisson-Boltzmann equation model. To further demonstrate the utility of the present PDE transform based surface method, we solve the Poisson-Nernst-Planck (PNP) equations with a PDE transform surface of a protein. Second order convergence is observed for the electrostatic potential and concentrations. Finally, to test the capability and efficiency of the present PDE transform based surface generation method, we apply it to the construction of an excessively large biomolecule, a virus
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.
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.
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.
Multiscale analysis and computation for flows in heterogeneous media
Efendiev, Yalchin; Hou, T. Y.; Durlofsky, L. J.; Tchelepi, H.
2016-08-04
Our work in this project is aimed at making fundamental advances in multiscale methods for flow and transport in highly heterogeneous porous media. The main thrust of this research is to develop a systematic multiscale analysis and efficient coarse-scale models that can capture global effects and extend existing multiscale approaches to problems with additional physics and uncertainties. A key emphasis is on problems without an apparent scale separation. Multiscale solution methods are currently under active investigation for the simulation of subsurface flow in heterogeneous formations. These procedures capture the effects of fine-scale permeability variations through the calculation of specialized coarse-scale basis functions. Most of the multiscale techniques presented to date employ localization approximations in the calculation of these basis functions. For some highly correlated (e.g., channelized) formations, however, global effects are important and these may need to be incorporated into the multiscale basis functions. Other challenging issues facing multiscale simulations are the extension of existing multiscale techniques to problems with additional physics, such as compressibility, capillary effects, etc. In our project, we explore the improvement of multiscale methods through the incorporation of additional (single-phase flow) information and the development of a general multiscale framework for flows in the presence of uncertainties, compressible flow and heterogeneous transport, and geomechanics. We have considered (1) adaptive local-global multiscale methods, (2) multiscale methods for the transport equation, (3) operator-based multiscale methods and solvers, (4) multiscale methods in the presence of uncertainties and applications, (5) multiscale finite element methods for high contrast porous media and their generalizations, and (6) multiscale methods for geomechanics. Below, we present a brief overview of each of these contributions.
Multiscale Simulation Framework for Coupled Fluid Flow and Mechanical Deformation
Hou, Thomas; Efendiev, Yalchin; Tchelepi, Hamdi; Durlofsky, Louis
2016-05-24
Our work in this project is aimed at making fundamental advances in multiscale methods for flow and transport in highly heterogeneous porous media. The main thrust of this research is to develop a systematic multiscale analysis and efficient coarse-scale models that can capture global effects and extend existing multiscale approaches to problems with additional physics and uncertainties. A key emphasis is on problems without an apparent scale separation. Multiscale solution methods are currently under active investigation for the simulation of subsurface flow in heterogeneous formations. These procedures capture the effects of fine-scale permeability variations through the calculation of specialized coarse-scale basis functions. Most of the multiscale techniques presented to date employ localization approximations in the calculation of these basis functions. For some highly correlated (e.g., channelized) formations, however, global effects are important and these may need to be incorporated into the multiscale basis functions. Other challenging issues facing multiscale simulations are the extension of existing multiscale techniques to problems with additional physics, such as compressibility, capillary effects, etc. In our project, we explore the improvement of multiscale methods through the incorporation of additional (single-phase flow) information and the development of a general multiscale framework for flows in the presence of uncertainties, compressible flow and heterogeneous transport, and geomechanics. We have considered (1) adaptive local-global multiscale methods, (2) multiscale methods for the transport equation, (3) operator-based multiscale methods and solvers, (4) multiscale methods in the presence of uncertainties and applications, (5) multiscale finite element methods for high contrast porous media and their generalizations, and (6) multiscale methods for geomechanics.
Mechanisms of mutant PDE6 proteins underlying retinal diseases.
Gopalakrishna, Kota N; Boyd, Kimberly; Artemyev, Nikolai O
2017-09-01
Mutations in PDE6 genes encoding the effector enzymes in rods and cones underlie severe retinal diseases including retinitis pigmentosa (RP), autosomal dominant congenital stationary night blindness (adCSNB), and achromatopsia (ACHM). Here we examined a spectrum of pathogenic missense mutations in PDE6 using the system based on co-expression of cone PDE6C with its specialized chaperone AIPL1 and the regulatory Pγ subunit as a potent co-chaperone. We uncovered two mechanisms of PDE6C mutations underlying ACHM: (a) folding defects leading to expression of catalytically inactive proteins and (b) markedly diminished ability of Pγ to co-chaperone mutant PDE6C proteins thereby dramatically reducing the levels of functional enzyme. The mechanism of the Rambusch adCSNB associated with the H258N substitution in PDE6B was probed through the analysis of the model mutant PDE6C-H262N. We identified two interrelated deficits of PDE6C-H262N: disruption of the inhibitory interaction of Pγ with mutant PDE6C that markedly reduced the ability of Pγ to augment the enzyme folding. Thus, we conclude that the Rambusch adCSNB is triggered by low levels of the constitutively active PDE6. Finally, we examined PDE6C-L858V, which models PDE6B-L854V, an RP-linked mutation that alters the protein isoprenyl modification. This analysis suggests that the type of prenyl modifications does not impact the folding of PDE6, but it modulates the enzyme affinity for its trafficking partner PDE6D. Hence, the pathogenicity of PDE6B-L854V likely arises from its trafficking deficiency. Taken together, our results demonstrate the effectiveness of the PDE6C expression system to evaluate pathogenicity and elucidate the mechanisms of PDE6 mutations in retinal diseases. Copyright © 2017 Elsevier Inc. All rights reserved.
Scalable solvers and applications
Ribbens, C J
2000-10-27
The purpose of this report is to summarize research activities carried out under Lawrence Livermore National Laboratory (LLNL) research subcontract B501073. This contract supported the principal investigator (P1), Dr. Calvin Ribbens, during his sabbatical visit to LLNL from August 1999 through June 2000. Results and conclusions from the work are summarized below in two major sections. The first section covers contributions to the Scalable Linear Solvers and hypre projects in the Center for Applied Scientific Computing (CASC). The second section describes results from collaboration with Patrice Turchi of LLNL's Chemistry and Materials Science Directorate (CMS). A list of publications supported by this subcontract appears at the end of the report.
Kolandaivelu, Saravanan; Chang, Bo; Ramamurthy, Visvanathan
2011-01-01
Rod and cone photoreceptor neurons utilize discrete PDE6 enzymes that are crucial for phototransduction. Rod PDE6 is composed of heterodimeric catalytic subunits (αβ), while the catalytic core of cone PDE6 (α′) is a homodimer. It is not known if variations between PDE6 subunits preclude rod PDE6 catalytic subunits from coupling to the cone phototransduction pathway. To study this issue, we generated a cone-dominated mouse model lacking cone PDE6 (Nrl−/− cpfl1). In this animal model, using several independent experimental approaches, we demonstrated the expression of rod PDE6 (αβ) and the absence of cone PDE6 (α′) catalytic subunits. The rod PDE6 enzyme expressed in cone cells is active and contributes to the hydrolysis of cGMP in response to light. In addition, rod PDE6 expressed in cone cells couples to the light signaling pathway to produce S-cone responses. However, S-cone responses and light-dependent cGMP hydrolysis were eliminated when the β-subunit of rod PDE6 was removed (Nrl−/− cpfl1 rd). We conclude that either rod or cone PDE6 can effectively couple to the cone phototransduction pathway to mediate visual signaling. Interestingly, we also found that functional PDE6 is required for trafficking of M-opsin to cone outer segments. PMID:21799013
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.
IGA-ADS: Isogeometric analysis FEM using ADS solver
NASA Astrophysics Data System (ADS)
Łoś, Marcin M.; Woźniak, Maciej; Paszyński, Maciej; Lenharth, Andrew; Hassaan, Muhamm Amber; Pingali, Keshav
2017-08-01
In this paper we present a fast explicit solver for solution of non-stationary problems using L2 projections with isogeometric finite element method. The solver has been implemented within GALOIS framework. It enables parallel multi-core simulations of different time-dependent problems, in 1D, 2D, or 3D. We have prepared the solver framework in a way that enables direct implementation of the selected PDE and corresponding boundary conditions. In this paper we describe the installation, implementation of exemplary three PDEs, and execution of the simulations on multi-core Linux cluster nodes. We consider three case studies, including heat transfer, linear elasticity, as well as non-linear flow in heterogeneous media. The presented package generates output suitable for interfacing with Gnuplot and ParaView visualization software. The exemplary simulations show near perfect scalability on Gilbert shared-memory node with four Intel® Xeon® CPU E7-4860 processors, each possessing 10 physical cores (for a total of 40 cores).
ODE/PDE analysis of corneal curvature.
Płociniczak, Lukasz; Griffiths, Graham W; Schiesser, William E
2014-10-01
The starting point for this paper is a nonlinear, two-point boundary value ordinary differential equation (BVODE) that defines corneal curvature according to a static force balance. A numerical solution to the BVODE is computed by first converting the BVODE to a parabolic partial differential equation (PDE) by adding an initial value (t, pseudo-time) derivative to the BVODE. A numerical solution to the PDE is then computed by the method of lines (MOL) with the calculation proceeding to a sufficiently large value of t such that the derivative in t reduces to essentially zero. The PDE solution at this point is also the solution for the BVODE. This procedure is implemented in R (an open source scientific programming system) and the programming is discussed in some detail. A series approximation to the solution is derived from which an estimate for the rate of convergence is obtained. This is compared to a fitted exponential model. Also, two linear approximations are derived, one of which leads to a closed form solution. Both provide solutions very close to that obtained from the full nonlinear model. An estimate for the cornea radius of curvature is also derived. The paper concludes with a discussion of the features of the solution to the ODE/PDE system.
NASA Astrophysics Data System (ADS)
Holmström, M.; Nilsson, H.
2012-09-01
We present a hybrid plasma solver (particle ions, fluid mass-less electrons). The software is built on the public available FLASH software, developed at the University of Chicago [1], that provide adaptive grids and is fully parallelized. FLASH is a general parallel solver for compressible flow problems. It is written in Fortran 90, well structured into modules, has good support, and is open source. The parallelization is done using a block-structured adaptive cartesian grid with the Message-Passing Interface (MPI) library as the underlying communication layer. The hybrid solver in FLASH uses cell centered finite differences [2] and conserves energy well [3]. Recently we have added to the hybrid solver the capability of handling vacuum regions, non-uniform resistivity, external fields, and hyperresistivity. We also present an application of the solver to the interaction between the Moon and the solar wind [4], as illustrated in Fig. 1.
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.
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).
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
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.
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.
Parallel, Implicit, Finite Element Solver
NASA Astrophysics Data System (ADS)
Lowrie, Weston; Shumlak, Uri; Meier, Eric; Marklin, George
2007-11-01
A parallel, implicit, finite element solver is described for solutions to the ideal MHD equations and the Pseudo-1D Euler equations. The solver uses the conservative flux source form of the equations. This helps simplify the discretization of the finite element method by keeping the specification of the physics separate. An implicit time advance is used to allow sufficiently large time steps. The Portable Extensible Toolkit for Scientific Computation (PETSc) is implemented for parallel matrix solvers and parallel data structures. Results for several test cases are described as well as accuracy of the method.
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.
2009-09-04
reinforcement / matrix interface bonded interfaces microvascular channels composite...Composites Characterization Scales reinforcement / matrix interface bonded interfaces microvascular channels composite layer properties structural response cm nm µm mm ...AFOSR-MURI Functionally Graded Hybrid Composites Multiscale Characterization Characterization of Composite Layers • Graded Ceramic/Metal Matrix
PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction
Knight, Walter E.; Chen, Si; Zhang, Yishuai; Oikawa, Masayoshi; Wu, Meiping; Zhou, Qian; Miller, Clint L.; Cai, Yujun; Mickelsen, Deanne M.; Moravec, Christine; Small, Eric M.; Abe, Junichi; Yan, Chen
2016-01-01
Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance. PMID:27791092
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)
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)
Nonlocality as a function of PDE type
NASA Astrophysics Data System (ADS)
Maker, David
2007-08-01
Here we postulate a geometrical 2D closed path invariant ds=ds t+ds Φ (geometrical interpretation) with the observer's own 2D ds=ds t+ds Φ then giving a total direct sum 2⊕2=4 degrees of freedom for the resulting (observer translation) Dirac equation pde and its ψ. There are several, more or less technical, ways of stating the consequences of that new "observer interpretation" Dirac equation pde. Two such ways are "wave function collapse," and in a more common sense vein "Bertlmann's socks." Note that wavefunction collapse to ψ then (and experimental nonlocality implications) is the "observables translation" of that fundamental postulate and so not itself postulated. Also that geometrical postulate does not allow a Bohmian hidden variable interpretation because of its fundamental nature (i.e., we cannot go any deeper). For example that postulate states no x or p that we would be certain of in some hidden variable context. Thus we can ignore here the straw man arguments of J.S. Bell that are in response to Bohmian hidden variable theories only. Thus there cannot result Bell's kink at θ=0 in the correlation function between the polarization measurements on the two ends of an EPR experimental apparatus (Bell, 1987). Recall this kink required correlating in a hidden variable, classical statistical mechanical context, with resulting superluminal implications. Also note here the "observer interpretation" boundary condition conservation of angular momentum of the initial singlet state for our 4D Dirac pde results in this being a time independent solution to this pde. Thus wave function collapse to the measured value in no way implies superluminal communication. In laymen terms it is just the Bertlmann's socks common sense fact that we knew before hand about the original singlet state of the central emitter, no superluminal communication between the left and right ends of the Aspect apparatus was required to know about this. Thus our new observer representation
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.
Notes on the ExactPack Implementation of the DSD Rate Stick Solver
Kaul, Ann
2016-08-01
It has been shown above that the discretization scheme implemented in the ExactPack solver for the DSD Rate Stick equation is consistent with the Rate Stick PDE. In addition, a stability analysis has provided a CFL condition for a stable time step. Together, consistency and stability imply convergence of the scheme, which is expected to be close to first-order in time and second-order in space. It is understood that the nonlinearity of the underlying PDE will affect this rate somewhat. In the solver I implemented in ExactPack, I used the one-sided boundary condition described above at the outer boundary. In addition, I used 80% of the time step calculated in the stability analysis above. By making these two changes, I was able to implement a solver that calculates the solution without any arbitrary limits placed on the values of the curvature at the boundary. Thus, the calculation is driven directly by the conditions at the boundary as formulated in the DSD theory. The chosen scheme is completely coherent and defensible from a mathematical standpoint.
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
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.
The emperor's new clothes: PDE5 and the heart.
Degen, Chantal V; Bishu, Kalkidan; Zakeri, Rosita; Ogut, Ozgur; Redfield, Margaret M; Brozovich, Frank V
2015-01-01
Phosphodiesterase-5 (PDE5) is highly expressed in the pulmonary vasculature, but its expression in the myocardium is controversial. Cyclic guanosine monophosphate (cGMP) activates protein kinase G (PKG), which has been hypothesized to blunt cardiac hypertrophy and negative remodeling in heart failure. Although PDE5 has been suggested to play a significant role in the breakdown of cGMP in cardiomyocytes and hence PKG regulation in the myocardium, the RELAX trial, which tested effect of PDE5 inhibition on exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) failed to show a beneficial effect. These results highlight the controversy regarding the role and expression of PDE5 in the healthy and failing heart. This study used one- and two-dimensional electrophoresis and Western blotting to examine PDE5 expression in mouse (before and after trans-aortic constriction), dog (control and HFpEF) as well as human (healthy and failing) heart. We were unable to detect PDE5 in any cardiac tissue lysate, whereas PDE5 was present in the murine and bovine lung samples used as positive controls. These results indicate that if PDE5 is expressed in cardiac tissue, it is present in very low quantities, as PDE5 was not detected in either humans or any model of heart failure examined. Therefore in cardiac muscle, it is unlikely that PDE5 is involved the regulation of cGMP-PKG signaling, and hence PDE5 does not represent a suitable drug target for the treatment of cardiac hypertrophy. These results highlight the importance of rigorous investigation prior to clinical trial design.
The Emperor's New Clothes: PDE5 and the Heart
Degen, Chantal V.; Bishu, Kalkidan; Zakeri, Rosita; Ogut, Ozgur; Redfield, Margaret M.; Brozovich, Frank V.
2015-01-01
Phosphodiesterase-5 (PDE5) is highly expressed in the pulmonary vasculature, but its expression in the myocardium is controversial. Cyclic guanosine monophosphate (cGMP) activates protein kinase G (PKG), which has been hypothesized to blunt cardiac hypertrophy and negative remodeling in heart failure. Although PDE5 has been suggested to play a significant role in the breakdown of cGMP in cardiomyocytes and hence PKG regulation in the myocardium, the RELAX trial, which tested effect of PDE5 inhibition on exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) failed to show a beneficial effect. These results highlight the controversy regarding the role and expression of PDE5 in the healthy and failing heart. This study used one- and two-dimensional electrophoresis and Western blotting to examine PDE5 expression in mouse (before and after trans-aortic constriction), dog (control and HFpEF) as well as human (healthy and failing) heart. We were unable to detect PDE5 in any cardiac tissue lysate, whereas PDE5 was present in the murine and bovine lung samples used as positive controls. These results indicate that if PDE5 is expressed in cardiac tissue, it is present in very low quantities, as PDE5 was not detected in either humans or any model of heart failure examined. Therefore in cardiac muscle, it is unlikely that PDE5 is involved the regulation of cGMP-PKG signaling, and hence PDE5 does not represent a suitable drug target for the treatment of cardiac hypertrophy. These results highlight the importance of rigorous investigation prior to clinical trial design. PMID:25747598
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.
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.
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.
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
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.
A Multiscale Software Tool for Field/Circuit Co-Simulation
2011-12-15
Lumped Port 2 on the right end of the microstrip line. The simulated S-parameters, S11 and S21, of the active microwave amplifier circuit are shown in...REPORT A Multiscale Software Tool for Field/ Circuit Simulation Final Report 14. ABSTRACT 16. SECURITY CLASSIFICATION OF: This report is developed under...topic #A08-T004, contract W911NF-09-C-0159. As the final report, we have developed a new multiscale field/ circuit solver by combining three efficient
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.
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.
Sponziello, Marialuisa; Verrienti, Antonella; Rosignolo, Francesca; De Rose, Roberta Francesca; Pecce, Valeria; Maggisano, Valentina; Durante, Cosimo; Bulotta, Stefania; Damante, Giuseppe; Giacomelli, Laura; Di Gioia, Cira Rosaria Tiziana; Filetti, Sebastiano; Russo, Diego; Celano, Marilena
2015-11-01
Recent studies have revealed in normal thyroid tissue the presence of the transcript of several phosphodiesterases (PDEs), enzymes responsible for the hydrolysis of cyclic nucleotides. In this work, we analyzed the expression of PDE5 in a series of human papillary thyroid carcinomas (PTCs) presenting or not BRAF V600E mutation and classified according to ATA risk criteria. Furthermore, we tested the effects of two PDE5 inhibitors (sildenafil, tadalafil) against human thyroid cancer cells. PDE5 gene and protein expression were analyzed in two different cohorts of PTCs by real-time PCR using a TaqMan micro-fluid card system and Western blot. MTT and migration assay were used to evaluate the effects of PDE5 inhibitors on proliferation and migration of TPC-1, BCPAP, and 8505C cells. In a first series of 36 PTCs, we found higher expression levels of PDE5A in tumors versus non-tumor (normal) tissues. PTCs with BRAF mutation showed higher levels of mRNA compared with those without mutation. No significant differences were detected between subgroups with low and intermediate ATA risk. Upregulation of PDE5 was also detected in tumor tissue proteins. Similar results were obtained analyzing the second cohort of 50 PTCs. Moreover, all tumor tissues with high PDE5 levels showed reduction of Thyroglobulin, TSH receptor, Thyroperoxidase, and NIS transcripts. In thyroid cancer cells in vitro, sildenafil and tadalafil determined a reduction of proliferation and cellular migration. Our findings demonstrate for the first time an overexpression of PDE5 in PTCs, and the ability of PDE5 inhibitors to block the proliferation of thyroid cancer cells in culture, therefore, suggesting that specific inhibition of PDE5 may be proposed for the treatment of these tumors.
Kimura, Yoshio; Nakatuma, Hiromi; Sato, Naoko; Ohtani, Mika
2006-01-01
A tBLASTn search of the Myxococcus xanthus genome database at The Institute for Genomic Research (TIGR) identified three genes (pdeA, pdeB, and pdeC) that encode proteins homologous to 3',5'-cyclic nucleotide phosphodiesterase. pdeA, pdeB, and pdeC mutants, constructed by replacing a part of the gene with the kanamycin or tetracycline resistance gene, showed normal growth, development, and germination under nonstress conditions. However, the spores of mutants, especially the pdeA and pdeB mutants, placed under osmotic stress germinated earlier than the wild-type spores. The phenotype was the opposite of that of the receptor-type adenylyl cyclase (cyaA or cyaB) mutant. Also, pdeA and pdeB mutants were found to have impaired growth under the condition of high-temperature stress. Intracellular cyclic AMP (cAMP) levels of pdeA or pdeB mutant cells under these stressful conditions were about 1.3-fold to 2.0-fold higher than those of wild-type cells. These results suggest that PdeA and PdeB may be involved in osmotic adaptation during spore germination and temperature adaptation during vegetative growth through the regulation of cAMP levels.
Selective Extraction of Entangled Textures via Adaptive PDE Transform.
Wang, Yang; Wei, Guo-Wei; Yang, Siyang
2012-01-01
Texture and feature extraction is an important research area with a wide range of applications in science and technology. Selective extraction of entangled textures is a challenging task due to spatial entanglement, orientation mixing, and high-frequency overlapping. The partial differential equation (PDE) transform is an efficient method for functional mode decomposition. The present work introduces adaptive PDE transform algorithm to appropriately threshold the statistical variance of the local variation of functional modes. The proposed adaptive PDE transform is applied to the selective extraction of entangled textures. Successful separations of human face, clothes, background, natural landscape, text, forest, camouflaged sniper and neuron skeletons have validated the proposed method.
Selective Extraction of Entangled Textures via Adaptive PDE Transform
Wang, Yang; Wei, Guo-Wei; Yang, Siyang
2012-01-01
Texture and feature extraction is an important research area with a wide range of applications in science and technology. Selective extraction of entangled textures is a challenging task due to spatial entanglement, orientation mixing, and high-frequency overlapping. The partial differential equation (PDE) transform is an efficient method for functional mode decomposition. The present work introduces adaptive PDE transform algorithm to appropriately threshold the statistical variance of the local variation of functional modes. The proposed adaptive PDE transform is applied to the selective extraction of entangled textures. Successful separations of human face, clothes, background, natural landscape, text, forest, camouflaged sniper and neuron skeletons have validated the proposed method. PMID:22315584
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.
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.
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.
Optimal control of coupled PDE networks with automated code generation
NASA Astrophysics Data System (ADS)
Papadopoulos, D.
2012-09-01
The purpose of this work is to present a framework for the optimal control of coupled PDE networks. A coupled PDE network is a system of partial differential equations coupled together. Such systems can be represented as a directed graph. A domain specific language (DSL)—an extension of the DOT language—is used for the description of such a coupled PDE network. The adjoint equations and the gradient, required for its optimal control, are computed with the help of a computer algebra system (CAS). Automated code generation techniques have been used for the generation of the PDE systems of both the direct and the adjoint equations. Both the direct and adjoint equations are solved with the standard finite element method. Finally, for the numerical optimization of the system standard optimization techniques are used such as BFGS and Newton conjugate gradient.
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
Multiscale modeling of mucosal immune responses.
Mei, Yongguo; Abedi, Vida; Carbo, Adria; Zhang, Xiaoying; Lu, Pinyi; Philipson, Casandra; Hontecillas, Raquel; Hoops, Stefan; Liles, Nathan; Bassaganya-Riera, Josep
2015-01-01
Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut inflammation. Our modeling predictions dissect the mechanisms by which effector CD4+ T cell responses contribute to tissue damage in the gut mucosa following immune dysregulation.Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T
Alexander, M S; Gasperini, M J; Tsai, P T; Gibbs, D E; Spinazzola, J M; Marshall, J L; Feyder, M J; Pletcher, M T; Chekler, E L P; Morris, C A; Sahin, M; Harms, J F; Schmidt, C J; Kleiman, R J; Kunkel, L M
2016-09-27
Duchenne muscular dystrophy is caused by mutations in the DYSTROPHIN gene. Although primarily associated with muscle wasting, a significant portion of patients (approximately 25%) are also diagnosed with autism spectrum disorder. We describe social behavioral deficits in dystrophin-deficient mice and present evidence of cerebellar deficits in cGMP production. We demonstrate therapeutic potential for selective inhibitors of the cGMP-specific PDE5A and PDE9A enzymes to restore social behaviors in dystrophin-deficient mice.
PDE8 controls CD4(+) T cell motility through the PDE8A-Raf-1 kinase signaling complex.
Basole, Chaitali P; Nguyen, Rebecca K; Lamothe, Katie; Vang, Amanda; Clark, Robert; Baillie, George S; Epstein, Paul M; Brocke, Stefan
2017-08-26
The levels of cAMP are regulated by phosphodiesterase enzymes (PDEs), which are targets for the treatment of inflammatory disorders. We have previously shown that PDE8 regulates T cell motility. Here, for the first time, we report that PDE8A exerts part of its control of T cell function through the V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) kinase signaling pathway. To examine T cell motility under physiologic conditions, we analyzed T cell interactions with endothelial cells and ligands in flow assays. The highly PDE8-selective enzymatic inhibitor PF-04957325 suppresses adhesion of in vivo myelin oligodendrocyte glycoprotein (MOG) activated inflammatory CD4(+) T effector (Teff) cells to brain endothelial cells under shear stress. Recently, PDE8A was shown to associate with Raf-1 creating a compartment of low cAMP levels around Raf-1 thereby protecting it from protein kinase A (PKA) mediated inhibitory phosphorylation. To test the function of this complex in Teff cells, we used a cell permeable peptide that selectively disrupts the PDE8A-Raf-1 interaction. The disruptor peptide inhibits the Teff-endothelial cell interaction more potently than the enzymatic inhibitor. Furthermore, the LFA-1/ICAM-1 interaction was identified as a target of disruptor peptide mediated reduction of adhesion, spreading and locomotion of Teff cells under flow. Mechanistically, we observed that disruption of the PDE8A-Raf-1 complex profoundly alters Raf-1 signaling in Teff cells. Collectively, our studies demonstrate that PDE8A inhibition by enzymatic inhibitors or PDE8A-Raf-1 kinase complex disruptors decreases Teff cell adhesion and migration under flow, and represents a novel approach to target T cells in inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.
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.
Zhang, Chong; Xu, Ying; Zhang, Han-Ting; Gurney, Mark E.; O’Donnell, James M.
2017-01-01
Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions. PMID:28054669
NASA Astrophysics Data System (ADS)
Gong, Weiwei; Zhou, Xu
2017-06-01
In Computer Science, the Boolean Satisfiability Problem(SAT) is the problem of determining if there exists an interpretation that satisfies a given Boolean formula. SAT is one of the first problems that was proven to be NP-complete, which is also fundamental to artificial intelligence, algorithm and hardware design. This paper reviews the main algorithms of the SAT solver in recent years, including serial SAT algorithms, parallel SAT algorithms, SAT algorithms based on GPU, and SAT algorithms based on FPGA. The development of SAT is analyzed comprehensively in this paper. Finally, several possible directions for the development of the SAT problem are proposed.
Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)
Zhang, Han-Ting; Huang, Ying; Masood, Anbrin; Stolinski, Lisa R; Li, Yunfeng; Zhang, Lei; Dlaboga, Daniel; Jin, S-L Catherine; Conti, Marco; O’Donnell, James M
2009-01-01
Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression- and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4B−/−). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4B−/− mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4B−/− mice. Compared to PDE4B + / + littermates, PDE4B−/− mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light–dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4B−/− mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4B−/− mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4B−/− mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior PMID:17700644
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.
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 εκαr . 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 ( εκαr 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
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
Grinberg, Leopold; Fedosov, Dmitry A.; Karniadakis, George Em
2012-01-01
Cardiovascular pathologies, such as a brain aneurysm, are affected by the global blood circulation as well as by the local microrheology. Hence, developing computational models for such cases requires the coupling of disparate spatial and temporal scales often governed by diverse mathematical descriptions, e.g., by partial differential equations (continuum) and ordinary differential equations for discrete particles (atomistic). However, interfacing atomistic-based with continuum-based domain discretizations is a challenging problem that requires both mathematical and computational advances. We present here a hybrid methodology that enabled us to perform the first multi-scale simulations of platelet depositions on the wall of a brain aneurysm. The large scale flow features in the intracranial network are accurately resolved by using the high-order spectral element Navier-Stokes solver εκ αr. The blood rheology inside the aneurysm is modeled using a coarse-grained stochastic molecular dynamics approach (the dissipative particle dynamics method) implemented in the parallel code LAMMPS. The continuum and atomistic domains overlap with interface conditions provided by effective forces computed adaptively to ensure continuity of states across the interface boundary. A two-way interaction is allowed with the time-evolving boundary of the (deposited) platelet clusters tracked by an immersed boundary method. The corresponding heterogeneous solvers ( εκ αr and LAMMPS) are linked together by a computational multilevel message passing interface that facilitates modularity and high parallel efficiency. Results of multiscale simulations of clot formation inside the aneurysm in a patient-specific arterial tree are presented. We also discuss the computational challenges involved and present scalability results of our coupled solver on up to 300K computer processors. Validation of such coupled atomistic-continuum models is a main open issue that has to be addressed in future
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
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
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
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
Newton Solver Stabilization for Stokes Solvers in Geodynamic Problems
NASA Astrophysics Data System (ADS)
Fraters, Menno; Bangerth, Wolfgang; Thieulot, Cedric; Spakman, Wim
2017-04-01
The most commonly used method by the geodynamical community for solving non-linear equations is the Picard fixed-point iteration. However, the Newton method has recently gained interest within this community because it formally leads to quadratic convergence close to the solution as compared to the global linear convergence of the Picard iteration. In mantle dynamics, a blend of pressure and strain-rate dependent visco-plastic rheologies is often used. While for power-law rheologies the Jacobian is guaranteed to be Symmetric Positive Definite (SPD), for more complex (compressible) rheologies, the Jacobian may become non-SPD. Here we present a new method for efficiently enforce the Jacobian to be SPD, necessary for our current highly efficient Stokes solvers, with a minimum loss in convergence rate. Furthermore, we show results for both incompressible and compressible models.
Systemic and metabolic effects of PDE5-inhibitor drugs.
Aversa, Antonio
2010-03-15
Phosphodiesterase type-5 inhibitor (PDE5-i) drugs were first marketed in 1998 (sildenafil) for 'ondemand' treatment of male erectile dysfunction (ED) of any origin. They selectively inhibit intrapenile PDE5 isoenzyme which in turn increases intracellular cyclic guanosine monophosphate levels, thus resulting in prolonged relaxation of cavernosum smooth muscle cells and facilitating the erectile process. Since 2003, two new molecules (tadalafil and vardenafil) have been introduced, resulting in greater interest in these compounds and leading patients to ask for more prescriptions from their doctors. The vast use of PDE5-i in diabetic and cardiovascular ED patients led researchers to investigate their possible extra sexual effects. Several studies investigating their effects on endothelium, coronary and pulmonary circulation, inferior oesophageal sphincter and kidney functions have appeared and, finally, sildenafil was approved for the treatment of pulmonary arterial hypertension. Recent animal studies highlighted a possible interaction between chronic PDE5 inhibition and glucose homeostasis which occurs through a marked improvement of high fat diet induced insulin resistance. If this data is extended to humans, a new scenario will be opened for the chronic use of PDE5-i for sexual rehabilitation along with cardiovascular and metabolic benefits.
