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

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

An efficient variable projection formulation for separable nonlinear least squares problems.

PubMed

Gan, Min; Li, Han-Xiong

2014-05-01

We consider in this paper a class of nonlinear least squares problems in which the model can be represented as a linear combination of nonlinear functions. The variable projection algorithm projects the linear parameters out of the problem, leaving the nonlinear least squares problems involving only the nonlinear parameters. To implement the variable projection algorithm more efficiently, we propose a new variable projection functional based on matrix decomposition. The advantage of the proposed formulation is that the size of the decomposed matrix may be much smaller than those of previous ones. The Levenberg-Marquardt algorithm using finite difference method is then applied to minimize the new criterion. Numerical results show that the proposed approach achieves significant reduction in computing time.

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.

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

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.

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.

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.

Implementation of Free-Formulation-Based Flat Shell Elements into NASA Comet Code and Development of Nonlinear Shallow Shell Element

NASA Technical Reports Server (NTRS)

Barut, A.; Madenci, Erdogan; Tessler, A.

1997-01-01

This study presents a transient nonlinear finite element analysis within the realm of a multi-body dynamics formulation for determining the dynamic response of a moderately thick laminated shell undergoing a rapid and large rotational motion and nonlinear elastic deformations. Nonlinear strain measure and rotation, as well as 'the transverse shear deformation, are explicitly included in the formulation in order to capture the proper motion-induced stiffness of the laminate. The equations of motion are derived from the virtual work principle. The analysis utilizes a shear deformable shallow shell element along with the co-rotational form of the updated Lagrangian formulation. The shallow shell element formulation is based on the Reissner-Mindlin and Marguerre theory.

Spillover, nonlinearity, and flexible structures

NASA Technical Reports Server (NTRS)

Bass, Robert W.; Zes, Dean

1991-01-01

Many systems whose evolution in time is governed by Partial Differential Equations (PDEs) are linearized around a known equilibrium before Computer Aided Control Engineering (CACE) is considered. In this case, there are infinitely many independent vibrational modes, and it is intuitively evident on physical grounds that infinitely many actuators would be needed in order to control all modes. A more precise, general formulation of this grave difficulty (spillover problem) is due to A.V. Balakrishnan. A possible route to circumvention of this difficulty lies in leaving the PDE in its original nonlinear form, and adding the essentially finite dimensional control action prior to linearization. One possibly applicable technique is the Liapunov Schmidt rigorous reduction of singular infinite dimensional implicit function problems to finite dimensional implicit function problems. Omitting details of Banach space rigor, the formalities of this approach are given.

Regional evaporation estimates in the eastern monsoon region of China: Assessment of a nonlinear formulation of the complementary principle

NASA Astrophysics Data System (ADS)

Liu, Xiaomang; Liu, Changming; Brutsaert, Wilfried

2016-12-01

The performance of a nonlinear formulation of the complementary principle for evaporation estimation was investigated in 241 catchments with different climate conditions in the eastern monsoon region of China. Evaporation (Ea) calculated by the water balance equation was used as the reference. Ea estimated by the calibrated nonlinear formulation was generally in good agreement with the water balance results, especially in relatively dry catchments. The single parameter in the nonlinear formulation, namely αe as a weak analog of the alpha parameter of Priestley and Taylor (), tended to exhibit larger values in warmer and humid near-coastal areas, but smaller values in colder, drier environments inland, with a significant dependency on the aridity index (AI). The nonlinear formulation combined with the equation relating the one parameter and AI provides a promising method to estimate regional Ea with standard and routinely measured meteorological data.

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

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

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.

Coupled variational formulations of linear elasticity and the DPG methodology

NASA Astrophysics Data System (ADS)

Fuentes, Federico; Keith, Brendan; Demkowicz, Leszek; Le Tallec, Patrick

2017-11-01

This article presents a general approach akin to domain-decomposition methods to solve a single linear PDE, but where each subdomain of a partitioned domain is associated to a distinct variational formulation coming from a mutually well-posed family of broken variational formulations of the original PDE. It can be exploited to solve challenging problems in a variety of physical scenarios where stability or a particular mode of convergence is desired in a part of the domain. The linear elasticity equations are solved in this work, but the approach can be applied to other equations as well. The broken variational formulations, which are essentially extensions of more standard formulations, are characterized by the presence of mesh-dependent broken test spaces and interface trial variables at the boundaries of the elements of the mesh. This allows necessary information to be naturally transmitted between adjacent subdomains, resulting in coupled variational formulations which are then proved to be globally well-posed. They are solved numerically using the DPG methodology, which is especially crafted to produce stable discretizations of broken formulations. Finally, expected convergence rates are verified in two different and illustrative examples.

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

Explicit formulation of second and third order optical nonlinearity in the FDTD framework

NASA Astrophysics Data System (ADS)

Varin, Charles; Emms, Rhys; Bart, Graeme; Fennel, Thomas; Brabec, Thomas

2018-01-01

The finite-difference time-domain (FDTD) method is a flexible and powerful technique for rigorously solving Maxwell's equations. However, three-dimensional optical nonlinearity in current commercial and research FDTD softwares requires solving iteratively an implicit form of Maxwell's equations over the entire numerical space and at each time step. Reaching numerical convergence demands significant computational resources and practical implementation often requires major modifications to the core FDTD engine. In this paper, we present an explicit method to include second and third order optical nonlinearity in the FDTD framework based on a nonlinear generalization of the Lorentz dispersion model. A formal derivation of the nonlinear Lorentz dispersion equation is equally provided, starting from the quantum mechanical equations describing nonlinear optics in the two-level approximation. With the proposed approach, numerical integration of optical nonlinearity and dispersion in FDTD is intuitive, transparent, and fully explicit. A strong-field formulation is also proposed, which opens an interesting avenue for FDTD-based modelling of the extreme nonlinear optics phenomena involved in laser filamentation and femtosecond micromachining of dielectrics.

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.

SEACAS Theory Manuals: Part 1. Problem Formulation in Nonlinear Solid Mechancis

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

Attaway, S.W.; Laursen, T.A.; Zadoks, R.I.

1998-08-01

This report gives an introduction to the basic concepts and principles involved in the formulation of nonlinear problems in solid mechanics. By way of motivation, the discussion begins with a survey of some of the important sources of nonlinearity in solid mechanics applications, using wherever possible simple one dimensional idealizations to demonstrate the physical concepts. This discussion is then generalized by presenting generic statements of initial/boundary value problems in solid mechanics, using linear elasticity as a template and encompassing such ideas as strong and weak forms of boundary value problems, boundary and initial conditions, and dynamic and quasistatic idealizations. Themore » notational framework used for the linearized problem is then extended to account for finite deformation of possibly inelastic solids, providing the context for the descriptions of nonlinear continuum mechanics, constitutive modeling, and finite element technology given in three companion reports.« less

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

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.

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.

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

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.

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.

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

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.

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

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

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

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

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.

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.

Multithreaded Model for Dynamic Load Balancing Parallel Adaptive PDE Computations

NASA Technical Reports Server (NTRS)

Chrisochoides, Nikos

1995-01-01

We present a multithreaded model for the dynamic load-balancing of numerical, adaptive computations required for the solution of Partial Differential Equations (PDE's) on multiprocessors. Multithreading is used as a means of exploring concurrency in the processor level in order to tolerate synchronization costs inherent to traditional (non-threaded) parallel adaptive PDE solvers. Our preliminary analysis for parallel, adaptive PDE solvers indicates that multithreading can be used an a mechanism to mask overheads required for the dynamic balancing of processor workloads with computations required for the actual numerical solution of the PDE's. Also, multithreading can simplify the implementation of dynamic load-balancing algorithms, a task that is very difficult for traditional data parallel adaptive PDE computations. Unfortunately, multithreading does not always simplify program complexity, often makes code re-usability not an easy task, and increases software complexity.

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.

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.

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

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

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

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

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

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

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

NASA Technical Reports Server (NTRS)

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

1997-01-01

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

A 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.

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

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.

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.

A nonlinear model predictive control formulation for obstacle avoidance in high-speed autonomous ground vehicles in unstructured environments

NASA Astrophysics Data System (ADS)

Liu, Jiechao; Jayakumar, Paramsothy; Stein, Jeffrey L.; Ersal, Tulga

2018-06-01

This paper presents a nonlinear model predictive control (MPC) formulation for obstacle avoidance in high-speed, large-size autono-mous ground vehicles (AGVs) with high centre of gravity (CoG) that operate in unstructured environments, such as military vehicles. The term 'unstructured' in this context denotes that there are no lanes or traffic rules to follow. Existing MPC formulations for passenger vehicles in structured environments do not readily apply to this context. Thus, a new nonlinear MPC formulation is developed to navigate an AGV from its initial position to a target position at high-speed safely. First, a new cost function formulation is used that aims to find the shortest path to the target position, since no reference trajectory exists in unstructured environments. Second, a region partitioning approach is used in conjunction with a multi-phase optimal control formulation to accommodate the complicated forms the obstacle-free region can assume due to the presence of multiple obstacles in the prediction horizon in an unstructured environment. Third, the no-wheel-lift-off condition, which is the major dynamical safety concern for high-speed, high-CoG AGVs, is ensured by limiting the steering angle within a range obtained offline using a 14 degrees-of-freedom vehicle dynamics model. Thus, a safe, high-speed navigation is enabled in an unstructured environment. Simulations of an AGV approaching multiple obstacles are provided to demonstrate the effectiveness of the algorithm.

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.

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

PDE3A mutations cause autosomal dominant hypertension with brachydactyly.

PubMed

Maass, Philipp G; Aydin, Atakan; Luft, Friedrich C; Schächterle, Carolin; Weise, Anja; Stricker, Sigmar; Lindschau, Carsten; Vaegler, Martin; Qadri, Fatimunnisa; Toka, Hakan R; Schulz, Herbert; Krawitz, Peter M; Parkhomchuk, Dmitri; Hecht, Jochen; Hollfinger, Irene; Wefeld-Neuenfeld, Yvette; Bartels-Klein, Eireen; Mühl, Astrid; Kann, Martin; Schuster, Herbert; Chitayat, David; Bialer, Martin G; Wienker, Thomas F; Ott, Jürg; Rittscher, Katharina; Liehr, Thomas; Jordan, Jens; Plessis, Ghislaine; Tank, Jens; Mai, Knut; Naraghi, Ramin; Hodge, Russell; Hopp, Maxwell; Hattenbach, Lars O; Busjahn, Andreas; Rauch, Anita; Vandeput, Fabrice; Gong, Maolian; Rüschendorf, Franz; Hübner, Norbert; Haller, Hermann; Mundlos, Stefan; Bilginturan, Nihat; Movsesian, Matthew A; Klussmann, Enno; Toka, Okan; Bähring, Sylvia

2015-06-01

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.

A geometric nonlinear degenerated shell element using a mixed formulation with independently assumed strain fields. Final Report; Ph.D. Thesis, 1989

NASA Technical Reports Server (NTRS)

Graf, Wiley E.

1991-01-01

A mixed formulation is chosen to overcome deficiencies of the standard displacement-based shell model. Element development is traced from the incremental variational principle on through to the final set of equilibrium equations. Particular attention is paid to developing specific guidelines for selecting the optimal set of strain parameters. A discussion of constraint index concepts and their predictive capability related to locking is included. Performance characteristics of the elements are assessed in a wide variety of linear and nonlinear plate/shell problems. Despite limiting the study to geometric nonlinear analysis, a substantial amount of additional insight concerning the finite element modeling of thin plate/shell structures is provided. For example, in nonlinear analysis, given the same mesh and load step size, mixed elements converge in fewer iterations than equivalent displacement-based models. It is also demonstrated that, in mixed formulations, lower order elements are preferred. Additionally, meshes used to obtain accurate linear solutions do not necessarily converge to the correct nonlinear solution. Finally, a new form of locking was identified associated with employing elements designed for biaxial bending in uniaxial bending applications.

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

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

A survey of the core-congruential formulation for geometrically nonlinear TL finite elements

NASA Technical Reports Server (NTRS)

Felippa, Carlos A.; Crivelli, Luis A.; Haugen, Bjorn

1994-01-01

This article presents a survey of the core-congruential formulation (CCF) for geometrically nonlinear mechanical finite elements based on the total Lagrangian (TL) kinematic description. Although the key ideas behind the CCF can be traced back to Rajasekaran and Murray in 1973, it has not subsequently received serious attention. The CCF is distinguished by a two-phase development of the finite element stiffness equations. The initial phase developed equations for individual particles. These equations are expressed in terms of displacement gradients as degrees of freedom. The second phase involves congruential-type transformations that eventually binds the element particles of an individual element in terms of its node-displacement degrees of freedom. Two versions of the CCF, labeled direct and generalized, are distinguished. The direct CCF (DCCF) is first described in general form and then applied to the derivation of geometrically nonlinear bar, and plane stress elements using the Green-Lagrange strain measure. The more complex generalized CCF (GCCF) is described and applied to the derivation of 2D and 3D Timoshenko beam elements. Several advantages of the CCF, notably the physically clean separation of material and geometric stiffnesses, and its independence with respect to the ultimate choice of shape functions and element degrees of freedom, are noted. Application examples involving very large motions solved with the 3D beam element display the range of applicability of this formulation, which transcends the kinematic limitations commonly attributed to the TL description.

In silico design of novel hERG-neutral sildenafil-like PDE5 inhibitors.

PubMed

Kayık, Gülru; Tüzün, Nurcan Ş; Durdagi, Serdar

2017-10-01

Cyclic nucleotide phosphodiesterase enzymes (PDEs) have functions in regulating the levels of intracellular second messengers, 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP), via hydrolysis and decomposing mechanisms in cells. They take essential roles in modulating various cellular activities such as memory and smooth muscle functions. PDE type 5 (PDE5) inhibitors enhance the vasodilatory effects of cGMP in the corpus cavernosum and they are used to treat erectile dysfunction. Patch clamp experiments showed that the IC 50 values of the human ether-à-go-go-related gene (hERG1) potassium (K) ion channel blocking affinity of PDE5 inhibitors sildenafil, vardenafil, and tadalafil as 33, 12, and 100 μM, respectively. hERG1 channel is responsible for the regulation of the action potential of human ventricular myocyte by contributing the rapid component of delayed rectifier K + current (I Kr ) component of the cardiac action potential. In this work, interaction patterns and binding affinity predictions of selected PDE5 inhibitors against the hERG1 channel are studied. It is attempted to develop PDE5 inhibitor analogs with lower binding affinity to hERG1 ion channel while keeping their pharmacological activity against their principal target PDE5 using in silico methods. Based on detailed analyses of docking poses and predicted interaction energies, novel analogs of PDE5 inhibitors with lower predicted binding affinity to hERG1 channels without loosing their principal target activity were proposed. Moreover, molecular dynamics (MD) simulations and post-processing MD analyses (i.e. Molecular Mechanics/Generalized Born Surface Area calculations) were performed. Detailed analysis of molecular simulations helped us to better understand the PDE5 inhibitor-target binding interactions in the atomic level. Results of this study can be useful for designing of novel and safe PDE5 inhibitors with enhanced activity and other tailored

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.

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.

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.

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.

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.

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

PubMed

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

2013-09-01

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

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.

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

Novel PDE4 Inhibitors Derived from Chinese Medicine Forsythia

PubMed Central

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

2014-01-01

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

Deformations of infinite-dimensional Lie algebras, exotic cohomology, and integrable nonlinear partial differential equations

NASA Astrophysics Data System (ADS)

Morozov, Oleg I.

2018-06-01

The important unsolved problem in theory of integrable systems is to find conditions guaranteeing existence of a Lax representation for a given PDE. The exotic cohomology of the symmetry algebras opens a way to formulate such conditions in internal terms of the PDE s under the study. In this paper we consider certain examples of infinite-dimensional Lie algebras with nontrivial second exotic cohomology groups and show that the Maurer-Cartan forms of the associated extensions of these Lie algebras generate Lax representations for integrable systems, both known and new ones.

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.

[Update of PDE5 inhibitors as treatment of ED].

PubMed

Lu, Yong-ning; Chen, Bin

2005-07-01

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

Regularization techniques for backward--in--time evolutionary PDE problems

NASA Astrophysics Data System (ADS)

Gustafsson, Jonathan; Protas, Bartosz

2007-11-01

Backward--in--time evolutionary PDE problems have applications in the recently--proposed retrograde data assimilation. We consider the terminal value problem for the Kuramoto--Sivashinsky equation (KSE) in a 1D periodic domain as our model system. The KSE, proposed as a model for interfacial and combustion phenomena, is also often adopted as a toy model for hydrodynamic turbulence because of its multiscale and chaotic dynamics. Backward--in--time problems are typical examples of ill-posed problem, where disturbances are amplified exponentially during the backward march. Regularization is required to solve such problems efficiently and we consider approaches in which the original ill--posed problem is approximated with a less ill--posed problem obtained by adding a regularization term to the original equation. While such techniques are relatively well--understood for linear problems, they less understood in the present nonlinear setting. We consider regularization terms with fixed magnitudes and also explore a novel approach in which these magnitudes are adapted dynamically using simple concepts from the Control Theory.

CAD of control systems: Application of nonlinear programming to a linear quadratic formulation

NASA Technical Reports Server (NTRS)

Fleming, P.

1983-01-01

The familiar suboptimal regulator design approach is recast as a constrained optimization problem and incorporated in a Computer Aided Design (CAD) package where both design objective and constraints are quadratic cost functions. This formulation permits the separate consideration of, for example, model following errors, sensitivity measures and control energy as objectives to be minimized or limits to be observed. Efficient techniques for computing the interrelated cost functions and their gradients are utilized in conjunction with a nonlinear programming algorithm. The effectiveness of the approach and the degree of insight into the problem which it affords is illustrated in a helicopter regulation design example.

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

Discovery of a novel orally active PDE-4 inhibitor effective in an ovalbumin-induced asthma murine model.

PubMed

Kwak, Hyun Jeong; Nam, Ji Yeon; Song, Jin Sook; No, Zaesung; Yang, Sung Don; Cheon, Hyae Gyeong

2012-06-15

Phosphodiesterase-4 (PDE-4) is responsible for metabolizing adenosine 3',5'-cyclic monophosphate that reduces the activation of a wide range of inflammatory cells including eosinophils. PDE-4 inhibitors are under development for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Herein, we report a novel PDE-4 inhibitor, PDE-423 (3-[1-(3-cyclopropylmethoxy-4-difluoromethoxybenzyl)-1H-pyrazol-3-yl]-benzoic acid), which shows good in vitro and in vivo oral activities. PDE-423 exhibited in vitro IC(50)s of 140 nM and 550 nM in enzyme assay and cell-based assay, respectively. In vivo study using ovalbumin-induced asthmatic mice revealed that PDE-423 reduced methacholine-stimulated airway hyperreactivity in a dose-dependent manner by once daily oral administration (ED(50)=18.3 mg/kg), in parallel with decreased eosinophil peroxidase activity and improved lung histology. In addition, PDE-423 was effective in diminishing lipopolysaccharide-induced neutrophilia in vivo as well as in vitro. Oral administration of PDE-423 (100 mg/kg) had no effect on the duration of xylazine/ketamine-induced anesthesia and did not induce vomiting incidence in ferrets up to the dose of 1000 mg/kg. The present study indicates that a novel PDE-4 inhibitor, PDE-423, has good pharmacological profiles implicating this as a potential candidate for the development of a new anti-asthmatic drug. Copyright © 2012 Elsevier B.V. All rights reserved.

Effect of Operating Frequency on PDE Driven Ejector Thrust Performance

NASA Technical Reports Server (NTRS)

Santoro, Robert J.; Pal, Sibtosh; Landry, K.; Shehadeh, R.; Bouvet, N.; Lee, S.-Y.

2005-01-01

Results of an on-going study of pulse detonation engine driven ejectors are presented and discussed. The experiments were conducted using a pulse detonation engine (PDE) designed to operate at frequencies up to 50 Hz. The PDE used in these experiments utilizes an equi-molar mixture of oxygen and nitrogen as the oxidizer, and ethylene (C2H4) as the fuel, with the propellant mixture having an equivalence ratio of one. A line of sight laser absorption technique was used to determine the time needed for proper filling of the tube. Thrust measurements were made using an integrated spring damper system coupled with a linear variable displacement transducer. The baseline thrust of the PDE was first measured at each desired frequency and agrees with experimental and modeling results found in the literature. Thrust augmentation measurements were then made for constant diameter ejectors. The ejectors had varying lengths, and two different inlet geometries were tested for each ejector configuration. The parameter space for the study included PDE operation frequency, ejector length, overlap distance and the radius of curvature for the ejector inlets. For the studied experimental matrix, the results showed a maximum thrust augmentation of 106% at an operational frequency of 30 Hz.

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.

Advantages of multigrid methods for certifying the accuracy of PDE modeling

NASA Technical Reports Server (NTRS)

Forester, C. K.

1981-01-01

Numerical techniques for assessing and certifying the accuracy of the modeling of partial differential equations (PDE) to the user's specifications are analyzed. Examples of the certification process with conventional techniques are summarized for the three dimensional steady state full potential and the two dimensional steady Navier-Stokes equations using fixed grid methods (FG). The advantages of the Full Approximation Storage (FAS) scheme of the multigrid technique of A. Brandt compared with the conventional certification process of modeling PDE are illustrated in one dimension with the transformed potential equation. Inferences are drawn for how MG will improve the certification process of the numerical modeling of two and three dimensional PDE systems. Elements of the error assessment process that are common to FG and MG are analyzed.

A Green's function formulation for a nonlinear potential flow solution applicable to transonic flow

NASA Technical Reports Server (NTRS)

Baker, A. J.; Fox, C. H., Jr.

1977-01-01

Routine determination of inviscid subsonic flow fields about wing-body-tail configurations employing a Green's function approach for numerical solution of the perturbation velocity potential equation is successfully extended into the high subsonic subcritical flow regime and into the shock-free supersonic flow regime. A modified Green's function formulation, valid throughout a range of Mach numbers including transonic, that takes an explicit accounting of the intrinsic nonlinearity in the parent governing partial differential equations is developed. Some considerations pertinent to flow field predictions in the transonic flow regime are discussed.

A three-dimensional nonlinear Timoshenko beam based on the core-congruential formulation

NASA Technical Reports Server (NTRS)

Crivelli, Luis A.; Felippa, Carlos A.

1992-01-01

A three-dimensional, geometrically nonlinear two-node Timoshenkoo beam element based on the total Larangrian description is derived. The element behavior is assumed to be linear elastic, but no restrictions are placed on magnitude of finite rotations. The resulting element has twelve degrees of freedom: six translational components and six rotational-vector components. The formulation uses the Green-Lagrange strains and second Piola-Kirchhoff stresses as energy-conjugate variables and accounts for the bending-stretching and bending-torsional coupling effects without special provisions. The core-congruential formulation (CCF) is used to derived the discrete equations in a staged manner. Core equations involving the internal force vector and tangent stiffness matrix are developed at the particle level. A sequence of matrix transformations carries these equations to beam cross-sections and finally to the element nodal degrees of freedom. The choice of finite rotation measure is made in the next-to-last transformation stage, and the choice of over-the-element interpolation in the last one. The tangent stiffness matrix is found to retain symmetry if the rotational vector is chosen to measure finite rotations. An extensive set of numerical examples is presented to test and validate the present element.

On the removal of boundary errors caused by Runge-Kutta integration of non-linear partial differential equations

NASA Technical Reports Server (NTRS)

Abarbanel, Saul; Gottlieb, David; Carpenter, Mark H.

1994-01-01

It has been previously shown that the temporal integration of hyperbolic partial differential equations (PDE's) may, because of boundary conditions, lead to deterioration of accuracy of the solution. A procedure for removal of this error in the linear case has been established previously. In the present paper we consider hyperbolic (PDE's) (linear and non-linear) whose boundary treatment is done via the SAT-procedure. A methodology is present for recovery of the full order of accuracy, and has been applied to the case of a 4th order explicit finite difference scheme.

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

PDE5 Inhibitors Enhance Celecoxib Killing in Multiple Tumor Types

PubMed Central

BOOTH, LAURENCE; ROBERTS, JANE L.; CRUICKSHANKS, NICHOLA; TAVALLAI, SEYEDMEHRAD; WEBB, TIMOTHY; SAMUEL, PETER; CONLEY, ADAM; BINION, BRITTANY; YOUNG, HAROLD F.; POKLEPOVIC, ANDREW; SPIEGEL, SARAH; DENT, PAUL

2015-01-01

The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer. PMID:25303541

Lagrangian averaging, nonlinear waves, and shock regularization

NASA Astrophysics Data System (ADS)

Bhat, Harish S.

In this thesis, we explore various models for the flow of a compressible fluid as well as model equations for shock formation, one of the main features of compressible fluid flows. We begin by reviewing the variational structure of compressible fluid mechanics. We derive the barotropic compressible Euler equations from a variational principle in both material and spatial frames. Writing the resulting equations of motion requires certain Lie-algebraic calculations that we carry out in detail for expository purposes. Next, we extend the derivation of the Lagrangian averaged Euler (LAE-alpha) equations to the case of barotropic compressible flows. The derivation in this thesis involves averaging over a tube of trajectories etaepsilon centered around a given Lagrangian flow eta. With this tube framework, the LAE-alpha equations are derived by following a simple procedure: start with a given action, expand via Taylor series in terms of small-scale fluid fluctuations xi, truncate, average, and then model those terms that are nonlinear functions of xi. We then analyze a one-dimensional subcase of the general models derived above. We prove the existence of a large family of traveling wave solutions. Computing the dispersion relation for this model, we find it is nonlinear, implying that the equation is dispersive. We carry out numerical experiments that show that the model possesses smooth, bounded solutions that display interesting pattern formation. Finally, we examine a Hamiltonian partial differential equation (PDE) that regularizes the inviscid Burgers equation without the addition of standard viscosity. Here alpha is a small parameter that controls a nonlinear smoothing term that we have added to the inviscid Burgers equation. We show the existence of a large family of traveling front solutions. We analyze the initial-value problem and prove well-posedness for a certain class of initial data. We prove that in the zero-alpha limit, without any standard viscosity

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

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

Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds.

PubMed

Prosdocimi, Tommaso; Mollica, Luca; Donini, Stefano; Semrau, Marta S; Lucarelli, Anna Paola; Aiolfi, Egidio; Cavalli, Andrea; Storici, Paola; Alfei, Silvana; Brullo, Chiara; Bruno, Olga; Parisini, Emilio

2018-05-01

Selected members of the large rolipram-related GEBR family of type 4 phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term potentiation and to improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, few if any structure-activity relationship studies have been performed to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone. Furthermore, we assessed the stability of the observed ligand conformations in the context of the intact enzyme using molecular dynamics simulations. The longer and more flexible ligands appear to be capable of forming contacts with the regulatory portion of the enzyme, thus possibly allowing some degree of selectivity between the different PDE4 isoforms.

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

Prediction of nonlinear soil effects

USGS Publications Warehouse

Hartzell, S.; Bonilla, L.F.; Williams, R.A.

