Efficient Implementation of Multigrid Solvers on Message-Passing Parrallel Systems

NASA Technical Reports Server (NTRS)

Lou, John

1994-01-01

We discuss our implementation strategies for finite difference multigrid partial differential equation (PDE) solvers on message-passing systems. Our target parallel architecture is Intel parallel computers: the Delta and Paragon system.

High Performance Radiation Transport Simulations on TITAN

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

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

2012-01-01

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

Parameter Estimation of Partial Differential Equation Models.

PubMed

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

2013-01-01

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

Program Code Generator for Cardiac Electrophysiology Simulation with Automatic PDE Boundary Condition Handling

PubMed Central

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 generate code for physiological simulations and provides a tool for studying cardiac electrophysiology. PMID:26356082

Fourth-order partial differential equation noise removal on welding images

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

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

2015-10-22

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

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

PubMed

Richter, Wito; Conti, Marco

2004-07-16

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

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.

Extreme-Scale Bayesian Inference for Uncertainty Quantification of Complex Simulations

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

Biros, George

Uncertainty quantification (UQ)—that is, quantifying uncertainties in complex mathematical models and their large-scale computational implementations—is widely viewed as one of the outstanding challenges facing the field of CS&E over the coming decade. The EUREKA project set to address the most difficult class of UQ problems: those for which both the underlying PDE model as well as the uncertain parameters are of extreme scale. In the project we worked on these extreme-scale challenges in the following four areas: 1. Scalable parallel algorithms for sampling and characterizing the posterior distribution that exploit the structure of the underlying PDEs and parameter-to-observable map. Thesemore » include structure-exploiting versions of the randomized maximum likelihood method, which aims to overcome the intractability of employing conventional MCMC methods for solving extreme-scale Bayesian inversion problems by appealing to and adapting ideas from large-scale PDE-constrained optimization, which have been very successful at exploring high-dimensional spaces. 2. Scalable parallel algorithms for construction of prior and likelihood functions based on learning methods and non-parametric density estimation. Constructing problem-specific priors remains a critical challenge in Bayesian inference, and more so in high dimensions. Another challenge is construction of likelihood functions that capture unmodeled couplings between observations and parameters. We will create parallel algorithms for non-parametric density estimation using high dimensional N-body methods and combine them with supervised learning techniques for the construction of priors and likelihood functions. 3. Bayesian inadequacy models, which augment physics models with stochastic models that represent their imperfections. The success of the Bayesian inference framework depends on the ability to represent the uncertainty due to imperfections of the mathematical model of the phenomena of interest. This is a central challenge in UQ, especially for large-scale models. We propose to develop the mathematical tools to address these challenges in the context of extreme-scale problems. 4. Parallel scalable algorithms for Bayesian optimal experimental design (OED). Bayesian inversion yields quantified uncertainties in the model parameters, which can be propagated forward through the model to yield uncertainty in outputs of interest. This opens the way for designing new experiments to reduce the uncertainties in the model parameters and model predictions. Such experimental design problems have been intractable for large-scale problems using conventional methods; we will create OED algorithms that exploit the structure of the PDE model and the parameter-to-output map to overcome these challenges. Parallel algorithms for these four problems were created, analyzed, prototyped, implemented, tuned, and scaled up for leading-edge supercomputers, including UT-Austin’s own 10 petaflops Stampede system, ANL’s Mira system, and ORNL’s Titan system. While our focus is on fundamental mathematical/computational methods and algorithms, we will assess our methods on model problems derived from several DOE mission applications, including multiscale mechanics and ice sheet dynamics.« less

Ab Initio QM/MM Study Shows a Highly Dissociated SN2 Hydrolysis Mechanism for the cGMP-Specific Phosphodiesterase-5.

PubMed

Li, Zhe; Wu, Yinuo; Feng, Ling-Jun; Wu, Ruibo; Luo, Hai-Bin

2014-12-09

Phosphodiesterases (PDEs) are the sole enzymes hydrolyzing the important second messengers cGMP and cAMP and have been identified as therapeutic targets for several diseases. The most successful examples are PDE5 inhibitors (i.e., sildenafil and tadalafil), which have been approved for the treatment of male erectile dysfunction and pulmonary hypertension. However, the side effects mostly due to nonselective inhibition toward other PDE isoforms, set back the clinical usage of PDE5 inhibitors. Until now, the exact catalytic mechanism of the substrate cGMP by PDE5 is still unclear. Herein, the first computational study on the catalytic hydrolysis mechanism of cGMP for PDE5 (catalytic domain) is performed by employing the state-of-the-art ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. Our simulations show a SN2 type reaction procedure via a highly dissociated transition state with a reaction barrier of 8.88 kcal/mol, which is quite different from the previously suggested hydrolysis mechanism of cAMP for PDE4. Furthermore, the subsequent ligand exchange and the release of the product GMP have also been investigated by binding energy analysis and MD simulations. It is deduced that ligand exchange would be the rate-determining step of the whole reaction, which is consistent with many previous experimental results. The obtained mechanistic insights should be valuable for not only the rational design of more specific inhibitors toward PDE5 but also understanding the general hydrolysis mechanism of cGMP-specific PDEs.

Parallels between control PDE's (Partial Differential Equations) and systems of ODE's (Ordinary Differential Equations)

NASA Technical Reports Server (NTRS)

Hunt, L. R.; Villarreal, Ramiro

1987-01-01

System theorists understand that the same mathematical objects which determine controllability for nonlinear control systems of ordinary differential equations (ODEs) also determine hypoellipticity for linear partial differentail equations (PDEs). Moreover, almost any study of ODE systems begins with linear systems. It is remarkable that Hormander's paper on hypoellipticity of second order linear p.d.e.'s starts with equations due to Kolmogorov, which are shown to be analogous to the linear PDEs. Eigenvalue placement by state feedback for a controllable linear system can be paralleled for a Kolmogorov equation if an appropriate type of feedback is introduced. Results concerning transformations of nonlinear systems to linear systems are similar to results for transforming a linear PDE to a Kolmogorov equation.

Quantitative Analysis of Hepatitis C NS5A Viral Protein Dynamics on the ER Surface.

PubMed

Knodel, Markus M; Nägel, Arne; Reiter, Sebastian; Vogel, Andreas; Targett-Adams, Paul; McLauchlan, John; Herrmann, Eva; Wittum, Gabriel

2018-01-08

Exploring biophysical properties of virus-encoded components and their requirement for virus replication is an exciting new area of interdisciplinary virological research. To date, spatial resolution has only rarely been analyzed in computational/biophysical descriptions of virus replication dynamics. However, it is widely acknowledged that intracellular spatial dependence is a crucial component of virus life cycles. The hepatitis C virus-encoded NS5A protein is an endoplasmatic reticulum (ER)-anchored viral protein and an essential component of the virus replication machinery. Therefore, we simulate NS5A dynamics on realistic reconstructed, curved ER surfaces by means of surface partial differential equations (sPDE) upon unstructured grids. We match the in silico NS5A diffusion constant such that the NS5A sPDE simulation data reproduce experimental NS5A fluorescence recovery after photobleaching (FRAP) time series data. This parameter estimation yields the NS5A diffusion constant. Such parameters are needed for spatial models of HCV dynamics, which we are developing in parallel but remain qualitative at this stage. Thus, our present study likely provides the first quantitative biophysical description of the movement of a viral component. Our spatio-temporal resolved ansatz paves new ways for understanding intricate spatial-defined processes central to specfic aspects of virus life cycles.

Quantitative Analysis of Hepatitis C NS5A Viral Protein Dynamics on the ER Surface

PubMed Central

Nägel, Arne; Reiter, Sebastian; Vogel, Andreas; McLauchlan, John; Herrmann, Eva; Wittum, Gabriel

2018-01-01

Exploring biophysical properties of virus-encoded components and their requirement for virus replication is an exciting new area of interdisciplinary virological research. To date, spatial resolution has only rarely been analyzed in computational/biophysical descriptions of virus replication dynamics. However, it is widely acknowledged that intracellular spatial dependence is a crucial component of virus life cycles. The hepatitis C virus-encoded NS5A protein is an endoplasmatic reticulum (ER)-anchored viral protein and an essential component of the virus replication machinery. Therefore, we simulate NS5A dynamics on realistic reconstructed, curved ER surfaces by means of surface partial differential equations (sPDE) upon unstructured grids. We match the in silico NS5A diffusion constant such that the NS5A sPDE simulation data reproduce experimental NS5A fluorescence recovery after photobleaching (FRAP) time series data. This parameter estimation yields the NS5A diffusion constant. Such parameters are needed for spatial models of HCV dynamics, which we are developing in parallel but remain qualitative at this stage. Thus, our present study likely provides the first quantitative biophysical description of the movement of a viral component. Our spatio-temporal resolved ansatz paves new ways for understanding intricate spatial-defined processes central to specfic aspects of virus life cycles. PMID:29316722

The Programming Language Python In Earth System Simulations

NASA Astrophysics Data System (ADS)

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

2004-12-01

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

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

NASA Astrophysics Data System (ADS)

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

2015-04-01

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

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.

Domain decomposition in time for PDE-constrained optimization

DOE PAGES

Barker, Andrew T.; Stoll, Martin

2015-08-28

Here, PDE-constrained optimization problems have a wide range of applications, but they lead to very large and ill-conditioned linear systems, especially if the problems are time dependent. In this paper we outline an approach for dealing with such problems by decomposing them in time and applying an additive Schwarz preconditioner in time, so that we can take advantage of parallel computers to deal with the very large linear systems. We then illustrate the performance of our method on a variety of problems.

Xyce Parallel Electronic Simulator : users' guide, version 2.0.

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

Hoekstra, Robert John; Waters, Lon J.; Rankin, Eric Lamont

2004-06-01

This manual describes the use of the Xyce Parallel Electronic Simulator. Xyce has been designed as a SPICE-compatible, high-performance analog circuit simulator capable of simulating electrical circuits at a variety of abstraction levels. Primarily, Xyce has been written to support the simulation needs of the Sandia National Laboratories electrical designers. This development has focused on improving capability the current state-of-the-art in the following areas: {sm_bullet} Capability to solve extremely large circuit problems by supporting large-scale parallel computing platforms (up to thousands of processors). Note that this includes support for most popular parallel and serial computers. {sm_bullet} Improved performance for allmore » numerical kernels (e.g., time integrator, nonlinear and linear solvers) through state-of-the-art algorithms and novel techniques. {sm_bullet} Device models which are specifically tailored to meet Sandia's needs, including many radiation-aware devices. {sm_bullet} A client-server or multi-tiered operating model wherein the numerical kernel can operate independently of the graphical user interface (GUI). {sm_bullet} Object-oriented code design and implementation using modern coding practices that ensure that the Xyce Parallel Electronic Simulator will be maintainable and extensible far into the future. Xyce is a parallel code in the most general sense of the phrase - a message passing of computing platforms. These include serial, shared-memory and distributed-memory parallel implementation - which allows it to run efficiently on the widest possible number parallel as well as heterogeneous platforms. Careful attention has been paid to the specific nature of circuit-simulation problems to ensure that optimal parallel efficiency is achieved as the number of processors grows. One feature required by designers is the ability to add device models, many specific to the needs of Sandia, to the code. To this end, the device package in the Xyce These input formats include standard analytical models, behavioral models look-up Parallel Electronic Simulator is designed to support a variety of device model inputs. tables, and mesh-level PDE device models. Combined with this flexible interface is an architectural design that greatly simplifies the addition of circuit models. One of the most important feature of Xyce is in providing a platform for computational research and development aimed specifically at the needs of the Laboratory. With Xyce, Sandia now has an 'in-house' capability with which both new electrical (e.g., device model development) and algorithmic (e.g., faster time-integration methods) research and development can be performed. Ultimately, these capabilities are migrated to end users.« less

Inversion of potential field data using the finite element method on parallel computers

NASA Astrophysics Data System (ADS)

Gross, L.; Altinay, C.; Shaw, S.

2015-11-01

In this paper we present a formulation of the joint inversion of potential field anomaly data as an optimization problem with partial differential equation (PDE) constraints. The problem is solved using the iterative Broyden-Fletcher-Goldfarb-Shanno (BFGS) method with the Hessian operator of the regularization and cross-gradient component of the cost function as preconditioner. We will show that each iterative step requires the solution of several PDEs namely for the potential fields, for the adjoint defects and for the application of the preconditioner. In extension to the traditional discrete formulation the BFGS method is applied to continuous descriptions of the unknown physical properties in combination with an appropriate integral form of the dot product. The PDEs can easily be solved using standard conforming finite element methods (FEMs) with potentially different resolutions. For two examples we demonstrate that the number of PDE solutions required to reach a given tolerance in the BFGS iteration is controlled by weighting regularization and cross-gradient but is independent of the resolution of PDE discretization and that as a consequence the method is weakly scalable with the number of cells on parallel computers. We also show a comparison with the UBC-GIF GRAV3D code.

AZTEC: A parallel iterative package for the solving linear systems

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

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

1996-12-31

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

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

PubMed

Zhang, Han-Ting

2009-01-01

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

Output Feedback-Based Boundary Control of Uncertain Coupled Semilinear Parabolic PDE Using Neurodynamic Programming.

PubMed

Talaei, Behzad; Jagannathan, Sarangapani; Singler, John

2018-04-01

In this paper, neurodynamic programming-based output feedback boundary control of distributed parameter systems governed by uncertain coupled semilinear parabolic partial differential equations (PDEs) under Neumann or Dirichlet boundary control conditions is introduced. First, Hamilton-Jacobi-Bellman (HJB) equation is formulated in the original PDE domain and the optimal control policy is derived using the value functional as the solution of the HJB equation. Subsequently, a novel observer is developed to estimate the system states given the uncertain nonlinearity in PDE dynamics and measured outputs. Consequently, the suboptimal boundary control policy is obtained by forward-in-time estimation of the value functional using a neural network (NN)-based online approximator and estimated state vector obtained from the NN observer. Novel adaptive tuning laws in continuous time are proposed for learning the value functional online to satisfy the HJB equation along system trajectories while ensuring the closed-loop stability. Local uniformly ultimate boundedness of the closed-loop system is verified by using Lyapunov theory. The performance of the proposed controller is verified via simulation on an unstable coupled diffusion reaction process.

Phosphodiesterase Type 5 Inhibitors, Sport and Doping.

PubMed

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

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

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

NASA Astrophysics Data System (ADS)

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

2015-12-01

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

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

PubMed

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

2015-12-01

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

Pulsed Ejector Wave Propogation Test Program

NASA Technical Reports Server (NTRS)

Fernandez, Rene; Slater, John W.; Paxson, Daniel E.

2003-01-01

The development of, and initial test data from, a nondetonating Pulse Detonation Engine (PDE) simulator tested in the NASA Glenn 1 x 1 foot Supersonic Wind Tunnel (SWT) is presented in this paper. The concept is a pulsed ejector driven by the simulated exhaust of a PDE. This pro- gram is applicable to a PDE entombed in a ramjet flowpath, i.e., a PDE combined-cycle propulsion system. The ejector primary flow is a pulsed, uiiderexpanded, supersonic nozzle simulating the supersonic waves ema- nating from a PDE, while the ejector secondary flow is the 1 x 1 foot SWT test section operated at subsonic Mach numbers. The objective is not to study the detonation details, but the wave physics including t,he start- ing vortices, the extent of propagation of the wave front, the reflection of the wave from the secondary flowpath walls, and the timing of these events of a pulsed ejector, and correlate these with Computational Fluid Dynamics (CFD) code predictions. Pulsed ejectors have been shown to result in a 3 to 1 improvement in LID (length-to-diameter) and a near 2 to 1 improvement in thrust augmentation over a steady ejector. This program will also explore the extent of upstream interactions between an inlet and large, periodically applied, backpressures to the inlet as would be present due to combustion tube detonations in a PDE. These interactions could result in inlet unstart or buzz for a supersonic mixed compression inlet. The design of the present experiment entailed the use of an 2-t diagram characteristics code to study the nozzle filling and purging timescales as well as a series of CFD analyses conducted using the WIND code. The WIND code is a general purpose CFD code for solution of the Reynolds averaged Navier-Stokes equations and can be applied to both steady state and time-accurate calculations. The first, proof-of-concept, test entry (spring 2001) pressure distributions shown here indicate the simulation concept was successful and therefore the experimental approach is sound.

Pharmacophore Based Virtual Screening Approach to Identify Selective PDE4B Inhibitors

PubMed Central

Gaurav, Anand; Gautam, Vertika

2017-01-01

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

Array-based Hierarchical Mesh Generation in Parallel

DOE PAGES

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

2015-11-03

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

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

PubMed

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

2012-05-15

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

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

PubMed Central

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

2012-01-01

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

Building Blocks for Reliable Complex Nonlinear Numerical Simulations

NASA Technical Reports Server (NTRS)

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

2002-01-01

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

Building Blocks for Reliable Complex Nonlinear Numerical Simulations

NASA Technical Reports Server (NTRS)

Yee, H. C.

2005-01-01

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

Building Blocks for Reliable Complex Nonlinear Numerical Simulations. Chapter 2

NASA Technical Reports Server (NTRS)

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

2001-01-01

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

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).

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

PubMed

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

2012-02-28

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

Modeling of Multi-Tube Pulse Detonation Engine Operation

NASA Technical Reports Server (NTRS)

Ebrahimi, Houshang B.; Mohanraj, Rajendran; Merkle, Charles L.

2001-01-01

The present paper explores some preliminary issues concerning the operational characteristics of multiple-tube pulsed detonation engines (PDEs). The study is based on a two-dimensional analysis of the first-pulse operation of two detonation tubes exhausting through a common nozzle. Computations are first performed to assess isolated tube behavior followed by results for multi-tube flow phenomena. The computations are based on an eight-species, finite-rate transient flow-field model. The results serve as an important precursor to understanding appropriate propellant fill procedures and shock wave propagation in multi-tube, multi-dimensional simulations. Differences in behavior between single and multi-tube PDE models are discussed, The influence of multi-tube geometry and the preferred times for injecting the fresh propellant mixture during multi-tube PDE operation are studied.

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.

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

PubMed

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

2010-04-22

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

Simulating biochemical physics with computers: 1. Enzyme catalysis by phosphotriesterase and phosphodiesterase; 2. Integration-free path-integral method for quantum-statistical calculations

NASA Astrophysics Data System (ADS)

Wong, Kin-Yiu

We have simulated two enzymatic reactions with molecular dynamics (MD) and combined quantum mechanical/molecular mechanical (QM/MM) techniques. One reaction is the hydrolysis of the insecticide paraoxon catalyzed by phosphotriesterase (PTE). PTE is a bioremediation candidate for environments contaminated by toxic nerve gases (e.g., sarin) or pesticides. Based on the potential of mean force (PMF) and the structural changes of the active site during the catalysis, we propose a revised reaction mechanism for PTE. Another reaction is the hydrolysis of the second-messenger cyclic adenosine 3'-5'-monophosphate (cAMP) catalyzed by phosphodiesterase (PDE). Cyclicnucleotide PDE is a vital protein in signal-transduction pathways and thus a popular target for inhibition by drugs (e.g., ViagraRTM). A two-dimensional (2-D) free-energy profile has been generated showing that the catalysis by PDE proceeds in a two-step SN2-type mechanism. Furthermore, to characterize a chemical reaction mechanism in experiment, a direct probe is measuring kinetic isotope effects (KIEs). KIEs primarily arise from internuclear quantum-statistical effects, e.g., quantum tunneling and quantization of vibration. To systematically incorporate the quantum-statistical effects during MD simulations, we have developed an automated integration-free path-integral (AIF-PI) method based on Kleinert's variational perturbation theory for the centroid density of Feynman's path integral. Using this analytic method, we have performed ab initio pathintegral calculations to study the origin of KIEs on several series of proton-transfer reactions from carboxylic acids to aryl substituted alpha-methoxystyrenes in water. In addition, we also demonstrate that the AIF-PI method can be used to systematically compute the exact value of zero-point energy (beyond the harmonic approximation) by simply minimizing the centroid effective potential.

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

PubMed Central

Wong, Kin-Yiu; Gao, Jiali

2011-01-01

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

PDE-based geophysical modelling using finite elements: examples from 3D resistivity and 2D magnetotellurics

NASA Astrophysics Data System (ADS)

Schaa, R.; Gross, L.; du Plessis, J.

2016-04-01

We present a general finite-element solver, escript, tailored to solve geophysical forward and inverse modeling problems in terms of partial differential equations (PDEs) with suitable boundary conditions. Escript’s abstract interface allows geoscientists to focus on solving the actual problem without being experts in numerical modeling. General-purpose finite element solvers have found wide use especially in engineering fields and find increasing application in the geophysical disciplines as these offer a single interface to tackle different geophysical problems. These solvers are useful for data interpretation and for research, but can also be a useful tool in educational settings. This paper serves as an introduction into PDE-based modeling with escript where we demonstrate in detail how escript is used to solve two different forward modeling problems from applied geophysics (3D DC resistivity and 2D magnetotellurics). Based on these two different cases, other geophysical modeling work can easily be realized. The escript package is implemented as a Python library and allows the solution of coupled, linear or non-linear, time-dependent PDEs. Parallel execution for both shared and distributed memory architectures is supported and can be used without modifications to the scripts.

Code Samples Used for Complexity and Control

NASA Astrophysics Data System (ADS)

Ivancevic, Vladimir G.; Reid, Darryn J.

2015-11-01

The following sections are included: * MathematicaⓇ Code * Generic Chaotic Simulator * Vector Differential Operators * NLS Explorer * 2C++ Code * C++ Lambda Functions for Real Calculus * Accelerometer Data Processor * Simple Predictor-Corrector Integrator * Solving the BVP with the Shooting Method * Linear Hyperbolic PDE Solver * Linear Elliptic PDE Solver * Method of Lines for a Set of the NLS Equations * C# Code * Iterative Equation Solver * Simulated Annealing: A Function Minimum * Simple Nonlinear Dynamics * Nonlinear Pendulum Simulator * Lagrangian Dynamics Simulator * Complex-Valued Crowd Attractor Dynamics * Freeform Fortran Code * Lorenz Attractor Simulator * Complex Lorenz Attractor * Simple SGE Soliton * Complex Signal Presentation * Gaussian Wave Packet * Hermitian Matrices * Euclidean L2-Norm * Vector/Matrix Operations * Plain C-Code: Levenberg-Marquardt Optimizer * Free Basic Code: 2D Crowd Dynamics with 3000 Agents

Design and Testing of an H2/O2 Predetonator for a Simulated Rotating Detonation Engine Channel

DTIC Science & Technology

2013-03-01

Diameter PDE Pulse Detonation Engines RDE Rotating Detonation Engine WPAFB Wright Patterson Air Force Base ZND Zeldovich, von Neumann and Doring xv...DESIGN AND TESTING OF AN H2/O2 PREDETONATOR FOR A SIMULATED ROTATING DETONATION ENGINE CHANNEL THESIS Stephen J. Miller, 2Lt, USAF AFIT-ENY-13-M-23...RELEASE; DISTRIBUTION UNLIMITED AFIT-ENY-13-M-23 DESIGN AND TESTING OF AN H2/O2 PREDETONATOR FOR A SIMULATED ROTATING DETONATION ENGINE CHANNEL Stephen

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

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

Brannick, J.

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

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

NASA Astrophysics Data System (ADS)

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

2015-03-01

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

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

PubMed

Lee, Mary; Sharifi, Roohollah

2018-03-01

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

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

PubMed

Wong, Kin-Yiu; Gao, Jiali

2011-07-01

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

Boundary control for a constrained two-link rigid-flexible manipulator with prescribed performance

NASA Astrophysics Data System (ADS)

Cao, Fangfei; Liu, Jinkun

2018-05-01

In this paper, we consider a boundary control problem for a constrained two-link rigid-flexible manipulator. The nonlinear system is described by hybrid ordinary differential equation-partial differential equation (ODE-PDE) dynamic model. Based on the coupled ODE-PDE model, boundary control is proposed to regulate the joint positions and eliminate the elastic vibration simultaneously. With the help of prescribed performance functions, the tracking error can converge to an arbitrarily small residual set and the convergence rate is no less than a certain pre-specified value. Asymptotic stability of the closed-loop system is rigorously proved by the LaSalle's Invariance Principle extended to infinite-dimensional system. Numerical simulations are provided to demonstrate the effectiveness of the proposed controller.

A 3D model for rain-induced landslides based on molecular dynamics with fractal and fractional water diffusion

NASA Astrophysics Data System (ADS)

Martelloni, Gianluca; Bagnoli, Franco; Guarino, Alessio

2017-09-01

We present a three-dimensional model of rain-induced landslides, based on cohesive spherical particles. The rainwater infiltration into the soil follows either the fractional or the fractal diffusion equations. We analytically solve the fractal partial differential equation (PDE) for diffusion with particular boundary conditions to simulate a rainfall event. We developed a numerical integration scheme for the PDE, compared with the analytical solution. We adapt the fractal diffusion equation obtaining the gravimetric water content that we use as input of a triggering scheme based on Mohr-Coulomb limit-equilibrium criterion. This triggering is then complemented by a standard molecular dynamics algorithm, with an interaction force inspired by the Lennard-Jones potential, to update the positions and velocities of particles. We present our results for homogeneous and heterogeneous systems, i.e., systems composed by particles with same or different radius, respectively. Interestingly, in the heterogeneous case, we observe segregation effects due to the different volume of the particles. Finally, we analyze the parameter sensibility both for the triggering and the propagation phases. Our simulations confirm the results of a previous two-dimensional model and therefore the feasible applicability to real cases.

Parallel hyperbolic PDE simulation on clusters: Cell versus GPU

NASA Astrophysics Data System (ADS)

Rostrup, Scott; De Sterck, Hans

2010-12-01

Increasingly, high-performance computing is looking towards data-parallel computational devices to enhance computational performance. Two technologies that have received significant attention are IBM's Cell Processor and NVIDIA's CUDA programming model for graphics processing unit (GPU) computing. In this paper we investigate the acceleration of parallel hyperbolic partial differential equation simulation on structured grids with explicit time integration on clusters with Cell and GPU backends. The message passing interface (MPI) is used for communication between nodes at the coarsest level of parallelism. Optimizations of the simulation code at the several finer levels of parallelism that the data-parallel devices provide are described in terms of data layout, data flow and data-parallel instructions. Optimized Cell and GPU performance are compared with reference code performance on a single x86 central processing unit (CPU) core in single and double precision. We further compare the CPU, Cell and GPU platforms on a chip-to-chip basis, and compare performance on single cluster nodes with two CPUs, two Cell processors or two GPUs in a shared memory configuration (without MPI). We finally compare performance on clusters with 32 CPUs, 32 Cell processors, and 32 GPUs using MPI. Our GPU cluster results use NVIDIA Tesla GPUs with GT200 architecture, but some preliminary results on recently introduced NVIDIA GPUs with the next-generation Fermi architecture are also included. This paper provides computational scientists and engineers who are considering porting their codes to accelerator environments with insight into how structured grid based explicit algorithms can be optimized for clusters with Cell and GPU accelerators. It also provides insight into the speed-up that may be gained on current and future accelerator architectures for this class of applications. Program summaryProgram title: SWsolver Catalogue identifier: AEGY_v1_0 Program summary URL: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 synthetic cGMP-sensitive gene switch providing Viagra(®)-controlled gene expression in mammalian cells and mice.

PubMed

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

2015-05-01

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

Multiscale Mathematics for Biomass Conversion to Renewable Hydrogen

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

Plechac, Petr; Vlachos, Dionisios; Katsoulakis, Markos

2013-09-05

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

OpenMP Parallelization and Optimization of Graph-Based Machine Learning Algorithms

DOE PAGES

Meng, Zhaoyi; Koniges, Alice; He, Yun Helen; ...

2016-09-21

In this paper, we investigate the OpenMP parallelization and optimization of two novel data classification algorithms. The new algorithms are based on graph and PDE solution techniques and provide significant accuracy and performance advantages over traditional data classification algorithms in serial mode. The methods leverage the Nystrom extension to calculate eigenvalue/eigenvectors of the graph Laplacian and this is a self-contained module that can be used in conjunction with other graph-Laplacian based methods such as spectral clustering. We use performance tools to collect the hotspots and memory access of the serial codes and use OpenMP as the parallelization language to parallelizemore » the most time-consuming parts. Where possible, we also use library routines. We then optimize the OpenMP implementations and detail the performance on traditional supercomputer nodes (in our case a Cray XC30), and test the optimization steps on emerging testbed systems based on Intel’s Knights Corner and Landing processors. We show both performance improvement and strong scaling behavior. Finally, a large number of optimization techniques and analyses are necessary before the algorithm reaches almost ideal scaling.« less

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

PubMed Central

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

2002-01-01

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

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

NASA Astrophysics Data System (ADS)

Taranets, R.; Chugunova, M.

2018-03-01

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

Estimating varying coefficients for partial differential equation models.

PubMed

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

2017-09-01

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

Detonation Propagation Through Ducts in a Pulsed Detonation Engine

DTIC Science & Technology

2011-03-01

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

Biomolecular surface construction by PDE transform

PubMed Central

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

2011-01-01

This work proposes a new framework for the surface generation based on the partial differential equation (PDE) transform. The PDE transform has recently been introduced as a general approach for the mode decomposition of images, signals, and data. It relies on the use of arbitrarily high order PDEs to achieve the time-frequency localization, control the spectral distribution, and regulate the spatial resolution. The present work provides a new variational derivation of high order PDE transforms. The fast Fourier transform is utilized to accomplish the PDE transform so as to avoid stringent stability constraints in solving high order PDEs. As a consequence, the time integration of high order PDEs can be done efficiently with the fast Fourier transform. The present approach is validated with a variety of test examples in two and three-dimensional settings. We explore the impact of the PDE transform parameters, such as the PDE order and propagation time, on the quality of resulting surfaces. Additionally, we utilize a set of 10 proteins to compare the computational efficiency of the present surface generation method and the MSMS approach in Cartesian meshes. Moreover, we analyze the present method by examining some benchmark indicators of biomolecular surface, i.e., surface area, surface enclosed volume, solvation free energy and surface electrostatic potential. A test set of 13 protein molecules is used in the present investigation. The electrostatic analysis is carried out via the Poisson-Boltzmann equation model. To further demonstrate the utility of the present PDE transform based surface method, we solve the Poisson-Nernst-Planck (PNP) equations with a PDE transform surface of a protein. Second order convergence is observed for the electrostatic potential and concentrations. Finally, to test the capability and efficiency of the present PDE transform based surface generation method, we apply it to the construction of an excessively large biomolecule, a virus surface capsid. Virus surface morphologies of different resolutions are attained by adjusting the propagation time. Therefore, the present PDE transform provides a multiresolution analysis in the surface visualization. Extensive numerical experiment and comparison with an established surface model indicate that the present PDE transform is a robust, stable and efficient approach for biomolecular surface generation in Cartesian meshes. PMID:22582140

Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.

PubMed

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

2017-04-27

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

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

PubMed

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

2012-08-01

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

Exploring the structure determinants of pyrazinone derivatives as PDE5 3HC8 inhibitors: an in silico analysis.

PubMed

Li, Yan; Wu, Wenzhao; Ren, Hong; Wang, Jinghui; Zhang, Shuwei; Li, Guohui; Yang, Ling

2012-09-01

Phosphodiesterase type 5 (PDE5) inhibitors are clinically indicated for the treatment of erectile dysfunction, pulmonary hypertension and various other diseases. In this work, both ligand- and receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 122 pyrazinone derivatives as PDE inhibitors. The resultant optimum 3D-QSAR model exhibits a proper predictive ability as indicated by the statistical results of Q² of 0.584, R(ncv)² of 0.884 and R(pre)² of 0.817, respectively. In addition, docking analysis and molecular dynamics (MD) simulation were also applied to elucidate the probable binding modes of these inhibitors. Our main findings are: (1) Introduction of bulky, electropositive and hydrophobic substituents at 12- and 19-positions can increase the biological activities. (2) N atom at 8-position is detrimental to the inhibitor activity, and the effect of N atoms at 5- and 6-positions on compound activity is co-determined by both the hydrophobic force and the π-π stacking interaction. (3) Bulky and hydrophilic substitutions are favored at the 27-position of ring D. (4) Electronegative and hydrophilic substitutions around 5- and 6-positions increase the inhibitory activity. (5) Hydrophobic forces and π-π stacking interaction with Phe786 and Phe820 are crucial in determining the binding of pyrazinone derivatives to PDE5. (6) Bulky substitutions around ring C favors selectivity against PDE11, while bulky groups near the 21-position disfavor the selectivity. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate future rational designs of novel PDE5 inhibitors with improved activity and selectivity. Copyright © 2012 Elsevier Inc. All rights reserved.

Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors.

PubMed

Varnes, Jeffrey G; Geschwindner, Stefan; Holmquist, Christopher R; Forst, Janet; Wang, Xia; Dekker, Niek; Scott, Clay W; Tian, Gaochao; Wood, Michael W; Albert, Jeffrey S

2016-01-01

Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires high resolution structural information to guide optimization. In fragment-assisted drug discovery (FADD), fragments provide information to guide selection and design but do not serve as starting points for elaboration. We describe FADD and high-throughput screening (HTS) campaign strategies conducted in parallel against PDE10A where fragment hit co-crystallography was not available. The fragment screen led to prioritized fragment hits (IC50's ∼500μM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4μM hit, which, after preparation of a small number of analogs, was elaborated into a 16nM lead. This approach highlights the strength of FADD, as fragment methods were applied despite the absence of co-crystallographical information to efficiently identify a lead compound for further optimization. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

PubMed

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

2015-01-01

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

Reduced-order model for dynamic optimization of pressure swing adsorption processes

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

Agarwal, A.; Biegler, L.; Zitney, S.

2007-01-01

Over the past decades, pressure swing adsorption (PSA) processes have been widely used as energy-efficient gas and liquid separation techniques, especially for high purity hydrogen purification from refinery gases. The separation processes are based on solid-gas equilibrium and operate under periodic transient conditions. Models for PSA processes are therefore multiple instances of partial differential equations (PDEs) in time and space with periodic boundary conditions that link the processing steps together. The solution of this coupled stiff PDE system is governed by steep concentrations and temperature fronts moving with time. As a result, the optimization of such systems for either designmore » or operation represents a significant computational challenge to current differential algebraic equation (DAE) optimization techniques and nonlinear programming algorithms. Model reduction is one approach to generate cost-efficient low-order models which can be used as surrogate models in the optimization problems. The study develops a reduced-order model (ROM) based on proper orthogonal decomposition (POD), which is a low-dimensional approximation to a dynamic PDE-based model. Initially, a representative ensemble of solutions of the dynamic PDE system is constructed by solving a higher-order discretization of the model using the method of lines, a two-stage approach that discretizes the PDEs in space and then integrates the resulting DAEs over time. Next, the ROM method applies the Karhunen-Loeve expansion to derive a small set of empirical eigenfunctions (POD modes) which are used as basis functions within a Galerkin's projection framework to derive a low-order DAE system that accurately describes the dominant dynamics of the PDE system. The proposed method leads to a DAE system of significantly lower order, thus replacing the one obtained from spatial discretization before and making optimization problem computationally-efficient. The method has been applied to the dynamic coupled PDE-based model of a two-bed four-step PSA process for separation of hydrogen from methane. Separate ROMs have been developed for each operating step with different POD modes for each of them. A significant reduction in the order of the number of states has been achieved. The gas-phase mole fraction, solid-state loading and temperature profiles from the low-order ROM and from the high-order simulations have been compared. Moreover, the profiles for a different set of inputs and parameter values fed to the same ROM were compared with the accurate profiles from the high-order simulations. Current results indicate the proposed ROM methodology as a promising surrogate modeling technique for cost-effective optimization purposes. Moreover, deviations from the ROM for different set of inputs and parameters suggest that a recalibration of the model is required for the optimization studies. Results for these will also be presented with the aforementioned results.« less

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

PubMed

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

2003-01-01

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

Studies on a silicon-photomultiplier-based camera for Imaging Atmospheric Cherenkov Telescopes

NASA Astrophysics Data System (ADS)

Arcaro, C.; Corti, D.; De Angelis, A.; Doro, M.; Manea, C.; Mariotti, M.; Rando, R.; Reichardt, I.; Tescaro, D.

2017-12-01

Imaging Atmospheric Cherenkov Telescopes (IACTs) represent a class of instruments which are dedicated to the ground-based observation of cosmic VHE gamma ray emission based on the detection of the Cherenkov radiation produced in the interaction of gamma rays with the Earth atmosphere. One of the key elements of such instruments is a pixelized focal-plane camera consisting of photodetectors. To date, photomultiplier tubes (PMTs) have been the common choice given their high photon detection efficiency (PDE) and fast time response. Recently, silicon photomultipliers (SiPMs) are emerging as an alternative. This rapidly evolving technology has strong potential to become superior to that based on PMTs in terms of PDE, which would further improve the sensitivity of IACTs, and see a price reduction per square millimeter of detector area. We are working to develop a SiPM-based module for the focal-plane cameras of the MAGIC telescopes to probe this technology for IACTs with large focal plane cameras of an area of few square meters. We will describe the solutions we are exploring in order to balance a competitive performance with a minimal impact on the overall MAGIC camera design using ray tracing simulations. We further present a comparative study of the overall light throughput based on Monte Carlo simulations and considering the properties of the major hardware elements of an IACT.

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

PubMed

Yates, Christian A; Flegg, Mark B

2015-05-06

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

Change rates and prevalence of a dichotomous variable: simulations and applications.

PubMed

Brinks, Ralph; Landwehr, Sandra

2015-01-01

A common modelling approach in public health and epidemiology divides the population under study into compartments containing persons that share the same status. Here we consider a three-state model with the compartments: A, B and Dead. States A and B may be the states of any dichotomous variable, for example, Healthy and Ill, respectively. The transitions between the states are described by change rates, which depend on calendar time and on age. So far, a rigorous mathematical calculation of the prevalence of property B has been difficult, which has limited the use of the model in epidemiology and public health. We develop a partial differential equation (PDE) that simplifies the use of the three-state model. To demonstrate the validity of the PDE, it is applied to two simulation studies, one about a hypothetical chronic disease and one about dementia in Germany. In two further applications, the PDE may provide insights into smoking behaviour of males in Germany and the knowledge about the ovulatory cycle in Egyptian women.

Parallel-In-Time For Moving Meshes

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

Falgout, R. D.; Manteuffel, T. A.; Southworth, B.

2016-02-04

With steadily growing computational resources available, scientists must develop e ective ways to utilize the increased resources. High performance, highly parallel software has be- come a standard. However until recent years parallelism has focused primarily on the spatial domain. When solving a space-time partial di erential equation (PDE), this leads to a sequential bottleneck in the temporal dimension, particularly when taking a large number of time steps. The XBraid parallel-in-time library was developed as a practical way to add temporal parallelism to existing se- quential codes with only minor modi cations. In this work, a rezoning-type moving mesh is appliedmore » to a di usion problem and formulated in a parallel-in-time framework. Tests and scaling studies are run using XBraid and demonstrate excellent results for the simple model problem considered herein.« less

CPU and GPU-based Numerical Simulations of Combustion Processes

DTIC Science & Technology

2012-04-27

Distribution unlimited UCLA MAE Research and Technology Review April 27, 2012 Magnetohydrodynamic Augmentation of the Pulse Detonation Rocket Engines...Pulse Detonation Rocket-Induced MHD Ejector (PDRIME) – Energy extract from exhaust flow by MHD generator – Seeded air stream acceleration by MHD...accelerator for thrust enhancement and control • Alternative concept: Magnetic piston – During PDE blowdown process, MHD extracts energy and

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

PubMed

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

2009-03-14

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

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

NASA Astrophysics Data System (ADS)

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

2009-03-01

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

Biomolecular surface construction by PDE transform.

PubMed

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

2012-03-01

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

Is chronic inhibition of phosphodiesterase type 5 cardioprotective and safe? A meta-analysis of randomized controlled trials.

PubMed

Giannetta, Elisa; Feola, Tiziana; Gianfrilli, Daniele; Pofi, Riccardo; Dall'Armi, Valentina; Badagliacca, Roberto; Barbagallo, Federica; Lenzi, Andrea; Isidori, Andrea M

2014-10-20

The myocardial effects of phosphodiesterase type 5 inhibitors (PDE5i) have recently received consideration in several preclinical studies. The risk/benefit ratio in humans remains unclear. We performed a meta-analysis of randomized, placebo-controlled trials (RCTs) to evaluate the efficacy and safety of PDE5i on cardiac morphology and function. From March 2012 to December 2013 (update: May 2014), we searched English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and SCOPUS-selecting RCTs of continuous PDE5i administration that reported cardiovascular outcomes: cardiac geometry and performance, afterload, endothelial function and safety. The pooled estimate of a weighted mean difference between treatment and placebo was obtained for all outcomes using a random effects model. A test for heterogeneity was performed and the I2 statistic calculated. Overall, 1,622 subjects were treated, with 954 randomized to PDE5i and 772 to placebo in 24 RCTs. According to our analysis, sustained PDE5 inhibition produced: (1) an anti-remodeling effect by reducing cardiac mass (-12.21 g/m2, 95% confidence interval (CI): -18.85; -5.57) in subjects with left ventricular hypertrophy (LVH) and by increasing end-diastolic volume (5.00 mL/m2; 95% CI: 3.29; 6.71) in non-LVH patients; (2) an improvement in cardiac performance by increasing cardiac index (0.30 L/min/m2, 95% CI: 0.202; 0.406) and ejection fraction (3.56%, 95% CI: 1.79; 5.33). These effects are parallel to a decline of N-terminal-pro brain natriuretic peptide (NT-proBNP) in subjects with severe LVH (-486.7 pg/ml, 95% CI: -712; -261). PDE5i administration also produced: (3) no changes in afterload parameters and (4) an improvement in flow-mediated vasodilation (3.31%, 95% CI: 0.53; 6.08). Flushing, headache, epistaxis and gastric symptoms were the commonest side effects. This meta-analysis suggests for the first time that PDE5i have anti-remodeling properties and improve cardiac inotropism, independently of afterload changes, with a good safety profile. Given the reproducibility of the findings and tolerability across different populations, PDE5i could be reasonably offered to men with cardiac hypertrophy and early stage heart failure. Given the limited gender data, a larger trial on the sex-specific response to long-term PDE5i treatment is required.

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

NASA Astrophysics Data System (ADS)

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

2018-02-01

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

Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors.

PubMed

Chino, Ayaka; Seo, Ryushi; Amano, Yasushi; Namatame, Ichiji; Hamaguchi, Wataru; Honbou, Kazuya; Mihara, Takuma; Yamazaki, Mayako; Tomishima, Masaki; Masuda, Naoyuki

2018-01-01

In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

JANNAF 24th Airbreathing Propulsion Subcommittee and 36th Combustion Subcommittee Joint Meeting. Volume 1

NASA Technical Reports Server (NTRS)

Fry, Ronald S. (Editor); Gannaway, Mary T. (Editor)

1999-01-01

Volume 1, the first of three volumes is a compilation of 16 unclassified/unlimited-technical papers presented at the Joint Army-Navy-NASA-Air Force (JANNAF) 24th Airbreathing Propulsion Subcommittee and 36th Combustion Subcommittee held jointly with the 181 Propulsion Systems Hazards Subcommittee. The meeting was held on 18-21 October 1999 at NASA Kennedy Space Center and The DoubleTree Oceanfront Hotel, Cocoa Beach, Florida. Topics covered include overviews of RBCC and PDE hypersonic technology, Hyper-X propulsion ground testing, development of JP-8 for hypersonic vehicle applications, numerical simulation of dual-mode SJ combustion, V&V of M&S computer codes, MHD SJ and Rocket Based Combined Cycle (RBCC) launch vehicle concepts, and Pulse Detonation Engine (PDE) propulsion technology development including fundamental investigations, modeling, aerodynamics, operation and performance.