Systemic and metabolic effects of PDE5-inhibitor drugs
Aversa, Antonio
2010-01-01
Phosphodiesterase type-5 inhibitor (PDE5-i) drugs were first marketed in 1998 (sildenafil) for 'ondemand' treatment of male erectile dysfunction (ED) of any origin. They selectively inhibit intrapenile PDE5 isoenzyme which in turn increases intracellular cyclic guanosine monophosphate levels, thus resulting in prolonged relaxation of cavernosum smooth muscle cells and facilitating the erectile process. Since 2003, two new molecules (tadalafil and vardenafil) have been introduced, resulting in greater interest in these compounds and leading patients to ask for more prescriptions from their doctors. The vast use of PDE5-i in diabetic and cardiovascular ED patients led researchers to investigate their possible extra sexual effects. Several studies investigating their effects on endothelium, coronary and pulmonary circulation, inferior oesophageal sphincter and kidney functions have appeared and, finally, sildenafil was approved for the treatment of pulmonary arterial hypertension. Recent animal studies highlighted a possible interaction between chronic PDE5 inhibition and glucose homeostasis which occurs through a marked improvement of high fat diet induced insulin resistance. If this data is extended to humans, a new scenario will be opened for the chronic use of PDE5-i for sexual rehabilitation along with cardiovascular and metabolic benefits. PMID:21537421
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.
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...
Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1).
Kakkar, R; Raju, R V; Sharma, R K
1999-07-01
Ca2+/calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) is one of the key enzymes involved in the complex interactions between the cyclic nucleotide and Ca2+ second messenger systems. Currently, three genes encode PDE1, and alternate splicing of these genes gives rise to functionally different isozymes which exhibit distinct catalytic and regulatory properties. Some isozymes have similar kinetic and immunological properties but are differentially regulated by Ca2+ and calmodulin. These isozymes also differ in their mechanism of regulation by phosphorylation. Analysis of various regulatory reactions involving Ca2+ and cyclic adenosine monophosphate (cAMP) has revealed the importance of the time dependence of these reactions during cell activation; however, no measurement is available for the time of occurrence of specific regulatory reactions. cAMP-signalling systems provide a pivotal centre for achieving crosstalk regulation by various signalling pathways. It has been proposed that polypeptide sequences enriched in proline (P), glutamate (E), serine (S) and threonine (T), known as PEST motifs, serve as putative intramolecular signals for rapid proteolytic degradation by calpains. Calpains are Ca(2+)-dependent cysteine proteases that regulate various enzymes, transcription factors and structural proteins through limited proteolysis. Isozyme PDE1A2 has a PEST motif and acts as a substrate for m-calpain. In this paper, we have described PDE1A2 regulation by calpains and its physiological implications. cAMP is an important component of the signal transduction pathway and plays an integral role in various physiological processes such as gene transcription, various neuronal functions, cardiac muscle contraction, vascular relaxation, cell proliferation and a host of other functions. It is important to identify the cellular processes where PDE isoform(s) and cAMP response are altered. This will lead to better understanding of the pathology of disease states
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.
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)
Boscheri, Walter; Balsara, Dinshaw S.; Dumbser, Michael
2014-06-01
In this paper we use the genuinely multidimensional HLL Riemann solvers recently developed by Balsara et al. in [13] to construct a new class of computationally efficient high order Lagrangian ADER-WENO one-step ALE finite volume schemes on unstructured triangular meshes. A nonlinear WENO reconstruction operator allows the algorithm to achieve high order of accuracy in space, while high order of accuracy in time is obtained by the use of an ADER time-stepping technique based on a local space-time Galerkin predictor. The multidimensional HLL and HLLC Riemann solvers operate at each vertex of the grid, considering the entire Voronoi neighborhood of each node and allow for larger time steps than conventional one-dimensional Riemann solvers. The results produced by the multidimensional Riemann solver are then used twice in our one-step ALE algorithm: first, as a node solver that assigns a unique velocity vector to each vertex, in order to preserve the continuity of the computational mesh; second, as a building block for genuinely multidimensional numerical flux evaluation that allows the scheme to run with larger time steps compared to conventional finite volume schemes that use classical one-dimensional Riemann solvers in normal direction. The space-time flux integral computation is carried out at the boundaries of each triangular space-time control volume using the Simpson quadrature rule in space and Gauss-Legendre quadrature in time. A rezoning step may be necessary in order to overcome element overlapping or crossing-over. Since our one-step ALE finite volume scheme is based directly on a space-time conservation formulation of the governing PDE system, the remapping stage is not needed, making our algorithm a so-called direct ALE method.
Alexander, M S; Gasperini, M J; Tsai, P T; Gibbs, D E; Spinazzola, J M; Marshall, J L; Feyder, M J; Pletcher, M T; Chekler, E L P; Morris, C A; Sahin, M; Harms, J F; Schmidt, C J; Kleiman, R J; Kunkel, L M
2016-01-01
Duchenne muscular dystrophy is caused by mutations in the DYSTROPHIN gene. Although primarily associated with muscle wasting, a significant portion of patients (approximately 25%) are also diagnosed with autism spectrum disorder. We describe social behavioral deficits in dystrophin-deficient mice and present evidence of cerebellar deficits in cGMP production. We demonstrate therapeutic potential for selective inhibitors of the cGMP-specific PDE5A and PDE9A enzymes to restore social behaviors in dystrophin-deficient mice. PMID:27676442
Terascale Optimal PDE Simulations (TOPS) Center
Professor Olof B. Widlund
2007-07-09
Our work has focused on the development and analysis of domain decomposition algorithms for a variety of problems arising in continuum mechanics modeling. In particular, we have extended and analyzed FETI-DP and BDDC algorithms; these iterative solvers were first introduced and studied by Charbel Farhat and his collaborators, see [11, 45, 12], and by Clark Dohrmann of SANDIA, Albuquerque, see [43, 2, 1], respectively. These two closely related families of methods are of particular interest since they are used more extensively than other iterative substructuring methods to solve very large and difficult problems. Thus, the FETI algorithms are part of the SALINAS system developed by the SANDIA National Laboratories for very large scale computations, and as already noted, BDDC was first developed by a SANDIA scientist, Dr. Clark Dohrmann. The FETI algorithms are also making inroads in commercial engineering software systems. We also note that the analysis of these algorithms poses very real mathematical challenges. The success in developing this theory has, in several instances, led to significant improvements in the performance of these algorithms. A very desirable feature of these iterative substructuring and other domain decomposition algorithms is that they respect the memory hierarchy of modern parallel and distributed computing systems, which is essential for approaching peak floating point performance. The development of improved methods, together with more powerful computer systems, is making it possible to carry out simulations in three dimensions, with quite high resolution, relatively easily. This work is supported by high quality software systems, such as Argonne's PETSc library, which facilitates code development as well as the access to a variety of parallel and distributed computer systems. The success in finding scalable and robust domain decomposition algorithms for very large number of processors and very large finite element problems is, e
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.
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.
Is PDE4 too difficult a drug target?
Higgs, Gerry
2010-05-01
The search for selective inhibitors of PDE4 as novel anti-inflammatory drugs has continued for more than 30 years. Although several compounds have demonstrated therapeutic effects in diseases such as asthma, COPD, atopic dermatitis and psoriasis, none have reached the market. A persistent challenge in the development of PDE4 inhibitors has been drug-induced gastrointestinal adverse effects, such as nausea. However, extensive clinical trials with well-tolerated doses of roflumilast (Daxas; Nycomed/Mitsubishi Tanabe Pharma Corp/Forest Laboratories Inc) in COPD, a disease that is generally unresponsive to existing therapies, have demonstrated significant therapeutic improvements. In addition, GlaxoSmithKline plc is developing 256066, an inhaled formulation of a PDE4 inhibitor that has demonstrated efficacy in trials in asthma, and apremilast from Celgene Corp has been reported to be effective for the treatment of psoriasis. Despite the challenges and complications that have been encountered during the development of PDE4 inhibitors, these drugs may provide a genuinely novel class of anti-inflammatory agents, and there are several compounds in development that could fulfill that promise.
PDE5 Inhibitors Enhance Celecoxib Killing in Multiple Tumor Types
BOOTH, LAURENCE; ROBERTS, JANE L.; CRUICKSHANKS, NICHOLA; TAVALLAI, SEYEDMEHRAD; WEBB, TIMOTHY; SAMUEL, PETER; CONLEY, ADAM; BINION, BRITTANY; YOUNG, HAROLD F.; POKLEPOVIC, ANDREW; SPIEGEL, SARAH; DENT, PAUL
2015-01-01
The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer. PMID:25303541
Student's Lab Assignments in PDE Course with MAPLE.
ERIC Educational Resources Information Center
Ponidi, B. Alhadi
Computer-aided software has been used intensively in many mathematics courses, especially in computational subjects, to solve initial value and boundary value problems in Partial Differential Equations (PDE). Many software packages were used in student lab assignments such as FORTRAN, PASCAL, MATLAB, MATHEMATICA, and MAPLE in order to accelerate…
NASA 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.
Performance prediction of finite-difference solvers for different computer architectures
NASA Astrophysics Data System (ADS)
Louboutin, Mathias; Lange, Michael; Herrmann, Felix J.; Kukreja, Navjot; Gorman, Gerard
2017-08-01
The life-cycle of a partial differential equation (PDE) solver is often characterized by three development phases: the development of a stable numerical discretization; development of a correct (verified) implementation; and the optimization of the implementation for different computer architectures. Often it is only after significant time and effort has been invested that the performance bottlenecks of a PDE solver are fully understood, and the precise details varies between different computer architectures. One way to mitigate this issue is to establish a reliable performance model that allows a numerical analyst to make reliable predictions of how well a numerical method would perform on a given computer architecture, before embarking upon potentially long and expensive implementation and optimization phases. The availability of a reliable performance model also saves developer effort as it both informs the developer on what kind of optimisations are beneficial, and when the maximum expected performance has been reached and optimisation work should stop. We show how discretization of a wave-equation can be theoretically studied to understand the performance limitations of the method on modern computer architectures. We focus on the roofline model, now broadly used in the high-performance computing community, which considers the achievable performance in terms of the peak memory bandwidth and peak floating point performance of a computer with respect to algorithmic choices. A first principles analysis of operational intensity for key time-stepping finite-difference algorithms is presented. With this information available at the time of algorithm design, the expected performance on target computer systems can be used as a driver for algorithm design.
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.
Parallelizing alternating direction implicit solver on GPUs
USDA-ARS?s Scientific Manuscript database
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...
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.
Improved Stiff ODE Solvers for Combustion CFD
NASA Astrophysics Data System (ADS)
Imren, A.; Haworth, D. C.
2016-11-01
Increasingly large chemical mechanisms are needed to predict autoignition, heat release and pollutant emissions in computational fluid dynamics (CFD) simulations of in-cylinder processes in compression-ignition engines and other applications. Calculation of chemical source terms usually dominates the computational effort, and several strategies have been proposed to reduce the high computational cost associated with realistic chemistry in CFD. Central to most strategies is a stiff ordinary differential equation (ODE) solver to compute the change in composition due to chemical reactions over a computational time step. Most work to date on stiff ODE solvers for computational combustion has focused on backward differential formula (BDF) methods, and has not explicitly considered the implications of how the stiff ODE solver couples with the CFD algorithm. In this work, a fresh look at stiff ODE solvers is taken that includes how the solver is integrated into a turbulent combustion CFD code, and the advantages of extrapolation-based solvers in this regard are demonstrated. Benefits in CPU time and accuracy are demonstrated for homogeneous systems and compression-ignition engines, for chemical mechanisms that range in size from fewer than 50 to more than 7,000 species.
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.
PDE8 regulates rapid Teff cell adhesion and proliferation independent of ICER.
Vang, Amanda G; Ben-Sasson, Shlomo Z; Dong, Hongli; Kream, Barbara; DeNinno, Michael P; Claffey, Michelle M; Housley, William; Clark, Robert B; Epstein, Paul M; Brocke, Stefan
2010-08-09
Abolishing the inhibitory signal of intracellular cAMP by phosphodiesterases (PDEs) is a prerequisite for effector T (Teff) cell function. While PDE4 plays a prominent role, its control of cAMP levels in Teff cells is not exclusive. T cell activation has been shown to induce PDE8, a PDE isoform with 40- to 100-fold greater affinity for cAMP than PDE4. Thus, we postulated that PDE8 is an important regulator of Teff cell functions. We found that Teff cells express PDE8 in vivo. Inhibition of PDE8 by the PDE inhibitor dipyridamole (DP) activates cAMP signaling and suppresses two major integrins involved in Teff cell adhesion. Accordingly, DP as well as the novel PDE8-selective inhibitor PF-4957325-00 suppress firm attachment of Teff cells to endothelial cells. Analysis of downstream signaling shows that DP suppresses proliferation and cytokine expression of Teff cells from Crem-/- mice lacking the inducible cAMP early repressor (ICER). Importantly, endothelial cells also express PDE8. DP treatment decreases vascular adhesion molecule and chemokine expression, while upregulating the tight junction molecule claudin-5. In vivo, DP reduces CXCL12 gene expression as determined by in situ probing of the mouse microvasculature by cell-selective laser-capture microdissection. Collectively, our data identify PDE8 as a novel target for suppression of Teff cell functions, including adhesion to endothelial cells.
Skoumbourdis, Amanda P.; LeClair, Christopher A.; Stefan, Eduard; Turjanski, Adrian G.; Maguire, William; Titus, Steven A.; Huang, Ruili; Auld, Douglas S.; Inglese, James; Austin, Christopher P.; Michnick, Stephen W.; Xia, Menghang; Thomas, Craig J.
2010-01-01
An expansion of structure-activity studies on a series of substituted 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine PDE4 inhibitors and the introduction of a related [1,2,4]triazolo[4,3-b]pyridazine based inhibitor of PDE4 is presented. The development of SAR included strategic incorporation of known substituents on the critical catachol diether moiety of the 6-phenyl appendage on each heterocyclic core. From these studies, (R)-3-(2,5-dimethoxyphenyl)-6-(4-methoxy-3-(tetrahydrofuran-3-yloxy)phenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (10) and (R)-3-(2,5-dimethoxyphenyl)-6-(4-methoxy-3-(tetrahydrofuran-3-yloxy)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine (18) were identified as highly potent PDE4A inhibitors. Each of these analogues was submitted across a panel of 21 PDE family members and was shown to be highly selective for PDE4 isoforms (PDE4A, PDE4B, PDE4C, PDE4D). Both 10 and 18 were then evaluated in divergent cell-based assays to assess their relevant use as probes of PDE4 activity. Finally, docking studies with selective ligands (including 10 and 18) were undertaken to better understand this chemotypes ability to bind and inhibit PDE4 selectively. PMID:19464886
Brullo, Chiara; Massa, Matteo; Villa, Carla; Ricciarelli, Roberta; Rivera, Daniela; Pronzato, Maria Adelaide; Fedele, Ernesto; Barocelli, Elisabetta; Bertoni, Simona; Flammini, Lisa; Bruno, Olga
2015-07-01
A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity.
AKAP3 Selectively Binds PDE4A Isoforms in Bovine Spermatozoa1
Bajpai, Malini; Fiedler, Sarah E.; Huang, Zaohua; Vijayaraghavan, Srinivasan; Olson, Gary E.; Livera, Gabriel; Conti, Marco; Carr, Daniel W.
2006-01-01
Cyclic AMP plays an important role in regulating sperm motility and acrosome reaction through activation of cAMP-dependent protein kinase A (PKA). Phosphodiesterases (PDEs) modulate the levels of cyclic nucleotides by catalyzing their degradation. Although PDE inhibitors specific to PDE1 and PDE4 are known to alter sperm motility and capacitation in humans, little is known about the role or subcellular distribution of PDEs in spermatozoa. The localization of PKA is regulated by A-kinase anchoring proteins (AKAPs), which may also control the intracellular distribution of PDE. The present study was undertaken to investigate the role and localization of PDE4 during sperm capacitation. Addition of Rolipram or RS25344, PDE4-specific inhibitors significantly increased the progressive motility of bovine spermatozoa. Immunolocalization techniques detected both PDE4A and AKAP3 (formerly known as AKAP110) in the principal piece of bovine spermatozoa. The PDE4A5 isoform was detected primarily in the Triton X-100-soluble fraction of caudal epididymal spermatozoa. However, in ejaculated spermatozoa it was seen primarily in the SDS-soluble fraction, indicating a shift in PDE4A5 localization into insoluble organelles during sperm capacitation. AKAP3 was detected only in the SDS-soluble fraction of both caudal and ejaculated sperm. Immunoprecipitation experiments using COS cells cotransfected with AKAP3 and either Pde4a5 or Pde4d provide evidence that PDE4A5 but not PDE4D interacts with AKAP3. Pulldown assays using sperm cell lysates confirm this interaction in vitro. These data suggest that AKAP3 binds both PKA and PDE4A and functions as a scaffolding protein in spermatozoa to regulate local cAMP concentrations and modulate sperm functions. PMID:16177223
cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors.
Bolger, Graeme B; Bizzi, Mariana F; Pinheiro, Sergio V; Trivellin, Giampaolo; Smoot, Lisa; Accavitti, Mary-Ann; Korbonits, Márta; Ribeiro-Oliveira, Antonio
2016-05-01
PDE4 cyclic nucleotide phosphodiesterases regulate cAMP abundance in cells and therefore regulate numerous processes, including cell growth and differentiation. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein (also called XAP2 or ARA-9). Germline mutations in AIP occur in approximately 20% of patients with Familial Isolated Pituitary Adenoma (FIPA) and 20% of childhood-onset simplex somatotroph adenomas. We therefore examined the protein expression of PDE4A4 and the closely related isoform PDE4A8 in normal human pituitary tissue and in pituitary adenomas. PDE4A4 had low expression in normal pituitary but was significantly overexpressed in somatotroph, lactotroph, corticotroph and clinically nonfunctioning gonadotroph adenomas (P<0.0001 for all subtypes). Likewise, PDE4A8 was expressed in normal pituitary and was also significantly overexpressed in the adenoma subtypes (P<0.0001 for all). Among the different adenoma subtypes, corticotroph and lactotroph adenomas were the highest and lowest expressed for PDE4A4, respectively, whereas the opposite was observed for PDE4A8. Naturally occurring oncogenic variants in AIP were shown by a two-hybrid assay to disrupt the ability of AIP to interact with PDE4A5. A reverse two-hybrid screen identified numerous additional variants in the tetratricopeptide repeat (TPR) region of AIP that also disrupted its ability to interact with PDE4A5. The expression of PDE4A4 and PDE4A8 in normal pituitary, their increased expression in adenomatous pituitary cells where AIP is meant to participate, and the disruption of the PDE4A4-AIP interaction by AIP mutants may play a role in pituitary tumorigenesis.
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.
Interactive Medical Image Segmentation using PDE Control of Active Contours
Karasev, Peter; Kolesov, Ivan; Fritscher, Karl; Vela, Patricio; Mitchell, Phillip; Tannenbaum, Allen
2014-01-01
Segmentation of injured or unusual anatomic structures in medical imagery is a problem that has continued to elude fully automated solutions. In this paper, the goal of easy-to-use and consistent interactive segmentation is transformed into a control synthesis problem. A nominal level set PDE is assumed to be given; this open-loop system achieves correct segmentation under ideal conditions, but does not agree with a human expert's ideal boundary for real image data. Perturbing the state and dynamics of a level set PDE via the accumulated user input and an observer-like system leads to desirable closed-loop behavior. The input structure is designed such that a user can stabilize the boundary in some desired state without needing to understand any mathematical parameters. Effectiveness of the technique is illustrated with applications to the challenging segmentations of a patellar tendon in MR and a shattered femur in CT. PMID:23893712
Interactive medical image segmentation using PDE control of active contours.
Karasev, Peter; Kolesov, Ivan; Fritscher, Karl; Vela, Patricio; Mitchell, Phillip; Tannenbaum, Allen
2013-11-01
Segmentation of injured or unusual anatomic structures in medical imagery is a problem that has continued to elude fully automated solutions. In this paper, the goal of easy-to-use and consistent interactive segmentation is transformed into a control synthesis problem. A nominal level set partial differential equation (PDE) is assumed to be given; this open-loop system achieves correct segmentation under ideal conditions, but does not agree with a human expert's ideal boundary for real image data. Perturbing the state and dynamics of a level set PDE via the accumulated user input and an observer-like system leads to desirable closed-loop behavior. The input structure is designed such that a user can stabilize the boundary in some desired state without needing to understand any mathematical parameters. Effectiveness of the technique is illustrated with applications to the challenging segmentations of a patellar tendon in magnetic resonance and a shattered femur in computed tomography.
A local PDE model of aggregation formation in bacterial colonies
NASA Astrophysics Data System (ADS)
Chavy-Waddy, Paul-Christopher; Kolokolnikov, Theodore
2016-10-01
We study pattern formation in a model of cyanobacteria motion recently proposed by Galante, Wisen, Bhaya and Levy. By taking a continuum limit of their model, we derive a novel fourth-order nonlinear parabolic PDE equation that governs the behaviour of the model. This PDE is {{u}t}=-{{u}xx}-{{u}xxxx}+α {{≤ft(\\frac{{{u}x}{{u}xx}}{u}\\right)}x} . We then derive the instability thresholds for the onset of pattern formation. We also compute analytically the spatial profiles of the steady state aggregation density. These profiles are shown to be of the form \\text{sec}{{\\text{h}}p} where the exponent p is related to the parameters of the model. Full numerical simulations give a favorable comparison between the continuum and the underlying discrete system, and show that the aggregation profiles are stable above the critical threshold.
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.
Adapative non-hydrostatic dynamics for exploring multiscale climate interactions
NASA Astrophysics Data System (ADS)
Collins, William; Johansen, Hans; Benedict, Jim; Rosa, Daniele; O'Brien, Travis; Johnson, Jeff; Goodfriend, Elijah; Keen, Noel
2015-04-01
Many of the atmospheric phenomena with the greatest potential impact in future warmer climates are inherently multiscale. Such meteorological systems include hurricanes and tropical cyclones, atmospheric rivers, and other types of hydrometeorological extremes. These phenomena are challenging to simulate in conventional climate models due to the relatively coarse uniform model resolutions relative to the native nonhydrostatic scales of the phenomenological dynamics. To enable studies of these systems with sufficient local resolution for the multiscale dynamics yet with sufficient speed for climate-change studies, we have built a new type of atmospheric model by combining adaptive mesh dynamics with the cloud-resolving physics from the Multiscale Modeling Framework (MMF). The model features adaptive mesh refinement in both space and time, nonhydrostatic dynamics, and high-order numerical accuracy. By using both space-and time-adaptive mesh refinement, the solver allocates computational effort only where greater accuracy is needed, in particular to resolve emergent multiscale phenomena such as synoptic storm systems. We show initial simulations of tropical cyclones using this new model that can be refined over several orders of magnitude without loss of accuracy to study the evolution of these cyclones at ultra-high resolution while simultaneously retaining the two-way interactions between the cyclones and the rest of the climate system.
Multiscale modeling and simulation of brain blood flow.
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.
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 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
Perdikaris, Paris; Grinberg, Leopold; Karniadakis, George Em
2016-02-15
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.
Multiscale modeling and simulation of brain blood flow
Perdikaris, Paris; Grinberg, Leopold; Karniadakis, George Em
2016-01-01
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. PMID:26909005
Inductive ionospheric solver for magnetospheric MHD simulations
NASA Astrophysics Data System (ADS)
Vanhamäki, H.
2011-01-01
We present a new scheme for solving the ionospheric boundary conditions required in magnetospheric MHD simulations. In contrast to the electrostatic ionospheric solvers currently in use, the new solver takes ionospheric induction into account by solving Faraday's law simultaneously with Ohm's law and current continuity. From the viewpoint of an MHD simulation, the new inductive solver is similar to the electrostatic solvers, as the same input data is used (field-aligned current [FAC] and ionospheric conductances) and similar output is produced (ionospheric electric field). The inductive solver is tested using realistic, databased models of an omega-band and westward traveling surge. Although the tests were performed with local models and MHD simulations require a global ionospheric solution, we may nevertheless conclude that the new solution scheme is feasible also in practice. In the test cases the difference between static and electrodynamic solutions is up to ~10 V km-1 in certain locations, or up to 20-40% of the total electric field. This is in agreement with previous estimates. It should also be noted that if FAC is replaced by the ground magnetic field (or ionospheric equivalent current) in the input data set, exactly the same formalism can be used to construct an inductive version of the KRM method originally developed by Kamide et al. (1981).
XRF map identification problems based on a PDE electrodeposition model
NASA Astrophysics Data System (ADS)
Sgura, Ivonne; Bozzini, Benedetto
2017-04-01
In this paper we focus on the following map identification problem (MIP): given a morphochemical reaction–diffusion (RD) PDE system modeling an electrodepostion process, we look for a time t *, belonging to the transient dynamics and a set of parameters \\mathbf{p} , such that the PDE solution, for the morphology h≤ft(x,y,{{t}\\ast};\\mathbf{p}\\right) and for the chemistry θ ≤ft(x,y,{{t}\\ast};\\mathbf{p}\\right) approximates a given experimental map M *. Towards this aim, we introduce a numerical algorithm using singular value decomposition (SVD) and Frobenius norm to give a measure of error distance between experimental maps for h and θ and simulated solutions of the RD-PDE system on a fixed time integration interval. The technique proposed allows quantitative use of microspectroscopy images, such as XRF maps. Specifically, in this work we have modelled the morphology and manganese distributions of nanostructured components of innovative batteries and we have followed their changes resulting from ageing under operating conditions. The availability of quantitative information on space-time evolution of active materials in terms of model parameters will allow dramatic improvements in knowledge-based optimization of battery fabrication and operation.
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.
Approximation error in PDE-based modelling of vehicular platoons
NASA Astrophysics Data System (ADS)
Hao, He; Barooah, Prabir
2012-08-01
We study the problem of how much error is introduced in approximating the dynamics of a large vehicular platoon by using a partial differential equation, as was done in Barooah, Mehta, and Hespanha [Barooah, P., Mehta, P.G., and Hespanha, J.P. (2009), 'Mistuning-based Decentralised Control of Vehicular Platoons for Improved Closed Loop Stability', IEEE Transactions on Automatic Control, 54, 2100-2113], Hao, Barooah, and Mehta [Hao, H., Barooah, P., and Mehta, P.G. (2011), 'Stability Margin Scaling Laws of Distributed Formation Control as a Function of Network Structure', IEEE Transactions on Automatic Control, 56, 923-929]. In particular, we examine the difference between the stability margins of the coupled-ordinary differential equations (ODE) model and its partial differential equation (PDE) approximation, which we call the approximation error. The stability margin is defined as the absolute value of the real part of the least stable pole. The PDE model has proved useful in the design of distributed control schemes (Barooah et al. 2009; Hao et al. 2011); it provides insight into the effect of gains of local controllers on the closed-loop stability margin that is lacking in the coupled-ODE model. Here we show that the ratio of the approximation error to the stability margin is O(1/N), where N is the number of vehicles. Thus, the PDE model is an accurate approximation of the coupled-ODE model when N is large. Numerical computations are provided to corroborate the analysis.
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
2016-04-07
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. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Diggle, Christine P.; Sukoff Rizzo, Stacey J.; Popiolek, Michael; Hinttala, Reetta; Schülke, Jan-Philip; Kurian, Manju A.; Carr, Ian M.; Markham, Alexander F.; Bonthron, David T.; Watson, Christopher; Sharif, Saghira Malik; Reinhart, Veronica; James, Larry C.; Vanase-Frawley, Michelle A.; Charych, Erik; Allen, Melanie; Harms, John; Schmidt, Christopher J.; Ng, Joanne; Pysden, Karen; Strick, Christine; Vieira, Päivi; Mankinen, Katariina; Kokkonen, Hannaleena; Kallioinen, Matti; Sormunen, Raija; Rinne, Juha O.; Johansson, Jarkko; Alakurtti, Kati; Huilaja, Laura; Hurskainen, Tiina; Tasanen, Kaisa; Anttila, Eija; Marques, Tiago Reis; Howes, Oliver; Politis, Marius; Fahiminiya, Somayyeh; Nguyen, Khanh Q.; Majewski, Jacek; Uusimaa, Johanna; Sheridan, Eamonn; Brandon, Nicholas J.
2016-01-01
Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species. PMID:27058446
Compressible turbulence and shock-capturing using a variational multiscale method
NASA Astrophysics Data System (ADS)
Garai, Anirban; Burgess, Nicholas; Murman, Scott; Diosady, Laslo
2016-11-01
We have previously developed a dynamic extension of Hughes' variational multiscale method which is implemented in an entropy-stable Discontinuous-Galerkin spectral-element solver. This solver and sub-grid model have been examined on standard low-speed benchmark flows, e.g. homogeneous turbulence, channel flow, etc. Here we extend the approach to higher speeds where compressibility effects are no longer insignificant, and the flowfields develop unsteady shocklets and shock waves. Homogeneous isotropic turbulence at high turbulent Mach number is tested for two cases - decaying and passing through a normal shock. Numerical simulations using the multiscale sub-grid model, no sub-grid model, and a variation of Barter and Darmofal's shock-capturing scheme are examined in isolation and combination. The computed results are compared against theoretical observations and previous computational results.
An approximate Riemann solver for hypervelocity flows
NASA Technical Reports Server (NTRS)
Jacobs, Peter A.
1991-01-01
We describe an approximate Riemann solver for the computation of hypervelocity flows in which there are strong shocks and viscous interactions. The scheme has three stages, the first of which computes the intermediate states assuming isentropic waves. A second stage, based on the strong shock relations, may then be invoked if the pressure jump across either wave is large. The third stage interpolates the interface state from the two initial states and the intermediate states. The solver is used as part of a finite-volume code and is demonstrated on two test cases. The first is a high Mach number flow over a sphere while the second is a flow over a slender cone with an adiabatic boundary layer. In both cases the solver performs well.
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.
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.