2004-01-01

Mathematical models of soil nonlinearity in common use and recently developed nonlinear codes compared to investigate the range of their predictions. We consider equivalent linear formulations with and without frequency-dependent moduli and damping ratios and nonlinear formulations for total and effective stress. Average velocity profiles to 150 m depth with midrange National Earthquake Hazards Reduction Program site classifications (B, BC, C, D, and E) in the top 30 m are used to compare the response of a wide range of site conditions from rock to soft soil. Nonlinear soil models are compared using the amplification spectrum, calculated as the ratio of surface ground motion to the input motion at the base of the velocity profile. Peak input motions from 0.1g to 0.9g are considered. For site class B, no significant differences exist between the models considered in this article. For site classes BC and C, differences are small at low input motions (0.1g to 0.2g), but become significant at higher input levels. For site classes D and E the overdamping of frequencies above about 4 Hz by the equivalent linear solution with frequency-independent parameters is apparent for the entire range of input motions considered. The equivalent linear formulation with frequency-dependent moduli and damping ratios under damps relative to the nonlinear models considered for site class C with larger input motions and most input levels for site classes D and E. At larger input motions the underdamping for site classes D and E is not as severe as the overdamping with the frequency-independent formulation, but there are still significant differences in the time domain. A nonlinear formulation is recommended for site classes D and E and for site classes BC and C with input motions greater than a few tenths of the acceleration of gravity. The type of nonlinear formulation to use is driven by considerations of the importance of water content and the availability of laboratory soils data. Our

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

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.

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

Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling

PubMed Central

Yun, Sanguk; Budatha, Madhusudhan; Dahlman, James E.; Coon, Brian G.; Cameron, Ryan T.; Langer, Robert; Anderson, Daniel G.; Baillie, George; Schwartz, Martin A.

2016-01-01

Atherosclerosis is primarily a disease of lipid metabolism and inflammation; however, it is also closely associated with endothelial extracellular matrix (ECM) remodelling, with fibronectin accumulating in the laminin–collagen basement membrane. To investigate how fibronectin modulates inflammation in arteries, we replaced the cytoplasmic tail of the fibronectin receptor integrin α5 with that of the collagen/laminin receptor integrin α2. This chimaera suppressed inflammatory signalling in endothelial cells on fibronectin and in knock-in mice. Fibronectin promoted inflammation by suppressing anti-inflammatory cAMP. cAMP was activated through endothelial prostacyclin secretion; however, this was ECM-independent. Instead, cells on fibronectin suppressed cAMP via enhanced phosphodiesterase (PDE) activity, through direct binding of integrin α5 to phosphodiesterase-4D5 (PDE4D5), which induced PP2A-dependent dephosphorylation of PDE4D5 on the inhibitory site Ser651. In vivo knockdown of PDE4D5 inhibited inflammation at athero-prone sites. These data elucidate a molecular mechanism linking ECM remodelling and inflammation, thereby identifying a new class of therapeutic targets. PMID:27595237

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.

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.

A Nonlinear Physics-Based Optimal Control Method for Magnetostrictive Actuators

NASA Technical Reports Server (NTRS)

Smith, Ralph C.

1998-01-01

This paper addresses the development of a nonlinear optimal control methodology for magnetostrictive actuators. At moderate to high drive levels, the output from these actuators is highly nonlinear and contains significant magnetic and magnetomechanical hysteresis. These dynamics must be accommodated by models and control laws to utilize the full capabilities of the actuators. A characterization based upon ferromagnetic mean field theory provides a model which accurately quantifies both transient and steady state actuator dynamics under a variety of operating conditions. The control method consists of a linear perturbation feedback law used in combination with an optimal open loop nonlinear control. The nonlinear control incorporates the hysteresis and nonlinearities inherent to the transducer and can be computed offline. The feedback control is constructed through linearization of the perturbed system about the optimal system and is efficient for online implementation. As demonstrated through numerical examples, the combined hybrid control is robust and can be readily implemented in linear PDE-based structural models.

3-D zebrafish embryo image filtering by nonlinear partial differential equations.

PubMed

Rizzi, Barbara; Campana, Matteo; Zanella, Cecilia; Melani, Camilo; Cunderlik, Robert; Krivá, Zuzana; Bourgine, Paul; Mikula, Karol; Peyriéras, Nadine; Sarti, Alessandro

2007-01-01

We discuss application of nonlinear PDE based methods to filtering of 3-D confocal images of embryogenesis. We focus on the mean curvature driven and the regularized Perona-Malik equations, where standard as well as newly suggested edge detectors are used. After presenting the related mathematical models, the practical results are given and discussed by visual inspection and quantitatively using the mean Hausdorff distance.

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

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.

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.

An application of nonlinear programming to the design of regulators of a linear-quadratic formulation

NASA Technical Reports Server (NTRS)

Fleming, P.

1983-01-01

A design technique is proposed for linear regulators in which a feedback controller of fixed structure is chosen to minimize an integral quadratic objective function subject to the satisfaction of integral quadratic constraint functions. Application of a nonlinear programming algorithm to this mathematically tractable formulation results in an efficient and useful computer aided design tool. Particular attention is paid to computational efficiency and various recommendations are made. Two design examples illustrate the flexibility of the approach and highlight the special insight afforded to the designer. One concerns helicopter longitudinal dynamics and the other the flight dynamics of an aerodynamically unstable aircraft.

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

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

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.

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…

[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.

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.

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…

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.

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.

Aeroelastic coupling of geometrically nonlinear structures and linear unsteady aerodynamics: Two formulations

NASA Astrophysics Data System (ADS)

Demasi, L.; Livne, E.

2009-07-01

Two different time domain formulations of integrating commonly used frequency-domain unsteady aerodynamic models based on a modal approach with full order finite element models for structures with geometric nonlinearities are presented. Both approaches are tailored to flight vehicle configurations where geometric stiffness effects are important but where deformations are moderate, flow is attached, and linear unsteady aerodynamic modeling is adequate, such as low aspect ratio wings or joined-wing and strut-braced wings at small to moderate angles of attack. Results obtained using the two approaches are compared using both planar and non-planar wing configurations. Sub-critical and post-flutter speeds are considered. It is demonstrated that the two methods lead to the same steady solution for the sub-critical case after the transients subside. It is also shown that the two methods predict the amplitude and frequency of limit cycle oscillation (when present) with the same accuracy.

Updated Lagrangian finite element formulations of various biological soft tissue non-linear material models: a comprehensive procedure and review.

PubMed

Townsend, Molly T; Sarigul-Klijn, Nesrin

2016-01-01

Simplified material models are commonly used in computational simulation of biological soft tissue as an approximation of the complicated material response and to minimize computational resources. However, the simulation of complex loadings, such as long-duration tissue swelling, necessitates complex models that are not easy to formulate. This paper strives to offer the updated Lagrangian formulation comprehensive procedure of various non-linear material models for the application of finite element analysis of biological soft tissues including a definition of the Cauchy stress and the spatial tangential stiffness. The relationships between water content, osmotic pressure, ionic concentration and the pore pressure stress of the tissue are discussed with the merits of these models and their applications.

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.

[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.

Nongeostrophic theory of zonally averaged circulation. I - Formulation

NASA Technical Reports Server (NTRS)

Tung, Ka Kit

1986-01-01

A nongeostrophic theory of zonally averaged circulation is formulated using the nonlinear primitive equations (mass conservation, thermodynamics, and zonal momentum) on a sphere. The relationship between the mean meridional circulation and diabatic heating rate is studied. Differences between results of nongeostropic theory and the geostrophic formulation concerning the role of eddy forcing of the diabatic circulation and the nonlinear nearly inviscid limit versus the geostrophic limit are discussed. Consideration is given to the Eliassen-Palm flux divergence, the Eliassen-Palm pseudodivergence, the nonacceleration theorem, and the nonlinear nongeostrophic Taylor relationship.

A non-linear programming approach to the computer-aided design of regulators using a linear-quadratic formulation

NASA Technical Reports Server (NTRS)

Fleming, P.

1985-01-01

A design technique is proposed for linear regulators in which a feedback controller of fixed structure is chosen to minimize an integral quadratic objective function subject to the satisfaction of integral quadratic constraint functions. Application of a non-linear programming algorithm to this mathematically tractable formulation results in an efficient and useful computer-aided design tool. Particular attention is paid to computational efficiency and various recommendations are made. Two design examples illustrate the flexibility of the approach and highlight the special insight afforded to the designer.

A kinetic formulation of piezoresistance in N-type silicon: Application to non-linear effects

NASA Astrophysics Data System (ADS)

Charbonnieras, A. R.; Tellier, C. R.

1999-07-01

This paper is devoted to the theoretical study of the influence of the temperature and of the doping on the piezoresistance of N-type silicon. In the first step the fractional change in the resistivity caused by stresses is calculated in the framework of a multivalley model using a kinetic transport formulation based on the Boltzmann transport equation. In the second step shifts in the minima of the conduction band and the resulting shift of the Fermi level are expressed in terms of deformation potentials and of stresses. General expressions for the fundamental linear, π_{11} and π_{12}, and non-linear, π_{111}, π_{112}, π_{122} and π_{123}, piezoresistance coefficients are then derived. Plots of the non-linear piezoresistance coefficients against the reduced shift of the Fermi level or against temperature allow us to characterize the influence of doping and temperature. Finally some attempts are made to estimate the non-linearity for heavily doped semiconductor gauges. Cette publication est consacrée à l'étude théorique de l'influence de la température et du dopage sur la piezorésistivité du silicium type N. Dans une première étape nous adoptons le modèle de vallées et nous utilisons une formulation cinétique du transport électronique faisant appel à l'équation de transport de Boltzmann pour calculer la variation de la résistivité du semiconducteur sous contrainte. Dans la deuxième étape nous exprimons les déplacements des minima de la bande de conduction et du niveau de Fermi en termes de potentiels de déformation et de contraintes. Nous proposons ensuite des expressions générales pour les coefficients piezorésistifs fondamentaux linéaires, π_{11} et π_{12}, et non-linéaires, π_{111}, π_{112}, π_{122} et π_{123}. Des représentations graphiques des variations des coefficients non-linéaires permettent de caractériser l'influence du dopage et de la température. Enfin nous fournissons une première pré-estimation des effets

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

Student's Lab Assignments in PDE Course with MAPLE.

ERIC Educational Resources Information Center

Ponidi, B. Alhadi

Computer-aided software has been used intensively in many mathematics courses, especially in computational subjects, to solve initial value and boundary value problems in Partial Differential Equations (PDE). Many software packages were used in student lab assignments such as FORTRAN, PASCAL, MATLAB, MATHEMATICA, and MAPLE in order to accelerate…

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.

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.

A Galerkin method for linear PDE systems in circular geometries with structural acoustic applications

NASA Technical Reports Server (NTRS)

Smith, Ralph C.

1994-01-01

A Galerkin method for systems of PDE's in circular geometries is presented with motivating problems being drawn from structural, acoustic, and structural acoustic applications. Depending upon the application under consideration, piecewise splines or Legendre polynomials are used when approximating the system dynamics with modifications included to incorporate the analytic solution decay near the coordinate singularity. This provides an efficient method which retains its accuracy throughout the circular domain without degradation at singularity. Because the problems under consideration are linear or weakly nonlinear with constant or piecewise constant coefficients, transform methods for the problems are not investigated. While the specific method is developed for the two dimensional wave equations on a circular domain and the equation of transverse motion for a thin circular plate, examples demonstrating the extension of the techniques to a fully coupled structural acoustic system are used to illustrate the flexibility of the method when approximating the dynamics of more complex systems.

Rigorous Model Reduction for a Damped-Forced Nonlinear Beam Model: An Infinite-Dimensional Analysis

NASA Astrophysics Data System (ADS)

Kogelbauer, Florian; Haller, George

2018-06-01

We use invariant manifold results on Banach spaces to conclude the existence of spectral submanifolds (SSMs) in a class of nonlinear, externally forced beam oscillations. SSMs are the smoothest nonlinear extensions of spectral subspaces of the linearized beam equation. Reduction in the governing PDE to SSMs provides an explicit low-dimensional model which captures the correct asymptotics of the full, infinite-dimensional dynamics. Our approach is general enough to admit extensions to other types of continuum vibrations. The model-reduction procedure we employ also gives guidelines for a mathematically self-consistent modeling of damping in PDEs describing structural vibrations.

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

PubMed Central

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

2011-01-01

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

Research in nonlinear structural and solid mechanics

NASA Technical Reports Server (NTRS)

Mccomb, H. G., Jr. (Compiler); Noor, A. K. (Compiler)

1980-01-01

Nonlinear analysis of building structures and numerical solution of nonlinear algebraic equations and Newton's method are discussed. Other topics include: nonlinear interaction problems; solution procedures for nonlinear problems; crash dynamics and advanced nonlinear applications; material characterization, contact problems, and inelastic response; and formulation aspects and special software for nonlinear analysis.

Toxicological evaluation of a dietary supplement formulated for male sexual health prior to market release.

PubMed

Clewell, A; Qureshi, I; Endres, J; Horváth, J; Financsek, I; Neal-Kababick, J; Jade, K; Schauss, A G

2010-06-01

The dietary supplement, 112 Degrees, was formulated with the goal of supporting sexual functioning in men. Due to rampant problems with drug adulteration for this category of products, a comprehensive screening for active pharmaceutical agents, with an emphasis on drugs prescribed for erectile dysfunction such as type 5 phosphodiesterase (PDE-5) inhibitors, and known unapproved PDE-5 drug analogues, was performed along with preclinical toxicology studies prior to the introduction of this product into the marketplace. 112 Degrees was found to be free of all pharmaceutical adulterants tested, and was not mutagenic, clastogenic, or genotoxic as demonstrated by the Ames test, chromosomal aberration assay, and mouse micronucleus assay, respectively. The LD(50) in the 14-day acute oral toxicity study was greater than 5000 mg/kg, the highest dose tested. (c) 2009 Elsevier Inc. All rights reserved.

He's Frequency Formulation for Nonlinear Oscillators

ERIC Educational Resources Information Center

Geng, Lei; Cai, Xu-Chu

2007-01-01

Based on an ancient Chinese algorithm, J H He suggested a simple but effective method to find the frequency of a nonlinear oscillator. In this paper, a modified version is suggested to improve the accuracy of the frequency; two examples are given, revealing that the obtained solutions are of remarkable accuracy and are valid for the whole solution…

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.

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.

Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes

PubMed Central

Shi, Qian; Li, Minghui; Mika, Delphine; Fu, Qin; Kim, Sungjin; Phan, Jason; Shen, Ao; Vandecasteele, Gregoire; Xiang, Yang K.

2017-01-01

Aims Cardiac β-adrenergic receptor (βAR) signalling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between βARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists. Methods and results Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists. Activation of Gs-coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and Gq-coupled α1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of β1AR and β2AR at putative protein kinase A (PKA) phosphorylation sites; but activation of Gi-coupled α2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote β2AR phosphorylation effectively inhibit βAR agonist isoproterenol-induced PKA phosphorylation of phospholamban and contractile function in ventricular cardiomyocytes. Heterologous GPCR stimuli have minimal to small effect on isoproterenol-induced β2AR activation and G-protein coupling for cyclic adenosine monophosphate (cAMP) production. However, these GPCR stimuli significantly promote phosphorylation of phosphodiesterase 4D (PDE4D), and recruit PDE4D to the phosphorylated β2AR in a β-arrestin 2 dependent manner without promoting β2AR endocytosis. The increased binding between β2AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in β2AR, inhibition of PDE4, or genetic ablation of PDE4D or β-arrestin 2 abolishes this heterologous inhibitory effect. Ablation of β-arrestin 2 or PDE4D gene also rescues β-adrenergic stimuli-induced myocyte contractile function. Conclusions These data reveal essential roles of β-arrestin 2 and PDE4D in a common mechanism for heterologous

Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa

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

Danciger, M.; Blaney, J.; Gao, Y.Q.

1995-11-01

We have studied 24 small families with presumed autosomal recessive inheritance of retinitis pigmentosa by a combination of haplotype analysis and exon screening. Initial analysis of the families was made with a dinucleotide repeat polymorphism adjacent to the gene for rod cGMP-phosphodiesterase (PDE6B). This was followed by denaturing gradient gel electrophoresis (DGGE) and single-strand conformation polymorphism electrophoresis (SSCPE) of the 22 exons and a portion of the 5{prime} untranslated region of the PDE6B gene in the probands of each family in which the PDE6B locus could not be ruled out from segregating with disease. Two probands were found with compoundmore » heterozygous mutations: Gly576Asp and His620(1-bp del) mutations were present in one proband, and a Lys706X null mutation and an AG to AT splice acceptor site mutation in intron 2 were present in the other. Only the affecteds of each of the two families carried both corresponding mutations. 29 refs., 3 figs., 1 tab.« less

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.

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

On multilevel RBF collocation to solve nonlinear PDEs arising from endogenous stochastic volatility models

NASA Astrophysics Data System (ADS)

Bastani, Ali Foroush; Dastgerdi, Maryam Vahid; Mighani, Abolfazl

2018-06-01

The main aim of this paper is the analytical and numerical study of a time-dependent second-order nonlinear partial differential equation (PDE) arising from the endogenous stochastic volatility model, introduced in [Bensoussan, A., Crouhy, M. and Galai, D., Stochastic equity volatility related to the leverage effect (I): equity volatility behavior. Applied Mathematical Finance, 1, 63-85, 1994]. As the first step, we derive a consistent set of initial and boundary conditions to complement the PDE, when the firm is financed by equity and debt. In the sequel, we propose a Newton-based iteration scheme for nonlinear parabolic PDEs which is an extension of a method for solving elliptic partial differential equations introduced in [Fasshauer, G. E., Newton iteration with multiquadrics for the solution of nonlinear PDEs. Computers and Mathematics with Applications, 43, 423-438, 2002]. The scheme is based on multilevel collocation using radial basis functions (RBFs) to solve the resulting locally linearized elliptic PDEs obtained at each level of the Newton iteration. We show the effectiveness of the resulting framework by solving a prototypical example from the field and compare the results with those obtained from three different techniques: (1) a finite difference discretization; (2) a naive RBF collocation and (3) a benchmark approximation, introduced for the first time in this paper. The numerical results confirm the robustness, higher convergence rate and good stability properties of the proposed scheme compared to other alternatives. We also comment on some possible research directions in this field.

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

PubMed

Santillo, Michael F; Mapa, Mapa S T

2018-02-28

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

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

PubMed Central

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

2015-01-01

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

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.

On the dynamics of approximating schemes for dissipative nonlinear equations

NASA Technical Reports Server (NTRS)

Jones, Donald A.

1993-01-01

Since one can rarely write down the analytical solutions to nonlinear dissipative partial differential equations (PDE's), it is important to understand whether, and in what sense, the behavior of approximating schemes to these equations reflects the true dynamics of the original equations. Further, because standard error estimates between approximations of the true solutions coming from spectral methods - finite difference or finite element schemes, for example - and the exact solutions grow exponentially in time, this analysis provides little value in understanding the infinite time behavior of a given approximating scheme. The notion of the global attractor has been useful in quantifying the infinite time behavior of dissipative PDEs, such as the Navier-Stokes equations. Loosely speaking, the global attractor is all that remains of a sufficiently large bounded set in phase space mapped infinitely forward in time under the evolution of the PDE. Though the attractor has been shown to have some nice properties - it is compact, connected, and finite dimensional, for example - it is in general quite complicated. Nevertheless, the global attractor gives a way to understand how the infinite time behavior of approximating schemes such as the ones coming from a finite difference, finite element, or spectral method relates to that of the original PDE. Indeed, one can often show that such approximations also have a global attractor. We therefore only need to understand how the structure of the attractor for the PDE behaves under approximation. This is by no means a trivial task. Several interesting results have been obtained in this direction. However, we will not go into the details. We mention here that approximations generally lose information about the system no matter how accurate they are. There are examples that show certain parts of the attractor may be lost by arbitrary small perturbations of the original equations.

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

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.

Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes.

PubMed

Shi, Qian; Li, Minghui; Mika, Delphine; Fu, Qin; Kim, Sungjin; Phan, Jason; Shen, Ao; Vandecasteele, Gregoire; Xiang, Yang K

2017-05-01

Cardiac β-adrenergic receptor (βAR) signalling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between βARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists. Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists. Activation of Gs-coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and Gq-coupled α1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of β1AR and β2AR at putative protein kinase A (PKA) phosphorylation sites; but activation of Gi-coupled α2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote β2AR phosphorylation effectively inhibit βAR agonist isoproterenol-induced PKA phosphorylation of phospholamban and contractile function in ventricular cardiomyocytes. Heterologous GPCR stimuli have minimal to small effect on isoproterenol-induced β2AR activation and G-protein coupling for cyclic adenosine monophosphate (cAMP) production. However, these GPCR stimuli significantly promote phosphorylation of phosphodiesterase 4D (PDE4D), and recruit PDE4D to the phosphorylated β2AR in a β-arrestin 2 dependent manner without promoting β2AR endocytosis. The increased binding between β2AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in β2AR, inhibition of PDE4, or genetic ablation of PDE4D or β-arrestin 2 abolishes this heterologous inhibitory effect. Ablation of β-arrestin 2 or PDE4D gene also rescues β-adrenergic stimuli-induced myocyte contractile function. These data reveal essential roles of β-arrestin 2 and PDE4D in a common mechanism for heterologous desensitization of cardiac �

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.

Assessing the performance of formulations for nonlinear feedback of surface gravity waves on ocean currents over coastal waters

NASA Astrophysics Data System (ADS)

Wang, Pengcheng; Sheng, Jinyu; Hannah, Charles

2017-08-01

This study presents applications of a two-way coupled wave-circulation modelling system over coastal waters, with a special emphasis of performance assessments of two different methods for nonlinear feedback of ocean surface gravity waves on three-dimensional (3D) ocean currents. These two methods are the vortex force (VF) formulation suggested by Bennis et al. (2011) and the latest version of radiation stress (RS) formulation suggested by Mellor (2015). The coupled modelling system is first applied to two idealized test cases of surf-zone scales to validate implementations of these two methods in the coupled wave-circulation system. Model results show that the latest version of RS has difficulties in producing the undertow over the surf zone. The coupled system is then applied to Lunenburg Bay (LB) of Nova Scotia during Hurricane Juan in 2003. The coupled system using both the VF and RS formulations generates much stronger and more realistic 3D circulation in the Bay during Hurricane Juan than the circulation-only model, demonstrating the importance of surface wave forces to the 3D ocean circulation over coastal waters. However, the RS formulation generates some weak unphysical currents outside the wave breaking zone due to a less reasonable representation for the vertical distribution of the RS gradients over a slopping bottom. These weak unphysical currents are significantly magnified in a two-way coupled system when interacting with large surface waves, degrading the model performance in simulating currents at one observation site. Our results demonstrate that the VF formulation with an appropriate parameterization of wave breaking effects is able to produce reasonable results for applications over coastal waters during extreme weather events. The RS formulation requires a complex wave theory rather than the linear wave theory for the approximation of a vertical RS term to improve its performance under both breaking and non-breaking wave conditions.

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

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

PubMed

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

2017-09-01

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

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

The Nonlinear Steepest Descent Method to Long-Time Asymptotics of the Coupled Nonlinear Schrödinger Equation

NASA Astrophysics Data System (ADS)

Geng, Xianguo; Liu, Huan

2018-04-01

The Riemann-Hilbert problem for the coupled nonlinear Schrödinger equation is formulated on the basis of the corresponding 3× 3 matrix spectral problem. Using the nonlinear steepest descent method, we obtain leading-order asymptotics for the Cauchy problem of the coupled nonlinear Schrödinger equation.

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.

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…

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.

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.

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

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.

Noninvasive aortic bloodflow by Pulsed Doppler Echocardiography (PDE) compared to cardiac output by the direct Fick procedure

NASA Technical Reports Server (NTRS)

1980-01-01

Left ventricular stroke volume was estimated from the systolic velocity integral in the ascending aorta by pulsed Doppler Echocardiography (PDE) and the cross sectional area of the aorta estimated by M mode echocardiography on 15 patients with coronary disease undergoing right catheterization for diagnostic purposes. Cardiac output was calculated from stroke volume and heart volume using the PDE method as well as the Fick procedure for comparison. The mean value for the cardiac output via the PDE method (4.42 L/min) was only 6% lower than for the cardiac output obtained from the Fick procedure (4.69 L/min) and the correlation between the two methods was excellent (r=0.967, p less than .01). The good agreement between the two methods demonstrates that the PDE technique offers a reliable noninvasive alternative for estimating cardiac output, requiring no active cooperation by the subject. It was concluded that the Doppler method is superior to the Fick method in that it provides beat by beat information on cardiac performance.

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.

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.

Reconfigurable Analog PDE computation for Baseband and RFComputation

DTIC Science & Technology

2017-03-01

waveguiding PDEs. One-dimensional ladder topologies enable linear delays, linear-phase analog filters , as well as analog beamforming, potentially at RF...performance. This discussion focuses on ODE / PDE analog computation available in SoC FPAA structures. One such computation is a ladder filter (Fig...Implementation of a one-dimensional ladder filter for computing inductor (L) and capacitor (C) lines. These components can be implemented in CABs or as

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

PubMed

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

2018-06-02

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

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

PubMed

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

2017-02-15

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

Dynamic analysis of nonlinear rotor-housing systems

NASA Technical Reports Server (NTRS)

Noah, Sherif T.

1988-01-01

Nonlinear analysis methods are developed which will enable the reliable prediction of the dynamic behavior of the space shuttle main engine (SSME) turbopumps in the presence of bearing clearances and other local nonlinearities. A computationally efficient convolution method, based on discretized Duhamel and transition matrix integral formulations, is developed for the transient analysis. In the formulation, the coupling forces due to the nonlinearities are treated as external forces acting on the coupled subsystems. Iteration is utilized to determine their magnitudes at each time increment. The method is applied to a nonlinear generic model of the high pressure oxygen turbopump (HPOTP). As compared to the fourth order Runge-Kutta numerical integration methods, the convolution approach proved to be more accurate and more highly efficient. For determining the nonlinear, steady-state periodic responses, an incremental harmonic balance method was also developed. The method was successfully used to determine dominantly harmonic and subharmonic responses fo the HPOTP generic model with bearing clearances. A reduction method similar to the impedance formulation utilized with linear systems is used to reduce the housing-rotor models to their coordinates at the bearing clearances. Recommendations are included for further development of the method, for extending the analysis to aperiodic and chaotic regimes and for conducting critical parameteric studies of the nonlinear response of the current SSME turbopumps.

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.

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.

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

DOE PAGES

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

2018-01-30

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

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

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

Osborn, Sarah; Zulian, Patrick; Benson, Thomas

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

Ca2+ -activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction.