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

DOE PAGES

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

2016-08-18

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

A special case of the Poisson PDE formulated for Earth's surface and its capability to approximate the terrain mass density employing land-based gravity data, a case study in the south of Iran

NASA Astrophysics Data System (ADS)

AllahTavakoli, Yahya; Safari, Abdolreza; Vaníček, Petr

2016-12-01

This paper resurrects a version of Poisson's Partial Differential Equation (PDE) associated with the gravitational field at the Earth's surface and illustrates how the PDE possesses a capability to extract the mass density of Earth's topography from land-based gravity data. Herein, first we propound a theorem which mathematically introduces this version of Poisson's PDE adapted for the Earth's surface and then we use this PDE to develop a method of approximating the terrain mass density. Also, we carry out a real case study showing how the proposed approach is able to be applied to a set of land-based gravity data. In the case study, the method is summarized by an algorithm and applied to a set of gravity stations located along a part of the north coast of the Persian Gulf in the south of Iran. The results were numerically validated via rock-samplings as well as a geological map. Also, the method was compared with two conventional methods of mass density reduction. The numerical experiments indicate that the Poisson PDE at the Earth's surface has the capability to extract the mass density from land-based gravity data and is able to provide an alternative and somewhat more precise method of estimating the terrain mass density.

acme: The Amendable Coal-Fire Modeling Exercise. A C++ Class Library for the Numerical Simulation of Coal-Fires

NASA Astrophysics Data System (ADS)

Wuttke, Manfred W.

2017-04-01

At LIAG, we use numerical models to develop and enhance understanding of coupled transport processes and to predict the dynamics of the system under consideration. Topics include geothermal heat utilization, subrosion processes, and spontaneous underground coal fires. Although the details make it inconvenient if not impossible to apply a single code implementation to all systems, their investigations go along similar paths: They all depend on the solution of coupled transport equations. We thus saw a need for a modular code system with open access for the various communities to maximize the shared synergistic effects. To this purpose we develop the oops! ( open object-oriented parallel solutions) - toolkit, a C++ class library for the numerical solution of mathematical models of coupled thermal, hydraulic and chemical processes. This is used to develop problem-specific libraries like acme( amendable coal-fire modeling exercise), a class library for the numerical simulation of coal-fires and applications like kobra (Kohlebrand, german for coal-fire), a numerical simulation code for standard coal-fire models. Basic principle of the oops!-code system is the provision of data types for the description of space and time dependent data fields, description of terms of partial differential equations (pde), their discretisation and solving methods. Coupling of different processes, described by their particular pde is modeled by an automatic timescale-ordered operator-splitting technique. acme is a derived coal-fire specific application library, depending on oops!. If specific functionalities of general interest are implemented and have been tested they will be assimilated into the main oops!-library. Interfaces to external pre- and post-processing tools are easily implemented. Thus a construction kit which can be arbitrarily amended is formed. With the kobra-application constructed with acme we study the processes and propagation of shallow coal seam fires in particular in Xinjiang, China, as well as analyze and interpret results from lab experiments.

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

PubMed Central

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

2014-01-01

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

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.

Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center.

PubMed

Freund, Yvonne R; Akama, Tsutomu; Alley, M R K; Antunes, Joana; Dong, Chen; Jarnagin, Kurt; Kimura, Richard; Nieman, James A; Maples, Kirk R; Plattner, Jacob J; Rock, Fernando; Sharma, Rashmi; Singh, Rajeshwar; Sanders, Virginia; Zhou, Yasheen

2012-09-21

We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-α, IL-2, IFN-γ, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Identification of cancer cytotoxic modulators of PDE3A by predictive chemogenomics

PubMed Central

de Waal, Luc; Lewis, Timothy A.; Rees, Matthew G.; Tsherniak, Aviad; Wu, Xiaoyun; Choi, Peter S.; Gechijian, Lara; Hartigan, Christina; Faloon, Patrick W.; Hickey, Mark J.; Tolliday, Nicola; Carr, Steven A.; Clemons, Paul A.; Munoz, Benito; Wagner, Bridget K.; Shamji, Alykhan F.; Koehler, Angela N.; Schenone, Monica; Burgin, Alex B.; Schreiber, Stuart L.; Greulich, Heidi; Meyerson, Matthew

2015-01-01

High cancer death rates indicate the need for new anti-cancer therapeutic agents. Approaches to discover new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds by phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the phosphodiesterase 3A gene, PDE3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells while others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrated that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggesting a neomorphic activity. Co-expression of SLFN12 with PDE3A correlates with DNMDP sensitivity, while depletion of SLFN12 results in decreased DNMDP sensitivity. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery. PMID:26656089

Oxidation- and Creep-Enhanced Fatigue of Haynes 188 Alloy-Oxide Scale System Under Simulated Pulse Detonation Engine Conditions

NASA Technical Reports Server (NTRS)

Zhu, Dongming; Fox, Dennis S.; Miller, Robert A.

2002-01-01

The development of the pulse detonation engine (PDE) requires robust design of the engine components that are capable of enduring harsh detonation environments. In this study, a high cycle thermal fatigue test rig was developed for evaluating candidate PDE combustor materials using a CO2 laser. The high cycle thermal fatigue behavior of Haynes 188 alloy was investigated under an enhanced pulsed laser test condition of 30 Hz cycle frequency (33 ms pulse period, and 10 ms pulse width including 0.2 ms pulse spike). The temperature swings generated by the laser pulses near the specimen surface were characterized by using one-dimensional finite difference modeling combined with experimental measurements. The temperature swings resulted in significant thermal cyclic stresses in the oxide scale/alloy system, and induced extensive surface cracking. Striations of various sizes were observed at the cracked surfaces and oxide/alloy interfaces under the cyclic stresses. The test results indicated that oxidation and creep-enhanced fatigue at the oxide scale/alloy interface was an important mechanism for the surface crack initiation and propagation under the simulated PDE condition.

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

PubMed

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

2018-01-01

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

PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.

PubMed

Nelson, Michael D; Rader, Florian; Tang, Xiu; Tavyev, Jane; Nelson, Stanley F; Miceli, M Carrie; Elashoff, Robert M; Sweeney, H Lee; Victor, Ronald G

2014-06-10

To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis. © 2014 American Academy of Neurology.

Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors with Antioxidant Activities

NASA Astrophysics Data System (ADS)

Li, Jinxuan; Chen, Jing-Yi; Deng, Ya-Lin; Zhou, Qian; Wu, Yinuo; Wu, Deyan; Luo, Hai-Bin

2018-05-01

Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of thirteen designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

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

NASA Astrophysics Data System (ADS)

Zheng, Dianfeng

2016-11-01

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

Poly- Versus Mono-Energetic Dual-Spectrum Non-Intrusive Inspection of Cargo Containers

NASA Astrophysics Data System (ADS)

Martz, Harry E.; Glenn, Steven M.; Smith, Jerel A.; Divin, Charles J.; Azevedo, Stephen G.

2017-07-01

In this paper, based on an invited talk at SORMA (May 2016), we present an overview of x-ray sources, detectors and system configurations for non-intrusive inspection (NII) of cargo containers. Our emphasis is on dual-energy x-ray NII for detecting high-atomic-number (Z ≥ 72) materials such as tungsten shielding and special nuclear materials (SNM). Standard single-energy (MeV and above) x-rays needed to penetrate and image cargo provide little SNM contrast, whereas dual-energy x-ray NII is demonstrated as a way to improve the selectivity of materials with Z<;72 vs. those with Z ≥ 72. For two possible dual-energy x-ray source technologies - polyenergetic dual-energy (PDE) and quasi-monoenergetic x-ray sources (QMXS) - we investigate their trade-offs and future prospects using experimental and simulated results. The reduced scatter and larger separation of low- and high-energy photons provided by QMXS offers improved high-Z material contrast, but practical considerations such as flux and pulse rate need to be solved before making a deployable system. Straight-ray simulations show factor of four increases in contrast for QMXS over PDE scans of tin (Z=50) and iron (Z=26) relative to a uranium plate (Z=92) behind 20 cm of iron simulated cargo.

Parallel Allostery by cAMP and PDE Coordinates Activation and Termination Phases in cAMP Signaling.

PubMed

Krishnamurthy, Srinath; Tulsian, Nikhil Kumar; Chandramohan, Arun; Anand, Ganesh S

2015-09-15

The second messenger molecule cAMP regulates the activation phase of the cAMP signaling pathway through high-affinity interactions with the cytosolic cAMP receptor, the protein kinase A regulatory subunit (PKAR). Phosphodiesterases (PDEs) are enzymes responsible for catalyzing hydrolysis of cAMP to 5' AMP. It was recently shown that PDEs interact with PKAR to initiate the termination phase of the cAMP signaling pathway. While the steps in the activation phase are well understood, steps in the termination pathway are unknown. Specifically, the binding and allosteric networks that regulate the dynamic interplay between PKAR, PDE, and cAMP are unclear. In this study, PKAR and PDE from Dictyostelium discoideum (RD and RegA, respectively) were used as a model system to monitor complex formation in the presence and absence of cAMP. Amide hydrogen/deuterium exchange mass spectrometry was used to monitor slow conformational transitions in RD, using disordered regions as conformational probes. Our results reveal that RD regulates its interactions with cAMP and RegA at distinct loci by undergoing slow conformational transitions between two metastable states. In the presence of cAMP, RD and RegA form a stable ternary complex, while in the absence of cAMP they maintain transient interactions. RegA and cAMP each bind at orthogonal sites on RD with resultant contrasting effects on its dynamics through parallel allosteric relays at multiple important loci. RD thus serves as an integrative node in cAMP termination by coordinating multiple allosteric relays and governing the output signal response. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

a Speculative Study on Negative-Dimensional Potential and Wave Problems by Implicit Calculus Modeling Approach

NASA Astrophysics Data System (ADS)

Chen, Wen; Wang, Fajie

Based on the implicit calculus equation modeling approach, this paper proposes a speculative concept of the potential and wave operators on negative dimensionality. Unlike the standard partial differential equation (PDE) modeling, the implicit calculus modeling approach does not require the explicit expression of the PDE governing equation. Instead the fundamental solution of physical problem is used to implicitly define the differential operator and to implement simulation in conjunction with the appropriate boundary conditions. In this study, we conjecture an extension of the fundamental solution of the standard Laplace and Helmholtz equations to negative dimensionality. And then by using the singular boundary method, a recent boundary discretization technique, we investigate the potential and wave problems using the fundamental solution on negative dimensionality. Numerical experiments reveal that the physics behaviors on negative dimensionality may differ on positive dimensionality. This speculative study might open an unexplored territory in research.

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

PubMed

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

2016-06-13

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

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

PubMed

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

2016-12-01

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

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2009-01-01

We present a partial-differential-equation (PDE)-constrained approach for optimizing a molecule's electrostatic interactions with a target molecule. The approach, which we call reverse-Schur co-optimization, can be more than two orders of magnitude faster than the traditional approach to electrostatic optimization. The efficiency of the co-optimization approach may enhance the value of electrostatic optimization for ligand-design efforts-in such projects, it is often desirable to screen many candidate ligands for their viability, and the optimization of electrostatic interactions can improve ligand binding affinity and specificity. The theoretical basis for electrostatic optimization derives from linear-response theory, most commonly continuum models, and simple assumptions about molecular binding processes. Although the theory has been used successfully to study a wide variety of molecular binding events, its implications have not yet been fully explored, in part due to the computational expense associated with the optimization. The co-optimization algorithm achieves improved performance by solving the optimization and electrostatic simulation problems simultaneously, and is applicable to both unconstrained and constrained optimization problems. Reverse-Schur co-optimization resembles other well-known techniques for solving optimization problems with PDE constraints. Model problems as well as realistic examples validate the reverse-Schur method, and demonstrate that our technique and alternative PDE-constrained methods scale very favorably compared to the standard approach. Regularization, which ordinarily requires an explicit representation of the objective function, can be included using an approximate Hessian calculated using the new BIBEE/P (boundary-integral-based electrostatics estimation by preconditioning) method.

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

PubMed Central

Bardhan, Jaydeep P.; Altman, Michael D.

2009-01-01

We present a partial-differential-equation (PDE)-constrained approach for optimizing a molecule’s electrostatic interactions with a target molecule. The approach, which we call reverse-Schur co-optimization, can be more than two orders of magnitude faster than the traditional approach to electrostatic optimization. The efficiency of the co-optimization approach may enhance the value of electrostatic optimization for ligand-design efforts–in such projects, it is often desirable to screen many candidate ligands for their viability, and the optimization of electrostatic interactions can improve ligand binding affinity and specificity. The theoretical basis for electrostatic optimization derives from linear-response theory, most commonly continuum models, and simple assumptions about molecular binding processes. Although the theory has been used successfully to study a wide variety of molecular binding events, its implications have not yet been fully explored, in part due to the computational expense associated with the optimization. The co-optimization algorithm achieves improved performance by solving the optimization and electrostatic simulation problems simultaneously, and is applicable to both unconstrained and constrained optimization problems. Reverse-Schur co-optimization resembles other well-known techniques for solving optimization problems with PDE constraints. Model problems as well as realistic examples validate the reverse-Schur method, and demonstrate that our technique and alternative PDE-constrained methods scale very favorably compared to the standard approach. Regularization, which ordinarily requires an explicit representation of the objective function, can be included using an approximate Hessian calculated using the new BIBEE/P (boundary-integral-based electrostatics estimation by preconditioning) method. PMID:23055839

A New Attempt of 2-D Numerical Ice Flow Model to Reconstruct Paleoclimate from Mountain Glaciers

NASA Astrophysics Data System (ADS)

Candaş, Adem; Akif Sarıkaya, Mehmet

2017-04-01

A new two dimensional (2D) numerical ice flow model is generated to simulate the steady-state glacier extent for a wide range of climate conditions. The simulation includes the flow of ice enforced by the annual mass balance gradient of a valley glacier. The annual mass balance is calculated by the difference of the net accumulation and ablation of snow and (or) ice. The generated model lets users to compare the simulated and field observed ice extent of paleoglaciers. As a result, model results provide the conditions about the past climates since simulated ice extent is a function of predefined climatic conditions. To predict the glacier shape and distribution in two dimension, time dependent partial differential equation (PDE) is solved. Thus, a 2D glacier flow model code is constructed in MATLAB and a finite difference method is used to solve this equation. On the other hand, Parallel Ice Sheet Model (PISM) is used to regenerate paleoglaciers in the same area where the MATLAB code is applied. We chose the Mount Dedegöl, an extensively glaciated mountain in SW Turkey, to apply both models. Model results will be presented and discussed in this presentation. This study was supported by TÜBİTAK 114Y548 project.

A parallel algorithm for switch-level timing simulation on a hypercube multiprocessor

NASA Technical Reports Server (NTRS)

Rao, Hariprasad Nannapaneni

1989-01-01

The parallel approach to speeding up simulation is studied, specifically the simulation of digital LSI MOS circuitry on the Intel iPSC/2 hypercube. The simulation algorithm is based on RSIM, an event driven switch-level simulator that incorporates a linear transistor model for simulating digital MOS circuits. Parallel processing techniques based on the concepts of Virtual Time and rollback are utilized so that portions of the circuit may be simulated on separate processors, in parallel for as large an increase in speed as possible. A partitioning algorithm is also developed in order to subdivide the circuit for parallel processing.

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

PubMed

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

2015-01-01

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

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

PubMed

Talaei, Behzad; Jagannathan, Sarangapani; Singler, John

2018-04-01

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

A model and variance reduction method for computing statistical outputs of stochastic elliptic partial differential equations

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

Vidal-Codina, F., E-mail: fvidal@mit.edu; Nguyen, N.C., E-mail: cuongng@mit.edu; Giles, M.B., E-mail: mike.giles@maths.ox.ac.uk

We present a model and variance reduction method for the fast and reliable computation of statistical outputs of stochastic elliptic partial differential equations. Our method consists of three main ingredients: (1) the hybridizable discontinuous Galerkin (HDG) discretization of elliptic partial differential equations (PDEs), which allows us to obtain high-order accurate solutions of the governing PDE; (2) the reduced basis method for a new HDG discretization of the underlying PDE to enable real-time solution of the parameterized PDE in the presence of stochastic parameters; and (3) a multilevel variance reduction method that exploits the statistical correlation among the different reduced basismore » approximations and the high-fidelity HDG discretization to accelerate the convergence of the Monte Carlo simulations. The multilevel variance reduction method provides efficient computation of the statistical outputs by shifting most of the computational burden from the high-fidelity HDG approximation to the reduced basis approximations. Furthermore, we develop a posteriori error estimates for our approximations of the statistical outputs. Based on these error estimates, we propose an algorithm for optimally choosing both the dimensions of the reduced basis approximations and the sizes of Monte Carlo samples to achieve a given error tolerance. We provide numerical examples to demonstrate the performance of the proposed method.« less

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

PubMed

Santillo, Michael F; Mapa, Mapa S T

2018-02-28

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

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

NASA Astrophysics Data System (ADS)

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

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

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

PubMed Central

2015-01-01

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

Phosphodiesterases regulate airway smooth muscle function in health and disease.

PubMed

Krymskaya, Vera P; Panettieri, Reynold A

2007-01-01

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

New Therapeutic Applications of Phosphodiesterase 5 Inhibitors (PDE5-Is).

PubMed

Ribaudo, Giovanni; Pagano, Mario Angelo; Bova, Sergio; Zagotto, Giuseppe

2016-01-01

Phosphodiesterase 5 inhibitors (PDE5-Is) sildenafil, vardenafil, tadalafil and the recently approved avanafil represent the first-line choice for both on-demand and chronic treatment of erectile dysfunction (ED). In addition to this, sildenafil and tadalafil, have also been approved for the treatment of pulmonary arterial hypertension. Due to its expression and localization in many tissues, PDE5 and its regulation has been reported to be involved in several other diseases. We aim to provide an updated overview of the emerging therapeutic applications of PDE5-Is besides ED, taking into account the latest ongoing research reports. We searched online databases (Pubmed, Reaxys, Scopus) to lay the bases for an accurate, quality criteria-based literature update. We focused our attention on most recent research reports, in particular when supported by pre-clinical and clinical data. The regulation of PDE5 may influence pathological conditions such as, among the others, heart failure, cystic fibrosis, cancer, CNS-related diseases, diabetes and dysfunctions affecting male urinary/reproductive system. Sildenafil, vardenafil, tadalafil and the other chemical entities considered PDE5-Is showed overall positive results and significant improvements in the studied disease, thus some discordant results, in particular when comparing pre-clinical and clinical data, have to be pointed out, suggesting that further insights are needed especially to assess the exact molecular pathway underlying.

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.

Computationally efficient statistical differential equation modeling using homogenization

USGS Publications Warehouse

Hooten, Mevin B.; Garlick, Martha J.; Powell, James A.

2013-01-01

Statistical models using partial differential equations (PDEs) to describe dynamically evolving natural systems are appearing in the scientific literature with some regularity in recent years. Often such studies seek to characterize the dynamics of temporal or spatio-temporal phenomena such as invasive species, consumer-resource interactions, community evolution, and resource selection. Specifically, in the spatial setting, data are often available at varying spatial and temporal scales. Additionally, the necessary numerical integration of a PDE may be computationally infeasible over the spatial support of interest. We present an approach to impose computationally advantageous changes of support in statistical implementations of PDE models and demonstrate its utility through simulation using a form of PDE known as “ecological diffusion.” We also apply a statistical ecological diffusion model to a data set involving the spread of mountain pine beetle (Dendroctonus ponderosae) in Idaho, USA.

Analysis of Aluminum-Nitride SOI for High-Temperature Electronics

NASA Technical Reports Server (NTRS)

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

2000-01-01

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

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

PubMed

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

2015-07-01

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

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

PubMed

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

2017-06-16

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

Cigarette Smoke-Induced Emphysema and Pulmonary Hypertension Can Be Prevented by Phosphodiesterase 4 and 5 Inhibition in Mice

PubMed Central

Pichl, Alexandra; Bednorz, Mariola; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo; Seeger, Werner; Grimminger, Friedrich; Weissmann, Norbert

2015-01-01

Rationale Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies available. Recent findings suggest a key role of NO and sGC-cGMP signaling for the pathogenesis of the disease. Previous data suggest a downregulation/inactivation of the cGMP producing soluble guanylate cyclase, and sGC stimulation prevented cigarette smoke-induced emphysema and pulmonary hypertension (PH) in mice. We thus aimed to investigate if the inhibition of the cGMP degrading phosphodiesterase (PDE)5 has similar effects. Results were compared to the effects of a PDE 4 inhibitor (cAMP elevating) and a combination of both. Methods C57BL6/J mice were chronically exposed to cigarette smoke and in parallel either treated with Tadalafil (PDE5 inhibitor), Piclamilast (PDE4 inhibitor) or both. Functional measurements (lung compliance, hemodynamics) and structural investigations (alveolar and vascular morphometry) as well as the heart ratio were determined after 6 months of tobacco smoke exposure. In addition, the number of alveolar macrophages in the respective lungs was counted. Results Preventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and right ventricular hypertrophy induced by cigarette smoke exposure. Single, but not combination treatment prevented or reduced smoke-induced increase in alveolar macrophages. Conclusion Cigarette smoke-induced emphysema and PH could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice. PMID:26058042

Precision measurement of the photon detection efficiency of silicon photomultipliers using two integrating spheres.

PubMed

Yang, Seul Ki; Lee, J; Kim, Sug-Whan; Lee, Hye-Young; Jeon, Jin-A; Park, I H; Yoon, Jae-Ryong; Baek, Yang-Sik

2014-01-13

We report a new and improved photon counting method for the precision PDE measurement of SiPM detectors, utilizing two integrating spheres connected serially and calibrated reference detectors. First, using a ray tracing simulation and irradiance measurement results with a reference photodiode, we investigated irradiance characteristics of the measurement instrument, and analyzed dominating systematic uncertainties in PDE measurement. Two SiPM detectors were then used for PDE measurements between wavelengths of 368 and 850 nm and for bias voltages varying from around 70V. The resulting PDEs of the SiPMs show good agreement with those from other studies, yet with an improved accuracy of 1.57% (1σ). This was achieved by the simultaneous measurement with the NIST calibrated reference detectors, which suppressed the time dependent variation of source light. The technical details of the instrumentation, measurement results and uncertainty analysis are reported together with their implications.

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

PubMed

Granovsky, A E; Artemyev, N O

2000-12-29

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

A numerical investigation into the ability of the Poisson PDE to extract the mass-density from land-based gravity data: A case study of salt diapirs in the north coast of the Persian Gulf

NASA Astrophysics Data System (ADS)

AllahTavakoli, Yahya; Safari, Abdolreza

2017-08-01

This paper is counted as a numerical investigation into the capability of Poisson's Partial Differential Equation (PDE) at Earth's surface to extract the near-surface mass-density from land-based gravity data. For this purpose, first it focuses on approximating the gradient tensor of Earth's gravitational potential by means of land-based gravity data. Then, based on the concepts of both the gradient tensor and Poisson's PDE at the Earth's surface, certain formulae are proposed for the mass-density determination. Furthermore, this paper shows how the generalized Tikhonov regularization strategy can be used for enhancing the efficiency of the proposed approach. Finally, in a real case study, the formulae are applied to 6350 gravity stations located within a part of the north coast of the Persian Gulf. The case study numerically indicates that the proposed formulae, provided by Poisson's PDE, has the ability to convert land-based gravity data into the terrain mass-density which has been used for depicting areas of salt diapirs in the region of the case study.

Simulation and optimization of pressure swing adsorption systmes using reduced-order modeling

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

Agarwal, A.; Biegler, L.; Zitney, S.

2009-01-01

Over the past three decades, pressure swing adsorption (PSA) processes have been widely used as energyefficient gas separation techniques, especially for high purity hydrogen purification from refinery gases. Models for PSA processes are multiple instances of partial differential equations (PDEs) in time and space with periodic boundary conditions that link the processing steps together. The solution of this coupled stiff PDE system is governed by steep fronts moving with time. As a result, the optimization of such systems represents a significant computational challenge to current differential algebraic equation (DAE) optimization techniques and nonlinear programming algorithms. Model reduction is one approachmore » to generate cost-efficient low-order models which can be used as surrogate models in the optimization problems. This study develops a reducedorder model (ROM) based on proper orthogonal decomposition (POD), which is a low-dimensional approximation to a dynamic PDE-based model. The proposed method leads to a DAE system of significantly lower order, thus replacing the one obtained from spatial discretization and making the optimization problem computationally efficient. The method has been applied to the dynamic coupled PDE-based model of a twobed four-step PSA process for separation of hydrogen from methane. Separate ROMs have been developed for each operating step with different POD modes for each of them. A significant reduction in the order of the number of states has been achieved. The reduced-order model has been successfully used to maximize hydrogen recovery by manipulating operating pressures, step times and feed and regeneration velocities, while meeting product purity and tight bounds on these parameters. Current results indicate the proposed ROM methodology as a promising surrogate modeling technique for cost-effective optimization purposes.« less

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

PubMed

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

2010-03-01

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

Automating Embedded Analysis Capabilities and Managing Software Complexity in Multiphysics Simulation, Part II: Application to Partial Differential Equations

DOE PAGES

Pawlowski, Roger P.; Phipps, Eric T.; Salinger, Andrew G.; ...

2012-01-01

A template-based generic programming approach was presented in Part I of this series of papers [Sci. Program. 20 (2012), 197–219] that separates the development effort of programming a physical model from that of computing additional quantities, such as derivatives, needed for embedded analysis algorithms. In this paper, we describe the implementation details for using the template-based generic programming approach for simulation and analysis of partial differential equations (PDEs). We detail several of the hurdles that we have encountered, and some of the software infrastructure developed to overcome them. We end with a demonstration where we present shape optimization and uncertaintymore » quantification results for a 3D PDE application.« less

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

NASA Technical Reports Server (NTRS)

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

1998-01-01

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

Simulation of Acoustic Noise Generated by an Airbreathing, Beam-Powered Launch Vehicle

NASA Astrophysics Data System (ADS)

Kennedy, W. C.; Van Laak, P.; Scarton, H. A.; Myrabo, L. N.

2005-04-01

A simple acoustic model is developed for predicting the noise signature vs. power level for advanced laser-propelled lightcraft — capable of single-stage flights into low Earth orbit. This model predicts the noise levels generated by a pulsed detonation engine (PDE) during the initial lift-off and acceleration phase, for two representative `tractor-beam' lightcraft designs: a 1-place `Mercury' vehicle (2.5-m diameter, 900-kg); and a larger 5-place `Apollo' vehicle (5-m diameter, 5555-kg) — both the subject of an earlier study. The use of digital techniques to simulate the expected PDE noise signature is discussed, and three examples of fly-by noise signatures are presented. The reduction, or complete elimination of perceptible noise from such engines, can be accomplished by shifting the pulse frequency into the supra-audible or sub-audible range.

26th JANNAF Airbreathing Propulsion Subcommittee Meeting. Volume 1

NASA Technical Reports Server (NTRS)

Fry, Ronald S. (Editor); Gannaway, Mary T. (Editor)

2002-01-01

This volume, the first of four volumes, is a collection of 28 unclassified/unlimited-distribution papers which were presented at the Joint Army-Navy-NASA-Air Force (JANNAF) 26th Airbreathing Propulsion Subcommittee (APS) was held jointly with the 38th Combustion Subcommittee (CS), 20th Propulsion Systems Hazards Subcommittee (PSHS), and 2nd Modeling and Simulation Subcommittee. The meeting was held 8-12 April 2002 at the Bayside Inn at The Sandestin Golf & Beach Resort and Eglin Air Force Base, Destin, Florida. Topics covered include: scramjet and ramjet R&D program overviews; tactical propulsion; space access; NASA GTX status; PDE technology; actively cooled engine structures; modeling and simulation of complex hydrocarbon fuels and unsteady processes; and component modeling and simulation.

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

PubMed

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

2014-07-09

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

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

PubMed

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

2018-01-21

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

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

PubMed

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

2017-04-01

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

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

PubMed

Mang, Samuel; Bucher, Hannes; Nickolaus, Peter

2016-01-01

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

Experimental Study of a Pulse Detonation Engine Driven Ejector

NASA Technical Reports Server (NTRS)

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

2005-01-01

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

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.

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

PubMed Central

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

2016-01-01

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

Terascale Optimal PDE Simulations (TOPS) Center

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

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 ofmore » 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.g., illustrated in [24, 25, 26]. This work is based on [29, 31]. Our work over these five and half years has, in our opinion, helped advance the knowledge of domain decomposition methods significantly. We see these methods as providing valuable alternatives to other iterative methods, in particular, those based on multi-grid. In our opinion, our accomplishments also match the goals of the TOPS project quite closely.« less

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

NASA Technical Reports Server (NTRS)

Cohl, H.

1994-01-01

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

Toward GPGPU accelerated human electromechanical cardiac simulations

PubMed Central

Vigueras, Guillermo; Roy, Ishani; Cookson, Andrew; Lee, Jack; Smith, Nicolas; Nordsletten, David

2014-01-01

In this paper, we look at the acceleration of weakly coupled electromechanics using the graphics processing unit (GPU). Specifically, we port to the GPU a number of components of Heart—a CPU-based finite element code developed for simulating multi-physics problems. On the basis of a criterion of computational cost, we implemented on the GPU the ODE and PDE solution steps for the electrophysiology problem and the Jacobian and residual evaluation for the mechanics problem. Performance of the GPU implementation is then compared with single core CPU (SC) execution as well as multi-core CPU (MC) computations with equivalent theoretical performance. Results show that for a human scale left ventricle mesh, GPU acceleration of the electrophysiology problem provided speedups of 164 × compared with SC and 5.5 times compared with MC for the solution of the ODE model. Speedup of up to 72 × compared with SC and 2.6 × compared with MC was also observed for the PDE solve. Using the same human geometry, the GPU implementation of mechanics residual/Jacobian computation provided speedups of up to 44 × compared with SC and 2.0 × compared with MC. © 2013 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons, Ltd. PMID:24115492

Implementation of Parallel Dynamic Simulation on Shared-Memory vs. Distributed-Memory Environments

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

Jin, Shuangshuang; Chen, Yousu; Wu, Di

2015-12-09

Power system dynamic simulation computes the system response to a sequence of large disturbance, such as sudden changes in generation or load, or a network short circuit followed by protective branch switching operation. It consists of a large set of differential and algebraic equations, which is computational intensive and challenging to solve using single-processor based dynamic simulation solution. High-performance computing (HPC) based parallel computing is a very promising technology to speed up the computation and facilitate the simulation process. This paper presents two different parallel implementations of power grid dynamic simulation using Open Multi-processing (OpenMP) on shared-memory platform, and Messagemore » Passing Interface (MPI) on distributed-memory clusters, respectively. The difference of the parallel simulation algorithms and architectures of the two HPC technologies are illustrated, and their performances for running parallel dynamic simulation are compared and demonstrated.« less

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

PubMed

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

2016-08-24

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

Compatible Spatial Discretizations for Partial Differential Equations

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

Arnold, Douglas, N, ed.

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

Probabilistic Density Function Method for Stochastic ODEs of Power Systems with Uncertain Power Input

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

Wang, Peng; Barajas-Solano, David A.; Constantinescu, Emil

Wind and solar power generators are commonly described by a system of stochastic ordinary differential equations (SODEs) where random input parameters represent uncertainty in wind and solar energy. The existing methods for SODEs are mostly limited to delta-correlated random parameters (white noise). Here we use the Probability Density Function (PDF) method for deriving a closed-form deterministic partial differential equation (PDE) for the joint probability density function of the SODEs describing a power generator with time-correlated power input. The resulting PDE is solved numerically. A good agreement with Monte Carlo Simulations shows accuracy of the PDF method.

A scalable parallel black oil simulator on distributed memory parallel computers

NASA Astrophysics Data System (ADS)

Wang, Kun; Liu, Hui; Chen, Zhangxin

2015-11-01

This paper presents our work on developing a parallel black oil simulator for distributed memory computers based on our in-house parallel platform. The parallel simulator is designed to overcome the performance issues of common simulators that are implemented for personal computers and workstations. The finite difference method is applied to discretize the black oil model. In addition, some advanced techniques are employed to strengthen the robustness and parallel scalability of the simulator, including an inexact Newton method, matrix decoupling methods, and algebraic multigrid methods. A new multi-stage preconditioner is proposed to accelerate the solution of linear systems from the Newton methods. Numerical experiments show that our simulator is scalable and efficient, and is capable of simulating extremely large-scale black oil problems with tens of millions of grid blocks using thousands of MPI processes on parallel computers.

Mesh Algorithms for PDE with Sieve I: Mesh Distribution

DOE PAGES

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

Numerical investigation of combustion phenomena in pulse detonation engine with different fuels

NASA Astrophysics Data System (ADS)

Alam, Noor; Sharma, K. K.; Pandey, K. M.

2018-05-01

The effects of different fuel-air mixture on the cyclic operation of pulse detonation engine (PDE) are numerically investigated. The present simulation is to be consider 1200 mm long straight tube combustor channel and 60 mm internal diameter, and filled with stoichiometric ethane-air and ethylene-air (C2H6-air & C2H4) fuel mixture at atmospheric pressure and temperature of 0.1 MPa and 300 K respectively. The obstacles of blockage ratio (BR) 0.5 and having 60 mm spacing among them are allocated inside the combustor tube. There are realizable k-ɛ turbulence model used to analyze characteristic of combustion flame. The objective of present simulation is to analyze the variation in combustion mechanism for two different fuels with one-step reduced chemical reaction model. The obstacles were creating perturbation inside the PDE tube. Therefore, flame surface area increases and reduces deflagration-to-detonation transition (DDT) run-up length.

Pulse Detonation Engine Test Bed Developed

NASA Technical Reports Server (NTRS)

Breisacher, Kevin J.

2002-01-01

A detonation is a supersonic combustion wave. A Pulse Detonation Engine (PDE) repetitively creates a series of detonation waves to take advantage of rapid burning and high peak pressures to efficiently produce thrust. NASA Glenn Research Center's Combustion Branch has developed a PDE test bed that can reproduce the operating conditions that might be encountered in an actual engine. It allows the rapid and cost-efficient evaluation of the technical issues and technologies associated with these engines. The test bed is modular in design. It consists of various length sections of both 2- and 2.6- in. internal-diameter combustor tubes. These tubes can be bolted together to create a variety of combustor configurations. A series of bosses allow instrumentation to be inserted on the tubes. Dynamic pressure sensors and heat flux gauges have been used to characterize the performance of the test bed. The PDE test bed is designed to utilize an existing calorimeter (for heat load measurement) and windowed (for optical access) combustor sections. It uses hydrogen as the fuel, and oxygen and nitrogen are mixed to simulate air. An electronic controller is used to open the hydrogen and air valves (or a continuous flow of air is used) and to fire the spark at the appropriate times. Scheduled tests on the test bed include an evaluation of the pumping ability of the train of detonation waves for use in an ejector and an evaluation of the pollutants formed in a PDE combustor. Glenn's Combustion Branch uses the National Combustor Code (NCC) to perform numerical analyses of PDE's as well as to evaluate alternative detonative combustion devices. Pulse Detonation Engine testbed.

A new method for extracting near-surface mass-density anomalies from land-based gravity data, based on a special case of Poisson's PDE at the Earth's surface: A case study of salt diapirs in the south of Iran

NASA Astrophysics Data System (ADS)

AllahTavakoli, Y.; Safari, A.; Ardalan, A.; Bahroudi, A.

2015-12-01

The current research provides a method for tracking near-surface mass-density anomalies via using only land-based gravity data, which is based on a special version of Poisson's Partial Differential Equation (PDE) of the gravitational field at Earth's surface. The research demonstrates how the Poisson's PDE can provide us with a capability to extract the near-surface mass-density anomalies from land-based gravity data. Herein, this version of the Poisson's PDE is mathematically introduced to the Earth's surface and then it is used to develop the new method for approximating the mass-density via derivatives of the Earth's gravitational field (i.e. via the gradient tensor). Herein, the author believes that the PDE can give us new knowledge about the behavior of the Earth's gravitational field at the Earth's surface which can be so useful for developing new methods of Earth's mass-density determination. In a case study, the proposed method is applied to a set of gravity stations located in the south of Iran. The results were numerically validated via certain knowledge about the geological structures in the area of the case study. Also, the method was compared with two standard methods of mass-density determination. All the numerical experiments show that the proposed approach is well-suited for tracking near-surface mass-density anomalies via using only the gravity data. Finally, the approach is also applied to some petroleum exploration studies of salt diapirs in the south of Iran.

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

PubMed Central

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

2015-01-01

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

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

PubMed Central

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

2011-01-01

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

Hybrid Solution-Adaptive Unstructured Cartesian Method for Large-Eddy Simulation of Detonation in Multi-Phase Turbulent Reactive Mixtures

DTIC Science & Technology

2012-03-27

pulse- detonation engines ( PDE ), stage separation, supersonic cav- ity oscillations, hypersonic aerodynamics, detonation induced structural...ADAPTIVE UNSTRUCTURED CARTESIAN METHOD FOR LARGE-EDDY SIMULATION OF DETONATION IN MULTI-PHASE TURBULENT REACTIVE MIXTURES 5b. GRANT NUMBER FA9550...CCL Report TR-2012-03-03 Hybrid Solution-Adaptive Unstructured Cartesian Method for Large-Eddy Simulation of Detonation in Multi-Phase Turbulent

Random number generators for large-scale parallel Monte Carlo simulations on FPGA

NASA Astrophysics Data System (ADS)

Lin, Y.; Wang, F.; Liu, B.

2018-05-01

Through parallelization, field programmable gate array (FPGA) can achieve unprecedented speeds in large-scale parallel Monte Carlo (LPMC) simulations. FPGA presents both new constraints and new opportunities for the implementations of random number generators (RNGs), which are key elements of any Monte Carlo (MC) simulation system. Using empirical and application based tests, this study evaluates all of the four RNGs used in previous FPGA based MC studies and newly proposed FPGA implementations for two well-known high-quality RNGs that are suitable for LPMC studies on FPGA. One of the newly proposed FPGA implementations: a parallel version of additive lagged Fibonacci generator (Parallel ALFG) is found to be the best among the evaluated RNGs in fulfilling the needs of LPMC simulations on FPGA.

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

NASA Astrophysics Data System (ADS)

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

2017-11-01

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

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

PubMed

Zhu, Bing; Strada, Samuel J

2007-01-01

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

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

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

Estep, Donald

2015-11-30

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

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

PubMed

Granovsky, A E; Artemyev, N O

2001-06-15

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

Creating Weather System Ensembles Through Synergistic Process Modeling and Machine Learning

NASA Astrophysics Data System (ADS)

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

2017-12-01

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

Characterising the three-dimensional ozone distribution of a tidally locked Earth-like planet

NASA Astrophysics Data System (ADS)

Proedrou, Elisavet; Hocke, Klemens

2016-06-01

We simulate the 3D ozone distribution of a tidally locked Earth-like exoplanet using the high-resolution, 3D chemistry-climate model CESM1(WACCM) and study how the ozone layer of a tidally locked Earth (TLE) (Ω _{TLE}= 1/365 days) differs from that of our present-day Earth (PDE) (Ω _{PDE}= 1/1 day). The middle atmosphere reaches a steady state asymptotically within the first 80 days of the simulation. An upwelling, centred on the subsolar point, is present on the day side while a downwelling, centred on the antisolar point, is present on the night side. In the mesosphere, we find similar global ozone distributions for the TLE and the PDE, with decreased ozone on the day side and enhanced ozone on the night side. In the lower mesosphere, a jet stream transitions into a large-scale vortex around a low-pressure system, located at low latitudes of the TLE night side. In the middle stratosphere, the concentration of odd oxygen is approximately equal to that of the ozone [({O}x) ≈ ({O}3)]. At these altitudes, the lifetime of odd oxygen is ˜16 h and the transport processes significantly contribute to the global distribution of stratospheric ozone. Compared to the PDE, where the strong Coriolis force acts as a mixing barrier between low and high latitudes, the transport processes of the TLE are governed by jet streams variable in the zonal and meridional directions. In the middle stratosphere of the TLE, we find high ozone values on the day side, due to the increased production of atomic oxygen on the day side, where it immediately recombines with molecular oxygen to form ozone. In contrast, the ozone is depleted on the night side, due to changes in the solar radiation distribution and the presence of a downwelling. As a result of the reduced Coriolis force, the tropical and extratropical air masses are well mixed and the global temperature distribution of the TLE stratosphere has smaller horizontal gradients than the PDE. Compared to the PDE, the total ozone column global mean is reduced by ˜19.3 %. The day side and the night side total ozone column means are reduced by 23.21 and 15.52 %, respectively. Finally, we present the total ozone column (TOC) maps as viewed by a remote observer for four phases of the TLE during its revolution around the star. The mean TOC values of the four phases of the TLE vary by up to 23 %.

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

PubMed

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

2002-03-26

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

Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.

PubMed

Goto, Taiji; Shiina, Akiko; Yoshino, Toshiharu; Mizukami, Kiyoshi; Hirahara, Kazuki; Suzuki, Osamu; Sogawa, Yoshitaka; Takahashi, Tomoko; Mikkaichi, Tsuyoshi; Nakao, Naoki; Takahashi, Mizuki; Hasegawa, Masashi; Sasaki, Shigeki

2013-11-15

5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200 nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3 nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16 mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-α) production in mouse splenocytes (IC50=0.21 nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0 mg/kg, i.t.). Copyright © 2013 Elsevier Ltd. All rights reserved.

Research on odor interaction between aldehyde compounds via a partial differential equation (PDE) model.

PubMed

Yan, Luchun; Liu, Jiemin; Qu, Chen; Gu, Xingye; Zhao, Xia

2015-01-28

In order to explore the odor interaction of binary odor mixtures, a series of odor intensity evaluation tests were performed using both individual components and binary mixtures of aldehydes. Based on the linear relation between the logarithm of odor activity value and odor intensity of individual substances, the relationship between concentrations of individual constituents and their joint odor intensity was investigated by employing a partial differential equation (PDE) model. The obtained results showed that the binary odor interaction was mainly influenced by the mixing ratio of two constituents, but not the concentration level of an odor sample. Besides, an extended PDE model was also proposed on the basis of the above experiments. Through a series of odor intensity matching tests for several different binary odor mixtures, the extended PDE model was proved effective at odor intensity prediction. Furthermore, odorants of the same chemical group and similar odor type exhibited similar characteristics in the binary odor interaction. The overall results suggested that the PDE model is a more interpretable way of demonstrating the odor interactions of binary odor mixtures.