Sahu, Maitrayee; Sahu, Abhiram
2015-01-01
Leptin signaling in the hypothalamus is critical for normal food intake and body weight regulation. Cumulative evidence suggests that besides the signal transducer and activator of transcription-3 (STAT3) pathway, several non-STAT3 pathways including the phosphodiesterase-3B (PDE3B) pathway mediate leptin signaling in the hypothalamus. We have shown that PDE3B is localized in various hypothalamic sites implicated in the regulation of energy homeostasis and that the anorectic and body weight reducing effects of leptin are mediated by the activation of PDE3B. It is still unknown if PDE3B is expressed in the long form of the leptin-receptor (ObRb)-expressing neurons in the hypothalamus and whether leptin induces STAT3 activation in PDE3B-expressing neurons. In this study, we examined co-localization of PDE3B with ObRb neurons in various hypothalamic nuclei in ObRb-GFP mice that were treated with leptin (5mg/kg, ip) for 2 hr. Results showed that most of the ObRb neurons in the arcuate nucleus (ARC, 93%), ventromedial nucleus (VMN, 94%), dorsomedial nucleus (DMN, 95%), ventral premammillary nucleus (PMv, 97%) and lateral hypothalamus (LH, 97%) co-expressed PDE3B. We next examined co-localization of p-STAT3 and PDE3B in the hypothalamus in C57BL6 mice that were treated with leptin (5mg/kg, ip) for 1 hr. The results showed that almost all p-STAT3 positive neurons in different hypothalamic nuclei including ARC, VMN, DMN, LH and PMv areas expressed PDE3B. These results suggest the possibility for a direct role for the PDE3B pathway in mediating leptin action in the hypothalamus. PMID:26297880
Sahu, Maitrayee; Sahu, Abhiram
2015-11-01
Leptin signaling in the hypothalamus is critical for normal food intake and body weight regulation. Cumulative evidence suggests that besides the signal transducer and activator of transcription-3 (STAT3) pathway, several non-STAT3 pathways including the phosphodiesterase-3B (PDE3B) pathway mediate leptin signaling in the hypothalamus. We have shown that PDE3B is localized in various hypothalamic sites implicated in the regulation of energy homeostasis and that the anorectic and body weight reducing effects of leptin are mediated by the activation of PDE3B. It is still unknown if PDE3B is expressed in the long form of the leptin-receptor (ObRb)-expressing neurons in the hypothalamus and whether leptin induces STAT3 activation in PDE3B-expressing neurons. In this study, we examined co-localization of PDE3B with ObRb neurons in various hypothalamic nuclei in ObRb-GFP mice that were treated with leptin (5mg/kg, ip) for 2h. Results showed that most of the ObRb neurons in the arcuate nucleus (ARC, 93%), ventromedial nucleus (VMN, 94%), dorsomedial nucleus (DMN, 95%), ventral premammillary nucleus (PMv, 97%) and lateral hypothalamus (LH, 97%) co-expressed PDE3B. We next examined co-localization of p-STAT3 and PDE3B in the hypothalamus in C57BL6 mice that were treated with leptin (5mg/kg, ip) for 1h. The results showed that almost all p-STAT3 positive neurons in different hypothalamic nuclei including ARC, VMN, DMN, LH and PMv areas expressed PDE3B. These results suggest the possibility for a direct role for the PDE3B pathway in mediating leptin action in the hypothalamus. Copyright © 2015 Elsevier Inc. All rights reserved.
Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase.
Fisher, D A; Smith, J F; Pillar, J S; St Denis, S H; Cheng, J B
1998-06-19
We have cloned and characterized the first human isozyme in a new family of cyclic nucleotide phosphodiesterases, PDE9A. By sequence homology in the catalytic domain, PDE9A is almost equidistant from all eight known mammalian PDE families but is most similar to PDE8A (34% amino acid identity) and least like PDE5A (28% amino acid identity). We report the cloning of human cDNA encoding a full-length protein of 593 amino acids, including a 261-amino acid region located near the C terminus that is homologous to the approximately 270-amino acid catalytic domain of other PDEs. PDE9A is expressed in all eight tissues examined as a approximately 2. 0-kilobase mRNA, with highest levels in spleen, small intestine, and brain. The full-length PDE9A was expressed in baculovirus fused to an N-terminal 9-amino acid FLAG tag. Kinetic analysis of the baculovirus-expressed enzyme shows it to be a very high affinity cGMP-specific PDE with a Km of 170 nM for cGMP and 230 microM for cAMP. The Km for cGMP makes PDE9A one of the highest affinity PDEs known. The Vmax for cGMP (4.9 nmol/min/microg recombinant enzyme) is about twice as fast as that of PDE4 for cAMP. The enzyme is about twice as active in vitro in 1-10 mM Mn2+ than in the same concentration of Mg2+ or Ca2+. PDE9A is insensitive (up to 100 microM) to a variety of PDE inhibitors including rolipram, vinpocetine, SKF-94120, dipyridamole, and 3-isobutyl-1-methyl-xanthine but is inhibited (IC50 = 35 microM) by zaprinast, a PDE5 inhibitor. PDE9A lacks a region homologous to the allosteric cGMP-binding regulatory regions found in the cGMP-binding PDEs: PDE2, PDE5, and PDE6.
Potential of Targeting PDE1C/2A for Suppressing Metastatic Ovarian Cancers
2014-07-01
molecular mechanisms associated with forskolin /PDE2 inhibitor-induced apoptosis of aggressive ovarian cancer cells and 2) to evaluate the translation value...of treating aggressive ovarian cancer cells with forskolin and PDE2 inhibitor in an intraperitoneal xenograft model. In first year of the funding...we showed that knockdown of PDE2A rendered ovarian cancer cells susceptible for forskolin -induced cell growth inhibition/apoptosis. We further showed
González-García, C; Bravo, B; Ballester, A; Gómez-Pérez, R; Eguiluz, C; Redondo, M; Martínez, A; Gil, C; Ballester, S
2013-01-01
BACKGROUND AND PURPOSE PDE4 inhibition suppresses experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, side effects hinder PDE4 inhibitors clinical use. PDE7 inhibition might constitute an alternative therapeutic strategy, but few data about the anti-inflammatory potential of PDE7 inhibitors are currently available. We have used the EAE model to perform a comparative evaluation of PDE4 and PDE7 inhibition as strategies for MS treatment. EXPERIMENTAL APPROACH Two PDE7 inhibitors, the sulfonamide derivative BRL50481 and the recently described quinazoline compound TC3.6, were assayed to modulate EAE in SJL mice, in comparison with the well-known PDE4 inhibitor Rolipram. We evaluated clinical signs, presence of inflammatory infiltrates in CNS and anti-inflammatory markers. We also analysed the effect of these inhibitors on the inflammatory profile of spleen cells in vitro. KEY RESULTS TC3.6 prevented EAE with efficacy similar to Rolipram, while BRL50481 had no effect on the disease. Differences between both PDE7 inhibitors are discussed. Data from Rolipram and TC3.6 showed that PDE4 and PDE7 inhibition work through both common and distinct pathways. Rolipram administration caused an increase in IL-10 and IL-27 expression which was not found after TC3.6 treatment. On the other hand, both inhibitors reduced IL-17 levels, prevented infiltration in CNS and increased the expression of the T regulator cell marker Foxp3. CONCLUSIONS AND IMPLICATIONS These results provide new information about the effects of Rolipram on EAE, underline PDE7 inhibition as a new therapeutic target for inflammatory diseases and show the value of TC3.6 to prevent EAE, with possible consequences for new therapeutic tools in MS. PMID:23869659
Novel Scalable 3-D MT Inverse Solver
NASA Astrophysics Data System (ADS)
Kuvshinov, A. V.; Kruglyakov, M.; Geraskin, A.
2016-12-01
We present a new, robust and fast, three-dimensional (3-D) magnetotelluric (MT) inverse solver. As a forward modelling engine a highly-scalable solver extrEMe [1] is used. The (regularized) inversion is based on an iterative gradient-type optimization (quasi-Newton method) and exploits adjoint sources approach for fast calculation of 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 (single-site and/or inter-site) responses, and supports massive parallelization. Different parallelization strategies implemented in the code allow for optimal usage of available computational resources for a given problem set up. To parameterize an inverse domain a mask approach 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 high-performance clusters demonstrate practically linear scalability of the code up to thousands of nodes. 1. Kruglyakov, M., A. Geraskin, A. Kuvshinov, 2016. Novel accurate and scalable 3-D MT forward solver based on a contracting integral equation method, Computers and Geosciences, in press.
Equation solvers for distributed-memory computers
NASA Technical Reports Server (NTRS)
Storaasli, Olaf O.
1994-01-01
A large number of scientific and engineering problems require the rapid solution of large systems of simultaneous equations. The performance of parallel computers in this area now dwarfs traditional vector computers by nearly an order of magnitude. This talk describes the major issues involved in parallel equation solvers with particular emphasis on the Intel Paragon, IBM SP-1 and SP-2 processors.
Kim, Jong-So; Bailey, Michael J; Ho, Anthony K; Møller, Morten; Gaildrat, Pascaline; Klein, David C
2007-04-01
The pineal gland is a photoneuroendocrine transducer that influences circadian and circannual dynamics of many physiological functions via the daily rhythm in melatonin production and release. Melatonin synthesis is stimulated at night by a photoneural system through which pineal adenylate cyclase is adrenergically activated, resulting in an elevation of cAMP. cAMP enhances melatonin synthesis through actions on several elements of the biosynthetic pathway. cAMP degradation also appears to increase at night due to an increase in phosphodiesterase (PDE) activity, which peaks in the middle of the night. Here, it was found that this nocturnal increase in PDE activity results from an increase in the abundance of PDE4B2 mRNA (approximately 5-fold; doubling time, approximately 2 h). The resulting level is notably higher (>6-fold) than in all other tissues examined, none of which exhibit a robust daily rhythm. The increase in PDE4B2 mRNA is followed by increases in PDE4B2 protein and PDE4 enzyme activity. Results from in vivo and in vitro studies indicate that these changes are due to activation of adrenergic receptors and a cAMP-dependent protein kinase A mechanism. Inhibition of PDE4 activity during the late phase of adrenergic stimulation enhances cAMP and melatonin levels. The evidence that PDE4B2 plays a negative feedback role in adrenergic/cAMP signaling in the pineal gland provides the first proof that cAMP control of PDE4B2 is a physiologically relevant control mechanism in cAMP signaling.
Physics-based hybrid method for multiscale transport in porous media
NASA Astrophysics Data System (ADS)
Yousefzadeh, Mehrdad; Battiato, Ilenia
2017-09-01
Despite advancements in the development of multiscale models for flow and reactive transport in porous media, the accurate, efficient and physics-based coupling of multiple scales in hybrid models remains a major theoretical and computational challenge. Improving the predictivity of macroscale predictions by means of multiscale algorithms relative to classical at-scale models is the primary motivation for the development of multiscale simulators. Yet, very few are the quantitative studies that explicitly address the predictive capability of multiscale coupling algorithms as it is still generally not possible to have a priori estimates of the errors that are present when complex flow processes are modeled. We develop a nonintrusive pore-/continuum-scale hybrid model whose coupling error is bounded by the upscaling error, i.e. we build a predictive tightly coupled multiscale scheme. This is accomplished by slightly enlarging the subdomain where continuum-scale equations are locally invalid and analytically defining physics-based coupling conditions at the interfaces separating the two computational sub-domains, while enforcing state variable and flux continuity. The proposed multiscale coupling approach retains the advantages of domain decomposition approaches, including the use of existing solvers for each subdomain, while it gains flexibility in the choice of the numerical discretization method and maintains the coupling errors bounded by the upscaling error. We implement the coupling in finite volumes and test the proposed method by modeling flow and transport through a reactive channel and past an array of heterogeneously reactive cylinders.
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.
alphaPDE: A new multivariate technique for parameter estimation
Knuteson, B.; Miettinen, H.; Holmstrom, L.
2002-06-01
We present alphaPDE, a new multivariate analysis technique for parameter estimation. The method is based on a direct construction of joint probability densities of known variables and the parameters to be estimated. We show how posterior densities and best-value estimates are then obtained for the parameters of interest by a straightforward manipulation of these densities. The method is essentially non-parametric and allows for an intuitive graphical interpretation. We illustrate the method by outlining how it can be used to estimate the mass of the top quark, and we explain how the method is applied to an ensemble of events containing background.
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.
Wavefront Propagation for Reaction-Diffusion Systems of PDE
1989-03-01
scaled reaction- diffusion system: C C 1 (u)in R n X (O,cc)uk = cdkAu + - fn u = gk on Rn x 40k Here the constants dk (15kSm), and the functions n m m...m) 3 is a bounded, smooth subset of R n . Under these assumptions there exists a unique smooth solution u€ of the PDE (1.1) , with C u > 0 in Rn x...the Kolmogorov-Petrovskii- Piskunov nonlinearity, discussed in (6]. Our main result, Theorem 1, asserts that under hypotheses (FI) - (F5) uC (x,t
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.
Nankervis, Jacob L; Feil, Susanne C; Hancock, Nancy C; Zheng, Zhaohua; Ng, Hooi-Ling; Morton, Craig J; Holien, Jessica K; Ho, Patricia W M; Frazzetto, Mark M; Jennings, Ian G; Manallack, David T; Martin, T John; Thompson, Philip E; Parker, Michael W
2011-12-01
PDE4 inhibitors have been identified as therapeutic targets for a variety of conditions, particularly inflammatory diseases. We have serendipitously identified a novel class of phosphodiesterase 4 (PDE4) inhibitor during a study to discover antagonists of the parathyroid hormone receptor. X-ray crystallographic studies of PDE4D2 complexed to four potent inhibitors reveal the atomic details of how they inhibit the enzyme and a notable contrast to another recently reported thiophene-based inhibitor. Copyright Â© 2011 Elsevier Ltd. All rights reserved.
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.
Lattice Boltzmann solver of Rossler equation
NASA Astrophysics Data System (ADS)
Yan, Guangwu; Ruan, Li
2000-06-01
We proposed a lattice Boltzmann model for the Rossler equation. Using a method of multiscales in the lattice Boltzmann model, we get the diffusion reaction as a special case. If the diffusion effect disappeared, we can obtain the lattice Boltzmann solution of the Rossler equation on the mesescopic scale. The numerical results show the method can be used to simulate Rossler equation.
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.
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.
Subbotina, Anna; Ravna, Aina W; Lysaa, Roy A; Abagyan, Ruben; Bugno, Ryszard; Sager, Georg
2017-06-01
To determine the ability of 11 sildenafil analogues to discriminate between cyclic nucleotide phosphodiesterases (cnPDEs) and to characterise their inhibitory potencies (Ki values) of PDE5A1-dependent guanosine cyclic monophosphate (cGMP) hydrolysis. Sildenafil analogues were identified by virtual ligand screening (VLS) and screened for their ability to inhibit adenosine cyclic monophosphate (cAMP) hydrolysis by PDE1A1, PDE1B1, PDE2A1, PDE3A, PDE10A1 and PDE10A2, and cGMP hydrolysis by PDE5A, PDE6C, PDE9A2 for a low (1 nm) and high concentration (10 μm). Complete IC50 plots for all analogues were performed for PDE5A-dependent cGMP hydrolysis. Docking studies and scoring were made using the ICM molecular modelling software. The analogues in a low concentration showed no or low inhibition of PDE1A1, PDE1B1, PDE2A1, PDE3A, PDE10A1 and PDE10A2. In contrast, PDE5A and PDE6C were markedly inhibited to a similar extent by the analogues in a low concentration, whereas PDE9A2 was much less inhibited. The analogues showed a relative narrow range of Ki values for PDE5A inhibition (1.2-14 nm). The sildenafil molecule was docked in the structure of PDE5A1 co-crystallised with sildenafil. All the analogues had similar binding poses as sildenafil. Sildenafil analogues that inhibit cellular cGMP efflux are potent inhibitors of PDE5A and PDE6C. © 2017 The Authors. Journal of Pharmacy and Pharmacology published by John Wiley & Sons Ltd on behalf of Royal Pharmaceutical Society.
Implicit compressible flow solvers on unstructured meshes
NASA Astrophysics Data System (ADS)
Nagaoka, Makoto; Horinouchi, Nariaki
1993-09-01
An implicit solver for compressible flows using Bi-CGSTAB method is proposed. The Euler equations are discretized with the delta-form by the finite volume method on the cell-centered triangular unstructured meshes. The numerical flux is calculated by Roe's upwind scheme. The linearized simultaneous equations with the irregular nonsymmetric sparse matrix are solved by the Bi-CGSTAB method with the preconditioner of incomplete LU factorization. This method is also vectorized by the multi-colored ordering. Although the solver requires more computational memory, it shows faster and more robust convergence than the other conventional methods: three-stage Runge-Kutta method, point Gauss-Seidel method, and Jacobi method for two-dimensional inviscid steady flows.
Implicit Riemann solvers for the Pn equations.
Mehlhorn, Thomas Alan; McClarren, Ryan; Brunner, Thomas A.; Holloway, James Paul
2005-03-01
The spherical harmonics (P{sub n}) approximation to the transport equation for time dependent problems has previously been treated using Riemann solvers and explicit time integration. Here we present an implicit time integration method for the P n equations using Riemann solvers. Both first-order and high-resolution spatial discretization schemes are detailed. One facet of the high-resolution scheme is that a system of nonlinear equations must be solved at each time step. This nonlinearity is the result of slope reconstruction techniques necessary to avoid the introduction of artifical extrema in the numerical solution. Results are presented that show auspicious agreement with analytical solutions using time steps well beyond the CFL limit.
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 modeling 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 challenging problems important to Sandia's mission that Aleph was specifically designed to address.
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…
Discovery of oxazole-based PDE4 inhibitors with picomolar potency.
Kuang, Rongze; Shue, Ho-Jane; Xiao, Li; Blythin, David J; Shih, Neng-Yang; Chen, Xiao; Gu, Danlin; Schwerdt, John; Lin, Ling; Ting, Pauline C; Cao, Jianhua; Aslanian, Robert; Piwinski, John J; Prelusky, Daniel; Wu, Ping; Zhang, Ji; Zhang, Xiang; Celly, Chander S; Billah, Motasim; Wang, Peng
2012-04-01
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Cheguru, Pallavi; Majumder, Anurima; Artemyev, Nikolai O
2015-01-01
Phosphodiesterase-6 (PDE6) is an essential effector enzyme in vertebrate photoreceptor cells. Mutations in rod and cone PDE6 cause recessive retinitis pigmentosa and achromatopsia, respectively. The mechanisms of missense PDE6 mutations underlying severe visual disorders are poorly understood. To probe these mechanisms, we expressed seven known missense mutants of cone PDE6C in rods of transgenic Xenopus laevis and examined their stability and compartmentalization. PDE6C proteins with mutations in the catalytic domain, H602L and E790K, displayed modestly reduced proteolytic stability, but they were properly targeted to the outer segment of photoreceptor cells. Mutations in the regulatory GAF domains, R104W, Y323N, and P391L led to a proteolytic degradation of the proteins involving a cleavage in the GAFb domain. Lastly, the R29W and M455V mutations residing outside the conserved PDE6 domains produced a pattern of subcellular compartmentalization different from that of PDE6C. Thus, our results suggest a spectrum of mechanisms of missense PDE6C mutations in achromatopsia including catalytic defects, protein mislocalization, or a specific sequence of proteolytic degradation.
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…
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
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
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…
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.
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)
The Openpipeflow Navier-Stokes solver
NASA Astrophysics Data System (ADS)
Willis, Ashley P.
Pipelines are used in a huge range of industrial processes involving fluids, and the ability to accurately predict properties of the flow through a pipe is of fundamental engineering importance. Armed with parallel MPI, Arnoldi and Newton-Krylov solvers, the Openpipeflow code can be used in a range of settings, from large-scale simulation of highly turbulent flow, to the detailed analysis of nonlinear invariant solutions (equilibria and periodic orbits) and their influence on the dynamics of the flow.
Domain Decomposition for the SPN Solver MINOS
NASA Astrophysics Data System (ADS)
Jamelot, Erell; Baudron, Anne-Marie; Lautard, Jean-Jacques
2012-12-01
In this article we present a domain decomposition method for the mixed SPN equations, discretized with Raviart-Thomas-Nédélec 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® code.
Gerris Flow Solver: Implementation and Application
2013-05-12
Zienkiewicz, 1966). It is the solver for the Imperial College Ocean Model (ICOM), which uses 3D adaptive mesh methods (Ford et al., 2004). The finite...method (Popinet, 2003). The 3D Gerris model was used to study air turbulence associated with a complex shape with good match to observations (Popinet...et al., 2004). The Ocean module of Gerris was described by Popinet and Rickard (2004) as an adaptive, finite-volume, 3D , incompressible, N-S fluid
A multiscale hybrid algorithm for fluctuating hydrodynamics
NASA Astrophysics Data System (ADS)
Williams, Sarah Anne
We develop an algorithmic hybrid for simulating multiscale fluid flow with microscopic fluctuations. Random fluctuations occur in fluids at microscopic scales, and these microscopic fluctuations can lead to macroscopic system effects. For example, in the Rayleigh-Taylor problem, where a relatively heavy gas sits on top of a relatively light gas, spontaneous microscopic fluctuation at the interface of the gases leads to turbulent mixing. Given near-term computational power, the physical and temporal domain on which these systems can be studied using traditional particle simulations is extremely limited. Therefore, we seek algorithmic solutions to increase the effective computing power available to study such problems. We develop an explicit numerical solver for the Landau-Lifshitz Navier-Stokes (LLNS) equations, which incorporate thermal fluctuations into macroscopic hydrodynamics via stochastic; fluxes. A major goal is to correctly preserve the influence of the microscopic fluctuations on the behavior of the system. We show that several classical approaches fail to accurately reproduce fluctuations in energy or density, and we introduce a customized conservative centered scheme with a third-order Runge-Kutta temporal integrator that is specficially designed to produce correct fluctuations in all conserved quantities. We then use the adaptive mesh and algorithm refinement (AMAR) paradigm to create a multiscale hybrid method by coupling our LLNS solver with the direct simulation Monte Carlo (DSMC) particle method. We present numerical tests of systems in and out of equilibrium, including time-dependent systems, and demonstrate dynamic adaptive refinement. Mean system behavior and second moment statistics of our simulations match theoretical values and benchmarks well. We find that particular attention should be paid to the spectrum of the flux at the interface between the particle and continuum methods, specifically at non-hydrodynamic time scales. As an extension of
A multigrid solver for the semiconductor equations
NASA Technical Reports Server (NTRS)
Bachmann, Bernhard
1993-01-01
We present a multigrid solver for the exponential fitting method. The solver is applied to the current continuity equations of semiconductor device simulation in two dimensions. The exponential fitting method is based on a mixed finite element discretization using the lowest-order Raviart-Thomas triangular element. This discretization method yields a good approximation of front layers and guarantees current conservation. The corresponding stiffness matrix is an M-matrix. 'Standard' multigrid solvers, however, cannot be applied to the resulting system, as this is dominated by an unsymmetric part, which is due to the presence of strong convection in part of the domain. To overcome this difficulty, we explore the connection between Raviart-Thomas mixed methods and the nonconforming Crouzeix-Raviart finite element discretization. In this way we can construct nonstandard prolongation and restriction operators using easily computable weighted L(exp 2)-projections based on suitable quadrature rules and the upwind effects of the discretization. The resulting multigrid algorithm shows very good results, even for real-world problems and for locally refined grids.
Strong-continuation, contrast-invariant inpainting with a third-order optimal PDE.
Bertalmío, Marcelo
2006-07-01
PDE-based image inpainting has become a very active area of research after the pioneering works of Masnou and Morel, Bertalmío et al., and Ballester et al. In this paper, we take a different approach, inspired by the excellent work of Caselles et al. We view the inpainting problem as a particular case of image interpolation in which we intend to propagate level lines. Expressing this in terms of local neighborhoods and using a Taylor expansion we derive a third-order PDE that performs inpainting. This PDE is optimal in the sense that it is the most accurate third-order PDE which can ensure continuation of level lines. The continuation is strong, allowing the restoration of thin structures occluded by a wide gap. The result is also contrast invariant. This is a novel PDE, which, in both its accuracy and contrast invariance, outperforms the approaches cited above.
Maréchal, Loïze; Guillemette, Christine; Goupil, Serge; Blondin, Patrick; Leclerc, Pierre; Richard, François J
2017-02-01
Cyclic adenosine monophosphate (cAMP) plays a crucial role as a signaling molecule for sperm functions such as capacitation, motility and acrosome reaction. It is well known that cAMP degradation by phosphodiesterase (PDE) enzyme has a major impact on sperm functions. The present study was undertaken to characterize cAMP-PDE activity in human semen. cAMP-PDE activity was measured in human sperm and seminal plasma using family specific PDE inhibitors. Three sperm fractionation methods were applied to assess cAMP-PDE activity in spermatozoa. Western blots were used to validate the presence of specific family in sperm and seminal plasma. Using three sperm fractionation methods, we demonstrated that in human sperm, the major cAMP-PDE activity is papaverine-sensitive and thus ascribed to PDE10. In seminal plasma, total cAMP-PDE activity was 1.14±0.39fmol of cAMP hydrolyzed per minute per μg of protein. Using specific inhibitors, we showed that the major cAMP-PDE activity found in human seminal plasma is ascribed to PDE4 and PDE11. Western blot analysis, immunoprecipitation with a specific monoclonal antibody, and mass spectrometry confirmed the presence of PDE10 in human spermatozoa. This study provides the first demonstration of the presence of functional PDE10 in human spermatozoa and functional PDE4 and PDE11 in human seminal plasma. Since the contribution of cyclic nucleotides in several sperm functions is well known, the finding that PDE10 is an active enzyme in human spermatozoa is novel and may lead to new insight into fertility. Copyright © 2016 Elsevier B.V. All rights reserved.
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
Differential Regulation of PDE5 Expression in Left and Right Ventricles of Feline Hypertrophy Models
Shan, Xiaoyin; Margulies, Kenneth B.
2011-01-01
Background Though long known to affect smooth muscle biology, recent studies indicate that phosphodiesterase 5 (PDE5) is also expressed in myocardium. Recognizing that the regulation of PDE5 in hypertrophy is not well understood, we assessed the response of PDE5 expression and the level of cGMP-dependent kinase I (cGKI) in the left and right ventricles of feline hypertrophy models. Methodology/Principal Findings Using a cDNA library of feline aortic smooth muscle cells, we identified and cloned PDE5 cDNA for the first time in this species. The sequence shares 98% identity with its human orthologue at the amino acid level. E. coli expression of the cloned allele allowed selection of antibodies with appropriate specificity, facilitating the analysis of PDE5 expression in feline models created by selective proximal aortic (Ao) or pulmonary artery (PA) banding that resulted in hypertrophy of the left ventricle (LV) and right ventricle (RV), respectively. We demonstrated that PDE5 expression responded differentially with a decreased expression in the LV and an increased expression in the RV in the Ao-banded model. Similarly, in the PA-banded model, LV showed reduced expression while the RV expression was unaltered. In addition, the expression of cGKI was significantly decreased in the RV of Ao-banded group, correlating inversely with the increase in PDE5 expression. Conclusions/Significance The differential regulation of PDE5 and cGKI expression suggests that the mechanisms involved in hypertrophy could be different in RV vs. LV. Reciprocal PDE5 and cGKI expression in the RV of Ao-banded model suggests functional significance for PDE5 up-regulation. PMID:21625548
Evolution Nonlinear Diffusion-Convection PDE Models for Spectrogram Enhancement
NASA Astrophysics Data System (ADS)
Dugnol, B.; Fernández, C.; Galiano, G.; Velasco, J.
2008-09-01
In previous works we studied the application of PDE-based image processing techniques applied to the spectrogram of audio signals in order to improve the readability of the signal. In particular we considered the implementation of the nonlinear diffusive model proposed by Álvarez, Lions and Morel [1](ALM) combined with a convective term inspired by the differential reassignment proposed by Chassandre-Mottin, Daubechies, Auger and Flandrin [2]-[3]. In this work we consider the possibility of replacing the diffusive model of ALM by diffusive terms in divergence form. In particular we implement finite element approximations of nonlinear diffusive terms studied by Chen, Levine, Rao [4] and Antontsev, Shmarev [5]-[8] with a convective term.
GNGA for general regions: Semilinear elliptic PDE and crossing eigenvalues
NASA Astrophysics Data System (ADS)
Hineman, Jay L.; Neuberger, John M.
2007-07-01
We consider the semilinear elliptic PDE Δ u + f( λ, u) = 0 with the zero-Dirichlet boundary condition on a family of regions, namely stadions. Linear problems on such regions have been widely studied in the past. We seek to observe the corresponding phenomena in our nonlinear setting. Using the Gradient Newton Galerkin Algorithm (GNGA) of Neuberger and Swift, we document bifurcation, nodal structure, and symmetry of solutions. This paper provides the first published instance where the GNGA is applied to general regions. Our investigation involves both the dimension of the stadions and the value λ as parameters. We find that the so-called crossings and avoided crossings of eigenvalues as the dimension of the stadions vary influences the symmetry and variational structure of nonlinear solutions in a natural way.
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
MMS (Magnetospheric Multiscale) Arrival
2014-11-12
Operations are underway to remove two of the the Magnetospheric Multiscale spacecraft from their protective shipping container in the airlock of Building 2 at the Astrotech payload processing facility in Titusville, Florida, near Kennedy Space Center. The Magnetospheric Multiscale mission, or MMS, is a Solar Terrestrial Probes mission comprising four identically instrumented spacecraft that will use Earth’s magnetosphere as a laboratory to study the microphysics of three fundamental plasma processes: magnetic reconnection, energetic particle acceleration and turbulence. These two spacecraft comprise the mission's upper stack. The two MMS spacecraft comprising the lower stack arrived at Astrotech on Oct. 29. Launch aboard a United Launch Alliance Atlas V rocket from Space Launch Complex 41 on Cape Canaveral Air Force Station is targeted for March 12, 2015.
MMS (Magnetospheric Multiscale) Arrival
2014-11-12
Two Magnetospheric Multiscale spacecraft, enclosed in a protective shipping container, are positioned into the airlock of Building 2 of the Astrotech payload processing facility in Titusville, Florida, near Kennedy Space Center. The Magnetospheric Multiscale mission, or MMS, is a Solar Terrestrial Probes mission comprising four identically instrumented spacecraft that will use Earth’s magnetosphere as a laboratory to study the microphysics of three fundamental plasma processes: magnetic reconnection, energetic particle acceleration and turbulence. These two spacecraft comprise the mission's upper stack. The two MMS spacecraft comprising the lower stack arrived at Astrotech on Oct. 29. Launch aboard a United Launch Alliance Atlas V rocket from Space Launch Complex 41 on Cape Canaveral Air Force Station is targeted for March 12, 2015.
MMS (Magnetospheric Multiscale) Arrival
2014-11-12
The airlock door opens at Building 2 of the Astrotech payload processing facility in Titusville, Florida, near Kennedy Space Center, for ingress of the protective shipping container enclosing the Magnetospheric Multiscale spacecraft. The Magnetospheric Multiscale mission, or MMS, is a Solar Terrestrial Probes mission comprising four identically instrumented spacecraft that will use Earth’s magnetosphere as a laboratory to study the microphysics of three fundamental plasma processes: magnetic reconnection, energetic particle acceleration and turbulence. These two spacecraft comprise the mission's upper stack. The two MMS spacecraft comprising the lower stack arrived at Astrotech on Oct. 29. Launch aboard a United Launch Alliance Atlas V rocket from Space Launch Complex 41 on Cape Canaveral Air Force Station is targeted for March 12, 2015.
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
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
2014-09-30
were developed. Two of them include non-hydrostatic flows behind a seamount (Fig. 1) and non-hydrostatic bottom gravity currents (Fig. 2). In the... seamount test case, flows with varying Reynolds number were studied. The resulting different parameter regimes highlight different multiscale physics at...the seamount including vortex generation, lee waves and unstable flows (to name a few). These different flow regimes are currently being used to
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
2016-02-01
High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through 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 gene PDE3A, encoding phosphodiesterase 3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells, whereas 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), suggestive of a neomorphic activity. Coexpression of SLFN12 with PDE3A correlates with DNMDP sensitivity, whereas 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.
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.