PubMed

González-Corrochano, R; La Fuente, Jm; Cuevas, P; Fernández, A; Chen, Mx; Sáenz de Tejada, I; Angulo, J

2013-05-01

We have evaluated the influence of calcium-activated potassium channels (KCa ) activation on cGMP-mediated relaxation in human penile tissues from non-diabetic and diabetic patients, and on the effects of PDE5 inhibitors on erectile responses in control and diabetic rats. Cavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resistance arteries (HPRA) obtained from these specimens were evaluated. Intracavernosal pressure (ICP) increases to cavernosal nerve electrical stimulation were determined in anaesthetized diabetic and non-diabetic rats. Concentration-dependent vasodilation to the PDE5 inhibitor, sildenafil, in HPRA was sensitive to endothelium removal, NO/cGMP pathway inhibition and KCa blockade. Accordingly, activation of KCa with NS-8 (10 μM) significantly potentiated sildenafil-induced relaxations in HPRA (EC50 0.49 ± 0.22 vs. 5.21 ± 0.63 μM). In HCC, sildenafil-induced relaxation was unaffected by KCa blockade or activation. Potentiating effects in HPRA were reproduced with an alternative PDE5 inhibitor (tadalafil) and KCa activator (NS1619) and prevented by removing the endothelium. Large-conductance KCa (BK) and intermediate-conductance KCa (IK) contribute to NS-8-induced effects and were immunodetected in human and rat penile arteries. NS-8 potentiated sildenafil-induced enhancement of erectile responses in rats. Activation of KCa recovered the impaired relaxation to sildenafil in diabetic HPRA while sildenafil completely reversed diabetes-induced ED in rats only when combined with KCa activation. Activation of KCa improves vasodilatory capacity of PDE5 inhibitors in diabetic and non-diabetic HPRA, resulting in the recovery of erectile function in diabetic rats. These results suggest a therapeutic potential for KCa activation in diabetic ED. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

Exploring equivalence domain in nonlinear inverse problems using Covariance Matrix Adaption Evolution Strategy (CMAES) and random sampling

NASA Astrophysics Data System (ADS)

Grayver, Alexander V.; Kuvshinov, Alexey V.

2016-05-01

This paper presents a methodology to sample equivalence domain (ED) in nonlinear partial differential equation (PDE)-constrained inverse problems. For this purpose, we first applied state-of-the-art stochastic optimization algorithm called Covariance Matrix Adaptation Evolution Strategy (CMAES) to identify low-misfit regions of the model space. These regions were then randomly sampled to create an ensemble of equivalent models and quantify uncertainty. CMAES is aimed at exploring model space globally and is robust on very ill-conditioned problems. We show that the number of iterations required to converge grows at a moderate rate with respect to number of unknowns and the algorithm is embarrassingly parallel. We formulated the problem by using the generalized Gaussian distribution. This enabled us to seamlessly use arbitrary norms for residual and regularization terms. We show that various regularization norms facilitate studying different classes of equivalent solutions. We further show how performance of the standard Metropolis-Hastings Markov chain Monte Carlo algorithm can be substantially improved by using information CMAES provides. This methodology was tested by using individual and joint inversions of magneotelluric, controlled-source electromagnetic (EM) and global EM induction data.

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.

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

PubMed Central

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

2015-01-01

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

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.

Nonlinear mechanical behavior of thermoplastic matrix materials for advanced composites

NASA Technical Reports Server (NTRS)

Arenz, R. J.; Landel, R. F.

1989-01-01

Two recent theories of nonlinear mechanical response are quantitatively compared and related to experimental data. Computer techniques are formulated to handle the numerical integration and iterative procedures needed to solve the associated sets of coupled nonlinear differential equations. Problems encountered during these formulations are discussed and some open questions described. Bearing in mind these cautions, the consequences of changing parameters that appear in the formulations on the resulting engineering properties are discussed. Hence, engineering approaches to the analysis of thermoplastic matrix material can be suggested.

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.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

PubMed

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

2015-01-07

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS. Copyright © 2015 the authors 0270-6474/15/350396-13$15.00/0.

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.

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.

Radiosynthesis and initial characterization of a PDE10A specific PET tracer [18F]AMG 580 in non-human primates.

PubMed

Hwang, Dah-Ren; Hu, Essa; Allen, Jennifer R; Davis, Carl; Treanor, James; Miller, Silke; Chen, Hang; Shi, Bingzhi; Narayanan, Tanjorie K; Barret, Olivier; Alagille, David; Yu, Zhigang; Slifstein, Mark

2015-08-01

Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important second messengers for neurotransmission. Inhibition of PDE10A has been identified as a potential target for treatment of various neuropsychiatric disorders. To assist drug development, we have identified a selective PDE10A positron emission tomography (PET) tracer, AMG 580. We describe here the radiosynthesis of [(18)F]AMG 580 and in vitro and in vivo characterization results. The potency and selectivity were determined by in vitro assay using [(3)H]AMG 580 and baboon brain tissues. [(18)F]AMG 580 was prepared by a 1-step [(18)F]fluorination procedure. Dynamic brain PET scans were performed in non-human primates. Regions-of-interest were defined on individuals' MRIs and transferred to the co-registered PET images. Data were analyzed using two tissue compartment analysis (2TC), Logan graphical (Logan) analysis with metabolite-corrected input function and the simplified reference tissue model (SRTM) method. A PDE10A inhibitor and unlabeled AMG 580 were used to demonstrate the PDE10A specificity. KD was estimated by Scatchard analysis of high and low affinity PET scans. AMG 580 has an in vitro KD of 71.9 pM. Autoradiography showed specific uptake in striatum. Mean activity of 121 ± 18 MBq was used in PET studies. In Rhesus, the baseline BPND for putamen and caudate was 3.38 and 2.34, respectively, via 2TC, and 3.16, 2.34 via Logan, and 2.92, and 2.01 via SRTM. A dose dependent decrease of BPND was observed by the pre-treatment with a PDE10A inhibitor. In baboons, 0.24 mg/kg dose of AMG 580 resulted in about 70% decrease of BPND. The in vivo KD of [(18)F]AMG 580 was estimated to be around 0.44 nM in baboons. [(18)F]AMG 580 is a selective and potent PDE10A PET tracer with excellent specific striatal binding in non-human primates. It warrants further evaluation in humans. Copyright © 2015 Elsevier Inc. All rights reserved.

High order ADER schemes for a unified first order hyperbolic formulation of continuum mechanics: Viscous heat-conducting fluids and elastic solids

NASA Astrophysics Data System (ADS)

Dumbser, Michael; Peshkov, Ilya; Romenski, Evgeniy; Zanotti, Olindo

2016-06-01

This paper is concerned with the numerical solution of the unified first order hyperbolic formulation of continuum mechanics recently proposed by Peshkov and Romenski [110], further denoted as HPR model. In that framework, the viscous stresses are computed from the so-called distortion tensor A, which is one of the primary state variables in the proposed first order system. A very important key feature of the HPR model is its ability to describe at the same time the behavior of inviscid and viscous compressible Newtonian and non-Newtonian fluids with heat conduction, as well as the behavior of elastic and visco-plastic solids. Actually, the model treats viscous and inviscid fluids as generalized visco-plastic solids. This is achieved via a stiff source term that accounts for strain relaxation in the evolution equations of A. Also heat conduction is included via a first order hyperbolic system for the thermal impulse, from which the heat flux is computed. The governing PDE system is hyperbolic and fully consistent with the first and the second principle of thermodynamics. It is also fundamentally different from first order Maxwell-Cattaneo-type relaxation models based on extended irreversible thermodynamics. The HPR model represents therefore a novel and unified description of continuum mechanics, which applies at the same time to fluid mechanics and solid mechanics. In this paper, the direct connection between the HPR model and the classical hyperbolic-parabolic Navier-Stokes-Fourier theory is established for the first time via a formal asymptotic analysis in the stiff relaxation limit. From a numerical point of view, the governing partial differential equations are very challenging, since they form a large nonlinear hyperbolic PDE system that includes stiff source terms and non-conservative products. We apply the successful family of one-step ADER-WENO finite volume (FV) and ADER discontinuous Galerkin (DG) finite element schemes to the HPR model in the stiff

How to characterize the nonlinear amplifier?

NASA Technical Reports Server (NTRS)

Kallistratova, Dmitri Kouznetsov; Cotera, Carlos Flores

1994-01-01

The conception of the amplification of the coherent field is formulated. The definition of the coefficient of the amplification as the relation between the mean value of the field at the output to the value at the input and the definition of the noise as the difference between the number of photons in the output mode and square of the modulus of the mean value of the output amplitude are considered. Using a simple example it is shown that by these definitions the noise of the nonlinear amplifier may be less than the noise of the ideal linear amplifier of the same amplification coefficient. Proposals to search another definition of basic parameters of the nonlinear amplifiers are discussed. This definition should enable us to formulate the universal fundamental lower limit of the noise which should be valid for linear quantum amplifiers as for nonlinear ones.

Splice-site mutations identified in PDE6A responsible for retinitis pigmentosa in consanguineous Pakistani families

PubMed Central

Khan, Shahid Y.; Ali, Shahbaz; Naeem, Muhammad Asif; Khan, Shaheen N.; Husnain, Tayyab; Butt, Nadeem H.; Qazi, Zaheeruddin A.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Hejtmancik, J. Fielding

2015-01-01

Purpose This study was conducted to localize and identify causal mutations associated with autosomal recessive retinitis pigmentosa (RP) in consanguineous familial cases of Pakistani origin. Methods Ophthalmic examinations that included funduscopy and electroretinography (ERG) were performed to confirm the affectation status. Blood samples were collected from all participating individuals, and genomic DNA was extracted. A genome-wide scan was performed, and two-point logarithm of odds (LOD) scores were calculated. Sanger sequencing was performed to identify the causative variants. Subsequently, we performed whole exome sequencing to rule out the possibility of a second causal variant within the linkage interval. Sequence conservation was performed with alignment analyses of PDE6A orthologs, and in silico splicing analysis was completed with Human Splicing Finder version 2.4.1. Results A large multigenerational consanguineous family diagnosed with early-onset RP was ascertained. An ophthalmic clinical examination consisting of fundus photography and electroretinography confirmed the diagnosis of RP. A genome-wide scan was performed, and suggestive two-point LOD scores were observed with markers on chromosome 5q. Haplotype analyses identified the region; however, the region did not segregate with the disease phenotype in the family. Subsequently, we performed a second genome-wide scan that excluded the entire genome except the chromosome 5q region harboring PDE6A. Next-generation whole exome sequencing identified a splice acceptor site mutation in intron 16: c.2028–1G>A, which was completely conserved in PDE6A orthologs and was absent in ethnically matched 350 control chromosomes, the 1000 Genomes database, and the NHLBI Exome Sequencing Project. Subsequently, we investigated our entire cohort of RP familial cases and identified a second family who harbored a splice acceptor site mutation in intron 10: c.1408–2A>G. In silico analysis suggested that these

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.

A solution procedure for mixed-integer nonlinear programming formulation of supply chain planning with quantity discounts under demand uncertainty

NASA Astrophysics Data System (ADS)

Yin, Sisi; Nishi, Tatsushi

2014-11-01

Quantity discount policy is decision-making for trade-off prices between suppliers and manufacturers while production is changeable due to demand fluctuations in a real market. In this paper, quantity discount models which consider selection of contract suppliers, production quantity and inventory simultaneously are addressed. The supply chain planning problem with quantity discounts under demand uncertainty is formulated as a mixed-integer nonlinear programming problem (MINLP) with integral terms. We apply an outer-approximation method to solve MINLP problems. In order to improve the efficiency of the proposed method, the problem is reformulated as a stochastic model replacing the integral terms by using a normalisation technique. We present numerical examples to demonstrate the efficiency of the proposed method.

Algorithmic Perspectives on Problem Formulations in MDO

NASA Technical Reports Server (NTRS)

Alexandrov, Natalia M.; Lewis, Robert Michael

2000-01-01

This work is concerned with an approach to formulating the multidisciplinary optimization (MDO) problem that reflects an algorithmic perspective on MDO problem solution. The algorithmic perspective focuses on formulating the problem in light of the abilities and inabilities of optimization algorithms, so that the resulting nonlinear programming problem can be solved reliably and efficiently by conventional optimization techniques. We propose a modular approach to formulating MDO problems that takes advantage of the problem structure, maximizes the autonomy of implementation, and allows for multiple easily interchangeable problem statements to be used depending on the available resources and the characteristics of the application problem.

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

PubMed

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

2008-09-04

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

Linear and nonlinear dynamic analysis of redundant load path bearingless rotor systems

NASA Technical Reports Server (NTRS)

Murthy, V. R.; Shultz, Louis A.

1994-01-01

The goal of this research is to develop the transfer matrix method to treat nonlinear autonomous boundary value problems with multiple branches. The application is the complete nonlinear aeroelastic analysis of multiple-branched rotor blades. Once the development is complete, it can be incorporated into the existing transfer matrix analyses. There are several difficulties to be overcome in reaching this objective. The conventional transfer matrix method is limited in that it is applicable only to linear branch chain-like structures, but consideration of multiple branch modeling is important for bearingless rotors. Also, hingeless and bearingless rotor blade dynamic characteristics (particularly their aeroelasticity problems) are inherently nonlinear. The nonlinear equations of motion and the multiple-branched boundary value problem are treated together using a direct transfer matrix method. First, the formulation is applied to a nonlinear single-branch blade to validate the nonlinear portion of the formulation. The nonlinear system of equations is iteratively solved using a form of Newton-Raphson iteration scheme developed for differential equations of continuous systems. The formulation is then applied to determine the nonlinear steady state trim and aeroelastic stability of a rotor blade in hover with two branches at the root. A comprehensive computer program is developed and is used to obtain numerical results for the (1) free vibration, (2) nonlinearly deformed steady state, (3) free vibration about the nonlinearly deformed steady state, and (4) aeroelastic stability tasks. The numerical results obtained by the present method agree with results from other methods.

New nonlinear control algorithms for multiple robot arms

NASA Technical Reports Server (NTRS)

Tarn, T. J.; Bejczy, A. K.; Yun, X.

1988-01-01

Multiple coordinated robot arms are modeled by considering the arms as closed kinematic chains and as a force-constrained mechanical system working on the same object simultaneously. In both formulations, a novel dynamic control method is discussed. It is based on feedback linearization and simultaneous output decoupling technique. By applying a nonlinear feedback and a nonlinear coordinate transformation, the complicated model of the multiple robot arms in either formulation is converted into a linear and output decoupled system. The linear system control theory and optimal control theory are used to design robust controllers in the task space. The first formulation has the advantage of automatically handling the coordination and load distribution among the robot arms. In the second formulation, it was found that by choosing a general output equation it became possible simultaneously to superimpose the position and velocity error feedback with the force-torque error feedback in the task space.

Nonlinear elasticity in rocks: A comprehensive three-dimensional description

DOE PAGES

Lott, Martin; Remillieux, Marcel; Garnier, Vincent; ...

2017-07-17

Here we study theoretically and experimentally the mechanisms of nonlinear and nonequilibrium dynamics in geomaterials through dynamic acoustoelasticity testing. In the proposed theoretical formulation, the classical theory of nonlinear elasticity is extended to include the effects of conditioning. This formulation is adapted to the context of dynamic acoustoelasticity testing in which a low-frequency “pump” wave induces a strain field in the sample and modulates the propagation of a high-frequency “probe” wave. Experiments are conducted to validate the formulation in a long thin bar of Berea sandstone. Several configurations of the pump and probe are examined: the pump successively consists ofmore » the first longitudinal and first torsional mode of vibration of the sample while the probe is successively based on (pressure) $P$ and (shear) $S$ waves. The theoretical predictions reproduce many features of the elastic response observed experimentally, in particular, the coupling between nonlinear and nonequilibrium dynamics and the three-dimensional effects resulting from the tensorial nature of elasticity.« less

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.

Nonlinear resistivity for magnetohydrodynamical models

DOE PAGES

Lingam, M.; Hirvijoki, E.; Pfefferlé, D.; ...

2017-04-20

A new formulation of the plasma resistivity that stems from the collisional momentum-transfer rate between electrons and ions is presented. The resistivity computed herein is shown to depend not only on the temperature and density but also on all other polynomial velocity-space moments of the distribution function, such as the pressure tensor and heat flux vector. The full expression for the collisional momentum-transfer rate is determined and is used to formulate the nonlinear anisotropic resistivity. The new formalism recovers the Spitzer resistivity, as well as the concept of thermal force if the heat flux is assumed to be proportional tomore » a temperature gradient. Furthermore, if the pressure tensor is related to viscous stress, the latter enters the expression for the resistivity. The relative importance of the nonlinear term(s) with respect to the well-established electron inertia and Hall terms is also examined. Lastly, the subtle implications of the nonlinear resistivity, and its dependence on the fluid variables, are discussed in the context of magnetized plasma environments and phenomena such as magnetic reconnection.« less

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

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.

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.

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.

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.

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.

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

A PDE approach for quantifying and visualizing tumor progression and regression

NASA Astrophysics Data System (ADS)

Sintay, Benjamin J.; Bourland, J. Daniel

2009-02-01

Quantification of changes in tumor shape and size allows physicians the ability to determine the effectiveness of various treatment options, adapt treatment, predict outcome, and map potential problem sites. Conventional methods are often based on metrics such as volume, diameter, or maximum cross sectional area. This work seeks to improve the visualization and analysis of tumor changes by simultaneously analyzing changes in the entire tumor volume. This method utilizes an elliptic partial differential equation (PDE) to provide a roadmap of boundary displacement that does not suffer from the discontinuities associated with other measures such as Euclidean distance. Streamline pathways defined by Laplace's equation (a commonly used PDE) are used to track tumor progression and regression at the tumor boundary. Laplace's equation is particularly useful because it provides a smooth, continuous solution that can be evaluated with sub-pixel precision on variable grid sizes. Several metrics are demonstrated including maximum, average, and total regression and progression. This method provides many advantages over conventional means of quantifying change in tumor shape because it is observer independent, stable for highly unusual geometries, and provides an analysis of the entire three-dimensional tumor volume.

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

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

PubMed

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

2014-01-01

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

Nonlinear wave propagation in discrete and continuous systems

NASA Astrophysics Data System (ADS)

Rothos, V. M.

2016-09-01

In this review we try to capture some of the recent excitement induced by a large volume of theoretical and computational studies addressing nonlinear Schrödinger models (discrete and continuous) and the localized structures that they support. We focus on some prototypical structures, namely the breather solutions and solitary waves. In particular, we investigate the bifurcation of travelling wave solution in Discrete NLS system applying dynamical systems methods. Next, we examine the combined effects of cubic and quintic terms of the long range type in the dynamics of a double well potential. The relevant bifurcations, the stability of the branches and their dynamical implications are examined both in the reduced (ODE) and in the full (PDE) setting. We also offer an outlook on interesting possibilities for future work on this theme.

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.

PDE4 and mAKAPβ are nodal organizers of β2-ARs nuclear PKA signaling in cardiac myocytes.

PubMed

Bedioune, Ibrahim; Lefebvre, Florence; Lechêne, Patrick; Varin, Audrey; Domergue, Valérie; Kapiloff, Michael S; Fischmeister, Rodolphe; Vandecasteele, Grégoire

2018-05-03

β1- and β2-adrenergic receptors (β-ARs) produce different acute contractile effects on the heart partly because they impact on different cytosolic pools of cAMP-dependent protein kinase (PKA). They also exert different effects on gene expression but the underlying mechanisms remain unknown. The aim of this study was to understand the mechanisms by which β1- and β2-ARs regulate nuclear PKA activity in cardiomyocytes. We used cytoplasmic and nuclear targeted biosensors to examine cAMP signals and PKA activity in adult rat ventricular myocytes upon selective β1- or β2-ARs stimulation. Both β1- and β2-AR stimulation increased cAMP and activated PKA in the cytoplasm. While the two receptors also increased cAMP in the nucleus, only β1-ARs increased nuclear PKA activity and up-regulated the PKA target gene and pro-apoptotic factor, inducible cAMP element repressor (ICER). Inhibition of PDE4, but not Gi, PDE3, GRK2 nor caveolae disruption disclosed nuclear PKA activation and ICER induction by β2-ARs. Both nuclear and cytoplasmic PKI prevented nuclear PKA activation and ICER induction by β1-ARs, indicating that PKA activation outside the nucleus is required for subsequent nuclear PKA activation and ICER mRNA expression. Cytoplasmic PKI also blocked ICER induction by β2-AR stimulation (with concomitant PDE4 inhibition). However, in this case nuclear PKI decreased ICER up-regulation by only 30%, indicating that other mechanisms are involved. Down-regulation of mAKAPβ partially inhibited nuclear PKA activation upon β1-AR stimulation, and drastically decreased nuclear PKA activation upon β2-AR stimulation in the presence of PDE4 inhibition. β1- and β2-ARs differentially regulate nuclear PKA activity and ICER expression in cardiomyocytes. PDE4 insulates a mAKAPβ-targeted PKA pool at the nuclear envelope that prevents nuclear PKA activation upon β2-AR stimulation.

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

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

PubMed Central

Emala, Charles W.

2013-01-01

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

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

PubMed

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

2013-06-01

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

Nonlinear transient analysis via energy minimization

NASA Technical Reports Server (NTRS)

Kamat, M. P.; Knight, N. F., Jr.

1978-01-01

The formulation basis for nonlinear transient analysis of finite element models of structures using energy minimization is provided. Geometric and material nonlinearities are included. The development is restricted to simple one and two dimensional finite elements which are regarded as being the basic elements for modeling full aircraft-like structures under crash conditions. The results indicate the effectiveness of the technique as a viable tool for this purpose.

Long-wave model for strongly anisotropic growth of a crystal step.

PubMed

Khenner, Mikhail

2013-08-01

A continuum model for the dynamics of a single step with the strongly anisotropic line energy is formulated and analyzed. The step grows by attachment of adatoms from the lower terrace, onto which atoms adsorb from a vapor phase or from a molecular beam, and the desorption is nonnegligible (the "one-sided" model). Via a multiscale expansion, we derived a long-wave, strongly nonlinear, and strongly anisotropic evolution PDE for the step profile. Written in terms of the step slope, the PDE can be represented in a form similar to a convective Cahn-Hilliard equation. We performed the linear stability analysis and computed the nonlinear dynamics. Linear stability depends on whether the stiffness is minimum or maximum in the direction of the step growth. It also depends nontrivially on the combination of the anisotropy strength parameter and the atomic flux from the terrace to the step. Computations show formation and coarsening of a hill-and-valley structure superimposed onto a long-wavelength profile, which independently coarsens. Coarsening laws for the hill-and-valley structure are computed for two principal orientations of a maximum step stiffness, the increasing anisotropy strength, and the varying atomic flux.

State Space Formulation of Nonlinear Vibration Responses Collected from a Dynamic Rotor-Bearing System: An Extension of Bearing Diagnostics to Bearing Prognostics.

PubMed

Tse, Peter W; Wang, Dong

2017-02-14

Bearings are widely used in various industries to support rotating shafts. Their failures accelerate failures of other adjacent components and may cause unexpected machine breakdowns. In recent years, nonlinear vibration responses collected from a dynamic rotor-bearing system have been widely analyzed for bearing diagnostics. Numerous methods have been proposed to identify different bearing faults. However, these methods are unable to predict the future health conditions of bearings. To extend bearing diagnostics to bearing prognostics, this paper reports the design of a state space formulation of nonlinear vibration responses collected from a dynamic rotor-bearing system in order to intelligently predict bearing remaining useful life (RUL). Firstly, analyses of nonlinear vibration responses were conducted to construct a bearing health indicator (BHI) so as to assess the current bearing health condition. Secondly, a state space model of the BHI was developed to mathematically track the health evolution of the BHI. Thirdly, unscented particle filtering was used to predict bearing RUL. Lastly, a new bearing acceleration life testing setup was designed to collect natural bearing degradation data, which were used to validate the effectiveness of the proposed bearing prognostic method. Results show that the prediction accuracy of the proposed bearing prognostic method is promising and the proposed bearing prognostic method is able to reflect future bearing health conditions.

State Space Formulation of Nonlinear Vibration Responses Collected from a Dynamic Rotor-Bearing System: An Extension of Bearing Diagnostics to Bearing Prognostics

PubMed Central

Tse, Peter W.; Wang, Dong

2017-01-01

Bearings are widely used in various industries to support rotating shafts. Their failures accelerate failures of other adjacent components and may cause unexpected machine breakdowns. In recent years, nonlinear vibration responses collected from a dynamic rotor-bearing system have been widely analyzed for bearing diagnostics. Numerous methods have been proposed to identify different bearing faults. However, these methods are unable to predict the future health conditions of bearings. To extend bearing diagnostics to bearing prognostics, this paper reports the design of a state space formulation of nonlinear vibration responses collected from a dynamic rotor-bearing system in order to intelligently predict bearing remaining useful life (RUL). Firstly, analyses of nonlinear vibration responses were conducted to construct a bearing health indicator (BHI) so as to assess the current bearing health condition. Secondly, a state space model of the BHI was developed to mathematically track the health evolution of the BHI. Thirdly, unscented particle filtering was used to predict bearing RUL. Lastly, a new bearing acceleration life testing setup was designed to collect natural bearing degradation data, which were used to validate the effectiveness of the proposed bearing prognostic method. Results show that the prediction accuracy of the proposed bearing prognostic method is promising and the proposed bearing prognostic method is able to reflect future bearing health conditions. PMID:28216586

Nonlinear Waves

DTIC Science & Technology

1989-06-15

Hamiltonian Formulation of the Kadomtsev - Petviashvili and Benjamin-Ono Equations , A.S. Fokas and P.M. Santini, J. Math. Phys. 29 (3) 604-617 (1988...Prototypes are the so-called Kadomtsev -Petviashvilli and Davey-Stewartson equations . These equations arise in a variety of physical instances such as water...plasma physics. Moreover the study of solutions to some of the underlying nonlinear evolution equations has led naturally to the investigation and new

Interface Technology for Geometrically Nonlinear Analysis of Multiple Connected Subdomains

NASA Technical Reports Server (NTRS)

Ransom, Jonathan B.

1997-01-01

Interface technology for geometrically nonlinear analysis is presented and demonstrated. This technology is based on an interface element which makes use of a hybrid variational formulation to provide for compatibility between independently modeled connected subdomains. The interface element developed herein extends previous work to include geometric nonlinearity and to use standard linear and nonlinear solution procedures. Several benchmark nonlinear applications of the interface technology are presented and aspects of the implementation are discussed.

Development of solution techniques for nonlinear structural analysis

NASA Technical Reports Server (NTRS)

Vos, R. G.; Andrews, J. S.

1974-01-01

Nonlinear structural solution methods in the current research literature are classified according to order of the solution scheme, and it is shown that the analytical tools for these methods are uniformly derivable by perturbation techniques. A new perturbation formulation is developed for treating an arbitrary nonlinear material, in terms of a finite-difference generated stress-strain expansion. Nonlinear geometric effects are included in an explicit manner by appropriate definition of an applicable strain tensor. A new finite-element pilot computer program PANES (Program for Analysis of Nonlinear Equilibrium and Stability) is presented for treatment of problems involving material and geometric nonlinearities, as well as certain forms on nonconservative loading.

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.

FRF decoupling of nonlinear systems

NASA Astrophysics Data System (ADS)

Kalaycıoğlu, Taner; Özgüven, H. Nevzat

2018-03-01

Structural decoupling problem, i.e. predicting dynamic behavior of a particular substructure from the knowledge of the dynamics of the coupled structure and the other substructure, has been well investigated for three decades and led to several decoupling methods. In spite of the inherent nonlinearities in a structural system in various forms such as clearances, friction and nonlinear stiffness, all decoupling studies are for linear systems. In this study, decoupling problem for nonlinear systems is addressed for the first time. A method, named as FRF Decoupling Method for Nonlinear Systems (FDM-NS), is proposed for calculating FRFs of a substructure decoupled from a coupled nonlinear structure where nonlinearity can be modeled as a single nonlinear element. Depending on where nonlinear element is, i.e., either in the known or unknown subsystem, or at the connection point, the formulation differs. The method requires relative displacement information between two end points of the nonlinear element, in addition to point and transfer FRFs at some points of the known subsystem. However, it is not necessary to excite the system from the unknown subsystem even when the nonlinear element is in that subsystem. The validation of FDM-NS is demonstrated with two different case studies using nonlinear lumped parameter systems. Finally, a nonlinear experimental test structure is used in order to show the real-life application and accuracy of FDM-NS.