Targeted Ablation of the Pde6h Gene in Mice Reveals Cross-species Differences in Cone and Rod Phototransduction Protein Isoform Inventory*

PubMed Central

Brennenstuhl, Christina; Tanimoto, Naoyuki; Burkard, Markus; Wagner, Rebecca; Bolz, Sylvia; Trifunovic, Dragana; Kabagema-Bilan, Clement; Paquet-Durand, Francois; Beck, Susanne C.; Huber, Gesine; Seeliger, Mathias W.; Ruth, Peter; Wissinger, Bernd; Lukowski, Robert

2015-01-01

Phosphodiesterase-6 (PDE6) is a multisubunit enzyme that plays a key role in the visual transduction cascade in rod and cone photoreceptors. Each type of photoreceptor utilizes discrete catalytic and inhibitory PDE6 subunits to fulfill its physiological tasks, i.e. the degradation of cyclic guanosine-3′,5′-monophosphate at specifically tuned rates and kinetics. Recently, the human PDE6H gene was identified as a novel locus for autosomal recessive (incomplete) color blindness. However, the three different classes of cones were not affected to the same extent. Short wave cone function was more preserved than middle and long wave cone function indicating that some basic regulation of the PDE6 multisubunit enzyme was maintained albeit by a unknown mechanism. To study normal and disease-related functions of cone Pde6h in vivo, we generated Pde6h knock-out (Pde6h−/−) mice. Expression of PDE6H in murine eyes was restricted to both outer segments and synaptic terminals of short and long/middle cone photoreceptors, whereas Pde6h−/− retinae remained PDE6H-negative. Combined in vivo assessment of retinal morphology with histomorphological analyses revealed a normal overall integrity of the retinal organization and an unaltered distribution of the different cone photoreceptor subtypes upon Pde6h ablation. In contrast to human patients, our electroretinographic examinations of Pde6h−/− mice suggest no defects in cone/rod-driven retinal signaling and therefore preserved visual functions. To this end, we were able to demonstrate the presence of rod PDE6G in cones indicating functional substitution of PDE6. The disparities between human and murine phenotypes caused by mutant Pde6h/PDE6H suggest species-to-species differences in the vulnerability of biochemical and neurosensory pathways of the visual signal transduction system. PMID:25739440

Effects of PDE4 Pathway Inhibition in Rat Experimental Stroke

PubMed Central

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

2015-01-01

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

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

PubMed

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

2003-03-25

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

Evaluation of vardenafil for the treatment of subjective tinnitus: a controlled pilot study

PubMed Central

Mazurek, Birgit; Haupt, Heidemarie; Szczepek, Agnieszka J; Sandmann, Jörg; Gross, Johann; Klapp, Burghard F; Kiesewetter, Holger; Kalus, Ulrich; Stöver, Timo; Caffier, Philipp P

2009-01-01

Background Vardenafil (Levitra®) represents a potent and highly selective phosphodiesterase type 5 (PDE5) inhibitor, which is established for treatment of various diseases. There are several unpublished reports from patients stating that vardenafil has a considerable therapeutic effect on their concomitant tinnitus. This pilot study was conducted to specifically assess the effect of vardenafil in patients with chronic tinnitus. Methods This trial was based on a prospective, randomized, double-blind, placebo-controlled, parallel group design. Fourty-two consecutive subjects with mon- or binaural chronic tinnitus received 10 mg vardenafil (N = 21) or matching placebo tablets (N = 21) administered orally twice a day over a period of 12 weeks. Clinical examination and data acquisition took place at each visit: at baseline, after 4 weeks, after 12 weeks (end of treatment with study medication), and at non-medicated follow-up after 16 weeks. Assessment of clinical effectiveness was based on a standardized tinnitus questionnaire (TQ), the Short Form 36 health survey (SF-36), audiometric measurements (mode, pitch and loudness of tinnitus; auditory thresholds) and biomarkers of oxidative stress in patients' blood (malondialdehyde, protein carbonyl, homocysteine and total antioxidative status). Therapeutic efficacy was evaluated by comparison of subjective and objective parameters with baseline data between both treatment groups (ANCOVA). Results Vardenafil had no superior efficacy over placebo in the treatment of chronic tinnitus during this study. The primary efficacy criterion 'TQ total score' failed to demonstrate significant improvement compared to placebo. Subjective reports of TQ subscales and general quality of life areas (SF-36), objective audiometric examinations as well as investigated biomarkers for oxidative stress did not reveal any significant treatment effects. The safety profile was favorable and consistent with that in other vardenafil studies. Conclusion Although hypoxia and ischemia play a special role in the pathogenesis of tinnitus, the PDE5-inhibitor-induced increase of nitric oxide-mediated vasodilatation exerted no specific influence on tinnitus symptomatology. Considering the unclear risk of rarely associated hearing impairment, systemic application of vardenafil or other PDE5 inhibitors prove to be not appropriate for therapy of chronic tinnitus. PMID:19222841

AKAP3 Selectively Binds PDE4A Isoforms in Bovine Spermatozoa1

PubMed Central

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

2006-01-01

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

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

PubMed

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

2015-09-15

Recent studies have demonstrated that functionally discrete pools of phosphodiesterase (PDE) activity regulate distinct cellular functions. While the importance of localized pools of enzyme activity has become apparent, few studies have estimated enzyme activity within discrete subcellular compartments. Here we present an approach to estimate near-membrane PDE activity. First, total PDE activity is measured using traditional PDE activity assays. Second, known cAMP concentrations are dialyzed into single cells and the spatial spread of cAMP is monitored using cyclic nucleotide-gated channels. Third, mathematical models are used to estimate the spatial distribution of PDE activity within cells. Using this three-tiered approach, we observed two pharmacologically distinct pools of PDE activity, a rolipram-sensitive pool and an 8-methoxymethyl IBMX (8MM-IBMX)-sensitive pool. We observed that the rolipram-sensitive PDE (PDE4) was primarily responsible for cAMP hydrolysis near the plasma membrane. Finally, we observed that PDE4 was capable of blunting cAMP levels near the plasma membrane even when 100 μM cAMP were introduced into the cell via a patch pipette. Two compartment models predict that PDE activity near the plasma membrane, near cyclic nucleotide-gated channels, was significantly lower than total cellular PDE activity and that a slow spatial spread of cAMP allowed PDE activity to effectively hydrolyze near-membrane cAMP. These results imply that cAMP levels near the plasma membrane are distinct from those in other subcellular compartments; PDE activity is not uniform within cells; and localized pools of AC and PDE activities are responsible for controlling cAMP levels within distinct subcellular compartments. Copyright © 2015 the American Physiological Society.

Kaempferia parviflora, a plant used in traditional medicine to enhance sexual performance contains large amounts of low affinity PDE5 inhibitors

PubMed Central

Temkitthawon, Prapapan; Hinds, Thomas R.; Beavo, Joseph A.; Viyoch, Jarupa; Suwanborirux, Khanit; Pongamornkul, Wittaya; Sawasdee, Pattara; Ingkaninan, Kornkanok

2014-01-01

Aim of the study A number of medicinal plants are used in traditional medicine to treat erectile dysfunction. Since cyclic nucleotide PDEs inhibitors underlie several current treatments for this condition, we sought to show whether these plants might contain substantial amounts of PDE5 inhibitors. Materials and methods Forty one plant extracts and eight 7-methoxyflavones from Kaempferia parviflora Wall. ex Baker were screened for PDE5 and PDE6 inhibitory activities using the two-step radioactive assay. The PDE5 and PDE6 were prepared from mice lung and chicken retinas, respectively. All plant extracts were tested at 50 μg/ml whereas the pure compounds were tested at 10 μM. Results From forty one plant extracts tested, four showed the PDE5 inhibitory effect. The chemical constituents isolated from rhizomes of Kaempferia parviflora were further investigated on inhibitory activity against PDE5 and PDE6. The results showed that 7-methoxyflavones from this plant showed inhibition toward both enzymes. The most potent PDE5 inhibitor was 5,7-dimethoxyflavone (IC50 = 10.64 ± 2.09 μM, selectivity on PDE5 over PDE6 = 3.71). Structure activity relationship showed that the methoxyl group at C-5 position of 7-methoxyflavones was necessary for PDE5 inhibition. Conclusions Kaempferia parviflora rhizome extract and its 7-methoxyflavone constituents had moderate inhibitory activity against PDE5. This finding provides an explanation for enhancing sexual performance in the traditional use of Kaempferia parviflora. Moreover, 5,7-dimethoxyflavones should make a useful lead compound to further develop clinically efficacious PDE5 inhibitors. PMID:21884777

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

PubMed

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

2014-08-01

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

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

PubMed

Granovsky, A E; Artemyev, N O

2001-11-06

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

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

PubMed Central

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

2015-01-01

Recent studies have demonstrated that functionally discrete pools of phosphodiesterase (PDE) activity regulate distinct cellular functions. While the importance of localized pools of enzyme activity has become apparent, few studies have estimated enzyme activity within discrete subcellular compartments. Here we present an approach to estimate near-membrane PDE activity. First, total PDE activity is measured using traditional PDE activity assays. Second, known cAMP concentrations are dialyzed into single cells and the spatial spread of cAMP is monitored using cyclic nucleotide-gated channels. Third, mathematical models are used to estimate the spatial distribution of PDE activity within cells. Using this three-tiered approach, we observed two pharmacologically distinct pools of PDE activity, a rolipram-sensitive pool and an 8-methoxymethyl IBMX (8MM-IBMX)-sensitive pool. We observed that the rolipram-sensitive PDE (PDE4) was primarily responsible for cAMP hydrolysis near the plasma membrane. Finally, we observed that PDE4 was capable of blunting cAMP levels near the plasma membrane even when 100 μM cAMP were introduced into the cell via a patch pipette. Two compartment models predict that PDE activity near the plasma membrane, near cyclic nucleotide-gated channels, was significantly lower than total cellular PDE activity and that a slow spatial spread of cAMP allowed PDE activity to effectively hydrolyze near-membrane cAMP. These results imply that cAMP levels near the plasma membrane are distinct from those in other subcellular compartments; PDE activity is not uniform within cells; and localized pools of AC and PDE activities are responsible for controlling cAMP levels within distinct subcellular compartments. PMID:26201952

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

PubMed Central

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

2016-01-01

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

The limit of photoreceptor sensitivity: molecular mechanisms of dark noise in retinal cones.

PubMed

Holcman, David; Korenbrot, Juan I

2005-06-01

Detection threshold in cone photoreceptors requires the simultaneous absorption of several photons because single photon photocurrent is small in amplitude and does not exceed intrinsic fluctuations in the outer segment dark current (dark noise). To understand the mechanisms that limit light sensitivity, we characterized the molecular origin of dark noise in intact, isolated bass single cones. Dark noise is caused by continuous fluctuations in the cytoplasmic concentrations of both cGMP and Ca(2+) that arise from the activity in darkness of both guanylate cyclase (GC), the enzyme that synthesizes cGMP, and phosphodiesterase (PDE), the enzyme that hydrolyzes it. In cones loaded with high concentration Ca(2+) buffering agents, we demonstrate that variation in cGMP levels arise from fluctuations in the mean PDE enzymatic activity. The rates of PDE activation and inactivation determine the quantitative characteristics of the dark noise power density spectrum. We developed a mathematical model based on the dynamics of PDE activity that accurately predicts this power spectrum. Analysis of the experimental data with the theoretical model allows us to determine the rates of PDE activation and deactivation in the intact photoreceptor. In fish cones, the mean lifetime of active PDE at room temperature is approximately 55 ms. In nonmammalian rods, in contrast, active PDE lifetime is approximately 555 ms. This remarkable difference helps explain why cones are noisier than rods and why cone photocurrents are smaller in peak amplitude and faster in time course than those in rods. Both these features make cones less light sensitive than rods.

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

PubMed Central

Kelly, Michy P.

2017-01-01

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

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

PubMed

Du, Haixia; Qin, Hong

2007-01-01

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

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.

Myocardial Response to Milrinone in Single Right Ventricle Heart Disease.

PubMed

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

2016-07-01

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

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.

A Systems Approach to Scalable Transportation Network Modeling

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

Perumalla, Kalyan S

2006-01-01

Emerging needs in transportation network modeling and simulation are raising new challenges with respect to scal-ability of network size and vehicular traffic intensity, speed of simulation for simulation-based optimization, and fidel-ity of vehicular behavior for accurate capture of event phe-nomena. Parallel execution is warranted to sustain the re-quired detail, size and speed. However, few parallel simulators exist for such applications, partly due to the challenges underlying their development. Moreover, many simulators are based on time-stepped models, which can be computationally inefficient for the purposes of modeling evacuation traffic. Here an approach is presented to de-signing a simulator with memory andmore » speed efficiency as the goals from the outset, and, specifically, scalability via parallel execution. The design makes use of discrete event modeling techniques as well as parallel simulation meth-ods. Our simulator, called SCATTER, is being developed, incorporating such design considerations. Preliminary per-formance results are presented on benchmark road net-works, showing scalability to one million vehicles simu-lated on one processor.« less

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

PubMed Central

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

2009-01-01

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

MYOCARDIAL RESPONSE TO MILRINONE IN SINGLE RIGHT VENTRICLE HEART DISEASE

PubMed Central

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

2016-01-01

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

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

PubMed

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

2013-05-01

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

Hybrid approaches for multiple-species stochastic reaction–diffusion models

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

Spill, Fabian, E-mail: fspill@bu.edu; Department of Mechanical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139; Guerrero, Pilar

2015-10-15

Reaction–diffusion models are used to describe systems in fields as diverse as physics, chemistry, ecology and biology. The fundamental quantities in such models are individual entities such as atoms and molecules, bacteria, cells or animals, which move and/or react in a stochastic manner. If the number of entities is large, accounting for each individual is inefficient, and often partial differential equation (PDE) models are used in which the stochastic behaviour of individuals is replaced by a description of the averaged, or mean behaviour of the system. In some situations the number of individuals is large in certain regions and smallmore » in others. In such cases, a stochastic model may be inefficient in one region, and a PDE model inaccurate in another. To overcome this problem, we develop a scheme which couples a stochastic reaction–diffusion system in one part of the domain with its mean field analogue, i.e. a discretised PDE model, in the other part of the domain. The interface in between the two domains occupies exactly one lattice site and is chosen such that the mean field description is still accurate there. In this way errors due to the flux between the domains are small. Our scheme can account for multiple dynamic interfaces separating multiple stochastic and deterministic domains, and the coupling between the domains conserves the total number of particles. The method preserves stochastic features such as extinction not observable in the mean field description, and is significantly faster to simulate on a computer than the pure stochastic model. - Highlights: • A novel hybrid stochastic/deterministic reaction–diffusion simulation method is given. • Can massively speed up stochastic simulations while preserving stochastic effects. • Can handle multiple reacting species. • Can handle moving boundaries.« less

PDE4 as a target for cognition enhancement

PubMed Central

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

2014-01-01

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

Prestack reverse time migration for tilted transversely isotropic media

NASA Astrophysics Data System (ADS)

Jang, Seonghyung; Hien, Doan Huy

2013-04-01

According to having interest in unconventional resource plays, anisotropy problem is naturally considered as an important step for improving the seismic image quality. Although it is well known prestack depth migration for the seismic reflection data is currently one of the powerful tools for imaging complex geological structures, it may lead to migration error without considering anisotropy. Asymptotic analysis of wave propagation in transversely isotropic (TI) media yields a dispersion relation of couple P- and SV wave modes that can be converted to a fourth order scalar partial differential equation (PDE). By setting the shear wave velocity equal zero, the fourth order PDE, called an acoustic wave equation for TI media, can be reduced to couple of second order PDE systems and we try to solve the second order PDE by the finite difference method (FDM). The result of this P wavefield simulation is kinematically similar to elastic and anisotropic wavefield simulation. We develop prestack depth migration algorithm for tilted transversely isotropic media using reverse time migration method (RTM). RTM is a method for imaging the subsurface using inner product of source wavefield extrapolation in forward and receiver wavefield extrapolation in backward. We show the subsurface image in TTI media using the inner product of partial derivative wavefield with respect to physical parameters and observation data. Since the partial derivative wavefields with respect to the physical parameters require extremely huge computing time, so we implemented the imaging condition by zero lag crosscorrelation of virtual source and back propagating wavefield instead of partial derivative wavefields. The virtual source is calculated directly by solving anisotropic acoustic wave equation, the back propagating wavefield on the other hand is calculated by the shot gather used as the source function in the anisotropic acoustic wave equation. According to the numerical model test for a simple geological model including syncline and anticline, the prestack depth migration using TTI-RTM in weak anisotropic media shows the subsurface image is similar to the true geological model used to generate the shot gathers.

Equalizer technology followed by DIGE-based proteomics for detection of cellular proteins in artificial peritoneal dialysis effluents.

PubMed

Lichtenauer, Anton Michael; Herzog, Rebecca; Tarantino, Silvia; Aufricht, Christoph; Kratochwill, Klaus

2014-05-01

Peritoneal dialysis effluent (PDE) represents a rich pool of potential biomarkers for monitoring disease and therapy. Until now, proteomic studies have been hindered by the plasma-like composition of the PDE. Beads covered with a peptide library are a promising approach to remove high abundant proteins and concentrate the sample in one step. In this study, a novel approach for proteomic biomarker identification in PDEs consisting of a depletion and concentration step followed by 2D gel based protein quantification was established. To prove this experimental concept a model system of artificial PDEs was established by spiking unused peritoneal dialysis (PD) fluids with cellular proteins reflecting control conditions or cell stress. Using this procedure, we were able to reduce the amount of high abundant plasma proteins and concentrate low abundant proteins while preserving changes in abundance of proteins with cellular origin. The alterations in abundance of the investigated marker for cell stress, the heat shock proteins, showed similar abundance profiles in the artificial PDE as in pure cell culture samples. Our results demonstrate the efficacy of this system in detecting subtle changes in cellular protein expression triggered by unphysiological stress stimuli typical in PD, which could serve as biomarkers. Further studies using patients' PDE will be necessary to prove the concept in clinical PD and to assess whether this technique is also informative regarding enriching low abundant plasma derived protein biomarker in the PDE. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A derivation and scalable implementation of the synchronous parallel kinetic Monte Carlo method for simulating long-time dynamics

NASA Astrophysics Data System (ADS)

Byun, Hye Suk; El-Naggar, Mohamed Y.; Kalia, Rajiv K.; Nakano, Aiichiro; Vashishta, Priya

2017-10-01

Kinetic Monte Carlo (KMC) simulations are used to study long-time dynamics of a wide variety of systems. Unfortunately, the conventional KMC algorithm is not scalable to larger systems, since its time scale is inversely proportional to the simulated system size. A promising approach to resolving this issue is the synchronous parallel KMC (SPKMC) algorithm, which makes the time scale size-independent. This paper introduces a formal derivation of the SPKMC algorithm based on local transition-state and time-dependent Hartree approximations, as well as its scalable parallel implementation based on a dual linked-list cell method. The resulting algorithm has achieved a weak-scaling parallel efficiency of 0.935 on 1024 Intel Xeon processors for simulating biological electron transfer dynamics in a 4.2 billion-heme system, as well as decent strong-scaling parallel efficiency. The parallel code has been used to simulate a lattice of cytochrome complexes on a bacterial-membrane nanowire, and it is broadly applicable to other problems such as computational synthesis of new materials.

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

PubMed

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

2010-05-01

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

Defining the Phosphodiesterase Superfamily Members in Rat Brain Microvessels

PubMed Central

2011-01-01

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

Parallelization and automatic data distribution for nuclear reactor simulations

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

Liebrock, L.M.

1997-07-01

Detailed attempts at realistic nuclear reactor simulations currently take many times real time to execute on high performance workstations. Even the fastest sequential machine can not run these simulations fast enough to ensure that the best corrective measure is used during a nuclear accident to prevent a minor malfunction from becoming a major catastrophe. Since sequential computers have nearly reached the speed of light barrier, these simulations will have to be run in parallel to make significant improvements in speed. In physical reactor plants, parallelism abounds. Fluids flow, controls change, and reactions occur in parallel with only adjacent components directlymore » affecting each other. These do not occur in the sequentialized manner, with global instantaneous effects, that is often used in simulators. Development of parallel algorithms that more closely approximate the real-world operation of a reactor may, in addition to speeding up the simulations, actually improve the accuracy and reliability of the predictions generated. Three types of parallel architecture (shared memory machines, distributed memory multicomputers, and distributed networks) are briefly reviewed as targets for parallelization of nuclear reactor simulation. Various parallelization models (loop-based model, shared memory model, functional model, data parallel model, and a combined functional and data parallel model) are discussed along with their advantages and disadvantages for nuclear reactor simulation. A variety of tools are introduced for each of the models. Emphasis is placed on the data parallel model as the primary focus for two-phase flow simulation. Tools to support data parallel programming for multiple component applications and special parallelization considerations are also discussed.« less

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

PubMed Central

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

1996-01-01

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

Partial differential equation transform — Variational formulation and Fourier analysis

PubMed Central

Wang, Yang; Wei, Guo-Wei; Yang, Siyang

2011-01-01

Nonlinear partial differential equation (PDE) models are established approaches for image/signal processing, data analysis and surface construction. Most previous geometric PDEs are utilized as low-pass filters which give rise to image trend information. In an earlier work, we introduced mode decomposition evolution equations (MoDEEs), which behave like high-pass filters and are able to systematically provide intrinsic mode functions (IMFs) of signals and images. Due to their tunable time-frequency localization and perfect reconstruction, the operation of MoDEEs is called a PDE transform. By appropriate selection of PDE transform parameters, we can tune IMFs into trends, edges, textures, noise etc., which can be further utilized in the secondary processing for various purposes. This work introduces the variational formulation, performs the Fourier analysis, and conducts biomedical and biological applications of the proposed PDE transform. The variational formulation offers an algorithm to incorporate two image functions and two sets of low-pass PDE operators in the total energy functional. Two low-pass PDE operators have different signs, leading to energy disparity, while a coupling term, acting as a relative fidelity of two image functions, is introduced to reduce the disparity of two energy components. We construct variational PDE transforms by using Euler-Lagrange equation and artificial time propagation. Fourier analysis of a simplified PDE transform is presented to shed light on the filter properties of high order PDE transforms. Such an analysis also offers insight on the parameter selection of the PDE transform. The proposed PDE transform algorithm is validated by numerous benchmark tests. In one selected challenging example, we illustrate the ability of PDE transform to separate two adjacent frequencies of sin(x) and sin(1.1x). Such an ability is due to PDE transform’s controllable frequency localization obtained by adjusting the order of PDEs. The frequency selection is achieved either by diffusion coefficients or by propagation time. Finally, we explore a large number of practical applications to further demonstrate the utility of proposed PDE transform. PMID:22207904

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

PubMed Central

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

2016-01-01

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

A pathophysiological role of PDE3 in allergic airway inflammation

PubMed Central

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

2018-01-01

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

Proof of concept of an artificial muscle: theoretical model, numerical model, and hardware experiment.

PubMed

Haeufle, D F B; Günther, M; Blickhan, R; Schmitt, S

2011-01-01

Recently, the hyperbolic Hill-type force-velocity relation was derived from basic physical components. It was shown that a contractile element CE consisting of a mechanical energy source (active element AE), a parallel damper element (PDE), and a serial element (SE) exhibits operating points with hyperbolic force-velocity dependency. In this paper, the contraction dynamics of this CE concept were analyzed in a numerical simulation of quick release experiments against different loads. A hyperbolic force-velocity relation was found. The results correspond to measurements of the contraction dynamics of a technical prototype. Deviations from the theoretical prediction could partly be explained by the low stiffness of the SE, which was modeled analog to the metal spring in the hardware prototype. The numerical model and hardware prototype together, are a proof of this CE concept and can be seen as a well-founded starting point for the development of Hill-type artificial muscles. This opens up new vistas for the technical realization of natural movements with rehabilitation devices. © 2011 IEEE

Dynamic optimization of open-loop input signals for ramp-up current profiles in tokamak plasmas

NASA Astrophysics Data System (ADS)

Ren, Zhigang; Xu, Chao; Lin, Qun; Loxton, Ryan; Teo, Kok Lay

2016-03-01

Establishing a good current spatial profile in tokamak fusion reactors is crucial to effective steady-state operation. The evolution of the current spatial profile is related to the evolution of the poloidal magnetic flux, which can be modeled in the normalized cylindrical coordinates using a parabolic partial differential equation (PDE) called the magnetic diffusion equation. In this paper, we consider the dynamic optimization problem of attaining the best possible current spatial profile during the ramp-up phase of the tokamak. We first use the Galerkin method to obtain a finite-dimensional ordinary differential equation (ODE) model based on the original magnetic diffusion PDE. Then, we combine the control parameterization method with a novel time-scaling transformation to obtain an approximate optimal parameter selection problem, which can be solved using gradient-based optimization techniques such as sequential quadratic programming (SQP). This control parameterization approach involves approximating the tokamak input signals by piecewise-linear functions whose slopes and break-points are decision variables to be optimized. We show that the gradient of the objective function with respect to the decision variables can be computed by solving an auxiliary dynamic system governing the state sensitivity matrix. Finally, we conclude the paper with simulation results for an example problem based on experimental data from the DIII-D tokamak in San Diego, California.

Validation of PDE9A Gene Identified in GWAS Showing Strong Association with Milk Production Traits in Chinese Holstein.

PubMed

Yang, Shao-Hua; Bi, Xiao-Jun; Xie, Yan; Li, Cong; Zhang, Sheng-Li; Zhang, Qin; Sun, Dong-Xiao

2015-11-05

Phosphodiesterase9A (PDE9A) is a cyclic guanosine monophosphate (cGMP)-specific enzyme widely expressed among the tissues, which is important in activating cGMP-dependent signaling pathways. In our previous genome-wide association study, a single nucleotide polymorphism (SNP) (BTA-55340-no-rs(b)) located in the intron 14 of PDE9A, was found to be significantly associated with protein yield. In addition, we found that PDE9A was highly expressed in mammary gland by analyzing its mRNA expression in different tissues. The objectives of this study were to identify genetic polymorphisms of PDE9A and to determine the effects of these variants on milk production traits in dairy cattle. DNA sequencing identified 11 single nucleotide polymorphisms (SNPs) and six SNPs in 5' regulatory region were genotyped to test for the subsequent association analyses. After Bonferroni correction for multiple testing, all these identified SNPs were statistically significant for one or more milk production traits (p < 0.0001~0.0077). Interestingly, haplotype-based association analysis revealed similar effects on milk production traits (p < 0.01). In follow-up RNA expression analyses, two SNPs (c.-1376 G>A, c.-724 A>G) were involved in the regulation of gene expression. Consequently, our findings provide confirmatory evidences for associations of PDE9A variants with milk production traits and these identified SNPs may serve as genetic markers to accelerate Chinese Holstein breeding program.

A Metascalable Computing Framework for Large Spatiotemporal-Scale Atomistic Simulations

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

Nomura, K; Seymour, R; Wang, W

2009-02-17

A metascalable (or 'design once, scale on new architectures') parallel computing framework has been developed for large spatiotemporal-scale atomistic simulations of materials based on spatiotemporal data locality principles, which is expected to scale on emerging multipetaflops architectures. The framework consists of: (1) an embedded divide-and-conquer (EDC) algorithmic framework based on spatial locality to design linear-scaling algorithms for high complexity problems; (2) a space-time-ensemble parallel (STEP) approach based on temporal locality to predict long-time dynamics, while introducing multiple parallelization axes; and (3) a tunable hierarchical cellular decomposition (HCD) parallelization framework to map these O(N) algorithms onto a multicore cluster based onmore » hybrid implementation combining message passing and critical section-free multithreading. The EDC-STEP-HCD framework exposes maximal concurrency and data locality, thereby achieving: (1) inter-node parallel efficiency well over 0.95 for 218 billion-atom molecular-dynamics and 1.68 trillion electronic-degrees-of-freedom quantum-mechanical simulations on 212,992 IBM BlueGene/L processors (superscalability); (2) high intra-node, multithreading parallel efficiency (nanoscalability); and (3) nearly perfect time/ensemble parallel efficiency (eon-scalability). The spatiotemporal scale covered by MD simulation on a sustained petaflops computer per day (i.e. petaflops {center_dot} day of computing) is estimated as NT = 2.14 (e.g. N = 2.14 million atoms for T = 1 microseconds).« less

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

PubMed

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

2018-03-16

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

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

PubMed Central

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

2009-01-01

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

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

PubMed

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

2017-06-01

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

Implementation of a flexible and scalable particle-in-cell method for massively parallel computations in the mantle convection code ASPECT

NASA Astrophysics Data System (ADS)

Gassmöller, Rene; Bangerth, Wolfgang

2016-04-01

Particle-in-cell methods have a long history and many applications in geodynamic modelling of mantle convection, lithospheric deformation and crustal dynamics. They are primarily used to track material information, the strain a material has undergone, the pressure-temperature history a certain material region has experienced, or the amount of volatiles or partial melt present in a region. However, their efficient parallel implementation - in particular combined with adaptive finite-element meshes - is complicated due to the complex communication patterns and frequent reassignment of particles to cells. Consequently, many current scientific software packages accomplish this efficient implementation by specifically designing particle methods for a single purpose, like the advection of scalar material properties that do not evolve over time (e.g., for chemical heterogeneities). Design choices for particle integration, data storage, and parallel communication are then optimized for this single purpose, making the code relatively rigid to changing requirements. Here, we present the implementation of a flexible, scalable and efficient particle-in-cell method for massively parallel finite-element codes with adaptively changing meshes. Using a modular plugin structure, we allow maximum flexibility of the generation of particles, the carried tracer properties, the advection and output algorithms, and the projection of properties to the finite-element mesh. We present scaling tests ranging up to tens of thousands of cores and tens of billions of particles. Additionally, we discuss efficient load-balancing strategies for particles in adaptive meshes with their strengths and weaknesses, local particle-transfer between parallel subdomains utilizing existing communication patterns from the finite element mesh, and the use of established parallel output algorithms like the HDF5 library. Finally, we show some relevant particle application cases, compare our implementation to a modern advection-field approach, and demonstrate under which conditions which method is more efficient. We implemented the presented methods in ASPECT (aspect.dealii.org), a freely available open-source community code for geodynamic simulations. The structure of the particle code is highly modular, and segregated from the PDE solver, and can thus be easily transferred to other programs, or adapted for various application cases.

Constitutive Model Calibration via Autonomous Multiaxial Experimentation (Postprint)

DTIC Science & Technology

2016-09-17

test machine. Experimental data is reduced and finite element simulations are conducted in parallel with the test based on experimental strain...data is reduced and finite element simulations are conducted in parallel with the test based on experimental strain conditions. Optimization methods...be used directly in finite element simulations of more complex geometries. Keywords Axial/torsional experimentation • Plasticity • Constitutive model

Critical Software for Human Spaceflight

NASA Technical Reports Server (NTRS)

Preden, Antonio; Kaschner, Jens; Rettig, Felix; Rodriggs, Michael

2017-01-01

The NASA Orion vehicle that will fly to the moon in the next years is propelled along its mission by the European Service Module (ESM), developed by ESA and its prime contractor Airbus Defense and Space. This paper describes the development of the Propulsion Drive Electronics (PDE) Software that provides the interface between the propulsion hardware of the European Service Module with the Orion flight computers, and highlights the challenges that have been faced during the development. Particularly, the specific aspects relevant to Human Spaceflight in an international cooperation are presented, as the compliance to both European and US standards and the software criticality classification to the highest category A. An innovative aspect of the PDE SW is its Time- Triggered Ethernet interface with the Orion Flight Computers, which has never been flown so far on any European spacecraft. Finally the verification aspects are presented, applying the most exigent quality requirements defined in the European Cooperation for Space Standardization (ECSS) standards such as the structural coverage analysis of the object code and the recourse to an independent software verification and validation activity carried on in parallel by a different team.

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

PubMed

Mitra, Jyotirmoy; Bhattacharyya, Debasish

2014-09-01

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

Approaches to Cycle Analysis and Performance Metrics

NASA Technical Reports Server (NTRS)

Parson, Daniel E.

2003-01-01

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

Parallel Signal Processing and System Simulation using aCe

NASA Technical Reports Server (NTRS)

Dorband, John E.; Aburdene, Maurice F.

2003-01-01

Recently, networked and cluster computation have become very popular for both signal processing and system simulation. A new language is ideally suited for parallel signal processing applications and system simulation since it allows the programmer to explicitly express the computations that can be performed concurrently. In addition, the new C based parallel language (ace C) for architecture-adaptive programming allows programmers to implement algorithms and system simulation applications on parallel architectures by providing them with the assurance that future parallel architectures will be able to run their applications with a minimum of modification. In this paper, we will focus on some fundamental features of ace C and present a signal processing application (FFT).

Continuum Modeling and Control of Large Nonuniform Wireless Networks via Nonlinear Partial Differential Equations

DOE PAGES

Zhang, Yang; Chong, Edwin K. P.; Hannig, Jan; ...

2013-01-01

We inmore » troduce a continuum modeling method to approximate a class of large wireless networks by nonlinear partial differential equations (PDEs). This method is based on the convergence of a sequence of underlying Markov chains of the network indexed by N , the number of nodes in the network. As N goes to infinity, the sequence converges to a continuum limit, which is the solution of a certain nonlinear PDE. We first describe PDE models for networks with uniformly located nodes and then generalize to networks with nonuniformly located, and possibly mobile, nodes. Based on the PDE models, we develop a method to control the transmissions in nonuniform networks so that the continuum limit is invariant under perturbations in node locations. This enables the networks to maintain stable global characteristics in the presence of varying node locations.« less

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

PubMed Central

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

1993-01-01

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

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

PubMed Central

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

2012-01-01

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

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

PubMed

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

2010-03-01

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

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

PubMed

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

2013-01-01

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

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

PubMed

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

2007-07-01

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

Massively parallel simulator of optical coherence tomography of inhomogeneous turbid media.

PubMed

Malektaji, Siavash; Lima, Ivan T; Escobar I, Mauricio R; Sherif, Sherif S

2017-10-01

An accurate and practical simulator for Optical Coherence Tomography (OCT) could be an important tool to study the underlying physical phenomena in OCT such as multiple light scattering. Recently, many researchers have investigated simulation of OCT of turbid media, e.g., tissue, using Monte Carlo methods. The main drawback of these earlier simulators is the long computational time required to produce accurate results. We developed a massively parallel simulator of OCT of inhomogeneous turbid media that obtains both Class I diffusive reflectivity, due to ballistic and quasi-ballistic scattered photons, and Class II diffusive reflectivity due to multiply scattered photons. This Monte Carlo-based simulator is implemented on graphic processing units (GPUs), using the Compute Unified Device Architecture (CUDA) platform and programming model, to exploit the parallel nature of propagation of photons in tissue. It models an arbitrary shaped sample medium as a tetrahedron-based mesh and uses an advanced importance sampling scheme. This new simulator speeds up simulations of OCT of inhomogeneous turbid media by about two orders of magnitude. To demonstrate this result, we have compared the computation times of our new parallel simulator and its serial counterpart using two samples of inhomogeneous turbid media. We have shown that our parallel implementation reduced simulation time of OCT of the first sample medium from 407 min to 92 min by using a single GPU card, to 12 min by using 8 GPU cards and to 7 min by using 16 GPU cards. For the second sample medium, the OCT simulation time was reduced from 209 h to 35.6 h by using a single GPU card, and to 4.65 h by using 8 GPU cards, and to only 2 h by using 16 GPU cards. Therefore our new parallel simulator is considerably more practical to use than its central processing unit (CPU)-based counterpart. Our new parallel OCT simulator could be a practical tool to study the different physical phenomena underlying OCT, or to design OCT systems with improved performance. Copyright © 2017 Elsevier B.V. All rights reserved.

Geometry of PDE's. IV

NASA Astrophysics Data System (ADS)

Prástaro, Agostino

2008-02-01

Following our previous results on this subject [R.P. Agarwal, A. Prástaro, Geometry of PDE's. III(I): Webs on PDE's and integral bordism groups. The general theory, Adv. Math. Sci. Appl. 17 (2007) 239-266; R.P. Agarwal, A. Prástaro, Geometry of PDE's. III(II): Webs on PDE's and integral bordism groups. Applications to Riemannian geometry PDE's, Adv. Math. Sci. Appl. 17 (2007) 267-285; A. Prástaro, Geometry of PDE's and Mechanics, World Scientific, Singapore, 1996; A. Prástaro, Quantum and integral (co)bordism in partial differential equations, Acta Appl. Math. (5) (3) (1998) 243-302; A. Prástaro, (Co)bordism groups in PDE's, Acta Appl. Math. 59 (2) (1999) 111-201; A. Prástaro, Quantized Partial Differential Equations, World Scientific Publishing Co, Singapore, 2004, 500 pp.; A. Prástaro, Geometry of PDE's. I: Integral bordism groups in PDE's, J. Math. Anal. Appl. 319 (2006) 547-566; A. Prástaro, Geometry of PDE's. II: Variational PDE's and integral bordism groups, J. Math. Anal. Appl. 321 (2006) 930-948; A. Prástaro, Th.M. Rassias, Ulam stability in geometry of PDE's, Nonlinear Funct. Anal. Appl. 8 (2) (2003) 259-278; I. Stakgold, Boundary Value Problems of Mathematical Physics, I, The MacMillan Company, New York, 1967; I. Stakgold, Boundary Value Problems of Mathematical Physics, II, Collier-MacMillan, Canada, Ltd, Toronto, Ontario, 1968], integral bordism groups of the Navier-Stokes equation are calculated for smooth, singular and weak solutions, respectively. Then a characterization of global solutions is made on this ground. Enough conditions to assure existence of global smooth solutions are given and related to nullity of integral characteristic numbers of the boundaries. Stability of global solutions are related to some characteristic numbers of the space-like Cauchy dataE Global solutions of variational problems constrained by (NS) are classified by means of suitable integral bordism groups too.

Real-world hydrologic assessment of a fully-distributed hydrological model in a parallel computing environment

NASA Astrophysics Data System (ADS)

Vivoni, Enrique R.; Mascaro, Giuseppe; Mniszewski, Susan; Fasel, Patricia; Springer, Everett P.; Ivanov, Valeriy Y.; Bras, Rafael L.

2011-10-01

SummaryA major challenge in the use of fully-distributed hydrologic models has been the lack of computational capabilities for high-resolution, long-term simulations in large river basins. In this study, we present the parallel model implementation and real-world hydrologic assessment of the Triangulated Irregular Network (TIN)-based Real-time Integrated Basin Simulator (tRIBS). Our parallelization approach is based on the decomposition of a complex watershed using the channel network as a directed graph. The resulting sub-basin partitioning divides effort among processors and handles hydrologic exchanges across boundaries. Through numerical experiments in a set of nested basins, we quantify parallel performance relative to serial runs for a range of processors, simulation complexities and lengths, and sub-basin partitioning methods, while accounting for inter-run variability on a parallel computing system. In contrast to serial simulations, the parallel model speed-up depends on the variability of hydrologic processes. Load balancing significantly improves parallel speed-up with proportionally faster runs as simulation complexity (domain resolution and channel network extent) increases. The best strategy for large river basins is to combine a balanced partitioning with an extended channel network, with potential savings through a lower TIN resolution. Based on these advances, a wider range of applications for fully-distributed hydrologic models are now possible. This is illustrated through a set of ensemble forecasts that account for precipitation uncertainty derived from a statistical downscaling model.

Real-time electron dynamics for massively parallel excited-state simulations

NASA Astrophysics Data System (ADS)

Andrade, Xavier

The simulation of the real-time dynamics of electrons, based on time dependent density functional theory (TDDFT), is a powerful approach to study electronic excited states in molecular and crystalline systems. What makes the method attractive is its flexibility to simulate different kinds of phenomena beyond the linear-response regime, including strongly-perturbed electronic systems and non-adiabatic electron-ion dynamics. Electron-dynamics simulations are also attractive from a computational point of view. They can run efficiently on massively parallel architectures due to the low communication requirements. Our implementations of electron dynamics, based on the codes Octopus (real-space) and Qball (plane-waves), allow us to simulate systems composed of thousands of atoms and to obtain good parallel scaling up to 1.6 million processor cores. Due to the versatility of real-time electron dynamics and its parallel performance, we expect it to become the method of choice to apply the capabilities of exascale supercomputers for the simulation of electronic excited states.

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

PubMed

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

2010-06-01

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

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

PubMed

Bentley, J Kelley

2005-01-01

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

Parallel computing method for simulating hydrological processesof large rivers under climate change

NASA Astrophysics Data System (ADS)

Wang, H.; Chen, Y.

2016-12-01

Climate change is one of the proverbial global environmental problems in the world.Climate change has altered the watershed hydrological processes in time and space distribution, especially in worldlarge rivers.Watershed hydrological process simulation based on physically based distributed hydrological model can could have better results compared with the lumped models.However, watershed hydrological process simulation includes large amount of calculations, especially in large rivers, thus needing huge computing resources that may not be steadily available for the researchers or at high expense, this seriously restricted the research and application. To solve this problem, the current parallel method are mostly parallel computing in space and time dimensions.They calculate the natural features orderly thatbased on distributed hydrological model by grid (unit, a basin) from upstream to downstream.This articleproposes ahigh-performancecomputing method of hydrological process simulation with high speedratio and parallel efficiency.It combinedthe runoff characteristics of time and space of distributed hydrological model withthe methods adopting distributed data storage, memory database, distributed computing, parallel computing based on computing power unit.The method has strong adaptability and extensibility,which means it canmake full use of the computing and storage resources under the condition of limited computing resources, and the computing efficiency can be improved linearly with the increase of computing resources .This method can satisfy the parallel computing requirements ofhydrological process simulation in small, medium and large rivers.

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2017-02-22

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

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.

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

NASA Technical Reports Server (NTRS)

Vigue, Y.

1994-01-01

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

Existence and Optimality Conditions for Risk-Averse PDE-Constrained Optimization

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

Kouri, Drew Philip; Surowiec, Thomas M.

Uncertainty is ubiquitous in virtually all engineering applications, and, for such problems, it is inadequate to simulate the underlying physics without quantifying the uncertainty in unknown or random inputs, boundary and initial conditions, and modeling assumptions. Here in this paper, we introduce a general framework for analyzing risk-averse optimization problems constrained by partial differential equations (PDEs). In particular, we postulate conditions on the random variable objective function as well as the PDE solution that guarantee existence of minimizers. Furthermore, we derive optimality conditions and apply our results to the control of an environmental contaminant. Lastly, we introduce a new riskmore » measure, called the conditional entropic risk, that fuses desirable properties from both the conditional value-at-risk and the entropic risk measures.« less

Existence and Optimality Conditions for Risk-Averse PDE-Constrained Optimization

DOE PAGES

Kouri, Drew Philip; Surowiec, Thomas M.

2018-06-05

Uncertainty is ubiquitous in virtually all engineering applications, and, for such problems, it is inadequate to simulate the underlying physics without quantifying the uncertainty in unknown or random inputs, boundary and initial conditions, and modeling assumptions. Here in this paper, we introduce a general framework for analyzing risk-averse optimization problems constrained by partial differential equations (PDEs). In particular, we postulate conditions on the random variable objective function as well as the PDE solution that guarantee existence of minimizers. Furthermore, we derive optimality conditions and apply our results to the control of an environmental contaminant. Lastly, we introduce a new riskmore » measure, called the conditional entropic risk, that fuses desirable properties from both the conditional value-at-risk and the entropic risk measures.« less

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

PubMed

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

2013-11-14

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

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

PubMed

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

2008-02-01

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

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2017-08-01

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

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

PubMed Central

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

2016-01-01

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

Parallel STEPS: Large Scale Stochastic Spatial Reaction-Diffusion Simulation with High Performance Computers

PubMed Central

Chen, Weiliang; De Schutter, Erik

2017-01-01

Stochastic, spatial reaction-diffusion simulations have been widely used in systems biology and computational neuroscience. However, the increasing scale and complexity of models and morphologies have exceeded the capacity of any serial implementation. This led to the development of parallel solutions that benefit from the boost in performance of modern supercomputers. In this paper, we describe an MPI-based, parallel operator-splitting implementation for stochastic spatial reaction-diffusion simulations with irregular tetrahedral meshes. The performance of our implementation is first examined and analyzed with simulations of a simple model. We then demonstrate its application to real-world research by simulating the reaction-diffusion components of a published calcium burst model in both Purkinje neuron sub-branch and full dendrite morphologies. Simulation results indicate that our implementation is capable of achieving super-linear speedup for balanced loading simulations with reasonable molecule density and mesh quality. In the best scenario, a parallel simulation with 2,000 processes runs more than 3,600 times faster than its serial SSA counterpart, and achieves more than 20-fold speedup relative to parallel simulation with 100 processes. In a more realistic scenario with dynamic calcium influx and data recording, the parallel simulation with 1,000 processes and no load balancing is still 500 times faster than the conventional serial SSA simulation. PMID:28239346

Parallel STEPS: Large Scale Stochastic Spatial Reaction-Diffusion Simulation with High Performance Computers.