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
A meta-analysis of PDE-gene polymorphism and cerebral infarction risk
Wu, Wei-Lin; Feng, Xue-Wen; Qiu, Chen-Feng; Lin, Jing; Bao, Xian-Jun
2017-01-01
Previous studies identified that phosphodiesterase 4D (PDE4D) gene polymorphism might be associated with cerebral infarction or ischemic stroke, and hemorrhagic stroke in human populations. However, as yet, no meta-analysis has revealed any detailed association. We retrospectively reviewed studies regarding the relationship of PDE4D gene polymorphism with ischemic stroke (IS) published during the period January 2003 to September 2012. According to the inclusion criteria, 9 of 105 initial studies were included in the subsequent analysis. The PubMed, Embase and CNKI of China were searched to identify the relevant studies. A total of 186 young patients with IS were included for the meta-analysis and 232 matched control subjects were enrolled and results were presented. The association of PDE4D gene polymorphism with IS in various populations was examined. The results suggested that single nucleotide polymorphism (SNP), SNP 83 in PDE4D gene was significantly related with susceptibility to IS. The meta-analysis also showed that PDE4D gene was associated with an enhanced risk of IS. The meta-analysis suggested that PDE4D SNP 87 constitutes an independent risk factor for IS development. To the best of our knowledge, the present meta-analysis reveals a number of possible associations between PDE4D gene polymorphism and IS. PMID:28587358
Zheng, Xiaoxu; Zu, Lingyun; Becker, Lewis; Cai, Zheqing P
2014-01-01
Ischemic preconditioning (IPC) induces cardioprotection against ischemia-reperfusion (IR) injury by inhibiting the mitochondrial permeability transition pore (mPTP). Here, we tested the hypothesis that IPC-induced cardioprotection is mediated by the phosphatase PTEN and PDE4 (phosphodiesterase 4). Isolated hearts from wild-type mice (WT, n = 110) and myocyte-specific PTEN-knockout mice (PKO, n = 94) were exposed to IPC or control conditions followed by IR. Subcellular fractionation was performed by sucrose gradient ultracentrifugation. IPC limited myocardial infarct size (IS) in WT mice. The PDE4 inhibitor rolipram abolished the protective effect of IPC. However, small IS was found in PKO hearts after IR, and IPC did not decrease IS but enlarged it in PKO hearts. IPC promoted PDE4D localization to caveolin-3-enriched fractions in WT mice by increasing Akt levels at the caveolae. In PKO hearts, basal PDE4D levels were elevated at the caveolae, and IPC decreased PDE4D levels. Consistent with the subcellular PDE4D protein levels and its activity, elevation in intracellular Ca(2+) levels in the ischemic heart and opening of mPTP after IR were inhibited by IPC in WT mice, but not by IPC in PKO mice. IPC inhibits mPTP opening by regulating the PTEN/PDE4 signaling pathway. © 2014 S. Karger AG, Basel.
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.
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.
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.
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)
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.
Some topics of Navier-Stokes solvers
NASA Astrophysics Data System (ADS)
Honma, H.; Nishikawa, N.
1990-03-01
The process of numerical simulation consists of selection of some items: a mathematical model, a numerical scheme, the level of the computer, and post processing. From this point of view, recent numerical studies of viscous flows are described especially for the fluid engineering laboratories in the Chiba University. The examples of simulations are Mach reflection on a wedge using a kinetic model equation and a cylinder-plate juncture flow using incompressible Navier Stokes equation. Some attempts at graphic monitoring of fluid mechanical calculations are also shown for some combinations of computers with Computational Fluid Dynamics (CFD) solvers.
A finite different field solver for dipole modes
Nelson, E.M.
1992-08-01
A finite element field solver for dipole modes in axisymmetric structures has been written. The second-order elements used in this formulation yield accurate mode frequencies with no spurious modes. Quasi-periodic boundaries are included to allow travelling waves in periodic structures. The solver is useful in applications requiring precise frequency calculations such as detuned accelerator structures for linear colliders. Comparisons are made with measurements and with the popular but less accurate field solver URMEL.
Vencels, Juris; Delzanno, Gian Luca; Johnson, Alec; ...
2015-06-01
A spectral method for kinetic plasma simulations based on the expansion of the velocity distribution function in a variable number of Hermite polynomials is presented. The method is based on a set of non-linear equations that is solved to determine the coefficients of the Hermite expansion satisfying the Vlasov and Poisson equations. In this paper, we first show that this technique combines the fluid and kinetic approaches into one framework. Second, we present an adaptive strategy to increase and decrease the number of Hermite functions dynamically during the simulation. The technique is applied to the Landau damping and two-stream instabilitymore » test problems. Performance results show 21% and 47% saving of total simulation time in the Landau and two-stream instability test cases, respectively.« less
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.
Gutierrez, Juan B; Lai, Ming-Jun; Slavov, George
2015-12-01
We study a time dependent partial differential equation (PDE) which arises from classic models in ecology involving logistic growth with Allee effect by introducing a discrete weak solution. Existence, uniqueness and stability of the discrete weak solutions are discussed. We use bivariate splines to approximate the discrete weak solution of the nonlinear PDE. A computational algorithm is designed to solve this PDE. A convergence analysis of the algorithm is presented. We present some simulations of population development over some irregular domains. Finally, we discuss applications in epidemiology and other ecological problems. Copyright © 2015 Elsevier Inc. All rights reserved.
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.
A 3D approximate maximum likelihood localization solver
2016-09-23
A robust three-dimensional solver was needed to accurately and efficiently estimate the time sequence of locations of fish tagged with acoustic transmitters and vocalizing marine mammals to describe in sufficient detail the information needed to assess the function of dam-passage design alternatives and support Marine Renewable Energy. An approximate maximum likelihood solver was developed using measurements of time difference of arrival from all hydrophones in receiving arrays on which a transmission was detected. Field experiments demonstrated that the developed solver performed significantly better in tracking efficiency and accuracy than other solvers described in the literature.
A multi-scale network method for two-phase flow in porous media
NASA Astrophysics Data System (ADS)
Khayrat, Karim; Jenny, Patrick
2017-08-01
Pore-network models of porous media are useful in the study of pore-scale flow in porous media. In order to extract macroscopic properties from flow simulations in pore-networks, it is crucial the networks are large enough to be considered representative elementary volumes. However, existing two-phase network flow solvers are limited to relatively small domains. For this purpose, a multi-scale pore-network (MSPN) method, which takes into account flow-rate effects and can simulate larger domains compared to existing methods, was developed. In our solution algorithm, a large pore network is partitioned into several smaller sub-networks. The algorithm to advance the fluid interfaces within each subnetwork consists of three steps. First, a global pressure problem on the network is solved approximately using the multiscale finite volume (MSFV) method. Next, the fluxes across the subnetworks are computed. Lastly, using fluxes as boundary conditions, a dynamic two-phase flow solver is used to advance the solution in time. Simulation results of drainage scenarios at different capillary numbers and unfavourable viscosity ratios are presented and used to validate the MSPN method against solutions obtained by an existing dynamic network flow solver.
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
Explicit solvers in an implicit code
NASA Astrophysics Data System (ADS)
Martinez Montesinos, Beatriz; Kaus, Boris J. P.; Popov, Anton
2017-04-01
Many geodynamic processes occur over long timescales (millions of years), and are best solved with implicit solvers. Yet, some processes, such as hydrofracking, or wave propagation, occur over smaller timescales. In those cases, it might be advantageous to use an explicit rather than an implicit approach as it requires significantly less memory and computational costs. Here, we discuss our ongoing work to include explicit solvers in the parallel software package LaMEM (Lithosphere and Mantle Evolution Model). As a first step, we focus on modelling seismic wave propagation in heterogeneous 3D poro-elasto-plastic models. To do that, we add inertial terms to the momentum equations as well as elastic compressibility to the mass conservation equations in an explicit way using the staggered grid finite difference discretization method. Results are similar to that of existing wave propagation codes and are capable to simulate wave propagation in heterogeneous media. To simulate geomechanical problems, timestep restrictions posed by the seismic wave speed are usually too severe to allow simulating deformation on a timescale of months-years. The classical (FLAC) method introduces a mass-density scaling in which a non-physical (larger) density is employed in the momentum equations. We will discuss how this method fits simple benchmarks for elastic and elastoplastic deformation. As an application, we use the code to model different complex media subject to compression and we investigate how mass scaling influence in our results.
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.
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.
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.
NASA Astrophysics Data System (ADS)
Moura, Scott; Bendtsen, Jan; Ruiz, Victor
2014-07-01
This paper develops methods for model identification of aggregated thermostatically controlled loads (TCLs) in smart grids, via partial differential equation (PDE) techniques. Control of aggregated TCLs provides a promising opportunity to mitigate the mismatch between power generation and demand, thus enhancing grid reliability and enabling renewable energy penetration. To this end, this paper focuses on developing parameter identification algorithms for a PDE-based model of aggregated TCLs. First, a two-state boundary-coupled hyperbolic PDE model for homogenous TCL populations is derived. This model is extended to heterogeneous populations by including a diffusive term, which provides an elegant control-oriented model. Next, a passive parameter identification scheme and a swapping-based identification scheme are derived for the PDE model structure. Simulation results demonstrate the efficacy of each method under various autonomous and non-autonomous scenarios. The proposed models can subsequently be employed to provide system critical information for power system monitoring and control.
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.
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
Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish
Viringipurampeer, I A; Shan, X; Gregory-Evans, K; Zhang, J P; Mohammadi, Z; Gregory-Evans, C Y
2014-01-01
Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6cw59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6cw59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed. Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6cw59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment. PMID:24413151
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.
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. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Discovery of novel 1,4-dihydropyridine-based PDE4 inhibitors.
Poondra, Rajamohan R; Nallamelli, Ratnam V; Meda, Chandana Lakshmi Teja; Srinivas, B N V; Grover, Anushka; Muttabathula, Jyotsna; Voleti, Sreedhara R; Sridhar, Balasubramanian; Pal, Manojit; Parsa, Kishore V L
2013-02-15
Substituted 1,4-dihydropyridines were discovered as a novel and potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationships within this series have been carried out and studies revealed that the dihydropyridine core, with indole moiety and 3,4-dimethoxybenzyl group, is a potent analogue for PDE4 inhibition. These novel series of compounds were prepared via a 3-component reaction in a single pot. In vitro biological activity, modeling studies and crystallography data are also reported.
[A HPF application to parallelize a 2-D PDE model].
Contreras, Xiómara; Hernández, Emilio
2003-01-01
Many practical numerical applications would require a parallel implementation in order to obtain a satisfactory response in a reasonable amount of time. In this sense, this work shows a parallel implementation of an explicit scheme of finite difference (FD) proposed by Kelly et. al., to solve the Partial Differential Equation (PDE / EDDP) of the Wave Propagation problem in an elastic, homogeneous or heterogeneous, two-dimensional medium. High-Performance-Fortran (HPF) will be used here for this purpose. This report shows measures of time on a PC-Cluster using 1, 2, and 4 processors with different sizes of data grid. In addition, a comparative test is included in which the cluster was initially connected using a Fast-Ethernet card, and then connected by a Myrinet card, using a grid size of 2500 x 2500 in both cases. The execution time achieved with two processors was highly satisfactory for all cases. In analogous conditions, the performance obtained with a Myrinet interconnection was better than the one obtained with a Fast-Ethernet interconnection. The scheme mentioned above has showed an excellent numerical result as it could be seen on the images included in this work. Key words: Partial differential equation, wave equation, explicite finite differences scheme, parallel scheme.
Inertial Manifold and Large Deviations Approach to Reduced PDE Dynamics
NASA Astrophysics Data System (ADS)
Cardin, Franco; Favretti, Marco; Lovison, Alberto
2017-07-01
In this paper a certain type of reaction-diffusion equation—similar to the Allen-Cahn equation—is the starting point for setting up a genuine thermodynamic reduction i.e. involving a finite number of parameters or collective variables of the initial system. We firstly operate a finite Lyapunov-Schmidt reduction of the cited reaction-diffusion equation when reformulated as a variational problem. In this way we gain a finite-dimensional ODE description of the initial system which preserves the gradient structure of the original one and that is exact for the static case and only approximate for the dynamic case. Our main concern is how to deal with this approximate reduced description of the initial PDE. To start with, we note that our approximate reduced ODE is similar to the approximate inertial manifold introduced by Temam and coworkers for Navier-Stokes equations. As a second approach, we take into account the uncertainty (loss of information) introduced with the above mentioned approximate reduction by considering the stochastic version of the ODE. We study this reduced stochastic system using classical tools from large deviations, viscosity solutions and weak KAM Hamilton-Jacobi theory. In the last part we suggest a possible use of a result of our approach in the comprehensive treatment non equilibrium thermodynamics given by Macroscopic Fluctuation Theory.
Inertial Manifold and Large Deviations Approach to Reduced PDE Dynamics
NASA Astrophysics Data System (ADS)
Cardin, Franco; Favretti, Marco; Lovison, Alberto
2017-09-01
In this paper a certain type of reaction-diffusion equation—similar to the Allen-Cahn equation—is the starting point for setting up a genuine thermodynamic reduction i.e. involving a finite number of parameters or collective variables of the initial system. We firstly operate a finite Lyapunov-Schmidt reduction of the cited reaction-diffusion equation when reformulated as a variational problem. In this way we gain a finite-dimensional ODE description of the initial system which preserves the gradient structure of the original one and that is exact for the static case and only approximate for the dynamic case. Our main concern is how to deal with this approximate reduced description of the initial PDE. To start with, we note that our approximate reduced ODE is similar to the approximate inertial manifold introduced by Temam and coworkers for Navier-Stokes equations. As a second approach, we take into account the uncertainty (loss of information) introduced with the above mentioned approximate reduction by considering the stochastic version of the ODE. We study this reduced stochastic system using classical tools from large deviations, viscosity solutions and weak KAM Hamilton-Jacobi theory. In the last part we suggest a possible use of a result of our approach in the comprehensive treatment non equilibrium thermodynamics given by Macroscopic Fluctuation Theory.
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.
The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin
DiPilato, Lisa M.; Ahmad, Faiyaz; Harms, Matthew; Seale, Patrick; Manganiello, Vincent
2015-01-01
Inhibition of adipocyte lipolysis by insulin is important for whole-body energy homeostasis; its disruption has been implicated as contributing to the development of insulin resistance and type 2 diabetes mellitus. The main target of the antilipolytic action of insulin is believed to be phosphodiesterase 3B (PDE3B), whose phosphorylation by Akt leads to accelerated degradation of the prolipolytic second messenger cyclic AMP (cAMP). To test this hypothesis genetically, brown adipocytes lacking PDE3B were examined for their regulation of lipolysis. In Pde3b knockout (KO) adipocytes, insulin was unable to suppress β-adrenergic receptor-stimulated glycerol release. Reexpressing wild-type PDE3B in KO adipocytes fully rescued the action of insulin against lipolysis. Surprisingly, a mutant form of PDE3B that ablates the major Akt phosphorylation site, murine S273, also restored the ability of insulin to suppress lipolysis. Taken together, these data suggest that phosphorylation of PDE3B by Akt is not required for insulin to suppress adipocyte lipolysis. PMID:26031333
The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin.
DiPilato, Lisa M; Ahmad, Faiyaz; Harms, Matthew; Seale, Patrick; Manganiello, Vincent; Birnbaum, Morris J
2015-08-01
Inhibition of adipocyte lipolysis by insulin is important for whole-body energy homeostasis; its disruption has been implicated as contributing to the development of insulin resistance and type 2 diabetes mellitus. The main target of the antilipolytic action of insulin is believed to be phosphodiesterase 3B (PDE3B), whose phosphorylation by Akt leads to accelerated degradation of the prolipolytic second messenger cyclic AMP (cAMP). To test this hypothesis genetically, brown adipocytes lacking PDE3B were examined for their regulation of lipolysis. In Pde3b knockout (KO) adipocytes, insulin was unable to suppress β-adrenergic receptor-stimulated glycerol release. Reexpressing wild-type PDE3B in KO adipocytes fully rescued the action of insulin against lipolysis. Surprisingly, a mutant form of PDE3B that ablates the major Akt phosphorylation site, murine S273, also restored the ability of insulin to suppress lipolysis. Taken together, these data suggest that phosphorylation of PDE3B by Akt is not required for insulin to suppress adipocyte lipolysis. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4
Cedervall, Peder; Aulabaugh, Ann; Geoghegan, Kieran F.; McLellan, Thomas J.; Pandit, Jayvardhan
2015-03-09
Phosphodiesterase 4 (PDE4) is an essential contributor to intracellular signaling and an important drug target. The four members of this enzyme family (PDE4A to -D) are functional dimers in which each subunit contains two upstream conserved regions (UCR), UCR1 and -2, which precede the C-terminal catalytic domain. Alternative promoters, transcriptional start sites, and mRNA splicing lead to the existence of over 25 variants of PDE4, broadly classified as long, short, and supershort forms. We report the X-ray crystal structure of long form PDE4B containing UCR1, UCR2, and the catalytic domain, crystallized as a dimer in which a disulfide bond cross-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.
Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD
Komatsu, Kensei; Lee, Ji-Yun; Miyata, Masanori; Hyang Lim, Jae; Jono, Hirofumi; Koga, Tomoaki; Xu, Haidong; Yan, Chen; Kai, Hirofumi; Li, Jian-Dong
2013-01-01
The deubiquitinase CYLD acts as a key negative regulator to tightly control overactive inflammation. Most anti-inflammatory strategies have focused on directly targeting the positive regulator, which often results in significant side effects such as suppression of the host defence response. Here, we show that inhibition of phosphodiesterase 4B (PDE4B) markedly enhances upregulation of CYLD expression in response to bacteria, thereby suggesting that PDE4B acts as a negative regulator for CYLD. Interestingly, in Cyld-deficient mice, inhibition of PDE4B no longer suppresses inflammation. Moreover, PDE4B negatively regulates CYLD via specific activation of JNK2 but not JNK1. Importantly, ototopical post-inoculation administration of a PDE4 inhibitor suppresses inflammation in this animal model, thus demonstrating the therapeutic potential of targeting PDE4. These studies provide insights into how inflammation is tightly regulated via the inhibition of its negative regulator and may also lead to the development of new anti-inflammatory therapeutics that upregulate CYLD expression. PMID:23575688
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.
Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4
Cedervall, Peder; Aulabaugh, Ann; Geoghegan, Kieran F.; ...
2015-03-09
Phosphodiesterase 4 (PDE4) is an essential contributor to intracellular signaling and an important drug target. The four members of this enzyme family (PDE4A to -D) are functional dimers in which each subunit contains two upstream conserved regions (UCR), UCR1 and -2, which precede the C-terminal catalytic domain. Alternative promoters, transcriptional start sites, and mRNA splicing lead to the existence of over 25 variants of PDE4, broadly classified as long, short, and supershort forms. We report the X-ray crystal structure of long form PDE4B containing UCR1, UCR2, and the catalytic domain, crystallized as a dimer in which a disulfide bond cross-linksmore » cysteines engineered into UCR2 and the catalytic domain. Biochemical and mass spectrometric analyses showed that the UCR2-catalytic domain interaction occurs in trans, and established that this interaction regulates the catalytic activity of PDE4. By elucidating the key structural determinants of dimerization, we show that only long forms of PDE4 can be regulated by this mechanism. The results also provide a structural basis for the long-standing observation of high- and low-affinity binding sites for the prototypic inhibitor rolipram.« less
MacMullen, Courtney M; Fallahi, Mohammad; Davis, Ronald L
2017-03-30
PDE10A is a cAMP/cGMP phosphodiesterase important in signal transduction within medium spiny neurons of the human striatum. This gene region has been associated with bipolar disorder via case-control and linkage studies. The three most studied human PDE10A isoforms differ in both their N-termini and trafficking within the cell with PDE10A2 found predominantly at the plasma membrane and PDE10A1 and PDE10A19 remaining primarily within the cytosol. RNA-sequencing and 5' RLM-RACE studies of the human putamen and caudate nucleus revealed 16 new exons and 12 novel transcripts of PDE10A, 3 of which are predicted to produce proteins with unique N-termini. The novel first exons of these transcripts are highly conserved in non-human primate species and are rarely found in other mammals. One hundred and eight previously classified intronic SNPs were found within the novel PDE10A exons of which 78% were classified as rare variants. Since most of the rare variants localize to 5' UTR regions, they may influence PDE10A transcription, translation, or mRNA stability. Dysregulation of cAMP signaling has been proposed as a cause of bipolar disorder and PDE10A inhibitors have been investigated as potential therapeutics for schizophrenia. Understanding the mechanisms contributing to PDE10A expression in the human striatum may provide evidence linking this gene to the phenotypes observed in neuropsychiatric disorders.
Hegde, Shweta; Ji, Hao; Oliver, David; Patel, Neema S; Poupore, Nicolas; Shtutman, Michael; Kelly, Michy P
2016-10-29
Despite the fact that appropriate social behaviors are vital to thriving in one's environment, little is understood of the molecular mechanisms controlling social behaviors or how social experience sculpts these signaling pathways. Here, we determine if Phosphodiesterase 11A (PDE11A), an enzyme that is enriched in the ventral hippocampal formation (VHIPP) and that breaks down cAMP and cGMP, regulates social behaviors. PDE11 wild-type (WT), heterozygous (HT), and knockout (KO) mice were tested in various social approach assays and gene expression differences were measured by RNA sequencing. The effect of social isolation on PDE11A4 compartmentalization and subsequent social interactions and social memory was also assessed. Deletion of PDE11A triggered age- and sex-dependent deficits in social approach in specific social contexts but not others. Mice appear to detect altered social behaviors of PDE11A KO mice, because C57BL/6J mice prefer to spend time with a sex-matched PDE11A WT vs. its KO littermate; whereas, a PDE11A KO prefers to spend time with a novel PDE11A KO vs. its WT littermate. Not only is PDE11A required for intact social interactions, we found that 1month of social isolation vs. group housing decreased PDE11A4 protein expression specifically within the membrane fraction of VHIPP. This isolation-induced decrease in PDE11A4 expression appears functional because social isolation impairs subsequent social approach behavior and social memory in a PDE11A genotype-dependent manner. Pathway analyses following RNA sequencing suggests PDE11A is a key regulator of the oxytocin pathway and membrane signaling, consistent with its pivotal role in regulating social behavior. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
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.
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.
General purpose nonlinear system solver based on Newton-Krylov method.
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].
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.
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.
2015-03-01
Kim , Chris Anderson, Will Feldman, James von Brecht, Hui Sun, Marcus Roper, Joseph Teran, and Russell Caflisch have all supported me in their own ways...cum laude 2011- 2012 Graduate Teaching Assistant, UCLA 2012 Summer Undergraduate Research Project Mentor, UCLA REU 2012 -2015 Graduate Research...Methods in Applied Sciences, 22(supp01), 2012 . [7] Andrea L Bertozzi, Thomas Laurent, and Jesús Rosado. Lp theory for the multidimensional aggregation
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 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
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 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.
Efficient Integration of Coupled Electrical-Chemical Systems in Multiscale Neuronal Simulations
Brocke, Ekaterina; Bhalla, Upinder S.; Djurfeldt, Mikael; Hellgren Kotaleski, Jeanette; Hanke, Michael
2016-01-01
Multiscale modeling and simulations in neuroscience is gaining scientific attention due to its growing importance and unexplored capabilities. For instance, it can help to acquire better understanding of biological phenomena that have important features at multiple scales of time and space. This includes synaptic plasticity, memory formation and modulation, homeostasis. There are several ways to organize multiscale simulations depending on the scientific problem and the system to be modeled. One of the possibilities is to simulate different components of a multiscale system simultaneously and exchange data when required. The latter may become a challenging task for several reasons. First, the components of a multiscale system usually span different spatial and temporal scales, such that rigorous analysis of possible coupling solutions is required. Then, the components can be defined by different mathematical formalisms. For certain classes of problems a number of coupling mechanisms have been proposed and successfully used. However, a strict mathematical theory is missing in many cases. Recent work in the field has not so far investigated artifacts that may arise during coupled integration of different approximation methods. Moreover, in neuroscience, the coupling of widely used numerical fixed step size solvers may lead to unexpected inefficiency. In this paper we address the question of possible numerical artifacts that can arise during the integration of a coupled system. We develop an efficient strategy to couple the components comprising a multiscale test problem in neuroscience. We introduce an efficient coupling method based on the second-order backward differentiation formula (BDF2) numerical approximation. The method uses an adaptive step size integration with an error estimation proposed by Skelboe (2000). The method shows a significant advantage over conventional fixed step size solvers used in neuroscience for similar problems. We explore different
Efficient Integration of Coupled Electrical-Chemical Systems in Multiscale Neuronal Simulations.
Brocke, Ekaterina; Bhalla, Upinder S; Djurfeldt, Mikael; Hellgren Kotaleski, Jeanette; Hanke, Michael
2016-01-01
Multiscale modeling and simulations in neuroscience is gaining scientific attention due to its growing importance and unexplored capabilities. For instance, it can help to acquire better understanding of biological phenomena that have important features at multiple scales of time and space. This includes synaptic plasticity, memory formation and modulation, homeostasis. There are several ways to organize multiscale simulations depending on the scientific problem and the system to be modeled. One of the possibilities is to simulate different components of a multiscale system simultaneously and exchange data when required. The latter may become a challenging task for several reasons. First, the components of a multiscale system usually span different spatial and temporal scales, such that rigorous analysis of possible coupling solutions is required. Then, the components can be defined by different mathematical formalisms. For certain classes of problems a number of coupling mechanisms have been proposed and successfully used. However, a strict mathematical theory is missing in many cases. Recent work in the field has not so far investigated artifacts that may arise during coupled integration of different approximation methods. Moreover, in neuroscience, the coupling of widely used numerical fixed step size solvers may lead to unexpected inefficiency. In this paper we address the question of possible numerical artifacts that can arise during the integration of a coupled system. We develop an efficient strategy to couple the components comprising a multiscale test problem in neuroscience. We introduce an efficient coupling method based on the second-order backward differentiation formula (BDF2) numerical approximation. The method uses an adaptive step size integration with an error estimation proposed by Skelboe (2000). The method shows a significant advantage over conventional fixed step size solvers used in neuroscience for similar problems. We explore different
Böttcher, René; Dulla, Kalyan; van Strijp, Dianne; Dits, Natasja; Verhoef, Esther I.; Baillie, George S.; van Leenders, Geert J.L.H.; Houslay, Miles D.; Jenster, Guido; Hoffmann, Ralf
2016-01-01
Phosphodiesterase 4D7 was recently shown to be specifically over-expressed in localized prostate cancer, raising the question as to which regulatory mechanisms are involved and whether other isoforms of this gene family (PDE4D) are affected under the same conditions. We investigated PDE4D isoform composition in prostatic tissues using a total of seven independent expression datasets and also included data on DNA methylation, copy number and AR and ERG binding in PDE4D promoters to gain insight into their effect on PDE4D transcription. We show that expression of PDE4D isoforms is consistently altered in primary human prostate cancer compared to benign tissue, with PDE4D7 being up-regulated while PDE4D5 and PDE4D9 are down-regulated. Disease progression is marked by an overall down-regulation of long PDE4D isoforms, while short isoforms (PDE4D1/2) appear to be relatively unaffected. While these alterations seem to be independent of copy number alterations in the PDE4D locus and driven by AR and ERG binding, we also observed increased DNA methylation in the promoter region of PDE4D5, indicating a long lasting alteration of the isoform composition in prostate cancer tissues. We propose two independent metrics that may serve as diagnostic and prognostic markers for prostate disease: (PDE4D7 - PDE4D5) provides an effective means for distinguishing PCa from normal adjacent prostate, whereas PDE4D1/2 - (PDE4D5 + PDE4D7 + PDE4D9) offers strong prognostic potential to detect aggressive forms of PCa and is associated with metastasis free survival. Overall, our findings highlight the relevance of PDE4D as prostate cancer biomarker and potential drug target. PMID:27683107
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.
Atomistic hybrid DSMC/NEMD method for nonequilibrium multiscale simulations
NASA Astrophysics Data System (ADS)
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.
Multiscale modeling for materials design: Molecular square catalysts
NASA Astrophysics Data System (ADS)
Majumder, Debarshi
descriptions of the fluid phase with kinetic Monte Carlo (kMC) simulations of the catalyst domain. A number of catalytic domains, solved using kMC, were placed as patches along the length of the reactor and communicated with the continuum solver using patch dynamics concepts such as lifting, restriction and interpolation. This allowed the resolution of the species' profiles in both axial and radial directions of membrane reactors and monoliths, which is a novel strategy in the multiscale modeling of heterogeneous systems.
Multiscale modeling of proteins.
Tozzini, Valentina
2010-02-16
The activity within a living cell is based on a complex network of interactions among biomolecules, exchanging information and energy through biochemical processes. These events occur on different scales, from the nano- to the macroscale, spanning about 10 orders of magnitude in the space domain and 15 orders of magnitude in the time domain. Consequently, many different modeling techniques, each proper for a particular time or space scale, are commonly used. In addition, a single process often spans more than a single time or space scale. Thus, the necessity arises for combining the modeling techniques in multiscale approaches. In this Account, I first review the different modeling methods for bio-systems, from quantum mechanics to the coarse-grained and continuum-like descriptions, passing through the atomistic force field simulations. Special attention is devoted to their combination in different possible multiscale approaches and to the questions and problems related to their coherent matching in the space and time domains. These aspects are often considered secondary, but in fact, they have primary relevance when the aim is the coherent and complete description of bioprocesses. Subsequently, applications are illustrated by means of two paradigmatic examples: (i) the green fluorescent protein (GFP) family and (ii) the proteins involved in the human immunodeficiency virus (HIV) replication cycle. The GFPs are currently one of the most frequently used markers for monitoring protein trafficking within living cells; nanobiotechnology and cell biology strongly rely on their use in fluorescence microscopy techniques. A detailed knowledge of the actions of the virus-specific enzymes of HIV (specifically HIV protease and integrase) is necessary to study novel therapeutic strategies against this disease. Thus, the insight accumulated over years of intense study is an excellent framework for this Account. The foremost relevance of these two biomolecular systems was
Wang, Peng; Wu, Ping; Egan, Robert W; Billah, M Motasim
2003-09-18
Previously, four splice variants of human cGMP-specific phosphodiesterase (PDE) 9A (PDEs 9A1, 9A2, 9A3 and 9A4) have been identified. In this study, we have cloned a cDNA representing a new human PDE9A variant (PDE9A5). PDE9A5 encodes a protein of 492 amino acids, smaller than PDEs 9A1 and 9A2 but larger than PDEs 9A3 and 9A4. The exon structure of PDE9A5 is different from those of PDEs 9A1, 9A2, 9A3 and 9A4 in that, of the 20 exons of PDE9A gene, it lacks exons 2 and 5. PDE9A5 has been characterized in comparison with PDE9A1, the longest PDE9A variant. PDEs 9A5 and 9A1 have similar enzymatic properties. They both have a high affinity for cGMP with similar Km values (0.39 and 0.25 microM, respectively), although they have slightly different Vmax values (2.55 and 0.96 micromol/min/mg, respectively). They exhibit very similar divalent metal ion dependency and inhibitor sensitivity. Real-time quantitative PCR analysis shows that PDEs 9A5 and 9A1 exhibit differential tissue distribution. They are highly expressed in immune tissues (spleen, lymph node and thymus) and are more abundant in T cells than in B cells, neutrophils and monocytes. When transiently expressed in HEK293 cells, PDEs 9A5 and 9A1 proteins exhibit differential subcellular localization. PDE9A5 localizes exclusively in the cytoplasm, whereas PDE9A1 localizes in the nucleus only. The nuclear localization of PDE9A1 is dependent on a unique pat7 motif. By Western blot analysis, native PDE9A1 is detectable in the nucleus but not in the cytoplasm of T cells. Thus, to our knowledge, PDE9A1 is the only PDE isoform found to localize exclusively in the nucleus. We speculate that the physiological role of the PDE9A diversity may be imparting cGMP-metabolizing ability to specific cellular compartments in appropriate tissues.