Modeling of fatigue crack induced nonlinear ultrasonics using a highly parallelized explicit local interaction simulation approach

NASA Astrophysics Data System (ADS)

Shen, Yanfeng; Cesnik, Carlos E. S.

2016-04-01

This paper presents a parallelized modeling technique for the efficient simulation of nonlinear ultrasonics introduced by the wave interaction with fatigue cracks. The elastodynamic wave equations with contact effects are formulated using an explicit Local Interaction Simulation Approach (LISA). The LISA formulation is extended to capture the contact-impact phenomena during the wave damage interaction based on the penalty method. A Coulomb friction model is integrated into the computation procedure to capture the stick-slip contact shear motion. The LISA procedure is coded using the Compute Unified Device Architecture (CUDA), which enables the highly parallelized supercomputing on powerful graphic cards. Both the explicit contact formulation and the parallel feature facilitates LISA's superb computational efficiency over the conventional finite element method (FEM). The theoretical formulations based on the penalty method is introduced and a guideline for the proper choice of the contact stiffness is given. The convergence behavior of the solution under various contact stiffness values is examined. A numerical benchmark problem is used to investigate the new LISA formulation and results are compared with a conventional contact finite element solution. Various nonlinear ultrasonic phenomena are successfully captured using this contact LISA formulation, including the generation of nonlinear higher harmonic responses. Nonlinear mode conversion of guided waves at fatigue cracks is also studied.

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

PubMed

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

2016-05-01

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

[Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption].

PubMed

Silva, Adauto Carvalho; Toffoletto, Odaly; Lucio, Luiz Antonio Galvão; Santos, Paula Ferreira Dos; Afiune, Jorge Barros; Massud Filho, João; Tufik, Sergio

2010-02-01

Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74% when drug intake was associated with alcohol. These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

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

Electromagnetic nonlinear gyrokinetics with polarization drift

NASA Astrophysics Data System (ADS)

Duthoit, F.-X.; Hahm, T. S.; Wang, Lu

2014-08-01

A set of new nonlinear electromagnetic gyrokinetic Vlasov equation with polarization drift and gyrokinetic Maxwell equations is systematically derived by using the Lie-transform perturbation method in toroidal geometry. For the first time, we recover the drift-kinetic expression for parallel acceleration [R. M. Kulsrud, in Basic Plasma Physics, edited by A. A. Galeev and R. N. Sudan (North-Holland, Amsterdam, 1983)] from the nonlinear gyrokinetic equations, thereby bridging a gap between the two formulations. This formalism should be useful in addressing nonlinear ion Compton scattering of intermediate-mode-number toroidal Alfvén eigenmodes for which the polarization current nonlinearity [T. S. Hahm and L. Chen, Phys. Rev. Lett. 74, 266 (1995)] and the usual finite Larmor radius effects should compete.

[Efficacy and tolerance of PDE-5 in the treatment of erectile dysfunction in schizophrenic patients: A literature review].

PubMed

Bacconi, L; Gressier, F

2017-02-01

Sexual dysfunction is an important public health problem in men and is associated with reduced quality of life. It is more common in patients with schizophrenia. It is well-established that antipsychotic drugs cause sexual dysfunction with consequences on the quality of life of patients, adherence to treatment, and public health costs. Phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are indicated for the management of erectile dysfunction. However, there is little information on such treatment in schizophrenic patients. This literature review aimed to summarize the current data on the efficacy and tolerability of PDE-5 inhibitors in the erectile dysfunction in schizophrenic patients. PubMed, PsycInfo and Cochrane databases were searched for studies published until August 2014. Only 6 studies met the inclusion criteria. Three were randomized, double-blind, cross-over, placebo-controlled trials and three were open studies. Various scales were used to measure erectile and orgasmic function, desire, satisfaction during intercourse, overall satisfaction, quality of life and intensity of schizophrenic symptoms. In the 3 randomized studies (one with sildenafil 25-50 mg, one with lodenafil carbonate 80 mg/j and the last one with tadalafil 10 mg), the rate of participants who completed the trial was high (around 95 %). All three included patients with schizophrenia or schizophrenia spectrum disorders. Patients reported significant improvement on sexual dysfunction. However, no statistical difference was reported between lodenafil and placebo, on different scales, suggesting a very important placebo effect in patients with schizophrenia. All three found a good tolerance of PDE-5 inhibitors. Side effects were rare and were mainly nasal congestion, headaches, nausea and dizziness. There were no major side effects or drug interactions. Considering the 3 open studies, 2 involved sildenafil and one tadalafil. All concluded in improved erectile and orgasmic

Increase of Intracellular Cyclic AMP by PDE4 Inhibitors Affects HepG2 Cell Cycle Progression and Survival.

PubMed

Massimi, Mara; Cardarelli, Silvia; Galli, Francesca; Giardi, Maria Federica; Ragusa, Federica; Panera, Nadia; Cinque, Benedetta; Cifone, Maria Grazia; Biagioni, Stefano; Giorgi, Mauro

2017-06-01

Type 4 cyclic nucleotide phosphodiesterases (PDE4) are major members of a superfamily of enzymes (PDE) involved in modulation of intracellular signaling mediated by cAMP. Broadly expressed in most human tissues and present in large amounts in the liver, PDEs have in the last decade been key therapeutic targets for several inflammatory diseases. Recently, a significant body of work has underscored their involvement in different kinds of cancer, but with no attention paid to liver cancer. The present study investigated the effects of two PDE4 inhibitors, rolipram and DC-TA-46, on the growth of human hepatoma HepG2 cells. Treatment with these inhibitors caused a marked increase of intracellular cAMP level and a dose- and time-dependent effect on cell growth. The concentrations of inhibitors that halved cell proliferation to about 50% were used for cell cycle experiments. Rolipram (10 μM) and DC-TA-46 (0.5 μM) produced a decrease of cyclin expression, in particular of cyclin A, as well as an increase in p21, p27 and p53, as evaluated by Western blot analysis. Changes in the intracellular localization of cyclin D1 were also observed after treatments. In addition, both inhibitors caused apoptosis, as demonstrated by an Annexin-V cytofluorimetric assay and analysis of caspase-3/7 activity. Results demonstrated that treatment with PDE4 inhibitors affected HepG2 cell cycle and survival, suggesting that they might be useful as potential adjuvant, chemotherapeutic or chemopreventive agents in hepatocellular carcinoma. J. Cell. Biochem. 118: 1401-1411, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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

PubMed Central

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

2007-01-01

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

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

PubMed

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

2007-01-01

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

Performance bounds for nonlinear systems with a nonlinear ℒ2-gain property

NASA Astrophysics Data System (ADS)

Zhang, Huan; Dower, Peter M.

2012-09-01

Nonlinear ℒ2-gain is a finite gain concept that generalises the notion of conventional (linear) finite ℒ2-gain to admit the application of ℒ2-gain analysis tools of a broader class of nonlinear systems. The computation of tight comparison function bounds for this nonlinear ℒ2-gain property is important in applications such as small gain design. This article presents an approximation framework for these comparison function bounds through the formulation and solution of an optimal control problem. Key to the solution of this problem is the lifting of an ℒ2-norm input constraint, which is facilitated via the introduction of an energy saturation operator. This admits the solution of the optimal control problem of interest via dynamic programming and associated numerical methods, leading to the computation of the proposed bounds. Two examples are presented to demonstrate this approach.

PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner.

PubMed

Lehrke, Michael; Kahles, Florian; Makowska, Anna; Tilstam, Pathricia V; Diebold, Sebastian; Marx, Judith; Stöhr, Robert; Hess, Katharina; Endorf, Elizabeth B; Bruemmer, Dennis; Marx, Nikolaus; Findeisen, Hannes M

2015-04-01

Phosphodiesterase 4 (PDE4) activity mediates cAMP-dependent smooth muscle cell (SMC) activation following vascular injury. In this study we have investigated the effects of specific PDE4 inhibition with roflumilast on SMC proliferation and inflammatory activation in vitro and neointima formation following guide wire-induced injury of the femoral artery in mice in vivo. In vitro, roflumilast did not affect SMC proliferation, but diminished TNF-α induced expression of the vascular cell adhesion molecule 1 (VCAM-1). Specific activation of the cAMP effector Epac, but not PKA activation mimicked the effects of roflumilast on VCAM-1 expression. Consistently, the reduction of VCAM-1 expression was rescued following inhibition of Epac. TNF-α induced NFκB p65 translocation and VCAM-1 promoter activity were not altered by roflumilast in SMCs. However, roflumilast treatment and Epac activation repressed the induction of the activating epigenetic histone mark H3K4me2 at the VCAM-1 promoter, while PKA activation showed no effect. Furthermore, HDAC inhibition blocked the inhibitory effect of roflumilast on VCAM-1 expression. Both, roflumilast and Epac activation reduced monocyte adhesion to SMCs in vitro. Finally, roflumilast treatment attenuated femoral artery intima-media ratio by more than 50% after 4weeks. In summary, PDE4 inhibition regulates VCAM-1 through a novel Epac-dependent mechanism, which involves regulatory epigenetic components and reduces neointima formation following vascular injury. PDE4 inhibition and Epac activation might represent novel approaches for the treatment of vascular diseases, including atherosclerosis and in-stent restenosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

MicroRNA-19a/b-3p protect the heart from hypertension-induced pathological cardiac hypertrophy through PDE5A.

PubMed

Liu, Kun; Hao, Qiongyu; Wei, Jie; Li, Gong-Hao; Wu, Yong; Zhao, Yun-Feng

2018-04-16

PDE5A is a leading factor contributing to cGMP signaling and cardiac hypertrophy. However, microRNA-mediated posttranscriptional regulation of PDE5A has not been reported. The aim of this study is to screen the microRNAs that are able to regulate PDE5A and explore the function of the microRNAs in cardiac hypertrophy and remodeling. Although miR-19a/b-3p (microRNA-19a-3p and microRNA-19b-3p) have been reported to be differentially expressed during cardiac hypertrophy, the direct targets and the functions of this microRNA family for regulation of cardiac hypertrophy have not yet been investigated. The present study identified some direct targets and the underlying functions of miR-19a/b-3p by using bioinformatics tools and gene manipulations within mouse neonatal cardiomyocytes. Transfection of miR-19a/b-3p down-regulated endogenous expressions of PDE5A at both mRNA and protein levels with real-time PCR and western blot. Luciferase reporter assays showed that PDE5A was a direct target of miR-19a/b-3p. In mouse models of cardiac hypertrophy, we found that miR-19a/b-3p was expressed in cardiomyocytes and that its expression was reduced in pressure overload-induced hypertrophic hearts. miR-19a/b-3p transgenic mice prevented the progress of cardiac hypertrophy and cardiac remodeling in response to angiotensin II infusion with echocardiographic assessment and pressure-volume relation analysis. Our study elucidates that PDE5A is a novel direct target of miR-19a/b-3p, and demonstrates that antihypertrophic roles of the miR-19a/b-3p family in Ang II-induced hypertrophy and cardiac remodeling, suggests that endogenous miR-19a/b-3p might have clinical potential to suppress cardiac hypertrophy and heart failure.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any

Formulation of the linear model from the nonlinear simulation for the F18 HARV

NASA Technical Reports Server (NTRS)

Hall, Charles E., Jr.

1991-01-01

The F-18 HARV is a modified F-18 Aircraft which is capable of flying in the post-stall regime in order to achieve superagility. The onset of aerodynamic stall, and continued into the post-stall region, is characterized by nonlinearities in the aerodynamic coefficients. These aerodynamic coefficients are not expressed as analytic functions, but rather in the form of tabular data. The nonlinearities in the aerodynamic coefficients yield a nonlinear model of the aircraft's dynamics. Nonlinear system theory has made many advances, but this area is not sufficiently developed to allow its application to this problem, since many of the theorems are existance theorems and that the systems are composed of analytic functions. Thus, the feedback matrices and the state estimators are obtained from linear system theory techniques. It is important, in order to obtain the correct feedback matrices and state estimators, that the linear description of the nonlinear flight dynamics be as accurate as possible. A nonlinear simulation is run under the Advanced Continuous Simulation Language (ACSL). The ACSL simulation uses FORTRAN subroutines to interface to the look-up tables for the aerodynamic data. ACSL has commands to form the linear representation for the system. Other aspects of this investigation are discussed.

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.

Nonlinear programming extensions to rational function approximation methods for unsteady aerodynamic forces

NASA Technical Reports Server (NTRS)

Tiffany, Sherwood H.; Adams, William M., Jr.

1988-01-01

The approximation of unsteady generalized aerodynamic forces in the equations of motion of a flexible aircraft are discussed. Two methods of formulating these approximations are extended to include the same flexibility in constraining the approximations and the same methodology in optimizing nonlinear parameters as another currently used extended least-squares method. Optimal selection of nonlinear parameters is made in each of the three methods by use of the same nonlinear, nongradient optimizer. The objective of the nonlinear optimization is to obtain rational approximations to the unsteady aerodynamics whose state-space realization is lower order than that required when no optimization of the nonlinear terms is performed. The free linear parameters are determined using the least-squares matrix techniques of a Lagrange multiplier formulation of an objective function which incorporates selected linear equality constraints. State-space mathematical models resulting from different approaches are described and results are presented that show comparative evaluations from application of each of the extended methods to a numerical example.

Suppression of nonlinear oscillations in combustors with partial length acoustic liners

NASA Technical Reports Server (NTRS)

Espander, W. R.; Mitchell, C. E.; Baer, M. R.

1975-01-01

An analytical model is formulated for a three-dimensional nonlinear stability problem in a rocket motor combustion chamber. The chamber is modeled as a right circular cylinder with a short (multi-orifice) nozzle, and an acoustic linear covering an arbitrary portion of the cylindrical periphery. The combustion is concentrated at the injector and the gas flow field is characterized by a mean Mach number. The unsteady combustion processes are formulated using the Crocco time lag model. The resulting equations are solved using a Green's function method combined with numerical evaluation techniques. The influence of acoustic liners on the nonlinear waveforms is predicted. Nonlinear stability limits and regions where triggering is possible are also predicted for both lined and unlined combustors in terms of the combustion parameters.

Electromagnetic nonlinear gyrokinetics with polarization drift

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

Duthoit, F.-X.; Hahm, T. S., E-mail: tshahm@snu.ac.kr; Wang, Lu

2014-08-15

A set of new nonlinear electromagnetic gyrokinetic Vlasov equation with polarization drift and gyrokinetic Maxwell equations is systematically derived by using the Lie-transform perturbation method in toroidal geometry. For the first time, we recover the drift-kinetic expression for parallel acceleration [R. M. Kulsrud, in Basic Plasma Physics, edited by A. A. Galeev and R. N. Sudan (North-Holland, Amsterdam, 1983)] from the nonlinear gyrokinetic equations, thereby bridging a gap between the two formulations. This formalism should be useful in addressing nonlinear ion Compton scattering of intermediate-mode-number toroidal Alfvén eigenmodes for which the polarization current nonlinearity [T. S. Hahm and L. Chen,more » Phys. Rev. Lett. 74, 266 (1995)] and the usual finite Larmor radius effects should compete.« less

Screening of synthetic PDE-5 inhibitors and their analogues as adulterants: analytical techniques and challenges.

PubMed

Patel, Dhavalkumar Narendrabhai; Li, Lin; Kee, Chee-Leong; Ge, Xiaowei; Low, Min-Yong; Koh, Hwee-Ling

2014-01-01

The popularity of phosphodiesterase type 5 (PDE-5) enzyme inhibitors for the treatment of erectile dysfunction has led to the increase in prevalence of illicit sexual performance enhancement products. PDE-5 inhibitors, namely sildenafil, tadalafil and vardenafil, and their unapproved designer analogues are being increasingly used as adulterants in the herbal products and health supplements marketed for sexual performance enhancement. To date, more than 50 unapproved analogues of prescription PDE-5 inhibitors were found as adulterants in the literature. To avoid detection of such adulteration by standard screening protocols, the perpetrators of such illegal products are investing time and resources to synthesize exotic analogues and devise novel means for adulteration. A comprehensive review of conventional and advance analytical techniques to detect and characterize the adulterants is presented. The rapid identification and structural elucidation of unknown analogues as adulterants is greatly enhanced by the wide myriad of analytical techniques employed, including high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), liquid chromatography mass-spectrometry (LC-MS), nuclear magnetic resonance (NMR) spectroscopy, vibrational spectroscopy, liquid chromatography-Fourier transform ion cyclotron resonance-mass spectrometry (LC-FT-ICR-MS), liquid chromatograph-hybrid triple quadrupole linear ion trap mass spectrometer with information dependent acquisition, ultra high performance liquid chromatography-time of flight-mass spectrometry (UHPLC-TOF-MS), ion mobility spectroscopy (IMS) and immunoassay methods. The many challenges in detecting and characterizing such adulterants, and the need for concerted effort to curb adulteration in order to safe guard public safety and interest are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Nonlinear Schrödinger equations with single power nonlinearity and harmonic potential

NASA Astrophysics Data System (ADS)

Cipolatti, R.; de Macedo Lira, Y.; Trallero-Giner, C.

2018-03-01

We consider a generalized nonlinear Schrödinger equation (GNLS) with a single power nonlinearity of the form λ ≤ft\\vert \\varphi \\right\\vert p , with p  >  0 and λ\\in{R} , in the presence of a harmonic confinement. We report the conditions that p and λ must fulfill for the existence and uniqueness of ground states of the GNLS. We discuss the Cauchy problem and summarize which conditions are required for the nonlinear term λ ≤ft\\vert \\varphi \\right\\vert p to render the ground state solutions orbitally stable. Based on a new variational method we provide exact formulæ for the minimum energy for each index p and the changing range of values of the nonlinear parameter λ. Also, we report an approximate close analytical expression for the ground state energy, performing a comparative analysis of the present variational calculations with those obtained by a generalized Thomas-Fermi approach, and soliton solutions for the respective ranges of p and λ where these solutions can be implemented to describe the minimum energy.

Nonlinear programming extensions to rational function approximations of unsteady aerodynamics

NASA Technical Reports Server (NTRS)

Tiffany, Sherwood H.; Adams, William M., Jr.

1987-01-01

This paper deals with approximating unsteady generalized aerodynamic forces in the equations of motion of a flexible aircraft. Two methods of formulating these approximations are extended to include both the same flexibility in constraining them and the same methodology in optimizing nonlinear parameters as another currently used 'extended least-squares' method. Optimal selection of 'nonlinear' parameters is made in each of the three methods by use of the same nonlinear (nongradient) optimizer. The objective of the nonlinear optimization is to obtain rational approximations to the unsteady aerodynamics whose state-space realization is of lower order than that required when no optimization of the nonlinear terms is performed. The free 'linear' parameters are determined using least-squares matrix techniques on a Lagrange multiplier formulation of an objective function which incorporates selected linear equality constraints. State-space mathematical models resulting from the different approaches are described, and results are presented which show comparative evaluations from application of each of the extended methods to a numerical example. The results obtained for the example problem show a significant (up to 63 percent) reduction in the number of differential equations used to represent the unsteady aerodynamic forces in linear time-invariant equations of motion as compared to a conventional method in which nonlinear terms are not optimized.

Efficacy of Selective PDE4D Negative Allosteric Modulators in the Object Retrieval Task in Female Cynomolgus Monkeys (Macaca fascicularis)

PubMed Central

Sutcliffe, Jane S.; Beaumont, Vahri; Watson, James M.; Chew, Chang Sing; Beconi, Maria; Hutcheson, Daniel M.; Dominguez, Celia; Munoz-Sanjuan, Ignacio

2014-01-01

Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline. PMID:25050979

Probabilistic finite elements for transient analysis in nonlinear continua

NASA Technical Reports Server (NTRS)

Liu, W. K.; Belytschko, T.; Mani, A.

1985-01-01

The probabilistic finite element method (PFEM), which is a combination of finite element methods and second-moment analysis, is formulated for linear and nonlinear continua with inhomogeneous random fields. Analogous to the discretization of the displacement field in finite element methods, the random field is also discretized. The formulation is simplified by transforming the correlated variables to a set of uncorrelated variables through an eigenvalue orthogonalization. Furthermore, it is shown that a reduced set of the uncorrelated variables is sufficient for the second-moment analysis. Based on the linear formulation of the PFEM, the method is then extended to transient analysis in nonlinear continua. The accuracy and efficiency of the method is demonstrated by application to a one-dimensional, elastic/plastic wave propagation problem. The moments calculated compare favorably with those obtained by Monte Carlo simulation. Also, the procedure is amenable to implementation in deterministic FEM based computer programs.

Nonrecursive formulations of multibody dynamics and concurrent multiprocessing

NASA Technical Reports Server (NTRS)

Kurdila, Andrew J.; Menon, Ramesh

1993-01-01

Since the late 1980's, research in recursive formulations of multibody dynamics has flourished. Historically, much of this research can be traced to applications of low dimensionality in mechanism and vehicle dynamics. Indeed, there is little doubt that recursive order N methods are the method of choice for this class of systems. This approach has the advantage that a minimal number of coordinates are utilized, parallelism can be induced for certain system topologies, and the method is of order N computational cost for systems of N rigid bodies. Despite the fact that many authors have dismissed redundant coordinate formulations as being of order N(exp 3), and hence less attractive than recursive formulations, we present recent research that demonstrates that at least three distinct classes of redundant, nonrecursive multibody formulations consistently achieve order N computational cost for systems of rigid and/or flexible bodies. These formulations are as follows: (1) the preconditioned range space formulation; (2) penalty methods; and (3) augmented Lagrangian methods for nonlinear multibody dynamics. The first method can be traced to its foundation in equality constrained quadratic optimization, while the last two methods have been studied extensively in the context of coercive variational boundary value problems in computational mechanics. Until recently, however, they have not been investigated in the context of multibody simulation, and present theoretical questions unique to nonlinear dynamics. All of these nonrecursive methods have additional advantages with respect to recursive order N methods: (1) the formalisms retain the highly desirable order N computational cost; (2) the techniques are amenable to concurrent simulation strategies; (3) the approaches do not depend upon system topology to induce concurrency; and (4) the methods can be derived to balance the computational load automatically on concurrent multiprocessors. In addition to the presentation of

Nonlinear analysis of composite thin-walled helicopter blades

NASA Astrophysics Data System (ADS)

Kalfon, J. P.; Rand, O.

Nonlinear theoretical modeling of laminated thin-walled composite helicopter rotor blades is presented. The derivation is based on nonlinear geometry with a detailed treatment of the body loads in the axial direction which are induced by the rotation. While the in-plane warping is neglected, a three-dimensional generic out-of-plane warping distribution is included. The formulation may also handle varying thicknesses and mass distribution along the cross-sectional walls. The problem is solved by successive iterations in which a system of equations is constructed and solved for each cross-section. In this method, the differential equations in the spanwise directions are formulated and solved using a finite-differences scheme which allows simple adaptation of the spanwise discretization mesh during iterations.

Evaluation of nonlinear structural dynamic responses using a fast-running spring-mass formulation

NASA Astrophysics Data System (ADS)

Benjamin, A. S.; Altman, B. S.; Gruda, J. D.

In today's world, accurate finite-element simulations of large nonlinear systems may require meshes composed of hundreds of thousands of degrees of freedom. Even with today's fast computers and the promise of ever-faster ones in the future, central processing unit (CPU) expenditures for such problems could be measured in days. Many contemporary engineering problems, such as those found in risk assessment, probabilistic structural analysis, and structural design optimization, cannot tolerate the cost or turnaround time for such CPU-intensive analyses, because these applications require a large number of cases to be run with different inputs. For many risk assessment applications, analysts would prefer running times to be measurable in minutes. There is therefore a need for approximation methods which can solve such problems far more efficiently than the very detailed methods and yet maintain an acceptable degree of accuracy. For this purpose, we have been working on two methods of approximation: neural networks and spring-mass models. This paper presents our work and results to date for spring-mass modeling and analysis, since we are further along in this area than in the neural network formulation. It describes the physical and numerical models contained in a code we developed called STRESS, which stands for 'Spring-mass Transient Response Evaluation for structural Systems'. The paper also presents results for a demonstration problem, and compares these with results obtained for the same problem using PRONTO3D, a state-of-the-art finite element code which was also developed at Sandia.

Chemical reaction for Carreau-Yasuda nanofluid flow past a nonlinear stretching sheet considering Joule heating

NASA Astrophysics Data System (ADS)

Khan, Mair; Shahid, Amna; Malik, M. Y.; Salahuddin, T.

2018-03-01

Current analysis has been made to scrutinize the consequences of chemical response against magneto-hydrodynamic Carreau-Yasuda nanofluid flow induced by a non-linear stretching surface considering zero normal flux, slip and convective boundary conditions. Joule heating effect is also considered. Appropriate similarity approach is used to convert leading system of PDE's for Carreau-Yasuda nanofluid into nonlinear ODE's. Well known mathematical scheme namely shooting method is utilized to solve the system numerically. Physical parameters, namely Weissenberg number We , thermal slip parameter δ , thermophoresis number NT, non-linear stretching parameter n, magnetic field parameter M, velocity slip parameter k , Lewis number Le, Brownian motion parameter NB, Prandtl number Pr, Eckert number Ec and chemical reaction parameter γ upon temperature, velocity and concentration profiles are visualized through graphs and tables. Numerical influence of mass and heat transfer rates and friction factor are also represented in tabular as well as graphical form respectively. Skin friction coefficient reduces when Weissenberg number We is incremented. Rate of heat transfer enhances for large values of Brownian motion constraint NB. By increasing Lewis quantity Le rate of mass transfer declines.

Multilevel algorithms for nonlinear optimization

NASA Technical Reports Server (NTRS)

Alexandrov, Natalia; Dennis, J. E., Jr.

1994-01-01

Multidisciplinary design optimization (MDO) gives rise to nonlinear optimization problems characterized by a large number of constraints that naturally occur in blocks. We propose a class of multilevel optimization methods motivated by the structure and number of constraints and by the expense of the derivative computations for MDO. The algorithms are an extension to the nonlinear programming problem of the successful class of local Brown-Brent algorithms for nonlinear equations. Our extensions allow the user to partition constraints into arbitrary blocks to fit the application, and they separately process each block and the objective function, restricted to certain subspaces. The methods use trust regions as a globalization strategy, and they have been shown to be globally convergent under reasonable assumptions. The multilevel algorithms can be applied to all classes of MDO formulations. Multilevel algorithms for solving nonlinear systems of equations are a special case of the multilevel optimization methods. In this case, they can be viewed as a trust-region globalization of the Brown-Brent class.

Nonlinear mechanics of non-rigid origami: an efficient computational approach

NASA Astrophysics Data System (ADS)

Liu, K.; Paulino, G. H.