PubMed

Chen, Weiliang; De Schutter, Erik

2017-01-01

Stochastic, spatial reaction-diffusion simulations have been widely used in systems biology and computational neuroscience. However, the increasing scale and complexity of models and morphologies have exceeded the capacity of any serial implementation. This led to the development of parallel solutions that benefit from the boost in performance of modern supercomputers. In this paper, we describe an MPI-based, parallel operator-splitting implementation for stochastic spatial reaction-diffusion simulations with irregular tetrahedral meshes. The performance of our implementation is first examined and analyzed with simulations of a simple model. We then demonstrate its application to real-world research by simulating the reaction-diffusion components of a published calcium burst model in both Purkinje neuron sub-branch and full dendrite morphologies. Simulation results indicate that our implementation is capable of achieving super-linear speedup for balanced loading simulations with reasonable molecule density and mesh quality. In the best scenario, a parallel simulation with 2,000 processes runs more than 3,600 times faster than its serial SSA counterpart, and achieves more than 20-fold speedup relative to parallel simulation with 100 processes. In a more realistic scenario with dynamic calcium influx and data recording, the parallel simulation with 1,000 processes and no load balancing is still 500 times faster than the conventional serial SSA simulation.

Combination of 2D/3D ligand-based similarity search in rapid virtual screening from multimillion compound repositories. Selection and biological evaluation of potential PDE4 and PDE5 inhibitors.

PubMed

Dobi, Krisztina; Hajdú, István; Flachner, Beáta; Fabó, Gabriella; Szaszkó, Mária; Bognár, Melinda; Magyar, Csaba; Simon, István; Szisz, Dániel; Lőrincz, Zsolt; Cseh, Sándor; Dormán, György

2014-05-28

Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost effective approach. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compound databases but the generated library requires further focusing by various 2D/3D chemoinformatics tools. We report here a combination of the 2D approach with a ligand-based 3D method (Screen3D) which applies flexible matching to align reference and target compounds in a dynamic manner and thus to assess their structural and conformational similarity. In the first case study we compared the 2D and 3D similarity scores on an existing dataset derived from the biological evaluation of a PDE5 focused library. Based on the obtained similarity metrices a fusion score was proposed. The fusion score was applied to refine the 2D similarity search in a second case study where we aimed at selecting and evaluating a PDE4B focused library. The application of this fused 2D/3D similarity measure led to an increase of the hit rate from 8.5% (1st round, 47% inhibition at 10 µM) to 28.5% (2nd round at 50% inhibition at 10 µM) and the best two hits had 53 nM inhibitory activities.

Pricing index-based catastrophe bonds: Part 1: Formulation and discretization issues using a numerical PDE approach

NASA Astrophysics Data System (ADS)

Unger, André J. A.

2010-02-01

This work is the first installment in a two-part series, and focuses on the development of a numerical PDE approach to price components of a Bermudan-style callable catastrophe (CAT) bond. The bond is based on two underlying stochastic variables; the PCS index which posts quarterly estimates of industry-wide hurricane losses as well as a single-factor CIR interest rate model for the three-month LIBOR. The aggregate PCS index is analogous to losses claimed under traditional reinsurance in that it is used to specify a reinsurance layer. The proposed CAT bond model contains a Bermudan-style call feature designed to allow the reinsurer to minimize their interest rate risk exposure on making substantial fixed coupon payments using capital from the reinsurance premium. Numerical PDE methods are the fundamental strategy for pricing early-exercise constraints, such as the Bermudan-style call feature, into contingent claim models. Therefore, the objective and unique contribution of this first installment in the two-part series is to develop a formulation and discretization strategy for the proposed CAT bond model utilizing a numerical PDE approach. Object-oriented code design is fundamental to the numerical methods used to aggregate the PCS index, and implement the call feature. Therefore, object-oriented design issues that relate specifically to the development of a numerical PDE approach for the component of the proposed CAT bond model that depends on the PCS index and LIBOR are described here. Formulation, numerical methods and code design issues that relate to aggregating the PCS index and introducing the call option are the subject of the companion paper.

Crisaborole: Phosphodiesterase inhibitor for treatment of atopic dermatitis.

PubMed

Paton, D M

2017-04-01

Atopic dermatitis (AD) is an extremely common condition affecting as many as 10-20% of children and 2-10% of adults. A particularly distressing symptom of AD is pruritus. One of the important aspects of AD is inflammation associated with increased activity of phosphodiesterase 4 (PDE4), resulting in decreased intracellular levels of cyclic adenosine monophosphate, which in turn causes increased production of inflammatory cytokines. Crisaborole was developed as a small-molecule, boron-based, selective PDE4 inhibitor that can be used topically. Clinical trials have demonstrated its efficacy in treating patients with mild to moderate AD, resulting in significant relief of pruritus. Unlike PDE4 inhibitors that act systemically, crisaborole does not cause significant gastrointestinal adverse effects. The most common adverse effect has been temporary stinging and burning in about 4% of patients upon application of the 2% ointment. To date there is no evidence of atrophy, telangiectasia or hypopigmentation resulting from its use. Crisaborole is the first topically applied PDE4 inhibitor to be approved by the FDA for use in AD. Copyright 2017 Clarivate Analytics.

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

PubMed

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

2017-09-01

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

Microplate-based method to screen inhibitors of isozymes of cyclic nucleotide phosphodiesterase fused to SUMO.

PubMed

Chen, Chunyan; Liu, Miaomiao; Wu, Jing; Yang, Xiaolan; Hu, Xiaolei; Pu, Jun; Long, Gaobo; Xie, Yanling; Jiang, Hairong; Yuan, Yonghua; Liao, Fei

2014-12-01

The feasibility for microplate-based screening of inhibitors of isozymes of cyclic nucleotide phosphodiesterase (PDE) was tested via the coupled action of a phosphatase on adenosine-5'-monophosphate and an improved malachite green assay of phosphate. Human full-length PDE4B2 and truncated mutant (152-528aa) were expressed in Escherichia coli via fusion to SUMO, which after purification through Ni-NTA column exhibited specific activities >0.017 U mg(-1). In the presence of proteins <30 mg L(-1), absorbance for 10 µΜ phosphate was measurable; a PDE isozyme of specific activity over 0.008 U mg(-1) after reaction for 20 min thus suited for microplate-based screening of inhibitors. By using Biotek ELX 800 microplate reader, affinities of two forms of PEDE4B2 for cAMP, rolipram and papaverine varied over three magnitudes and were consistent with those by routine assay, respectively. Hence, the proposed method was promising for high-throughput-screening of inhibitors of phosphate-releasing enzymes bearing specific activities over 0.008 U mg(-1).

A Reduced Model for the Magnetorotational Instability

NASA Astrophysics Data System (ADS)

Jamroz, Ben; Julien, Keith; Knobloch, Edgar

2008-11-01

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

Combination therapy for erectile dysfunction: an update review.

PubMed

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

2011-05-01

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

Recurrent Targeted Genes of Hepatitis B Virus in the Liver Cancer Genomes Identified by a Next-Generation Sequencing–Based Approach

PubMed Central

Ding, Dong; Lou, Xiaoyan; Hua, Dasong; Yu, Wei; Li, Lisha; Wang, Jun; Gao, Feng; Zhao, Na; Ren, Guoping; Li, Lanjuan; Lin, Biaoyang

2012-01-01

Integration of the viral DNA into host chromosomes was found in most of the hepatitis B virus (HBV)–related hepatocellular carcinomas (HCCs). Here we devised a massive anchored parallel sequencing (MAPS) method using next-generation sequencing to isolate and sequence HBV integrants. Applying MAPS to 40 pairs of HBV–related HCC tissues (cancer and adjacent tissues), we identified 296 HBV integration events corresponding to 286 unique integration sites (UISs) with precise HBV–Human DNA junctions. HBV integration favored chromosome 17 and preferentially integrated into human transcript units. HBV targeted genes were enriched in GO terms: cAMP metabolic processes, T cell differentiation and activation, TGF beta receptor pathway, ncRNA catabolic process, and dsRNA fragmentation and cellular response to dsRNA. The HBV targeted genes include 7 genes (PTPRJ, CNTN6, IL12B, MYOM1, FNDC3B, LRFN2, FN1) containing IPR003961 (Fibronectin, type III domain), 7 genes (NRG3, MASP2, NELL1, LRP1B, ADAM21, NRXN1, FN1) containing IPR013032 (EGF-like region, conserved site), and three genes (PDE7A, PDE4B, PDE11A) containing IPR002073 (3′, 5′-cyclic-nucleotide phosphodiesterase). Enriched pathways include hsa04512 (ECM-receptor interaction), hsa04510 (Focal adhesion), and hsa04012 (ErbB signaling pathway). Fewer integration events were found in cancers compared to cancer-adjacent tissues, suggesting a clonal expansion model in HCC development. Finally, we identified 8 genes that were recurrent target genes by HBV integration including fibronectin 1 (FN1) and telomerase reverse transcriptase (TERT1), two known recurrent target genes, and additional novel target genes such as SMAD family member 5 (SMAD5), phosphatase and actin regulator 4 (PHACTR4), and RNA binding protein fox-1 homolog (C. elegans) 1 (RBFOX1). Integrating analysis with recently published whole-genome sequencing analysis, we identified 14 additional recurrent HBV target genes, greatly expanding the HBV recurrent target list. This global survey of HBV integration events, together with recently published whole-genome sequencing analyses, furthered our understanding of the HBV–related HCC. PMID:23236287

n-body simulations using message passing parallel computers.

NASA Astrophysics Data System (ADS)

Grama, A. Y.; Kumar, V.; Sameh, A.

The authors present new parallel formulations of the Barnes-Hut method for n-body simulations on message passing computers. These parallel formulations partition the domain efficiently incurring minimal communication overhead. This is in contrast to existing schemes that are based on sorting a large number of keys or on the use of global data structures. The new formulations are augmented by alternate communication strategies which serve to minimize communication overhead. The impact of these communication strategies is experimentally studied. The authors report on experimental results obtained from an astrophysical simulation on an nCUBE2 parallel computer.

A hybrid algorithm for parallel molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Mangiardi, Chris M.; Meyer, R.

2017-10-01

This article describes algorithms for the hybrid parallelization and SIMD vectorization of molecular dynamics simulations with short-range forces. The parallelization method combines domain decomposition with a thread-based parallelization approach. The goal of the work is to enable efficient simulations of very large (tens of millions of atoms) and inhomogeneous systems on many-core processors with hundreds or thousands of cores and SIMD units with large vector sizes. In order to test the efficiency of the method, simulations of a variety of configurations with up to 74 million atoms have been performed. Results are shown that were obtained on multi-core systems with Sandy Bridge and Haswell processors as well as systems with Xeon Phi many-core processors.

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

PubMed Central

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

2013-01-01

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

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

PubMed

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

2018-05-01

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

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

PubMed

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

2012-05-01

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

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

PubMed

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

2017-02-01

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

A novel thermoregulatory role for PDE10A in mouse and human adipocytes.

PubMed

Hankir, Mohammed K; Kranz, Mathias; Gnad, Thorsten; Weiner, Juliane; Wagner, Sally; Deuther-Conrad, Winnie; Bronisch, Felix; Steinhoff, Karen; Luthardt, Julia; Klöting, Nora; Hesse, Swen; Seibyl, John P; Sabri, Osama; Heiker, John T; Blüher, Matthias; Pfeifer, Alexander; Brust, Peter; Fenske, Wiebke K

2016-07-01

Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small-animal PET/MRI and the novel radioligand [(18)F]-AQ28A, we found marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice. Pharmacological inactivation of PDE10A with the highly selective inhibitor MP-10 recruited BAT and potentiated thermogenesis in vivo In diet-induced obese mice, chronic administration of MP-10 caused weight loss associated with increased energy expenditure, browning of white adipose tissue, and improved insulin sensitivity. Analysis of human PET data further revealed marked levels of PDE10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Finally, the inhibition of PDE10A with MP-10 stimulated thermogenic gene expression in human brown adipocytes and induced browning of human white adipocytes. Collectively, our findings highlight a novel thermoregulatory role for PDE10A in mouse and human adipocytes and promote PDE10A inhibitors as promising candidates for the treatment of obesity and diabetes. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

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

PubMed

Strahm, Emmanuel; Rane, Anders; Ekström, Lena

2014-01-01

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

Genome-Based Comparison of Cyclic Di-GMP Signaling in Pathogenic and Commensal Escherichia coli Strains

PubMed Central

Povolotsky, Tatyana L.

2015-01-01

ABSTRACT The ubiquitous bacterial second messenger cyclic di-GMP (c-di-GMP) has recently become prominent as a trigger for biofilm formation in many bacteria. It is generated by diguanylate cyclases (DGCs; with GGDEF domains) and degraded by specific phosphodiesterases (PDEs; containing either EAL or HD-GYP domains). Most bacterial species contain multiples of these proteins with some having specific functions that are based on direct molecular interactions in addition to their enzymatic activities. Escherichia coli K-12 laboratory strains feature 29 genes encoding GGDEF and/or EAL domains, resulting in a set of 12 DGCs, 13 PDEs, and four enzymatically inactive “degenerate” proteins that act by direct macromolecular interactions. We present here a comparative analysis of GGDEF/EAL domain-encoding genes in 61 genomes of pathogenic, commensal, and probiotic E. coli strains (including enteric pathogens such as enteroaggregative, enterohemorrhagic, enteropathogenic, enterotoxigenic, and adherent and invasive Escherichia coli and the 2011 German outbreak O104:H4 strain, as well as extraintestinal pathogenic E. coli, such as uropathogenic and meningitis-associated E. coli). We describe additional genes for two membrane-associated DGCs (DgcX and DgcY) and four PDEs (the membrane-associated PdeT, as well as the EAL domain-only proteins PdeW, PdeX, and PdeY), thus showing the pangenome of E. coli to contain at least 35 GGDEF/EAL domain proteins. A core set of only eight proteins is absolutely conserved in all 61 strains: DgcC (YaiC), DgcI (YliF), PdeB (YlaB), PdeH (YhjH), PdeK (YhjK), PdeN (Rtn), and the degenerate proteins CsrD and CdgI (YeaI). In all other GGDEF/EAL domain genes, diverse point and frameshift mutations, as well as small or large deletions, were discovered in various strains. IMPORTANCE Our analysis reveals interesting trends in pathogenic Escherichia coli that could reflect different host cell adherence mechanisms. These may either benefit from or be counteracted by the c-di-GMP-stimulated production of amyloid curli fibers and cellulose. Thus, EAEC, which adhere in a “stacked brick” biofilm mode, have a potential for high c-di-GMP accumulation due to DgcX, a strongly expressed additional DGC. In contrast, EHEC and UPEC, which use alternative adherence mechanisms, tend to have extra PDEs, suggesting that low cellular c-di-GMP levels are crucial for these strains under specific conditions. Overall, our study also indicates that GGDEF/EAL domain proteins evolve rapidly and thereby contribute to adaptation to host-specific and environmental niches of various types of E. coli. PMID:26303830

Genome-Based Comparison of Cyclic Di-GMP Signaling in Pathogenic and Commensal Escherichia coli Strains.

PubMed

Povolotsky, Tatyana L; Hengge, Regine

2016-01-01

The ubiquitous bacterial second messenger cyclic di-GMP (c-di-GMP) has recently become prominent as a trigger for biofilm formation in many bacteria. It is generated by diguanylate cyclases (DGCs; with GGDEF domains) and degraded by specific phosphodiesterases (PDEs; containing either EAL or HD-GYP domains). Most bacterial species contain multiples of these proteins with some having specific functions that are based on direct molecular interactions in addition to their enzymatic activities. Escherichia coli K-12 laboratory strains feature 29 genes encoding GGDEF and/or EAL domains, resulting in a set of 12 DGCs, 13 PDEs, and four enzymatically inactive "degenerate" proteins that act by direct macromolecular interactions. We present here a comparative analysis of GGDEF/EAL domain-encoding genes in 61 genomes of pathogenic, commensal, and probiotic E. coli strains (including enteric pathogens such as enteroaggregative, enterohemorrhagic, enteropathogenic, enterotoxigenic, and adherent and invasive Escherichia coli and the 2011 German outbreak O104:H4 strain, as well as extraintestinal pathogenic E. coli, such as uropathogenic and meningitis-associated E. coli). We describe additional genes for two membrane-associated DGCs (DgcX and DgcY) and four PDEs (the membrane-associated PdeT, as well as the EAL domain-only proteins PdeW, PdeX, and PdeY), thus showing the pangenome of E. coli to contain at least 35 GGDEF/EAL domain proteins. A core set of only eight proteins is absolutely conserved in all 61 strains: DgcC (YaiC), DgcI (YliF), PdeB (YlaB), PdeH (YhjH), PdeK (YhjK), PdeN (Rtn), and the degenerate proteins CsrD and CdgI (YeaI). In all other GGDEF/EAL domain genes, diverse point and frameshift mutations, as well as small or large deletions, were discovered in various strains. Our analysis reveals interesting trends in pathogenic Escherichia coli that could reflect different host cell adherence mechanisms. These may either benefit from or be counteracted by the c-di-GMP-stimulated production of amyloid curli fibers and cellulose. Thus, EAEC, which adhere in a "stacked brick" biofilm mode, have a potential for high c-di-GMP accumulation due to DgcX, a strongly expressed additional DGC. In contrast, EHEC and UPEC, which use alternative adherence mechanisms, tend to have extra PDEs, suggesting that low cellular c-di-GMP levels are crucial for these strains under specific conditions. Overall, our study also indicates that GGDEF/EAL domain proteins evolve rapidly and thereby contribute to adaptation to host-specific and environmental niches of various types of E. coli. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

DISC1, PDE4B, and NDE1 at the centrosome and synapse

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

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

Disrupted-In-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and other major mental illnesses. Its protein binding partners include the Nuclear Distribution Factor E Homologs (NDE1 and NDEL1), LIS1, and phosphodiesterases 4B and 4D (PDE4B and PDE4D). We demonstrate that NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. LIS1 and NDEL1 have been previously suggested to be synaptic, and we now demonstrate localisation of DISC1, NDE1, and PDE4B at synapses in cultured neurons. NDE1 is phosphorylated by cAMP-dependantmore » Protein Kinase A (PKA), whose activity is, in turn, regulated by the cAMP hydrolysis activity of phosphodiesterases, including PDE4. We propose that DISC1 acts as an assembly scaffold for all of these proteins and that the NDE1/NDEL1/LIS1/dynein complex is modulated by cAMP levels via PKA and PDE4.« less

Streaming parallel GPU acceleration of large-scale filter-based spiking neural networks.

PubMed

Slażyński, Leszek; Bohte, Sander

2012-01-01

The arrival of graphics processing (GPU) cards suitable for massively parallel computing promises affordable large-scale neural network simulation previously only available at supercomputing facilities. While the raw numbers suggest that GPUs may outperform CPUs by at least an order of magnitude, the challenge is to develop fine-grained parallel algorithms to fully exploit the particulars of GPUs. Computation in a neural network is inherently parallel and thus a natural match for GPU architectures: given inputs, the internal state for each neuron can be updated in parallel. We show that for filter-based spiking neurons, like the Spike Response Model, the additive nature of membrane potential dynamics enables additional update parallelism. This also reduces the accumulation of numerical errors when using single precision computation, the native precision of GPUs. We further show that optimizing simulation algorithms and data structures to the GPU's architecture has a large pay-off: for example, matching iterative neural updating to the memory architecture of the GPU speeds up this simulation step by a factor of three to five. With such optimizations, we can simulate in better-than-realtime plausible spiking neural networks of up to 50 000 neurons, processing over 35 million spiking events per second.

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

PubMed Central

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

2013-01-01

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

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

PubMed

Röhrig, Teresa; Liesenfeld, David; Richling, Elke

2017-05-17

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

Parallel discrete-event simulation of FCFS stochastic queueing networks

NASA Technical Reports Server (NTRS)

Nicol, David M.

1988-01-01

Physical systems are inherently parallel. Intuition suggests that simulations of these systems may be amenable to parallel execution. The parallel execution of a discrete-event simulation requires careful synchronization of processes in order to ensure the execution's correctness; this synchronization can degrade performance. Largely negative results were recently reported in a study which used a well-known synchronization method on queueing network simulations. Discussed here is a synchronization method (appointments), which has proven itself to be effective on simulations of FCFS queueing networks. The key concept behind appointments is the provision of lookahead. Lookahead is a prediction on a processor's future behavior, based on an analysis of the processor's simulation state. It is shown how lookahead can be computed for FCFS queueing network simulations, give performance data that demonstrates the method's effectiveness under moderate to heavy loads, and discuss performance tradeoffs between the quality of lookahead, and the cost of computing lookahead.

On the suitability of the connection machine for direct particle simulation

NASA Technical Reports Server (NTRS)

Dagum, Leonard

1990-01-01

The algorithmic structure was examined of the vectorizable Stanford particle simulation (SPS) method and the structure is reformulated in data parallel form. Some of the SPS algorithms can be directly translated to data parallel, but several of the vectorizable algorithms have no direct data parallel equivalent. This requires the development of new, strictly data parallel algorithms. In particular, a new sorting algorithm is developed to identify collision candidates in the simulation and a master/slave algorithm is developed to minimize communication cost in large table look up. Validation of the method is undertaken through test calculations for thermal relaxation of a gas, shock wave profiles, and shock reflection from a stationary wall. A qualitative measure is provided of the performance of the Connection Machine for direct particle simulation. The massively parallel architecture of the Connection Machine is found quite suitable for this type of calculation. However, there are difficulties in taking full advantage of this architecture because of lack of a broad based tradition of data parallel programming. An important outcome of this work has been new data parallel algorithms specifically of use for direct particle simulation but which also expand the data parallel diction.

Parallel computing of physical maps--a comparative study in SIMD and MIMD parallelism.

PubMed

Bhandarkar, S M; Chirravuri, S; Arnold, J

1996-01-01

Ordering clones from a genomic library into physical maps of whole chromosomes presents a central computational problem in genetics. Chromosome reconstruction via clone ordering is usually isomorphic to the NP-complete Optimal Linear Arrangement problem. Parallel SIMD and MIMD algorithms for simulated annealing based on Markov chain distribution are proposed and applied to the problem of chromosome reconstruction via clone ordering. Perturbation methods and problem-specific annealing heuristics are proposed and described. The SIMD algorithms are implemented on a 2048 processor MasPar MP-2 system which is an SIMD 2-D toroidal mesh architecture whereas the MIMD algorithms are implemented on an 8 processor Intel iPSC/860 which is an MIMD hypercube architecture. A comparative analysis of the various SIMD and MIMD algorithms is presented in which the convergence, speedup, and scalability characteristics of the various algorithms are analyzed and discussed. On a fine-grained, massively parallel SIMD architecture with a low synchronization overhead such as the MasPar MP-2, a parallel simulated annealing algorithm based on multiple periodically interacting searches performs the best. For a coarse-grained MIMD architecture with high synchronization overhead such as the Intel iPSC/860, a parallel simulated annealing algorithm based on multiple independent searches yields the best results. In either case, distribution of clonal data across multiple processors is shown to exacerbate the tendency of the parallel simulated annealing algorithm to get trapped in a local optimum.

Automatic Thread-Level Parallelization in the Chombo AMR Library

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

Christen, Matthias; Keen, Noel; Ligocki, Terry

2011-05-26

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

Effect of phosphodiesterase inhibitors in the bladder.

PubMed

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

2015-01-01

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

Pharmacological Prevention and Reversion of Erectile Dysfunction After Radical Prostatectomy, by Modulation of Nitric Oxide/cGMP Pathways

DTIC Science & Technology

2010-03-01

cancer in men. Now, we have shown that much lower doses of sildenafil, combined or not with a nitric oxide donor, molsidomine, also correct the CVOD...ED) subsequent to radical prostatectomy for prostate cancer can be prevented and even reversed by long-term sustained treatment with PDE5...erectile dysfunction subsequent to radical prostatectomy for prostate cancer , based on the long term sustained administration of PDE5 inhibitors. Our

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

PubMed

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

2011-01-01

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

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

PubMed

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

2014-04-01

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

Octree-based, GPU implementation of a continuous cellular automaton for the simulation of complex, evolving surfaces

NASA Astrophysics Data System (ADS)

Ferrando, N.; Gosálvez, M. A.; Cerdá, J.; Gadea, R.; Sato, K.

2011-03-01

Presently, dynamic surface-based models are required to contain increasingly larger numbers of points and to propagate them over longer time periods. For large numbers of surface points, the octree data structure can be used as a balance between low memory occupation and relatively rapid access to the stored data. For evolution rules that depend on neighborhood states, extended simulation periods can be obtained by using simplified atomistic propagation models, such as the Cellular Automata (CA). This method, however, has an intrinsic parallel updating nature and the corresponding simulations are highly inefficient when performed on classical Central Processing Units (CPUs), which are designed for the sequential execution of tasks. In this paper, a series of guidelines is presented for the efficient adaptation of octree-based, CA simulations of complex, evolving surfaces into massively parallel computing hardware. A Graphics Processing Unit (GPU) is used as a cost-efficient example of the parallel architectures. For the actual simulations, we consider the surface propagation during anisotropic wet chemical etching of silicon as a computationally challenging process with a wide-spread use in microengineering applications. A continuous CA model that is intrinsically parallel in nature is used for the time evolution. Our study strongly indicates that parallel computations of dynamically evolving surfaces simulated using CA methods are significantly benefited by the incorporation of octrees as support data structures, substantially decreasing the overall computational time and memory usage.

Address tracing for parallel machines

NASA Technical Reports Server (NTRS)

Stunkel, Craig B.; Janssens, Bob; Fuchs, W. Kent

1991-01-01

Recently implemented parallel system address-tracing methods based on several metrics are surveyed. The issues specific to collection of traces for both shared and distributed memory parallel computers are highlighted. Five general categories of address-trace collection methods are examined: hardware-captured, interrupt-based, simulation-based, altered microcode-based, and instrumented program-based traces. The problems unique to shared memory and distributed memory multiprocessors are examined separately.

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

PubMed

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

2015-01-01

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

CUBE: Information-optimized parallel cosmological N-body simulation code

NASA Astrophysics Data System (ADS)

Yu, Hao-Ran; Pen, Ue-Li; Wang, Xin

2018-05-01

CUBE, written in Coarray Fortran, is a particle-mesh based parallel cosmological N-body simulation code. The memory usage of CUBE can approach as low as 6 bytes per particle. Particle pairwise (PP) force, cosmological neutrinos, spherical overdensity (SO) halofinder are included.

Performance and environmental impact assessment of pulse detonation based engine systems

NASA Astrophysics Data System (ADS)

Glaser, Aaron J.

Experimental research was performed to investigate the feasibility of using pulse detonation based engine systems for practical aerospace applications. In order to carry out this work a new pulse detonation combustion research facility was developed at the University of Cincinnati. This research covered two broad areas of application interest. The first area is pure PDE applications where the detonation tube is used to generate an impulsive thrust directly. The second focus area is on pulse detonation based hybrid propulsion systems. Within each of these areas various studies were performed to quantify engine performance. Comparisons of the performance between detonation and conventional deflagration based engine cycles were made. Fundamental studies investigating detonation physics and flow dynamics were performed in order to gain physical insight into the observed performance trends. Experimental studies were performed on PDE-driven straight and diverging ejectors to determine the system performance. Ejector performance was quantified by thrust measurements made using a damped thrust stand. The effects of PDE operating parameters and ejector geometric parameters on thrust augmentation were investigated. For all cases tested, the maximum thrust augmentation is found to occur at a downstream ejector placement. The optimum ejector geometry was determined to have an overall length of LEJECT/DEJECT =5.61, including an intermediate-straight section length of LSTRT /DEJECT=2, and diverging exhaust section with 4 deg half-angle. A maximum thrust augmentation of 105% was observed while employing the optimized ejector geometry and operating the PDE at a fill-fraction of 0.6 and a frequency of 10 Hz. When operated at a fill-fraction of 1.0 and a frequency of 30 Hz, the thrust augmentation of the optimized PDE-driven ejector system was observed to be 71%. Static pressure was measured along the interior surface of the ejector, including the inlet and exhaust sections. The diverging ejector pressure distribution shows that the diverging section acts as a subsonic diffuser. To provide a better explanation of the observed performance trends, shadowgraph images of the detonation wave and starting vortex interacting with the ejector inlet were obtained. The acoustic signature of a pulse detonation engine was characterized in both the near-field and far-field regimes. Experimental measurements were performed in an anechoic test facility designed for jet noise testing. Both shock strength and speed were mapped as a function of radial distance and direction from the PDE exhaust plane. It was found that the PDE generated pressure field can be reasonably modeled by a theoretical point-source explosion. The effect of several exit nozzle configurations on the PDE acoustic signature was studies. These included various chevron nozzles, a perforated nozzle, and a set of proprietary noise attenuation mufflers. Experimental studies were carried out to investigate the performance of a hybrid propulsion system integrating an axial flow turbine with multiple pulse detonation combustors. The integrated system consisted of a circular array of six pulse detonation combustor (PDC) tubes exhausting through an axial flow turbine. Turbine component performance was quantified by measuring the amount of power generated by the turbine section. Direct comparisons of specific power output and turbine efficiency between a PDC-driven turbine and a turbine driven by steady-flow combustors were made. It was found that the PDC-driven turbine had comparable performance to that of a steady-burner-driven turbine across the operating map of the turbine.

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

PubMed

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

2016-09-01

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

Prenatal drug exposure and peer victimization in early adolescence: testing childhood anxiety/depression and aggression as possible mediators.

PubMed

Buckingham-Howes, Stacy; Oberlander, Sarah E; Kim, Elizabeth M; Black, Maureen M

2012-06-01

Children who are prenatally exposed to drugs may be at risk for emotion dysregulation, including childhood anxiety/depression and aggression, potentially increasing their risk for peer victimization. The objectives of this study were to investigate how prenatal drug exposure relates to adolescent peer victimization and the mediating effects of childhood anxiety/depression and aggression. Seventy-six prenatally drug exposed (PDE) and 38 nonexposed (NE) adolescent-caregiver dyads followed since birth and middle childhood, respectively, participated in an evaluation during adolescence. In middle childhood, caregivers reported on their child's anxiety/depression and aggression, and children reported on violence exposure. In adolescence, caregivers and adolescents responded to a parallel single-item measure of peer victimization. Analyses were conducted using multivariate linear and logistic regression models, adjusting for covariates, including violence exposure. One-third (33.3%, n = 35) of the sample endorsed peer victimization: 40.8% PDE and 17.6% NE, p = .01. In middle childhood, PDE youth had more aggressive behaviors (11.92 vs 7.45, p < .01) and anxiety/depression symptoms (3.43 vs 1.76, p < .01) than NE youth. Anxious/depressed behavior during childhood mediated the association between prenatal drug exposure and adolescent peer victimization. Aggression was not a significant mediator. The consequences of prenatal drug exposure extend into adolescence. Prenatal drug exposure may interfere with emotion regulation, resulting in anxious/depressed behavior during childhood and significantly increasing the risk for peer victimization during adolescence, even in the presence of violence exposure. Strategies to reduce anxious/depressed behavior among children with a history of prenatal drug exposure may reduce adolescent peer victimization.

Applications of Laser Diagnostics

DTIC Science & Technology

2005-03-01

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

Laser High-Cycle Thermal Fatigue of Pulse Detonation Engine Combustor Materials Tested

NASA Technical Reports Server (NTRS)

Zhu, Dong-Ming; Fox, Dennis S.; Miller, Robert A.

2001-01-01

Pulse detonation engines (PDE's) have received increasing attention for future aerospace propulsion applications. Because the PDE is designed for a high-frequency, intermittent detonation combustion process, extremely high gas temperatures and pressures can be realized under the nearly constant-volume combustion environment. The PDE's can potentially achieve higher thermodynamic cycle efficiency and thrust density in comparison to traditional constant-pressure combustion gas turbine engines (ref. 1). However, the development of these engines requires robust design of the engine components that must endure harsh detonation environments. In particular, the detonation combustor chamber, which is designed to sustain and confine the detonation combustion process, will experience high pressure and temperature pulses with very short durations (refs. 2 and 3). Therefore, it is of great importance to evaluate PDE combustor materials and components under simulated engine temperatures and stress conditions in the laboratory. In this study, a high-cycle thermal fatigue test rig was established at the NASA Glenn Research Center using a 1.5-kW CO2 laser. The high-power laser, operating in the pulsed mode, can be controlled at various pulse energy levels and waveform distributions. The enhanced laser pulses can be used to mimic the time-dependent temperature and pressure waves encountered in a pulsed detonation engine. Under the enhanced laser pulse condition, a maximum 7.5-kW peak power with a duration of approximately 0.1 to 0.2 msec (a spike) can be achieved, followed by a plateau region that has about one-fifth of the maximum power level with several milliseconds duration. The laser thermal fatigue rig has also been developed to adopt flat and rotating tubular specimen configurations for the simulated engine tests. More sophisticated laser optic systems can be used to simulate the spatial distributions of the temperature and shock waves in the engine. Pulse laser high-cycle thermal fatigue behavior has been investigated on a flat Haynes 188 alloy specimen, under the test condition of 30-Hz cycle frequency (33-msec pulse period and 10-msec pulse width including a 0.2-msec pulse spike; ref. 4). Temperature distributions were calculated with one-dimensional finite difference models. The calculations show that that the 0.2-msec pulse spike can cause an additional 40 C temperature fluctuation with an interaction depth of 0.08 mm near the specimen surface region. This temperature swing will be superimposed onto the temperature swing of 80 C that is induced by the 10-msec laser pulse near the 0.53-mm-deep surface interaction region.

A parallel finite element procedure for contact-impact problems using edge-based smooth triangular element and GPU

NASA Astrophysics Data System (ADS)

Cai, Yong; Cui, Xiangyang; Li, Guangyao; Liu, Wenyang

2018-04-01

The edge-smooth finite element method (ES-FEM) can improve the computational accuracy of triangular shell elements and the mesh partition efficiency of complex models. In this paper, an approach is developed to perform explicit finite element simulations of contact-impact problems with a graphical processing unit (GPU) using a special edge-smooth triangular shell element based on ES-FEM. Of critical importance for this problem is achieving finer-grained parallelism to enable efficient data loading and to minimize communication between the device and host. Four kinds of parallel strategies are then developed to efficiently solve these ES-FEM based shell element formulas, and various optimization methods are adopted to ensure aligned memory access. Special focus is dedicated to developing an approach for the parallel construction of edge systems. A parallel hierarchy-territory contact-searching algorithm (HITA) and a parallel penalty function calculation method are embedded in this parallel explicit algorithm. Finally, the program flow is well designed, and a GPU-based simulation system is developed, using Nvidia's CUDA. Several numerical examples are presented to illustrate the high quality of the results obtained with the proposed methods. In addition, the GPU-based parallel computation is shown to significantly reduce the computing time.

Optimized Hypervisor Scheduler for Parallel Discrete Event Simulations on Virtual Machine Platforms

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

Yoginath, Srikanth B; Perumalla, Kalyan S

2013-01-01

With the advent of virtual machine (VM)-based platforms for parallel computing, it is now possible to execute parallel discrete event simulations (PDES) over multiple virtual machines, in contrast to executing in native mode directly over hardware as is traditionally done over the past decades. While mature VM-based parallel systems now offer new, compelling benefits such as serviceability, dynamic reconfigurability and overall cost effectiveness, the runtime performance of parallel applications can be significantly affected. In particular, most VM-based platforms are optimized for general workloads, but PDES execution exhibits unique dynamics significantly different from other workloads. Here we first present results frommore » experiments that highlight the gross deterioration of the runtime performance of VM-based PDES simulations when executed using traditional VM schedulers, quantitatively showing the bad scaling properties of the scheduler as the number of VMs is increased. The mismatch is fundamental in nature in the sense that any fairness-based VM scheduler implementation would exhibit this mismatch with PDES runs. We also present a new scheduler optimized specifically for PDES applications, and describe its design and implementation. Experimental results obtained from running PDES benchmarks (PHOLD and vehicular traffic simulations) over VMs show over an order of magnitude improvement in the run time of the PDES-optimized scheduler relative to the regular VM scheduler, with over 20 reduction in run time of simulations using up to 64 VMs. The observations and results are timely in the context of emerging systems such as cloud platforms and VM-based high performance computing installations, highlighting to the community the need for PDES-specific support, and the feasibility of significantly reducing the runtime overhead for scalable PDES on VM platforms.« less

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

PubMed

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

2016-08-01

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

Weighted graph based ordering techniques for preconditioned conjugate gradient methods

NASA Technical Reports Server (NTRS)

Clift, Simon S.; Tang, Wei-Pai

1994-01-01

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

Providing a parallel and distributed capability for JMASS using SPEEDES

NASA Astrophysics Data System (ADS)

Valinski, Maria; Driscoll, Jonathan; McGraw, Robert M.; Meyer, Bob

2002-07-01

The Joint Modeling And Simulation System (JMASS) is a Tri-Service simulation environment that supports engineering and engagement-level simulations. As JMASS is expanded to support other Tri-Service domains, the current set of modeling services must be expanded for High Performance Computing (HPC) applications by adding support for advanced time-management algorithms, parallel and distributed topologies, and high speed communications. By providing support for these services, JMASS can better address modeling domains requiring parallel computationally intense calculations such clutter, vulnerability and lethality calculations, and underwater-based scenarios. A risk reduction effort implementing some HPC services for JMASS using the SPEEDES (Synchronous Parallel Environment for Emulation and Discrete Event Simulation) Simulation Framework has recently concluded. As an artifact of the JMASS-SPEEDES integration, not only can HPC functionality be brought to the JMASS program through SPEEDES, but an additional HLA-based capability can be demonstrated that further addresses interoperability issues. The JMASS-SPEEDES integration provided a means of adding HLA capability to preexisting JMASS scenarios through an implementation of the standard JMASS port communication mechanism that allows players to communicate.

Proteomic analysis in peritoneal dialysis patients with different peritoneal transport characteristics.

PubMed

Wen, Qiong; Zhang, Li; Mao, Hai-Ping; Tang, Xue-Qing; Rong, Rong; Fan, Jin-Jin; Yu, Xue-Qing

2013-08-30

Peritoneal membranes can be categorized as high, high average, low average, and low transporters, based on the removal or transport rate of solutes. In this study, we used proteomic analysis to determine the differences in proteins removed by different types of peritoneal membranes. Peritoneal transport characteristics in patients who received peritoneal dialysis therapy were assessed by a peritoneal equilibration test. Two-dimensional differential gel electrophoresis technology followed by quantitative analysis was performed to study the variation in protein expression from peritoneal dialysis effluents (PDE) among different groups. Proteins were identified by MALDI-TOF-MS/MS analyses. Further validation in PDE or serum was performed utilizing ELISA analysis. Proteomics analysis revealed ten protein spots with significant differences in intensity levels among different groups, including vitamin D-binding protein, complement C3, apolipoprotein-A1, complement factor C4A, haptoglobin, alpha-1 antitrypsin, immunoglobulin kappa light chain, alpha-2-microglobulin, retinol-binding protein 4 and transthyretin. The levels of vitamin D-binding protein, complement C3, and apolipoprotein-A1 in PDE derived from different groups were greatly varied (P<0.05). However, no significant difference was found in the serum levels of these proteins among different groups (P>0.05 for all groups). This study provides a novel overview of the differences in PDE proteomes of four types of peritoneal membranes. Vitamin D-binding protein, complement C3, and apolipoprotein-A1 showed enhanced expression in PDE of patients with high transporter. Copyright © 2013 Elsevier Inc. All rights reserved.

Profound neonatal hypoglycemia and lactic acidosis caused by pyridoxine-dependent epilepsy.

PubMed

Mercimek-Mahmutoglu, Saadet; Horvath, Gabriella A; Coulter-Mackie, Marion; Nelson, Tanya; Waters, Paula J; Sargent, Michael; Struys, Eduard; Jakobs, Cornelis; Stockler-Ipsiroglu, Sylvia; Connolly, Mary B

2012-05-01

Pyridoxine-dependent epilepsy (PDE) was first described in 1954. The ALDH7A1 gene mutations resulting in α-aminoadipic semialdehyde dehydrogenase deficiency as a cause of PDE was identified only in 2005. Neonatal epileptic encephalopathy is the presenting feature in >50% of patients with classic PDE. We report the case of a 13-month-old girl with profound neonatal hypoglycemia (0.6 mmol/L; reference range >2.4), lactic acidosis (11 mmol/L; reference range <2), and bilateral symmetrical temporal lobe hemorrhages and thalamic changes on cranial MRI. She developed multifocal and myoclonic seizures refractory to multiple antiepileptic drugs that responded to pyridoxine. The diagnosis of α-aminoadipic semialdehyde dehydrogenase deficiency was confirmed based on the elevated urinary α-aminoadipic semialdehyde excretion, compound heterozygosity for a known splice mutation c.834G>A (p.Val278Val), and a novel putative pathogenic missense mutation c.1192G>C (p.Gly398Arg) in the ALDH7A1 gene. She has been seizure-free since 1.5 months of age on treatment with pyridoxine alone. She has motor delay and central hypotonia but normal language and social development at the age of 13 months. This case is the first description of a patient with PDE due to mutations in the ALDH7A1 gene who presented with profound neonatal hypoglycemia and lactic acidosis masquerading as a neonatal-onset gluconeogenesis defect. PDE should be included in the differential diagnosis of hypoglycemia and lactic acidosis in addition to medically refractory neonatal seizures.

A hybrid parallel framework for the cellular Potts model simulations

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

Jiang, Yi; He, Kejing; Dong, Shoubin

2009-01-01

The Cellular Potts Model (CPM) has been widely used for biological simulations. However, most current implementations are either sequential or approximated, which can't be used for large scale complex 3D simulation. In this paper we present a hybrid parallel framework for CPM simulations. The time-consuming POE solving, cell division, and cell reaction operation are distributed to clusters using the Message Passing Interface (MPI). The Monte Carlo lattice update is parallelized on shared-memory SMP system using OpenMP. Because the Monte Carlo lattice update is much faster than the POE solving and SMP systems are more and more common, this hybrid approachmore » achieves good performance and high accuracy at the same time. Based on the parallel Cellular Potts Model, we studied the avascular tumor growth using a multiscale model. The application and performance analysis show that the hybrid parallel framework is quite efficient. The hybrid parallel CPM can be used for the large scale simulation ({approx}10{sup 8} sites) of complex collective behavior of numerous cells ({approx}10{sup 6}).« less

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

PubMed

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

2017-12-30

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

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

PubMed

Ioakeimidis, Nikolaos; Kostis, John B

2014-01-01

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

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

NASA Astrophysics Data System (ADS)

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

2011-08-01

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

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

PubMed Central

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

1991-01-01

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

Current drug therapy of patients with BPH-LUTS with the special emphasis on PDE5 inhibitors

PubMed Central

Govorov, Alexander; Kasyan, George; Priymak, Diana; Pushkar, Dmitry

2016-01-01

Introduction Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptom (LUTS) development in men [1]. The intensity of the symptoms may vary from mild to severe, significantly affecting the quality of life. Erectile dysfunction (ED) is one of the most challenging issues in modern urology that significantly influences the quality of life in men worldwide. The objective of this literature review was to analyze the current drug therapies of patients with BPH-LUTS, with the special emphasis on PDE5 inhibitors. Material and methods The authors searched the literature for the period from 2000 until 2015 in MEDLINE and PubMed. Results Twenty-three articles were selected based on their reliability. A detailed analysis of the selected papers was performed. Primary attention was given to articles describing the use of PDE5. Works describing the use of different groups of drugs in patients with BPH-LUTS were also selected. Conclusions The current literature analysis suggests that the introduction of PDE5 inhibitors in clinical practice for the treatment of patients with BPH-LUTS will allow for significant expansion of the therapeutic options for the treatment of this disease. PMID:28127458

Sub-efficacious doses of phosphodiesterase 4 and 5 inhibitors improve memory in a mouse model of Alzheimer's disease.