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
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
Genome-wide Association Analysis Identifies PDE4D as an Asthma-Susceptibility Gene
Himes, Blanca E.; Hunninghake, Gary M.; Baurley, James W.; Rafaels, Nicholas M.; Sleiman, Patrick; Strachan, David P.; Wilk, Jemma B.; Willis-Owen, Saffron A.G.; Klanderman, Barbara; Lasky-Su, Jessica; Lazarus, Ross; Murphy, Amy J.; Soto-Quiros, Manuel E.; Avila, Lydiana; Beaty, Terri; Mathias, Rasika A.; Ruczinski, Ingo; Barnes, Kathleen C.; Celedón, Juan C.; Cookson, William O.C.; Gauderman, W. James; Gilliland, Frank D.; Hakonarson, Hakon; Lange, Christoph; Moffatt, Miriam F.; O'Connor, George T.; Raby, Benjamin A.; Silverman, Edwin K.; Weiss, Scott T.
2009-01-01
Asthma, a chronic airway disease with known heritability, affects more than 300 million people around the world. A genome-wide association (GWA) study of asthma with 359 cases from the Childhood Asthma Management Program (CAMP) and 846 genetically matched controls from the Illumina ICONdb public resource was performed. The strongest region of association seen was on chromosome 5q12 in PDE4D. The phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila) gene (PDE4D) is a regulator of airway smooth-muscle contractility, and PDE4 inhibitors have been developed as medications for asthma. Allelic p values for top SNPs in this region were 4.3 × 10−07 for rs1588265 and 9.7 × 10−07 for rs1544791. Replications were investigated in ten independent populations with different ethnicities, study designs, and definitions of asthma. In seven white and Hispanic replication populations, two PDE4D SNPs had significant results with p values less than 0.05, and five had results in the same direction as the original population but had p values greater than 0.05. Combined p values for 18,891 white and Hispanic individuals (4,342 cases) in our replication populations were 4.1 × 10−04 for rs1588265 and 9.2 × 10−04 for rs1544791. In three black replication populations, which had different linkage disequilibrium patterns than the other populations, original findings were not replicated. Further study of PDE4D variants might lead to improved understanding of the role of PDE4D in asthma pathophysiology and the efficacy of PDE4 inhibitor medications. PMID:19426955
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. Copyright © 2015 John Wiley & Sons, Ltd.
PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury
Paterniti, Irene; Mazzon, Emanuela; Gil, Carmen; Impellizzeri, Daniela; Palomo, Valle; Redondo, Myriam; Perez, Daniel I.; Esposito, Emanuela; Martinez, Ana; Cuzzocrea, Salvatore
2011-01-01
Background Primary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation. Methodology/Principal Findings Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5–T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-α, IL-6, COX-2 and iNOS expression. Conclusions/Significance All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI. PMID:21297958
Dissecting the cofactor-dependent and independent bindings of PDE4 inhibitors.
Liu, S; Laliberté, F; Bobechko, B; Bartlett, A; Lario, P; Gorseth, E; Van Hamme, J; Gresser, M J; Huang, Z
2001-08-28
Type 4 phosphodiesterases (PDE4s) are metallohydrolases that catalyze the hydrolysis of cAMP to AMP. At the bottom of its active site lie two divalent metal ions in a binuclear motif which are involved in both cAMP binding and catalysis [(2000) Science 288, 1822-1825; (2000) Biochemistry 39, 6449-6458]. Using a SPA-based equilibrium [(3)H]rolipram binding assay, we have determined that Mg(2+), Mn(2+), and Co(2+) all mediated a high-affinity (K(d) between 3 and 8 nM) and near stoichiometric (R)-rolipram binding to PDE4. In their absence, (R)-rolipram binds stoichiometrically to the metal ion-free apoenzyme with a K(d) of approximately 150 nM. The divalent cation dose responses in mediating the high-affinity rolipram/PDE4 interaction mirror their efficacy in catalysis, suggesting that both metal ions of the holoenzyme are involved in mediating the high-affinity (R)-rolipram/PDE4 interaction. The specific rolipram binding to the apo- and holoenzyme is differentially displaced by cAMP, AMP, and other inhibitors, providing a robust tool to dissect the components of metal ion-dependent and independent PDE4/ligand interactions. cAMP binds to the holoenzyme with a K(s) of 1.9 microM and nonproductively to the apoenzyme with a K(d) of 179 microM. In comparison, AMP binds to the holo- and apoenzyme with K(d) values of 7 and 11 mM, respectively. The diminished Mg(2+)-dependent component of AMP binding to PDE4 suggests that most of the Mg(2+)/phosphate interaction in the cAMP/PDE4 complex is disrupted upon the hydrolysis of the cyclic phosphoester bond, leading to the rapid release of AMP.
Comparison of open-source linear programming solvers.
Gearhart, Jared Lee; Adair, Kristin Lynn; Durfee, Justin David.; 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.
Phosphodiesterase-5A (PDE5A) is localized to the endothelial caveolae and modulates NOS3 activity
Gebska, Milena A.; Stevenson, Blake K.; Hemnes, Anna R.; Bivalacqua, Trinity J.; Haile, Azeb; Hesketh, Geoffrey G.; Murray, Christopher I.; Zaiman, Ari L.; Halushka, Marc K.; Krongkaew, Nispa; Strong, Travis D.; Cooke, Carol A.; El-Haddad, Hazim; Tuder, Rubin M.; Berkowitz, Dan E.; Champion, Hunter C.
2011-01-01
Aims It has been well demonstrated that phosphodiesterase-5A (PDE5A) is expressed in smooth muscle cells and plays an important role in regulation of vascular tone. The role of endothelial PDE5A, however, has not been yet characterized. The present study was undertaken to determine the presence, localization, and potential physiologic significance of PDE5A within vascular endothelial cells. Methods and results We demonstrate primary location of human, mouse, and bovine endothelial PDE5A at or near caveolae. We found that the spatial localization of PDE5A at the level of caveolin-rich lipid rafts allows for a feedback loop between endothelial PDE5A and nitric oxide synthase (NOS3). Treatment of human endothelium with PDE5A inhibitors resulted in a significant increase in NOS3 activity, whereas overexpression of PDE5A using an adenoviral vector, both in vivo and in cell culture, resulted in decreased NOS3 activity and endothelium-dependent vasodilation. The molecular mechanism responsible for these interactions is primarily regulated by cGMP-dependent second messenger. PDE5A overexpression also resulted in a significant decrease in protein kinase 1 (PKG1) activity. Overexpression of PKG1 rapidly activated NOS3, whereas silencing of the PKG1 gene with siRNA inhibited both NOS3 phosphorylation (S1179) and activity, indicating a novel role for PKG1 in direct regulation of NOS3. Conclusion Our data collectively suggest another target for PDE5A inhibition in endothelial dysfunction and provide another physiologic significance for PDE5A in the modulation of endothelial-dependent flow-mediated vasodilation. Using both in vitro and in vivo models, as well as human data, we show that inhibition of endothelial PDE5A improves endothelial function. PMID:21421555
Phosphodiesterase-5A (PDE5A) is localized to the endothelial caveolae and modulates NOS3 activity.
Gebska, Milena A; Stevenson, Blake K; Hemnes, Anna R; Bivalacqua, Trinity J; Haile, Azeb; Hesketh, Geoffrey G; Murray, Christopher I; Zaiman, Ari L; Halushka, Marc K; Krongkaew, Nispa; Strong, Travis D; Cooke, Carol A; El-Haddad, Hazim; Tuder, Rubin M; Berkowitz, Dan E; Champion, Hunter C
2011-05-01
It has been well demonstrated that phosphodiesterase-5A (PDE5A) is expressed in smooth muscle cells and plays an important role in regulation of vascular tone. The role of endothelial PDE5A, however, has not been yet characterized. The present study was undertaken to determine the presence, localization, and potential physiologic significance of PDE5A within vascular endothelial cells. We demonstrate primary location of human, mouse, and bovine endothelial PDE5A at or near caveolae. We found that the spatial localization of PDE5A at the level of caveolin-rich lipid rafts allows for a feedback loop between endothelial PDE5A and nitric oxide synthase (NOS3). Treatment of human endothelium with PDE5A inhibitors resulted in a significant increase in NOS3 activity, whereas overexpression of PDE5A using an adenoviral vector, both in vivo and in cell culture, resulted in decreased NOS3 activity and endothelium-dependent vasodilation. The molecular mechanism responsible for these interactions is primarily regulated by cGMP-dependent second messenger. PDE5A overexpression also resulted in a significant decrease in protein kinase 1 (PKG1) activity. Overexpression of PKG1 rapidly activated NOS3, whereas silencing of the PKG1 gene with siRNA inhibited both NOS3 phosphorylation (S1179) and activity, indicating a novel role for PKG1 in direct regulation of NOS3. Our data collectively suggest another target for PDE5A inhibition in endothelial dysfunction and provide another physiologic significance for PDE5A in the modulation of endothelial-dependent flow-mediated vasodilation. Using both in vitro and in vivo models, as well as human data, we show that inhibition of endothelial PDE5A improves endothelial function.
The Magentospheric Multiscale Constellation
NASA Technical Reports Server (NTRS)
Tooley, C. R.; Black, R. K.; Robertson, B. P.; Stone, J. M.; Pope, S. E.; Davis, G. T.
2015-01-01
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.
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.
The Magentospheric Multiscale Constellation
NASA Technical Reports Server (NTRS)
Tooley, C. R.; Black, R. K.; Robertson, B. P.; Stone, J. M.; Pope, S. E.; Davis, G. T.
2015-01-01
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.
Magnetospheric Multiscale (MMS)
2017-09-27
Propulsion engineer measures the flight filters during the receiving inspection. Learn more about MMS at www.nasa.gov/mms Credit NASA/Goddard The Magnetospheric Multiscale, or MMS, will study how the sun and the Earth's magnetic fields connect and disconnect, an explosive process that can accelerate particles through space to nearly the speed of light. This process is called magnetic reconnection and can occur throughout all space. NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram
Dans, Pablo D; Walther, Jürgen; Gómez, Hansel; Orozco, Modesto
2016-04-01
DNA is not only among the most important molecules in life, but a meeting point for biology, physics and chemistry, being studied by numerous techniques. Theoretical methods can help in gaining a detailed understanding of DNA structure and function, but their practical use is hampered by the multiscale nature of this molecule. In this regard, the study of DNA covers a broad range of different topics, from sub-Angstrom details of the electronic distributions of nucleobases, to the mechanical properties of millimeter-long chromatin fibers. Some of the biological processes involving DNA occur in femtoseconds, while others require years. In this review, we describe the most recent theoretical methods that have been considered to study DNA, from the electron to the chromosome, enriching our knowledge on this fascinating molecule. Copyright © 2015 Elsevier Ltd. All rights reserved.
The Magnetospheric Multiscale Constellation
NASA Technical Reports Server (NTRS)
Tooley, C. R.; Black, R. K.; Robertson, B. P.; Stone, J. M.; Pope, S. E.; Davis, G. T.
2015-01-01
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.
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. -- Highlights: •New simple and general path-conservative formulation of the HLLEM Riemann solver. •Application to general conservative and non
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
García, Ana M; Brea, José; González-García, Alejandro; Pérez, Concepción; Cadavid, María Isabel; Loza, María Isabel; Martinez, Ana; Gil, Carmen
2017-09-04
Phosphodiesterase (PDE) enzymes regulate the levels of cyclic nucleotides, cAMP, and/or cGMP, being attractive therapeutic targets. In order to modulate PDE activity in a selective way, we focused our efforts on the search of allosteric modulators. Based on the crystal structure of the PDE10A GAF-B domain, a virtual screening study allowed the discovery of new hits that were also tested experimentally, showing inhibitory activities in the micromolar range. Moreover, these new PDE10A inhibitors were able to decrease the nitrite production in LPS-stimulated cells, thus demonstrating their potential as anti-inflammatory agents.
An iterative solver for the 3D Helmholtz equation
NASA Astrophysics Data System (ADS)
Belonosov, Mikhail; Dmitriev, Maxim; Kostin, Victor; Neklyudov, Dmitry; Tcheverda, Vladimir
2017-09-01
We develop a frequency-domain iterative solver for numerical simulation of acoustic waves in 3D heterogeneous media. It is based on the application of a unique preconditioner to the Helmholtz equation that ensures convergence for Krylov subspace iteration methods. Effective inversion of the preconditioner involves the Fast Fourier Transform (FFT) and numerical solution of a series of boundary value problems for ordinary differential equations. Matrix-by-vector multiplication for iterative inversion of the preconditioned matrix involves inversion of the preconditioner and pointwise multiplication of grid functions. Our solver has been verified by benchmarking against exact solutions and a time-domain solver.
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)
GPU accelerated kinetic solvers for rarefied gas dynamics
NASA Astrophysics Data System (ADS)
Zabelok, Sergey A.; Kolobov, Vladimir I.; Arslanbekov, Robert R.
2012-11-01
GPU-acceleration is applied to the Boltzmann solver with adaptive Cartesian mesh in the Unified Flow Solver framework. NVIDIA CUDA technology is used with threads being grouped in thread blocks by points of Korobov sequences in each cell for computing the collision integral and by points in coordinate space for the free-molecular flow stage. GPU-accelerated Boltzmann solver with octree Cartesian mesh has been tested on several computer systems. Speedup of several times for GPU-based code compared to single-core CPU computations on the same machines has been observed.
Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory.
Havekes, Robbert; Park, Alan J; Tolentino, Rosa E; Bruinenberg, Vibeke M; Tudor, Jennifer C; Lee, Yool; Hansen, Rolf T; Guercio, Leonardo A; Linton, Edward; Neves-Zaph, Susana R; Meerlo, Peter; Baillie, George S; Houslay, Miles D; Abel, Ted
2016-08-24
Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular compartments. The
Integration based profile likelihood calculation for PDE constrained parameter estimation problems
NASA Astrophysics Data System (ADS)
Boiger, R.; Hasenauer, J.; Hroß, S.; Kaltenbacher, B.
2016-12-01
Partial differential equation (PDE) models are widely used in engineering and natural sciences to describe spatio-temporal processes. The parameters of the considered processes are often unknown and have to be estimated from experimental data. Due to partial observations and measurement noise, these parameter estimates are subject to uncertainty. This uncertainty can be assessed using profile likelihoods, a reliable but computationally intensive approach. In this paper, we present the integration based approach for the profile likelihood calculation developed by (Chen and Jennrich 2002 J. Comput. Graph. Stat. 11 714-32) and adapt it to inverse problems with PDE constraints. While existing methods for profile likelihood calculation in parameter estimation problems with PDE constraints rely on repeated optimization, the proposed approach exploits a dynamical system evolving along the likelihood profile. We derive the dynamical system for the unreduced estimation problem, prove convergence and study the properties of the integration based approach for the PDE case. To evaluate the proposed method, we compare it with state-of-the-art algorithms for a simple reaction-diffusion model for a cellular patterning process. We observe a good accuracy of the method as well as a significant speed up as compared to established methods. Integration based profile calculation facilitates rigorous uncertainty analysis for computationally demanding parameter estimation problems with PDE constraints.
Wang, Jun-Wei; Wu, Huai-Ning; Li, Han-Xiong
2012-06-01
In this paper, a distributed fuzzy control design based on Proportional-spatial Derivative (P-sD) is proposed for the exponential stabilization of a class of nonlinear spatially distributed systems described by parabolic partial differential equations (PDEs). Initially, a Takagi-Sugeno (T-S) fuzzy parabolic PDE model is proposed to accurately represent the nonlinear parabolic PDE system. Then, based on the T-S fuzzy PDE model, a novel distributed fuzzy P-sD state feedback controller is developed by combining the PDE theory and the Lyapunov technique, such that the closed-loop PDE system is exponentially stable with a given decay rate. The sufficient condition on the existence of an exponentially stabilizing fuzzy controller is given in terms of a set of spatial differential linear matrix inequalities (SDLMIs). A recursive algorithm based on the finite-difference approximation and the linear matrix inequality (LMI) techniques is also provided to solve these SDLMIs. Finally, the developed design methodology is successfully applied to the feedback control of the Fitz-Hugh-Nagumo equation.
PDE12 removes mitochondrial RNA poly(A) tails and controls translation in human mitochondria.
Rorbach, Joanna; Nicholls, Thomas J J; Minczuk, Michal
2011-09-01
Polyadenylation of mRNA in human mitochondria is crucial for gene expression and perturbation of poly(A) tail length has been linked to a human neurodegenerative disease. Here we show that 2'-phosphodiesterase (2'-PDE), (hereafter PDE12), is a mitochondrial protein that specifically removes poly(A) extensions from mitochondrial mRNAs both in vitro and in mitochondria of cultured cells. In eukaryotes, poly(A) tails generally stabilize mature mRNAs, whereas in bacteria they increase mRNA turnover. In human mitochondria, the effects of increased PDE12 expression were transcript dependent. An excess of PDE12 led to an increase in the level of three mt-mRNAs (ND1, ND2 and CytB) and two (CO1 and CO2) were less abundant than in mitochondria of control cells and there was no appreciable effect on the steady-state level of the remainder of the mitochondrial transcripts. The alterations in poly(A) tail length accompanying elevated PDE12 expression were associated with severe inhibition of mitochondrial protein synthesis, and consequently respiratory incompetence. Therefore, we propose that mRNA poly(A) tails are important in regulating protein synthesis in human mitochondria, as it is the case for nuclear-encoded eukaryotic mRNA.
PDE12 removes mitochondrial RNA poly(A) tails and controls translation in human mitochondria
Rorbach, Joanna; Nicholls, Thomas J. J.; Minczuk, Michal
2011-01-01
Polyadenylation of mRNA in human mitochondria is crucial for gene expression and perturbation of poly(A) tail length has been linked to a human neurodegenerative disease. Here we show that 2′-phosphodiesterase (2′-PDE), (hereafter PDE12), is a mitochondrial protein that specifically removes poly(A) extensions from mitochondrial mRNAs both in vitro and in mitochondria of cultured cells. In eukaryotes, poly(A) tails generally stabilize mature mRNAs, whereas in bacteria they increase mRNA turnover. In human mitochondria, the effects of increased PDE12 expression were transcript dependent. An excess of PDE12 led to an increase in the level of three mt-mRNAs (ND1, ND2 and CytB) and two (CO1 and CO2) were less abundant than in mitochondria of control cells and there was no appreciable effect on the steady-state level of the remainder of the mitochondrial transcripts. The alterations in poly(A) tail length accompanying elevated PDE12 expression were associated with severe inhibition of mitochondrial protein synthesis, and consequently respiratory incompetence. Therefore, we propose that mRNA poly(A) tails are important in regulating protein synthesis in human mitochondria, as it is the case for nuclear-encoded eukaryotic mRNA. PMID:21666256
A penalty method for PDE-constrained optimization in inverse problems
NASA Astrophysics Data System (ADS)
van Leeuwen, T.; Herrmann, F. J.
2016-01-01
Many inverse and parameter estimation problems can be written as PDE-constrained optimization problems. The goal is to infer the parameters, typically coefficients of the PDE, from partial measurements of the solutions of the PDE for several right-hand sides. Such PDE-constrained problems can be solved by finding a stationary point of the Lagrangian, which entails simultaneously updating the parameters and the (adjoint) state variables. For large-scale problems, such an all-at-once approach is not feasible as it requires storing all the state variables. In this case one usually resorts to a reduced approach where the constraints are explicitly eliminated (at each iteration) by solving the PDEs. These two approaches, and variations thereof, are the main workhorses for solving PDE-constrained optimization problems arising from inverse problems. In this paper, we present an alternative method that aims to combine the advantages of both approaches. Our method is based on a quadratic penalty formulation of the constrained optimization problem. By eliminating the state variable, we develop an efficient algorithm that has roughly the same computational complexity as the conventional reduced approach while exploiting a larger search space. Numerical results show that this method indeed reduces some of the nonlinearity of the problem and is less sensitive to the initial iterate.
A Block-Oriented Equation Solver for the CRAY-1.
1980-12-01
3-D mechanisms, and (2) the solution of dis- cretized partial differential equations (PDE’s) such as arise in oil reservoir simulation . This report...on Reservoir Simulation , Soc. Pet. Engrs., Denver, Jan. 31, 1979, pp. 7-15. [151. D. A. Calahan, "A Collection of Equation-Solving Codes for the CRAY-I
Flow Solver for Incompressible Rectangular Domains
NASA Technical Reports Server (NTRS)
Kalb, Virginia L.
2008-01-01
This is an extension of the Flow Solver for Incompressible 2-D Drive Cavity software described in the preceding article. It solves the Navier-Stokes equations for incompressible flow using finite differencing on a uniform, staggered grid. There is a runtime choice of either central differencing or modified upwinding for the convective term. The domain must be rectangular, but may have a rectangular walled region within it. Currently, the position of the interior region and exterior boundary conditions are changed by modifying parameters in the code and recompiling. These features make it possible to solve a variety of classical fluid flow problems such as an L-shaped cavity, channel flow, or wake flow past a square cylinder. The code uses fourth-order Runge-Kutta time-stepping and overall second-order spatial accuracy. This software permits the walled region to be positioned such that flow past a square cylinder, an L-shaped cavity, and the flow over a back-facing step can all be solved by reconfiguration. Also, this extension has an automatic detection of periodicity, as well as use of specialized data structure for ease of configuring domain decomposition and computing convergence in overlap regions.
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.
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.
Generic task problem solvers in Soar
NASA Technical Reports Server (NTRS)
Johnson, Todd R.; Smith, Jack W., Jr.; Chandrasekaran, B.
1989-01-01
Two trends can be discerned in research in problem solving architectures in the last few years. On one hand, interest in task-specific architectures has grown, wherein types of problems of general utility are identified, and special architectures that support the development of problem solving systems for those types of problems are proposed. These architectures help in the acquisition and specification of knowledge by providing inference methods that are appropriate for the type of problem. However, knowledge based systems which use only one type of problem solving method are very brittle, and adding more types of methods requires a principled approach to integrating them in a flexible way. Contrasting with this trend is the proposal for a flexible, general architecture contained in the work on Soar. Soar has features which make it attractive for flexible use of all potentially relevant knowledge or methods. But as the theory Soar does not make commitments to specific types of problem solvers or provide guidance for their construction. It was investigated how task-specific architectures can be constructed in Soar to retain as many of the advantages as possible of both approaches. Examples were used from the Generic Task approach for building knowledge based systems. Though this approach was developed and applied for a number of problems, the ideas are applicable to other task-specific approaches as well.
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.
PDE based scheme for multi-modal medical image watermarking.
Aherrahrou, N; Tairi, H
2015-11-25
This work deals with copyright protection of digital images, an issue that needs protection of intellectual property rights. It is an important issue with a large number of medical images interchanged on the Internet every day. So, it is a challenging task to ensure the integrity of received images as well as authenticity. Digital watermarking techniques have been proposed as valid solution for this problem. It is worth mentioning that the Region Of Interest (ROI)/Region Of Non Interest (RONI) selection can be seen as a significant limitation from which suffers most of ROI/RONI based watermarking schemes and that in turn affects and limit their applicability in an effective way. Generally, the ROI/RONI is defined by a radiologist or a computer-aided selection tool. And thus, this will not be efficient for an institute or health care system, where one has to process a large number of images. Therefore, developing an automatic ROI/RONI selection is a challenge task. The major aim of this work is to develop an automatic selection algorithm of embedding region based on the so called Partial Differential Equation (PDE) method. Thus avoiding ROI/RONI selection problems including: (1) computational overhead, (2) time consuming, and (3) modality dependent selection. The algorithm is evaluated in terms of imperceptibility, robustness, tamper localization and recovery using MRI, Ultrasound, CT and X-ray grey scale medical images. From experimental results that we have conducted on a database of 100 medical images of four modalities, it can be inferred that our method can achieve high imperceptibility, while showing good robustness against attacks. Furthermore, the experiment results confirm the effectiveness of the proposed algorithm in detecting and recovering the various types of tampering. The highest PSNR value reached over the 100 images is 94,746 dB, while the lowest PSNR value is 60,1272 dB, which demonstrates the higher imperceptibility nature of the proposed
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.
Performance of NASA Equation Solvers on Computational Mechanics Applications
NASA Technical Reports Server (NTRS)
Storaasli, Olaf O.
1996-01-01
This paper describes the performance of a new family of NASA-developed equation solvers used for large-scale (i.e. 551,705 equations) structural analysis. To minimize computer time and memory, the solvers are divided by application and matrix characteristics (sparse/dense, real/complex, symmetric/nonsymmetric, size: in-core/out of core) and exploit the hardware features of current and future computers. In this paper, the equation solvers, which are written in FORTRAN, and are therefore easily transportable, are shown to be faster than specialized computer library routines utilizing assembly code. Twenty NASA structural benchmark models with NASA solver timings reside on World Wide Web with a challenge to beat them.
WAKES: Wavelet Adaptive Kinetic Evolution Solvers
NASA Astrophysics Data System (ADS)
Mardirian, Marine; Afeyan, Bedros; Larson, David
2016-10-01
We are developing a general capability to adaptively solve phase space evolution equations mixing particle and continuum techniques in an adaptive manner. The multi-scale approach is achieved using wavelet decompositions which allow phase space density estimation to occur with scale dependent increased accuracy and variable time stepping. Possible improvements on the SFK method of Larson are discussed, including the use of multiresolution analysis based Richardson-Lucy Iteration, adaptive step size control in explicit vs implicit approaches. Examples will be shown with KEEN waves and KEEPN (Kinetic Electrostatic Electron Positron Nonlinear) waves, which are the pair plasma generalization of the former, and have a much richer span of dynamical behavior. WAKES techniques are well suited for the study of driven and released nonlinear, non-stationary, self-organized structures in phase space which have no fluid, limit nor a linear limit, and yet remain undamped and coherent well past the drive period. The work reported here is based on the Vlasov-Poisson model of plasma dynamics. Work supported by a Grant from the AFOSR.
Experiences Running a Parallel Answer Set Solver on Blue Gene
NASA Astrophysics Data System (ADS)
Schneidenbach, Lars; Schnor, Bettina; Gebser, Martin; Kaminski, Roland; Kaufmann, Benjamin; Schaub, Torsten
This paper presents the concept of parallelisation of a solver for Answer Set Programming (ASP). While there already exist some approaches to parallel ASP solving, there was a lack of a parallel version of the powerful clasp solver. We implemented a parallel version of clasp based on message-passing. Experimental results on Blue Gene P/L indicate the potential of such an approach.
Vandenwijngaert, Sara; Pokreisz, Peter; Hermans, Hadewich; Gillijns, Hilde; Pellens, Marijke; Bax, Noortje A. M.; Coppiello, Giulia; Oosterlinck, Wouter; Balogh, Agnes; Papp, Zoltan; Bouten, Carlijn V. C.; Bartunek, Jozef; D'hooge, Jan; Luttun, Aernout; Verbeken, Erik; Herregods, Marie Christine; Herijgers, Paul; Bloch, Kenneth D.; Janssens, Stefan
2013-01-01
Background The intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC). Methodology/Principal Findings In patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5-TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dtmax and dP/dtmin with prolonged tau (P<0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro. Conclusions/Significance Myocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target. PMID:23527037
Tuntivanich, Nalinee; Pittler, Steven J.; Fischer, Andy J.; Omar, Ghezal; Kiupel, Matti; Weber, Arthur; Yao, Suxia; Steibel, Juan Pedro; Khan, Naheed Wali; Petersen-Jones, Simon M.
2013-01-01
Purpose To characterize a canine model of autosomal recessive RP due to a PDE6A gene mutation. Methods Affected and breed- and age-matched control puppies were studied by electroretinography (ERG), light and electron microscopy, immunohistochemistry and by assay for retinal PDE6 levels and enzymatic activity. Results The mutant puppies failed to develop normal rod-mediated ERG responses and had reduced light-adapted a-wave amplitudes from an early age. The residual ERG waveforms originated primarily from cone-driven responses. Development of photoreceptor outer segments was halted and rod cells were lost by apoptosis. Immunohistochemistry demonstrated a marked reduction in rod-opsin immunostaining outer segments and relative preservation of cones early in the disease process. With exception of rod bipolar cells that appeared to be reduced in number relatively early in the disease process other inner retinal cells were preserved in the early stages of the disease although there was marked and early activation of Müller glia. Western blotting showed that the PDE6A mutation not only resulted in a lack of PDE6A protein but the affected retinas also lacked the other PDE6 subunits, suggesting expression of PDE6A is required for normal expression of PDE6B and PDE6G. Affected retinas lacked PDE6 enzymatic activity. Conclusions This represents the first characterization of a PDE6A model of autosomal recessive retinitis pigmentosa and the PDE6A mutant dog shows promise as a large animal model for investigation of therapies to rescue mutant rod photoreceptors and to preserve cone photoreceptors in the face a rapid loss of rod cells. PMID:18775863
Advantages of multigrid methods for certifying the accuracy of PDE modeling
NASA Technical Reports Server (NTRS)
Forester, C. K.
1981-01-01
Numerical techniques for assessing and certifying the accuracy of the modeling of partial differential equations (PDE) to the user's specifications are analyzed. Examples of the certification process with conventional techniques are summarized for the three dimensional steady state full potential and the two dimensional steady Navier-Stokes equations using fixed grid methods (FG). The advantages of the Full Approximation Storage (FAS) scheme of the multigrid technique of A. Brandt compared with the conventional certification process of modeling PDE are illustrated in one dimension with the transformed potential equation. Inferences are drawn for how MG will improve the certification process of the numerical modeling of two and three dimensional PDE systems. Elements of the error assessment process that are common to FG and MG are analyzed.
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.
Sampled-Data Fuzzy Control for Nonlinear Coupled Parabolic PDE-ODE Systems.
Wang, Zi-Peng; Wu, Huai-Ning; Li, Han-Xiong
2017-09-01
In this paper, a sampled-data fuzzy control problem is addressed for a class of nonlinear coupled systems, which are described by a parabolic partial differential equation (PDE) and an ordinary differential equation (ODE). Initially, the nonlinear coupled system is accurately represented by the Takagi-Sugeno (T-S) fuzzy coupled parabolic PDE-ODE model. Then, based on the T-S fuzzy model, a novel time-dependent Lyapunov functional is used to design a sampled-data fuzzy controller such that the closed-loop coupled system is exponentially stable, where the sampled-data fuzzy controller consists of the ODE state feedback and the PDE static output feedback under spatially averaged measurements. The stabilization condition is presented in terms of a set of linear matrix inequalities. Finally, simulation results on the control of a hypersonic rocket car are given to illustrate the effectiveness of the proposed design method.
Advantages of multigrid methods for certifying the accuracy of PDE modeling
NASA Technical Reports Server (NTRS)
Forester, C. K.
1981-01-01
Numerical techniques for assessing and certifying the accuracy of the modeling of partial differential equations (PDE) to the user's specifications are analyzed. Examples of the certification process with conventional techniques are summarized for the three dimensional steady state full potential and the two dimensional steady Navier-Stokes equations using fixed grid methods (FG). The advantages of the Full Approximation Storage (FAS) scheme of the multigrid technique of A. Brandt compared with the conventional certification process of modeling PDE are illustrated in one dimension with the transformed potential equation. Inferences are drawn for how MG will improve the certification process of the numerical modeling of two and three dimensional PDE systems. Elements of the error assessment process that are common to FG and MG are analyzed.
Anton, Luis; MartI, Jose M; Ibanez, Jose M; Aloy, Miguel A.; Mimica, Petar; Miralles, Juan A.