2017-10-01

Origami-inspired designs possess attractive applications to science and engineering (e.g. deployable, self-assembling, adaptable systems). The special geometric arrangement of panels and creases gives rise to unique mechanical properties of origami, such as reconfigurability, making origami designs well suited for tunable structures. Although often being ignored, origami structures exhibit additional soft modes beyond rigid folding due to the flexibility of thin sheets that further influence their behaviour. Actual behaviour of origami structures usually involves significant geometric nonlinearity, which amplifies the influence of additional soft modes. To investigate the nonlinear mechanics of origami structures with deformable panels, we present a structural engineering approach for simulating the nonlinear response of non-rigid origami structures. In this paper, we propose a fully nonlinear, displacement-based implicit formulation for performing static/quasi-static analyses of non-rigid origami structures based on `bar-and-hinge' models. The formulation itself leads to an efficient and robust numerical implementation. Agreement between real models and numerical simulations demonstrates the ability of the proposed approach to capture key features of origami behaviour.

Nonlinear mechanics of non-rigid origami: an efficient computational approach.

PubMed

Liu, K; Paulino, G H

2017-10-01

Origami-inspired designs possess attractive applications to science and engineering (e.g. deployable, self-assembling, adaptable systems). The special geometric arrangement of panels and creases gives rise to unique mechanical properties of origami, such as reconfigurability, making origami designs well suited for tunable structures. Although often being ignored, origami structures exhibit additional soft modes beyond rigid folding due to the flexibility of thin sheets that further influence their behaviour. Actual behaviour of origami structures usually involves significant geometric nonlinearity, which amplifies the influence of additional soft modes. To investigate the nonlinear mechanics of origami structures with deformable panels, we present a structural engineering approach for simulating the nonlinear response of non-rigid origami structures. In this paper, we propose a fully nonlinear, displacement-based implicit formulation for performing static/quasi-static analyses of non-rigid origami structures based on 'bar-and-hinge' models. The formulation itself leads to an efficient and robust numerical implementation. Agreement between real models and numerical simulations demonstrates the ability of the proposed approach to capture key features of origami behaviour.

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.

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

Mixed Integer PDE Constrained Optimization for the Control of a Wildfire Hazard

DTIC Science & Technology

2017-01-01

are nodes suitable for extinguishing the fire. We introduce a discretization of the time horizon [0, T] by the set of time T := {0, At,..., ntZ\\t = T...of the constraints and objective with a discrete counterpart. The PDE is replaced by a linear system obtained from a convergent finite difference...method [5] and the integral is replaced by a quadrature formula. The domain is discretized by replacing 17 with an equidistant grid of length Ax

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

PubMed

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

2015-12-01

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

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 "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.

Stability of nonuniform rotor blades in hover using a mixed formulation

NASA Technical Reports Server (NTRS)

Stephens, W. B.; Hodges, D. H.; Avila, J. H.; Kung, R. M.

1980-01-01

A mixed formulation for calculating static equilibrium and stability eigenvalues of nonuniform rotor blades in hover is presented. The static equilibrium equations are nonlinear and are solved by an accurate and efficient collocation method. The linearized perturbation equations are solved by a one step, second order integration scheme. The numerical results correlate very well with published results from a nearly identical stability analysis based on a displacement formulation. Slight differences in the results are traced to terms in the equations that relate moments to derivatives of rotations. With the present ordering scheme, in which terms of the order of squares of rotations are neglected with respect to unity, it is not possible to achieve completely equivalent models based on mixed and displacement formulations. The one step methods reveal that a second order Taylor expansion is necessary to achieve good convergence for nonuniform rotating blades. Numerical results for a hypothetical nonuniform blade, including the nonlinear static equilibrium solution, were obtained with no more effort or computer time than that required for a uniform blade.

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

PubMed

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

2012-01-01

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

Comparison of efficacy and satisfaction profile, between penile prosthesis implantation and oral PDE5 inhibitor tadalafil therapy, in men with nerve-sparing radical prostatectomy erectile dysfunction.

PubMed

Megas, Georgios; Papadopoulos, Georgios; Stathouros, Georgios; Moschonas, Dimitrios; Gkialas, Ioannis; Ntoumas, Konstantinos

2013-07-01

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Erectile dysfunction after nerve-sparing radical retropubic prostatectomy constitutes a challenge to the urologist. The mainstay of medical treatment after radical prostatectomy to restore spontaneous erectile function remains phosphodiesterase (PDE5) inhibitors, despite the fact that data from animal studies suggesting that PDE5 inhibitors can prevent smooth muscle apoptosis and fibrosis have not yet been extrapolated to humans because of a lack of standardized protocols. If the above treatment fails, second-line therapies such as intraurethral prostaglandins, penile injection therapy and vacuum devices are offered. When less invasive therapies are ineffective, interventions that preserve sexual function such as penile prosthesis implantation become the treatment of choice. Our study reveals the alternative of penile prosthesis implantation as first-line treatment in erectile dysfunction after nerve-sparing radical prostatectomy. It also highlights its superiority to the oral PDE5 inhibitor treatment, regarding the erection, frequency, firmness, maintenance and penetration ability. This suggests that a concept of an early penile intervention in the future would be promising for those patients who wish to remain sexually active without depending on oral formulations with doubtful and delayed results. To evaluate the outcome of penile prosthesis surgery in comparison to oral phosphodiesterase type 5 (PDE5) inhibitor administration, in men with erectile dysfunction after nerve-sparing radical prostatectomy, as early penile intervention therapy. A total of 174 patients treated by nerve-sparing retropubic radical prostatectomy (RRP) for clinically localized prostate cancer, between January 2006 and September 2009 enrolled in the study, 153 patients fulfilled the inclusion criteria, and 69 (45%) patients presented with post-RRP erectile dysfunction 6 months after primary surgery. Fifty-four patients were disease

Nonlinear flight control design using backstepping methodology

NASA Astrophysics Data System (ADS)

Tran, Thanh Trung

The subject of nonlinear flight control design using backstepping control methodology is investigated in the dissertation research presented here. Control design methods based on nonlinear models of the dynamic system provide higher utility and versatility because the design model more closely matches the physical system behavior. Obtaining requisite model fidelity is only half of the overall design process, however. Design of the nonlinear control loops can lessen the effects of nonlinearity, or even exploit nonlinearity, to achieve higher levels of closed-loop stability, performance, and robustness. The goal of the research is to improve control quality for a general class of strict-feedback dynamic systems and provide flight control architectures to augment the aircraft motion. The research is divided into two parts: theoretical control development for the strict-feedback form of nonlinear dynamic systems and application of the proposed theory for nonlinear flight dynamics. In the first part, the research is built on two components: transforming the nonlinear dynamic model to a canonical strict-feedback form and then applying backstepping control theory to the canonical model. The research considers a process to determine when this transformation is possible, and when it is possible, a systematic process to transfer the model is also considered when practical. When this is not the case, certain modeling assumptions are explored to facilitate the transformation. After achieving the canonical form, a systematic design procedure for formulating a backstepping control law is explored in the research. Starting with the simplest subsystem and ending with the full system, pseudo control concepts based on Lyapunov control functions are used to control each successive subsystem. Typically each pseudo control must be solved from a nonlinear algebraic equation. At the end of this process, the physical control input must be re-expressed in terms of the physical states by

Optimality conditions for the numerical solution of optimization problems with PDE constraints :

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

Aguilo Valentin, Miguel Alejandro; Ridzal, Denis

2014-03-01

A theoretical framework for the numerical solution of partial di erential equation (PDE) constrained optimization problems is presented in this report. This theoretical framework embodies the fundamental infrastructure required to e ciently implement and solve this class of problems. Detail derivations of the optimality conditions required to accurately solve several parameter identi cation and optimal control problems are also provided in this report. This will allow the reader to further understand how the theoretical abstraction presented in this report translates to the application.

Non-predictor control of a class of feedforward nonlinear systems with unknown time-varying delays

NASA Astrophysics Data System (ADS)

Koo, Min-Sung; Choi, Ho-Lim

2016-08-01

This paper generalises the several recent results on the control of feedforward time-delay nonlinear systems. First, in view of system formulation, there are unknown time-varying delays in both states and main control input. Also, the considered nonlinear system has extended feedforward nonlinearities. Second, in view of control solution, our proposed controller is a non-predictor feedback controller whereas smith-predictor type controllers are used in the several existing results. Moreover, our controller does not need any information on the unknown delays except their upper bounds. Thus, our result has certain merits in both system formulation and control solution perspective. The analysis and example are given for clear illustration.

Bayesian Analysis of Structural Equation Models with Nonlinear Covariates and Latent Variables

ERIC Educational Resources Information Center

Song, Xin-Yuan; Lee, Sik-Yum

2006-01-01

In this article, we formulate a nonlinear structural equation model (SEM) that can accommodate covariates in the measurement equation and nonlinear terms of covariates and exogenous latent variables in the structural equation. The covariates can come from continuous or discrete distributions. A Bayesian approach is developed to analyze the…

Valuation of financial models with non-linear state spaces

NASA Astrophysics Data System (ADS)

Webber, Nick

2001-02-01

A common assumption in valuation models for derivative securities is that the underlying state variables take values in a linear state space. We discuss numerical implementation issues in an interest rate model with a simple non-linear state space, formulating and comparing Monte Carlo, finite difference and lattice numerical solution methods. We conclude that, at least in low dimensional spaces, non-linear interest rate models may be viable.

Decision tree analyses of key patient characteristics in Middle Eastern/North African and Latin American men treated with long-acting and short-acting PDE5 inhibitors for erectile dysfunction.

PubMed

Rubio-Aurioles, Eusebio; El-Meliegy, Amr; Abdulwahed, Samer; Henneges, Carsten; Sorsaburu, Sebastian; Gurbuz, Sirel

2015-02-01

Phosphodiesterase type 5 (PDE5) inhibitors have discontinuation rates as high as 60% in men with erectile dysfunction. Treatment satisfaction has been significantly associated with treatment continuation. Understanding key characteristics in terms of treatment preference, relationship, and lifestyle issues could provide direction on how to improve compliance with PDE5 inhibitor treatment globally. The objective was to identify subgroups of interest in the pooled database of two observational studies conducted in Latin America (LA) and Middle East/North Africa (MENA) exploring patient characteristics and prescription of either a long- or short-acting PDE5 inhibitor at baseline. Two identical prospective, non-interventional, observational, studies in MENA (N = 493) and LA (N = 511) treated men with an 'on demand' (pro re nata, PRN) PDE5 inhibitor (sildenafil, tadalafil, vardenafil, or lodenafil) during 6 months. In this post-hoc meta-analysis of two observational studies with equal design, pooled data were analyzed to determine patient characteristics and PDE5 inhibitor prescribed/used most likely to be associated with patient expectations, satisfaction, self-esteem, and patient-partner relationships. Decision tree analyses, with and without weighting, were used to identify and describe key features. In each analysis of patient expectations, patient-partner relationship, and self-esteem, we describe the two major subgroups at baseline for each decision tree. Analyses of patient expectations and sexual self-esteem revealed that patients prescribed long-acting PDE5 inhibitors (59%) highlighted the importance of treatment effect duration, second to partner satisfaction with treatment, while patients prescribed short-acting PDE5 inhibitors (32%) placed less importance on treatment effect duration but considerable importance on treatment effect lasting until intercourse completion. Further insights regarding patients, partner relationship characteristics, and

Success Stories in Control: Nonlinear Dynamic Inversion Control

NASA Technical Reports Server (NTRS)

Bosworth, John T.

2010-01-01

NASA plays an important role in advancing the state of the art in flight control systems. In the case of Nonlinear Dynamic Inversion (NDI) NASA supported initial implementation of the theory in an aircraft and demonstration in a space vehicle. Dr. Dale Enns of Honeywell Aerospace Advanced Technology performed this work in cooperation with NASA and under NASA contract. Honeywell and Lockheed Martin were subsequently contracted by AFRL to create "Design Guidelines for Multivariable Control Theory". This foundational work directly contributed to the advancement of the technology and the credibility of the control law as a design option. As a result Honeywell collaborated with Lockheed Martin to produce a Nonlinear Dynamic Inversion controller for the X-35 and subsequently Lockheed Martin did the same for the production Lockheed Martin F-35 vehicle. The theory behind NDI is to use a systematic generalized approach to controlling a vehicle. Using general aircraft nonlinear equations of motion and onboard aerodynamic, mass properties, and engine models specific to the vehicle, a relationship between control effectors and desired aircraft motion can be formulated. Using this formulation a control combination is used that provides a predictable response to commanded motion. Control loops around this formulation shape the response as desired and provide robustness to modeling errors. Once the control law is designed it can be used on a similar class of vehicle with only an update to the vehicle specific onboard models.

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

PubMed

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

2017-09-01

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

Computer-Aided Transformation of PDE Models: Languages, Representations, and a Calculus of Operations

DTIC Science & Technology

2016-01-05

discretizations . We maintain that what is clear at the mathematical level should be equally clear in computation. In this small STIR project, we separate the...concerns of describing and discretizing such models by defining an input language representing PDE, including steady-state and tran- sient, linear and...solvers, such as [8, 9], focused on the solvers themselves and particular families of discretizations (e. g. finite elements), and now it is natural to

Differential effects of black raspberry and strawberry extracts on BaPDE-induced activation of transcription factors and their target genes.

PubMed

Li, Jingxia; Zhang, Dongyun; Stoner, Gary D; Huang, Chuanshu

2008-04-01

The chemopreventive properties of edible berries have been demonstrated both in vitro and in vivo, however, the specific molecular mechanisms underlying their anti-cancer effects are largely unknown. Our previous studies have shown that a methanol extract fraction of freeze-dried black raspberries inhibits benzoapyrene (BaP)-induced transformation of Syrian hamster embryo cells. This fraction also blocks activation of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB) induced by benzoapyrene diol-epoxide (BaPDE) in mouse epidermal JB6 Cl 41 cells. To determine if different berry types exhibit specific mechanisms for their anti-cancer effects, we compared the effects of extract fractions from both black raspberries and strawberries on BaPDE-induced activation of various signaling pathways in Cl 41 cells. Black raspberry fractions inhibited the activation of AP-1, NF-kappaB, and nuclear factor of activated T cells (NFAT) by BaPDE as well as their upstream PI-3K/Akt-p70(S6K) and mitogen-activated protein kinase pathways. In contrast, strawberry fractions inhibited NFAT activation, but did not inhibit the activation of AP-1, NF-kappaB or the PI-3K/Akt-p70(S6K) and mitogen-activated protein kinase pathways. Consistent with the effects on NFAT activation, tumor necrosis factor-alpha (TNF-alpha) induction by BaPDE was blocked by extract fractions of both black raspberries and strawberries, whereas vascular endothelial growth factor (VEGF) expression, which depends on AP-1 activation, was suppressed by black raspberry fractions but not strawberry fractions. These results suggest that black raspberry and strawberry components may target different signaling pathways in exerting their anti-carcinogenic effects. (c) 2007 Wiley-Liss, Inc.

Differential Effects of Black Raspberry and Strawberry Extracts on BaPDE-Induced Activation of Transcription Factors and Their Target Genes

PubMed Central

Li, Jingxia; Zhang, Dongyun; Stoner, Gary D.; Huang, Chuanshu

2013-01-01

The chemopreventive properties of edible berries have been demonstrated both in vitro and in vivo, however, the specific molecular mechanisms underlying their anti-cancer effects are largely unknown. Our previous studies have shown that a methanol extract fraction of freeze-dried black raspberries inhibits benzoapyrene (BaP)-induced transformation of Syrian hamster embryo cells. This fraction also blocks activation of activator protein-1 (AP-1) and nuclear factor κB (NF-κB) induced by benzoapyrene diol-epoxide (BaPDE) in mouse epidermal JB6 Cl 41 cells. To determine if different berry types exhibit specific mechanisms for their anti-cancer effects, we compared the effects of extract fractions from both black raspberries and strawberries on BaPDE-induced activation of various signaling pathways in Cl 41 cells. Black raspberry fractions inhibited the activation of AP-1, NF-κB, and nuclear factor of activated T cells (NFAT) by BaPDE as well as their upstream PI-3K/Akt-p70S6K and mitogen-activated protein kinase pathways. In contrast, strawberry fractions inhibited NFAT activation, but did not inhibit the activation of AP-1, NF-κB or the PI-3K/Akt-p70S6K and mitogen-activated protein kinase pathways. Consistent with the effects on NFAT activation, tumor necrosis factor-α (TNF-α) induction by BaPDE was blocked by extract fractions of both black raspberries and strawberries, whereas vascular endothelial growth factor (VEGF) expression, which depends on AP-1 activation, was suppressed by black raspberry fractions but not strawberry fractions. These results suggest that black raspberry and strawberry components may target different signaling pathways in exerting their anti-carcinogenic effects. PMID:18085529

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

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.

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

Nonlinear Entanglement and its Application to Generating Cat States

NASA Astrophysics Data System (ADS)

Shen, Y.; Assad, S. M.; Grosse, N. B.; Li, X. Y.; Reid, M. D.; Lam, P. K.

2015-03-01

The Einstein-Podolsky-Rosen (EPR) paradox, which was formulated to argue for the incompleteness of quantum mechanics, has since metamorphosed into a resource for quantum information. The EPR entanglement describes the strength of linear correlations between two objects in terms of a pair of conjugate observables in relation to the Heisenberg uncertainty limit. We propose that entanglement can be extended to include nonlinear correlations. We examine two driven harmonic oscillators that are coupled via third-order nonlinearity can exhibit quadraticlike nonlinear entanglement which, after a projective measurement on one of the oscillators, collapses the other into a cat state of tunable size.

Nonlinear entanglement and its application to generating cat States.

PubMed

Shen, Y; Assad, S M; Grosse, N B; Li, X Y; Reid, M D; Lam, P K

2015-03-13

The Einstein-Podolsky-Rosen (EPR) paradox, which was formulated to argue for the incompleteness of quantum mechanics, has since metamorphosed into a resource for quantum information. The EPR entanglement describes the strength of linear correlations between two objects in terms of a pair of conjugate observables in relation to the Heisenberg uncertainty limit. We propose that entanglement can be extended to include nonlinear correlations. We examine two driven harmonic oscillators that are coupled via third-order nonlinearity can exhibit quadraticlike nonlinear entanglement which, after a projective measurement on one of the oscillators, collapses the other into a cat state of tunable size.

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.

α-Blockers, 5-α-Reductase Inhibitors, Acetylcholine, β3 Agonists, and Phosphodiesterase-5s in Medical Management of Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia: How Much Do the Different Formulations Actually Matter in the Classes?

PubMed

Chughtai, Bilal; Thomas, Dominique; Kaplan, Steven

2016-08-01

Many monotherapies are currently available to clinically treat and alleviate symptoms of lower urinary tract symptoms secondary to benign prostatic hyperplasia: α-blockers, 5ARIs, PDE5Is, β-3-andrenoceptor agonists, and anticholinergic agents. Current studies have evaluated the effective of these treatments in comparison to other groups or in combination therapies. The current review evaluates the effectiveness of class formulations. Based on the findings, α-blockers, specifically doxazosin and terazosin, were most effective in reducing IPSS scores and peak urinary flow rate, while being most cost-effective. However, further clinical investigations are required to evaluate the clinical implications of different formulations. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed

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

2013-10-01

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

Non-linear duality invariant partially massless models?

DOE PAGES

Cherney, D.; Deser, S.; Waldron, A.; ...

2015-12-15

We present manifestly duality invariant, non-linear, equations of motion for maximal depth, partially massless higher spins. These are based on a first order, Maxwell-like formulation of the known partially massless systems. Lastly, our models mimic Dirac–Born–Infeld theory but it is unclear whether they are Lagrangian.

Computation of Nonlinear Hydrodynamic Loads on Floating Wind Turbines Using Fluid-Impulse Theory: Preprint

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

Kok Yan Chan, G.; Sclavounos, P. D.; Jonkman, J.

2015-04-02

A hydrodynamics computer module was developed for the evaluation of the linear and nonlinear loads on floating wind turbines using a new fluid-impulse formulation for coupling with the FAST program. The recently developed formulation allows the computation of linear and nonlinear loads on floating bodies in the time domain and avoids the computationally intensive evaluation of temporal and nonlinear free-surface problems and efficient methods are derived for its computation. The body instantaneous wetted surface is approximated by a panel mesh and the discretization of the free surface is circumvented by using the Green function. The evaluation of the nonlinear loadsmore » is based on explicit expressions derived by the fluid-impulse theory, which can be computed efficiently. Computations are presented of the linear and nonlinear loads on the MIT/NREL tension-leg platform. Comparisons were carried out with frequency-domain linear and second-order methods. Emphasis was placed on modeling accuracy of the magnitude of nonlinear low- and high-frequency wave loads in a sea state. Although fluid-impulse theory is applied to floating wind turbines in this paper, the theory is applicable to other offshore platforms as well.« less

Formulation and Application of the Generalized Multilevel Facets Model

ERIC Educational Resources Information Center

Wang, Wen-Chung; Liu, Chih-Yu

2007-01-01

In this study, the authors develop a generalized multilevel facets model, which is not only a multilevel and two-parameter generalization of the facets model, but also a multilevel and facet generalization of the generalized partial credit model. Because the new model is formulated within a framework of nonlinear mixed models, no efforts are…

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 homotopy analysis method for the option pricing PDE in illiquid markets

NASA Astrophysics Data System (ADS)

E-Khatib, Youssef

2012-09-01

One of the shortcomings of the Black and Scholes model on option pricing is the assumption that trading the underlying asset does not affect the underlying asset price. This can happen in perfectly liquid markets and it is evidently not viable in markets with imperfect liquidity (illiquid markets). It is well-known that markets with imperfect liquidity are more realistic. Thus, the presence of price impact while studying options is very important. This paper investigates a solution for the option pricing PDE in illiquid markets using the homotopy analysis method.

On the origin of dual Lax pairs and their r-matrix structure

NASA Astrophysics Data System (ADS)

Avan, Jean; Caudrelier, Vincent

2017-10-01

We establish the algebraic origin of the following observations made previously by the authors and coworkers: (i) A given integrable PDE in 1 + 1 dimensions within the Zakharov-Shabat scheme related to a Lax pair can be cast in two distinct, dual Hamiltonian formulations; (ii) Associated to each formulation is a Poisson bracket and a phase space (which are not compatible in the sense of Magri); (iii) Each matrix in the Lax pair satisfies a linear Poisson algebra a la Sklyanin characterized by the same classical r matrix. We develop the general concept of dual Lax pairs and dual Hamiltonian formulation of an integrable field theory. We elucidate the origin of the common r-matrix structure by tracing it back to a single Lie-Poisson bracket on a suitable coadjoint orbit of the loop algebra sl(2 , C) ⊗ C(λ ,λ-1) . The results are illustrated with the examples of the nonlinear Schrödinger and Gerdjikov-Ivanov hierarchies.

A methodology for designing robust multivariable nonlinear control systems. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Grunberg, D. B.

1986-01-01

A new methodology is described for the design of nonlinear dynamic controllers for nonlinear multivariable systems providing guarantees of closed-loop stability, performance, and robustness. The methodology is an extension of the Linear-Quadratic-Gaussian with Loop-Transfer-Recovery (LQG/LTR) methodology for linear systems, thus hinging upon the idea of constructing an approximate inverse operator for the plant. A major feature of the methodology is a unification of both the state-space and input-output formulations. In addition, new results on stability theory, nonlinear state estimation, and optimal nonlinear regulator theory are presented, including the guaranteed global properties of the extended Kalman filter and optimal nonlinear regulators.

Hamiltonian formulation of systems with balanced loss-gain and exactly solvable models

NASA Astrophysics Data System (ADS)

Ghosh, Pijush K.; Sinha, Debdeep

2018-01-01

A Hamiltonian formulation of generic many-body systems with balanced loss and gain is presented. It is shown that a Hamiltonian formulation is possible only if the balancing of loss and gain terms occurs in a pairwise fashion. It is also shown that with the choice of a suitable co-ordinate, the Hamiltonian can always be reformulated in the background of a pseudo-Euclidean metric. If the equations of motion of some of the well-known many-body systems like Calogero models are generalized to include balanced loss and gain, it appears that the same may not be amenable to a Hamiltonian formulation. A few exactly solvable systems with balanced loss and gain, along with a set of integrals of motion are constructed. The examples include a coupled chain of nonlinear oscillators and a many-particle Calogero-type model with four-body inverse square plus two-body pair-wise harmonic interactions. For the case of nonlinear oscillators, stable solution exists even if the loss and gain parameter has unbounded upper range. Further, the range of the parameter for which the stable solutions are obtained is independent of the total number of the oscillators. The set of coupled nonlinear equations are solved exactly for the case when the values of all the constants of motions except the Hamiltonian are equal to zero. Exact, analytical classical solutions are presented for all the examples considered.

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.

Inversion of geothermal heat flux in a thermomechanically coupled nonlinear Stokes ice sheet model

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

Zhu, Hongyu; Petra, Noemi; Stadler, Georg

We address the inverse problem of inferring the basal geothermal heat flux from surface velocity observations using a steady-state thermomechanically coupled nonlinear Stokes ice flow model. This is a challenging inverse problem since the map from basal heat flux to surface velocity observables is indirect: the heat flux is a boundary condition for the thermal advection–diffusion equation, which couples to the nonlinear Stokes ice flow equations; together they determine the surface ice flow velocity. This multiphysics inverse problem is formulated as a nonlinear least-squares optimization problem with a cost functional that includes the data misfit between surface velocity observations andmore » model predictions. A Tikhonov regularization term is added to render the problem well posed. We derive adjoint-based gradient and Hessian expressions for the resulting partial differential equation (PDE)-constrained optimization problem and propose an inexact Newton method for its solution. As a consequence of the Petrov–Galerkin discretization of the energy equation, we show that discretization and differentiation do not commute; that is, the order in which we discretize the cost functional and differentiate it affects the correctness of the gradient. Using two- and three-dimensional model problems, we study the prospects for and limitations of the inference of the geothermal heat flux field from surface velocity observations. The results show that the reconstruction improves as the noise level in the observations decreases and that short-wavelength variations in the geothermal heat flux are difficult to recover. We analyze the ill-posedness of the inverse problem as a function of the number of observations by examining the spectrum of the Hessian of the cost functional. Motivated by the popularity of operator-split or staggered solvers for forward multiphysics problems – i.e., those that drop two-way coupling terms to yield a one-way coupled forward Jacobian �

Inversion of geothermal heat flux in a thermomechanically coupled nonlinear Stokes ice sheet model

DOE PAGES

Zhu, Hongyu; Petra, Noemi; Stadler, Georg; ...