PubMed

Gulisano, Walter; Tropea, Maria Rosaria; Arancio, Ottavio; Palmeri, Agostino; Puzzo, Daniela

2018-06-06

Cyclic nucleotides cAMP and cGMP cooperate to ensure memory acquisition and consolidation. Increasing their levels by phosphodiesterase inhibitors (PDE-Is) enhanced cognitive functions and rescued memory loss in different models of aging and Alzheimer's disease (AD). However, side effects due to the high doses used limited their application in humans. Based on previous studies suggesting that combinations of sub-efficacious doses of cAMP- and cGMP-specific PDE-Is improved synaptic plasticity and memory in physiological conditions, here we aimed to study whether this treatment was effective to counteract the AD phenotype in APPswe mice. We found that a 3-week chronic treatment with a combination of sub-efficacious doses of the cAMP-specific PDE4-I roflumilast (0.01 mg/kg) and the cGMP-specific PDE5-I vardenafil (0.1 mg/kg) improved recognition, spatial and contextual fear memory. Importantly, the cognitive enhancement persisted for 2 months beyond administration. This long-lasting action, and the possibility to minimize side effects due to the low doses used, might open feasible therapeutic strategies against AD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Current drug therapy of patients with BPH-LUTS with the special emphasis on PDE5 inhibitors.

PubMed

Kolontarev, Konstantin; Govorov, Alexander; Kasyan, George; Priymak, Diana; Pushkar, Dmitry

2016-01-01

Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptom (LUTS) development in men [1]. The intensity of the symptoms may vary from mild to severe, significantly affecting the quality of life. Erectile dysfunction (ED) is one of the most challenging issues in modern urology that significantly influences the quality of life in men worldwide. The objective of this literature review was to analyze the current drug therapies of patients with BPH-LUTS, with the special emphasis on PDE5 inhibitors. The authors searched the literature for the period from 2000 until 2015 in MEDLINE and PubMed. Twenty-three articles were selected based on their reliability. A detailed analysis of the selected papers was performed. Primary attention was given to articles describing the use of PDE5. Works describing the use of different groups of drugs in patients with BPH-LUTS were also selected. The current literature analysis suggests that the introduction of PDE5 inhibitors in clinical practice for the treatment of patients with BPH-LUTS will allow for significant expansion of the therapeutic options for the treatment of this disease.

A parallel simulated annealing algorithm for standard cell placement on a hypercube computer

NASA Technical Reports Server (NTRS)

Jones, Mark Howard

1987-01-01

A parallel version of a simulated annealing algorithm is presented which is targeted to run on a hypercube computer. A strategy for mapping the cells in a two dimensional area of a chip onto processors in an n-dimensional hypercube is proposed such that both small and large distance moves can be applied. Two types of moves are allowed: cell exchanges and cell displacements. The computation of the cost function in parallel among all the processors in the hypercube is described along with a distributed data structure that needs to be stored in the hypercube to support parallel cost evaluation. A novel tree broadcasting strategy is used extensively in the algorithm for updating cell locations in the parallel environment. Studies on the performance of the algorithm on example industrial circuits show that it is faster and gives better final placement results than the uniprocessor simulated annealing algorithms. An improved uniprocessor algorithm is proposed which is based on the improved results obtained from parallelization of the simulated annealing algorithm.

pWeb: A High-Performance, Parallel-Computing Framework for Web-Browser-Based Medical Simulation.

PubMed

Halic, Tansel; Ahn, Woojin; De, Suvranu

2014-01-01

This work presents a pWeb - a new language and compiler for parallelization of client-side compute intensive web applications such as surgical simulations. The recently introduced HTML5 standard has enabled creating unprecedented applications on the web. Low performance of the web browser, however, remains the bottleneck of computationally intensive applications including visualization of complex scenes, real time physical simulations and image processing compared to native ones. The new proposed language is built upon web workers for multithreaded programming in HTML5. The language provides fundamental functionalities of parallel programming languages as well as the fork/join parallel model which is not supported by web workers. The language compiler automatically generates an equivalent parallel script that complies with the HTML5 standard. A case study on realistic rendering for surgical simulations demonstrates enhanced performance with a compact set of instructions.

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

PubMed Central

Pauwelyn, Vicky; Lefebvre, Romain A.

2018-01-01

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

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

PubMed

Sugita, Minoru; Miyakawa, Michiko

2010-07-01

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

Two-Dimensional Modeling of Heat and Moisture Dynamics in Swedish Roads: Model Set up and Parameter Sensitivity

NASA Astrophysics Data System (ADS)

Rasul, H.; Wu, M.; Olofsson, B.

2017-12-01

Modelling moisture and heat changes in road layers is very important to understand road hydrology and for better construction and maintenance of roads in a sustainable manner. In cold regions due to the freezing/thawing process in the partially saturated material of roads, the modeling task will become more complicated than simple model of flow through porous media without freezing/thawing pores considerations. This study is presenting a 2-D model simulation for a section of highway with considering freezing/thawing and vapor changes. Partial deferential equations (PDEs) are used in formulation of the model. Parameters are optimized from modelling results based on the measured data from test station on E18 highway near Stockholm. Impacts of phase change considerations in the modelling are assessed by comparing the modeled soil moisture with TDR-measured data. The results show that the model can be used for prediction of water and ice content in different layers of the road and at different seasons. Parameter sensitivities are analyzed by implementing a calibration strategy. In addition, the phase change consideration is evaluated in the modeling process, by comparing the PDE model with another model without considerations of freezing/thawing in roads. The PDE model shows high potential in understanding the moisture dynamics in the road system.

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

NASA Astrophysics Data System (ADS)

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

2017-12-01

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

On the instability of wave-fields with JONSWAP spectra to inhomogeneous disturbances, and the consequent long-time evolution

NASA Astrophysics Data System (ADS)

Ribal, A.; Stiassnie, M.; Babanin, A.; Young, I.

2012-04-01

The instability of two-dimensional wave-fields and its subsequent evolution in time are studied by means of the Alber equation for narrow-banded random surface-waves in deep water subject to inhomogeneous disturbances. A linear partial differential equation (PDE) is obtained after applying an inhomogeneous disturbance to the Alber's equation and based on the solution of this PDE, the instability of the ocean wave surface is studied for a JONSWAP spectrum, which is a realistic ocean spectrum with variable directional spreading and steepness. The steepness of the JONSWAP spectrum depends on γ and α which are the peak-enhancement factor and energy scale of the spectrum respectively and it is found that instability depends on the directional spreading, α and γ. Specifically, if the instability stops due to the directional spreading, increase of the steepness by increasing α or γ can reactivate it. This result is in qualitative agreement with the recent large-scale experiment and new theoretical results. In the instability area of α-γ plane, a long-time evolution has been simulated by integrating Alber's equation numerically and recurrent evolution is obtained which is the stochastic counterpart of the Fermi-Pasta-Ulam recurrence obtained for the cubic Schrödinger equation.

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

PubMed

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

2008-11-15

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

GENESIS: a hybrid-parallel and multi-scale molecular dynamics simulator with enhanced sampling algorithms for biomolecular and cellular simulations.

PubMed

Jung, Jaewoon; Mori, Takaharu; Kobayashi, Chigusa; Matsunaga, Yasuhiro; Yoda, Takao; Feig, Michael; Sugita, Yuji

2015-07-01

GENESIS (Generalized-Ensemble Simulation System) is a new software package for molecular dynamics (MD) simulations of macromolecules. It has two MD simulators, called ATDYN and SPDYN. ATDYN is parallelized based on an atomic decomposition algorithm for the simulations of all-atom force-field models as well as coarse-grained Go-like models. SPDYN is highly parallelized based on a domain decomposition scheme, allowing large-scale MD simulations on supercomputers. Hybrid schemes combining OpenMP and MPI are used in both simulators to target modern multicore computer architectures. Key advantages of GENESIS are (1) the highly parallel performance of SPDYN for very large biological systems consisting of more than one million atoms and (2) the availability of various REMD algorithms (T-REMD, REUS, multi-dimensional REMD for both all-atom and Go-like models under the NVT, NPT, NPAT, and NPγT ensembles). The former is achieved by a combination of the midpoint cell method and the efficient three-dimensional Fast Fourier Transform algorithm, where the domain decomposition space is shared in real-space and reciprocal-space calculations. Other features in SPDYN, such as avoiding concurrent memory access, reducing communication times, and usage of parallel input/output files, also contribute to the performance. We show the REMD simulation results of a mixed (POPC/DMPC) lipid bilayer as a real application using GENESIS. GENESIS is released as free software under the GPLv2 licence and can be easily modified for the development of new algorithms and molecular models. WIREs Comput Mol Sci 2015, 5:310-323. doi: 10.1002/wcms.1220.

Design of object-oriented distributed simulation classes

NASA Technical Reports Server (NTRS)

Schoeffler, James D. (Principal Investigator)

1995-01-01

Distributed simulation of aircraft engines as part of a computer aided design package is being developed by NASA Lewis Research Center for the aircraft industry. The project is called NPSS, an acronym for 'Numerical Propulsion Simulation System'. NPSS is a flexible object-oriented simulation of aircraft engines requiring high computing speed. It is desirable to run the simulation on a distributed computer system with multiple processors executing portions of the simulation in parallel. The purpose of this research was to investigate object-oriented structures such that individual objects could be distributed. The set of classes used in the simulation must be designed to facilitate parallel computation. Since the portions of the simulation carried out in parallel are not independent of one another, there is the need for communication among the parallel executing processors which in turn implies need for their synchronization. Communication and synchronization can lead to decreased throughput as parallel processors wait for data or synchronization signals from other processors. As a result of this research, the following have been accomplished. The design and implementation of a set of simulation classes which result in a distributed simulation control program have been completed. The design is based upon MIT 'Actor' model of a concurrent object and uses 'connectors' to structure dynamic connections between simulation components. Connectors may be dynamically created according to the distribution of objects among machines at execution time without any programming changes. Measurements of the basic performance have been carried out with the result that communication overhead of the distributed design is swamped by the computation time of modules unless modules have very short execution times per iteration or time step. An analytical performance model based upon queuing network theory has been designed and implemented. Its application to realistic configurations has not been carried out.

Design of Object-Oriented Distributed Simulation Classes

NASA Technical Reports Server (NTRS)

Schoeffler, James D.

1995-01-01

Distributed simulation of aircraft engines as part of a computer aided design package being developed by NASA Lewis Research Center for the aircraft industry. The project is called NPSS, an acronym for "Numerical Propulsion Simulation System". NPSS is a flexible object-oriented simulation of aircraft engines requiring high computing speed. It is desirable to run the simulation on a distributed computer system with multiple processors executing portions of the simulation in parallel. The purpose of this research was to investigate object-oriented structures such that individual objects could be distributed. The set of classes used in the simulation must be designed to facilitate parallel computation. Since the portions of the simulation carried out in parallel are not independent of one another, there is the need for communication among the parallel executing processors which in turn implies need for their synchronization. Communication and synchronization can lead to decreased throughput as parallel processors wait for data or synchronization signals from other processors. As a result of this research, the following have been accomplished. The design and implementation of a set of simulation classes which result in a distributed simulation control program have been completed. The design is based upon MIT "Actor" model of a concurrent object and uses "connectors" to structure dynamic connections between simulation components. Connectors may be dynamically created according to the distribution of objects among machines at execution time without any programming changes. Measurements of the basic performance have been carried out with the result that communication overhead of the distributed design is swamped by the computation time of modules unless modules have very short execution times per iteration or time step. An analytical performance model based upon queuing network theory has been designed and implemented. Its application to realistic configurations has not been carried out.

Parallel programming with Easy Java Simulations

NASA Astrophysics Data System (ADS)

Esquembre, F.; Christian, W.; Belloni, M.

2018-01-01

Nearly all of today's processors are multicore, and ideally programming and algorithm development utilizing the entire processor should be introduced early in the computational physics curriculum. Parallel programming is often not introduced because it requires a new programming environment and uses constructs that are unfamiliar to many teachers. We describe how we decrease the barrier to parallel programming by using a java-based programming environment to treat problems in the usual undergraduate curriculum. We use the easy java simulations programming and authoring tool to create the program's graphical user interface together with objects based on those developed by Kaminsky [Building Parallel Programs (Course Technology, Boston, 2010)] to handle common parallel programming tasks. Shared-memory parallel implementations of physics problems, such as time evolution of the Schrödinger equation, are available as source code and as ready-to-run programs from the AAPT-ComPADRE digital library.

Parallelization of a Fully-Distributed Hydrologic Model using Sub-basin Partitioning

NASA Astrophysics Data System (ADS)

Vivoni, E. R.; Mniszewski, S.; Fasel, P.; Springer, E.; Ivanov, V. Y.; Bras, R. L.

2005-12-01

A primary obstacle towards advances in watershed simulations has been the limited computational capacity available to most models. The growing trend of model complexity, data availability and physical representation has not been matched by adequate developments in computational efficiency. This situation has created a serious bottleneck which limits existing distributed hydrologic models to small domains and short simulations. In this study, we present novel developments in the parallelization of a fully-distributed hydrologic model. Our work is based on the TIN-based Real-time Integrated Basin Simulator (tRIBS), which provides continuous hydrologic simulation using a multiple resolution representation of complex terrain based on a triangulated irregular network (TIN). While the use of TINs reduces computational demand, the sequential version of the model is currently limited over large basins (>10,000 km2) and long simulation periods (>1 year). To address this, a parallel MPI-based version of the tRIBS model has been implemented and tested using high performance computing resources at Los Alamos National Laboratory. Our approach utilizes domain decomposition based on sub-basin partitioning of the watershed. A stream reach graph based on the channel network structure is used to guide the sub-basin partitioning. Individual sub-basins or sub-graphs of sub-basins are assigned to separate processors to carry out internal hydrologic computations (e.g. rainfall-runoff transformation). Routed streamflow from each sub-basin forms the major hydrologic data exchange along the stream reach graph. Individual sub-basins also share subsurface hydrologic fluxes across adjacent boundaries. We demonstrate how the sub-basin partitioning provides computational feasibility and efficiency for a set of test watersheds in northeastern Oklahoma. We compare the performance of the sequential and parallelized versions to highlight the efficiency gained as the number of processors increases. We also discuss how the coupled use of TINs and parallel processing can lead to feasible long-term simulations in regional watersheds while preserving basin properties at high-resolution.

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

DTIC Science & Technology

2009-01-01

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

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

PubMed

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

2008-11-01

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

Reasons and predictive factors for discontinuation of PDE-5 inhibitors despite successful intercourse in erectile dysfunction patients

PubMed Central

Kim, S-C; Lee, Y-S; Seo, K-K; Jung, G-W; Kim, T-H

2014-01-01

This study was aimed to identify characteristics of ED patients who discontinued PDE5i despite successful intercourse. Data were collected using a questionnaire from 34 urologic clinics regardless of the effect (success or failure) of PDE5i treatment by visiting the clinics (717), e-mail (64) or post (101) for 882 ED patients who had previously taken any kind of PDE5i on demand four or more times. Discontinuation of PDE5i was defined if the patient had never taken PDE5i for the previous 1 year despite successful intercourse. Of the 882 patients, 485 were included in the final analysis. Difference in the socio-demographic, ED- and partner-related data between the continuation and discontinuation group and factors influencing discontinuation of the PDE5i were analyzed. Among 485 respondents (mean age, 53.6), 116 (23.9%) had discontinued PDE5i use despite successful intercourse. Most common reasons for the discontinuation were ‘reluctant medication-dependent intercourse' (31.0%), ‘spontaneous recovery of erectile function without further treatment' (30.2%), and ‘high cost' (26.7%). In multiple logistic regression analysis, independent factors influencing discontinuation of the drug were cause of ED (psychogenic), short duration of ED, low education (⩽ middle school), and religion (Catholic). In partner-related compliance, only partner's religion (Catholic) was a significant factor. PMID:24305610

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

PubMed Central

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

2017-01-01

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

A parallel implementation of an off-lattice individual-based model of multicellular populations

NASA Astrophysics Data System (ADS)

Harvey, Daniel G.; Fletcher, Alexander G.; Osborne, James M.; Pitt-Francis, Joe

2015-07-01

As computational models of multicellular populations include ever more detailed descriptions of biophysical and biochemical processes, the computational cost of simulating such models limits their ability to generate novel scientific hypotheses and testable predictions. While developments in microchip technology continue to increase the power of individual processors, parallel computing offers an immediate increase in available processing power. To make full use of parallel computing technology, it is necessary to develop specialised algorithms. To this end, we present a parallel algorithm for a class of off-lattice individual-based models of multicellular populations. The algorithm divides the spatial domain between computing processes and comprises communication routines that ensure the model is correctly simulated on multiple processors. The parallel algorithm is shown to accurately reproduce the results of a deterministic simulation performed using a pre-existing serial implementation. We test the scaling of computation time, memory use and load balancing as more processes are used to simulate a cell population of fixed size. We find approximate linear scaling of both speed-up and memory consumption on up to 32 processor cores. Dynamic load balancing is shown to provide speed-up for non-regular spatial distributions of cells in the case of a growing population.

Moose: An Open-Source Framework to Enable Rapid Development of Collaborative, Multi-Scale, Multi-Physics Simulation Tools

NASA Astrophysics Data System (ADS)

Slaughter, A. E.; Permann, C.; Peterson, J. W.; Gaston, D.; Andrs, D.; Miller, J.

2014-12-01

The Idaho National Laboratory (INL)-developed Multiphysics Object Oriented Simulation Environment (MOOSE; www.mooseframework.org), is an open-source, parallel computational framework for enabling the solution of complex, fully implicit multiphysics systems. MOOSE provides a set of computational tools that scientists and engineers can use to create sophisticated multiphysics simulations. Applications built using MOOSE have computed solutions for chemical reaction and transport equations, computational fluid dynamics, solid mechanics, heat conduction, mesoscale materials modeling, geomechanics, and others. To facilitate the coupling of diverse and highly-coupled physical systems, MOOSE employs the Jacobian-free Newton-Krylov (JFNK) method when solving the coupled nonlinear systems of equations arising in multiphysics applications. The MOOSE framework is written in C++, and leverages other high-quality, open-source scientific software packages such as LibMesh, Hypre, and PETSc. MOOSE uses a "hybrid parallel" model which combines both shared memory (thread-based) and distributed memory (MPI-based) parallelism to ensure efficient resource utilization on a wide range of computational hardware. MOOSE-based applications are inherently modular, which allows for simulation expansion (via coupling of additional physics modules) and the creation of multi-scale simulations. Any application developed with MOOSE supports running (in parallel) any other MOOSE-based application. Each application can be developed independently, yet easily communicate with other applications (e.g., conductivity in a slope-scale model could be a constant input, or a complete phase-field micro-structure simulation) without additional code being written. This method of development has proven effective at INL and expedites the development of sophisticated, sustainable, and collaborative simulation tools.

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

PubMed

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

2017-03-01

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

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

PubMed Central

Schwarz, Simon; Ravens, Ursula; Knaut, Michael

2016-01-01

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

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

PubMed

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

2017-09-22

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

Experimental Study of Propulsion Performance by Single-Pulse Rotating Detonation with Gaseous Fuels-Oxygen Mixtures

NASA Astrophysics Data System (ADS)

Toshimitsu, Kazuhiko; Hara, Kosei; Mikajiri, Shuuto; Takiguchi, Naoki

2016-12-01

A rotating detonation engine (RDE) is one of candidates of aerospace engines for supersonic cruse, which is better for propulsion system than a pulse detonation engine (PDE) from the view of continuous thrust and simple structure. The propulsion performance of a proto-type RDE and a PDE by single pulse explosion with methane-oxygen is investigated. Furthermore, the performance of the RDE with acetylene-oxygen gas mixtures is investigated. Its impulse is estimated through ballistic pendulum method with maximum displacement and damping ratio. The comparison of specific impulses of the mixture gases at atmospheric pressure is shown. The specific impulses of the RDE and the PDE are almost same with methane-oxygen gas. Furthermore, the fuel-base specific impulse of the RDE with acetylene-oxygen gas is about over twice as large as one of methane-oxygen, and its maximum specific impulse is 1100 seconds.

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.

Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4

DOE PAGES

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

2015-03-09

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

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

PubMed

Li, Ben; Stenstrom, M K

2014-01-01

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

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

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

Kevrekidis, Ioannis

2017-03-22

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

Tutorial: Parallel Computing of Simulation Models for Risk Analysis.

PubMed

Reilly, Allison C; Staid, Andrea; Gao, Michael; Guikema, Seth D

2016-10-01

Simulation models are widely used in risk analysis to study the effects of uncertainties on outcomes of interest in complex problems. Often, these models are computationally complex and time consuming to run. This latter point may be at odds with time-sensitive evaluations or may limit the number of parameters that are considered. In this article, we give an introductory tutorial focused on parallelizing simulation code to better leverage modern computing hardware, enabling risk analysts to better utilize simulation-based methods for quantifying uncertainty in practice. This article is aimed primarily at risk analysts who use simulation methods but do not yet utilize parallelization to decrease the computational burden of these models. The discussion is focused on conceptual aspects of embarrassingly parallel computer code and software considerations. Two complementary examples are shown using the languages MATLAB and R. A brief discussion of hardware considerations is located in the Appendix. © 2016 Society for Risk Analysis.

Parallel Implementation of Triangular Cellular Automata for Computing Two-Dimensional Elastodynamic Response on Arbitrary Domains

NASA Astrophysics Data System (ADS)

Leamy, Michael J.; Springer, Adam C.

In this research we report parallel implementation of a Cellular Automata-based simulation tool for computing elastodynamic response on complex, two-dimensional domains. Elastodynamic simulation using Cellular Automata (CA) has recently been presented as an alternative, inherently object-oriented technique for accurately and efficiently computing linear and nonlinear wave propagation in arbitrarily-shaped geometries. The local, autonomous nature of the method should lead to straight-forward and efficient parallelization. We address this notion on symmetric multiprocessor (SMP) hardware using a Java-based object-oriented CA code implementing triangular state machines (i.e., automata) and the MPI bindings written in Java (MPJ Express). We use MPJ Express to reconfigure our existing CA code to distribute a domain's automata to cores present on a dual quad-core shared-memory system (eight total processors). We note that this message passing parallelization strategy is directly applicable to computer clustered computing, which will be the focus of follow-on research. Results on the shared memory platform indicate nearly-ideal, linear speed-up. We conclude that the CA-based elastodynamic simulator is easily configured to run in parallel, and yields excellent speed-up on SMP hardware.

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

NASA Astrophysics Data System (ADS)

Blonigan, Patrick J.

2017-11-01

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

Solar wind interaction with Venus and Mars in a parallel hybrid code

NASA Astrophysics Data System (ADS)

Jarvinen, Riku; Sandroos, Arto

2013-04-01

We discuss the development and applications of a new parallel hybrid simulation, where ions are treated as particles and electrons as a charge-neutralizing fluid, for the interaction between the solar wind and Venus and Mars. The new simulation code under construction is based on the algorithm of the sequential global planetary hybrid model developed at the Finnish Meteorological Institute (FMI) and on the Corsair parallel simulation platform also developed at the FMI. The FMI's sequential hybrid model has been used for studies of plasma interactions of several unmagnetized and weakly magnetized celestial bodies for more than a decade. Especially, the model has been used to interpret in situ particle and magnetic field observations from plasma environments of Mars, Venus and Titan. Further, Corsair is an open source MPI (Message Passing Interface) particle and mesh simulation platform, mainly aimed for simulations of diffusive shock acceleration in solar corona and interplanetary space, but which is now also being extended for global planetary hybrid simulations. In this presentation we discuss challenges and strategies of parallelizing a legacy simulation code as well as possible applications and prospects of a scalable parallel hybrid model for the solar wind interactions of Venus and Mars.

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

PubMed

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

2016-11-01

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

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

PubMed Central

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

2014-01-01

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

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

PubMed Central

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

2009-01-01

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

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

PubMed Central

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

2018-01-01

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

Petascale turbulence simulation using a highly parallel fast multipole method on GPUs

NASA Astrophysics Data System (ADS)

Yokota, Rio; Barba, L. A.; Narumi, Tetsu; Yasuoka, Kenji

2013-03-01

This paper reports large-scale direct numerical simulations of homogeneous-isotropic fluid turbulence, achieving sustained performance of 1.08 petaflop/s on GPU hardware using single precision. The simulations use a vortex particle method to solve the Navier-Stokes equations, with a highly parallel fast multipole method (FMM) as numerical engine, and match the current record in mesh size for this application, a cube of 40963 computational points solved with a spectral method. The standard numerical approach used in this field is the pseudo-spectral method, relying on the FFT algorithm as the numerical engine. The particle-based simulations presented in this paper quantitatively match the kinetic energy spectrum obtained with a pseudo-spectral method, using a trusted code. In terms of parallel performance, weak scaling results show the FMM-based vortex method achieving 74% parallel efficiency on 4096 processes (one GPU per MPI process, 3 GPUs per node of the TSUBAME-2.0 system). The FFT-based spectral method is able to achieve just 14% parallel efficiency on the same number of MPI processes (using only CPU cores), due to the all-to-all communication pattern of the FFT algorithm. The calculation time for one time step was 108 s for the vortex method and 154 s for the spectral method, under these conditions. Computing with 69 billion particles, this work exceeds by an order of magnitude the largest vortex-method calculations to date.

Aztec user`s guide. Version 1

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

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

1995-10-01

Aztec is an iterative library that greatly simplifies the parallelization process when solving the linear systems of equations Ax = b where A is a user supplied n x n sparse matrix, b is a user supplied vector of length n and x is a vector of length n to be computed. Aztec is intended as a software tool for users who want to avoid cumbersome parallel programming details but who have large sparse linear systems which require an efficiently utilized parallel processing system. A collection of data transformation tools are provided that allow for easy creation of distributed sparsemore » unstructured matrices for parallel solution. Once the distributed matrix is created, computation can be performed on any of the parallel machines running Aztec: nCUBE 2, IBM SP2 and Intel Paragon, MPI platforms as well as standard serial and vector platforms. Aztec includes a number of Krylov iterative methods such as conjugate gradient (CG), generalized minimum residual (GMRES) and stabilized biconjugate gradient (BICGSTAB) to solve systems of equations. These Krylov methods are used in conjunction with various preconditioners such as polynomial or domain decomposition methods using LU or incomplete LU factorizations within subdomains. Although the matrix A can be general, the package has been designed for matrices arising from the approximation of partial differential equations (PDEs). In particular, the Aztec package is oriented toward systems arising from PDE applications.« less

A fast ultrasonic simulation tool based on massively parallel implementations

NASA Astrophysics Data System (ADS)

Lambert, Jason; Rougeron, Gilles; Lacassagne, Lionel; Chatillon, Sylvain

2014-02-01

This paper presents a CIVA optimized ultrasonic inspection simulation tool, which takes benefit of the power of massively parallel architectures: graphical processing units (GPU) and multi-core general purpose processors (GPP). This tool is based on the classical approach used in CIVA: the interaction model is based on Kirchoff, and the ultrasonic field around the defect is computed by the pencil method. The model has been adapted and parallelized for both architectures. At this stage, the configurations addressed by the tool are : multi and mono-element probes, planar specimens made of simple isotropic materials, planar rectangular defects or side drilled holes of small diameter. Validations on the model accuracy and performances measurements are presented.

Cigarette Smoke Upregulates PDE3 and PDE4 to Decrease cAMP in Airway Cells.

PubMed

Zuo, Haoxiao; Han, Bing; Poppinga, Wilfred J; Ringnalda, Lennard; Kistemaker, Loes E M; Halayko, Andrew J; Gosens, Reinoud; Nikolaev, Viacheslav O; Schmidt, Martina

2018-05-03

3', 5'-cyclic adenosine monophosphate (cAMP) is a central second messenger that broadly regulates cell function and can underpin pathophysiology. In chronic obstructive pulmonary disease (COPD), a lung disease primarily provoked by cigarette smoke (CS), the induction of cAMP-dependent pathways, via inhibition of hydrolyzing phosphodiesterases (PDEs), is a prime therapeutic strategy. Mechanisms that disrupt cAMP signaling in airway cells, in particular regulation of endogenous PDEs are poorly understood. We used a novel Förster resonance energy transfer (FRET) based cAMP biosensor in mouse in vivo, ex vivo precision cut lung slices (PCLS), and in human in vitro cell models to track the effects of CS exposure. Under fenoterol stimulated conditions, FRET responses to cilostamide were significantly increased in in vivo, ex vivo PCLS exposed to CS and in human airway smooth muscle cells exposed to CS extract. FRET signals to rolipram were only increased in the in vivo CS model. Under basal conditions, FRET responses to cilostamide and rolipram were significantly increased in in vivo, ex vivo PCLS exposed to CS. Elevated FRET signals to rolipram correlated with a protein upregulation of PDE4 subtypes. In ex vivo PCLS exposed to CS extract, rolipram reversed downregulation of ciliary beating frequency, whereas only cilostamide significantly increased airway relaxation of methacholine pre-contracted airways. We show that CS upregulates expression and activity of both PDE3 and PDE4, which regulate real-time cAMP dynamics. These mechanisms determine the availability of cAMP and can contribute to CS-induced pulmonary pathophysiology. This article is protected by copyright. All rights reserved.

Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5.

PubMed

Sawant, Sanghapal D; Lakshma Reddy, G; Dar, Mohd Ishaq; Srinivas, M; Gupta, Gourav; Sahu, Promod Kumar; Mahajan, Priya; Nargotra, Amit; Singh, Surjeet; Sharma, Subhash C; Tikoo, Manoj; Singh, Gurdarshan; Vishwakarma, Ram A; Syed, Sajad Hussain

2015-05-01

Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy-N-(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide, that is, compound-4a, an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 inhibitor. A series of compounds was synthesized by replacing N-methylpiperazine moiety (ring-C) of sildenafil structure with different N-substitutions towards sulfonamide end. Compound-4a showed lower IC₅₀ value (1.5 nM) against PDE5 than parent sildenafil (5.6 nM) in in vitro enzyme assay. The isoform selectivity of the compound-4a against other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound-4a exhibited good physicochemical properties like solubility, caco-2 permeability, cLogP along with optimal PK profile having no significant CYP enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension].

PubMed

Beltrán-Gámez, Miguel E; Sandoval-Zárate, Julio; Pulido, Tomás

2015-01-01

In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comisión Federal de Protección contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively. Copyright © 2014 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

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

PubMed Central

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

2008-01-01

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

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

PubMed Central

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

2008-01-01

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

PDE and cognitive processing: beyond the memory domain.

PubMed

Heckman, P R A; Blokland, A; Ramaekers, J; Prickaerts, J

2015-03-01

Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Both cAMP and cGMP signaling are essential for a variety of cellular functions and exert their effects both pre- and post-synaptically. Either of these second messengers relays and amplifies incoming signals at receptors on the cell surface making them important elements in signal transduction cascades and essential in cellular signaling in a variety of cell functions including neurotransmitter release and neuroprotection. Consequently, these processes can be influenced by PDE-Is as they increase cAMP and/or cGMP concentrations. PDE-Is have been considered as possible therapeutic agents to treat impaired memory function linked to several brain disorders, including depression, schizophrenia and Alzheimer's disease (AD). This review will, however, focus on the possible role of phosphodiesterases (PDEs) in cognitive decline beyond the memory domain. Here we will discuss the involvement of PDEs on three related domains: attention, information filtering (sensory- and sensorimotor gating) and response inhibition (drug-induced hyperlocomotion). Currently, these are emerging cognitive domains in the field of PDE research. Here we discuss experimental studies and the potential beneficial effects of PDE-I drugs on these cognitive domains, as effects of PDE-Is on these domains could potentially influence effects on memory performance. Overall, PDE4 seems to be the most promising target for all domains discussed in this review. Copyright © 2014 Elsevier Inc. All rights reserved.

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

PubMed

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

2016-12-01

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

Association between a variation in the phosphodiesterase 4D gene and bone mineral density.

PubMed

Reneland, Richard H; Mah, Steven; Kammerer, Stefan; Hoyal, Carolyn R; Marnellos, George; Wilson, Scott G; Sambrook, Philip N; Spector, Tim D; Nelson, Matthew R; Braun, Andreas

2005-03-07

Fragility fractures caused by osteoporosis are a major cause of morbidity and mortality in aging populations. Bone mineral density (BMD) is a useful surrogate marker for risk of fracture and is a highly heritable trait. The genetic variants underlying this genetic contribution are largely unknown. We performed a large-scale association study investigating more than 25,000 single nucleotide polymorphisms (SNPs) located within 16,000 genes. Allele frequencies were estimated in contrasting DNA pools from white females selected for low (<0.87 g/cm2, n = 319) and high (> 1.11 g/cm2, n = 321) BMD at the lumbar spine. Significant findings were verified in two additional sample collections. Based on allele frequency differences between DNA pools and subsequent individual genotyping, one of the candidate loci indicated was the phosphodiesterase 4D (PDE4D) gene region on chromosome 5q12. We subsequently tested the marker SNP, rs1498608, in a second sample of 138 white females with low (<0.91 g/cm2) and 138 females with high (>1.04 g/cm2) lumbar spine BMD. Odds ratios were 1.5 (P = 0.035) in the original sample and 2.1 (P = 0.018) in the replication sample. Association fine mapping with 80 SNPs located within 50 kilobases of the marker SNP identified a 20 kilobase region of association containing exon 6 of PDE4D. In a second, family-based replication sample with a preponderance of females with low BMD, rs1498608 showed an opposite relationship with BMD at different sites (p = 0.00044-0.09). We also replicated the previously reported association of the Ser37Ala polymorphism in BMP2, known to interact biologically with PDE4D, with BMD. This study indicates that variants in the gene encoding PDE4D account for some of the genetic contribution to bone mineral density variation in humans. The contrasting results from different samples indicate that the effect may be context-dependent. PDE4 inhibitors have been shown to increase bone mass in normal and osteopenic mice, but up until now there have been no reports implicating any member of the PDE4 gene family in human osteoporosis.

Relationship of phosphodiesterase 4D (PDE4D) gene polymorphisms with risk of ischemic stroke: a hospital based case-control study.

PubMed

Kumar, Amit; Misra, Shubham; Kumar, Pradeep; Sagar, Ram; Gulati, Arti; Prasad, Kameshwar

2017-08-01

Stroke remains a leading cause of death and disability worldwide. Ischemic stroke (IS) accounts for around 80-85% of total stroke and is a complex polygenic multi-factorial disorder which is affected by a complex combination of vascular, environmental, and genetic factors. The study was conducted with an aim to examine the relationship of single nucleotide polymorphisms (SNPs) of PDE4D (T83C, C87T, and C45T) gene with increasing risk of IS in patients in North Indian population. In this hospital-based case-control study, 250 IS subjects and 250 age-and sex-matched control subjects were enrolled from the Neurosciences Centre, A.I.I.M.S., New Delhi, India. Deoxyribonucleic acids (DNAs) were extracted using the conventional Phenol-Chloroform isolation method. Different genotypes were determined by Polymerase chain reaction- Restriction fragment length polymorphism method. Odds ratio (OR) and 95% Confidence Interval (CI) of relationship of polymorphisms with risk of IS were calculated by conditional multivariable regression analysis. High blood pressure, low socioeconomic status, dyslipidemia, diabetes, and family history of stroke were observed to be statistically significant risk factors for IS. Multivariable adjusted analysis demonstrated a statistically significant relationship between SNP 83 of PDE4D gene polymorphism and increasing odds of IS under the dominant model of inheritance (OR, 1.59; 95% CI, 1.02 to 2.50; p value = 0.04) after adjustment of potential confounding variables. Stratified analysis on the basis of TOAST classification demonstrated a statistically significant association for increasing 2.73 times odds for developing large vessel disease stroke as compared to controls (OR, 2.73; 95% CI, 1.16 to 0.02; p value = 0.02). We did not find any significant association of SNPs (C87T and C45T) of the PDE4D gene with the risk of IS. SNP 83 of PDE4D gene may increase the risk for developing IS whereas SNP 87 and SNP45 of PDE4D may not be associated with the risk of IS in the North Indian population. Prospective cohort studies are required to corroborate these findings.

A geometric level set model for ultrasounds analysis

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

Sarti, A.; Malladi, R.

We propose a partial differential equation (PDE) for filtering and segmentation of echocardiographic images based on a geometric-driven scheme. The method allows edge-preserving image smoothing and a semi-automatic segmentation of the heart chambers, that regularizes the shapes and improves edge fidelity especially in presence of distinct gaps in the edge map as is common in ultrasound imagery. A numerical scheme for solving the proposed PDE is borrowed from level set methods. Results on human in vivo acquired 2D, 2D+time,3D, 3D+time echocardiographic images are shown.

Alternating Direction Implicit (ADI) schemes for a PDE-based image osmosis model

NASA Astrophysics Data System (ADS)

Calatroni, L.; Estatico, C.; Garibaldi, N.; Parisotto, S.

2017-10-01

We consider Alternating Direction Implicit (ADI) splitting schemes to compute efficiently the numerical solution of the PDE osmosis model considered by Weickert et al. in [10] for several imaging applications. The discretised scheme is shown to preserve analogous properties to the continuous model. The dimensional splitting strategy traduces numerically into the solution of simple tridiagonal systems for which standard matrix factorisation techniques can be used to improve upon the performance of classical implicit methods, even for large time steps. Applications to the shadow removal problem are presented.

GENESIS: a hybrid-parallel and multi-scale molecular dynamics simulator with enhanced sampling algorithms for biomolecular and cellular simulations

PubMed Central

Jung, Jaewoon; Mori, Takaharu; Kobayashi, Chigusa; Matsunaga, Yasuhiro; Yoda, Takao; Feig, Michael; Sugita, Yuji

2015-01-01

GENESIS (Generalized-Ensemble Simulation System) is a new software package for molecular dynamics (MD) simulations of macromolecules. It has two MD simulators, called ATDYN and SPDYN. ATDYN is parallelized based on an atomic decomposition algorithm for the simulations of all-atom force-field models as well as coarse-grained Go-like models. SPDYN is highly parallelized based on a domain decomposition scheme, allowing large-scale MD simulations on supercomputers. Hybrid schemes combining OpenMP and MPI are used in both simulators to target modern multicore computer architectures. Key advantages of GENESIS are (1) the highly parallel performance of SPDYN for very large biological systems consisting of more than one million atoms and (2) the availability of various REMD algorithms (T-REMD, REUS, multi-dimensional REMD for both all-atom and Go-like models under the NVT, NPT, NPAT, and NPγT ensembles). The former is achieved by a combination of the midpoint cell method and the efficient three-dimensional Fast Fourier Transform algorithm, where the domain decomposition space is shared in real-space and reciprocal-space calculations. Other features in SPDYN, such as avoiding concurrent memory access, reducing communication times, and usage of parallel input/output files, also contribute to the performance. We show the REMD simulation results of a mixed (POPC/DMPC) lipid bilayer as a real application using GENESIS. GENESIS is released as free software under the GPLv2 licence and can be easily modified for the development of new algorithms and molecular models. WIREs Comput Mol Sci 2015, 5:310–323. doi: 10.1002/wcms.1220 PMID:26753008

On the utility of graphics cards to perform massively parallel simulation of advanced Monte Carlo methods

PubMed Central

Lee, Anthony; Yau, Christopher; Giles, Michael B.; Doucet, Arnaud; Holmes, Christopher C.

2011-01-01

We present a case-study on the utility of graphics cards to perform massively parallel simulation of advanced Monte Carlo methods. Graphics cards, containing multiple Graphics Processing Units (GPUs), are self-contained parallel computational devices that can be housed in conventional desktop and laptop computers and can be thought of as prototypes of the next generation of many-core processors. For certain classes of population-based Monte Carlo algorithms they offer massively parallel simulation, with the added advantage over conventional distributed multi-core processors that they are cheap, easily accessible, easy to maintain, easy to code, dedicated local devices with low power consumption. On a canonical set of stochastic simulation examples including population-based Markov chain Monte Carlo methods and Sequential Monte Carlo methods, we nd speedups from 35 to 500 fold over conventional single-threaded computer code. Our findings suggest that GPUs have the potential to facilitate the growth of statistical modelling into complex data rich domains through the availability of cheap and accessible many-core computation. We believe the speedup we observe should motivate wider use of parallelizable simulation methods and greater methodological attention to their design. PMID:22003276

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

PubMed

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

1994-06-15

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

Solving large-scale PDE-constrained Bayesian inverse problems with Riemann manifold Hamiltonian Monte Carlo

NASA Astrophysics Data System (ADS)

Bui-Thanh, T.; Girolami, M.

2014-11-01

We consider the Riemann manifold Hamiltonian Monte Carlo (RMHMC) method for solving statistical inverse problems governed by partial differential equations (PDEs). The Bayesian framework is employed to cast the inverse problem into the task of statistical inference whose solution is the posterior distribution in infinite dimensional parameter space conditional upon observation data and Gaussian prior measure. We discretize both the likelihood and the prior using the H1-conforming finite element method together with a matrix transfer technique. The power of the RMHMC method is that it exploits the geometric structure induced by the PDE constraints of the underlying inverse problem. Consequently, each RMHMC posterior sample is almost uncorrelated/independent from the others providing statistically efficient Markov chain simulation. However this statistical efficiency comes at a computational cost. This motivates us to consider computationally more efficient strategies for RMHMC. At the heart of our construction is the fact that for Gaussian error structures the Fisher information matrix coincides with the Gauss-Newton Hessian. We exploit this fact in considering a computationally simplified RMHMC method combining state-of-the-art adjoint techniques and the superiority of the RMHMC method. Specifically, we first form the Gauss-Newton Hessian at the maximum a posteriori point and then use it as a fixed constant metric tensor throughout RMHMC simulation. This eliminates the need for the computationally costly differential geometric Christoffel symbols, which in turn greatly reduces computational effort at a corresponding loss of sampling efficiency. We further reduce the cost of forming the Fisher information matrix by using a low rank approximation via a randomized singular value decomposition technique. This is efficient since a small number of Hessian-vector products are required. The Hessian-vector product in turn requires only two extra PDE solves using the adjoint technique. Various numerical results up to 1025 parameters are presented to demonstrate the ability of the RMHMC method in exploring the geometric structure of the problem to propose (almost) uncorrelated/independent samples that are far away from each other, and yet the acceptance rate is almost unity. The results also suggest that for the PDE models considered the proposed fixed metric RMHMC can attain almost as high a quality performance as the original RMHMC, i.e. generating (almost) uncorrelated/independent samples, while being two orders of magnitude less computationally expensive.

An asymptotically exact reduced PDE model for the magnetorotational instability: derivation and numerical simulations

NASA Astrophysics Data System (ADS)

Jamroz, Ben; Julien, Keith; Knobloch, Edgar

2008-12-01

Taking advantage of disparate spatio-temporal scales relevant to astrophysics and laboratory experiments, we derive asymptotically exact reduced partial differential equation models for the magnetorotational instability. These models extend recent single-mode formulations leading to saturation in the presence of weak dissipation, and are characterized by a back-reaction on the imposed shear. Numerical simulations performed for a broad class of initial conditions indicate an initial phase of growth dominated by the optimal (fastest growing) magnetorotational instability fingering mode, followed by a vertical coarsening to a box-filling mode.

Applying Parallel Processing Techniques to Tether Dynamics Simulation

NASA Technical Reports Server (NTRS)

Wells, B. Earl

1996-01-01

The focus of this research has been to determine the effectiveness of applying parallel processing techniques to a sizable real-world problem, the simulation of the dynamics associated with a tether which connects two objects in low earth orbit, and to explore the degree to which the parallelization process can be automated through the creation of new software tools. The goal has been to utilize this specific application problem as a base to develop more generally applicable techniques.

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

PubMed Central

Balhadère, Pascale V.; Talbot, Nicholas J.