2010-05-01
We obtain renormalized sets of right and left eigenvectors of the flux vector Jacobians of the relativistic MHD equations, which are regular and span a complete basis in any physical state including degenerate ones. The renormalization procedure relies on the characterization of the degeneracy types in terms of the normal and tangential components of the magnetic field to the wave front in the fluid rest frame. Proper expressions of the renormalized eigenvectors in conserved variables are obtained through the corresponding matrix transformations. Our work completes previous analysis that present different sets of right eigenvectors for non-degenerate and degenerate states, and can be seen as a relativistic generalization of earlier work performed in classical MHD. Based on the full wave decomposition (FWD) provided by the renormalized set of eigenvectors in conserved variables, we have also developed a linearized (Roe-type) Riemann solver. Extensive testing against one- and two-dimensional standard numerical problems allows us to conclude that our solver is very robust. When compared with a family of simpler solvers that avoid the knowledge of the full characteristic structure of the equations in the computation of the numerical fluxes, our solver turns out to be less diffusive than HLL and HLLC, and comparable in accuracy to the HLLD solver. The amount of operations needed by the FWD solver makes it less efficient computationally than those of the HLL family in one-dimensional problems. However, its relative efficiency increases in multidimensional simulations.
NASA Astrophysics Data System (ADS)
Antón, Luis; Miralles, Juan A.; Martí, José M.; Ibáñez, José M.; Aloy, Miguel A.; Mimica, Petar
2010-05-01
We obtain renormalized sets of right and left eigenvectors of the flux vector Jacobians of the relativistic MHD equations, which are regular and span a complete basis in any physical state including degenerate ones. The renormalization procedure relies on the characterization of the degeneracy types in terms of the normal and tangential components of the magnetic field to the wave front in the fluid rest frame. Proper expressions of the renormalized eigenvectors in conserved variables are obtained through the corresponding matrix transformations. Our work completes previous analysis that present different sets of right eigenvectors for non-degenerate and degenerate states, and can be seen as a relativistic generalization of earlier work performed in classical MHD. Based on the full wave decomposition (FWD) provided by the renormalized set of eigenvectors in conserved variables, we have also developed a linearized (Roe-type) Riemann solver. Extensive testing against one- and two-dimensional standard numerical problems allows us to conclude that our solver is very robust. When compared with a family of simpler solvers that avoid the knowledge of the full characteristic structure of the equations in the computation of the numerical fluxes, our solver turns out to be less diffusive than HLL and HLLC, and comparable in accuracy to the HLLD solver. The amount of operations needed by the FWD solver makes it less efficient computationally than those of the HLL family in one-dimensional problems. However, its relative efficiency increases in multidimensional simulations.
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.
A multiscale approach to curvature modulated sorting in biological membranes.
Mercker, M; Ptashnyk, M; Kühnle, J; Hartmann, D; Weiss, M; Jäger, W
2012-05-21
Combining different theoretical approaches, curvature modulated sorting in lipid bilayers fixed on non-planar surfaces is investigated. First, we present a continuous model of lateral membrane dynamics, described by a nonlinear PDE of fourth order. We then prove the existence and uniqueness of solutions of the presented model and simulate membrane dynamics using a finite element approach. Adopting a truly multiscale approach, we use dissipative particle dynamics (DPD) to parameterize the continuous model, i.e. to derive a corresponding macroscopic model. Our model predicts that curvature modulated sorting can occur if lipids or proteins differ in at least one of their macroscopic elastic moduli. Gradients in the spontaneous curvature, the bending rigidity or the Gaussian rigidity create characteristic (metastable) curvature dependent patterns. The structure and dynamics of these membrane patterns are investigated qualitatively and quantitatively using simulations. These show that the decomposition time decreases and the stability of patterns increases with enlarging moduli differences or curvature gradients. Presented phase diagrams allow to estimate if and how stable curvature modulated sorting will occur for a given geometry and set of elastic parameters. In addition, we find that the use of upscaled models is imperative studying membrane dynamics. Compared with common linear approximations the system can evolve to different (meta)stable patterns. This emphasizes the importance of parameters and realistic dynamics in mathematical modeling of biological membranes. Copyright © 2012 Elsevier Ltd. All rights reserved.
PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis
Noel, Sabrina; Dhooghe, Barbara; Leal, Teresinha
2012-01-01
Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF), there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil, or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects, and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF. PMID:23024633
Pulmonary Hypertension Therapy and a Systematic Review of Efficacy and Safety of PDE-5 Inhibitors.
Unegbu, Chinwe; Noje, Corina; Coulson, John D; Segal, Jodi B; Romer, Lewis
2017-03-01
Pulmonary hypertension (PH) is a syndrome that is of growing concern to pediatricians worldwide. Recent data led to concerns about the safety of phosphodiesterase type 5 (PDE5) inhibitors in children and a US Food and Drug Administration safety advisory. Our objective is to provide insight into therapies for PH in children and to systematically review the comparative effectiveness and safety of PDE5 inhibitors in the management of pediatric patients with PH. We searched the following databases through February 2015: Medline, Embase, SCOPUS, and the Cochrane Central Register of Controlled Trials. We included studies that examined PDE5 inhibitor use in children with PH. Allowed comparators were either no medication or other classes of medication for management of PH. Study inclusion was via a 2-stage process with 2 reviewers and a predesigned form. Of 1270 papers identified by the literature search, 21 were included: 8 randomized controlled trials and 13 observational studies (9 retrospective, 4 prospective). There is strong evidence that PDE5 inhibitor use improves echocardiography measurements, cardiac catheterization parameters, and oxygenation compared with baseline or placebo in pediatric patients with PH. Evidence suggests that low- and moderate-dose sildenafil are safe regimens for children. There are a relatively small number of randomized controlled trials that address use of PDE5 inhibitors in pediatric patients with PH. PDE5 inhibitors are effective agents for cardiovascular and oxygenation end points in pediatric PH and important components of a multimodal pharmacotherapeutic approach to this growing challenge. Additional studies are needed to define optimal PH therapy in childhood.
New achievement and novel therapeutic applications of PDE5 inhibithors in older males.
Frajese, G V; Pozzi, F
2005-01-01
Erectile dysfunction (ED) increases in prevalence and severity because of aging processes and related organic, iatrogenic and social problems. Decline of testosterone (T) levels is observed with age and also in illnesses with a common basis of endothelial damage. The T deficiency may lead to decreased energy, mood depression, reduction of sexual desire, but no correlation has been reported between T level and severity of ED, which is mainly a neurovascular disease. In facts, inhibition of phosphodiesterase type 5 (PDE5) isoenzyme with sildenafil, tadalafil and vardenafil enhances vasodilatation in the corpus cavernosum and subsequent penile erection. Absolute pharmacological potency of PDE5 inhibitors is similar and non-selectivity defines the side-effects profile, while their elimination half-life explains not only the different duration of action, but also short and long-term tolerability. Efficacy of PDE5 inhibitors in younger patients is greater in respect to older subjects because of associated pathologies and the decline in hypothalamic-pituitary-gonadal function. T is essential in erectile function, controlling the expression and activity of PDE5 and therefore, androgen supplementation improves therapeutic response to PDE5 inhibitors in hypogonadal subjects. Since sexual behavior is a complex interplay of physical, psychological, and social factors, the possible effect of these drugs on androgen levels and brain function need to be deeply investigated. The ubiquitarious distribution of PDE5 and the availability of selective inhibitory molecules foster newer studies in the treatment of heart failure, pulmonary hypertension, inflammation, and depression. This new progress is certainly contributing to a better medical approach to sexuality and quality of life in aging people.
PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis.
Noel, Sabrina; Dhooghe, Barbara; Leal, Teresinha
2012-01-01
Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF), there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil, or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects, and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF.
Dynamic Multiscale Simulation of Polyelectrolyte Nanoassemblies
2008-08-21
REPORT Dynamic Multiscale Simulation of Polyelectrolyte Nanoassemblies 14. ABSTRACT 16. SECURITY CLASSIFICATION OF: The goal of this project is to...Std. Z39.18 - 31-May-2008 Dynamic Multiscale Simulation of Polyelectrolyte Nanoassemblies Report Title ABSTRACT The goal of this project is to...Total Number: Sub Contractors (DD882) Inventions (DD882) Final Progress Report Dynamic Multiscale Simulation of Polyelectrolyte Nanoassemblies
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.
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
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.
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.
Betzel, Richard F; Bassett, Danielle S
2016-11-11
The network architecture of the human brain has become a feature of increasing interest to the neuroscientific community, largely because of its potential to illuminate human cognition, its variation over development and aging, and its alteration in disease or injury. Traditional tools and approaches to study this architecture have largely focused on single scales-of topology, time, and space. Expanding beyond this narrow view, we focus this review on pertinent questions and novel methodological advances for the multi-scale brain. We separate our exposition into content related to multi-scale topological structure, multi-scale temporal structure, and multi-scale spatial structure. In each case, we recount empirical evidence for such structures, survey network-based methodological approaches to reveal these structures, and outline current frontiers and open questions. Although predominantly peppered with examples from human neuroimaging, we hope that this account will offer an accessible guide to any neuroscientist aiming to measure, characterize, and understand the full richness of the brain's multiscale network structure-irrespective of species, imaging modality, or spatial resolution.
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 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.
Multiscale image blind denoising.
Lebrun, Marc; Colom, Miguel; Morel, Jean-Michel
2015-10-01
Arguably several thousands papers are dedicated to image denoising. Most papers assume a fixed noise model, mainly white Gaussian or Poissonian. This assumption is only valid for raw images. Yet, in most images handled by the public and even by scientists, the noise model is imperfectly known or unknown. End users only dispose the result of a complex image processing chain effectuated by uncontrolled hardware and software (and sometimes by chemical means). For such images, recent progress in noise estimation permits to estimate from a single image a noise model, which is simultaneously signal and frequency dependent. We propose here a multiscale denoising algorithm adapted to this broad noise model. This leads to a blind denoising algorithm which we demonstrate on real JPEG images and on scans of old photographs for which the formation model is unknown. The consistency of this algorithm is also verified on simulated distorted images. This algorithm is finally compared with the unique state of the art previous blind denoising method.
The Magnetospheric Multiscale Magnetometers
NASA Technical Reports Server (NTRS)
Russell, C. T.; Anderson, B. J.; Baumjohann, W.; Bromund, K. R.; Dearborn, D.; Fischer, D.; Le, G.; Leinweber, H. K.; Leneman, D.; Magnes, W.;
2014-01-01
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 onboard 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.
N Termini of apPDE4 Isoforms Are Responsible for Targeting the Isoforms to Different Cellular Membranes
ERIC Educational Resources Information Center
Jang, Deok-Jin; Park, Soo-Won; Lee, Jin-A; Lee, Changhoon; Chae, Yeon-Su; Park, Hyungju; Kim, Min-Jeong; Choi, Sun-Lim; Lee, Nuribalhae; Kim, Hyoung; Kaang, Bong-Kiun
2010-01-01
Phosphodiesterases (PDEs) are known to play a key role in the compartmentalization of cAMP signaling; however, the molecular mechanisms underlying intracellular localization of different PDE isoforms are not understood. In this study, we have found that each of the supershort, short, and long forms of apPDE4 showed distinct localization in the…
D'Ursi, Pasqualina; Guariento, Sara; Trombetti, Gabriele; Orro, Alessandro; Cichero, Elena; Milanesi, Luciano; Bruno, Olga
2016-01-01
Abstract Alzheimer′s disease has recently emerged as a possible field of application for PDE4D inhibitors (PDE4DIs). The great structure similarity among the various PDE4 isoforms and, furthermore, the lack of the full length crystal structure of the enzyme, impaired the rational design of new selective PDE4DIs. In this paper, with the aim of exploring new insights into the PDE4D binding, we tackled the problem by performing a computational study based on docking simulations combined with molecular dynamics (D‐MD). Our work uniquely identified the binding mode and the key residues involved in the interaction with a number of in‐house catechol iminoether derivatives, acting as PDE4DIs. Moreover, the new binding mode was tested using a series of analogues previously reported by us and it was used to confirm their key structural features to allow PDE4D inhibition. The binding model disclosed within the current computational study may prove to be useful to further advance the design and synthesis of novel, more potent and selective, PDE4D inhibitors. PMID:27546041
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…
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
A Comparison of Stiff ODE Solvers for Astrochemical Kinetics Problems
NASA Astrophysics Data System (ADS)
Nejad, Lida A. M.
2005-09-01
The time dependent chemical rate equations arising from astrochemical kinetics problems are described by a system of stiff ordinary differential equations (ODEs). In this paper, using three astrochemical models of varying physical and computational complexity, and hence different degrees of stiffness, we present a comprehensive performance survey of a set of well-established ODE solver packages from the ODEPACK collection, namely LSODE, LSODES, VODE and VODPK. For completeness, we include results from the GEAR package in one of the test models. The results demonstrate that significant performance improvements can be obtained over GEAR which is still being used by many astrochemists by default. We show that a simple appropriate ordering of the species set results in a substantial improvement in the performance of the tested ODE solvers. The sparsity of the associated Jacobian matrix can be exploited and results using the sparse direct solver routine LSODES show an extensive reduction in CPU time without any loss in accuracy. We compare the performance and the computed abundances of one model with a 175 species set and a reduced set of 88 species, keeping all physical and chemical parameters identical with both sets.We found that the calculated abundances using two different size models agree quite well. However, with no extra computational effort and more reliable results, it is possible for the computation to be many times faster with the larger species set than the reduced set, depending on the use of solvers, the ordering and the chosen options. It is also shown that though a particular solver with certain chosen parameters may have severe difficulty or even fail to complete a run over the required integration time, another solver can easily complete the run with a wider range of control parameters and options. As a result of the superior performance of LSODES for the solution of astrochemical kinetics systems, we have tailor-made a sparse version of the VODE
Libé, Rossella; Horvath, Anelia; Vezzosi, Delphine; Fratticci, Amato; Coste, Joel; Perlemoine, Karine; Ragazzon, Bruno; Guillaud-Bataille, Marine; Groussin, Lionel; Clauser, Eric; Raffin-Sanson, Marie-Laure; Siegel, Jennifer; Moran, Jason; Drori-Herishanu, Limor; Faucz, Fabio Rueda; Lodish, Maya; Nesterova, Maria; Bertagna, Xavier; Bertherat, Jerome; Stratakis, Constantine A
2011-01-01
Carney complex (CNC) is an autosomal dominant multiple neoplasia, caused mostly by inactivating mutations of the regulatory subunit 1A of the protein kinase A (PRKAR1A). Primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine manifestation of CNC with a great inter-individual variability. Germline, protein-truncating mutations of phosphodiesterase type 11A (PDE11A) have been described to predispose to a variety of endocrine tumors, including adrenal and testicular tumors. Our objective was to investigate the role of PDE11A as a possible gene modifier of the phenotype in a series of 150 patients with CNC. A higher frequency of PDE11A variants in patients with CNC compared with healthy controls was found (25.3 vs. 6.8%, P < 0.0001). Among CNC patients, those with PPNAD were significantly more frequently carriers of PDE11A variants compared with patients without PPNAD (30.8 vs. 13%, P = 0.025). Furthermore, men with PPNAD were significantly more frequently carriers of PDE11A sequence variants (40.7%) than women with PPNAD (27.3%) (P < 0.001). A higher frequency of PDE11A sequence variants was also found in patients with large-cell calcifying Sertoli cell tumors (LCCSCT) compared with those without LCCSCT (50 vs. 10%, P = 0.0056). PDE11A variants were significantly associated with the copresence of PPNAD and LCCSCT in men: 81 vs. 20%, P < 0.004). The simultaneous inactivation of PRKAR1A and PDE11A by small inhibitory RNA led to an increase in cAMP-regulatory element-mediated transcriptional activity under basal conditions and after stimulation by forskolin. We demonstrate, in a large cohort of CNC patients, a high frequency of PDE11A variants, suggesting that PDE11A is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation.
Gomez, Laurent; Massari, Mark Eben; Vickers, Troy; Freestone, Graeme; Vernier, William; Ly, Kiev; Xu, Rui; McCarrick, Margaret; Marrone, Tami; Metz, Markus; Yan, Yingzhou G; Yoder, Zachary W; Lemus, Robert; Broadbent, Nicola J; Barido, Richard; Warren, Noelle; Schmelzer, Kara; Neul, David; Lee, Dong; Andersen, Carsten B; Sebring, Kristen; Aertgeerts, Kathleen; Zhou, Xianbo; Tabatabaei, Ali; Peters, Marco; Breitenbucher, J Guy
2017-03-09
A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.
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.
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. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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
A multiscale discontinuous Galerkin method.
Bochev, Pavel Blagoveston; Scovazzi, Guglielmo; Hughes, Thomas J. R.
2005-04-01
We propose a new class of Discontinuous Galerkin (DG) methods based on variational multiscale ideas. Our approach begins with an additive decomposition of the discontinuous finite element space into continuous (coarse) and discontinuous (fine) components. Variational multiscale analysis is used to define an interscale transfer operator that associates coarse and fine scale functions. Composition of this operator with a donor DG method yields a new formulation that combines the advantages of DG methods with the attractive and more efficient computational structure of a continuous Galerkin method. The new class of DG methods is illustrated for a scalar advection-diffusion problem.
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
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
The synthesis and biological evaluation of a novel series of phthalazine PDE4 inhibitors I.
Napoletano, M; Norcini, G; Pellacini, F; Marchini, F; Morazzoni, G; Ferlenga, P; Pradella, L
2000-10-02
This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described represent conformationally constrained analogues of RP 73401, Piclamilast. Preliminary evidences of reduced side effects of II compared to standards are also reported.
Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling
Yun, Sanguk; Budatha, Madhusudhan; Dahlman, James E.; Coon, Brian G.; Cameron, Ryan T.; Langer, Robert; Anderson, Daniel G.; Baillie, George; Schwartz, Martin A.
2016-01-01
Atherosclerosis is primarily a disease of lipid metabolism and inflammation; however, it is also closely associated with endothelial extracellular matrix (ECM) remodelling, with fibronectin accumulating in the laminin–collagen basement membrane. To investigate how fibronectin modulates inflammation in arteries, we replaced the cytoplasmic tail of the fibronectin receptor integrin α5 with that of the collagen/laminin receptor integrin α2. This chimaera suppressed inflammatory signalling in endothelial cells on fibronectin and in knock-in mice. Fibronectin promoted inflammation by suppressing anti-inflammatory cAMP. cAMP was activated through endothelial prostacyclin secretion; however, this was ECM-independent. Instead, cells on fibronectin suppressed cAMP via enhanced phosphodiesterase (PDE) activity, through direct binding of integrin α5 to phosphodiesterase-4D5 (PDE4D5), which induced PP2A-dependent dephosphorylation of PDE4D5 on the inhibitory site Ser651. In vivo knockdown of PDE4D5 inhibited inflammation at athero-prone sites. These data elucidate a molecular mechanism linking ECM remodelling and inflammation, thereby identifying a new class of therapeutic targets. PMID:27595237
Yan, Luchun; Liu, Jiemin; Qu, Chen; Gu, Xingye; Zhao, Xia
2015-01-28
In order to explore the odor interaction of binary odor mixtures, a series of odor intensity evaluation tests were performed using both individual components and binary mixtures of aldehydes. Based on the linear relation between the logarithm of odor activity value and odor intensity of individual substances, the relationship between concentrations of individual constituents and their joint odor intensity was investigated by employing a partial differential equation (PDE) model. The obtained results showed that the binary odor interaction was mainly influenced by the mixing ratio of two constituents, but not the concentration level of an odor sample. Besides, an extended PDE model was also proposed on the basis of the above experiments. Through a series of odor intensity matching tests for several different binary odor mixtures, the extended PDE model was proved effective at odor intensity prediction. Furthermore, odorants of the same chemical group and similar odor type exhibited similar characteristics in the binary odor interaction. The overall results suggested that the PDE model is a more interpretable way of demonstrating the odor interactions of binary odor mixtures.
Choi, Catherine H; Schoenfeld, Brian P; Weisz, Eliana D; Bell, Aaron J; Chambers, Daniel B; Hinchey, Joseph; Choi, Richard J; Hinchey, Paul; Kollaros, Maria; Gertner, Michael J; Ferrick, Neal J; Terlizzi, Allison M; Yohn, Nicole; Koenigsberg, Eric; Liebelt, David A; Zukin, R Suzanne; Woo, Newton H; Tranfaglia, Michael R; Louneva, Natalia; Arnold, Steven E; Siegel, Steven J; Bolduc, Francois V; McDonald, Thomas V; Jongens, Thomas A; McBride, Sean M J
2015-01-07
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.
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.
Deoda, Anand J; Singhal, Rekha S
2003-07-01
5'-Phosphodiesterase (5'-PDE) is an enzyme that hydrolyses RNA to a mixture of ribonucleotides, from which the flavour enhancers, 5'-guanosine monophosphate (5'-GMP) and 5'-inosine monophosphate (5'-IMP) can be isolated. In the present work, 5'-PDE was extracted and partially purified from germinated barley seeds. 5'-PDE activity was monitored using bis-p-nitrophenyl phosphate as the substrate. The enzyme acts on the substrate and releases the p-nitrophenol, which is measured at 420 nm. Ultrafiltration using a polysulfone membrane having molecular weight cut off (MWCO) of 20 kDa gave 12-fold concentration. Further purification using ammonium sulphate gave 18-fold concentration. Heat shock for 15 min at 60 degrees C after the ultrafiltration enhanced the concentration of 5'-PDE 9.10 fold, while a similar treatment after ammonium sulphate treatment enhanced it by 17.83-fold. The enzyme had a pH optimum of 5, and was stable at 0 degrees C. This partially purified enzyme could be used for hydrolysis of RNA to produce 5'-GMP and 5' adenosine monophosphate, a precursor of 5'-IMP.
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
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.
Performance Models for the Spike Banded Linear System Solver
Manguoglu, Murat; Saied, Faisal; Sameh, Ahmed; ...
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
A robust HLLC-type Riemann solver for strong shock
NASA Astrophysics Data System (ADS)
Shen, Zhijun; Yan, Wei; Yuan, Guangwei
2016-03-01
It is well known that for the Eulerian equations the numerical schemes that can accurately capture contact discontinuity usually suffer from some disastrous carbuncle phenomenon, while some more dissipative schemes, such as the HLL scheme, are free from this kind of shock instability. Hybrid schemes to combine a dissipative flux with a less dissipative flux can cure the shock instability, but also may lead to other problems, such as certain arbitrariness of choosing switching parameters or contact interface becoming smeared. In order to overcome these drawbacks, this paper proposes a simple and robust HLLC-type Riemann solver for inviscid, compressible gas flows, which is capable of preserving sharp contact surface and is free from instability. The main work is to construct a HLL-type Riemann solver and a HLLC-type Riemann solver by modifying the shear viscosity of the original HLL and HLLC methods. Both of the two new schemes are positively conservative under some typical wavespeed estimations. Moreover, a linear matrix stability analysis for the proposed schemes is accomplished, which illustrates the HLLC-type solver with shear viscosity is stable whereas the HLL-type solver with vorticity wave is unstable. Our arguments and numerical experiments demonstrate that the inadequate dissipation associated to the shear wave may be a unique reason to cause the instability.
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.
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
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
2016-04-07
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.
Koon, Chong Siew; Sidi, Hatta; Kumar, Jaya; Das, Srijit; Xi, Ong Wan; Hatta, Muhammad Hizri; Alfonso, Cesar
2017-02-15
Erectile function (EF) is a prerequisite for satisfactory sexual intercourse (SI) and central to male sexual functioning. Satisfactory SI eventually leads to orgasm - a biopsychophysiological state of euphoria - leading to a sense of bliss, enjoyment and positive mental well being. For a psychiatrist, treating ED is self-propelled to harmonize these pleasurable experiences alongside with encouragement of physical wellness and sensuality. Hence, the role of PDE-5i is pivotal in the context of treating ED constitutes a therapeutic challenge. PDE-5i work via the dopaminergic-oxytocin-nitric oxide pathway by increasing the availability of endothelial's guanosine monophosphate (GMP), immediately causing relaxation of the penile smooth muscle and an erection. The PDE-5i, like sildenafil, vardenafil and tadalafil, are effective in the treatment of ED with some benefits and disadvantages compared to other treatment modalities. Prescribed PDE-5i exclusively improve EF, fostering male's self-confidence and self-esteem. Treatment failures are associated with factors such as absent (or insufficient) sexual stimulation, psychosexual conflicts and the co-existence of medical disorders. Managing ED requires dealing with underlying medical diseases, addressing other co-morbid sexual dysfunctions like premature ejaculation (PE), and educating the patient on healthy life-styles beside being cautious with the potential side-effects and drug-drug interactions. Furthermore, by dealing with interpersonal dynamics within the couple and embracing adequate lifestyles (managing stress and revising one's sexual scripts), PDE-5i treatment benefits may be enhanced. In this review, we propose a holistic conceptual framework approach for psychiatric management of patients with ED.
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.
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...
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...
An adaptive fast multipole accelerated Poisson solver for complex geometries
NASA Astrophysics Data System (ADS)
Askham, T.; Cerfon, A. J.
2017-09-01
We present a fast, direct and adaptive Poisson solver for complex two-dimensional geometries based on potential theory and fast multipole acceleration. More precisely, the solver relies on the standard decomposition of the solution as the sum of a volume integral to account for the source distribution and a layer potential to enforce the desired boundary condition. The volume integral is computed by applying the FMM on a square box that encloses the domain of interest. For the sake of efficiency and convergence acceleration, we first extend the source distribution (the right-hand side in the Poisson equation) to the enclosing box as a C0 function using a fast, boundary integral-based method. We demonstrate on multiply connected domains with irregular boundaries that this continuous extension leads to high accuracy without excessive adaptive refinement near the boundary and, as a result, to an extremely efficient ;black box; fast solver.
Overset Techniques for Hypersonic Multibody Configurations with the DPLR Solver
NASA Technical Reports Server (NTRS)
Hyatt, Andrew James; Prabhu, Dinesh K.; Boger, David A.
2010-01-01
Three unit problems in shock-shock/shock-boundary layer interactions are considered in the evaluation overset techniques with the Data Parallel Line Relaxation (DPLR) computational fluid dynamics solver, a three dimensional Navier-Stokes solver . The unit problems considered are those of two stacked hemispherical cylinders (of different diameters and lengths, and at various orientations relative to each other or relative to the nozzle axis) tested in a hypersonic wind tunnel. These problems are taken as representative of a Two-Stage-To-Orbit design. The objective of the present presentation would be to discuss the techniques used to develop suitable overset grid systems and then evaluate their respective solutions by comparing to corresponding point matched grid solutions and experimental data. Both successful and unsuccessful techniques would be discussed. All solutions would be calculated using the DPLR solver and SUGGAR will be used to develop the domain connectivity information.
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.
Advanced Fast 3D Electromagnetic Solver for Microwave Tomography Imaging.
Simonov, Nikolai; Kim, Bo-Ra; Lee, Kwang-Jae; Jeon, Soon-Ik; Son, Seong-Ho
2017-06-07
This paper describes a fast forward electromagnetic solver (FFS) for the image reconstruction algorithm of our microwave tomography (MT) system. Our apparatus is a preclinical prototype of a biomedical imaging system, designed for the purpose of early breast cancer detection. It operates in the 3-6 GHz frequency band using a circular array of probe antennas immersed in a matching liquid; it produces image reconstructions of the permittivity and conductivity profiles of the breast under examination. Our reconstruction algorithm solves the electromagnetic inverse problem and takes into account the real electromagnetic properties of the probe antenna array as well as the influence of the patient's body and that of the upper metal screen sheet. This FFS algorithm is much faster than conventional electromagnetic simulation solvers. In comparison, in the same PC, the CST solver takes ~45 min, while the FFS takes ~1 s of effective simulation time for the same electromagnetic model of a numerical breast phantom.
Numerical comparison of Riemann solvers for astrophysical hydrodynamics
NASA Astrophysics Data System (ADS)
Klingenberg, Christian; Schmidt, Wolfram; Waagan, Knut
2007-11-01
The idea of this work is to compare a new positive and entropy stable approximate Riemann solver by Francois Bouchut with a state-of the-art algorithm for astrophysical fluid dynamics. We implemented the new Riemann solver into an astrophysical PPM-code, the Prometheus code, and also made a version with a different, more theoretically grounded higher order algorithm than PPM. We present shock tube tests, two-dimensional instability tests and forced turbulence simulations in three dimensions. We find subtle differences between the codes in the shock tube tests, and in the statistics of the turbulence simulations. The new Riemann solver increases the computational speed without significant loss of accuracy.
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.
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.
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.
Anchored PDE4 regulates chloride conductance in wild-type and ΔF508-CFTR human airway epithelia.
Blanchard, Elise; Zlock, Lorna; Lao, Anna; Mika, Delphine; Namkung, Wan; Xie, Moses; Scheitrum, Colleen; Gruenert, Dieter C; Verkman, Alan S; Finkbeiner, Walter E; Conti, Marco; Richter, Wito
2014-02-01
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that impair its expression and/or chloride channel function. Here, we provide evidence that type 4 cyclic nucleotide phosphodiesterases (PDE4s) are critical regulators of the cAMP/PKA-dependent activation of CFTR in primary human bronchial epithelial cells. In non-CF cells, PDE4 inhibition increased CFTR activity under basal conditions (ΔISC 7.1 μA/cm(2)) and after isoproterenol stimulation (increased ΔISC from 13.9 to 21.0 μA/cm(2)) and slowed the return of stimulated CFTR activity to basal levels by >3-fold. In cells homozygous for ΔF508-CFTR, the most common mutation found in CF, PDE4 inhibition alone produced minimal channel activation. However, PDE4 inhibition strongly amplified the effects of CFTR correctors, drugs that increase expression and membrane localization of CFTR, and/or CFTR potentiators, drugs that increase channel gating, to reach ∼ 25% of the chloride conductance observed in non-CF cells. Biochemical studies indicate that PDE4s are anchored to CFTR and mediate a local regulation of channel function. Taken together, our results implicate PDE4 as an important determinant of CFTR activity in airway epithelia, and support the use of PDE4 inhibitors to potentiate the therapeutic benefits of CFTR correctors and potentiators.
Multiscale modeling methods in biomechanics.
Bhattacharya, Pinaki; Viceconti, Marco
2017-01-19
More and more frequently, computational biomechanics deals with problems where the portion of physical reality to be modeled spans over such a large range of spatial and temporal dimensions, that it is impossible to represent it as a single space-time continuum. We are forced to consider multiple space-time continua, each representing the phenomenon of interest at a characteristic space-time scale. Multiscale models describe a complex process across multiple scales, and account for how quantities transform as we move from one scale to another. This review offers a set of definitions for this emerging field, and provides a brief summary of the most recent developments on multiscale modeling in biomechanics. Of all possible perspectives, we chose that of the modeling intent, which vastly affect the nature and the structure of each research activity. To the purpose we organized all papers reviewed in three categories: 'causal confirmation,' where multiscale models are used as materializations of the causation theories; 'predictive accuracy,' where multiscale modeling is aimed to improve the predictive accuracy; and 'determination of effect,' where multiscale modeling is used to model how a change at one scale manifests in an effect at another radically different space-time scale. Consistent with how the volume of computational biomechanics research is distributed across application targets, we extensively reviewed papers targeting the musculoskeletal and the cardiovascular systems, and covered only a few exemplary papers targeting other organ systems. The review shows a research subdomain still in its infancy, where causal confirmation papers remain the most common. For further resources related to this article, please visit the WIREs website.