2016-07-13

We address the inverse problem of inferring the basal geothermal heat flux from surface velocity observations using a steady-state thermomechanically coupled nonlinear Stokes ice flow model. This is a challenging inverse problem since the map from basal heat flux to surface velocity observables is indirect: the heat flux is a boundary condition for the thermal advection–diffusion equation, which couples to the nonlinear Stokes ice flow equations; together they determine the surface ice flow velocity. This multiphysics inverse problem is formulated as a nonlinear least-squares optimization problem with a cost functional that includes the data misfit between surface velocity observations andmore » model predictions. A Tikhonov regularization term is added to render the problem well posed. We derive adjoint-based gradient and Hessian expressions for the resulting partial differential equation (PDE)-constrained optimization problem and propose an inexact Newton method for its solution. As a consequence of the Petrov–Galerkin discretization of the energy equation, we show that discretization and differentiation do not commute; that is, the order in which we discretize the cost functional and differentiate it affects the correctness of the gradient. Using two- and three-dimensional model problems, we study the prospects for and limitations of the inference of the geothermal heat flux field from surface velocity observations. The results show that the reconstruction improves as the noise level in the observations decreases and that short-wavelength variations in the geothermal heat flux are difficult to recover. We analyze the ill-posedness of the inverse problem as a function of the number of observations by examining the spectrum of the Hessian of the cost functional. Motivated by the popularity of operator-split or staggered solvers for forward multiphysics problems – i.e., those that drop two-way coupling terms to yield a one-way coupled forward Jacobian �

Inversion of geothermal heat flux in a thermomechanically coupled nonlinear Stokes ice sheet model

NASA Astrophysics Data System (ADS)

Zhu, Hongyu; Petra, Noemi; Stadler, Georg; Isaac, Tobin; Hughes, Thomas J. R.; Ghattas, Omar

2016-07-01

We address the inverse problem of inferring the basal geothermal heat flux from surface velocity observations using a steady-state thermomechanically coupled nonlinear Stokes ice flow model. This is a challenging inverse problem since the map from basal heat flux to surface velocity observables is indirect: the heat flux is a boundary condition for the thermal advection-diffusion equation, which couples to the nonlinear Stokes ice flow equations; together they determine the surface ice flow velocity. This multiphysics inverse problem is formulated as a nonlinear least-squares optimization problem with a cost functional that includes the data misfit between surface velocity observations and model predictions. A Tikhonov regularization term is added to render the problem well posed. We derive adjoint-based gradient and Hessian expressions for the resulting partial differential equation (PDE)-constrained optimization problem and propose an inexact Newton method for its solution. As a consequence of the Petrov-Galerkin discretization of the energy equation, we show that discretization and differentiation do not commute; that is, the order in which we discretize the cost functional and differentiate it affects the correctness of the gradient. Using two- and three-dimensional model problems, we study the prospects for and limitations of the inference of the geothermal heat flux field from surface velocity observations. The results show that the reconstruction improves as the noise level in the observations decreases and that short-wavelength variations in the geothermal heat flux are difficult to recover. We analyze the ill-posedness of the inverse problem as a function of the number of observations by examining the spectrum of the Hessian of the cost functional. Motivated by the popularity of operator-split or staggered solvers for forward multiphysics problems - i.e., those that drop two-way coupling terms to yield a one-way coupled forward Jacobian - we study the

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

A conservative numerical scheme for modeling nonlinear acoustic propagation in thermoviscous homogeneous media

NASA Astrophysics Data System (ADS)

Diaz, Manuel A.; Solovchuk, Maxim A.; Sheu, Tony W. H.

2018-06-01

A nonlinear system of partial differential equations capable of describing the nonlinear propagation and attenuation of finite amplitude perturbations in thermoviscous media is presented. This system constitutes a full nonlinear wave model that has been formulated in the conservation form. Initially, this model is investigated analytically in the inviscid limit where it has been found that the resulting flux function fulfills the Lax-Wendroff theorem, and the scheme can match the solutions of the Westervelt and Burgers equations numerically. Here, high-order numerical descriptions of strongly nonlinear wave propagations become of great interest. For that matter we consider finite difference formulations of the weighted essentially non-oscillatory (WENO) schemes associated with explicit strong stability preserving Runge-Kutta (SSP-RK) time integration methods. Although this strategy is known to be computationally demanding, it is found to be effective when implemented to be solved in graphical processing units (GPUs). As we consider wave propagations in unbounded domains, perfectly matching layers (PML) have been also considered in this work. The proposed system model is validated and illustrated by using one- and two-dimensional benchmark test cases proposed in the literature for nonlinear acoustic propagation in homogeneous thermoviscous media.

Formulation of the aeroelastic stability and response problem of coupled rotor/support systems

NASA Technical Reports Server (NTRS)

Warmbrodt, W.; Friedmann, P.

1979-01-01

The consistent formulation of the governing nonlinear equations of motion for a coupled rotor/support system is presented. Rotor/support coupling is clearly documented by enforcing dynamic equilibrium between the rotor and the moving flexible support. The nonlinear periodic coefficient equations of motion are applicable to both coupled rotor/fuselage aeroelastic problems of helicopters in hover or forward flight and coupled rotor/tower dynamics of a large horizontal axis wind turbine (HAWT). Finally, the equations of motion are used to study the influence of flexible supports and nonlinear terms on rotor aeroelastic stability and response of a large two-bladed HAWT.

On the design of experiments for determining ternary mixture free energies from static light scattering data using a nonlinear partial differential equation

PubMed Central

Wahle, Chris W.; Ross, David S.; Thurston, George M.

2012-01-01

We mathematically design sets of static light scattering experiments to provide for model-independent measurements of ternary liquid mixing free energies to a desired level of accuracy. A parabolic partial differential equation (PDE), linearized from the full nonlinear PDE [D. Ross, G. Thurston, and C. Lutzer, J. Chem. Phys. 129, 064106 (2008)10.1063/1.2937902], describes how data noise affects the free energies to be inferred. The linearized PDE creates a net of spacelike characteristic curves and orthogonal, timelike curves in the composition triangle, and this net governs diffusion of information coming from light scattering measurements to the free energy. Free energy perturbations induced by a light scattering perturbation diffuse along the characteristic curves and towards their concave sides, with a diffusivity that is proportional to the local characteristic curvature radius. Consequently, static light scattering can determine mixing free energies in regions with convex characteristic curve boundaries, given suitable boundary data. The dielectric coefficient is a Lyapunov function for the dynamical system whose trajectories are PDE characteristics. Information diffusion is heterogeneous and system-dependent in the composition triangle, since the characteristics depend on molecular interactions and are tangent to liquid-liquid phase separation coexistence loci at critical points. We find scaling relations that link free energy accuracy, total measurement time, the number of samples, and the interpolation method, and identify the key quantitative tradeoffs between devoting time to measuring more samples, or fewer samples more accurately. For each total measurement time there are optimal sample numbers beyond which more will not improve free energy accuracy. We estimate the degree to which many-point interpolation and optimized measurement concentrations can improve accuracy and save time. For a modest light scattering setup, a sample calculation shows that

Formulation of the relativistic moment implicit particle-in-cell method

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

Noguchi, Koichi; Tronci, Cesare; Zuccaro, Gianluca

2007-04-15

A new formulation is presented for the implicit moment method applied to the time-dependent relativistic Vlasov-Maxwell system. The new approach is based on a specific formulation of the implicit moment method that allows us to retain the same formalism that is valid in the classical case despite the formidable complication introduced by the nonlinear nature of the relativistic equations of motion. To demonstrate the validity of the new formulation, an implicit finite difference algorithm is developed to solve the Maxwell's equations and equations of motion. A number of benchmark problems are run: two stream instability, ion acoustic wave damping, Weibelmore » instability, and Poynting flux acceleration. The numerical results are all in agreement with analytical solutions.« less

Nonlinear Transient Problems Using Structure Compatible Heat Transfer Code

NASA Technical Reports Server (NTRS)

Hou, Gene

2000-01-01

The report documents the recent effort to enhance a transient linear heat transfer code so as to solve nonlinear problems. The linear heat transfer code was originally developed by Dr. Kim Bey of NASA Largely and called the Structure-Compatible Heat Transfer (SCHT) code. The report includes four parts. The first part outlines the formulation of the heat transfer problem of concern. The second and the third parts give detailed procedures to construct the nonlinear finite element equations and the required Jacobian matrices for the nonlinear iterative method, Newton-Raphson method. The final part summarizes the results of the numerical experiments on the newly enhanced SCHT code.

Nonlinear surface waves at ferrite-metamaterial waveguide structure

NASA Astrophysics Data System (ADS)

Hissi, Nour El Houda; Mokhtari, Bouchra; Eddeqaqi, Noureddine Cherkaoui; Shabat, Mohammed Musa; Atangana, Jacques

2016-09-01

A new ferrite slab made of a metamaterial (MTM), surrounded by a nonlinear cover cladding and a ferrite substrate, was shown to support unusual types of electromagnetic surface waves. We impose the boundary conditions to derive the dispersion relation and others necessary to formulate the proposed structure. We analyse the dispersion properties of the nonlinear surface waves and we calculate the associated propagation index and the film-cover interface nonlinearity. In the calculation, several sets of the permeability of the MTM are considered. Results show that the waves behaviour depends on the values of the permeability of the MTM, the thickness of the waveguide and the film-cover interface nonlinearity. It is also shown that the use of the singular solutions to the electric field equation allows to identify several new properties of surface waves which do not exist in conventional waveguide.

Geometrically Nonlinear Finite Element Analysis of a Composite Space Reflector

NASA Technical Reports Server (NTRS)

Lee, Kee-Joo; Leet, Sung W.; Clark, Greg; Broduer, Steve (Technical Monitor)

2001-01-01

Lightweight aerospace structures, such as low areal density composite space reflectors, are highly flexible and may undergo large deflection under applied loading, especially during the launch phase. Accordingly, geometrically nonlinear analysis that takes into account the effect of finite rotation may be needed to determine the deformed shape for a clearance check and the stress and strain state to ensure structural integrity. In this study, deformation of the space reflector is determined under static conditions using a geometrically nonlinear solid shell finite element model. For the solid shell element formulation, the kinematics of deformation is described by six variables that are purely vector components. Because rotational angles are not used, this approach is free of the limitations of small angle increments. This also allows easy connections between substructures and large load increments with respect to the conventional shell formulation using rotational parameters. Geometrically nonlinear analyses were carried out for three cases of static point loads applied at selected points. A chart shows results for a case when the load is applied at the center point of the reflector dish. The computed results capture the nonlinear behavior of the composite reflector as the applied load increases. Also, they are in good agreement with the data obtained by experiments.

Mixed formulation for frictionless contact problems

NASA Technical Reports Server (NTRS)

Noor, Ahmed K.; Kim, Kyun O.

1989-01-01

Simple mixed finite element models and a computational precedure are presented for the solution of frictionless contact problems. The analytical formulation is based on a form of Reissner's large rotation theory of the structure with the effects of transverse shear deformation included. The contact conditions are incorporated into the formulation by using a perturbed Lagrangian approach with the fundamental unknowns consisting of the internal forces (stress resultants), the generalized displacements, and the Lagrange multipliers associated with the contact conditions. The element characteristic array are obtained by using a modified form of the two-field Hellinger-Reissner mixed variational principle. The internal forces and the Lagrange multipliers are allowed to be discontinuous at interelement boundaries. The Newton-Raphson iterative scheme is used for the solution of the nonlinear algebraic equations, and the determination of the contact area and the contact pressures.

Multiscale Approach For Simulating Nonlinear Wave Propagation In Materials with Localized Microdamage

NASA Astrophysics Data System (ADS)

Vanaverbeke, Sigfried; Van Den Abeele, Koen

2006-05-01

A multiscale model for the simulation of two-dimensional nonlinear wave propagation in microcracked materials exhibiting hysteretic nonlinearity is presented. We use trigger-like elements with a two state nonlinear stress-strain relation to simulate microcracks at the microlevel. A generalized Preisach space approach, based on the eigenstress-eigenstrain formulation, upscales the microscopic state relation to the mesoscopic level. The macroscopic response of the sample to an arbitrary excitation signal is then predicted using a staggered grid Elastodynamic Finite Integration Technique (EFIT) formalism. We apply the model to investigate spectral changes of a pulsed signal traversing a localized microdamaged region with hysteretic nonlinearity in a plate, and to study the influence of a superficial region with hysteretic nonlinearity on the nonlinear Rayleigh wave propagation.

Nonlinear standing wave excitation by series resonance-enhanced harmonics in low pressure capacitive discharges

NASA Astrophysics Data System (ADS)

Lieberman, M. A.; Lichtenberg, A. J.; Kawamura, Emi; Marakhtanov, A. M.

2015-09-01

It is well known that standing waves having radially center-high rf voltage profiles exist in high frequency capacitive discharges. It is also known that in radially uniform discharges, the capacitive sheath nonlinearities excite strong nonlinear series resonance harmonics that enhance the electron power deposition. In this work, we consider the coupling of the series resonance-enhanced harmonics to the standing waves. A one-dimensional, asymmetric radial transmission line model is developed incorporating the wave and nonlinear sheath physics and a self-consistent dc potential. The resulting coupled pde equation set is solved numerically to determine the discharge voltages and currents. A 10 mT argon base case is chosen with plasma density 2 ×1016 m-3, gap width 2 cm and conducting electrode radius 15 cm, driven by a high frequency 500 V source with source resistance 0.5 ohms. We find that nearby resonances lead to an enhanced ratio of 4.5 of the electron power per unit area on axis, compared to the average. The radial dependence of electron power with frequency shows significant variations, with the central enhancement and sharpness of the spatial resonances depending in a complicated way on the harmonic structure. Work supported by DOE Fusion Energy Science Contract DE-SC000193 and by a gift from the Lam Research Corporation.

The effect of isoenzyme-selective PDE inhibitors on methacholine-induced contraction of guinea-pig and rat ileum.

PubMed Central

Tomkinson, A.; Raeburn, D.

1996-01-01

1. We have examined the effects of the isoenzyme-selective phosphodiesterase (PDE) inhibitors, vinpocetine (type 1), siguazodan (type 3), rolipram (type 4) and zaprinast (type 5) and the non-selective PDE inhibitor enprofylline on methacholine (MCh) contractile concentration-response curves on guinea-pig and rat isolated ileum. 2. In guinea-pig ileum, vinpocetine (10-300 microM), zaprinast (1-300 microM) and enprofylline (100-1000 microM) produced a concentration-dependent depression of the maximum response (Emax) to MCh only without effect on the MCh EC50 values (rank order of potency: zaprinast > vinpocetine > enprofylline). In contrast, siguazodan (10-300 microM) and rolipram (10-300 microM) produced a rightward displacement of the MCh concentration-response curve (increase in EC50: rank order; rolipram > siguazodan), with effects on the MCh maximum seen only at higher concentrations. 3. In the rat ileum, vinpocetine (10-300 microM), zaprinast (0.1-300 microM) and enprofylline (100-1000 microM) caused depression of the MCh maximum contraction (rank order: zaprinast > vinpocetine > enprofylline). Low concentrations of rolipram and siguazodan had no significant effect on the MCh maximum. In the presence of higher concentrations (> 100 microM) of rolipram and siguazodan, a maximum response was not achieved at the highest concentration of MCh tested. As in the guinea-pig ileum, only rolipram (10-300 microM) and siguazodan (10-300 microM) produced a significant, concentration-dependent, rightward displacement of the MCh concentration-response curve (increase in EC50: rank order: rolipram > siguazodan). 4. In the guinea-pig ileum, isoprenaline (0.1 microM) produced a rightward displacement (approximately 3 fold) of the MCh concentration-response curve, accompanied by a significant depression of the maximum response. Increasing the isoprenaline concentration (1 microM) had no further effect on either parameter. Sodium nitroprusside (SNP, > or = 10 microM) produced a

Step-response of a torsional device with multiple discontinuous non-linearities: Formulation of a vibratory experiment

NASA Astrophysics Data System (ADS)

Krak, Michael D.; Dreyer, Jason T.; Singh, Rajendra

2016-03-01

A vehicle clutch damper is intentionally designed to contain multiple discontinuous non-linearities, such as multi-staged springs, clearances, pre-loads, and multi-staged friction elements. The main purpose of this practical torsional device is to transmit a wide range of torque while isolating torsional vibration between an engine and transmission. Improved understanding of the dynamic behavior of the device could be facilitated by laboratory measurement, and thus a refined vibratory experiment is proposed. The experiment is conceptually described as a single degree of freedom non-linear torsional system that is excited by an external step torque. The single torsional inertia (consisting of a shaft and torsion arm) is coupled to ground through parallel production clutch dampers, which are characterized by quasi-static measurements provided by the manufacturer. Other experimental objectives address physical dimensions, system actuation, flexural modes, instrumentation, and signal processing issues. Typical measurements show that the step response of the device is characterized by three distinct non-linear regimes (double-sided impact, single-sided impact, and no-impact). Each regime is directly related to the non-linear features of the device and can be described by peak angular acceleration values. Predictions of a simplified single degree of freedom non-linear model verify that the experiment performs well and as designed. Accordingly, the benchmark measurements could be utilized to validate non-linear models and simulation codes, as well as characterize dynamic parameters of the device including its dissipative properties.

Non-linear analytic and coanalytic problems ( L_p-theory, Clifford analysis, examples)

NASA Astrophysics Data System (ADS)

Dubinskii, Yu A.; Osipenko, A. S.

2000-02-01

Two kinds of new mathematical model of variational type are put forward: non-linear analytic and coanalytic problems. The formulation of these non-linear boundary-value problems is based on a decomposition of the complete scale of Sobolev spaces into the "orthogonal" sum of analytic and coanalytic subspaces. A similar decomposition is considered in the framework of Clifford analysis. Explicit examples are presented.

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.

Aeroelastic modeling of rotor blades with spanwise variable elastic axis offset: Classic issues revisited and new formulations

NASA Technical Reports Server (NTRS)

Bielawa, Richard L.

1988-01-01

In response to a systematic methodology assessment program directed to the aeroelastic stability of hingeless helicopter rotor blades, improved basic aeroelastic reformulations and new formulations relating to structural sweep were achieved. Correlational results are presented showing the substantially improved performance of the G400 aeroelastic analysis incorporating these new formulations. The formulations pertain partly to sundry solutions to classic problem areas, relating to dynamic inflow with vortex-ring state operation and basic blade kinematics, but mostly to improved physical modeling of elastic axis offset (structural sweep) in the presence of nonlinear structural twist. Specific issues addressed are an alternate modeling of the delta EI torsional excitation due to compound bending using a force integration approach, and the detailed kinematic representation of an elastically deflected point mass of a beam with both structural sweep and nonlinear twist.

Stiffness optimization of non-linear elastic structures

DOE PAGES

Wallin, Mathias; Ivarsson, Niklas; Tortorelli, Daniel

2017-11-13

Our paper revisits stiffness optimization of non-linear elastic structures. Due to the non-linearity, several possible stiffness measures can be identified and in this work conventional compliance, i.e. secant stiffness designs are compared to tangent stiffness designs. The optimization problem is solved by the method of moving asymptotes and the sensitivities are calculated using the adjoint method. And for the tangent cost function it is shown that although the objective involves the third derivative of the strain energy an efficient formulation for calculating the sensitivity can be obtained. Loss of convergence due to large deformations in void regions is addressed bymore » using a fictitious strain energy such that small strain linear elasticity is approached in the void regions. We formulate a well-posed topology optimization problem by using restriction which is achieved via a Helmholtz type filter. The numerical examples provided show that for low load levels, the designs obtained from the different stiffness measures coincide whereas for large deformations significant differences are observed.« less

Stiffness optimization of non-linear elastic structures

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

Wallin, Mathias; Ivarsson, Niklas; Tortorelli, Daniel

Our paper revisits stiffness optimization of non-linear elastic structures. Due to the non-linearity, several possible stiffness measures can be identified and in this work conventional compliance, i.e. secant stiffness designs are compared to tangent stiffness designs. The optimization problem is solved by the method of moving asymptotes and the sensitivities are calculated using the adjoint method. And for the tangent cost function it is shown that although the objective involves the third derivative of the strain energy an efficient formulation for calculating the sensitivity can be obtained. Loss of convergence due to large deformations in void regions is addressed bymore » using a fictitious strain energy such that small strain linear elasticity is approached in the void regions. We formulate a well-posed topology optimization problem by using restriction which is achieved via a Helmholtz type filter. The numerical examples provided show that for low load levels, the designs obtained from the different stiffness measures coincide whereas for large deformations significant differences are observed.« less

Linear and Non-Linear Piezoresistance Coefficients in Cubic Semiconductors. I. Theoretical Formulations

NASA Astrophysics Data System (ADS)

Durand, S.; Tellier, C. R.

1996-02-01

This paper constitutes the first part of a work devoted to applications of piezoresistance effects in germanium and silicon semiconductors. In this part, emphasis is placed on a formal explanation of non-linear effects. We propose a brief phenomenological description based on the multi-valleys model of semiconductors before to adopt a macroscopic tensorial model from which general analytical expressions for primed non-linear piezoresistance coefficients are derived. Graphical representations of linear and non-linear piezoresistance coefficients allows us to characterize the influence of the two angles of cut and of directions of alignment. The second part will primarily deal with specific applications for piezoresistive sensors. Cette publication constitue la première partie d'un travail consacré aux applications des effets piézorésistifs dans les semiconducteurs germanium et silicium. Cette partie traite essentiellement de la modélisation des effets non-linéaires. Après une description phénoménologique à partir du modèle de bande des semiconducteurs nous développons un modèle tensoriel macroscopique et nous proposons des équations générales analytiques exprimant les coefficients piézorésistifs non-linéaires dans des repères tournés. Des représentations graphiques des variations des coefficients piézorésistifs linéaires et non-linéaires permettent une pré-caractérisation de l'influence des angles de coupes et des directions d'alignement avant l'étude d'applications spécifiques qui feront l'objet de la deuxième partie.

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

PubMed

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

2018-03-01

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

New envelope solitons for Gerdjikov-Ivanov model in nonlinear fiber optics

NASA Astrophysics Data System (ADS)

Triki, Houria; Alqahtani, Rubayyi T.; Zhou, Qin; Biswas, Anjan

2017-11-01

Exact soliton solutions in a class of derivative nonlinear Schrödinger equations including a pure quintic nonlinearity are investigated. By means of the coupled amplitude-phase formulation, we derive a nonlinear differential equation describing the evolution of the wave amplitude in the non-Kerr quintic media. The resulting amplitude equation is then solved to get exact analytical chirped bright, kink, antikink, and singular soliton solutions for the model. It is also shown that the nonlinear chirp associated with these solitons is crucially dependent on the wave intensity and related to self-steepening and group velocity dispersion parameters. Parametric conditions on physical parameters for the existence of chirped solitons are also presented. These localized structures exist due to a balance among quintic nonlinearity, group velocity dispersion, and self-steepening effects.

Entropy-Based Approach To Nonlinear Stability

NASA Technical Reports Server (NTRS)

Merriam, Marshal L.

1991-01-01

NASA technical memorandum suggests schemes for numerical solution of differential equations of flow made more accurate and robust by invoking second law of thermodynamics. Proposes instead of using artificial viscosity to suppress such unphysical solutions as spurious numerical oscillations and nonlinear instabilities, one should formulate equations so that rate of production of entropy within each cell of computational grid be nonnegative, as required by second law.

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

A Thermodynamic Theory of Solid Viscoelasticity. Part 3: Nonlinear Glassy Viscoelasticity, Stability Constraints, Specifications

NASA Technical Reports Server (NTRS)

Freed, Alan; Leonov, Arkady I.

2002-01-01

This paper, the last in the series, continues developing the nonlinear constitutive relations for non-isothermal, compressible, solid viscoelasticity. We initially discuss a single integral approach, more suitable for the glassy state of rubber-like materials, with basic functionals involved in the thermodynamic description for this type of viscoelasticity. Then we switch our attention to analyzing stability constraints, imposed on the general formulation of the nonlinear theory of solid viscoelasticity. Finally, we discuss specific (known from the literature or new) expressions for material functions that are involved in the constitutive formulations of both the rubber-like and glassy-like, complementary parts of the theory.

New formulations for tsunami runup estimation

NASA Astrophysics Data System (ADS)

Kanoglu, U.; Aydin, B.; Ceylan, N.

2017-12-01

We evaluate shoreline motion and maximum runup in two folds: One, we use linear shallow water-wave equations over a sloping beach and solve as initial-boundary value problem similar to the nonlinear solution of Aydın and Kanoglu (2017, Pure Appl. Geophys., https://doi.org/10.1007/s00024-017-1508-z). Methodology we present here is simple; it involves eigenfunction expansion and, hence, avoids integral transform techniques. We then use several different types of initial wave profiles with and without initial velocity, estimate shoreline properties and confirm classical runup invariance between linear and nonlinear theories. Two, we use the nonlinear shallow water-wave solution of Kanoglu (2004, J. Fluid Mech. 513, 363-372) to estimate maximum runup. Kanoglu (2004) presented a simple integral solution for the nonlinear shallow water-wave equations using the classical Carrier and Greenspan transformation, and further extended shoreline position and velocity to a simpler integral formulation. In addition, Tinti and Tonini (2005, J. Fluid Mech. 535, 33-64) defined initial condition in a very convenient form for near-shore events. We use Tinti and Tonini (2005) type initial condition in Kanoglu's (2004) shoreline integral solution, which leads further simplified estimates for shoreline position and velocity, i.e. algebraic relation. We then use this algebraic runup estimate to investigate effect of earthquake source parameters on maximum runup and present results similar to Sepulveda and Liu (2016, Coast. Eng. 112, 57-68).

Probabilistic density function method for nonlinear dynamical systems driven by colored noise

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

Barajas-Solano, David A.; Tartakovsky, Alexandre M.

2016-05-01

We present a probability density function (PDF) method for a system of nonlinear stochastic ordinary differential equations driven by colored noise. The method provides an integro-differential equation for the temporal evolution of the joint PDF of the system's state, which we close by means of a modified Large-Eddy-Diffusivity-type closure. Additionally, we introduce the generalized local linearization (LL) approximation for deriving a computable PDF equation in the form of the second-order partial differential equation (PDE). We demonstrate the proposed closure and localization accurately describe the dynamics of the PDF in phase space for systems driven by noise with arbitrary auto-correlation time.more » We apply the proposed PDF method to the analysis of a set of Kramers equations driven by exponentially auto-correlated Gaussian colored noise to study the dynamics and stability of a power grid.« less

Non-linear analysis of wave progagation using transform methods and plates and shells using integral equations

NASA Astrophysics Data System (ADS)

Pipkins, Daniel Scott

Two diverse topics of relevance in modern computational mechanics are treated. The first involves the modeling of linear and non-linear wave propagation in flexible, lattice structures. The technique used combines the Laplace Transform with the Finite Element Method (FEM). The procedure is to transform the governing differential equations and boundary conditions into the transform domain where the FEM formulation is carried out. For linear problems, the transformed differential equations can be solved exactly, hence the method is exact. As a result, each member of the lattice structure is modeled using only one element. In the non-linear problem, the method is no longer exact. The approximation introduced is a spatial discretization of the transformed non-linear terms. The non-linear terms are represented in the transform domain by making use of the complex convolution theorem. A weak formulation of the resulting transformed non-linear equations yields a set of element level matrix equations. The trial and test functions used in the weak formulation correspond to the exact solution of the linear part of the transformed governing differential equation. Numerical results are presented for both linear and non-linear systems. The linear systems modeled are longitudinal and torsional rods and Bernoulli-Euler and Timoshenko beams. For non-linear systems, a viscoelastic rod and Von Karman type beam are modeled. The second topic is the analysis of plates and shallow shells under-going finite deflections by the Field/Boundary Element Method. Numerical results are presented for two plate problems. The first is the bifurcation problem associated with a square plate having free boundaries which is loaded by four, self equilibrating corner forces. The results are compared to two existing numerical solutions of the problem which differ substantially. non-linear model are compared to those

Consistent nonlinear deterministic and stochastic evolution equations for deep to shallow water wave shoaling

NASA Astrophysics Data System (ADS)

Vrecica, Teodor; Toledo, Yaron

2015-04-01

One-dimensional deterministic and stochastic evolution equations are derived for the dispersive nonlinear waves while taking dissipation of energy into account. The deterministic nonlinear evolution equations are formulated using operational calculus by following the approach of Bredmose et al. (2005). Their formulation is extended to include the linear and nonlinear effects of wave dissipation due to friction and breaking. The resulting equation set describes the linear evolution of the velocity potential for each wave harmonic coupled by quadratic nonlinear terms. These terms describe the nonlinear interactions between triads of waves, which represent the leading-order nonlinear effects in the near-shore region. The equations are translated to the amplitudes of the surface elevation by using the approach of Agnon and Sheremet (1997) with the correction of Eldeberky and Madsen (1999). The only current possibility for calculating the surface gravity wave field over large domains is by using stochastic wave evolution models. Hence, the above deterministic model is formulated as a stochastic one using the method of Agnon and Sheremet (1997) with two types of stochastic closure relations (Benney and Saffman's, 1966, and Hollway's, 1980). These formulations cannot be applied to the common wave forecasting models without further manipulation, as they include a non-local wave shoaling coefficients (i.e., ones that require integration along the wave rays). Therefore, a localization method was applied (see Stiassnie and Drimer, 2006, and Toledo and Agnon, 2012). This process essentially extracts the local terms that constitute the mean nonlinear energy transfer while discarding the remaining oscillatory terms, which transfer energy back and forth. One of the main findings of this work is the understanding that the approximated non-local coefficients behave in two essentially different manners. In intermediate water depths these coefficients indeed consist of rapidly

SEACAS Theory Manuals: Part II. Nonlinear Continuum Mechanics

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

Attaway, S.W.; Laursen, T.A.; Zadoks, R.I.