2001-01-01

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

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

PubMed

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

2015-05-01

Hypertrophy increases the risk of heart failure and arrhythmia. Prevention or reversal of the maladaptive hypertrophic phenotype has thus been proposed to treat heart failure. Chronic β-adrenergic receptor (β-AR) stimulation induces cardiomyocyte hypertrophy by elevating 3',5'-cyclic adenosine monophosphate (cAMP) levels and activating downstream effectors such protein kinase A (PKA). Conversely, hydrolysis of cAMP by phosphodiesterases (PDEs) spatiotemporally restricts cAMP signaling. Here, we demonstrate that PDE4, but not PDE3, is critical in regulating cardiomyocyte hypertrophy, and may represent a potential target for preventing maladaptive hypertrophy. We identify a sequence within the upstream conserved region 1 of PDE4D, termed UCR1C, as a novel activator of PDE4 long isoforms. UCR1C activates PDE4 in complex with A-kinase anchoring protein (AKAP)-Lbc resulting in decreased PKA signaling facilitated by AKAP-Lbc. Expression of UCR1C in cardiomyocytes inhibits hypertrophy in response to chronic β-AR stimulation. This effect is partially due to inhibition of nuclear PKA activity, which decreases phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In conclusion, PDE4 activation by UCR1C attenuates cardiomyocyte hypertrophy by specifically inhibiting nuclear PKA activity. Published by Elsevier Inc.

Towards selective phosphodiesterase 2A (PDE2A) inhibitors: a patent review (2010 - present).

PubMed

Trabanco, Andrés A; Buijnsters, Peter; Rombouts, Frederik J R

2016-08-01

The cyclic nucleotides cAMP and cGMP are ubiquitous intracellular second messengers regulating a large variety of biological processes. The intracellular concentration of these biologically relevant molecules is modulated by the activity of phosphodiesterases (PDEs), a class of enzymes that is grouped in 11 families. The expression of PDEs is tissue- and cell-specific allowing spatiotemporal integration of multiple signaling cascades. PDE2A is a dual substrate enzyme and is expressed in both the periphery and in the central nervous system, however its expression is highest in the brain, where it is mainly localized in the cortex, hippocampus, and striatum. This suggests that this enzyme may regulate intraneuronal cGMP and cAMP levels in brain areas involved in emotion, perception, concentration, learning and memory. This review covers the patent applications published between January 2010 and February 2016 on phosphodiesterase 2A inhibitors. Recent publications in the literature and in filed patent applications demonstrate the interest of pharmaceutical companies for PDE2A. This has increased the insights of its possible therapeutic role but the few clinical trials were terminated. Based on the ongoing interest in the field it is likely that new clinical trials can be expected and will unravel the therapeutic potential of PDE2A inhibition.

Multiphase flow experiments, mathematical modeling and numerical simulation of the water - gas - solute movement

NASA Astrophysics Data System (ADS)

Li, Y.; Ma, X.; Su, N.

2013-12-01

The movement of water and solute into and through the vadose zone is, in essence, an issue of immiscible displacement in pore-space network of a soil. Therefore, multiphase flow and transport in porous media, referring to three medium: air, water, and the solute, pose one of the largest unresolved challenges for porous medium fluid seepage. However, this phenomenon has always been largely neglected. It is expected that a reliable analysis model of the multi-phase flow in soil can truly reflect the process of natural movement about the infiltration, which is impossible to be observed directly. In such cases, geophysical applications of the nuclear magnetic resonance (NMR) provides the opportunity to measure the water movements into soils directly over a large scale from tiny pore to regional scale, accordingly enable it available both on the laboratory and on the field. In addition, the NMR provides useful information about the pore space properties. In this study, we proposed both laboratory and field experiments to measure the multi-phase flow parameters, together with optimize the model in computer programming based on the fractional partial differential equations (fPDE). In addition, we establish, for the first time, an infiltration model including solute flowing with water, which has huge influence on agriculture and soil environment pollution. Afterwards, with data collected from experiments, we simulate the model and analyze the spatial variability of parameters. Simulations are also conducted according to the model to evaluate the effects of airflow on water infiltration and other effects such as solute and absorption. It has significant meaning to oxygen irrigation aiming to higher crop yield, and shed more light into the dam slope stability. In summary, our framework is a first-time model added in solute to have a mathematic analysis with the fPDE and more instructive to agriculture activities.

Parallel implementation of the particle simulation method with dynamic load balancing: Toward realistic geodynamical simulation

NASA Astrophysics Data System (ADS)

Furuichi, M.; Nishiura, D.

2015-12-01

Fully Lagrangian methods such as Smoothed Particle Hydrodynamics (SPH) and Discrete Element Method (DEM) have been widely used to solve the continuum and particles motions in the computational geodynamics field. These mesh-free methods are suitable for the problems with the complex geometry and boundary. In addition, their Lagrangian nature allows non-diffusive advection useful for tracking history dependent properties (e.g. rheology) of the material. These potential advantages over the mesh-based methods offer effective numerical applications to the geophysical flow and tectonic processes, which are for example, tsunami with free surface and floating body, magma intrusion with fracture of rock, and shear zone pattern generation of granular deformation. In order to investigate such geodynamical problems with the particle based methods, over millions to billion particles are required for the realistic simulation. Parallel computing is therefore important for handling such huge computational cost. An efficient parallel implementation of SPH and DEM methods is however known to be difficult especially for the distributed-memory architecture. Lagrangian methods inherently show workload imbalance problem for parallelization with the fixed domain in space, because particles move around and workloads change during the simulation. Therefore dynamic load balance is key technique to perform the large scale SPH and DEM simulation. In this work, we present the parallel implementation technique of SPH and DEM method utilizing dynamic load balancing algorithms toward the high resolution simulation over large domain using the massively parallel super computer system. Our method utilizes the imbalances of the executed time of each MPI process as the nonlinear term of parallel domain decomposition and minimizes them with the Newton like iteration method. In order to perform flexible domain decomposition in space, the slice-grid algorithm is used. Numerical tests show that our approach is suitable for solving the particles with different calculation costs (e.g. boundary particles) as well as the heterogeneous computer architecture. We analyze the parallel efficiency and scalability on the super computer systems (K-computer, Earth simulator 3, etc.).

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

PubMed Central

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

2013-01-01

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

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

PubMed Central

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

2011-01-01

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

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

PubMed

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

2011-07-15

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

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

PubMed Central

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

2009-01-01

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

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

PubMed Central

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

2017-01-01

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

PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer.

PubMed

Das, Anindita; Durrant, David; Salloum, Fadi N; Xi, Lei; Kukreja, Rakesh C

2015-03-01

The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement of stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and anti-cancer benefits. Despite mixed results of these clinical trials, there is a continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients. Copyright © 2014 Elsevier Inc. All rights reserved.

[Comparison of the effects of phosphodiesterase III inhibitors, milrinone and olprinone, in infant corrective cardiac surgery].

PubMed

Sakimura, Shotaro; Yoshino, Jun; Izumi, Kaoru; Jimi, Nobuo; Sumiyoshi, Rieko; Mizuno, Keiichiro

2013-05-01

Clinical characteristics of phosphodiesterase (PDE) III inhibitors, milrinone and olprinone, is not fully understood in infants. We therefore retrospectively examined the hemodynamics, metabolism, and oxygenation of two different PDE III inhibitors in infants undergoing radical correction of ventricular septal defect with pulmonary hypertension. Twenty-six infants with pulmonary hypertension undergoing ventricular septum defect repair were retrospectively allocated to milrinone group (n= 13)and olprinone group(n=13). Hemodynamic parameters, acid-base balance, oxygenation and postoperative mechanical ventilation period were compared between the two groups at induction of anesthesia, weaning from cardiopulmonary bypass and the end of the surgery. The patients' mean age was 4.4 +/- 2.5 months. Demographic data were almost similar between the two groups. Milrinone and olprinone were administered at the rates of 0.5 and 0.3 microg x kg-1 x min-1 at the end of surgery, respectively. Hemodynamic variables, acid-base balance, Pao2 /FIo2 ratio and mechanical ventilation period were not significantly different between the two groups. No adverse side effects were observed during the study period. The effects of the PDE III inhibitors, milrinone and olprinone, on hemodynamic parameters, acid-base balance and oxygenation were similar in these infants. Both milrinone and olprinone could be used safely in infant cardiac surgery.

Parallel Implementation of the Discontinuous Galerkin Method

NASA Technical Reports Server (NTRS)

Baggag, Abdalkader; Atkins, Harold; Keyes, David

1999-01-01

This paper describes a parallel implementation of the discontinuous Galerkin method. Discontinuous Galerkin is a spatially compact method that retains its accuracy and robustness on non-smooth unstructured grids and is well suited for time dependent simulations. Several parallelization approaches are studied and evaluated. The most natural and symmetric of the approaches has been implemented in all object-oriented code used to simulate aeroacoustic scattering. The parallel implementation is MPI-based and has been tested on various parallel platforms such as the SGI Origin, IBM SP2, and clusters of SGI and Sun workstations. The scalability results presented for the SGI Origin show slightly superlinear speedup on a fixed-size problem due to cache effects.

Parallelization of Program to Optimize Simulated Trajectories (POST3D)

NASA Technical Reports Server (NTRS)

Hammond, Dana P.; Korte, John J. (Technical Monitor)

2001-01-01

This paper describes the parallelization of the Program to Optimize Simulated Trajectories (POST3D). POST3D uses a gradient-based optimization algorithm that reaches an optimum design point by moving from one design point to the next. The gradient calculations required to complete the optimization process, dominate the computational time and have been parallelized using a Single Program Multiple Data (SPMD) on a distributed memory NUMA (non-uniform memory access) architecture. The Origin2000 was used for the tests presented.

Airbreathing Pulse Detonation Engine Performance

NASA Technical Reports Server (NTRS)

Povinelli, Louis A.; Yungster, Shaye

2002-01-01

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

The safety of phosphodiesterase type 5 inhibitors for erectile dysfunction.

PubMed

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

2016-01-01

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

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

PubMed

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

2018-01-01

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

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

PubMed

Stehlik, Josef; Movsesian, Matthew A

2006-07-01

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

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

PubMed Central

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

2018-01-01

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

The Parallel System for Integrating Impact Models and Sectors (pSIMS)

NASA Technical Reports Server (NTRS)

Elliott, Joshua; Kelly, David; Chryssanthacopoulos, James; Glotter, Michael; Jhunjhnuwala, Kanika; Best, Neil; Wilde, Michael; Foster, Ian

2014-01-01

We present a framework for massively parallel climate impact simulations: the parallel System for Integrating Impact Models and Sectors (pSIMS). This framework comprises a) tools for ingesting and converting large amounts of data to a versatile datatype based on a common geospatial grid; b) tools for translating this datatype into custom formats for site-based models; c) a scalable parallel framework for performing large ensemble simulations, using any one of a number of different impacts models, on clusters, supercomputers, distributed grids, or clouds; d) tools and data standards for reformatting outputs to common datatypes for analysis and visualization; and e) methodologies for aggregating these datatypes to arbitrary spatial scales such as administrative and environmental demarcations. By automating many time-consuming and error-prone aspects of large-scale climate impacts studies, pSIMS accelerates computational research, encourages model intercomparison, and enhances reproducibility of simulation results. We present the pSIMS design and use example assessments to demonstrate its multi-model, multi-scale, and multi-sector versatility.

Partial differential equation-based approach for empirical mode decomposition: application on image analysis.

PubMed

Niang, Oumar; Thioune, Abdoulaye; El Gueirea, Mouhamed Cheikh; Deléchelle, Eric; Lemoine, Jacques

2012-09-01

The major problem with the empirical mode decomposition (EMD) algorithm is its lack of a theoretical framework. So, it is difficult to characterize and evaluate this approach. In this paper, we propose, in the 2-D case, the use of an alternative implementation to the algorithmic definition of the so-called "sifting process" used in the original Huang's EMD method. This approach, especially based on partial differential equations (PDEs), was presented by Niang in previous works, in 2005 and 2007, and relies on a nonlinear diffusion-based filtering process to solve the mean envelope estimation problem. In the 1-D case, the efficiency of the PDE-based method, compared to the original EMD algorithmic version, was also illustrated in a recent paper. Recently, several 2-D extensions of the EMD method have been proposed. Despite some effort, 2-D versions for EMD appear poorly performing and are very time consuming. So in this paper, an extension to the 2-D space of the PDE-based approach is extensively described. This approach has been applied in cases of both signal and image decomposition. The obtained results confirm the usefulness of the new PDE-based sifting process for the decomposition of various kinds of data. Some results have been provided in the case of image decomposition. The effectiveness of the approach encourages its use in a number of signal and image applications such as denoising, detrending, or texture analysis.

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

PubMed

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

2018-03-01

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

Multiplicative noise removal through fractional order tv-based model and fast numerical schemes for its approximation

NASA Astrophysics Data System (ADS)

Ullah, Asmat; Chen, Wen; Khan, Mushtaq Ahmad

2017-07-01

This paper introduces a fractional order total variation (FOTV) based model with three different weights in the fractional order derivative definition for multiplicative noise removal purpose. The fractional-order Euler Lagrange equation which is a highly non-linear partial differential equation (PDE) is obtained by the minimization of the energy functional for image restoration. Two numerical schemes namely an iterative scheme based on the dual theory and majorization- minimization algorithm (MMA) are used. To improve the restoration results, we opt for an adaptive parameter selection procedure for the proposed model by applying the trial and error method. We report numerical simulations which show the validity and state of the art performance of the fractional-order model in visual improvement as well as an increase in the peak signal to noise ratio comparing to corresponding methods. Numerical experiments also demonstrate that MMAbased methodology is slightly better than that of an iterative scheme.

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish.

PubMed

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

2014-05-01

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

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

PubMed

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

2014-05-01

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

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

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

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

1990-06-05

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

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

PubMed

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

2008-08-01

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

Influence of parameters controlling the extrusion step in fused filament fabrication (FFF) process applied to polymers using numerical simulation

NASA Astrophysics Data System (ADS)

Shahriar, Bakrani Balani; Arthur, Cantarel; France, Chabert; Valérie, Nassiet

2018-05-01

Extrusion is one of the oldest manufacturing processes; it is widely used for manufacturing finished and semi-finished products. Moreover, extrusion is also the main process in additive manufacturing technologies such as Fused Filament Fabrication (FFF). In FFF process, the parts are manufactured layer by layer using thermoplastic material. The latter in form of filament, is melted in the liquefier and then it is extruded and deposited on the previous layer. The mechanical properties of the printed parts rely on the coalescence of each extrudate with another one. The coalescence phenomenon is driven by the flow properties of the melted polymer when it comes out the nozzle just before the deposition step. This study aims to master the quality of the printed parts by controlling the effect of the parameters of the extruder on the flow properties in the FFF process. In the current study, numerical simulation of the polymer coming out of the extruder was carried out using Computational Fluid Dynamics (CFD) and two phase flow (TPF) simulation Level Set (LS) method by 2D axisymmetric module of COMSOL Multiphysics software. In order to pair the heat transfer with the flow simulation, an advection-diffusion equation was used. Advection-diffusion equation was implemented as a Partial Differential Equation (PDE) in the software. In order to define the variation of viscosity of the polymer with temperature, the rheological behaviors of two thermoplastics were measured by extensional rheometer and using a parallel-plate configuration of an oscillatory rheometer. The results highlight the influence of the environment temperature and the cooling rate on the temperature and viscosity of the extrudate exiting from the nozzle. Moreover, the temperature and its corresponding viscosity at different times have been determined using numerical simulation. At highest shear rates, the extrudate undergoes deformation from typical cylindrical shape. These results are required to predict the coalescence of filaments, a step towards understanding the mechanical properties of the printed parts.

Ideal cycle analysis of a regenerative pulse detonation engine for power production

NASA Astrophysics Data System (ADS)

Bellini, Rafaela

Over the last few decades, considerable research has been focused on pulse detonation engines (PDEs) as a promising replacement for existing propulsion systems with potential applications in aircraft ranging from the subsonic to the lower hypersonic regimes. On the other hand, very little attention has been given to applying detonation for electric power production. One method for assessing the performance of a PDE is through thermodynamic cycle analysis. Earlier works have adopted a thermodynamic cycle for the PDE that was based on the assumption that the detonation process could be approximated by a constant volume process, called the Humphrey cycle. The Fickett-Jacob cycle, which uses the one--dimensional Chapman--Jouguet (CJ) theory of detonation, has also been used to model the PDE cycle. However, an ideal PDE cycle must include a detonation based compression and heat release processes with a finite chemical reaction rate that is accounted for in the Zeldovich -- von Neumann -- Doring model of detonation where the shock is considered a discontinuous jump and is followed by a finite exothermic reaction zone. This work presents a thermodynamic cycle analysis for an ideal PDE cycle for power production. A code has been written that takes only one input value, namely the heat of reaction of a fuel-oxidizer mixture, based on which the program computes all the points on the ZND cycle (both p--v and T--s plots), including the von Neumann spike and the CJ point along with all the non-dimensionalized state properties at each point. In addition, the program computes the points on the Humphrey and Brayton cycles for the same input value. Thus, the thermal efficiencies of the various cycles can be calculated and compared. The heat release of combustion is presented in a generic form to make the program usable with a wide variety of fuels and oxidizers and also allows for its use in a system for the real time monitoring and control of a PDE in which the heat of reaction can be obtained as a function of fuel-oxidizer ratio. The Humphrey and ZND cycles are studied in comparison with the Brayton cycle for different fuel-air mixtures such as methane, propane and hydrogen. The validity and limitations of the ZND and Humphrey cycles related to the detonation process are discussed and the criteria for the selection of the best model for the PDE cycle are explained. It is seen that the ZND cycle is a more appropriate representation of the PDE cycle. Next, the thermal and electrical power generation efficiencies for the PDE are compared with those of the deflagration based Brayton cycle. While the Brayton cycle shows an efficiency of 0 at a compressor pressure ratio of 1, the thermal efficiency for the ZND cycle starts out at 42% for hydrogen--air and then climbs to a peak of 66% at a compression ratio of 7 before falling slowly for higher compression ratios. The Brayton cycle efficiency rises above the PDEs for compression ratios above 23. This finding supports the theoretical advantage of PDEs over the gas turbines because PDEs only require a fan or only a few compressor stages, thereby eliminating the need for heavy compressor machinery, making the PDEs less complex and therefore more cost effective than other engines. Lastly, a regeneration study is presented to analyze how the use of exhaust gases can improve the performance of the system. The thermal efficiencies for the regenerative ZND cycle are compared with the efficiencies for the non--regenerative cycle. For a hydrogen--air mixture the thermal efficiency increases from 52%, for a cycle without regeneration, to 78%, for the regenerative cycle. The efficiency is compared with the Carnot efficiency of 84% which is the maximum possible theoretical efficiency of the cycle. When compared to the Brayton cycle thermal efficiencies, the regenerative cycle shows efficiencies that are always higher for the pressure ratio studied of 5 ≤ pic ≤ 25, where pi c the compressor pressure ratio of the cycle. This observation strengthens the idea of using regeneration on PDEs.

Autonomous selection of PDE inpainting techniques vs. exemplar inpainting techniques for void fill of high resolution digital surface models

NASA Astrophysics Data System (ADS)

Rahmes, Mark; Yates, J. Harlan; Allen, Josef DeVaughn; Kelley, Patrick

2007-04-01

High resolution Digital Surface Models (DSMs) may contain voids (missing data) due to the data collection process used to obtain the DSM, inclement weather conditions, low returns, system errors/malfunctions for various collection platforms, and other factors. DSM voids are also created during bare earth processing where culture and vegetation features have been extracted. The Harris LiteSite TM Toolkit handles these void regions in DSMs via two novel techniques. We use both partial differential equations (PDEs) and exemplar based inpainting techniques to accurately fill voids. The PDE technique has its origin in fluid dynamics and heat equations (a particular subset of partial differential equations). The exemplar technique has its origin in texture analysis and image processing. Each technique is optimally suited for different input conditions. The PDE technique works better where the area to be void filled does not have disproportionately high frequency data in the neighborhood of the boundary of the void. Conversely, the exemplar based technique is better suited for high frequency areas. Both are autonomous with respect to detecting and repairing void regions. We describe a cohesive autonomous solution that dynamically selects the best technique as each void is being repaired.

The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo.

PubMed

Yamamoto, Satoshi; Sugahara, Shingo; Naito, Ryo; Ichikawa, Atsushi; Ikeda, Ken; Yamada, Toshimitsu; Shimizu, Yasuaki

2006-07-10

YM-393059, (+/-)-N-(4,6-dimethylpyrimidin-2-yl)-4-[2-(4-methoxy-3-methylphenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl]benzenesulfonamide difumarate, is a novel phosphodiesterase (PDE) inhibitor that inhibited the PDE7A isoenzyme with a high potency (IC50=14 nM) and PDE4 with a moderate potency (IC50=630 nM). In a cell-based assay, YM-393059 was found to inhibit anti-CD3 antibody, Staphylococcal enterotoxin B, and phytohaemagglutinin-induced interleukin (IL)-2 production in mouse splenocytes with IC50 values ranging from 0.48 to 1.1 microM. It also inhibited anti-CD3 antibody-induced interferon (IFN)-gamma and IL-4 production in splenocytes with IC50 values of 1.8 and 2.8 microM, respectively. YM-393059's inhibition of anti-CD3 antibody-stimulated cytokine (IL-2, IFN-gamma, and IL-4) production was 20- to 31-fold weaker than that of YM976, a selective PDE4 inhibitor. However, orally administered YM-393059 and YM976 inhibited anti-CD3 antibody-induced IL-2 production equipotently in mice. In addition, YM-393059 inhibited lipopolysaccharide-induced tumor necrosis factor-alpha production in vivo more potently than IL-2 (ED50 values of 2.1 mg/kg and 74 mg/kg). In contrast to YM976, YM-393059 did not shorten the duration of alpha2-adrenoceptor agonist-induced sleep in mice, which is a model for the assessment of the typical side effects caused by PDE4 inhibitors, nausea and emesis. YM-393059 is a novel and attractive compound for the treatment of a wide variety of T-cell-mediated diseases.

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

NASA Astrophysics Data System (ADS)

Ji, Sungchul

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

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

PubMed Central

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

2011-01-01

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

Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman Primate

PubMed Central

Li, Junfeng; Zhang, Xiang; Jin, Hongjun; Fan, Jinda; Flores, Hubert; Perlmutter, Joel S.; Tu, Zhude

2015-01-01

A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [11C]MP-10. Twenty of the 22 new analogues had high potency and selectivity for PDE10A: 18a–j, 19d–j, 20a–b, and 21b had IC50 values <5 nM for PDE10A. Seven F-18 labeled compounds [18F]18a–e, [18F]18g, and [18F]20a were radiosynthesized by 18F-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed ~2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [18F]18a–d and [18F]20a. Micro-PET studies of [18F]18d and [18F]20a in nonhuman primates provided clear visualization of striatum with suitable equilibrium kinetics and favorable metabolic stability. These results suggest this strategy may identify a 18F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington’s disease and schizophrenia. PMID:26430878

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

PubMed

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

2014-01-01

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

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

PubMed Central

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

2015-01-01

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

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

PubMed

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

2016-11-29

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

A parallel Monte Carlo code for planar and SPECT imaging: implementation, verification and applications in (131)I SPECT.

PubMed

Dewaraja, Yuni K; Ljungberg, Michael; Majumdar, Amitava; Bose, Abhijit; Koral, Kenneth F

2002-02-01

This paper reports the implementation of the SIMIND Monte Carlo code on an IBM SP2 distributed memory parallel computer. Basic aspects of running Monte Carlo particle transport calculations on parallel architectures are described. Our parallelization is based on equally partitioning photons among the processors and uses the Message Passing Interface (MPI) library for interprocessor communication and the Scalable Parallel Random Number Generator (SPRNG) to generate uncorrelated random number streams. These parallelization techniques are also applicable to other distributed memory architectures. A linear increase in computing speed with the number of processors is demonstrated for up to 32 processors. This speed-up is especially significant in Single Photon Emission Computed Tomography (SPECT) simulations involving higher energy photon emitters, where explicit modeling of the phantom and collimator is required. For (131)I, the accuracy of the parallel code is demonstrated by comparing simulated and experimental SPECT images from a heart/thorax phantom. Clinically realistic SPECT simulations using the voxel-man phantom are carried out to assess scatter and attenuation correction.

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…

Parallel computing in enterprise modeling.

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

Goldsby, Michael E.; Armstrong, Robert C.; Shneider, Max S.

2008-08-01

This report presents the results of our efforts to apply high-performance computing to entity-based simulations with a multi-use plugin for parallel computing. We use the term 'Entity-based simulation' to describe a class of simulation which includes both discrete event simulation and agent based simulation. What simulations of this class share, and what differs from more traditional models, is that the result sought is emergent from a large number of contributing entities. Logistic, economic and social simulations are members of this class where things or people are organized or self-organize to produce a solution. Entity-based problems never have an a priorimore » ergodic principle that will greatly simplify calculations. Because the results of entity-based simulations can only be realized at scale, scalable computing is de rigueur for large problems. Having said that, the absence of a spatial organizing principal makes the decomposition of the problem onto processors problematic. In addition, practitioners in this domain commonly use the Java programming language which presents its own problems in a high-performance setting. The plugin we have developed, called the Parallel Particle Data Model, overcomes both of these obstacles and is now being used by two Sandia frameworks: the Decision Analysis Center, and the Seldon social simulation facility. While the ability to engage U.S.-sized problems is now available to the Decision Analysis Center, this plugin is central to the success of Seldon. Because Seldon relies on computationally intensive cognitive sub-models, this work is necessary to achieve the scale necessary for realistic results. With the recent upheavals in the financial markets, and the inscrutability of terrorist activity, this simulation domain will likely need a capability with ever greater fidelity. High-performance computing will play an important part in enabling that greater fidelity.« less

pH Dependence of a 310-Helix versus a Turn in the M-Loop Region of PDE4: Observations on PDB Entries and an Electronic Structure Study.

PubMed

Usharani, Dandamudi; Srivani, Palakuri; Sastry, G Narahari; Jemmis, Eluvathingal D

2008-06-01

Available X-ray crystal structures of phosphodiesterase 4 (PDE 4) are classified into two groups based on a secondary structure difference of a 310-helix versus a turn in the M-loop region. The only variable that was discernible between these two sets is the pH at the crystallization conditions. Assuming that at lower pH there is a possibility of protonation, thermodynamics of protonation and deprotonation of the aspartic acid, cysteine side chains, and amide bonds are calculated. The models in the gas phase and in the explicit solvent using the ONIOM method are calculated at the B3LYP/6-31+G* and B3LYP/6-31+G*:UFF levels of theory, respectively. The molecular dynamics (MD) simulations are also performed on the M-loop region of a 310-helix and a turn with explicit water for 10 ns under NPT conditions. The isodesmic equations of the various protonation states show that the turn containing structure is thermodynamically more stable when proline or cysteine is protonated. The preference for the turn structure on protonation (pH = 6.5-7.5) is due to an increase in the number of the hydrogen bonding and electrostatic interactions gained by the surrounding environment such as adjacent residues and solvent molecules.

Inverse Electrocardiographic Source Localization of Ischemia: An Optimization Framework and Finite Element Solution

PubMed Central

Wang, Dafang; Kirby, Robert M.; MacLeod, Rob S.; Johnson, Chris R.

2013-01-01

With the goal of non-invasively localizing cardiac ischemic disease using body-surface potential recordings, we attempted to reconstruct the transmembrane potential (TMP) throughout the myocardium with the bidomain heart model. The task is an inverse source problem governed by partial differential equations (PDE). Our main contribution is solving the inverse problem within a PDE-constrained optimization framework that enables various physically-based constraints in both equality and inequality forms. We formulated the optimality conditions rigorously in the continuum before deriving finite element discretization, thereby making the optimization independent of discretization choice. Such a formulation was derived for the L2-norm Tikhonov regularization and the total variation minimization. The subsequent numerical optimization was fulfilled by a primal-dual interior-point method tailored to our problem’s specific structure. Our simulations used realistic, fiber-included heart models consisting of up to 18,000 nodes, much finer than any inverse models previously reported. With synthetic ischemia data we localized ischemic regions with roughly a 10% false-negative rate or a 20% false-positive rate under conditions up to 5% input noise. With ischemia data measured from animal experiments, we reconstructed TMPs with roughly 0.9 correlation with the ground truth. While precisely estimating the TMP in general cases remains an open problem, our study shows the feasibility of reconstructing TMP during the ST interval as a means of ischemia localization. PMID:23913980

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.

A Parallel Sliding Region Algorithm to Make Agent-Based Modeling Possible for a Large-Scale Simulation: Modeling Hepatitis C Epidemics in Canada.

PubMed

Wong, William W L; Feng, Zeny Z; Thein, Hla-Hla

2016-11-01

Agent-based models (ABMs) are computer simulation models that define interactions among agents and simulate emergent behaviors that arise from the ensemble of local decisions. ABMs have been increasingly used to examine trends in infectious disease epidemiology. However, the main limitation of ABMs is the high computational cost for a large-scale simulation. To improve the computational efficiency for large-scale ABM simulations, we built a parallelizable sliding region algorithm (SRA) for ABM and compared it to a nonparallelizable ABM. We developed a complex agent network and performed two simulations to model hepatitis C epidemics based on the real demographic data from Saskatchewan, Canada. The first simulation used the SRA that processed on each postal code subregion subsequently. The second simulation processed the entire population simultaneously. It was concluded that the parallelizable SRA showed computational time saving with comparable results in a province-wide simulation. Using the same method, SRA can be generalized for performing a country-wide simulation. Thus, this parallel algorithm enables the possibility of using ABM for large-scale simulation with limited computational resources.

Low-Intensity Shock Wave Therapy and Its Application to Erectile Dysfunction

PubMed Central

Lei, Hongen; Liu, Jing; Li, Huixi; Wang, Lin; Xu, Yongde; Tian, Wenjie; Lin, Guiting

2013-01-01

Although phosphodiesterase type 5 inhibitors (PDE5Is) are a revolution in the treatment of erectile dysfunction (ED) and have been marketed since 1998, they cannot restore pathological changes in the penis. Low-energy shock wave therapy (LESWT) has been developed for treating ED, and clinical studies have shown that LESWT has the potential to affect PDE5I non-responders with ED with few adverse effects. Animal studies have shown that LESWT significantly improves penile hemodynamics and restores pathological changes in the penis of diabetic ED animal models. Although the mechanisms remain to be investigated, recent studies have reported that LESWT could partially restore corpus cavernosum fibromuscular pathological changes, endothelial dysfunction, and peripheral neuropathy. LESWT could be a novel modality for treating ED, and particularly PDE5I non-responders with organic ED, in the near future. However, further extensive evidence-based basic and clinical studies are needed. This review intends to summarize the scientific background underlying the effect of LESWT on ED. PMID:24459653

Low-intensity shock wave therapy and its application to erectile dysfunction.

PubMed

Lei, Hongen; Liu, Jing; Li, Huixi; Wang, Lin; Xu, Yongde; Tian, Wenjie; Lin, Guiting; Xin, Zhongcheng

2013-12-01

Although phosphodiesterase type 5 inhibitors (PDE5Is) are a revolution in the treatment of erectile dysfunction (ED) and have been marketed since 1998, they cannot restore pathological changes in the penis. Low-energy shock wave therapy (LESWT) has been developed for treating ED, and clinical studies have shown that LESWT has the potential to affect PDE5I non-responders with ED with few adverse effects. Animal studies have shown that LESWT significantly improves penile hemodynamics and restores pathological changes in the penis of diabetic ED animal models. Although the mechanisms remain to be investigated, recent studies have reported that LESWT could partially restore corpus cavernosum fibromuscular pathological changes, endothelial dysfunction, and peripheral neuropathy. LESWT could be a novel modality for treating ED, and particularly PDE5I non-responders with organic ED, in the near future. However, further extensive evidence-based basic and clinical studies are needed. This review intends to summarize the scientific background underlying the effect of LESWT on ED.

A Novel Access to Arylated and Heteroarylated Beta-Carboline Based PDE5 Inhibitors

PubMed Central

Ahmed, Nermin S.; Gary, Bernard D.; Piazza, Gary A.; Tinsley, Heather N.; Laufer, Stefan; Abadi, Ashraf H.

2016-01-01

Starting from a previously reported lead compound GR30040X (a hydantoin tetrahydro-β-carboline derivative with a 4- pyridinyl ring at C- 5), a series of structurally related tetrahydro-β-carboline derivatives were prepared. The tet-rahydro-β-carboline skeleton was fused either to a hydantoin or to a piperazindione ring, the pendant aryl group attached to C-5 or C-6 was changed to a 3, 4-dimethoxyphenyl or a 3-pyridinyl ring; different N-substituents on the terminal ring were introduced, a straight chain ethyl group, a branched tert. butyl and P-chlorophenyl group rather than n-butyl group of the lead compound. All four possible diastereomers of target tetrahydro-β-carboline derivatives were prepared, separated by column chromatography and the significance of these stereochemical manipulations was studied. Synthesized compounds were evaluated for their inhibitory effect versus PDE5. Seven hits were obtained with appreciable inhibitory activity versus PDE5 with IC50s 0.14 - 4.99 μM. PMID:21054274

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

PubMed

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

2017-11-04

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

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

PubMed

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

2004-09-01

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

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

PubMed

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

2017-05-01

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

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

PubMed

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

2018-05-03

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

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

PubMed Central

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

2009-01-01

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

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

PubMed

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

2014-01-01

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

A New Parallel Boundary Condition for Turbulence Simulations in Stellarators

NASA Astrophysics Data System (ADS)

Martin, Mike F.; Landreman, Matt; Dorland, William; Xanthopoulos, Pavlos

2017-10-01

For gyrokinetic simulations of core turbulence, the ``twist-and-shift'' parallel boundary condition (Beer et al., PoP, 1995), which involves a shift in radial wavenumber proportional to the global shear and a quantization of the simulation domain's aspect ratio, is the standard choice. But as this condition was derived under the assumption of axisymmetry, ``twist-and-shift'' as it stands is formally incorrect for turbulence simulations in stellarators. Moreover, for low-shear stellarators like W7X and HSX, the use of a global shear in the traditional boundary condition places an inflexible constraint on the aspect ratio of the domain, requiring more grid points to fully resolve its extent. Here, we present a parallel boundary condition for ``stellarator-symmetric'' simulations that relies on the local shear along a field line. This boundary condition is similar to ``twist-and-shift'', but has an added flexibility in choosing the parallel length of the domain based on local shear consideration in order to optimize certain parameters such as the aspect ratio of the simulation domain.

Experimental confirmation of a PDE-based approach to design of feedback controls

NASA Technical Reports Server (NTRS)

Banks, H. T.; Smith, Ralph C.; Brown, D. E.; Silcox, R. J.; Metcalf, Vern L.

1995-01-01

Issues regarding the experimental implementation of partial differential equation based controllers are discussed in this work. While the motivating application involves the reduction of vibration levels for a circular plate through excitation of surface-mounted piezoceramic patches, the general techniques described here will extend to a variety of applications. The initial step is the development of a PDE model which accurately captures the physics of the underlying process. This model is then discretized to yield a vector-valued initial value problem. Optimal control theory is used to determine continuous-time voltages to the patches, and the approximations needed to facilitate discrete time implementation are addressed. Finally, experimental results demonstrating the control of both transient and steady state vibrations through these techniques are presented.

Numerical Analysis of a Pulse Detonation Cross Flow Heat Load Experiment

NASA Technical Reports Server (NTRS)

Paxson, Daniel E.; Naples, Andrew .; Hoke, John L.; Schauer, Fred

2011-01-01

A comparison between experimentally measured and numerically simulated, time-averaged, point heat transfer rates in a pulse detonation (PDE) engine is presented. The comparison includes measurements and calculations for heat transfer to a cylinder in crossflow and to the tube wall itself using a novel spool design. Measurements are obtained at several locations and under several operating conditions. The measured and computed results are shown to be in substantial agreement, thereby validating the modeling approach. The model, which is based in computational fluid dynamics (CFD) is then used to interpret the results. A preheating of the incoming fuel charge is predicted, which results in increased volumetric flow and subsequent overfilling. The effect is validated with additional measurements.

Computer Science Techniques Applied to Parallel Atomistic Simulation

NASA Astrophysics Data System (ADS)

Nakano, Aiichiro

1998-03-01

Recent developments in parallel processing technology and multiresolution numerical algorithms have established large-scale molecular dynamics (MD) simulations as a new research mode for studying materials phenomena such as fracture. However, this requires large system sizes and long simulated times. We have developed: i) Space-time multiresolution schemes; ii) fuzzy-clustering approach to hierarchical dynamics; iii) wavelet-based adaptive curvilinear-coordinate load balancing; iv) multilevel preconditioned conjugate gradient method; and v) spacefilling-curve-based data compression for parallel I/O. Using these techniques, million-atom parallel MD simulations are performed for the oxidation dynamics of nanocrystalline Al. The simulations take into account the effect of dynamic charge transfer between Al and O using the electronegativity equalization scheme. The resulting long-range Coulomb interaction is calculated efficiently with the fast multipole method. Results for temperature and charge distributions, residual stresses, bond lengths and bond angles, and diffusivities of Al and O will be presented. The oxidation of nanocrystalline Al is elucidated through immersive visualization in virtual environments. A unique dual-degree education program at Louisiana State University will also be discussed in which students can obtain a Ph.D. in Physics & Astronomy and a M.S. from the Department of Computer Science in five years. This program fosters interdisciplinary research activities for interfacing High Performance Computing and Communications with large-scale atomistic simulations of advanced materials. This work was supported by NSF (CAREER Program), ARO, PRF, and Louisiana LEQSF.

Dependability analysis of parallel systems using a simulation-based approach. M.S. Thesis

NASA Technical Reports Server (NTRS)

Sawyer, Darren Charles

1994-01-01

The analysis of dependability in large, complex, parallel systems executing real applications or workloads is examined in this thesis. To effectively demonstrate the wide range of dependability problems that can be analyzed through simulation, the analysis of three case studies is presented. For each case, the organization of the simulation model used is outlined, and the results from simulated fault injection experiments are explained, showing the usefulness of this method in dependability modeling of large parallel systems. The simulation models are constructed using DEPEND and C++. Where possible, methods to increase dependability are derived from the experimental results. Another interesting facet of all three cases is the presence of some kind of workload of application executing in the simulation while faults are injected. This provides a completely new dimension to this type of study, not possible to model accurately with analytical approaches.

A direct-execution parallel architecture for the Advanced Continuous Simulation Language (ACSL)

NASA Technical Reports Server (NTRS)

Carroll, Chester C.; Owen, Jeffrey E.

1988-01-01

A direct-execution parallel architecture for the Advanced Continuous Simulation Language (ACSL) is presented which overcomes the traditional disadvantages of simulations executed on a digital computer. The incorporation of parallel processing allows the mapping of simulations into a digital computer to be done in the same inherently parallel manner as they are currently mapped onto an analog computer. The direct-execution format maximizes the efficiency of the executed code since the need for a high level language compiler is eliminated. Resolution is greatly increased over that which is available with an analog computer without the sacrifice in execution speed normally expected with digitial computer simulations. Although this report covers all aspects of the new architecture, key emphasis is placed on the processing element configuration and the microprogramming of the ACLS constructs. The execution times for all ACLS constructs are computed using a model of a processing element based on the AMD 29000 CPU and the AMD 29027 FPU. The increase in execution speed provided by parallel processing is exemplified by comparing the derived execution times of two ACSL programs with the execution times for the same programs executed on a similar sequential architecture.

Computational Methods for Identification, Optimization and Control of PDE Systems

DTIC Science & Technology

2010-04-30

focused on the development of numerical methods and software specifically for the purpose of solving control, design, and optimization prob- lems where...that provide the foundations of simulation software must play an important role in any research of this type, the demands placed on numerical methods...y sus Aplicaciones , Ciudad de Cor- doba - Argentina, October 2007. 3. Inverse Problems in Deployable Space Structures, Fourth Conference on Inverse

FY06 NRL DoD High Performance Computing Modernization Program Annual Reports

DTIC Science & Technology

2007-10-31

our simulations yield important new information on the amount and form of the energy that is released by these explosive events. These results...coupled with the ideal-gas equation of state and a one-step Arrhenuis kinetics of energy release. The equations are solved using the explicit...practical applications, including hydrogen safety and pulse -detonation engines (PDE). For example, the results summarizing the effect of obstacle

Multi-vortex crystal lattices in Bose-Einstein condensates with a rotating trap.

PubMed

Xie, Shuangquan; Kevrekidis, Panayotis G; Kolokolnikov, Theodore

2018-05-01

We consider vortex dynamics in the context of Bose-Einstein condensates (BECs) with a rotating trap, with or without anisotropy. Starting with the Gross-Pitaevskii (GP) partial differential equation (PDE), we derive a novel reduced system of ordinary differential equations (ODEs) that describes stable configurations of multiple co-rotating vortices (vortex crystals). This description is found to be quite accurate quantitatively especially in the case of multiple vortices. In the limit of many vortices, BECs are known to form vortex crystal structures, whereby vortices tend to arrange themselves in a hexagonal-like spatial configuration. Using our asymptotic reduction, we derive the effective vortex crystal density and its radius. We also obtain an asymptotic estimate for the maximum number of vortices as a function of rotation rate. We extend considerations to the anisotropic trap case, confirming that a pair of vortices lying on the long (short) axis is linearly stable (unstable), corroborating the ODE reduction results with full PDE simulations. We then further investigate the many-vortex limit in the case of strong anisotropic potential. In this limit, the vortices tend to align themselves along the long axis, and we compute the effective one-dimensional vortex density, as well as the maximum admissible number of vortices. Detailed numerical simulations of the GP equation are used to confirm our analytical predictions.

Saturation of the magnetorotational instability at large Elsasser number

NASA Astrophysics Data System (ADS)

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

2008-09-01

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

Performance Characterization of Swept Ramp Obstacle Fields in Pulse Detonation Applications

DTIC Science & Technology

2010-03-01

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

How Schools and Students Respond to School Improvement Programs: The Case of Brazil's PDE

ERIC Educational Resources Information Center

Carnoy, Martin; Gove, Amber K.; Loeb, Susanna; Marshall, Jeffrey H.; Socias, Miguel

2008-01-01

This study uses rich empirical data from Brazil to assess how a government program (PDE) that decentralizes school management decisions changes what goes on in schools and how these changes affect student outcomes. It appears that the PDE resulted in some improvements in management and learning materials, but little change in other areas including…

N Termini of apPDE4 Isoforms Are Responsible for Targeting the Isoforms to Different Cellular Membranes

ERIC Educational Resources Information Center

Jang, Deok-Jin; Park, Soo-Won; Lee, Jin-A; Lee, Changhoon; Chae, Yeon-Su; Park, Hyungju; Kim, Min-Jeong; Choi, Sun-Lim; Lee, Nuribalhae; Kim, Hyoung; Kaang, Bong-Kiun

2010-01-01

Phosphodiesterases (PDEs) are known to play a key role in the compartmentalization of cAMP signaling; however, the molecular mechanisms underlying intracellular localization of different PDE isoforms are not understood. In this study, we have found that each of the supershort, short, and long forms of apPDE4 showed distinct localization in the…

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

PubMed

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

2014-12-01

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

Phosphodiesterase 4 inhibitors.

PubMed

Zebda, Rema; Paller, Amy S

2018-03-01

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

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

PubMed

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

2016-09-01

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

PENTACLE: Parallelized particle-particle particle-tree code for planet formation

NASA Astrophysics Data System (ADS)

Iwasawa, Masaki; Oshino, Shoichi; Fujii, Michiko S.; Hori, Yasunori

2017-10-01

We have newly developed a parallelized particle-particle particle-tree code for planet formation, PENTACLE, which is a parallelized hybrid N-body integrator executed on a CPU-based (super)computer. PENTACLE uses a fourth-order Hermite algorithm to calculate gravitational interactions between particles within a cut-off radius and a Barnes-Hut tree method for gravity from particles beyond. It also implements an open-source library designed for full automatic parallelization of particle simulations, FDPS (Framework for Developing Particle Simulator), to parallelize a Barnes-Hut tree algorithm for a memory-distributed supercomputer. These allow us to handle 1-10 million particles in a high-resolution N-body simulation on CPU clusters for collisional dynamics, including physical collisions in a planetesimal disc. In this paper, we show the performance and the accuracy of PENTACLE in terms of \\tilde{R}_cut and a time-step Δt. It turns out that the accuracy of a hybrid N-body simulation is controlled through Δ t / \\tilde{R}_cut and Δ t / \\tilde{R}_cut ˜ 0.1 is necessary to simulate accurately the accretion process of a planet for ≥106 yr. For all those interested in large-scale particle simulations, PENTACLE, customized for planet formation, will be freely available from https://github.com/PENTACLE-Team/PENTACLE under the MIT licence.