Role of AKAP 149-PKA-PDE4A complex in cell survival and cell differentiation processes.
Fernández-Araujo, A; Tobío, A; Alfonso, A; Botana, L M
2014-08-01
The cellular localization of A-kinase anchoring proteins (AKAPs), protein kinase A (PKAs) and phosphodiesterases (PDEs) is a key step to the spatiotemporal regulation of the second messenger adenosine 3',5'-cyclic monophosphate (cAMP). In this paper the cellular distribution of the mitochondrial AKAP 149-PKA-PDE4A complex and its implications in the cell death induced by YTX treatment, a known PDE modulator, was studied. K-562 cell line was incubated with YTX for 24 or 48 h. Under these conditions AKAP 149, PKA and type-4A PDE (PDE4A) levels were measured in the cytosol, in the plasma membrane and in the nucleus. Apoptotic hallmarks were also measured after the same conditions. In addition, YTX effect on cell viability was checked after AKAP 149 and PDE4A silencing. The results obtained show a decrease in AKAP 149-PKA-PDE4A levels in cytosol after YTX exposure. 24h after the toxin addition, the complex expression increased in the plasma membrane and after 48 h in the nucleus domain. Furthermore Bcl-2 levels were decreased and the expression of caspase 3 together with caspase 8 activity were increased after 24h of toxin incubation but not after 48 h. These results suggest apoptotic cell death at 24h and a non-apoptotic cell death after 48 h. When AKAP 149 and PDE4A were silenced YTX did not induce cellular death. In summary, AKAP 149-PKA-PDE4A complex localization is related with YTX effect in K-562 cell line. When this complex is mainly located in the plasma membrane apoptosis is activated while when the complex is in the nuclear domain non-apoptotic cellular death or cellular differentiation is activated. Therefore AKAP 149-PKA-PDE4A distribution and integrity have a key role in cellular survival.
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.
Nonlinear Least Squares Curve Fitting with Microsoft Excel Solver
NASA Astrophysics Data System (ADS)
Harris, Daniel C.
1998-01-01
"Solver" is a powerful tool in the Microsoft Excel spreadsheet that provides a simple means of fitting experimental data to nonlinear functions. The procedure is so easy to use and its mode of operation is so obvious that it is excellent for students to learn the underlying principle of lease squares curve fitting. This article introduces the method of fitting nonlinear functions with Solver and extends the treatment to weighted least squares and to the estimation of uncertainties in the least-squares parameters.
An Easy Method To Accelerate An Iterative Algebraic Equation Solver
Yao, Jin
2014-01-06
This article proposes to add a simple term to an iterative algebraic equation solver with an order n convergence rate, and to raise the order of convergence to (2n - 1). In particular, a simple algebraic equation solver with the 5th order convergence but uses only 4 function values in each iteration, is described in details. When this scheme is applied to a Newton-Raphson method of the quadratic convergence for a system of algebraic equations, a cubic convergence can be achieved with an low overhead cost of function evaluation that can be ignored as the size of the system increases.
NASA Astrophysics Data System (ADS)
Iacobellis, Vincent
Composite and nanocomposite materials exhibit behaviour which is inherently multiscale, extending from the atomistic to continuum levels. In composites, damage growth tends to occur at the nano and microstructural scale by means of crack growth and fibre-matrix debonding. Concurrent multiscale modeling provides a means of efficiently solving such localized phenomena, however its use in this application has been limited due to a number of existing issues in the multiscale field. These include the seamless transfer of information between continuum and atomistic domains, the small timesteps required for dynamic simulation, and limited research into concurrent multiscale modeling of amorphous polymeric materials. The objective of this thesis is thus twofold: to formulate a generalized approach to solving a coupled atomistic-to-continuum system that addresses these issues and to extend the application space of concurrent multiscale modeling to damage modeling in composite microstructures. To achieve these objectives, a finite element based multiscale technique termed the Bridging Cell Method (BCM), has been formulated with a focus on crystalline material systems. Case studies are then presented that show the effectiveness of the developed technique with respect to full atomistic simulations. The BCM is also demonstrated for applications of stress around a nanovoid, nanoindentation, and crack growth due to monotonic and cyclic loading. Next, the BCM is extended to modeling amorphous polymeric material systems where an adaptive solver and a two-step iterative solution algorithm are introduced. Finally, the amorphous and crystalline BCM is applied to modeling a polymer-graphite interface. This interface model is used to obtain cohesive zone parameters which are used in a cohesive zone model of fibre-matrix interfacial cracking in a composite microstructure. This allows for an investigation of the temperature dependent damage mechanics from the nano to microscale within
Nonhydrostatic adaptive mesh dynamics for multiscale climate models (Invited)
NASA Astrophysics Data System (ADS)
Collins, W.; Johansen, H.; McCorquodale, P.; Colella, P.; Ullrich, P. A.
2013-12-01
Many of the atmospheric phenomena with the greatest potential impact in future warmer climates are inherently multiscale. Such meteorological systems include hurricanes and tropical cyclones, atmospheric rivers, and other types of hydrometeorological extremes. These phenomena are challenging to simulate in conventional climate models due to the relatively coarse uniform model resolutions relative to the native nonhydrostatic scales of the phenomonological dynamics. To enable studies of these systems with sufficient local resolution for the multiscale dynamics yet with sufficient speed for climate-change studies, we have adapted existing adaptive mesh dynamics for the DOE-NSF Community Atmosphere Model (CAM). In this talk, we present an adaptive, conservative finite volume approach for moist non-hydrostatic atmospheric dynamics. The approach is based on the compressible Euler equations on 3D thin spherical shells, where the radial direction is treated implicitly (using a fourth-order Runga-Kutta IMEX scheme) to eliminate time step constraints from vertical acoustic waves. Refinement is performed only in the horizontal directions. The spatial discretization is the equiangular cubed-sphere mapping, with a fourth-order accurate discretization to compute flux averages on faces. By using both space-and time-adaptive mesh refinement, the solver allocates computational effort only where greater accuracy is needed. The resulting method is demonstrated to be fourth-order accurate for model problems, and robust at solution discontinuities and stable for large aspect ratios. We present comparisons using a simplified physics package for dycore comparisons of moist physics. Hadley cell lifting an advected tracer into upper atmosphere, with horizontal adaptivity
Sugiyama, Takuji; Narukawa, Yuji; Shibata, Shunsuke; Masui, Ryo; Kiuchia, Fumiyuki
2016-06-01
The MeOH extract of agarwood showed inhibitory activity against phosphodiesterase (PDE) 3A. Fractionation of the extract led to the isolation of two new 2-(2-phenylethyl)chromones, 6,8-dihydroxy-2-[2-(4'-methoxyphenyl)ethyl]chromone (6), and 6,7-dihydroxy-2-(2-phenylethyl)chromone (8), together with six known compounds. All isolated compounds were tested for their PDE 3A inhibitory activity using fluorescence polarization method. Compound 7 showed PDE 3A inhibitory activity with IC50 of 4.83 μM.
Sopko, Nikolai A.; Matsui, Hotaka; Hannan, Johanna L.; Berkowitz, Dan; Champion, Hunter C.; Hsu, Lewis L.; Musicki, Biljana; Burnett, Arthur L.; Bivalacqua, Trinity J.
2015-01-01
Introduction Recent research suggests that priapism in Sickle Cell Disease (SCD) is due to dysregulation of penile erection homeostasis including alteration of nitric oxide synthase (NOS) and phosphodiesterase 5 (PDE5) activities by excessive levels of reactive oxygen species (ROS) released during hemolysis. It is unknown if sub-acute exposure to hemolysis is sufficient or if chronic reconditioning of erectile tissues is required for perturbation of homeostatic pathways and whether PDE5 inhibitor (PDE5I) treatment can restore erectile homeostasis in the sub-acute setting. Aims To investigate the effects of sub-acute hemolysis (3 month exposure) on priapism and NO pathway regulation. Methods Mice underwent bone marrow transplantation with either SCD (BM-SS) or wild type (WT) bone marrow. BM-SS mice were treated with sildenafil 100mg/kg/day. We measured intracavernous pressure (ICP) measurements with or without cavernosal nerve stimulation (CNS) following bone marrow transplantation to assess for priapism. Main Outcome Measures ICP and frequency of erections were assessed. Penile tissues were analyzed for NOS, PKG, PDE5, and ROS activities. Results BM-SS mice demonstrated a priapism phenotype. PDE5I treatment reduced the frequency of erections in BM-SS mice (1.7 ± 1.1 vs. 5.5 ± 2.8 erections/hour, p<0.05). Penile tissues from BM-SS mice demonstrated decreased NOS, PKG, PDE5 and elevated ROS activities compared to that of control mice. PDE5I treatment increased NOS (11.6 ± 1.3% vs. 7.8 ± 2.3%, p<0.05) and PDE5 (76.3 ± 9.8% vs. 52.3 ± 11.1%, p<0.05) activities and decreased ROS activity (137.8 ± 12.1% vs. 199.1 ± 11.3%, p<0.05) compared to non-PDE5I treated BM-SS mice. PKG activity was increased beyond control levels with PDE5I treatment (158.4 ± 10.3%, p<0.05). Conclusion Short-term hemolysis is sufficient to establish a priapism phenotype and results in loss of erectile function. PDE5I treatment ameliorates priapism, in part, due to restored NO balance with
Xing, Qiang; Wei, Tengda; Chen, Zhihui; Wang, Yangfan; Lu, Yuan; Wang, Shi; Zhang, Lingling; Bao, Zhenmin
2017-03-01
The fine periodic growth patterns on shell surfaces have been widely used for studies in the ecology and evolution of scallops. Modern X-ray CT scanners and digital cameras can provide high-resolution image data that contain abundant information such as the shell formation rate, ontogenetic age, and life span of shellfish organisms. We introduced a novel multiscale image processing method based on matched filters with Gaussian kernels and partial differential equation (PDE) multiscale hierarchical decomposition to segment the small tubular and periodic structures in scallop shell images. The periodic patterns of structures (consisting of bifurcation points, crossover points of the rings and ribs, and the connected lines) could be found by our Space-based Depth-First Search (SDFS) algorithm. We created a MATLAB package to implement our method of periodic pattern extraction and pattern matching on the CT and digital scallop images available in this study. The results confirmed the hypothesis that the shell cyclic structure patterns encompass genetically specific information that can be used as an effective invariable biomarker for biological individual recognition. The package is available with a quick-start guide and includes three examples: http://mgb.ouc.edu.cn/novegene/html/code.php.
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
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
MacMullen, C M; Vick, K; Pacifico, R; Fallahi-Sichani, M; Davis, R L
2016-02-23
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.
Hegde, Shweta; Capell, Will R; Ibrahim, Baher A; Klett, Jennifer; Patel, Neema S; Sougiannis, Alexander T; Kelly, Michy P
2016-11-01
The capacity to form long-lasting social memories is critical to our health and survival. cAMP signaling in the ventral hippocampal formation (VHIPP) appears to be required for social memory formation, but the phosphodiesterase (PDE) involved remains unknown. Previously, we showed that PDE11A, which degrades cAMP and cGMP, is preferentially expressed in CA1 and subiculum of the VHIPP. Here, we determine whether PDE11A is expressed in neurons where it could directly influence synaptic plasticity and whether expression is required for the consolidation and/or retrieval of social memories. In CA1, and possibly CA2, PDE11A4 is expressed throughout neuronal cell bodies, dendrites (stratum radiatum), and axons (fimbria), but not astrocytes. Unlike PDE2A, PDE9A, or PDE10A, PDE11A4 expression begins very low at postnatal day 7 (P7) and dramatically increases until P28, at which time it stabilizes to young adult levels. This expression pattern is consistent with the fact that PDE11A is required for social long-term memory (LTM) formation during adolescence and adulthood. Male and female PDE11 knockout (KO) mice show normal short-term memory (STM) for social odor recognition (SOR) and social transmission of food preference (STFP), but no LTM 24 h post training. Importantly, PDE11A KO mice show normal LTM for nonsocial odor recognition. Deletion of PDE11A may impair memory consolidation by impairing requisite protein translation in the VHIPP. Relative to WT littermates, PDE11A KO mice show reduced expression of RSK2 and lowered phosphorylation of S6 (pS6-235/236). Together, these data suggest PDE11A is selectively required for the proper consolidation of recognition and associative social memories.
Temkitthawon, Prapapan; Hinds, Thomas R; Beavo, Joseph A; Viyoch, Jarupa; Suwanborirux, Khanit; Pongamornkul, Wittaya; Sawasdee, Pattara; Ingkaninan, Kornkanok
2011-10-11
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. 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. 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 (IC(50) = 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. 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. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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
Hegde, Shweta; Capell, Will R; Ibrahim, Baher A; Klett, Jennifer; Patel, Neema S; Sougiannis, Alexander T; Kelly, Michy P
2016-01-01
The capacity to form long-lasting social memories is critical to our health and survival. cAMP signaling in the ventral hippocampal formation (VHIPP) appears to be required for social memory formation, but the phosphodiesterase (PDE) involved remains unknown. Previously, we showed that PDE11A, which degrades cAMP and cGMP, is preferentially expressed in CA1 and subiculum of the VHIPP. Here, we determine whether PDE11A is expressed in neurons where it could directly influence synaptic plasticity and whether expression is required for the consolidation and/or retrieval of social memories. In CA1, and possibly CA2, PDE11A4 is expressed throughout neuronal cell bodies, dendrites (stratum radiatum), and axons (fimbria), but not astrocytes. Unlike PDE2A, PDE9A, or PDE10A, PDE11A4 expression begins very low at postnatal day 7 (P7) and dramatically increases until P28, at which time it stabilizes to young adult levels. This expression pattern is consistent with the fact that PDE11A is required for social long-term memory (LTM) formation during adolescence and adulthood. Male and female PDE11 knockout (KO) mice show normal short-term memory (STM) for social odor recognition (SOR) and social transmission of food preference (STFP), but no LTM 24 h post training. Importantly, PDE11A KO mice show normal LTM for nonsocial odor recognition. Deletion of PDE11A may impair memory consolidation by impairing requisite protein translation in the VHIPP. Relative to WT littermates, PDE11A KO mice show reduced expression of RSK2 and lowered phosphorylation of S6 (pS6–235/236). Together, these data suggest PDE11A is selectively required for the proper consolidation of recognition and associative social memories. PMID:27339393
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.…
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).
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.…
PSH3D fast Poisson solver for petascale DNS
NASA Astrophysics Data System (ADS)
Adams, Darren; Dodd, Michael; Ferrante, Antonino
2016-11-01
Direct numerical simulation (DNS) of high Reynolds number, Re >= O (105) , turbulent flows requires computational meshes >= O (1012) grid points, and, thus, the use of petascale supercomputers. DNS often requires the solution of a Helmholtz (or Poisson) equation for pressure, which constitutes the bottleneck of the solver. We have developed a parallel solver of the Helmholtz equation in 3D, PSH3D. The numerical method underlying PSH3D combines a parallel 2D Fast Fourier transform in two spatial directions, and a parallel linear solver in the third direction. For computational meshes up to 81923 grid points, our numerical results show that PSH3D scales up to at least 262k cores of Cray XT5 (Blue Waters). PSH3D has a peak performance 6 × faster than 3D FFT-based methods when used with the 'partial-global' optimization, and for a 81923 mesh solves the Poisson equation in 1 sec using 128k cores. Also, we have verified that the use of PSH3D with the 'partial-global' optimization in our DNS solver does not reduce the accuracy of the numerical solution of the incompressible Navier-Stokes equations.
Development of multiphase CFD flow solver in OpenFOAM
NASA Astrophysics Data System (ADS)
Rollins, Chad; Luo, Hong; Dinh, Nam
2016-11-01
We are developing a pressure-based multiphase (Eulerian) CFD solver using OpenFOAM with Reynolds-averaged turbulence stress modeling. Our goal is the evaluation and improvement of the current OpenFOAM two-fluid (Eulerian) solver in boiling channels with a motivation to produce a more consistent modeling and numerics treatment. The difficulty lies in the prescense of the many forces and models that are tightly non-linearly coupled in the solver. Therefore, the solver platform will allow not only the modeling, but the tracking as well, of the effects of the individual components (various interfacial forces/heat transfer models) and their interactions. This is essential for the development of a robust and efficient solution method. There has be a lot of work already performed in related areas that generally indicates a lack of robustness of the solution methods. The objective here is therefore to identify and develop remedies for numerical/modeling issues through a systematic approach to verification and validation, taking advantage of the open source nature of OpenFOAM. The presentation will discuss major findings, and suggest strategies for robust and consistent modeling (probably, a more consistent treatment of heat transfer models with two-fluid models in the near-wall cells).
Thinking Process of Naive Problem Solvers to Solve Mathematical Problems
ERIC Educational Resources Information Center
Mairing, Jackson Pasini
2017-01-01
Solving problems is not only a goal of mathematical learning. Students acquire ways of thinking, habits of persistence and curiosity, and confidence in unfamiliar situations by learning to solve problems. In fact, there were students who had difficulty in solving problems. The students were naive problem solvers. This research aimed to describe…
Hypersonic simulations using open-source CFD and DSMC solvers
NASA Astrophysics Data System (ADS)
Casseau, V.; Scanlon, T. J.; John, B.; Emerson, D. R.; Brown, R. E.
2016-11-01
Hypersonic hybrid hydrodynamic-molecular gas flow solvers are required to satisfy the two essential requirements of any high-speed reacting code, these being physical accuracy and computational efficiency. The James Weir Fluids Laboratory at the University of Strathclyde is currently developing an open-source hybrid code which will eventually reconcile the direct simulation Monte-Carlo method, making use of the OpenFOAM application called dsmcFoam, and the newly coded open-source two-temperature computational fluid dynamics solver named hy2Foam. In conjunction with employing the CVDV chemistry-vibration model in hy2Foam, novel use is made of the QK rates in a CFD solver. In this paper, further testing is performed, in particular with the CFD solver, to ensure its efficacy before considering more advanced test cases. The hy2Foam and dsmcFoam codes have shown to compare reasonably well, thus providing a useful basis for other codes to compare against.
A new fast direct solver for the boundary element method
NASA Astrophysics Data System (ADS)
Huang, S.; Liu, Y. J.
2017-04-01
A new fast direct linear equation solver for the boundary element method (BEM) is presented in this paper. The idea of the new fast direct solver stems from the concept of the hierarchical off-diagonal low-rank matrix. The hierarchical off-diagonal low-rank matrix can be decomposed into the multiplication of several diagonal block matrices. The inverse of the hierarchical off-diagonal low-rank matrix can be calculated efficiently with the Sherman-Morrison-Woodbury formula. In this paper, a more general and efficient approach to approximate the coefficient matrix of the BEM with the hierarchical off-diagonal low-rank matrix is proposed. Compared to the current fast direct solver based on the hierarchical off-diagonal low-rank matrix, the proposed method is suitable for solving general 3-D boundary element models. Several numerical examples of 3-D potential problems with the total number of unknowns up to above 200,000 are presented. The results show that the new fast direct solver can be applied to solve large 3-D BEM models accurately and with better efficiency compared with the conventional BEM.
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
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.
Time-varying Riemann solvers for conservation laws on networks
NASA Astrophysics Data System (ADS)
Garavello, Mauro; Piccoli, Benedetto
We consider a conservation law on a network and generic Riemann solvers at nodes depending on parameters, which can be seen as control functions. Assuming that the parameters have bounded variation as functions of time, we prove existence of solutions to Cauchy problems on the whole network.
Parallel Solver for H(div) Problems Using Hybridization and AMG
Lee, Chak S.; Vassilevski, Panayot S.
2016-01-15
In this paper, a scalable parallel solver is proposed for H(div) problems discretized by arbitrary order finite elements on general unstructured meshes. The solver is based on hybridization and algebraic multigrid (AMG). Unlike some previously studied H(div) solvers, the hybridization solver does not require discrete curl and gradient operators as additional input from the user. Instead, only some element information is needed in the construction of the solver. The hybridization results in a H1-equivalent symmetric positive definite system, which is then rescaled and solved by AMG solvers designed for H1 problems. Weak and strong scaling of the method are examined through several numerical tests. Our numerical results show that the proposed solver provides a promising alternative to ADS, a state-of-the-art solver [12], for H(div) problems. In fact, it outperforms ADS for higher order elements.
Multiscale models for synthetic biology.
Kaznessis, Yiannis N
2009-01-01
Reacting systems away from the thermodynamic limit cannot be accurately modeled with ordinary differential equations. These continuous-deterministic modeling formalisms, traditionally developed and used by chemical engineers can be distinctly false if the number of molecules of reacting chemical species is very small, or if reaction events are very rare. Then stochastic-discrete representations are appropriate. Importantly, in cases where in a network of reactions there are some parts that must be modeled discretely and stochastically, yet others can be modeled continuously and deterministically, the need for development of multiscale models emerges naturally. In computational synthetic biology, such cases arise often. In this work we present the development of multiscale models for synthetic biology applications, demonstrating accuracy, computational efficiency and utility.
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.
Zhang, Lei; Chen, Laigao; Beck, Elizabeth M; Chappie, Thomas A; Coelho, Richard V; Doran, Shawn D; Fan, Kuo-Hsien; Humphrey, John M; Hughes, Zoe; Kuszpit, Kyle; Lachapelle, Erik A; Lazzaro, John T; Mather, Robert J; Patel, Nandini C; Skaddan, Marc B; Sciabola, Simone; Verhoest, Patrick R; Young, Joseph Michael; Zasadny, Kenneth; Villalobos, Anabella
2017-09-28
As part of our effort in identifying PDE4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (Bmax) and bio-distribution determination, a PET-specific structure-activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS "cold tracer" method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the "cold tracer" study. In subsequent non-human primate (NHP) PET imaging studies, [18F]8 showed rapid brain uptake and high target specificity, indicating that [18F]8 is a promising PDE4B-preferring radioligand for clinical PET imaging.
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
Ribaudo, Giovanni; Vendrame, Tiziano; Bova, Sergio
2017-09-01
While osajin and pomiferin are known for their anticancer, antibacterial and antidiabetic properties, scandenone and auriculasin have been proposed as anti-inflammatory and antinociceptive agents. Curiously, these two couples of molecules are, from a chemical point of view, structural isomers which can all be extracted from Maclura pomifera. Although previous works described, separately, the isolation in reasonable amounts of the sole osajin/pomiferin couple or of scandenone/auriculasin, we report the extraction and characterization using direct spectral and chromatographical comparison of the four compounds. 2D NMR allowed to unambiguously assign the correct structures to the isomers. The compounds were screened in silico against PDE5 and their interaction pattern with the protein was compared with that of icarisid II, a natural PDE5 inhibitor.
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.
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.
Kim, Hyun Keol; Flexman, Molly; Yamashiro, Darrell J; Kandel, Jessica J; Hielscher, Andreas H
2010-09-08
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.
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.
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.
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
Multiscale Modeling and Multifunctional Composites
2013-07-17
8) Here, Frs and Drs represent stress and the strain influence functions. The phase transformation fields, ,λ µ , appearing in Eqs...concentration factors Ar , Br , and influence functions Drs , Frs , , 1,=r s Q . Two applications are presented; one is a benchmark, classical...Journal for Multiscale Computational Engineering 8, 69-80. Berger, H., Kari S., Gabbert U., Rodriguez- Ramos , R., Guinovart, R., Otero, J.A., Bravo
Multiscale vulnerability of complex networks.
Boccaletti, Stefano; Buldú, Javier; Criado, Regino; Flores, Julio; Latora, Vito; Pello, Javier; Romance, Miguel
2007-12-01
We present a novel approach to quantify the vulnerability of a complex network, i.e., the capacity of a graph to maintain its functional performance under random damages or malicious attacks. The proposed measure represents a multiscale evaluation of vulnerability, and makes use of combined powers of the links' betweenness. We show that the proposed approach is able to properly describe some cases for which earlier measures of vulnerability fail. The relevant applications of our method for technological network design are outlined.
Multi-Scale Autoregressive Processes
1989-06-01
rationnelles et leurs langages," Mas- son 1984, Collection "Etudes et Recherches en Informatique". [12] J.L. DUNAU, "Etude d’une classe de marches...June 1989 LIDS-P-1880 Multi-Scale Autoregressive Processes Michele Basseville’ Albert Benveniste’ Institut de Recherche en Informatique et Systemes...Centre National de la Recherche Scientifique (CNRS) and A.B. is also with Institut National de Recherche en Informatique et en Automatique (INRIA). The
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
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.
Synthesis and biological activities of novel beta-carbolines as PDE5 inhibitors.
Sui, Zhihua; Guan, Jihua; Macielag, Mark J; Jiang, Weiqin; Qiu, Yuhong; Kraft, Patricia; Bhattacharjee, Sheela; John, T Matthew; Craig, Elizabeth; Haynes-Johnson, Donna; Clancy, Joanna
2003-02-24
A series of N(2)-furoyl and N(2)pyrimidinyl beta-carbolines was discovered to possess potent inhibitory activity against PDE5. During the synthesis we developed a tandem resin quenching protocol, which allowed us to synthesize large number of target compounds in a rapid fashion. Representative compounds exhibit superior selectivity to sildenafil versus other isozymes of PDEs, and demonstrated in vivo efficacy in increasing introcavernosal pressure in dogs.
Positive association of phencyclidine-responsive genes, PDE4A and PLAT, with schizophrenia.
Deng, Xiangdong; Takaki, Hiromi; Wang, Lixiang; Kuroki, Tosihide; Nakahara, Tatsuo; Hashimoto, Kijiro; Ninomiya, Hideaki; Arinami, Tadao; Inada, Toshiya; Ujike, Hiroshi; Itokawa, Masanari; Tochigi, Mamoru; Watanabe, Yuichiro; Someya, Toshiyuki; Kunugi, Hiroshi; Iwata, Nakao; Ozaki, Norio; Shibata, Hiroki; Fukumaki, Yasuyuki
2011-12-01
As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4 hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing >2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P = 1.4 × 10(-6) ), PDE4A (P = 1.4 × 10(-6) ), and PLAT (P = 1 × 10(-3) ), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P = 6.8 × 10(-12) ) and PLAT (P = 0.015), but also detected single-point associations of one SNP in PDE4A (P = 0.0068) and two SNPs in PLAT (P = 0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population.
Tinsley, Heather N.; Gary, Bernard D.; Thaiparambil, Jose; Li, Nan; Lu, Wenyan; Li, Yonghe; Maxuitenko, Yulia Y.; Keeton, Adam B.; Piazza, Gary A.
2010-01-01
In experimental studies, nonsteroidal anti-inflammatory drugs (NSAIDs) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here we show that the NSAID, sulindac sulfide (SS) inhibits cGMP phosphodiesterase (PDE) activity in colon tumor cell lysates at concentrations that inhibit colon tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit colon tumor cell growth, while no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cAMP hydrolysis, SS inhibited the cGMP specific PDE5 isozyme and increased cGMP levels in colon tumor cells. Of numerous PDE isozyme specific inhibitors evaluated, only the PDE5 selective inhibitor MY5445 inhibited colon tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in colon tumor cell lines as well as in colon adenomas and adenocarcinomas compared to normal colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs. PMID:20876730
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.
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.
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.
Silva, Adauto Carvalho; Toffoletto, Odaly; Lucio, Luiz Antonio Galvão; Santos, Paula Ferreira Dos; Afiune, Jorge Barros; Massud Filho, João; Tufik, Sergio
2010-02-01
Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74% when drug intake was associated with alcohol. These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.
Boundary Control of Linear Uncertain 1-D Parabolic PDE Using Approximate Dynamic Programming.
Talaei, Behzad; Jagannathan, Sarangapani; Singler, John
2017-03-02
This paper develops a near optimal boundary control method for distributed parameter systems governed by uncertain linear 1-D parabolic partial differential equations (PDE) by using approximate dynamic programming. A quadratic surface integral is proposed to express the optimal cost functional for the infinite-dimensional state space. Accordingly, the Hamilton-Jacobi-Bellman (HJB) equation is formulated in the infinite-dimensional domain without using any model reduction. Subsequently, a neural network identifier is developed to estimate the unknown spatially varying coefficient in PDE dynamics. Novel tuning law is proposed to guarantee the boundedness of identifier approximation error in the PDE domain. A radial basis network (RBN) is subsequently proposed to generate an approximate solution for the optimal surface kernel function online. The tuning law for near optimal RBN weights is created, such that the HJB equation error is minimized while the dynamics are identified and closed-loop system remains stable. Ultimate boundedness (UB) of the closed-loop system is verified by using the Lyapunov theory. The performance of the proposed controller is successfully confirmed by simulation on an unstable diffusion-reaction process.
Low-complexity PDE-based approach for automatic microarray image processing.
Belean, Bogdan; Terebes, Romulus; Bot, Adrian
2015-02-01
Microarray image processing is known as a valuable tool for gene expression estimation, a crucial step in understanding biological processes within living organisms. Automation and reliability are open subjects in microarray image processing, where grid alignment and spot segmentation are essential processes that can influence the quality of gene expression information. The paper proposes a novel partial differential equation (PDE)-based approach for fully automatic grid alignment in case of microarray images. Our approach can handle image distortions and performs grid alignment using the vertical and horizontal luminance function profiles. These profiles are evolved using a hyperbolic shock filter PDE and then refined using the autocorrelation function. The results are compared with the ones delivered by state-of-the-art approaches for grid alignment in terms of accuracy and computational complexity. Using the same PDE formalism and curve fitting, automatic spot segmentation is achieved and visual results are presented. Considering microarray images with different spots layouts, reliable results in terms of accuracy and reduced computational complexity are achieved, compared with existing software platforms and state-of-the-art methods for microarray image processing.
Sheppard, Catherine L; Lee, Louisa C Y; Hill, Elaine V; Henderson, David J P; Anthony, Diana F; Houslay, Daniel M; Yalla, Krishna C; Cairns, Lynne S; Dunlop, Allan J; Baillie, George S; Huston, Elaine; Houslay, Miles D
2014-09-01
In Rat-1 cells, the dramatic decrease in the levels of both intracellular cyclic 3'5' adenosine monophosphate (cyclic AMP; cAMP) and in the activity of cAMP-activated protein kinase A (PKA) observed in mitosis was paralleled by a profound increase in cAMP hydrolyzing phosphodiesterase-4 (PDE4) activity. The decrease in PKA activity, which occurs during mitosis, was attributable to PDE4 activation as the PDE4 selective inhibitor, rolipram, but not the phosphodiesterase-3 (PDE3) inhibitor, cilostamide, specifically ablated this cell cycle-dependent effect. PDE4 inhibition caused Rat-1 cells to move from S phase into G2/M more rapidly, to transit through G2/M more quickly and to remain in G1 for a longer period. Inhibition of PDE3 elicited no observable effects on cell cycle dynamics. Selective immunopurification of each of the four PDE4 sub-families identified PDE4D as being selectively activated in mitosis. Subsequent analysis uncovered PDE4D9, an isoform whose expression can be regulated by Disrupted-In-Schizophrenia 1 (DISC1)/activating transcription factor 4 (ATF4) complex, as the sole PDE4 species activated during mitosis in Rat-1 cells. PDE4D9 becomes activated in mitosis through dual phosphorylation at Ser585 and Ser245, involving the combined action of ERK and an unidentified 'switch' kinase that has previously been shown to be activated by H2O2. Additionally, in mitosis, PDE4D9 also becomes phosphorylated at Ser67 and Ser81, through the action of MK2 (MAPKAPK2) and AMP kinase (AMPK), respectively. The multisite phosphorylation of PDE4D9 by all four of these protein kinases leads to decreased mobility (band-shift) of PDE4D9 on SDS-PAGE. PDE4D9 is predominantly concentrated in the perinuclear region of Rat-1 cells but with a fraction distributed asymmetrically at the cell margins. Our investigations demonstrate that the diminished levels of cAMP and PKA activity that characterise mitosis are due to enhanced cAMP degradation by PDE4D9. PDE4D9, was found to
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
Zoraghi, Roya; Seebeck, Thomas
2002-01-01
Chemotherapy of human sleeping sickness, a fatal disease caused by the protozoan parasite Trypanosoma brucei, is in a dismal state, and the identification and characterization of new drug targets is an urgent prerequisite for an improvement of the dramatic situation in the field. Over the last several years, inhibitors of cyclic nucleotide-specific phosphodiesterases have proven to be highly successful drug candidates for an assortment of clinical conditions. Their potential as antiparasitic drugs has not been explored so far. This study reports the characterization of a cAMP-specific phosphodiesterase from T. brucei, TbPDE2C. This enzyme is a class I phosphodiesterase, and it is a member of a small enzyme family in T. brucei, TbPDE2. Inhibitors of this enzyme block the proliferation of bloodstream form trypanosomes in culture. RNA interference experiments demonstrated that the TbPDE2 family, and in particular TbPDE2C, are essential for maintaining intracellular cAMP concentrations within a physiological range. Bloodstream form trypanosomes are exquisitely sensitive to elevated concentrations of intracellular cAMP, and a disruption of TbPDE2C function quickly leads to the disruption of nuclear and cellular cell division, and to cell death. TbPDE2C might represent a novel drug target for the development of new and effective trypanocidal drugs. PMID:11930001
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.