1998-09-01

This report summarizes the key continuum mechanics concepts required for the systematic prescription and numerical solution of finite deformation solid mechanics problems. Topics surveyed include measures of deformation appropriate for media undergoing large deformations, stress measures appropriate for such problems, balance laws and their role in nonlinear continuum mechanics, the role of frame indifference in description of large deformation response, and the extension of these theories to encompass two dimensional idealizations, structural idealizations, and rigid body behavior. There are three companion reports that describe the problem formulation, constitutive modeling, and finite element technology for nonlinear continuum mechanics systems.

Relations between nonlinear Riccati equations and other equations in fundamental physics

NASA Astrophysics Data System (ADS)

Schuch, Dieter

2014-10-01

Many phenomena in the observable macroscopic world obey nonlinear evolution equations while the microscopic world is governed by quantum mechanics, a fundamental theory that is supposedly linear. In order to combine these two worlds in a common formalism, at least one of them must sacrifice one of its dogmas. Linearizing nonlinear dynamics would destroy the fundamental property of this theory, however, it can be shown that quantum mechanics can be reformulated in terms of nonlinear Riccati equations. In a first step, it will be shown that the information about the dynamics of quantum systems with analytical solutions can not only be obtainable from the time-dependent Schrödinger equation but equally-well from a complex Riccati equation. Comparison with supersymmetric quantum mechanics shows that even additional information can be obtained from the nonlinear formulation. Furthermore, the time-independent Schrödinger equation can also be rewritten as a complex Riccati equation for any potential. Extension of the Riccati formulation to include irreversible dissipative effects is straightforward. Via (real and complex) Riccati equations, other fields of physics can also be treated within the same formalism, e.g., statistical thermodynamics, nonlinear dynamical systems like those obeying a logistic equation as well as wave equations in classical optics, Bose- Einstein condensates and cosmological models. Finally, the link to abstract "quantizations" such as the Pythagorean triples and Riccati equations connected with trigonometric and hyperbolic functions will be shown.

Nonlocal and nonlinear electrostatics of a dipolar Coulomb fluid.

PubMed

Sahin, Buyukdagli; Ralf, Blossey

2014-07-16

We study a model Coulomb fluid consisting of dipolar solvent molecules of finite extent which generalizes the point-like dipolar Poisson-Boltzmann model (DPB) previously introduced by Coalson and Duncan (1996 J. Phys. Chem. 100 2612) and Abrashkin et al (2007 Phys. Rev. Lett. 99 077801). We formulate a nonlocal Poisson-Boltzmann equation (NLPB) and study both linear and nonlinear dielectric response in this model for the case of a single plane geometry. Our results shed light on the relevance of nonlocal versus nonlinear effects in continuum models of material electrostatics.

Numerical modelling of nonlinear full-wave acoustic propagation

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

Velasco-Segura, Roberto, E-mail: roberto.velasco@ccadet.unam.mx; Rendón, Pablo L., E-mail: pablo.rendon@ccadet.unam.mx

2015-10-28

The various model equations of nonlinear acoustics are arrived at by making assumptions which permit the observation of the interaction with propagation of either single or joint effects. We present here a form of the conservation equations of fluid dynamics which are deduced using slightly less restrictive hypothesis than those necessary to obtain the well known Westervelt equation. This formulation accounts for full wave diffraction, nonlinearity, and thermoviscous dissipative effects. A two-dimensional, finite-volume method using Roe’s linearisation has been implemented to obtain numerically the solution of the proposed equations. This code, which has been written for parallel execution on amore » GPU, can be used to describe moderate nonlinear phenomena, at low Mach numbers, in domains as large as 100 wave lengths. Applications range from models of diagnostic and therapeutic HIFU, to parametric acoustic arrays and nonlinear propagation in acoustic waveguides. Examples related to these applications are shown and discussed.« less

Online learning in optical tomography: a stochastic approach

NASA Astrophysics Data System (ADS)

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

2018-07-01

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

A note on the generation of phase plane plots on a digital computer. [for solution of nonlinear differential equations

NASA Technical Reports Server (NTRS)

Simon, M. K.

1980-01-01

A technique is presented for generating phase plane plots on a digital computer which circumvents the difficulties associated with more traditional methods of numerical solving nonlinear differential equations. In particular, the nonlinear differential equation of operation is formulated.

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

The effect of cilostazol, a phosphodiesterase 3 (PDE3) inhibitor, on human hair growth with the dual promoting mechanisms.

PubMed

Choi, Hye-In; Kim, Dong Young; Choi, Soon-Jin; Shin, Chang-Yup; Hwang, Sungjoo Tommy; Kim, Kyu Han; Kwon, Ohsang

2018-07-01

Cilostazol, a phosphodiesterase 3 (PDE3) inhibitor, increases the intracellular level of cyclic adenosine monophosphate to cause vasodilation. Topical application of cilostazol is reported to improve local blood flow and enhance wound healing; however, its effect on human hair follicles is unknown. The purpose of this study was to determine the effect of cilostazol on hair growth. We investigated the expression of PDE3 in human dermal papilla cells (DPCs), outer root sheath cells (ORSCs), and hair follicles. The effects of cilostazol on DPC and ORSC proliferation were evaluated using BrdU and WST-1 assays. The expression of various growth factors in DPCs was investigated by growth factor antibody array. Additionally, hair shaft elongation was measured using ex vivo hair follicle organ cultures, and anagen induction was evaluated in C57BL/6 mice. Finally, the effects of cilostazol on vessel formation and activation of the mitogen-activated protein kinase pathway were evaluated. We confirmed high mRNA and protein expression of PDE3 in human DPCs. Cilostazol not only enhanced the proliferation of human DPCs but also regulated the secretion of several growth factors responsible for hair growth. Furthermore, it promoted hair shaft elongation ex vivo, with increased proliferation of matrix keratinocytes. Cilostazol also accelerated anagen induction by stimulating vessel formation and upregulating the levels of phosphorylated extracellular signal-regulated kinase, c-Jun N-terminal kinase, and P38 after its topical application in C57BL/6 mice. Our results show that cilostazol promotes hair growth and may serve as a therapeutic agent for the treatment of alopecia. Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

An extended harmonic balance method based on incremental nonlinear control parameters

NASA Astrophysics Data System (ADS)

Khodaparast, Hamed Haddad; Madinei, Hadi; Friswell, Michael I.; Adhikari, Sondipon; Coggon, Simon; Cooper, Jonathan E.

2017-02-01

A new formulation for calculating the steady-state responses of multiple-degree-of-freedom (MDOF) non-linear dynamic systems due to harmonic excitation is developed. This is aimed at solving multi-dimensional nonlinear systems using linear equations. Nonlinearity is parameterised by a set of 'non-linear control parameters' such that the dynamic system is effectively linear for zero values of these parameters and nonlinearity increases with increasing values of these parameters. Two sets of linear equations which are formed from a first-order truncated Taylor series expansion are developed. The first set of linear equations provides the summation of sensitivities of linear system responses with respect to non-linear control parameters and the second set are recursive equations that use the previous responses to update the sensitivities. The obtained sensitivities of steady-state responses are then used to calculate the steady state responses of non-linear dynamic systems in an iterative process. The application and verification of the method are illustrated using a non-linear Micro-Electro-Mechanical System (MEMS) subject to a base harmonic excitation. The non-linear control parameters in these examples are the DC voltages that are applied to the electrodes of the MEMS devices.

SEACAS Theory Manuals: Part III. Finite Element Analysis in Nonlinear Solid Mechanics

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

Laursen, T.A.; Attaway, S.W.; Zadoks, R.I.

1999-03-01

This report outlines the application of finite element methodology to large deformation solid mechanics problems, detailing also some of the key technological issues that effective finite element formulations must address. The presentation is organized into three major portions: first, a discussion of finite element discretization from the global point of view, emphasizing the relationship between a virtual work principle and the associated fully discrete system, second, a discussion of finite element technology, emphasizing the important theoretical and practical features associated with an individual finite element; and third, detailed description of specific elements that enjoy widespread use, providing some examples ofmore » the theoretical ideas already described. Descriptions of problem formulation in nonlinear solid mechanics, nonlinear continuum mechanics, and constitutive modeling are given in three companion reports.« less

Clinical and hemodynamic improvements after adding ambrisentan to background PDE5i therapy in patients with pulmonary arterial hypertension exhibiting a suboptimal therapeutic response (ATHENA-1).

PubMed

Shapiro, Shelley; Torres, Fernando; Feldman, Jeremy; Keogh, Anne; Allard, Martine; Blair, Christiana; Gillies, Hunter; Tislow, James; Oudiz, Ronald J

2017-05-01

Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and premature death. While recent data supports the initial combination of ambrisentan (a selective ERA) and tadalafil (a PDE5i) in functional class II or III patients, there is no published data describing the safety and efficacy of ambrisentan when added to patients currently receiving a PDE5i and exhibiting a suboptimal response. The ATHENA-1 study describes the safety and efficacy of the addition of ambrisentan in this patient population. PAH patients with a suboptimal response to current PDE5i monotherapy were assigned ambrisentan in an open-label fashion and evaluated for up to 48 weeks. Cardiopulmonary hemodynamics (change in PVR as primary endpoint) were evaluated at week 24 and functional parameters and biomarkers were measured through week 48. Time to clinical worsening (TTCW) and survival are also described. Thirty-three subjects were included in the analysis. At week 24, statistically significant improvements in PVR (-32%), mPAP (-11%), and CI (+25%) were observed. Hemodynamic improvements at week 24 were further supported by improvements in the secondary endpoints: 6-min walk distance (+18 m), NT-proBNP (-31%), and maintenance or improvement in WHO FC in 97% of patients. Adverse events were consistent with known effects of ambrisentan. The hemodynamic, functional, and biomarker improvements observed in the ATHENA-1 study suggests that the sequential addition of ambrisentan to patients not having a satisfactory response to established PDE5i monotherapy is a reasonable option. Published by Elsevier Ltd.

Neural network robust tracking control with adaptive critic framework for uncertain nonlinear systems.

PubMed

Wang, Ding; Liu, Derong; Zhang, Yun; Li, Hongyi

2018-01-01

In this paper, we aim to tackle the neural robust tracking control problem for a class of nonlinear systems using the adaptive critic technique. The main contribution is that a neural-network-based robust tracking control scheme is established for nonlinear systems involving matched uncertainties. The augmented system considering the tracking error and the reference trajectory is formulated and then addressed under adaptive critic optimal control formulation, where the initial stabilizing controller is not needed. The approximate control law is derived via solving the Hamilton-Jacobi-Bellman equation related to the nominal augmented system, followed by closed-loop stability analysis. The robust tracking control performance is guaranteed theoretically via Lyapunov approach and also verified through simulation illustration. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Fast and Scalable Method for A-Optimal Design of Experiments for Infinite-dimensional Bayesian Nonlinear Inverse Problems with Application to Porous Medium Flow

NASA Astrophysics Data System (ADS)

Petra, N.; Alexanderian, A.; Stadler, G.; Ghattas, O.

2015-12-01

We address the problem of optimal experimental design (OED) for Bayesian nonlinear inverse problems governed by partial differential equations (PDEs). The inverse problem seeks to infer a parameter field (e.g., the log permeability field in a porous medium flow model problem) from synthetic observations at a set of sensor locations and from the governing PDEs. The goal of the OED problem is to find an optimal placement of sensors so as to minimize the uncertainty in the inferred parameter field. We formulate the OED objective function by generalizing the classical A-optimal experimental design criterion using the expected value of the trace of the posterior covariance. This expected value is computed through sample averaging over the set of likely experimental data. Due to the infinite-dimensional character of the parameter field, we seek an optimization method that solves the OED problem at a cost (measured in the number of forward PDE solves) that is independent of both the parameter and the sensor dimension. To facilitate this goal, we construct a Gaussian approximation to the posterior at the maximum a posteriori probability (MAP) point, and use the resulting covariance operator to define the OED objective function. We use randomized trace estimation to compute the trace of this covariance operator. The resulting OED problem includes as constraints the system of PDEs characterizing the MAP point, and the PDEs describing the action of the covariance (of the Gaussian approximation to the posterior) to vectors. We control the sparsity of the sensor configurations using sparsifying penalty functions, and solve the resulting penalized bilevel optimization problem via an interior-point quasi-Newton method, where gradient information is computed via adjoints. We elaborate our OED method for the problem of determining the optimal sensor configuration to best infer the log permeability field in a porous medium flow problem. Numerical results show that the number of PDE

Equivalent reduced model technique development for nonlinear system dynamic response

NASA Astrophysics Data System (ADS)

Thibault, Louis; Avitabile, Peter; Foley, Jason; Wolfson, Janet

2013-04-01

The dynamic response of structural systems commonly involves nonlinear effects. Often times, structural systems are made up of several components, whose individual behavior is essentially linear compared to the total assembled system. However, the assembly of linear components using highly nonlinear connection elements or contact regions causes the entire system to become nonlinear. Conventional transient nonlinear integration of the equations of motion can be extremely computationally intensive, especially when the finite element models describing the components are very large and detailed. In this work, the equivalent reduced model technique (ERMT) is developed to address complicated nonlinear contact problems. ERMT utilizes a highly accurate model reduction scheme, the System equivalent reduction expansion process (SEREP). Extremely reduced order models that provide dynamic characteristics of linear components, which are interconnected with highly nonlinear connection elements, are formulated with SEREP for the dynamic response evaluation using direct integration techniques. The full-space solution will be compared to the response obtained using drastically reduced models to make evident the usefulness of the technique for a variety of analytical cases.

Exhaustive Classification of the Invariant Solutions for a Specific Nonlinear Model Describing Near Planar and Marginally Long-Wave Unstable Interfaces for Phase Transition

NASA Astrophysics Data System (ADS)

Ahangari, Fatemeh

2018-05-01

Problems of thermodynamic phase transition originate inherently in solidification, combustion and various other significant fields. If the transition region among two locally stable phases is adequately narrow, the dynamics can be modeled by an interface motion. This paper is devoted to exhaustive analysis of the invariant solutions for a modified Kuramoto-Sivashinsky equation in two spatial and one temporal dimensions is presented. This nonlinear partial differential equation asymptotically characterizes near planar interfaces, which are marginally long-wave unstable. For this purpose, by applying the classical symmetry method for this model the classical symmetry operators are attained. Moreover, the structure of the Lie algebra of symmetries is discussed and the optimal system of subalgebras, which yields the preliminary classification of group invariant solutions is constructed. Mainly, the Lie invariants corresponding to the infinitesimal symmetry generators as well as associated similarity reduced equations are also pointed out. Furthermore, the nonclassical symmetries of this nonlinear PDE are also comprehensively investigated.

Dynamics of elastic nonlinear rotating composite beams with embedded actuators

NASA Astrophysics Data System (ADS)

Ghorashi, Mehrdaad

2009-08-01

A comprehensive study of the nonlinear dynamics of composite beams is presented. The study consists of static and dynamic solutions with and without active elements. The static solution provides the initial conditions for the dynamic analysis. The dynamic problems considered include the analyses of clamped (hingeless) and articulated (hinged) accelerating rotating beams. Numerical solutions for the steady state and transient responses have been obtained. It is shown that the transient solution of the nonlinear formulation of accelerating rotating beam converges to the steady state solution obtained by the shooting method. The effect of perturbing the steady state solution has also been calculated and the results are shown to be compatible with those of the accelerating beam analysis. Next, the coupled flap-lag rigid body dynamics of a rotating articulated beam with hinge offset and subjected to aerodynamic forces is formulated. The solution to this rigid-body problem is then used, together with the finite difference method, in order to produce the nonlinear elasto-dynamic solution of an accelerating articulated beam. Next, the static and dynamic responses of nonlinear composite beams with embedded Anisotropic Piezo-composite Actuators (APA) are presented. The effect of activating actuators at various directions on the steady state force and moments generated in a rotating composite beam has been presented. With similar results for the transient response, this analysis can be used in controlling the response of adaptive rotating beams.

Coherent states formulation of polymer field theory

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

Man, Xingkun; Villet, Michael C.; Materials Research Laboratory, University of California, Santa Barbara, California 93106

2014-01-14

We introduce a stable and efficient complex Langevin (CL) scheme to enable the first direct numerical simulations of the coherent-states (CS) formulation of polymer field theory. In contrast with Edwards’ well-known auxiliary-field (AF) framework, the CS formulation does not contain an embedded nonlinear, non-local, implicit functional of the auxiliary fields, and the action of the field theory has a fully explicit, semi-local, and finite-order polynomial character. In the context of a polymer solution model, we demonstrate that the new CS-CL dynamical scheme for sampling fluctuations in the space of coherent states yields results in good agreement with now-standard AF-CL simulations.more » The formalism is potentially applicable to a broad range of polymer architectures and may facilitate systematic generation of trial actions for use in coarse-graining and numerical renormalization-group studies.« less

(2 + 1)-dimensional dynamical black holes in Einstein-nonlinear Maxwell theory

NASA Astrophysics Data System (ADS)

Gurtug, O.; Mazharimousavi, S. Habib; Halilsoy, M.

2018-02-01

Radiative extensions of BTZ metric in 2 + 1 dimensions are found which are sourced by nonlinear Maxwell fields and a null current. This may be considered as generalization of the problem formulated long go by Vaidya and Bonnor. The mass and charge are functions of retarded/advanced null coordinate apt for decay/inflation. The new solutions are constructed through a Theorem that works remarkably well for any nonlinear electrodynamic model. Hawking temperature is analyzed for the case of the Born-Infeld electrodynamics.

Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability.

PubMed

Chino, Ayaka; Masuda, Naoyuki; Amano, Yasushi; Honbou, Kazuya; Mihara, Takuma; Yamazaki, Mayako; Tomishima, Masaki

2014-07-01

In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure-activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition. Copyright © 2014. Published by Elsevier Ltd.

A modified variational method for nonlinear vibration analysis of rotating beams including Coriolis effects

NASA Astrophysics Data System (ADS)

Tian, Jiajin; Su, Jinpeng; Zhou, Kai; Hua, Hongxing

2018-07-01

This paper presents a general formulation for nonlinear vibration analysis of rotating beams. A modified variational method combined with a multi-segment partitioning technique is employed to derive the free and transient vibration behaviors of the rotating beams. The strain energy and kinetic energy functional are formulated based on the order truncation principle of the fully geometrically nonlinear beam theory. The Coriolis effects as well as nonlinear effects due to the coupling of bending-stretching, bending-twist and twist-stretching are taken into account. The present method relaxes the need to explicitly meet the requirements of the boundary conditions for the admissible functions, and allows the use of any linearly independent, complete basis functions as admissible functions for rotating beams. Moreover, the method is readily used to deal with the nonlinear transient vibration problems for rotating beams subjected to dynamic loads. The accuracy, convergence and efficiency of the proposed method are examined by numerical examples. The influences of Coriolis and centrifugal forces on the vibration behaviors of the beams with various hub radiuses and slenderness ratios and rotating at different angular velocities are also investigated.

Comparing Consider-Covariance Analysis with Sigma-Point Consider Filter and Linear-Theory Consider Filter Formulations

NASA Technical Reports Server (NTRS)

Lisano, Michael E.

2007-01-01

Recent literature in applied estimation theory reflects growing interest in the sigma-point (also called unscented ) formulation for optimal sequential state estimation, often describing performance comparisons with extended Kalman filters as applied to specific dynamical problems [c.f. 1, 2, 3]. Favorable attributes of sigma-point filters are described as including a lower expected error for nonlinear even non-differentiable dynamical systems, and a straightforward formulation not requiring derivation or implementation of any partial derivative Jacobian matrices. These attributes are particularly attractive, e.g. in terms of enabling simplified code architecture and streamlined testing, in the formulation of estimators for nonlinear spaceflight mechanics systems, such as filter software onboard deep-space robotic spacecraft. As presented in [4], the Sigma-Point Consider Filter (SPCF) algorithm extends the sigma-point filter algorithm to the problem of consider covariance analysis. Considering parameters in a dynamical system, while estimating its state, provides an upper bound on the estimated state covariance, which is viewed as a conservative approach to designing estimators for problems of general guidance, navigation and control. This is because, whether a parameter in the system model is observable or not, error in the knowledge of the value of a non-estimated parameter will increase the actual uncertainty of the estimated state of the system beyond the level formally indicated by the covariance of an estimator that neglects errors or uncertainty in that parameter. The equations for SPCF covariance evolution are obtained in a fashion similar to the derivation approach taken with standard (i.e. linearized or extended) consider parameterized Kalman filters (c.f. [5]). While in [4] the SPCF and linear-theory consider filter (LTCF) were applied to an illustrative linear dynamics/linear measurement problem, in the present work examines the SPCF as applied to

Mixed formulation for seismic analysis of composite steel-concrete frame structures

NASA Astrophysics Data System (ADS)

Ayoub, Ashraf Salah Eldin

This study presents a new finite element model for the nonlinear analysis of structures made up of steel and concrete under monotonic and cyclic loads. The new formulation is based on a two-field mixed formulation. In the formulation, both forces and deformations are simultaneously approximated within the element through independent interpolation functions. The main advantages of the model is the accuracy in global and local response with very few elements while maintaining rapid numerical convergence and robustness even under severe cyclic loading. Overall four elements were developed based on the new formulation: an element that describes the behavior of anchored reinforcing bars, an element that describes the behavior of composite steel-concrete beams with deformable shear connectors, an element that describes the behavior of reinforced concrete beam-columns with bond-slip, and an element that describes the behavior of pretensioned or posttensioned, bonded or unbonded prestressed concrete structures. The models use fiber discretization of beam sections to describe nonlinear material response. The transfer of forces between steel and concrete is described with bond elements. Bond elements are modeled with distributed spring elements. The non-linear behavior of the composite element derives entirely from the constitutive laws of the steel, concrete and bond elements. Two additional elements are used for the prestressed concrete models, a friction element that models the effect of friction between the tendon and the duct during the posttensioning operation, and an anchorage element that describes the behavior of the prestressing tendon anchorage in posttensioned structures. Two algorithms for the numerical implementation of the new proposed model are presented; an algorithm that enforces stress continuity at element boundaries, and an algorithm in which stress continuity is relaxed locally inside the element. Stability of both algorithms is discussed. Comparison

Part I: Steady States in Two-Species Particle Aggregation. Part II: Sparse Representations for Multiscale PDE

DTIC Science & Technology

2015-03-01

University of California Los Angeles Part I: Steady States in Two-Species Particle Aggregation Part II: Sparse Representations for Multiscale PDE A ...Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a ...penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. 1. REPORT DATE MAR 2015

A nonlinear strategy for sensor based vehicle path control

NASA Technical Reports Server (NTRS)

Mayr, R.

1994-01-01

A method of transverse control which makes use of nonlinear formulations is presented. The strategy is utilized to stabilize a vehicle. The vehicle is autonomously guided and takes its control inputs from an optical sensing system. Additionally, the velocity of the vehicle is dictated by a longitudinal controller, which is also discussed.

Analytical formulation of orbiter-payload coupled by trunnion joints with Coulomb friction

NASA Technical Reports Server (NTRS)

Liu, Frank C.

1986-01-01

An orbiter and its payload substructure are linked together by five trunnion joints which have thirty degrees-of-freedom. Geometric compatibility conditions require fourteen of the interface physical coordinates of the orbiter and payload to be equal to each other and the remaining sixteen are free to have relative motions under Coulomb friction. The component modes synthesis method using fourteen inertia relief attachment modes for the formulation of the coupled system is presented. The exact nonlinear friction function is derived based on the characteristics of the joints. Formulation is applicable to an orbiter that carries any number of payload substructures.

Equivalent Linearization Analysis of Geometrically Nonlinear Random Vibrations Using Commercial Finite Element Codes

NASA Technical Reports Server (NTRS)

Rizzi, Stephen A.; Muravyov, Alexander A.

2002-01-01

Two new equivalent linearization implementations for geometrically nonlinear random vibrations are presented. Both implementations are based upon a novel approach for evaluating the nonlinear stiffness within commercial finite element codes and are suitable for use with any finite element code having geometrically nonlinear static analysis capabilities. The formulation includes a traditional force-error minimization approach and a relatively new version of a potential energy-error minimization approach, which has been generalized for multiple degree-of-freedom systems. Results for a simply supported plate under random acoustic excitation are presented and comparisons of the displacement root-mean-square values and power spectral densities are made with results from a nonlinear time domain numerical simulation.

Linear and nonlinear dynamic analysis by boundary element method. Ph.D. Thesis, 1986 Final Report

NASA Technical Reports Server (NTRS)

Ahmad, Shahid

1991-01-01

An advanced implementation of the direct boundary element method (BEM) applicable to free-vibration, periodic (steady-state) vibration and linear and nonlinear transient dynamic problems involving two and three-dimensional isotropic solids of arbitrary shape is presented. Interior, exterior, and half-space problems can all be solved by the present formulation. For the free-vibration analysis, a new real variable BEM formulation is presented which solves the free-vibration problem in the form of algebraic equations (formed from the static kernels) and needs only surface discretization. In the area of time-domain transient analysis, the BEM is well suited because it gives an implicit formulation. Although the integral formulations are elegant, because of the complexity of the formulation it has never been implemented in exact form. In the present work, linear and nonlinear time domain transient analysis for three-dimensional solids has been implemented in a general and complete manner. The formulation and implementation of the nonlinear, transient, dynamic analysis presented here is the first ever in the field of boundary element analysis. Almost all the existing formulation of BEM in dynamics use the constant variation of the variables in space and time which is very unrealistic for engineering problems and, in some cases, it leads to unacceptably inaccurate results. In the present work, linear and quadratic isoparametric boundary elements are used for discretization of geometry and functional variations in space. In addition, higher order variations in time are used. These methods of analysis are applicable to piecewise-homogeneous materials, such that not only problems of the layered media and the soil-structure interaction can be analyzed but also a large problem can be solved by the usual sub-structuring technique. The analyses have been incorporated in a versatile, general-purpose computer program. Some numerical problems are solved and, through comparisons

Instantaneous nonlinear assessment of complex cardiovascular dynamics by Laguerre-Volterra point process models.