Numerical characteristics of quantum computer simulation

NASA Astrophysics Data System (ADS)

Chernyavskiy, A.; Khamitov, K.; Teplov, A.; Voevodin, V.; Voevodin, Vl.

2016-12-01

The simulation of quantum circuits is significantly important for the implementation of quantum information technologies. The main difficulty of such modeling is the exponential growth of dimensionality, thus the usage of modern high-performance parallel computations is relevant. As it is well known, arbitrary quantum computation in circuit model can be done by only single- and two-qubit gates, and we analyze the computational structure and properties of the simulation of such gates. We investigate the fact that the unique properties of quantum nature lead to the computational properties of the considered algorithms: the quantum parallelism make the simulation of quantum gates highly parallel, and on the other hand, quantum entanglement leads to the problem of computational locality during simulation. We use the methodology of the AlgoWiki project (algowiki-project.org) to analyze the algorithm. This methodology consists of theoretical (sequential and parallel complexity, macro structure, and visual informational graph) and experimental (locality and memory access, scalability and more specific dynamic characteristics) parts. Experimental part was made by using the petascale Lomonosov supercomputer (Moscow State University, Russia). We show that the simulation of quantum gates is a good base for the research and testing of the development methods for data intense parallel software, and considered methodology of the analysis can be successfully used for the improvement of the algorithms in quantum information science.

Comparison of [11C]TZ1964B and [18F]MNI659 for PET imaging brain PDE10A in nonhuman primates.

PubMed

Liu, Hui; Jin, Hongjun; Yue, Xuyi; Han, Junbin; Yang, Hao; Flores, Hubert; Su, Yi; Alagille, David; Perlmutter, Joel S; Tamagnan, Gilles; Tu, Zhude

2016-10-01

Phosphodiesterase 10A (PDE10A) inhibitors show therapeutic effects for diseases with striatal pathology. PET radiotracers have been developed to quantify in vivo PDE10A levels and target engagement for therapeutic interventions. The aim of this study was to compare two potent and selective PDE10A radiotracers, [ 11 C]TZ1964B and [ 18 F]MNI659 in the nonhuman primate (NHP) brain. Double scans in the same cynomolgus monkey on the same day were performed after injection of [ 11 C]TZ1964B and [ 18 F]MNI659. Specific uptake was determined in two ways: nondisplaceable binding potential (BP ND ) was calculated using cerebellum as the reference region and the PDE-10A enriched striatum as the target region of interest (ROI); the area under the time-activity curve (AUC) for the striatum to cerebellum ratio was also calculated. High-performance liquid chromatography (HPLC) analysis of solvent-extracted NHP plasma identified the percentage of intact tracer versus radiolabeled metabolites samples post injection of each radiotracer. Both radiotracers showed high specific accumulation in NHP striatum. [ 11 C]TZ1964B has higher striatal retention and lower specific striatal uptake than [ 18 F]MNI659. The BP ND estimates of [ 11 C]TZ1964B were 3.72 by Logan Reference model (LoganREF) and 4.39 by simplified reference tissue model (SRTM); the BP ND estimates for [ 18 F]MNI659 were 5.08 (LoganREF) and 5.33 (SRTM). AUC ratios were 5.87 for [ 11 C]TZ1964B and 7.60 for [ 18 F]MNI659. Based on BP ND values in NHP striatum, coefficients of variation were ~10% for [ 11 C]TZ1964B and ~30% for [ 18 F]MNI659. Moreover, the metabolism study showed the percentage of parent compounds were ~70% for [ 11 C]TZ1964B and ~50% for [ 18 F]MNI659 60 min post injection. These data indicate that either [ 11 C]TZ1964B or [ 18 F]MNI659 could serve as suitable PDE10A PET radiotracers with distinguishing features for particular clinical application.

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain.

PubMed

Yang, Kai-Chun; Stepanov, Vladimir; Amini, Nahid; Martinsson, Stefan; Takano, Akihiro; Nielsen, Jacob; Bundgaard, Christoffer; Bang-Andersen, Benny; Grimwood, Sarah; Halldin, Christer; Farde, Lars; Finnema, Sjoerd J

2017-02-01

[ 11 C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [ 11 C]Lu AE92686 has high affinity for PDE10A (IC 50  = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [ 11 C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain. A total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [ 11 C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches. Regional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V T ) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V T values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V T values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while V T values in target regions remained stable. Both pretreatment drugs significantly decreased [ 11 C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP ND ) values, derived with the simplified reference tissue model (SRTM), were 13-17 in putamen and 3-5 in substantia nigra and correlated well to values from the Logan plot analysis. The method proposed for quantification of [ 11 C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [ 11 C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.

Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction: Pharmacology and Clinical Impact of the Sildenafil Citrate Orodispersible Tablet Formulation.

PubMed

Scaglione, Francesco; Donde, Shaantanu; Hassan, Tarek A; Jannini, Emmanuele A

2017-02-01

The purpose of this review is to provide an overview of the pharmacology, tolerability, and efficacy of the different phosphodiesterase type 5 (PDE5) inhibitors available for the treatment of erectile dysfunction (ED), with a special focus on the sildenafil orodispersible tablet (ODT) formulation. A literature search was performed in PubMed, EMBASE, and Cochrane Reviews using the terms erectile dysfunction, patient preference, sildenafil, and PDE5 inhibitors to identify articles published in English between May 1, 2006, and November 18, 2016. A total of 29 studies were included in this review. There are substantial data in the literature on the use of PDE5 inhibitors for the treatment of ED. Oral PDE5 inhibitors have been found to be efficacious in the treatment of ED based on results from standard tools used to assess treatment outcomes, such as the Global Assessment Questionnaire 1. In addition, PDE5 inhibitors are defined as well tolerated because of the low occurrence of serious adverse effects or discomfort. Mild adverse reactions, compared with a placebo, include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash. Both the film-coated tablet and ODT formulations of sildenafil with or without water have equivalent systemic exposure. However, use of a sildenafil ODT formulation offers a convenient alternative method of administration that would be advantageous for patients with ED. According to the published literature, the PDE5 inhibitors are considered an effective and well-tolerated option for the treatment of ED as determined by data generated from standard instruments used in the assessment of treatment outcomes in ED and reported types and severity of adverse effects. The sildenafil ODT formulation, which disintegrates rapidly in the mouth, is an alternative to the solid film-coated tablet formulation that offers administration benefit with the potential to improve treatment adherence, thereby enhancing the sexual health and sense of psychological well-being of patients and their partners. Copyright © 2017. Published by Elsevier Inc.

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

PubMed

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

2007-03-07

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

Numerical Analysis of a Rotating Detonation Engine in the Relative Reference Frame

NASA Technical Reports Server (NTRS)

Paxson, Daniel E.

2014-01-01

A two-dimensional, computational fluid dynamic (CFD) simulation of a semi-idealized rotating detonation engine (RDE) is described. The simulation operates in the detonation frame of reference and utilizes a relatively coarse grid such that only the essential primary flow field structure is captured. This construction yields rapidly converging, steady solutions. Results from the simulation are compared to those from a more complex and refined code, and found to be in reasonable agreement. The performance impacts of several RDE design parameters are then examined. Finally, for a particular RDE configuration, it is found that direct performance comparison can be made with a straight-tube pulse detonation engine (PDE). Results show that they are essentially equivalent.

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

NASA Astrophysics Data System (ADS)

Parand, K.; Nikarya, M.

2017-11-01

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

Thrust Augmentation Measurements Using a Pulse Detonation Engine Ejector

NASA Technical Reports Server (NTRS)

Santoro, Robert J.; Pal, Sibtosh

2005-01-01

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

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

PubMed

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

2018-01-01

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

Early Alcohol Exposure Disrupts Visual Cortex Plasticity in Mice

PubMed Central

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

2012-01-01

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

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

PubMed Central

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

2004-01-01

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

A hybrid parallel architecture for electrostatic interactions in the simulation of dissipative particle dynamics

NASA Astrophysics Data System (ADS)

Yang, Sheng-Chun; Lu, Zhong-Yuan; Qian, Hu-Jun; Wang, Yong-Lei; Han, Jie-Ping

2017-11-01

In this work, we upgraded the electrostatic interaction method of CU-ENUF (Yang, et al., 2016) which first applied CUNFFT (nonequispaced Fourier transforms based on CUDA) to the reciprocal-space electrostatic computation and made the computation of electrostatic interaction done thoroughly in GPU. The upgraded edition of CU-ENUF runs concurrently in a hybrid parallel way that enables the computation parallelizing on multiple computer nodes firstly, then further on the installed GPU in each computer. By this parallel strategy, the size of simulation system will be never restricted to the throughput of a single CPU or GPU. The most critical technical problem is how to parallelize a CUNFFT in the parallel strategy, which is conquered effectively by deep-seated research of basic principles and some algorithm skills. Furthermore, the upgraded method is capable of computing electrostatic interactions for both the atomistic molecular dynamics (MD) and the dissipative particle dynamics (DPD). Finally, the benchmarks conducted for validation and performance indicate that the upgraded method is able to not only present a good precision when setting suitable parameters, but also give an efficient way to compute electrostatic interactions for huge simulation systems. Program Files doi:http://dx.doi.org/10.17632/zncf24fhpv.1 Licensing provisions: GNU General Public License 3 (GPL) Programming language: C, C++, and CUDA C Supplementary material: The program is designed for effective electrostatic interactions of large-scale simulation systems, which runs on particular computers equipped with NVIDIA GPUs. It has been tested on (a) single computer node with Intel(R) Core(TM) i7-3770@ 3.40 GHz (CPU) and GTX 980 Ti (GPU), and (b) MPI parallel computer nodes with the same configurations. Nature of problem: For molecular dynamics simulation, the electrostatic interaction is the most time-consuming computation because of its long-range feature and slow convergence in simulation space, which approximately take up most of the total simulation time. Although the parallel method CU-ENUF (Yang et al., 2016) based on GPU has achieved a qualitative leap compared with previous methods in electrostatic interactions computation, the computation capability is limited to the throughput capacity of a single GPU for super-scale simulation system. Therefore, we should look for an effective method to handle the calculation of electrostatic interactions efficiently for a simulation system with super-scale size. Solution method: We constructed a hybrid parallel architecture, in which CPU and GPU are combined to accelerate the electrostatic computation effectively. Firstly, the simulation system is divided into many subtasks via domain-decomposition method. Then MPI (Message Passing Interface) is used to implement the CPU-parallel computation with each computer node corresponding to a particular subtask, and furthermore each subtask in one computer node will be executed in GPU in parallel efficiently. In this hybrid parallel method, the most critical technical problem is how to parallelize a CUNFFT (nonequispaced fast Fourier transform based on CUDA) in the parallel strategy, which is conquered effectively by deep-seated research of basic principles and some algorithm skills. Restrictions: The HP-ENUF is mainly oriented to super-scale system simulations, in which the performance superiority is shown adequately. However, for a small simulation system containing less than 106 particles, the mode of multiple computer nodes has no apparent efficiency advantage or even lower efficiency due to the serious network delay among computer nodes, than the mode of single computer node. References: (1) S.-C. Yang, H.-J. Qian, Z.-Y. Lu, Appl. Comput. Harmon. Anal. 2016, http://dx.doi.org/10.1016/j.acha.2016.04.009. (2) S.-C. Yang, Y.-L. Wang, G.-S. Jiao, H.-J. Qian, Z.-Y. Lu, J. Comput. Chem. 37 (2016) 378. (3) S.-C. Yang, Y.-L. Zhu, H.-J. Qian, Z.-Y. Lu, Appl. Chem. Res. Chin. Univ., 2017, http://dx.doi.org/10.1007/s40242-016-6354-5. (4) Y.-L. Zhu, H. Liu, Z.-W. Li, H.-J. Qian, G. Milano, Z.-Y. Lu, J. Comput. Chem. 34 (2013) 2197.

A consistent modelling methodology for secondary settling tanks: a reliable numerical method.

PubMed

Bürger, Raimund; Diehl, Stefan; Farås, Sebastian; Nopens, Ingmar; Torfs, Elena

2013-01-01

The consistent modelling methodology for secondary settling tanks (SSTs) leads to a partial differential equation (PDE) of nonlinear convection-diffusion type as a one-dimensional model for the solids concentration as a function of depth and time. This PDE includes a flux that depends discontinuously on spatial position modelling hindered settling and bulk flows, a singular source term describing the feed mechanism, a degenerating term accounting for sediment compressibility, and a dispersion term for turbulence. In addition, the solution itself is discontinuous. A consistent, reliable and robust numerical method that properly handles these difficulties is presented. Many constitutive relations for hindered settling, compression and dispersion can be used within the model, allowing the user to switch on and off effects of interest depending on the modelling goal as well as investigate the suitability of certain constitutive expressions. Simulations show the effect of the dispersion term on effluent suspended solids and total sludge mass in the SST. The focus is on correct implementation whereas calibration and validation are not pursued.

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

Demeure, I.M.

The research presented here is concerned with representation techniques and tools to support the design, prototyping, simulation, and evaluation of message-based parallel, distributed computations. The author describes ParaDiGM-Parallel, Distributed computation Graph Model-a visual representation technique for parallel, message-based distributed computations. ParaDiGM provides several views of a computation depending on the aspect of concern. It is made of two complementary submodels, the DCPG-Distributed Computing Precedence Graph-model, and the PAM-Process Architecture Model-model. DCPGs are precedence graphs used to express the functionality of a computation in terms of tasks, message-passing, and data. PAM graphs are used to represent the partitioning of a computationmore » into schedulable units or processes, and the pattern of communication among those units. There is a natural mapping between the two models. He illustrates the utility of ParaDiGM as a representation technique by applying it to various computations (e.g., an adaptive global optimization algorithm, the client-server model). ParaDiGM representations are concise. They can be used in documenting the design and the implementation of parallel, distributed computations, in describing such computations to colleagues, and in comparing and contrasting various implementations of the same computation. He then describes VISA-VISual Assistant, a software tool to support the design, prototyping, and simulation of message-based parallel, distributed computations. VISA is based on the ParaDiGM model. In particular, it supports the editing of ParaDiGM graphs to describe the computations of interest, and the animation of these graphs to provide visual feedback during simulations. The graphs are supplemented with various attributes, simulation parameters, and interpretations which are procedures that can be executed by VISA.« less

Modified current follower-based immittance function simulators

NASA Astrophysics Data System (ADS)

Alpaslan, Halil; Yuce, Erkan

2017-12-01

In this paper, four immittance function simulators consisting of a single modified current follower with single Z- terminal and a minimum number of passive components are proposed. The first proposed circuit can provide +L parallel with +R and the second proposed one can realise -L parallel with -R. The third proposed structure can provide +L series with +R and the fourth proposed one can realise -L series with -R. However, all the proposed immittance function simulators need a single resistive matching constraint. Parasitic impedance effects on all the proposed immittance function simulators are investigated. A second-order current-mode (CM) high-pass filter derived from the first proposed immittance function simulator is given as an application example. Also, a second-order CM low-pass filter derived from the third proposed immittance function simulator is given as an application example. A number of simulation results based on SPICE programme and an experimental test result are given to verify the theory.

Parallel simulation of tsunami inundation on a large-scale supercomputer

NASA Astrophysics Data System (ADS)

Oishi, Y.; Imamura, F.; Sugawara, D.

2013-12-01

An accurate prediction of tsunami inundation is important for disaster mitigation purposes. One approach is to approximate the tsunami wave source through an instant inversion analysis using real-time observation data (e.g., Tsushima et al., 2009) and then use the resulting wave source data in an instant tsunami inundation simulation. However, a bottleneck of this approach is the large computational cost of the non-linear inundation simulation and the computational power of recent massively parallel supercomputers is helpful to enable faster than real-time execution of a tsunami inundation simulation. Parallel computers have become approximately 1000 times faster in 10 years (www.top500.org), and so it is expected that very fast parallel computers will be more and more prevalent in the near future. Therefore, it is important to investigate how to efficiently conduct a tsunami simulation on parallel computers. In this study, we are targeting very fast tsunami inundation simulations on the K computer, currently the fastest Japanese supercomputer, which has a theoretical peak performance of 11.2 PFLOPS. One computing node of the K computer consists of 1 CPU with 8 cores that share memory, and the nodes are connected through a high-performance torus-mesh network. The K computer is designed for distributed-memory parallel computation, so we have developed a parallel tsunami model. Our model is based on TUNAMI-N2 model of Tohoku University, which is based on a leap-frog finite difference method. A grid nesting scheme is employed to apply high-resolution grids only at the coastal regions. To balance the computation load of each CPU in the parallelization, CPUs are first allocated to each nested layer in proportion to the number of grid points of the nested layer. Using CPUs allocated to each layer, 1-D domain decomposition is performed on each layer. In the parallel computation, three types of communication are necessary: (1) communication to adjacent neighbours for the finite difference calculation, (2) communication between adjacent layers for the calculations to connect each layer, and (3) global communication to obtain the time step which satisfies the CFL condition in the whole domain. A preliminary test on the K computer showed the parallel efficiency on 1024 cores was 57% relative to 64 cores. We estimate that the parallel efficiency will be considerably improved by applying a 2-D domain decomposition instead of the present 1-D domain decomposition in future work. The present parallel tsunami model was applied to the 2011 Great Tohoku tsunami. The coarsest resolution layer covers a 758 km × 1155 km region with a 405 m grid spacing. A nesting of five layers was used with the resolution ratio of 1/3 between nested layers. The finest resolution region has 5 m resolution and covers most of the coastal region of Sendai city. To complete 2 hours of simulation time, the serial (non-parallel) computation took approximately 4 days on a workstation. To complete the same simulation on 1024 cores of the K computer, it took 45 minutes which is more than two times faster than real-time. This presentation discusses the updated parallel computational performance and the efficient use of the K computer when considering the characteristics of the tsunami inundation simulation model in relation to the characteristics and capabilities of the K computer.

Adaptive multi-GPU Exchange Monte Carlo for the 3D Random Field Ising Model

NASA Astrophysics Data System (ADS)

Navarro, Cristóbal A.; Huang, Wei; Deng, Youjin

2016-08-01

This work presents an adaptive multi-GPU Exchange Monte Carlo approach for the simulation of the 3D Random Field Ising Model (RFIM). The design is based on a two-level parallelization. The first level, spin-level parallelism, maps the parallel computation as optimal 3D thread-blocks that simulate blocks of spins in shared memory with minimal halo surface, assuming a constant block volume. The second level, replica-level parallelism, uses multi-GPU computation to handle the simulation of an ensemble of replicas. CUDA's concurrent kernel execution feature is used in order to fill the occupancy of each GPU with many replicas, providing a performance boost that is more notorious at the smallest values of L. In addition to the two-level parallel design, the work proposes an adaptive multi-GPU approach that dynamically builds a proper temperature set free of exchange bottlenecks. The strategy is based on mid-point insertions at the temperature gaps where the exchange rate is most compromised. The extra work generated by the insertions is balanced across the GPUs independently of where the mid-point insertions were performed. Performance results show that spin-level performance is approximately two orders of magnitude faster than a single-core CPU version and one order of magnitude faster than a parallel multi-core CPU version running on 16-cores. Multi-GPU performance is highly convenient under a weak scaling setting, reaching up to 99 % efficiency as long as the number of GPUs and L increase together. The combination of the adaptive approach with the parallel multi-GPU design has extended our possibilities of simulation to sizes of L = 32 , 64 for a workstation with two GPUs. Sizes beyond L = 64 can eventually be studied using larger multi-GPU systems.

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

DTIC Science & Technology

2007-03-01

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

Transient Heat Transfer Properties in a Pulse Detonation Combustor

DTIC Science & Technology

2011-03-01

strategies for future systems. 15. NUMBER OF PAGES 89 14. SUBJECT TERMS Pulse Detonation Engines, PDE , Heat Transfer 16. PRICE CODE 17. SECURITY...GUI Graphical User Interface NPS Naval Postgraduate School PDC Pulse Detonation Combustion PDE Pulse Detonation Engine RPL Rocket...a tactical missile with a Pulse Detonation Engine ( PDE ) and provide greater range for the same amount of fuel as compared to other current

Role of selective cyclic GMP phosphodiesterase inhibition in the myorelaxant actions of M&B 22,948, MY-5445, vinpocetine and 1-methyl-3-isobutyl-8-(methylamino)xanthine.

PubMed Central

Souness, J. E.; Brazdil, R.; Diocee, B. K.; Jordan, R.

1989-01-01

1. The mechanism by which M&B 22,948, MY-5445, vinpocetine and 1-methyl-3-isobutyl-8-(methylamino)xanthine (MIMAX), which have been described as selective cyclic GMP phosphodiesterase (PDE) inhibitors, relax rat aorta was investigated. 2. Three cyclic nucleotide PDEs were identified in the soluble fraction of rat aorta; a Ca2+-insensitive form exhibiting substrate selectivity for cyclic GMP (cGMP PDE), a Ca2+/calmodulin-stimulated form which also preferentially hydrolyzed cyclic GMP (Ca2+ PDE), and a form demonstrating substrate selectivity for cyclic AMP (cAMP PDE). 3. M&B 22,948 and MIMAX inhibited cGMP PDE (Ki = 0.16 microM and 0.43 microM, respectively) and Ca2+ PDE (Ki = 9.9 microM and 0.55 microM, respectively), but exhibited weak activity against cAMP PDE (Ki = 249 microM and 42 microM, respectively). MY-5445 selectivity inhibited cGMP PDE (Ki = 1.3 microM) and vinpocetine selectively inhibited Ca2+ PDE (Ki = 14 microM). 4. M&B 22,948 and MIMAX induced dose-dependent increases in the accumulation of cyclic GMP, but not cyclic AMP, in rat aorta pieces. These effects were greatly reduced by endothelial denudation and by methylene blue (5 microM) which blocks the actions of endothelium-derived relaxant factor. MY-5445 and vinpocetine had no effect on rat aorta cyclic GMP or cyclic AMP accumulation. 5. All four compounds caused dose-related relaxation of 5-hydroxytryptamine (10 microM) contracted, endothelium-intact rat aorta, the effects of M&B 22,948 and MIMAX being greatly reduced by methylene blue (5 microM). Methylene blue also caused 10 fold and 100 fold rightward shifts in the dose-response curves of MY-5445 and vinpocetine, respectively. 6. The results are consistent with the smooth muscle relaxant actions of M&B 22,948 and MIMAX, but not vinpocetine and MY-5445, being mediated through a mechanism involving inhibition of cyclic GMP hydrolysis. PMID:2480168

Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24-month follow-up.

PubMed

Hooijmans, M T; Doorenweerd, N; Baligand, C; Verschuuren, J J G M; Ronen, I; Niks, E H; Webb, A G; Kan, H E

2017-01-01

To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5-15.4 years) and 12 age-matched healthy controls (range: 5-14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets. PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR. The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients.

Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24–month follow-up

PubMed Central

Doorenweerd, N.; Baligand, C.; Verschuuren, J. J. G. M.; Ronen, I.; Niks, E. H.; Webb, A. G.; Kan, H. E.

2017-01-01

Objectives To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. Methods Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5–15.4 years) and 12 age-matched healthy controls (range: 5–14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets. Results PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR. Discussion and conclusion The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients. PMID:28763477

The Association Between Phosphodiesterase Type 5 Inhibitor Use and Risk of Non-Arteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Meta-Analysis.

PubMed

Liu, Bing; Zhu, Linxin; Zhong, Jingxiang; Zeng, Guohua; Deng, Tuo

2018-06-05

Phosphodiesterase type 5 inhibitors (PDE5-Is) are first-line drugs for erectile dysfunction. Non-arteritic anterior ischemic optic neuropathy (NAION) has been linked with PDE5-I use. However, no meta-analysis or conclusive review has explored the association between NAION and PDE5-I use. To investigate the association between PDE5-I use and risk of NAION. A comprehensive literature search was conducted using online databases in October 2017 to obtain studies researching the association between PDE5-I application and occurrence of NAION. Summarized unadjusted risk ratios (RRs) with 95% CIs were calculated for the strength of this association. This study was conducted in accordance to Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and registered in PROSPERO under number CRD42017080865. The strength of association between PDE5-I use and risk of NAION was assessed through pooled unadjusted RRs and 95% CIs. 5 original articles with 6 clinical observations were included in the meta-analysis. No significant higher risk of NAION was observed after the use of PDE5-Is within a 1-month period (RR = 1.16, 95% CI = 0.98-1.39, P = .09). Subgroup analyses indicated 2 PDE5-Is were significantly related to NAION (tadalafil: RR = 2.14, 95% CI = 1.20-3.84, P = .01; sildenafil: RR = 2.25, 95% CI = 1.29-3.94, P = .004). Although we found no association between NAION and PDE5-I use, our results should be interpreted cautiously because we included only observational studies and could not control for potential confounders. Because NAION is a rare ocular disease and difficult to diagnose, this association should be confirmed in prospective comparative studies with larger samples and more rigorous designs. Liu B, Zhu L, Zhong J, et al. The Association Between Phosphodiesterase Type 5 Inhibitor Use and Risk of Non-Arteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Meta-Analysis. Sex Med 2018;X:XXX-XXX. Copyright © 2018. Published by Elsevier Inc.

On a partial differential equation method for determining the free energies and coexisting phase compositions of ternary mixtures from light scattering data.

PubMed

Ross, David S; Thurston, George M; Lutzer, Carl V

2008-08-14

In this paper we present a method for determining the free energies of ternary mixtures from light scattering data. We use an approximation that is appropriate for liquid mixtures, which we formulate as a second-order nonlinear partial differential equation. This partial differential equation (PDE) relates the Hessian of the intensive free energy to the efficiency of light scattering in the forward direction. This basic equation applies in regions of the phase diagram in which the mixtures are thermodynamically stable. In regions in which the mixtures are unstable or metastable, the appropriate PDE is the nonlinear equation for the convex hull. We formulate this equation along with continuity conditions for the transition between the two equations at cloud point loci. We show how to discretize this problem to obtain a finite-difference approximation to it, and we present an iterative method for solving the discretized problem. We present the results of calculations that were done with a computer program that implements our method. These calculations show that our method is capable of reconstructing test free energy functions from simulated light scattering data. If the cloud point loci are known, the method also finds the tie lines and tie triangles that describe thermodynamic equilibrium between two or among three liquid phases. A robust method for solving this PDE problem, such as the one presented here, can be a basis for optical, noninvasive means of characterizing the thermodynamics of multicomponent mixtures.

Why not make a PC cluster of your own? 5. AppleSeed: A Parallel Macintosh Cluster for Scientific Computing

NASA Astrophysics Data System (ADS)

Decyk, Viktor K.; Dauger, Dean E.

We have constructed a parallel cluster consisting of Apple Macintosh G4 computers running both Classic Mac OS as well as the Unix-based Mac OS X, and have achieved very good performance on numerically intensive, parallel plasma particle-in-cell simulations. Unlike other Unix-based clusters, no special expertise in operating systems is required to build and run the cluster. This enables us to move parallel computing from the realm of experts to the mainstream of computing.

Acceleration of the matrix multiplication of Radiance three phase daylighting simulations with parallel computing on heterogeneous hardware of personal computer

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

Zuo, Wangda; McNeil, Andrew; Wetter, Michael

2013-05-23

Building designers are increasingly relying on complex fenestration systems to reduce energy consumed for lighting and HVAC in low energy buildings. Radiance, a lighting simulation program, has been used to conduct daylighting simulations for complex fenestration systems. Depending on the configurations, the simulation can take hours or even days using a personal computer. This paper describes how to accelerate the matrix multiplication portion of a Radiance three-phase daylight simulation by conducting parallel computing on heterogeneous hardware of a personal computer. The algorithm was optimized and the computational part was implemented in parallel using OpenCL. The speed of new approach wasmore » evaluated using various daylighting simulation cases on a multicore central processing unit and a graphics processing unit. Based on the measurements and analysis of the time usage for the Radiance daylighting simulation, further speedups can be achieved by using fast I/O devices and storing the data in a binary format.« less

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

NASA Astrophysics Data System (ADS)

Zlotnik, Sergio

2017-04-01

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

Parallel Discrete Molecular Dynamics Simulation With Speculation and In-Order Commitment*†

PubMed Central

Khan, Md. Ashfaquzzaman; Herbordt, Martin C.

2011-01-01

Discrete molecular dynamics simulation (DMD) uses simplified and discretized models enabling simulations to advance by event rather than by timestep. DMD is an instance of discrete event simulation and so is difficult to scale: even in this multi-core era, all reported DMD codes are serial. In this paper we discuss the inherent difficulties of scaling DMD and present our method of parallelizing DMD through event-based decomposition. Our method is microarchitecture inspired: speculative processing of events exposes parallelism, while in-order commitment ensures correctness. We analyze the potential of this parallelization method for shared-memory multiprocessors. Achieving scalability required extensive experimentation with scheduling and synchronization methods to mitigate serialization. The speed-up achieved for a variety of system sizes and complexities is nearly 6× on an 8-core and over 9× on a 12-core processor. We present and verify analytical models that account for the achieved performance as a function of available concurrency and architectural limitations. PMID:21822327

Parallel Discrete Molecular Dynamics Simulation With Speculation and In-Order Commitment.

PubMed

Khan, Md Ashfaquzzaman; Herbordt, Martin C

2011-07-20

Discrete molecular dynamics simulation (DMD) uses simplified and discretized models enabling simulations to advance by event rather than by timestep. DMD is an instance of discrete event simulation and so is difficult to scale: even in this multi-core era, all reported DMD codes are serial. In this paper we discuss the inherent difficulties of scaling DMD and present our method of parallelizing DMD through event-based decomposition. Our method is microarchitecture inspired: speculative processing of events exposes parallelism, while in-order commitment ensures correctness. We analyze the potential of this parallelization method for shared-memory multiprocessors. Achieving scalability required extensive experimentation with scheduling and synchronization methods to mitigate serialization. The speed-up achieved for a variety of system sizes and complexities is nearly 6× on an 8-core and over 9× on a 12-core processor. We present and verify analytical models that account for the achieved performance as a function of available concurrency and architectural limitations.

Secure web-based invocation of large-scale plasma simulation codes

NASA Astrophysics Data System (ADS)

Dimitrov, D. A.; Busby, R.; Exby, J.; Bruhwiler, D. L.; Cary, J. R.

2004-12-01

We present our design and initial implementation of a web-based system for running, both in parallel and serial, Particle-In-Cell (PIC) codes for plasma simulations with automatic post processing and generation of visual diagnostics.

Rational rates of uniform decay for strong solutions to a fluid-structure PDE system

NASA Astrophysics Data System (ADS)

Avalos, George; Bucci, Francesca

2015-06-01

In this work we investigate the uniform stability properties of solutions to a well-established partial differential equation (PDE) model for a fluid-structure interaction. The PDE system under consideration comprises a Stokes flow which evolves within a three-dimensional cavity; moreover, a Kirchhoff plate equation is invoked to describe the displacements along a (fixed) portion - say, Ω - of the cavity wall. Contact between the respective fluid and structure dynamics occurs on the boundary interface Ω. The main result in the paper is as follows: the solutions to the composite PDE system, corresponding to smooth initial data, decay at the rate of O (1 / t). Our method of proof hinges upon the appropriate invocation of a relatively recent resolvent criterion for polynomial decays of C0-semigroups. While the characterization provided by said criterion originates in the context of operator theory and functional analysis, the work entailed here is wholly within the realm of PDE.

Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies.

PubMed

Hu, Essa; Chen, Ning; Kunz, Roxanne K; Hwang, Dah-Ren; Michelsen, Klaus; Davis, Carl; Ma, Ji; Shi, Jianxia; Lester-Zeiner, Dianna; Hungate, Randall; Treanor, James; Chen, Hang; Allen, Jennifer R

2016-07-14

We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding potential (BPND) in NHP than our previously reported tracer 1, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washout rate in vivo. Five candidates (2-6) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines (2, 3) and one keto-benzimidazole (5) exhibited PDE10A target specificity and brain uptake comparable to or better than 1 in the in vivo LC-MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [(18)F]-5 produced a significantly improved BPND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies.

Phosphodiesterase inhibitors in clinical urology.

PubMed

Ückert, Stefan; Kuczyk, Markus A; Oelke, Matthias

2013-05-01

To date, benign diseases of the male and female lower urinary and genital tract, such as erectile dysfunction, bladder overactivity, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and symptoms of female sexual dysfunction (including arousal and orgasmic disorders), can be therapeutically approached by influencing the function of the smooth musculature of the respective tissues. The use of isoenzyme-selective phosphodiesterase (PDE) inhibitors is considered a great opportunity to treat various diseases of the human urogenital tract. PDE inhibitors, in particular the PDE5 (cyclic GMP PDE) inhibitors avanafil, lodenafil, sildenafil, tadalafil, udenafil and vardenafil, are regarded as efficacious, having a fast onset of drug action and an improved effect-to-adverse event ratio, combining a high response rate with the advantage of an on-demand intake. The purpose of this review is to summarize recent as well as potential future indications, namely, erectile dysfunction, Peyronie's disease, overactive bladder, urinary stone disease, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and premature ejaculation, for the use of PDE inhibitors in clinical urology.

Effect of Operating Frequency and Fill Time on PDE-Ejector Thrust Performance

NASA Technical Reports Server (NTRS)

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

2005-01-01

Thrust measurements for a pulse detonation engine (PDE)-ejector system were determined for a range of operating frequencies. Various length tubular ejectors were utilized. The results were compared to the measurements of the thrust output of the PDE alone to determine the enhancement provided by each ejector configuration at the specified frequencies. Ethylene was chosen as the fuel, with an equi-molar mixture of nitrogen and oxygen acting as the oxidizer. The propellant was kept at an equivalence ratio of one during all the experiments. The system was operated for frequencies between 20 and 50 Hz. The parameter space of the study included PDE operation frequency, ejector length, overlap percentage, the radius of curvature for the ejector inlets, and duration of the time allowed between cycles. The results of the experiments showed a maximum thrust augmentation of 120% for a PDE-ejector configuration at a frequency of 40Hz with a fill time of 10 ms.

Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer's disease.

PubMed

Su, Tao; Zhang, Tianhua; Xie, Shishun; Yan, Jun; Wu, Yinuo; Li, Xingshu; Huang, Ling; Luo, Hai-Bin

2016-02-25

Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer's disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ(1-42) aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu(2+)-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.

Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma.

PubMed

Ge, Xuecai; Milenkovic, Ljiljana; Suyama, Kaye; Hartl, Tom; Purzner, Teresa; Winans, Amy; Meyer, Tobias; Scott, Matthew P

2015-09-15

Alterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic targets. Here we show that phosphodiesterase 4D (PDE4D) acts downstream of Neuropilins to control Hh transduction and medulloblastoma growth. PDE4D interacts directly with Neuropilins, positive regulators of Hh pathway. The Neuropilin ligand Semaphorin3 enhances this interaction, promoting PDE4D translocation to the plasma membrane and cAMP degradation. The consequent inhibition of protein kinase A (PKA) enhances Hh transduction. In the developing cerebellum, genetic removal of Neuropilins reduces Hh signaling activity and suppresses proliferation of granule neuron precursors. In mouse medulloblastoma allografts, PDE4D inhibitors suppress Hh transduction and inhibit tumor growth. Our findings reveal a new regulatory mechanism of Hh transduction, and highlight PDE4D as a promising target to treat Hh-related tumors.

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

Yu, Juan; Beltran, Chris J., E-mail: beltran.chris@mayo.edu; Herman, Michael G.

Purpose: To quantitatively and systematically assess dosimetric effects induced by spot positioning error as a function of spot spacing (SS) on intensity-modulated proton therapy (IMPT) plan quality and to facilitate evaluation of safety tolerance limits on spot position. Methods: Spot position errors (PE) ranging from 1 to 2 mm were simulated. Simple plans were created on a water phantom, and IMPT plans were calculated on two pediatric patients with a brain tumor of 28 and 3 cc, respectively, using a commercial planning system. For the phantom, a uniform dose was delivered to targets located at different depths from 10 tomore » 20 cm with various field sizes from 2{sup 2} to 15{sup 2} cm{sup 2}. Two nominal spot sizes, 4.0 and 6.6 mm of 1 σ in water at isocenter, were used for treatment planning. The SS ranged from 0.5 σ to 1.5 σ, which is 2–6 mm for the small spot size and 3.3–9.9 mm for the large spot size. Various perturbation scenarios of a single spot error and systematic and random multiple spot errors were studied. To quantify the dosimetric effects, percent dose error (PDE) depth profiles and the value of percent dose error at the maximum dose difference (PDE [ΔDmax]) were used for evaluation. Results: A pair of hot and cold spots was created per spot shift. PDE[ΔDmax] is found to be a complex function of PE, SS, spot size, depth, and global spot distribution that can be well defined in simple models. For volumetric targets, the PDE [ΔDmax] is not noticeably affected by the change of field size or target volume within the studied ranges. In general, reducing SS decreased the dose error. For the facility studied, given a single spot error with a PE of 1.2 mm and for both spot sizes, a SS of 1σ resulted in a 2% maximum dose error; a SS larger than 1.25 σ substantially increased the dose error and its sensitivity to PE. A similar trend was observed in multiple spot errors (both systematic and random errors). Systematic PE can lead to noticeable hot spots along the field edges, which may be near critical structures. However, random PE showed minimal dose error. Conclusions: Dose error dependence for PE was quantitatively and systematically characterized and an analytic tool was built to simulate systematic and random errors for patient-specific IMPT. This information facilitates the determination of facility specific spot position error thresholds.« less

A PDE-based methodology for modeling, parameter estimation and feedback control in structural and structural acoustic systems

NASA Technical Reports Server (NTRS)

Banks, H. T.; Brown, D. E.; Metcalf, Vern L.; Silcox, R. J.; Smith, Ralph C.; Wang, Yun

1994-01-01

A problem of continued interest concerns the control of vibrations in a flexible structure and the related problem of reducing structure-borne noise in structural acoustic systems. In both cases, piezoceramic patches bonded to the structures have been successfully used as control actuators. Through the application of a controlling voltage, the patches can be used to reduce structural vibrations which in turn lead to methods for reducing structure-borne noise. A PDE-based methodology for modeling, estimating physical parameters, and implementing a feedback control scheme for problems of this type is discussed. While the illustrating example is a circular plate, the methodology is sufficiently general so as to be applicable in a variety of structural and structural acoustic systems.

Algebraic Construction of Exact Difference Equations from Symmetry of Equations

NASA Astrophysics Data System (ADS)

Itoh, Toshiaki

2009-09-01

Difference equations or exact numerical integrations, which have general solutions, are treated algebraically. Eliminating the symmetries of the equation, we can construct difference equations (DCE) or numerical integrations equivalent to some ODEs or PDEs that means both have the same solution functions. When arbitrary functions are given, whether we can construct numerical integrations that have solution functions equal to given function or not are treated in this work. Nowadays, Lie's symmetries solver for ODE and PDE has been implemented in many symbolic software. Using this solver we can construct algebraic DCEs or numerical integrations which are correspond to some ODEs or PDEs. In this work, we treated exact correspondence between ODE or PDE and DCE or numerical integration with Gröbner base and Janet base from the view of Lie's symmetries.

Branch Detonation of a Pulse Detonation Engine With Flash Vaporized JP-8

DTIC Science & Technology

2006-12-01

Mark F. Reeder (Member) date iii Abstract Pulse Detonation Engines ( PDE ) operating on liquid hydrocarbon fuels are... Detonation Transition FF – Fill Fraction FN – Flow Number NPT – National Pipe Thread OH – Hydroxyl PDE – Pulse Detonation Engine PF – Purge...Introduction Motivation Research on Pulsed Detonation Engines ( PDE ) has increased over the past ten years due to the potential for increased

Initiation Mechanisms of Low-loss Swept-ramp Obstacles for Deflagration to Detonation Transition in Pulse Detonation Combustors

DTIC Science & Technology

2009-12-01

minimal pressure losses. 15. NUMBER OF PAGES 113 14. SUBJECT TERMS Pulse Detonation Combustors, PDC, Pulse Detonation Engines, PDE , PDE ...Postgraduate School PDC Pulse Detonation Combustor PDE Pulse Detonation Engine RAM Random Access Memory RDT Research, Design and Test RPL...inhibiting the implementation of this advanced propulsion system. The primary advantage offered by pulse detonation engines ( PDEs ) is the high efficiency

Treatment of psoriasis with crisaborole.

PubMed

Lee, Erica B; Lebwohl, Mark G; Wu, Jashin J

2018-06-08

Crisaborole, a topical phosphodiesterase-4 (PDE4) inhibitor, is effective in patients with atopic dermatitis. As systemic PDE4 inhibition has also been used with success in psoriasis, clinical trials are underway to determine the utility of topical PDE4 inhibitors in these patients. However, there is no current literature documenting use of crisaborole for psoriasis. Here, we present two cases in which patients with psoriasis were treated successfully with crisaborole.

Rutin inhibits B[a]PDE-induced cyclooxygenase-2 expression by targeting EGFR kinase activity.

PubMed

Choi, Seunghwan; Lim, Tae-Gyu; Hwang, Mun Kyung; Kim, Yoon-A; Kim, Jiyoung; Kang, Nam Joo; Jang, Tae Su; Park, Jun-Seong; Yeom, Myeong Hun; Lee, Ki Won

2013-11-15

Rutin is a well-known flavonoid that exists in various natural sources. Accumulative studies have represented the biological effects of rutin, such as anti-oxidative and anti-inflammatory effects. However, the underlying mechanisms of rutin and its direct targets are not understood. We investigated whether rutin reduced B[a]PDE-induced-COX-2 expression. The transactivation of AP-1 and NF-κB were inhibited by rutin. Rutin also attenuated B[a]PDE-induced Raf/MEK/ERK and Akt activation, but had no effect on the phosphorylation of EGFR. An in vitro kinase assay revealed rutin suppressed EGFR kinase activity. We also confirmed direct binding between rutin and EGFR, and found that the binding was regressed by ATP. The EGFR inhibitor also inhibited the B[a]PDE-induced MEK/ERK and Akt signaling pathways and subsequently, suppressed COX-2 expression and promoter activity, in addition to suppressing the transactivation of AP-1 and NF-κB. In EGFR(-/-)mouse embryonic fibroblast cells, B[a]PDE-induced COX-2 expression was also diminished. Collectively, rutin inhibits B[a]PDE-induced COX-2 expression by suppressing the Raf/MEK/ERK and Akt signaling pathways. EGFR appeared to be the direct target of rutin. Copyright © 2013 Elsevier Inc. All rights reserved.

Thrust Augmentation Measurements Using a Pulse Detonation Engine Ejector

NASA Technical Reports Server (NTRS)

Santoro, Robert J.; Pal, Sibtosh

2003-01-01

The present NASA GRC-funded three-year research project is focused on studying PDE driven ejectors applicable to a hybrid Pulse Detonation/Turbofan Engine. The objective of the study is to characterize the PDE-ejector thrust augmentation. A PDE-ejector system has been designed to provide critical experimental data for assessing the performance enhancements possible with this technology. Completed tasks include demonstration of a thrust stand for measuring average thrust for detonation tube multi-cycle operation, and design of a 72-in.-long, 2.25-in.-diameter (ID) detonation tube and modular ejector assembly. This assembly will allow testing of both straight and contoured ejector geometries. Initial ejectors that have been fabricated are 72-in.-long-constant-diameter tubes (4-, 5-, and 6-in.-diameter) instrumented with high-frequency pressure transducers. The assembly has been designed such that the detonation tube exit can be positioned at various locations within the ejector tube. PDE-ejector system experiments with gaseous ethylene/ nitrogen/oxygen propellants will commence in the very near future. The program benefits from collaborations with Prof. Merkle of University of Tennessee whose PDE-ejector analysis helps guide the experiments. The present research effort will increase the TRL of PDE-ejectors from its current level of 2 to a level of 3.