Multiscale molecular dynamics using the matched interface and boundary method
Geng Weihua; Wei, G.W.
2011-01-20
The Poisson-Boltzmann (PB) equation is an established multiscale model for electrostatic analysis of biomolecules and other dielectric systems. PB based molecular dynamics (MD) approach has a potential to tackle large biological systems. Obstacles that hinder the current development of PB based MD methods are concerns in accuracy, stability, efficiency and reliability. The presence of complex solvent-solute interface, geometric singularities and charge singularities leads to challenges in the numerical solution of the PB equation and electrostatic force evaluation in PB based MD methods. Recently, the matched interface and boundary (MIB) method has been utilized to develop the first second order accurate PB solver that is numerically stable in dealing with discontinuous dielectric coefficients, complex geometric singularities and singular source charges. The present work develops the PB based MD approach using the MIB method. New formulation of electrostatic forces is derived to allow the use of sharp molecular surfaces. Accurate reaction field forces are obtained by directly differentiating the electrostatic potential. Dielectric boundary forces are evaluated at the solvent-solute interface using an accurate Cartesian-grid surface integration method. The electrostatic forces located at reentrant surfaces are appropriately assigned to related atoms. Extensive numerical tests are carried out to validate the accuracy and stability of the present electrostatic force calculation. The new PB based MD method is implemented in conjunction with the AMBER package. MIB based MD simulations of biomolecules are demonstrated via a few example systems.
Multiscale molecular dynamics using the matched interface and boundary method
Geng, Weihua; Wei, G.W.
2010-01-01
The Poisson-Boltzmann (PB) equation is an established multiscale model for electrostatic analysis of biomolecules and other dielectric systems. PB based molecular dynamics (MD) approach has a potential to tackle large biological systems. Obstacles that hinder the current development of PB based MD methods are concerns in accuracy, stability, efficiency and reliability. The presence of complex solvent-solute interface, geometric singularities and charge singularities leads to challenges in the numerical solution of the PB equation and electrostatic force evaluation in PB based MD methods. Recently, the matched interface and boundary (MIB) method has been utilized to develop the first second order accurate PB solver that is numerically stable in dealing with discontinuous dielectric coefficients, complex geometric singularities and singular source charges. The present work develops the PB based MD approach using the MIB method. New formulation of electrostatic forces is derived to allow the use of sharp molecular surfaces. Accurate reaction field forces are obtained by directly differentiating the electrostatic potential. Dielectric boundary forces are evaluated at the solvent-solute interface using an accurate Cartesian-grid surface integration method. The electrostatic forces located at reentrant surfaces are appropriately assigned to related atoms. Extensive numerical tests are carried out to validate the accuracy and stability of the present electrostatic force calculation. The new PB based MD method is implemented in conjunction with the AMBER package. MIB based MD simulations of biomolecules are demonstrated via a few example systems. PMID:21088761
Multi-Scale Modeling of Wave Attenuation by Vegetation
NASA Astrophysics Data System (ADS)
Chen, Q. J.; Zhu, L.; Chakrabarti, A.
2016-02-01
In the past decade, interest in wave attenuation by vegetation has increased considerably as coastal scientists and engineers search for sustainable solutions to mitigate the impacts of climate change and natural hazards. It is well known that vegetation in wetlands can effectively reduce the flow speed, modify turbulence structure, attenuate wave energy, and affect sediment dynamics. Restoring coastal wetlands and reducing flood risks require improved understanding and better predictive capability of wave and surge attenuation over inundated coastal landscapes with vegetation. The interactions of surface weaves and natural vegetation span over a large range of scales, from turbulence and eddies at the vegetation stem scale to wave generation in vast inundated wetlands of hundreds of square miles under hurricane conditions. The study is focused on a phase-averaged energy-based model and phase-resolving Euler and Navier-Stokes (N-S) solvers with different representations of submerged vegetation. We will present recent advances in multi-scale modeling of wave attenuation by wetland vegetation. Numerical modeling results ranging from vegetation-resolved large eddy simulation under idealized conditions to incorporating vegetation-induced drag forces into conservation laws of momentum and energy for engineering applications will be shown. Effects of vegetation flexibility, turbulence closure, and various wave theories on the prediction of wave attenuation and the choice of vegetation drag coefficients will be discussed.
Ückert, S; Oelke, M; Albrecht, K; Breitmeier, D; Kuczyk, M A; Hedlund, P
2011-01-01
The clitoris contributes to the normal female sexual response cycle. A significance of cyclic guanosine monophosphate (GMP) has been assumed in the control of clitoral vascular smooth muscle. As only a few investigations on the physiology of the vascular and non-vascular clitoral tissue have been carried out, knowledge on the mechanisms controlling this particular female genital organ is still vague. It has been suggested that human clitoral corpus cavernosum smooth muscle is regulated by nitric oxide (NO)/cyclic GMP and related key enzymes, such as NO synthases (NOSs) and the phosphodiesterase type 5 (PDE5). The present study evaluated in the human clitoris, by means of immunohistochemistry, the expression and distribution of key enzymes of the cyclic GMP pathway, such as the endothelial NOS, PDE2, PDE11 and cyclic GMP-dependent protein kinase type I (cGKI) in relation to the PDE5. Immunohistochemistry revealed the presence of PDE2, PDE5 and cGKI in the smooth muscle wall of blood vessels transversing the supepithelial and stromal space. Immunosignals specific for PDE2 were also identified in interstitial-like cells located in the basal epithelial layer. Staining for PDE11A was observed in single nerve trunks located in the clitoral stroma. The results are in favor of a role of the cyclic GMP signaling in the control of clitoral blood flow. It seems likely that PDE2 and PDE11 are also involved in the mechanism of local (neuro)transmission in the clitoris.
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
Differential geometry based multiscale models.
Wei, Guo-Wei
2010-08-01
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 atomistic 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 are
Synergistic interactions between PDE4B and GSK-3: DISC1 mutant mice.
Lipina, Tatiana V; Wang, Min; Liu, Fang; Roder, John C
2012-03-01
Disrupted-In-Schizophrenia-1 (DISC1) is a strong genetic risk factor associated with psychiatric disorders. Two distinct mutations in the second exon of the DISC1 gene (Q31L and L100P) lead to either depression- or schizophrenia-like behavior in mice. Both phosphodiesterase-4B (PDE4B) and glycogen synthase kinase-3 (GSK-3) have common binding sites on N-terminal region of DISC1 and are implicated into etiology of schizophrenia and depression. It is not known if PDE4B and GSK-3 could converge signals in the cell via DISC1 at the same time. The purpose of the present study was to assess whether rolipram (PDE4 inhibitor) might synergize with TDZD-8 (GSK-3 blocker) to produce antipsychotic effects at low doses on the DISC1-L100P genetic model. Indeed, combined treatment of DISC1-L100P mice with rolipram (0.1 mg/kg) and TDZD-8 (2.5 mg/kg) in sub-threshold doses corrected their Pre-Pulse Inhibition (PPI) deficit and hyperactivity, without any side effects at these doses. We have suggested that rolipram-induced increase of cAMP level might influence GSK-3 function and, hence the efficacy of TDZD-8. Our second goal was to estimate how DISC1-Q31L with reduced PDE4B activity, and therefore mimicking rolipram-induced conditions, could alter pharmacological response to TDZD-8, GSK-3 activity and its interaction with DISC1. DISC1-Q31L mutants showed increased sensitivity to GSK-3 inhibitor compare to DISC1-L100P mice. TDZD-8 (2.5 mg/kg) was able to correct PPI deficit, reduce immobility in the forced swim test (FST) and increased social motivation/novelty. In parallel, biochemical analysis revealed significantly reduced binding of GSK-3 to the mutated DISC1-Q31L and increased enzymatic activity of GSK-3. Taken together, genetic variations in DISC1 influence formation of biochemical complex with PDE4 and GSK-3 and strength the possibility of synergistic interactions between these proteins.
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
Acoustic Target Classification Using Multiscale Methods
1998-01-01
other vehicular activities well; because it represents dominant spectral peaks better than a short time Fourier transform. In the wavelet transform based...approach; multiscale features are obtained with a wavelet transform . Multiscale classification methods were applied to acoustic data collected at...This study considers the classification of acoustic signatures using features extracted at multiple scales from hierarchical models and a wavelet
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
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.
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 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.
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.
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.
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.
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.
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.
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.
A 3-D upwind Euler solver for unstructured meshes
NASA Technical Reports Server (NTRS)
Barth, Timothy J.
1991-01-01
A three-dimensional finite-volume upwind Euler solver is developed for unstructured meshes. The finite-volume scheme solves for solution variables at vertices of the mesh and satisfies the integral conservation law on nonoverlapping polyhedral control volumes surrounding vertices of the mesh. The schene achieves improved solution accuracy by assuming a piecewise linear variation of the solution in each control volume. This improved spatial accuracy hinges heavily upon the calculation of the solution gradient in each control volume given pointwise values of the solution at vertices of the mesh. Several algorithms are discussed for obtaining these gradients. Details concerning implementation procedures and data structures are discussed. Sample calculations for inviscid Euler flow about isolated aircraft wings at subsonic and transonic speeds are compared with established Euler solvers as well as experiment.
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.
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.
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.
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 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.
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
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).
Direct linear programming solver in C for structural applications
NASA Astrophysics Data System (ADS)
Damkilde, L.; Hoyer, O.; Krenk, S.
1994-08-01
An optimization problem can be characterized by an object-function, which is maximized, and restrictions, which limit the variation of the variables. A subclass of optimization is Linear Programming (LP), where both the object-function and the restrictions are linear functions of the variables. The traditional solution methods for LP problems are based on the simplex method, and it is customary to allow only non-negative variables. Compared to other optimization routines the LP solvers are more robust and the optimum is reached in a finite number of steps and is not sensitive to the starting point. For structural applications many optimization problems can be linearized and solved by LP routines. However, the structural variables are not always non-negative, and this requires a reformation, where a variable x is substituted by the difference of two non-negative variables, x(sup + ) and x(sup - ). The transformation causes a doubling of the number of variables, and in a computer implementation the memory allocation doubles and for a typical problem the execution time at least doubles. This paper describes a LP solver written in C, which can handle a combination of non-negative variables and unlimited variables. The LP solver also allows restart, and this may reduce the computational costs if the solution to a similar LP problem is known a priori. The algorithm is based on the simplex method, and differs only in the logical choices. Application of the new LP solver will at the same time give both a more direct problem formulation and a more efficient program.
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.
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.
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
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.
An immersed interface vortex particle-mesh solver
NASA Astrophysics Data System (ADS)
Marichal, Yves; Chatelain, Philippe; Winckelmans, Gregoire
2014-11-01
An immersed interface-enabled vortex particle-mesh (VPM) solver is presented for the simulation of 2-D incompressible viscous flows, in the framework of external aerodynamics. Considering the simulation of free vortical flows, such as wakes and jets, vortex particle-mesh methods already provide a valuable alternative to standard CFD methods, thanks to the interesting numerical properties arising from its Lagrangian nature. Yet, accounting for solid bodies remains challenging, despite the extensive research efforts that have been made for several decades. The present immersed interface approach aims at improving the consistency and the accuracy of one very common technique (based on Lighthill's model) for the enforcement of the no-slip condition at the wall in vortex methods. Targeting a sharp treatment of the wall calls for substantial modifications at all computational levels of the VPM solver. More specifically, the solution of the underlying Poisson equation, the computation of the diffusion term and the particle-mesh interpolation are adapted accordingly and the spatial accuracy is assessed. The immersed interface VPM solver is subsequently validated on the simulation of some challenging impulsively started flows, such as the flow past a cylinder and that past an airfoil. Research Fellow (PhD student) of the F.R.S.-FNRS of Belgium.
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.
NONLINEAR MULTIGRID SOLVER EXPLOITING AMGe COARSE SPACES WITH APPROXIMATION PROPERTIES
Christensen, Max La Cour; Villa, Umberto E.; Engsig-Karup, Allan P.; Vassilevski, Panayot S.
2016-01-22
The paper introduces a nonlinear multigrid solver for mixed nite element discretizations based on the Full Approximation Scheme (FAS) and element-based Algebraic Multigrid (AMGe). The main motivation to use FAS for unstruc- tured problems is the guaranteed approximation property of the AMGe coarse spaces that were developed recently at Lawrence Livermore National Laboratory. These give the ability to derive stable and accurate coarse nonlinear discretization problems. The previous attempts (including ones with the original AMGe method, [5, 11]), were less successful due to lack of such good approximation properties of the coarse spaces. With coarse spaces with approximation properties, our FAS approach on un- structured meshes should be as powerful/successful as FAS on geometrically re ned meshes. For comparison, Newton's method and Picard iterations with an inner state-of-the-art linear solver is compared to FAS on a nonlinear saddle point problem with applications to porous media ow. It is demonstrated that FAS is faster than Newton's method and Picard iterations for the experiments considered here. Due to the guaranteed approximation properties of our AMGe, the coarse spaces are very accurate, providing a solver with the potential for mesh-independent convergence on general unstructured meshes.
Error control of iterative linear solvers for integrated groundwater models.
Dixon, Matthew F; Bai, Zhaojun; Brush, Charles F; Chung, Francis I; Dogrul, Emin C; Kadir, Tariq N
2011-01-01
An open problem that arises when using modern iterative linear solvers, such as the preconditioned conjugate gradient method or Generalized Minimum RESidual (GMRES) method, is how to choose the residual tolerance in the linear solver to be consistent with the tolerance on the solution error. This problem is especially acute for integrated groundwater models, which are implicitly coupled to another model, such as surface water models, and resolve both multiple scales of flow and temporal interaction terms, giving rise to linear systems with variable scaling. This article uses the theory of "forward error bound estimation" to explain the correspondence between the residual error in the preconditioned linear system and the solution error. Using examples of linear systems from models developed by the US Geological Survey and the California State Department of Water Resources, we observe that this error bound guides the choice of a practical measure for controlling the error in linear systems. We implemented a preconditioned GMRES algorithm and benchmarked it against the Successive Over-Relaxation (SOR) method, the most widely known iterative solver for nonsymmetric coefficient matrices. With forward error control, GMRES can easily replace the SOR method in legacy groundwater modeling packages, resulting in the overall simulation speedups as large as 7.74×. This research is expected to broadly impact groundwater modelers through the demonstration of a practical and general approach for setting the residual tolerance in line with the solution error tolerance and presentation of GMRES performance benchmarking results.
QED multi-dimensional vacuum polarization finite-difference solver
NASA Astrophysics Data System (ADS)
Carneiro, Pedro; Grismayer, Thomas; Silva, Luís; Fonseca, Ricardo
2015-11-01
The Extreme Light Infrastructure (ELI) is expected to deliver peak intensities of 1023 - 1024 W/cm2 allowing to probe nonlinear Quantum Electrodynamics (QED) phenomena in an unprecedented regime. Within the framework of QED, the second order process of photon-photon scattering leads to a set of extended Maxwell's equations [W. Heisenberg and H. Euler, Z. Physik 98, 714] effectively creating nonlinear polarization and magnetization terms that account for the nonlinear response of the vacuum. To model this in a self-consistent way, we present a multi dimensional generalized Maxwell equation finite difference solver with significantly enhanced dispersive properties, which was implemented in the OSIRIS particle-in-cell code [R.A. Fonseca et al. LNCS 2331, pp. 342-351, 2002]. We present a detailed numerical analysis of this electromagnetic solver. As an illustration of the properties of the solver, we explore several examples in extreme conditions. We confirm the theoretical prediction of vacuum birefringence of a pulse propagating in the presence of an intense static background field [arXiv:1301.4918 [quant-ph
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.
Non-linear curve fitting using Microsoft Excel solver.
Walsh, S; Diamond, D
1995-04-01
Solver, an analysis tool incorporated into Microsoft Excel V 5.0 for Windows, has been evaluated for solving non-linear equations. Test and experimental data sets have been processed, and the results suggest that solver can be successfully used for modelling data obtained in many analytical situations (e.g. chromatography and FIA peaks, fluorescence decays and ISE response characteristics). The relatively simple user interface, and the fact that Excel is commonly bundled free with new PCs makes it an ideal tool for those wishing to experiment with solving non-linear equations without having to purchase and learn a completely new package. The dynamic display of the iterative search process enables the user to monitor location of the optimum solution by the search algorithm. This, together with the almost universal availability of Excel, makes solver an ideal vehicle for teaching the principles of iterative non-linear curve fitting techniques. In addition, complete control of the modelling process lies with the user, who must present the raw data and enter the equation of the model, in contrast to many commercial packages bundled with instruments which perform these operations with a 'black-box' approach.
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
PDE2 at the crossway between cAMP and cGMP signalling in the heart.
Weber, Silvio; Zeller, Miriam; Guan, Kaomei; Wunder, Frank; Wagner, Michael; El-Armouche, Ali
2017-10-01
The cyclic nucleotides cAMP and cGMP are central second messengers in cardiac cells and critical regulators of cardiac physiology as well as pathophysiology. Consequently, subcellular compartmentalization allows for spatiotemporal control of cAMP/cGMP metabolism and subsequent regulation of their respective effector kinases PKA or PKG is most important for cardiac function in health and disease. While acute cAMP-mediated signalling is a mandatory prerequisite for the physiological fight-or-flight response, sustained activation of this pathway may lead to the progression of heart failure. In contrast, acute as well as sustained cGMP-mediated signalling can foster beneficial features, e.g. anti-hypertrophic and vasodilatory effects. These two signalling pathways seem to be intuitively counteracting and there is increasing evidence for a functionally relevant crosstalk between cAMP and cGMP signalling pathways on the level of cyclic nucleotide hydrolysing phosphodiesterases (PDEs). Among this diverse group of enzymes, PDE2 may fulfill a unique integrator role. Equipped with dual substrate specificity for cAMP as well as for cGMP, it is the only cAMP hydrolysing PDE, which is allosterically activated by cGMP. Recent studies have revealed strongly remodelled cAMP/cGMP microdomains and subcellular concentration profiles in different cardiac pathologies, leading to a putatively enhanced involvement of PDE2 in cAMP/cGMP breakdown and crosstalk compared to the other cardiac PDEs. This review sums up the current knowledge about molecular properties and regulation of PDE2 and explains the complex signalling network encompassing PDE2 in order to better understand the functional role of PDE2 in distinct cell types in cardiac health and disease. Moreover, this review gives an outlook in which way PDE2 may serve as a therapeutic target to treat cardiac disease. Copyright © 2017 Elsevier Inc. All rights reserved.
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
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.
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.
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.
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. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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
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
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
Amin, Sk Abdul; Bhargava, Sonam; Adhikari, Nilanjan; Gayen, Shovanlal; Jha, Tarun
2017-02-13
Phosphodiesterase 1 (PDE1) is a potential target for a number of neurodegenerative disorders such as Schizophrenia, Parkinson's and Alzheimer's diseases. A number of pyrazolo[3,4-d]pyrimidine PDE1 inhibitors were subjected to different molecular modelling techniques [such as regression-based quantitative structure-activity relationship (QSAR): multiple linear regression, support vector machine and artificial neural network; classification-based QSAR: Bayesian modelling and Recursive partitioning; Monte Carlo based QSAR; Open3DQSAR; pharmacophore mapping and molecular docking analyses] to get a detailed knowledge about the physicochemical and structural requirements for higher inhibitory activity. The planarity of the pyrimidinone ring plays an important role for PDE1 inhibition. The N-methylated function at the 5th position of the pyrazolo[3,4-d]pyrimidine core is required for interacting with the PDE1 enzyme. The cyclopentyl ring fused with the parent scaffold is necessary for PDE1 binding potency. The phenylamino substitution at 3rd position is crucial for PDE1 inhibition. The N2-substitution at the pyrazole moiety is important for PDE1 inhibition compared to the N1-substituted analogues. Moreover, the p-substituted benzyl side chain at N2-position helps to enhance the PDE1 inhibitory profile. Depending on these observations, some new molecules are predicted that may possess better PDE1 inhibition.
Begum, Najma; Shen, Weixing; Manganiello, Vincent
2011-12-01
Phosphodiesterase-3 (PDE3) is a major cAMP-hydrolyzing PDE in vascular smooth muscle cells (VSMCs) and oocytes. The exact role and contribution of the two PDE3 isoforms, PDE3A and PDE3B, in VSMC growth regulation and oocyte maturation was examined using PDE3A (3A) and PDE3B (3B) knockout (KO) mouse models. PDE3A-deficient VSMCs exhibit marked reduction in mitogen-induced cell growth due to cell cycle arrest at G₀-G₁ phase, which resulted from dysregulation of cAMP/protein kinase A (PKA)-activated and mitogen-activated protein kinase (MAPK)-signaling pathways, as well as from alterations in key cell cycle regulatory proteins. Similarly, PDE3A-deficient oocytes exhibit cell cycle arrest at G₂/M phase because increased cAMP/PKA signaling in KO oocytes most likely inhibits Cdc25B-catalyzed dephosphorylation/activation of Cdc2 (maturation promoting factor (MPF)), a key regulator of G₂/M transition. Copyright © 2011 Elsevier Ltd. All rights reserved.
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.
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.
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. Copyright © 2013 Elsevier B.V. All rights reserved.
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
Piccart, Elisabeth; De Backer, Jean-François; Gall, David; Lambot, Laurie; Raes, Adam; Vanhoof, Greet; Schiffmann, Serge; D'Hooge, Rudi
2014-07-15
The striatum is the main input structure to the basal ganglia and consists mainly out of medium spiny neurons. The numerous spines on their dendrites render them capable of integrating cortical glutamatergic inputs with a motivational dopaminergic signal that originates in the midbrain. This integrative function is thought to underly attribution of incentive salience, a process that is severely disrupted in schizophrenic patients. Phosphodiesterase 10A (PDE10A) is located mainly to the striatal medium spiny neurons and hydrolyses cAMP and cGMP, key determinants of MSN signaling. We show here that genetic depletion of PDE10A critically mediates attribution of salience to reward-predicting cues, evident in impaired performance in PDE10A knockout mice in an instrumentally conditioned reinforcement task. We furthermore report modest impairment of latent inhibition in PDE10A knockout mice, and unaltered prepulse inhibition. We suggest that the lack of effect on PPI is due to the pre-attentional nature of this task. Finally, we performed whole-cell patch clamp recordings and confirm suggested changes in intrinsic membrane excitability. A decrease in spontaneous firing in striatal medium spiny neurons was found. These data show that PDE10A plays a pivotal role in striatal signaling and striatum-mediated salience attribution.
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
A Fast PDE Algorithm Using Adaptive Scan and Search for Video Coding
NASA Astrophysics Data System (ADS)
Kim, Jong-Nam
In this paper, we propose an algorithm that reduces unnecessary computations, while keeping the same prediction quality as that of the full search algorithm. In the proposed algorithm, we can reduce unnecessary computations efficiently by calculating initial matching error point from first 1/N partial errors. We can increase the probability that hits minimum error point as soon as possible. Our algorithm decreases the computational amount by about 20% of the conventional PDE algorithm without any degradation of prediction quality. Our algorithm would be useful in real-time video coding applications using MPEG-2/4 AVC standards.
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.
PDE Based Unsharp Masking, Crispening and High Boost Filtering of Digital Images
NASA Astrophysics Data System (ADS)
Srivastava, Rajeev; Gupta, J. R. P.; Parthasarthy, Harish; Srivastava, Subodh
A partial differential equation (PDE) based technique is proposed and implemented to perform unsharp masking, crispening and high boost filtering of digital images. The traditional concept of unsharp masking and crispening of edges which uses Laplacian as intermediate step for smoothening the image has been extended and modified using the idea of Perona and Malik [1] which overcomes the disadvantages of Laplacian method. For descretization, finite differences scheme has been used. The scheme has been implemented using MATLAB 7.0 and performance is tested for various gray images of different resolutions and the obtained results justify the applicability of proposed scheme.
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.
Fast solvers for optimal control problems from pattern formation
NASA Astrophysics Data System (ADS)
Stoll, Martin; Pearson, John W.; Maini, Philip K.
2016-01-01
The modeling of pattern formation in biological systems using various models of reaction-diffusion type has been an active research topic for many years. We here look at a parameter identification (or PDE-constrained optimization) problem where the Schnakenberg and Gierer-Meinhardt equations, two well-known pattern formation models, form the constraints to an objective function. Our main focus is on the efficient solution of the associated nonlinear programming problems via a Lagrange-Newton scheme. In particular we focus on the fast and robust solution of the resulting large linear systems, which are of saddle point form. We illustrate this by considering several two- and three-dimensional setups for both models. Additionally, we discuss an image-driven formulation that allows us to identify parameters of the model to match an observed quantity obtained from an image.
Numerical solution of multiscale electromagnetic systems
NASA Astrophysics Data System (ADS)
Tobon Llano, Luis Eduardo
The Discontinuous Galerkin time domain (DGTD) method is promising in modeling of realistic multiscale electromagnetic systems. This method defines the basic concept for implementing the communication between multiple domains with different scales. Constructing a DGTD system consists of several careful choices: (a) governing equations; (b) element shape and corresponding basis functions for the spatial discretization of each subdomain; (c) numerical fluxes onto interfaces to bond all subdomains together; and (d) time stepping scheme based on properties of a discretized system. This work present the advances in each one of these steps. First, a unified framework based on the theory of differential forms and the finite element method is used to analyze the discretization of the Maxwell's equations. Based on this study, field intensities (E and H) are associated to 1-forms and curl-conforming basis functions; flux densities (D and B) are associated to 2-forms and divergence-conforming basis functions; and the constitutive relations are defined by Hodge operators. A different approach is the study of numerical dispersion. Semidiscrete analysis is the traditional method, but for high order elements modal analysis is prefered. From these analyses, we conclude that a correct discretization of fields belonging to different p-form (e.g., E and B ) uses basis functions with same order of interpolation; however, different order of interpolation must be used if two fields belong to the same p-form (e.g., E and H). An alternative method to evaluate numerical dispersion based on evaluation of dispersive Hodge operators is also presented. Both dispersion analyses are equivalent and reveal same fundamental results. Eigenvalues, eigenvector and transient results are studied to verify accuracy and computational costs of different schemes. Two different approaches are used for implementing the DG Method. The first is based on E and H fields, which use curl-conforming basis functions
Multiscale gas-kinetic simulation for continuum and near-continuum flows.
Xu, Kun; Liu, Hongwei
2007-01-01
It is well known that for increasingly rarefied flow fields, predictions from continuum formulations, such as the Navier-Stokes equations, lose accuracy. The inclusion of higher-order terms, such as Burnett or high-order moment equations, could improve the predictive capabilities of such continuum formulations, but there has been only limited success. Here, we present a multiscale model. On the macroscopic level, the flow variables are updated based on the mass, momentum, and energy conservation through the fluxes. On the other hand, the fluxes are constructed on the microscopic level based on the gas-kinetic equation, which is valid in both continuum and near-continuum flow regimes. Based on this model, the nonequilibrium shock structure, Poiseuille flow, nonlinear heat conduction problems, and unsteady Rayleigh problem will be studied. In the near-continuum flow regime, the current gas-kinetic simulation is more efficient than microscopic methods, such as the direction Boltzmann solver and direct-simulation Monte Carlo method. In the continuum flow limit, the current formulation will go back to the gas-kinetic Navier-Stokes flow solver automatically.
Pentia, Dana C.; Hosier, Suzanne; Cote, Rick H.
2010-01-01
The glutamic acid-rich protein-2 (GARP2) is a splice variant of the β-subunit of the cGMP-gated ion channel of rod photoreceptors. GARP2 is believed to interact with several membrane-associated phototransduction proteins in rod photoreceptors. In this study, we demonstrated that GARP2 is a high affinity PDE6-binding protein and that PDE6 co-purifies with GARP2 during several stages of chromatographic purification. We found that hydrophobic interaction chromatography succeeds in quantitatively separating GARP2 from the PDE6 holoenzyme. Furthermore, the 17-kDa prenyl-binding protein, abundant in retinal cells, selectively released PDE6 (but not GARP2) from rod outer segment membranes, demonstrating the specificity of the interaction between GARP2 and PDE6. Purified GARP2 was able to suppress 80% of the basal activity of the nonactivated, membrane-bound PDE6 holoenzyme at concentrations equivalent to its endogenous concentration in rod outer segment membranes. However, GARP2 was unable to reverse the transducin activation of PDE6 (in contrast to a previous study) nor did it significantly alter catalysis of the fully activated PDE6 catalytic dimer. The high binding affinity of GARP2 for PDE6 and its ability to regulate PDE6 activity in its dark-adapted state suggest a novel role for GARP2 as a regulator of spontaneous activation of rod PDE6, thereby serving to lower rod photoreceptor “dark noise” and allowing these sensory cells to operate at the single photon detection limit. PMID:16407240
A Robust Compressible Flow Solver for Studies on Solar Fuel Production in Microwave Plasma
NASA Astrophysics Data System (ADS)
Tadayon Mousavi, Samaneh; Koelman, Peter; Groen, Pieter Willem; van Dijk, Jan; Epg/ Applied Physics/ Eindhoven University Of Technology Team; Dutch InstituteFundamental Energy Research (Differ) Team
2016-09-01
n order to simulate the dissociation of CO2 with H2O admixture by microwave plasma for the production of solar fuels, we need a multicomponent solver that is able to capture the complex nature of the plasma by combining the chemistry, flow, and electromagnetic field. To achieve this goal, first we developed a robust finite volume compressible flow solver in C++. The solver is implemented in the framework of the PLASIMO software and will be used in complete plasma simulations later on. Due to the compressible nature of the solver, it can be used for simulation of dissociation of CO2 with H2O admixture by supersonic expansion in microwave plasmas. A spatially second order version of this solver is able to reveal the vortex flow structure of the plasmas. Capabilities of this solver are presented by benchmarking against well-established analytical and numerical test cases.
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.
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.