Central serous chorioretinopathy and phosphodiesterase-5 inhibitors: a case-control postmarketing surveillance study.

PubMed

French, Dustin D; Margo, Curtis E

2010-02-01

The purpose of this study was to determine if there is an increased risk of central serous chorioretinopathy (CSC) associated with prescription exposure to phosphodiesterase-5 (PDE-5) inhibitors. A case-control study linking 2 National Veterans Health Administration databases (clinical and pharmacy) for fiscal years 2004 to 2005. The likelihood of past exposure to PDE-5 inhibitors among newly diagnosed patients with CSC, identified through International Classification of Diseases, 9th Edition, Clinical Modification codes, was compared with 2 age-matched control groups after excluding subjects with risk factors for CSC. Among 577 men, aged 59 years and younger with newly diagnosed CSC during the study year, 111 were prescribed a PDE-5 inhibitor (19.2%). The proportions of age-matched controls prescribed a PDE-5 inhibitor in the 2 groups were 18.5% and 21.5%. The odds ratio of exposure was 1.05 (95% confidence limit: 0.74-1.22) and 0.87 (95% confidence limit: 0.68-1.12). Patients with CSC had no increase in prescription exposure to PDE-5 inhibitors than did age-matched control subjects. Although the findings in this study do not support an association between CSC and PDE-5 inhibitors, postmarketing surveillance methods for drug-related side effects have acknowledged limitations.

Sildenafil Can Affect Innate and Adaptive Immune System in Both Experimental Animals and Patients

PubMed Central

Boguska, Agnieszka

2017-01-01

Sildenafil, a type 5 phosphodiesterase inhibitor (PDE5-I), is primarily used for treating erectile dysfunction. Sildenafil inhibits the degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5. cGMP is a secondary messenger activating protein kinases and a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. PDE5 inhibitors (PDE-Is) found application in cardiology, nephrology, urology, dermatology, oncology, and gynecology. Positive result of sildenafil treatment is closely connected with its immunomodulatory effects. Sildenafil influences angiogenesis, platelet activation, proliferation of regulatory T cells, and production of proinflammatory cytokines and autoantibodies. Sildenafil action in humans and animals appears to be different. Surprisingly, it also acts differently in males and females organisms. Although the immunomodulatory effects of PDE5 inhibitors appear to be promising, none of them reached the point of being tested in clinical trials. Data on the influence of selective PDE5-Is on the human immune system are limited. The main objective of this review is to discuss the immunomodulatory effects of sildenafil in both patients and experimental animals. This is the first review of the current state of knowledge about the effects of sildenafil on the immune system. PMID:28316997

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

NASA Astrophysics Data System (ADS)

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

2017-01-01

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

Asymmetric Solar Wind driven substorms from ballooning-interchange and magnetic reconnection

NASA Astrophysics Data System (ADS)

Horton, W.

2013-12-01

For nonsymmetric currents closing in the northern and southern magnetopause, we find new onset conditions for the ballooning-interchange and magnetic reconnections modes. While these two eigenmodes have opposite symmetries in a classic symmetric geotail geometry as in Prichett-Coroniti-Pellat [GRL1997], this symmetry is broken for real solar winds and a tilted Earth magnetic dipole. Extending earlier work, we show a new model that includes distinct north I_[N] and south I_[S] magnetopause return currents and distinct N-S magnetopause boundary boundary conditions. These conditions drive asymmetric wave functions within the geotail. The wave functions in the high β magnetopause give new onset conditions for substorms. The nonlinear growth rates are estimated and nonlinear FLR-fluid simulations are performed. FLR fluid models with 5 to 7 pde's, are compared qualitatively with the PIC simulations of Prichett-Coroniti [ P-C 2013 and 2011] which used 4 billion particles on a Cray XT5 NSF computer. The P-C 2013 simulations capture some features of the THEMIS data and we look for the corresponding features in the FLR-fluid simulations. The classic reconnection parameter Delta^{'} has a complex generalization for the asymmetric solar wind and IMF on the magnetopause [Horton and Tajima, JGR 1988]. When the mid-tail B_z(x) is such as to give the ballooning-interchange instability we show that in the late stage of the evolutions the nonlinear convective derivatives in the pde-system change the symmetry of the structures producing large magnetic islands of the scale observed by CLUSTER substorm data [ Nakamura et al. 2006]. We conclude that asymmetric models are needed to give reliable forecasting of the onset of subtorms and storms.

Effect of phoshpodiesterase 4 (PDE4) inhibibtors on eotaxin expression in humen bronchial epithelial cells.

PubMed

Paplinska, M; Chazan, R; Grubek-Jaworska, H

2011-06-01

The increasing number of eosinophils into bronchoaelvolar space is observed during noninfectious inflammatory lung diseases. Eotaxins (eotaxin-1/CCL11, eotaxin-2/CCL24, eotaxin-3/CCL26) are the strongest chemotactic agents for eosinophils. Inhibitors of phosphodiesterase 4 (PDE4), the enzyme decomposing cAMP, are anti-inflammatory agents which act through cAMP elevation and inhibit numerous steps of allergic inflammation. The effect of PDE4 inhibitors on eotaxin expression is not known in details. The aim of our study was to evaluate the influence of PDE4 inhibitors: rolipram and RO-20-1724 on expression of eotaxins in bronchial epithelial cell line BEAS-2B. Cells were preincubated with PDE4 inhibitors or dexamethasone for 1 hour and then stimulated with IL-4 or IL-13 alone or in combination with TNF-α. After 48 hours eotaxin protein level was measured by ELISA and mRNA level by real time PCR. PDE4 inhibitors decreased CCL11 and CCL26 expression only in cultures co-stimulated with TNF-α. In cultures stimulated with IL-4 and TNF-α rolipram and RO-20-1724 diminished CCL11 mRNA expression by 34 and 37%, respectively, and CCL26 by 43 and 47%. In cultures stimulated with IL-13 and TNF-α rolipram and RO-20-1724 decreased expression of both eotaxins by about 50%. These results were confirmed at the protein level. The effect of PDE4 inhibitors on eotaxin expression in BEAS-2B cells, in our experimental conditions, depends on TNF-α contribution.

Flow Cytometric Analysis of Bimolecular Fluorescence Complementation: A High Throughput Quantitative Method to Study Protein-protein Interaction

PubMed Central

Wang, Li; Carnegie, Graeme K.

2013-01-01

Among methods to study protein-protein interaction inside cells, Bimolecular Fluorescence Complementation (BiFC) is relatively simple and sensitive. BiFC is based on the production of fluorescence using two non-fluorescent fragments of a fluorescent protein (Venus, a Yellow Fluorescent Protein variant, is used here). Non-fluorescent Venus fragments (VN and VC) are fused to two interacting proteins (in this case, AKAP-Lbc and PDE4D3), yielding fluorescence due to VN-AKAP-Lbc-VC-PDE4D3 interaction and the formation of a functional fluorescent protein inside cells. BiFC provides information on the subcellular localization of protein complexes and the strength of protein interactions based on fluorescence intensity. However, BiFC analysis using microscopy to quantify the strength of protein-protein interaction is time-consuming and somewhat subjective due to heterogeneity in protein expression and interaction. By coupling flow cytometric analysis with BiFC methodology, the fluorescent BiFC protein-protein interaction signal can be accurately measured for a large quantity of cells in a short time. Here, we demonstrate an application of this methodology to map regions in PDE4D3 that are required for the interaction with AKAP-Lbc. This high throughput methodology can be applied to screening factors that regulate protein-protein interaction. PMID:23979513

Flow cytometric analysis of bimolecular fluorescence complementation: a high throughput quantitative method to study protein-protein interaction.

PubMed

Wang, Li; Carnegie, Graeme K

2013-08-15

Among methods to study protein-protein interaction inside cells, Bimolecular Fluorescence Complementation (BiFC) is relatively simple and sensitive. BiFC is based on the production of fluorescence using two non-fluorescent fragments of a fluorescent protein (Venus, a Yellow Fluorescent Protein variant, is used here). Non-fluorescent Venus fragments (VN and VC) are fused to two interacting proteins (in this case, AKAP-Lbc and PDE4D3), yielding fluorescence due to VN-AKAP-Lbc-VC-PDE4D3 interaction and the formation of a functional fluorescent protein inside cells. BiFC provides information on the subcellular localization of protein complexes and the strength of protein interactions based on fluorescence intensity. However, BiFC analysis using microscopy to quantify the strength of protein-protein interaction is time-consuming and somewhat subjective due to heterogeneity in protein expression and interaction. By coupling flow cytometric analysis with BiFC methodology, the fluorescent BiFC protein-protein interaction signal can be accurately measured for a large quantity of cells in a short time. Here, we demonstrate an application of this methodology to map regions in PDE4D3 that are required for the interaction with AKAP-Lbc. This high throughput methodology can be applied to screening factors that regulate protein-protein interaction.

Preservation of nitric oxide-induced relaxation of porcine coronary artery: roles of the dimers of soluble guanylyl cyclase, phosphodiesterase type 5, and cGMP-dependent protein kinase.

PubMed

Liu, Juan; Chen, Zhengju; Ye, Liping; Liu, Huixia; Dou, Dou; Liu, Limei; Yu, Xiaoxing; Gao, Yuansheng

2014-10-01

Soluble guanylyl cyclase (sGC), phosphodiesterase type 5 (PDE5), and guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (PKG) are all dimeric. The present study was to determine the role of their dimeric status in nitric oxide-induced vasodilatation. In isolated porcine coronary arteries, after 20 h incubation with serum-free medium, serum-containing medium, or phosphate-buffered saline solution, the protein levels of the dimers of sGC, PDE5, and PKG were diminished while the monomer levels remained unchanged, associated with reduced cGMP elevation in response to DETA NONOate and decreased PDE5 activity; the activity of PKG was not significantly altered. DETA NONOate caused a greater relaxation in arteries incubated for 20 vs. 2 h. The relaxant response was largely abolished by 1H-[1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one, an sGC inhibitor. Zaprinast, a PDE5 inhibitor, had no effect on relaxation caused by DETA NONOate of arteries incubated for 20 h but augmented the response incubated for 2 h. A greater relaxation to 8-bromo-guanosine 3'5'-cyclic monophosphate occurred in arteries incubated for 20 than for 2 h. The protein level of the dimers but not monomers of PDE5 was reduced by dithiothreitol and unaffected by hydrogen peroxide, accompanied with decreased PDE5 activity and reduced response to DETA NONOate. These results demonstrate that the dimeric but not monomeric status of sGC and PDE5 of coronary arteries are closely related to their activities. The preserved vasodilator response after 20 h incubation may result in part from a synchronous reduction of the dimer levels of sGC and PDE5 as well as an augmented response to cGMP.

Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes

PubMed Central

Hackett, Geoffrey; Jones, Peter W; Strange, Richard C; Ramachandran, Sudarshan

2017-01-01

AIM To determine how statins, testosterone (T) replacement therapy (TRT) and phosphodiesterase 5-inhibitors (PDE5I) influence age related mortality in diabetic men. METHODS We studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual. RESULTS Age was associated with mortality (logistic regression, OR = 1.10, 95%CI: 1.08-1.13, P < 0.001). With all factors included, age (OR = 1.08, 95%CI: 1.06-1.11, P < 0.001), Low T/treated (OR = 0.38, 95%CI: 0.15-0.92, P = 0.033), PDE5I/treated (OR = 0.17, 95%CI: 0.053-0.56, P = 0.004) and statin/treated (OR = 0.59, 95%CI: 0.36-0.97, P = 0.038) were associated with lower mortality. Age related mortality was as described by Gompertz, r2 = 0.881 when Ln (mortality) was plotted against age. The probability of mortality and 95%CI (from logistic regression) of individuals, treated/untreated with the drugs, alone and in combination was plotted against age. Overlap of 95%CI lines was evident with statins and TRT. No overlap was evident with PDE5I alone and with statins and TRT, this suggesting a change in the relationship between age and mortality. CONCLUSION We show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men. PMID:28344753

[Anti-B[a]PDE-DNA formation in lymphomonocytes of humans environmentally exposed to polycyclic aromatic hydrocarbons].

PubMed

Pavanello, S; Pulliero, A; Lai, A; Gaiardo, A; Mastrangelo, G; Clonfero, E

2005-01-01

[Anti-B[a]PDE-DNA formation in lymphomonocytes of humans environmentally exposed to polycyclic aromatic hydrocarbons] We are currently evaluating anti-benzo[a]pyrenediolepoxide-(B[a]PDE)-DNA adduct levels in lymphomonocytes of humans exposed to polycyclic aromatic hydrocarbons (PAHs) to validate this indicator of biologically effective dose in a surrogate tissue. The study protocol (October 2002-June 2005) implies: (a) a signed informed consent by each participant; (b) recruitment of 600 Padua municipal workers during visits at our outpatient clinic; (c) administration of a questionnaire regarding non occupational sources of PAH (B[a]P) exposure; (d) collection of blood (15 ml) and urine (200 ml) samples. Anti-B[a]PDE-DNA adduct levels in lymphomonocytes are detected by HPLC-fluorescence analysis. To date, 438 subjects have been examined (age range 20-62 years; 52% males). We found that: (i) anti-B[a]PDE-DNA adduct levels are significantly lower than those we previously found in coke-oven workers (N=95) occupationally exposed to high levels of PAHs (1.51 +/- 2.68 versus 4.07 +/- 3.78 anti-B[a]PDE-adduct/10(8) nucleotides, p < 0.001; 37% versus 97% positive subjects with > or =1 adduct/10(8) nucleotides; p < 0.001); (ii) smokers (23%) have significantly higher adduct levels than non smokers (p < 0.001); iii) non smokers who consume PAH-rich meals > or =52 times/year (142 subjects, 42%) have significantly increased adduct levels than those <52 times/year (p < 0.01). Dietary and smoking habits did not influence the occupationally-induced adduct levels in coke-oven workers. This is the first study that examines anti-B[a]PDE-DNA adduct levels in a large cohort showing that anti-B[a]PDE-DNA adducts can be detected in humans environmentally exposed to low doses of PAH (B[a]P and are modulated by smoke and dietary habits.

Intraperitoneal Vancomycin Concentrations During Peritoneal Dialysis–Associated Peritonitis: Correlation with Serum Levels

PubMed Central

Fish, Richard; Nipah, Robert; Jones, Chris; Finney, Hazel; Fan, Stanley L.S.

2012-01-01

♦ Background: For the treatment of peritoneal dialysis–associated peritonitis (PDP), it has been suggested that serum concentrations of vancomycin be kept above 12 mg/L – 15 mg/L. However, studies correlating vancomycin concentrations in serum and peritoneal dialysate effluent (PDE) during active infection are sparse. We undertook the present study to investigate this issue and to determine whether achieving the recommended serum level of vancomycin results in therapeutic levels intraperitoneally. ♦ Methods: We studied patients treated with intraperitoneal (IP) vancomycin for non-gram-negative PDP. We gave a single dose (approximately 30 mg/kg) at presentation, and we subsequently measured vancomycin levels in PDE on day 5; we wanted to determine if efflux of vancomycin from serum to PDE during a 4-hour dwell was consistent and resulted in therapeutic levels. ♦ Results: Of the 48 episodes of PDP studied, serum vancomycin concentrations exceeding 12 mg/L were achieved in 98% of patients, but in 11 patients (23%), a PDE vancomycin level below 4 mg/L—the minimal inhibitory concentration (MIC) of many gram-positive organisms—was observed at the end of a 4-hour dwell on day 5. The correlation between the concentrations of vancomycin in serum and PDE (from efflux of antibiotic over 4 hours) was statistically significant, but poor (R2 = 0.18). ♦ Conclusions: Our data support the International Society for Peritoneal Dialysis statement that adequate serum vancomycin concentrations can be achieved with intermittent dosing (single dose every 5 days), but cannot guarantee therapeutic PDE levels in the treatment of PDP. Intermittent dosing of vancomycin may not consistently result in PDE concentrations markedly greater than MIC of many important pathogens. Although the clinical significance of this finding remains to be determined, it may be preferable to give smaller but more frequent doses of PDE vancomycin (continuous dosing) for adults with PDP (as is currently recommended for children). PMID:22045102

[Adenoviral short hairpin RNA targeting phosphodiesterase 5 attenuates cardiac remodeling and cardiac dysfunction following myocardial infarction in mice].

PubMed

Zhang, Jian; Jin, Zhe; Li, Longhu; Gang, Li; Yu, Qin; Wang, Meilan; Song, Ailin; Hong, Bingzhe

2014-04-01

To observe the impact of PDE5shRNA on cardiac remodeling and heart function following myocardial infarction in mice. Myocardial infarction (MI) was induced in mice by left coronary artery ligation. Mice were randomly assigned to sham group (n = 6), PDE5shRNA group (n = 12), common adenovirus group (n = 15) and DMEM group (n = 8). Four weeks post-MI, the survival rate was evaluated. Cardiac function was examined by echocardiography. HE staining and Masson staining were used to evaluate the myocardial infarction size and fibrosis. The number of blood vessels was evaluated by immunohistochemistry, PDE5 protein expression in the left ventricular was detected using Western blot, level of cGMP or PKG activity in the left ventricle was evaluated with ELISA. Four weeks post-MI, all mice survived in the sham group, 3(37%) mice died in the DMEM group, 1 (8%) died in the PDE5shRNA group and 5 died in the common adenovirus group (33%). Infarct size was significantly reduced in PDE5shRNA group compared with the common adenovirus group and DMEM group [(25.4 ± 2.9)% vs. (42.0 ± 3.2)% and (43.4 ± 2.6) %, P < 0.05]. Cardiac function was significantly improved in PDE5shRNA group compared to common adenovirus group and DMEM group[LVFS: (21.1 ± 3.7)% vs. (14.2 ± 2.9)% and (14.22 ± 2.91)%, all P < 0.05; LVEF: (48.2 ± 7.1)% vs. (34.6 ± 6.2)% and (38.1 ± 2.8)%, all P < 0.05; LVESD: (3.87 ± 0.45) mm vs.(4.91 ± 0.62) mm and (4.63 ± 0.37) mm, all P < 0.05]. The blood vessel density was also higher in PDE5shRNA group compared with common adenovirus group (infarct area:14.3 ± 2.0 vs. 6.6 ± 1.2, P < 0.05; periinfarct area: 23.6 ± 2.1 vs. 13.7 ± 2.4, P < 0.05). Compared with common adenovirus group, level of PDE5 was significantly downregulated and level of cGMP or PKG was significantly upregulated in PDE5shRNA group (all P < 0.05). Present study suggests PDE5shRNA improves cardiac function and attenuates cardiac remodeling through reducing infarction size and cardiac fibrosis and these beneficial effects are possibly mediated by activating cGMP/PKG signaling pathway.

USING THE ECLPSS SOFTWARE ENVIRONMENT TO BUILD A SPATIALLY EXPLICIT COMPONENT-BASED MODEL OF OZONE EFFECTS ON FOREST ECOSYSTEMS. (R827958)

EPA Science Inventory

We have developed a modeling framework to support grid-based simulation of ecosystems at multiple spatial scales, the Ecological Component Library for Parallel Spatial Simulation (ECLPSS). ECLPSS helps ecologists to build robust spatially explicit simulations of ...

Parallel Optimization of 3D Cardiac Electrophysiological Model Using GPU

PubMed Central

Xia, Yong; Zhang, Henggui

2015-01-01

Large-scale 3D virtual heart model simulations are highly demanding in computational resources. This imposes a big challenge to the traditional computation resources based on CPU environment, which already cannot meet the requirement of the whole computation demands or are not easily available due to expensive costs. GPU as a parallel computing environment therefore provides an alternative to solve the large-scale computational problems of whole heart modeling. In this study, using a 3D sheep atrial model as a test bed, we developed a GPU-based simulation algorithm to simulate the conduction of electrical excitation waves in the 3D atria. In the GPU algorithm, a multicellular tissue model was split into two components: one is the single cell model (ordinary differential equation) and the other is the diffusion term of the monodomain model (partial differential equation). Such a decoupling enabled realization of the GPU parallel algorithm. Furthermore, several optimization strategies were proposed based on the features of the virtual heart model, which enabled a 200-fold speedup as compared to a CPU implementation. In conclusion, an optimized GPU algorithm has been developed that provides an economic and powerful platform for 3D whole heart simulations. PMID:26581957

Parallel Optimization of 3D Cardiac Electrophysiological Model Using GPU.

PubMed

Xia, Yong; Wang, Kuanquan; Zhang, Henggui

2015-01-01

Large-scale 3D virtual heart model simulations are highly demanding in computational resources. This imposes a big challenge to the traditional computation resources based on CPU environment, which already cannot meet the requirement of the whole computation demands or are not easily available due to expensive costs. GPU as a parallel computing environment therefore provides an alternative to solve the large-scale computational problems of whole heart modeling. In this study, using a 3D sheep atrial model as a test bed, we developed a GPU-based simulation algorithm to simulate the conduction of electrical excitation waves in the 3D atria. In the GPU algorithm, a multicellular tissue model was split into two components: one is the single cell model (ordinary differential equation) and the other is the diffusion term of the monodomain model (partial differential equation). Such a decoupling enabled realization of the GPU parallel algorithm. Furthermore, several optimization strategies were proposed based on the features of the virtual heart model, which enabled a 200-fold speedup as compared to a CPU implementation. In conclusion, an optimized GPU algorithm has been developed that provides an economic and powerful platform for 3D whole heart simulations.

Parallelized computation for computer simulation of electrocardiograms using personal computers with multi-core CPU and general-purpose GPU.

PubMed

Shen, Wenfeng; Wei, Daming; Xu, Weimin; Zhu, Xin; Yuan, Shizhong

2010-10-01

Biological computations like electrocardiological modelling and simulation usually require high-performance computing environments. This paper introduces an implementation of parallel computation for computer simulation of electrocardiograms (ECGs) in a personal computer environment with an Intel CPU of Core (TM) 2 Quad Q6600 and a GPU of Geforce 8800GT, with software support by OpenMP and CUDA. It was tested in three parallelization device setups: (a) a four-core CPU without a general-purpose GPU, (b) a general-purpose GPU plus 1 core of CPU, and (c) a four-core CPU plus a general-purpose GPU. To effectively take advantage of a multi-core CPU and a general-purpose GPU, an algorithm based on load-prediction dynamic scheduling was developed and applied to setting (c). In the simulation with 1600 time steps, the speedup of the parallel computation as compared to the serial computation was 3.9 in setting (a), 16.8 in setting (b), and 20.0 in setting (c). This study demonstrates that a current PC with a multi-core CPU and a general-purpose GPU provides a good environment for parallel computations in biological modelling and simulation studies. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Mathematical model of macrophage-facilitated breast cancer cells invasion.

PubMed

Knútsdóttir, Hildur; Pálsson, Eirikur; Edelstein-Keshet, Leah

2014-09-21

Mortality from breast cancer stems from its tendency to invade into surrounding tissues and organs. Experiments have shown that this metastatic process is facilitated by macrophages in a short-ranged chemical signalling loop. Macrophages secrete epidermal growth factor, EGF, and respond to the colony stimulating factor 1, CSF-1. Tumor cells secrete CSF-1 and respond to EGF. In this way, the cells coordinate aggregation and cooperative migration. Here we investigate this process in a model for in vitro interactions using two distinct but related mathematical approaches. In the first, we analyze and simulate a set of partial differential equations to determine conditions for aggregation. In the second, we use a cell-based discrete 3D simulation to follow the fates and motion of individual cells during aggregation. Linear stability analysis of the PDE model reveals that decreasing the chemical secretion, chemotaxis coefficients or density of cells or increasing the chemical degradation in the model could eliminate the spontaneous aggregation of cells. Simulations with the discrete model show that the ratio between tumor cells and macrophages in aggregates increases when the EGF secretion parameter is increased. The results also show how CSF-1/CSF-1R autocrine signalling in tumor cells affects the ratio between the two cell types. Comparing the continuum results with simulations of a discrete cell-based model, we find good qualitative agreement. Copyright © 2014 Elsevier Ltd. All rights reserved.

Parallel phase-shifting self-interference digital holography with faithful reconstruction using compressive sensing

NASA Astrophysics Data System (ADS)

Wan, Yuhong; Man, Tianlong; Wu, Fan; Kim, Myung K.; Wang, Dayong

2016-11-01

We present a new self-interference digital holographic approach that allows single-shot capturing three-dimensional intensity distribution of the spatially incoherent objects. The Fresnel incoherent correlation holographic microscopy is combined with parallel phase-shifting technique to instantaneously obtain spatially multiplexed phase-shifting holograms. The compressive-sensing-based reconstruction algorithm is implemented to reconstruct the original object from the under sampled demultiplexed holograms. The scheme is verified with simulations. The validity of the proposed method is experimentally demonstrated in an indirectly way by simulating the use of specific parallel phase-shifting recording device.

Direct Initiation Through Detonation Branching in a Pulsed Detonation Engine

DTIC Science & Technology

2008-03-01

important features noted ................................. 33  Figure 20. GM Quad 4 engine head used as the PDE research engine with the detonation tube...Deflagration to Detonation Transition EF – Engine Frequency FF – Fill Fraction NPT – National Pipe Thread MPT – Male National Pipe Thread PDE – Pulsed... Detonation Engines ( PDE ) has increased greatly in recent years due in part to the potential for increased thermal efficiency derived from constant

Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction.

PubMed

Chen, Si; Knight, Walter E; Yan, Chen

2018-04-23

Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential.

[Cardiovascular disease and sexuality].

PubMed

Pfister, Otmar

2010-03-01

Sexual activity corresponds to light to moderate physical exercise and entails no significant risk to the majority of patients with cardiovascular disease. In patients suffering from severe angina or chronic heart failure, however, sexual activity might trigger coital angina or cardiac decompensation necessitating hospitalization. Nevertheless, even for patients with coronary artery disease the absolute risk of having a heart attack or fatal event during sexual activity is extremely low. Due to systemic atherosclerosis and concomitant endothelial dysfunction the prevalence of sexual dysfunction is higher in patients with cardiovascular disease as compared to the general population. PDE-5 inhibitors can be safely used by many patients suffering from both, cardiovascular disease and sexual dysfunction as long as no concomitant medication with nitrates exists. The concomitant use of PDE-5 inhibitors and nitrates is strictly contraindicated because of the risk of life-threatening hypotension. It is therefore of utmost importance to ask patients presenting with coital angina about PDE-5 inhibitor intake before the administration of nitrate-based anti-ischemic therapies. The recommendations of the Princeton Consensus Conference provide a useful framework for risk stratification and counseling of patients with cardiovascular disease regarding sexual activity.

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

PubMed Central

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

2007-01-01

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

Parallel replica dynamics with a heterogeneous distribution of barriers: Application to n-hexadecane pyrolysis

NASA Astrophysics Data System (ADS)

Kum, Oyeon; Dickson, Brad M.; Stuart, Steven J.; Uberuaga, Blas P.; Voter, Arthur F.

2004-11-01

Parallel replica dynamics simulation methods appropriate for the simulation of chemical reactions in molecular systems with many conformational degrees of freedom have been developed and applied to study the microsecond-scale pyrolysis of n-hexadecane in the temperature range of 2100-2500 K. The algorithm uses a transition detection scheme that is based on molecular topology, rather than energetic basins. This algorithm allows efficient parallelization of small systems even when using more processors than particles (in contrast to more traditional parallelization algorithms), and even when there are frequent conformational transitions (in contrast to previous implementations of the parallel replica algorithm). The parallel efficiency for pyrolysis initiation reactions was over 90% on 61 processors for this 50-atom system. The parallel replica dynamics technique results in reaction probabilities that are statistically indistinguishable from those obtained from direct molecular dynamics, under conditions where both are feasible, but allows simulations at temperatures as much as 1000 K lower than direct molecular dynamics simulations. The rate of initiation displayed Arrhenius behavior over the entire temperature range, with an activation energy and frequency factor of Ea=79.7 kcal/mol and log A/s-1=14.8, respectively, in reasonable agreement with experiment and empirical kinetic models. Several interesting unimolecular reaction mechanisms were observed in simulations of the chain propagation reactions above 2000 K, which are not included in most coarse-grained kinetic models. More studies are needed in order to determine whether these mechanisms are experimentally relevant, or specific to the potential energy surface used.

Parallel Agent-Based Simulations on Clusters of GPUs and Multi-Core Processors

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

Aaby, Brandon G; Perumalla, Kalyan S; Seal, Sudip K

2010-01-01

An effective latency-hiding mechanism is presented in the parallelization of agent-based model simulations (ABMS) with millions of agents. The mechanism is designed to accommodate the hierarchical organization as well as heterogeneity of current state-of-the-art parallel computing platforms. We use it to explore the computation vs. communication trade-off continuum available with the deep computational and memory hierarchies of extant platforms and present a novel analytical model of the tradeoff. We describe our implementation and report preliminary performance results on two distinct parallel platforms suitable for ABMS: CUDA threads on multiple, networked graphical processing units (GPUs), and pthreads on multi-core processors. Messagemore » Passing Interface (MPI) is used for inter-GPU as well as inter-socket communication on a cluster of multiple GPUs and multi-core processors. Results indicate the benefits of our latency-hiding scheme, delivering as much as over 100-fold improvement in runtime for certain benchmark ABMS application scenarios with several million agents. This speed improvement is obtained on our system that is already two to three orders of magnitude faster on one GPU than an equivalent CPU-based execution in a popular simulator in Java. Thus, the overall execution of our current work is over four orders of magnitude faster when executed on multiple GPUs.« less

Efficient Parallel Kernel Solvers for Computational Fluid Dynamics Applications

NASA Technical Reports Server (NTRS)

Sun, Xian-He

1997-01-01

Distributed-memory parallel computers dominate today's parallel computing arena. These machines, such as Intel Paragon, IBM SP2, and Cray Origin2OO, have successfully delivered high performance computing power for solving some of the so-called "grand-challenge" problems. Despite initial success, parallel machines have not been widely accepted in production engineering environments due to the complexity of parallel programming. On a parallel computing system, a task has to be partitioned and distributed appropriately among processors to reduce communication cost and to attain load balance. More importantly, even with careful partitioning and mapping, the performance of an algorithm may still be unsatisfactory, since conventional sequential algorithms may be serial in nature and may not be implemented efficiently on parallel machines. In many cases, new algorithms have to be introduced to increase parallel performance. In order to achieve optimal performance, in addition to partitioning and mapping, a careful performance study should be conducted for a given application to find a good algorithm-machine combination. This process, however, is usually painful and elusive. The goal of this project is to design and develop efficient parallel algorithms for highly accurate Computational Fluid Dynamics (CFD) simulations and other engineering applications. The work plan is 1) developing highly accurate parallel numerical algorithms, 2) conduct preliminary testing to verify the effectiveness and potential of these algorithms, 3) incorporate newly developed algorithms into actual simulation packages. The work plan has well achieved. Two highly accurate, efficient Poisson solvers have been developed and tested based on two different approaches: (1) Adopting a mathematical geometry which has a better capacity to describe the fluid, (2) Using compact scheme to gain high order accuracy in numerical discretization. The previously developed Parallel Diagonal Dominant (PDD) algorithm and Reduced Parallel Diagonal Dominant (RPDD) algorithm have been carefully studied on different parallel platforms for different applications, and a NASA simulation code developed by Man M. Rai and his colleagues has been parallelized and implemented based on data dependency analysis. These achievements are addressed in detail in the paper.

Research on Parallel Three Phase PWM Converters base on RTDS

NASA Astrophysics Data System (ADS)

Xia, Yan; Zou, Jianxiao; Li, Kai; Liu, Jingbo; Tian, Jun

2018-01-01

Converters parallel operation can increase capacity of the system, but it may lead to potential zero-sequence circulating current, so the control of circulating current was an important goal in the design of parallel inverters. In this paper, the Real Time Digital Simulator (RTDS) is used to model the converters parallel system in real time and study the circulating current restraining. The equivalent model of two parallel converters and zero-sequence circulating current(ZSCC) were established and analyzed, then a strategy using variable zero vector control was proposed to suppress the circulating current. For two parallel modular converters, hardware-in-the-loop(HIL) study based on RTDS and practical experiment were implemented, results prove that the proposed control strategy is feasible and effective.

Erectile Dysfunction Medication Use in Veterans Eligible for Medicare Part D.

PubMed

Spencer, Samantha H; Suda, Katie J; Smith, Bridget M; Huo, Zhiping; Bailey, Lauren; Stroupe, Kevin T

2016-07-01

Erectile dysfunction (ED) medications are therapeutically effective and associated with satisfaction. Medicare Part D included ED medications on the formulary during 2006 and inadvertently in 2007-2008. To characterize phosphodiesterase-5 inhibitor (PDE-5) medication use among veterans who were dually eligible for Veterans Affairs (VA) and Medicare Part D benefits. Veterans aged > 66 years who received PDE-5 inhibitors between 2005 and 2009 were included. Veterans were categorized by PDE-5 inhibitor claims: VA-only, Part D-only, or dual users of VA and Part D-reimbursed pharmacies. T-tests and chi-square tests were applied as appropriate. From 2005 to 2009, the majority (85.2%) of veterans used VA benefits exclusively for their PDE-5 inhibitors; 11.4% used Medicare Part D exclusively; and 3.4% were dual users. The Part D-only group was older, more frequently not black, had a VA copay, and had a higher income (P < 0.03). The VA group was more likely to have comorbidities, smoke, and have a history of substance abuse (P < 0.001). With the inception of Medicare Part D in 2006, the number of patients filling prescriptions for PDE-5 inhibitors (-68%) and total number of PDE-5 inhibitor 30-day equivalents dispensed (-86.7%) from the VA decreased. Part D prescriptions increased through 2006 (full coverage period) and 2007 (accidental partial coverage) and decreased in 2008. While Part D accounted for only 10% of PDE-5 inhibitor 30-day equivalents, it equaled 29.2% of dispensed tablets. In October 2007, VA PDE-5 inhibitor use returned to 2005 levels. Implementation of Medicare Part D reduced VA PDE-5 inhibitor acquisition. However, after removal of PDE-5 inhibitors from the Part D formulary, use of VA pharmacies for PDE-5 inhibitors resumed. Medication policies outside the VA can affect medication use. Veterans with access to non-VA health care may obtain medications from the private sector because of VA restrictions. This may be especially true for nonformulary and lifestyle medications. The authors received funding support for this research project from the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service as grant IIR 07-165-2. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or Health Services Research and Development Service. Study concept and design were contributed by Smith and Stroupe, assisted by the other authors. Huo, Bailey, and Stroupe took the lead in data collection, assisted by the other authors. Data interpretation was performed by Spencer and Suda, along with Smith and Stroupe and assisted by Huo and Bailey. The manuscript was primarily written by Spencer and Suda, with assistance from the other authors, and revised by Spencer, along with the other authors.

SOP conservative (medical and mechanical) treatment of erectile dysfunction.

PubMed

Porst, Hartmut; Burnett, Arthur; Brock, Gerald; Ghanem, Hussein; Giuliano, Francois; Glina, Sidney; Hellstrom, Wayne; Martin-Morales, Antonio; Salonia, Andrea; Sharlip, Ira

2013-01-01

Erectile dysfunction (ED) is the most frequently treated male sexual dysfunction worldwide. ED is a chronic condition that exerts a negative impact on male self-esteem and nearly all life domains including interpersonal, family, and business relationships. The aim of this study is to provide an updated overview on currently used and available conservative treatment options for ED with a special focus on their efficacy, tolerability, safety, merits, and limitations including the role of combination therapies for monotherapy failures. The methods used were PubMed and MEDLINE searches using the following keywords: ED, phosphodiesterase type 5 (PDE5) inhibitors, oral drug therapy, intracavernosal injection therapy, transurethral therapy, topical therapy, and vacuum-erection therapy/constriction devices. Additionally, expert opinions by the authors of this article are included. Level 1 evidence exists that changes in sedentary lifestyle with weight loss and optimal treatment of concomitant diseases/risk factors (e.g., diabetes, hypertension, and dyslipidemia) can either improve ED or add to the efficacy of ED-specific therapies, e.g., PDE5 inhibitors. Level 1 evidence also exists that treatment of hypogonadism with total testosterone < 300 ng/dL (10.4 nmol/L) can either improve ED or add to the efficacy of PDE5 inhibitors. There is level 1 evidence regarding the efficacy and safety of the following monotherapies in a spectrum-wide range of ED populations: PDE5 inhibitors, intracavernosal injection therapy with prostaglandin E1 (PGE1, synonymous alprostadil) or vasoactive intestinal peptide (VIP)/phentolamine, and transurethral PGE1 therapy. There is level 2 evidence regarding the efficacy and safety of the following ED treatments: vacuum-erection therapy in a wide range of ED populations, oral L-arginine (3-5 g), topical PGE1 in special ED populations, intracavernosal injection therapy with papaverine/phentolamine (bimix), or papaverine/phentolamine/PGE1 (trimix) combination mixtures. There is level 3 evidence regarding the efficacy and safety of oral yohimbine in nonorganic ED. There is level 3 evidence that combination therapies of PDE5 inhibitors + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone. There is level 4 evidence showing enhanced efficacy with the combination of vacuum-erection therapy + either PDE5 inhibitor or transurethral PGE1 or intracavernosal injection therapy. There is level 5 evidence (expert opinion) that combination therapy of PDE5 inhibitors + L-arginine or daily dosing of tadalafil + short-acting PDE5 inhibitors pro re nata may rescue PDE5 inhibitor monotherapy failures. There is level 5 evidence (expert opinion) that adding either PDE5 inhibitors or transurethral PGE1 may improve outcome of penile prosthetic surgery regarding soft (cold) glans syndrome. There is level 5 evidence (expert opinion) that the combination of PDE5 inhibitors and dapoxetine is effective and safe in patients suffering from both ED and premature ejaculation. © 2013 International Society for Sexual Medicine.

A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement

PubMed Central

Taylor, Peter N; Panicker, Vijay; Sayers, Adrian; Shields, Beverley; Iqbal, Ahmed; Bremner, Alexandra P; Beilby, John P; Leedman, Peter J; Hattersley, Andrew T; Vaidya, Bijay; Frayling, Timothy; Evans, Jonathan; Tobias, Jonathan H; Timpson, Nicholas J; Walsh, John P; Dayan, Colin M

2011-01-01

Objective Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T4). Design Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T4). Methods Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T3), and T4 levels. Results Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64×10−10 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T4 (P=0.023, −0.07 s.d./allele, 95% CI −0.137, −0.01), no association was seen with free T3 (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T4 in 1981 (−0.068 s.d./allele, 95% CI −0.167, 0.031) and 1994 (−0.07 s.d./allele, 95% CI −0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T4. Conclusion Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T4 levels that are consistent over time and lost in individuals on l-T4. These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid. PMID:21317282

How does pre-dialysis education need to change? Findings from a qualitative study with staff and patients.

PubMed

Combes, Gill; Sein, Kim; Allen, Kerry

2017-11-23

Pre-dialysis education (PDE) is provided to thousands of patients every year, helping them decide which renal replacement therapy (RRT) to choose. However, its effectiveness is largely unknown, with relatively little previous research into patients' views about PDE, and no research into staff views. This study reports findings relevant to PDE from a larger mixed methods study, providing insights into what staff and patients think needs to improve. Semi-structured interviews in four hospitals with 96 clinical and managerial staff and 93 dialysis patients, exploring experiences of and views about PDE, and analysed using thematic framework analysis. Most patients found PDE helpful and staff valued its role in supporting patient decision-making. However, patients wanted to see teaching methods and materials improve and biases eliminated. Staff were less aware than patients of how informal staff-patient conversations can influence patients' treatment decision-making. Many staff felt ill equipped to talk about all treatment options in a balanced and unbiased way. Patient decision-making was found to be complex and patients' abilities to make treatment decisions were adversely affected in the pre-dialysis period by emotional distress. Suggested improvements to teaching methods and educational materials are in line with previous studies and current clinical guidelines. All staff, irrespective of their role, need to be trained about all treatment options so that informal conversations with patients are not biased. The study argues for a more individualised approach to PDE which is more like counselling than education and would demand a higher level of skill and training for specialist PDE staff. The study concludes that even if these improvements are made to PDE, not all patients will benefit, because some find decision-making in the pre-dialysis period too complex or are unable to engage with education due to illness or emotional distress. It is therefore recommended that pre-dialysis treatment decisions are temporary, and that PDE is replaced with on-going RRT education which provides opportunities for personalised education and on-going review of patients' treatment choices. Emotional support to help overcome the distress of the transition to end-stage renal disease will also be essential to ensure all patients can benefit from RRT education.

PARALLEL HOP: A SCALABLE HALO FINDER FOR MASSIVE COSMOLOGICAL DATA SETS

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

Skory, Stephen; Turk, Matthew J.; Norman, Michael L.

2010-11-15

Modern N-body cosmological simulations contain billions (10{sup 9}) of dark matter particles. These simulations require hundreds to thousands of gigabytes of memory and employ hundreds to tens of thousands of processing cores on many compute nodes. In order to study the distribution of dark matter in a cosmological simulation, the dark matter halos must be identified using a halo finder, which establishes the halo membership of every particle in the simulation. The resources required for halo finding are similar to the requirements for the simulation itself. In particular, simulations have become too extensive to use commonly employed halo finders, suchmore » that the computational requirements to identify halos must now be spread across multiple nodes and cores. Here, we present a scalable-parallel halo finding method called Parallel HOP for large-scale cosmological simulation data. Based on the halo finder HOP, it utilizes message passing interface and domain decomposition to distribute the halo finding workload across multiple compute nodes, enabling analysis of much larger data sets than is possible with the strictly serial or previous parallel implementations of HOP. We provide a reference implementation of this method as a part of the toolkit {sup yt}, an analysis toolkit for adaptive mesh refinement data that include complementary analysis modules. Additionally, we discuss a suite of benchmarks that demonstrate that this method scales well up to several hundred tasks and data sets in excess of 2000{sup 3} particles. The Parallel HOP method and our implementation can be readily applied to any kind of N-body simulation data and is therefore widely applicable.« less

Going from microscopic to macroscopic on nonuniform growing domains.

PubMed

Yates, Christian A; Baker, Ruth E; Erban, Radek; Maini, Philip K

2012-08-01

Throughout development, chemical cues are employed to guide the functional specification of underlying tissues while the spatiotemporal distributions of such chemicals can be influenced by the growth of the tissue itself. These chemicals, termed morphogens, are often modeled using partial differential equations (PDEs). The connection between discrete stochastic and deterministic continuum models of particle migration on growing domains was elucidated by Baker, Yates, and Erban [Bull. Math. Biol. 72, 719 (2010)] in which the migration of individual particles was modeled as an on-lattice position-jump process. We build on this work by incorporating a more physically reasonable description of domain growth. Instead of allowing underlying lattice elements to instantaneously double in size and divide, we allow incremental element growth and splitting upon reaching a predefined threshold size. Such a description of domain growth necessitates a nonuniform partition of the domain. We first demonstrate that an individual-based stochastic model for particle diffusion on such a nonuniform domain partition is equivalent to a PDE model of the same phenomenon on a nongrowing domain, providing the transition rates (which we derive) are chosen correctly and we partition the domain in the correct manner. We extend this analysis to the case where the domain is allowed to change in size, altering the transition rates as necessary. Through application of the master equation formalism we derive a PDE for particle density on this growing domain and corroborate our findings with numerical simulations.