PubMed

Valenza, Gaetano; Citi, Luca; Barbieri, Riccardo

2013-01-01

We report an exemplary study of instantaneous assessment of cardiovascular dynamics performed using point-process nonlinear models based on Laguerre expansion of the linear and nonlinear Wiener-Volterra kernels. As quantifiers, instantaneous measures such as high order spectral features and Lyapunov exponents can be estimated from a quadratic and cubic autoregressive formulation of the model first order moment, respectively. Here, these measures are evaluated on heartbeat series coming from 16 healthy subjects and 14 patients with Congestive Hearth Failure (CHF). Data were gathered from the on-line repository PhysioBank, which has been taken as landmark for testing nonlinear indices. Results show that the proposed nonlinear Laguerre-Volterra point-process methods are able to track the nonlinear and complex cardiovascular dynamics, distinguishing significantly between CHF and healthy heartbeat series.

Generation of linear dynamic models from a digital nonlinear simulation

NASA Technical Reports Server (NTRS)

Daniele, C. J.; Krosel, S. M.

1979-01-01

The results and methodology used to derive linear models from a nonlinear simulation are presented. It is shown that averaged positive and negative perturbations in the state variables can reduce numerical errors in finite difference, partial derivative approximations and, in the control inputs, can better approximate the system response in both directions about the operating point. Both explicit and implicit formulations are addressed. Linear models are derived for the F 100 engine, and comparisons of transients are made with the nonlinear simulation. The problem of startup transients in the nonlinear simulation in making these comparisons is addressed. Also, reduction of the linear models is investigated using the modal and normal techniques. Reduced-order models of the F 100 are derived and compared with the full-state models.

Solution algorithms for nonlinear transient heat conduction analysis employing element-by-element iterative strategies

NASA Technical Reports Server (NTRS)

Winget, J. M.; Hughes, T. J. R.

1985-01-01

The particular problems investigated in the present study arise from nonlinear transient heat conduction. One of two types of nonlinearities considered is related to a material temperature dependence which is frequently needed to accurately model behavior over the range of temperature of engineering interest. The second nonlinearity is introduced by radiation boundary conditions. The finite element equations arising from the solution of nonlinear transient heat conduction problems are formulated. The finite element matrix equations are temporally discretized, and a nonlinear iterative solution algorithm is proposed. Algorithms for solving the linear problem are discussed, taking into account the form of the matrix equations, Gaussian elimination, cost, and iterative techniques. Attention is also given to approximate factorization, implementational aspects, and numerical results.

Bounding solutions of geometrically nonlinear viscoelastic problems

NASA Technical Reports Server (NTRS)

Stubstad, J. M.; Simitses, G. J.

1985-01-01

Integral transform techniques, such as the Laplace transform, provide simple and direct methods for solving viscoelastic problems formulated within a context of linear material response and using linear measures for deformation. Application of the transform operator reduces the governing linear integro-differential equations to a set of algebraic relations between the transforms of the unknown functions, the viscoelastic operators, and the initial and boundary conditions. Inversion either directly or through the use of the appropriate convolution theorem, provides the time domain response once the unknown functions have been expressed in terms of sums, products or ratios of known transforms. When exact inversion is not possible approximate techniques may provide accurate results. The overall problem becomes substantially more complex when nonlinear effects must be included. Situations where a linear material constitutive law can still be productively employed but where the magnitude of the resulting time dependent deformations warrants the use of a nonlinear kinematic analysis are considered. The governing equations will be nonlinear integro-differential equations for this class of problems. Thus traditional as well as approximate techniques, such as cited above, cannot be employed since the transform of a nonlinear function is not explicitly expressible.

Bounding solutions of geometrically nonlinear viscoelastic problems

NASA Technical Reports Server (NTRS)

Stubstad, J. M.; Simitses, G. J.

1986-01-01

Integral transform techniques, such as the Laplace transform, provide simple and direct methods for solving viscoelastic problems formulated within a context of linear material response and using linear measures for deformation. Application of the transform operator reduces the governing linear integro-differential equations to a set of algebraic relations between the transforms of the unknown functions, the viscoelastic operators, and the initial and boundary conditions. Inversion either directly or through the use of the appropriate convolution theorem, provides the time domain response once the unknown functions have been expressed in terms of sums, products or ratios of known transforms. When exact inversion is not possible approximate techniques may provide accurate results. The overall problem becomes substantially more complex when nonlinear effects must be included. Situations where a linear material constitutive law can still be productively employed but where the magnitude of the resulting time dependent deformations warrants the use of a nonlinear kinematic analysis are considered. The governing equations will be nonlinear integro-differential equations for this class of problems. Thus traditional as well as approximate techniques, such as cited above, cannot be employed since the transform of a nonlinear function is not explicitly expressible.

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

NASA Astrophysics Data System (ADS)

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

2016-01-01

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

Zero-sum two-player game theoretic formulation of affine nonlinear discrete-time systems using neural networks.

PubMed

Mehraeen, Shahab; Dierks, Travis; Jagannathan, S; Crow, Mariesa L

2013-12-01

In this paper, the nearly optimal solution for discrete-time (DT) affine nonlinear control systems in the presence of partially unknown internal system dynamics and disturbances is considered. The approach is based on successive approximate solution of the Hamilton-Jacobi-Isaacs (HJI) equation, which appears in optimal control. Successive approximation approach for updating control and disturbance inputs for DT nonlinear affine systems are proposed. Moreover, sufficient conditions for the convergence of the approximate HJI solution to the saddle point are derived, and an iterative approach to approximate the HJI equation using a neural network (NN) is presented. Then, the requirement of full knowledge of the internal dynamics of the nonlinear DT system is relaxed by using a second NN online approximator. The result is a closed-loop optimal NN controller via offline learning. A numerical example is provided illustrating the effectiveness of the approach.

Linear programming: an alternative approach for developing formulations for emergency food products.

PubMed

Sheibani, Ershad; Dabbagh Moghaddam, Arasb; Sharifan, Anousheh; Afshari, Zahra

2018-03-01

To minimize the mortality rates of individuals affected by disasters, providing high-quality food relief during the initial stages of an emergency is crucial. The goal of this study was to develop a formulation for a high-energy, nutrient-dense prototype using linear programming (LP) model as a novel method for developing formulations for food products. The model consisted of the objective function and the decision variables, which were the formulation costs and weights of the selected commodities, respectively. The LP constraints were the Institute of Medicine and the World Health Organization specifications of the content of nutrients in the product. Other constraints related to the product's sensory properties were also introduced to the model. Nonlinear constraints for energy ratios of nutrients were linearized to allow their use in the LP. Three focus group studies were conducted to evaluate the palatability and other aspects of the optimized formulation. New constraints were introduced to the LP model based on the focus group evaluations to improve the formulation. LP is an appropriate tool for designing formulations of food products to meet a set of nutritional requirements. This method is an excellent alternative to the traditional 'trial and error' method in designing formulations. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Notes on the ExactPack Implementation of the DSD Rate Stick Solver

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

Kaul, Ann

It has been shown above that the discretization scheme implemented in the ExactPack solver for the DSD Rate Stick equation is consistent with the Rate Stick PDE. In addition, a stability analysis has provided a CFL condition for a stable time step. Together, consistency and stability imply convergence of the scheme, which is expected to be close to first-order in time and second-order in space. It is understood that the nonlinearity of the underlying PDE will affect this rate somewhat. In the solver I implemented in ExactPack, I used the one-sided boundary condition described above at the outer boundary. Inmore » addition, I used 80% of the time step calculated in the stability analysis above. By making these two changes, I was able to implement a solver that calculates the solution without any arbitrary limits placed on the values of the curvature at the boundary. Thus, the calculation is driven directly by the conditions at the boundary as formulated in the DSD theory. The chosen scheme is completely coherent and defensible from a mathematical standpoint.« less

Nonlinear ideal magnetohydrodynamics instabilities

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

Pfirsch, D.; Sudan, R.N.

1993-07-01

Explosive phenomena such as internal disruptions in toroidal discharges and solar flares are difficult to explain in terms of linear instabilities. A plasma approaching a linear stability limit can, however, become nonlinearly and explosively unstable, with noninfinitesimal perturbations even before the marginal state is reached. For such investigations, a nonlinear extension of the usual MHD (magnetohydrodynamic) energy principle is helpful. (This was obtained by Merkel and Schlueter, Sitzungsberichted. Bayer. Akad. Wiss., Munich, 1976, No. 7, for Cartesian coordinate systems.) A coordinate system independent Eulerian formulation for the Lagrangian allowing for equilibria with flow and with built-in conservation laws for mass,more » magnetic flux, and entropy is developed in this paper which is similar to Newcomb's Lagrangian method of 1962 [Nucl. Fusion, Suppl., Pt. II, 452 (1962)]. For static equilibria nonlinear stability is completely determined by the potential energy. For a potential energy which contains second- and [ital n]th order or some more general contributions only, it is shown in full generality that linearly unstable and marginally stable systems are explosively unstable even for infinitesimal perturbations; linearly absolutely stable systems require finite initial perturbations. For equilibria with Abelian symmetries symmetry breaking initial perturbations are needed, which should be observed in numerical simulations. Nonlinear stability is proved for two simple examples, [ital m]=0 perturbations of a Bennet Z-pinch and [ital z]-independent perturbations of a [theta] pinch. The algebra for treating these cases reduces considerably if symmetries are taken into account from the outset, as suggested by M. N. Rosenbluth (private communication, 1992).« less

Nonlinear ideal magnetohydrodynamics instabilities

NASA Astrophysics Data System (ADS)

Pfirsch, D.; Sudan, R. N.

1993-07-01

Explosive phenomena such as internal disruptions in toroidal discharges and solar flares are difficult to explain in terms of linear instabilities. A plasma approaching a linear stability limit can, however, become nonlinearly and explosively unstable, with noninfinitesimal perturbations even before the marginal state is reached. For such investigations, a nonlinear extension of the usual MHD (magnetohydrodynamic) energy principle is helpful. (This was obtained by Merkel and Schlüter, Sitzungsberichted. Bayer. Akad. Wiss., Munich, 1976, No. 7, for Cartesian coordinate systems.) A coordinate system independent Eulerian formulation for the Lagrangian allowing for equilibria with flow and with built-in conservation laws for mass, magnetic flux, and entropy is developed in this paper which is similar to Newcomb's Lagrangian method of 1962 [Nucl. Fusion, Suppl., Pt. II, 452 (1962)]. For static equilibria nonlinear stability is completely determined by the potential energy. For a potential energy which contains second- and nth order or some more general contributions only, it is shown in full generality that linearly unstable and marginally stable systems are explosively unstable even for infinitesimal perturbations; linearly absolutely stable systems require finite initial perturbations. For equilibria with Abelian symmetries symmetry breaking initial perturbations are needed, which should be observed in numerical simulations. Nonlinear stability is proved for two simple examples, m=0 perturbations of a Bennet Z-pinch and z-independent perturbations of a θ pinch. The algebra for treating these cases reduces considerably if symmetries are taken into account from the outset, as suggested by M. N. Rosenbluth (private communication, 1992).

Weighted interior penalty discretization of fully nonlinear and weakly dispersive free surface shallow water flows

NASA Astrophysics Data System (ADS)

Di Pietro, Daniele A.; Marche, Fabien

2018-02-01

In this paper, we further investigate the use of a fully discontinuous Finite Element discrete formulation for the study of shallow water free surface flows in the fully nonlinear and weakly dispersive flow regime. We consider a decoupling strategy in which we approximate the solutions of the classical shallow water equations supplemented with a source term globally accounting for the non-hydrostatic effects. This source term can be computed through the resolution of elliptic second-order linear sub-problems, which only involve second order partial derivatives in space. We then introduce an associated Symmetric Weighted Internal Penalty discrete bilinear form, allowing to deal with the discontinuous nature of the elliptic problem's coefficients in a stable and consistent way. Similar discrete formulations are also introduced for several recent optimized fully nonlinear and weakly dispersive models. These formulations are validated again several benchmarks involving h-convergence, p-convergence and comparisons with experimental data, showing optimal convergence properties.

Isogeometric analysis of free-form Timoshenko curved beams including the nonlinear effects of large deformations

NASA Astrophysics Data System (ADS)

Hosseini, Seyed Farhad; Hashemian, Ali; Moetakef-Imani, Behnam; Hadidimoud, Saied

2018-03-01

In the present paper, the isogeometric analysis (IGA) of free-form planar curved beams is formulated based on the nonlinear Timoshenko beam theory to investigate the large deformation of beams with variable curvature. Based on the isoparametric concept, the shape functions of the field variables (displacement and rotation) in a finite element analysis are considered to be the same as the non-uniform rational basis spline (NURBS) basis functions defining the geometry. The validity of the presented formulation is tested in five case studies covering a wide range of engineering curved structures including from straight and constant curvature to variable curvature beams. The nonlinear deformation results obtained by the presented method are compared to well-established benchmark examples and also compared to the results of linear and nonlinear finite element analyses. As the nonlinear load-deflection behavior of Timoshenko beams is the main topic of this article, the results strongly show the applicability of the IGA method to the large deformation analysis of free-form curved beams. Finally, it is interesting to notice that, until very recently, the large deformations analysis of free-form Timoshenko curved beams has not been considered in IGA by researchers.

Application of variational and Galerkin equations to linear and nonlinear finite element analysis

NASA Technical Reports Server (NTRS)

Yu, Y.-Y.

1974-01-01

The paper discusses the application of the variational equation to nonlinear finite element analysis. The problem of beam vibration with large deflection is considered. The variational equation is shown to be flexible in both the solution of a general problem and in the finite element formulation. Difficulties are shown to arise when Galerkin's equations are used in the consideration of the finite element formulation of two-dimensional linear elasticity and of the linear classical beam.

The mechanism of action of doxofylline is unrelated to HDAC inhibition, PDE inhibition or adenosine receptor antagonism.

PubMed

van Mastbergen, J; Jolas, T; Allegra, L; Page, C P

2012-02-01

Xanthines such as theophylline have been used in the treatment of lung diseases since the early 1900's, but have a major drawback of a very narrow therapeutic window and many drug/drug interactions. This means that plasma levels have to be measured regularly and can make the use of theophylline problematic. With the increasing availability of other classes of drugs for the treatment of respiratory diseases, this has limited the use of xanthines, despite their clear clinical benefit in the treatment of patients with asthma and COPD. Doxofylline is a xanthine molecule having both bronchodilator and anti-inflammatory activity with an improved therapeutic window over conventional xanthines such as theophylline. However, the mechanistic basis of this improved therapeutic window is not understood. The present study has investigated some pharmacological activities of doxofylline in comparison with theophylline. Doxofylline does not directly inhibit any of the known HDAC enzymes, and did not inhibit any PDE enzyme sub types or act as an antagonist at any of the known adenosine receptors, except for PDE2A(1), and adenosine A(2A) and only at the highest tested concentration (10(-4) M). These results may explain the improved tolerability profile of doxofylline compared with theophylline. Copyright © 2011. Published by Elsevier Ltd.

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.

Nonlinear vibrations of thin arbitrarily laminated composite plates subjected to harmonic excitations using DKT elements

NASA Astrophysics Data System (ADS)

Chiang, C. K.; Xue, David Y.; Mei, Chuh

1993-04-01

A finite element formulation is presented for determining the large-amplitude free and steady-state forced vibration response of arbitrarily laminated anisotropic composite thin plates using the Discrete Kirchhoff Theory (DKT) triangular elements. The nonlinear stiffness and harmonic force matrices of an arbitrarily laminated composite triangular plate element are developed for nonlinear free and forced vibration analyses. The linearized updated-mode method with nonlinear time function approximation is employed for the solution of the system nonlinear eigenvalue equations. The amplitude-frequency relations for convergence with gridwork refinement, triangular plates, different boundary conditions, lamination angles, number of plies, and uniform versus concentrated loads are presented.

Nonlinear vibrations of thin arbitrarily laminated composite plates subjected to harmonic excitations using DKT elements

NASA Technical Reports Server (NTRS)

Chiang, C. K.; Xue, David Y.; Mei, Chuh

1993-01-01

A finite element formulation is presented for determining the large-amplitude free and steady-state forced vibration response of arbitrarily laminated anisotropic composite thin plates using the Discrete Kirchhoff Theory (DKT) triangular elements. The nonlinear stiffness and harmonic force matrices of an arbitrarily laminated composite triangular plate element are developed for nonlinear free and forced vibration analyses. The linearized updated-mode method with nonlinear time function approximation is employed for the solution of the system nonlinear eigenvalue equations. The amplitude-frequency relations for convergence with gridwork refinement, triangular plates, different boundary conditions, lamination angles, number of plies, and uniform versus concentrated loads are presented.

An Energy Decaying Scheme for Nonlinear Dynamics of Shells

NASA Technical Reports Server (NTRS)

Bottasso, Carlo L.; Bauchau, Olivier A.; Choi, Jou-Young; Bushnell, Dennis M. (Technical Monitor)

2000-01-01

A novel integration scheme for nonlinear dynamics of geometrically exact shells is developed based on the inextensible director assumption. The new algorithm is designed so as to imply the strict decay of the system total mechanical energy at each time step, and consequently unconditional stability is achieved in the nonlinear regime. Furthermore, the scheme features tunable high frequency numerical damping and it is therefore stiffly accurate. The method is tested for a finite element spatial formulation of shells based on mixed interpolations of strain tensorial components and on a two-parameter representation of director rotations. The robustness of the, scheme is illustrated with the help of numerical examples.

Optimal control in adaptive optics modeling of nonlinear systems

NASA Astrophysics Data System (ADS)

Herrmann, J.

The problem of using an adaptive optics system to correct for nonlinear effects like thermal blooming is addressed using a model containing nonlinear lenses through which Gaussian beams are propagated. The best correction of this nonlinear system can be formulated as a deterministic open loop optimal control problem. This treatment gives a limit for the best possible correction. Aspects of adaptive control and servo systems are not included at this stage. An attempt is made to determine that control in the transmitter plane which minimizes the time averaged area or maximizes the fluence in the target plane. The standard minimization procedure leads to a two-point-boundary-value problem, which is ill-conditioned in the case. The optimal control problem was solved using an iterative gradient technique. An instantaneous correction is introduced and compared with the optimal correction. The results of the calculations show that for short times or weak nonlinearities the instantaneous correction is close to the optimal correction, but that for long times and strong nonlinearities a large difference develops between the two types of correction. For these cases the steady state correction becomes better than the instantaneous correction and approaches the optimum correction.

Nonlinear Viscoelastic Characterization of the Porcine Spinal Cord

PubMed Central

Shetye, Snehal; Troyer, Kevin; Streijger, Femke; Lee, Jae H. T.; Kwon, Brian K.; Cripton, Peter; Puttlitz, Christian M.

2014-01-01

Although quasi-static and quasi-linear viscoelastic properties of the spinal cord have been reported previously, there are no published studies that have investigated the fully (strain-dependent) nonlinear viscoelastic properties of the spinal cord. In this study, stress relaxation experiments and dynamic cycling were performed on six fresh porcine lumbar cord specimens to examine their viscoelastic mechanical properties. The stress relaxation data were fitted to a modified superposition formulation and a novel finite ramp time correction technique was applied. The parameters obtained from this fitting methodology were used to predict the average dynamic cyclic viscoelastic behavior of the porcine cord. The data indicate that the porcine spinal cord exhibited fully nonlinear viscoelastic behavior. The average weighted RMSE for a Heaviside ramp fit was 2.8kPa, which was significantly greater (p < 0.001) than that of the nonlinear (comprehensive viscoelastic characterization (CVC) method) fit (0.365kPa). Further, the nonlinear mechanical parameters obtained were able to accurately predict the dynamic behavior, thus exemplifying the reliability of the obtained nonlinear parameters. These parameters will be important for future studies investigating various damage mechanisms of the spinal cord and studies developing high resolution finite elements models of the spine. PMID:24211612

A nonlinear viscoelastic constitutive equation - Yield predictions in multiaxial deformations

NASA Technical Reports Server (NTRS)

Shay, R. M., Jr.; Caruthers, J. M.

1987-01-01

Yield stress predictions of a nonlinear viscoelastic constitutive equation for amorphous polymer solids have been obtained and are compared with the phenomenological von Mises yield criterion. Linear viscoelasticity theory has been extended to include finite strains and a material timescale that depends on the instantaneous temperature, volume, and pressure. Results are presented for yield and the correct temperature and strain-rate dependence in a variety of multiaxial deformations. The present nonlinear viscoelastic constitutive equation can be formulated in terms of either a Cauchy or second Piola-Kirchhoff stress tensor, and in terms of either atmospheric or hydrostatic pressure.

Nonlinear Adaptive PID Control for Greenhouse Environment Based on RBF Network

PubMed Central

Zeng, Songwei; Hu, Haigen; Xu, Lihong; Li, Guanghui

2012-01-01

This paper presents a hybrid control strategy, combining Radial Basis Function (RBF) network with conventional proportional, integral, and derivative (PID) controllers, for the greenhouse climate control. A model of nonlinear conservation laws of enthalpy and matter between numerous system variables affecting the greenhouse climate is formulated. RBF network is used to tune and identify all PID gain parameters online and adaptively. The presented Neuro-PID control scheme is validated through simulations of set-point tracking and disturbance rejection. We compare the proposed adaptive online tuning method with the offline tuning scheme that employs Genetic Algorithm (GA) to search the optimal gain parameters. The results show that the proposed strategy has good adaptability, strong robustness and real-time performance while achieving satisfactory control performance for the complex and nonlinear greenhouse climate control system, and it may provide a valuable reference to formulate environmental control strategies for actual application in greenhouse production. PMID:22778587

Analytical formulation of orbiter-payload models coupled by trunnion joints with Coulomb friction

NASA Technical Reports Server (NTRS)

Liu, Frank C.

1987-01-01

An orbiter and its payload substructure are linked together by five trunnion joints which have thirty degrees-of-freedom. Geometric compatibility conditions require fourteen of the interface physical coordinates of the orbiter and payload to be equal to each other and the remaining sixteen are free to have relative motions under Coulomb friction. The component modes synthesis method using fourteen inertia relief attachment modes for the formulation of the coupled system is presented. The exact nonlinear friction function is derived based on the characteristics of the joints. Formulation is applicable to an orbiter that carries any number of payload substructures.

Evolutionary algorithm based heuristic scheme for nonlinear heat transfer equations.

PubMed

Ullah, Azmat; Malik, Suheel Abdullah; Alimgeer, Khurram Saleem

2018-01-01

In this paper, a hybrid heuristic scheme based on two different basis functions i.e. Log Sigmoid and Bernstein Polynomial with unknown parameters is used for solving the nonlinear heat transfer equations efficiently. The proposed technique transforms the given nonlinear ordinary differential equation into an equivalent global error minimization problem. Trial solution for the given nonlinear differential equation is formulated using a fitness function with unknown parameters. The proposed hybrid scheme of Genetic Algorithm (GA) with Interior Point Algorithm (IPA) is opted to solve the minimization problem and to achieve the optimal values of unknown parameters. The effectiveness of the proposed scheme is validated by solving nonlinear heat transfer equations. The results obtained by the proposed scheme are compared and found in sharp agreement with both the exact solution and solution obtained by Haar Wavelet-Quasilinearization technique which witnesses the effectiveness and viability of the suggested scheme. Moreover, the statistical analysis is also conducted for investigating the stability and reliability of the presented scheme.

Exact and Approximate Statistical Inference for Nonlinear Regression and the Estimating Equation Approach.

PubMed

Demidenko, Eugene

2017-09-01

The exact density distribution of the nonlinear least squares estimator in the one-parameter regression model is derived in closed form and expressed through the cumulative distribution function of the standard normal variable. Several proposals to generalize this result are discussed. The exact density is extended to the estimating equation (EE) approach and the nonlinear regression with an arbitrary number of linear parameters and one intrinsically nonlinear parameter. For a very special nonlinear regression model, the derived density coincides with the distribution of the ratio of two normally distributed random variables previously obtained by Fieller (1932), unlike other approximations previously suggested by other authors. Approximations to the density of the EE estimators are discussed in the multivariate case. Numerical complications associated with the nonlinear least squares are illustrated, such as nonexistence and/or multiple solutions, as major factors contributing to poor density approximation. The nonlinear Markov-Gauss theorem is formulated based on the near exact EE density approximation.

New modified multi-level residue harmonic balance method for solving nonlinearly vibrating double-beam problem

NASA Astrophysics Data System (ADS)

Rahman, Md. Saifur; Lee, Yiu-Yin

2017-10-01

In this study, a new modified multi-level residue harmonic balance method is presented and adopted to investigate the forced nonlinear vibrations of axially loaded double beams. Although numerous nonlinear beam or linear double-beam problems have been tackled and solved, there have been few studies of this nonlinear double-beam problem. The geometric nonlinear formulations for a double-beam model are developed. The main advantage of the proposed method is that a set of decoupled nonlinear algebraic equations is generated at each solution level. This heavily reduces the computational effort compared with solving the coupled nonlinear algebraic equations generated in the classical harmonic balance method. The proposed method can generate the higher-level nonlinear solutions that are neglected by the previous modified harmonic balance method. The results from the proposed method agree reasonably well with those from the classical harmonic balance method. The effects of damping, axial force, and excitation magnitude on the nonlinear vibrational behaviour are examined.

Theoretical and software considerations for nonlinear dynamic analysis

NASA Technical Reports Server (NTRS)

Schmidt, R. J.; Dodds, R. H., Jr.

1983-01-01

In the finite element method for structural analysis, it is generally necessary to discretize the structural model into a very large number of elements to accurately evaluate displacements, strains, and stresses. As the complexity of the model increases, the number of degrees of freedom can easily exceed the capacity of present-day software system. Improvements of structural analysis software including more efficient use of existing hardware and improved structural modeling techniques are discussed. One modeling technique that is used successfully in static linear and nonlinear analysis is multilevel substructuring. This research extends the use of multilevel substructure modeling to include dynamic analysis and defines the requirements for a general purpose software system capable of efficient nonlinear dynamic analysis. The multilevel substructuring technique is presented, the analytical formulations and computational procedures for dynamic analysis and nonlinear mechanics are reviewed, and an approach to the design and implementation of a general purpose structural software system is presented.

Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family.

PubMed

Hmani-Aifa, Mounira; Benzina, Zeineb; Zulfiqar, Fareeha; Dhouib, Houria; Shahzadi, Amber; Ghorbel, Abdelmonem; Rebaï, Ahmed; Söderkvist, Peter; Riazuddin, Sheikh; Kimberling, William J; Ayadi, Hammadi

2009-04-01

Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous disorder. ARRP could be associated with extraocular manifestations that define specific syndromes such as Usher syndrome (USH) characterized by retinal degeneration and congenital hearing loss (HL). The USH type II (USH2) associates RP and mild-to-moderate HL with preserved vestibular function. At least three genes USH2A, the very large G-protein-coupled receptor, GPR98, and DFNB31 are responsible for USH2 syndrome. Here, we report on the segregation of non-syndromic ARRP and USH2 syndrome in a consanguineous Tunisian family, which was previously used to define USH2B locus. With regard to the co-occurrence of these two different pathologies, clinical and genetic reanalysis of the extended family showed (i) phenotypic heterogeneity within USH2 patients and (ii) excluded linkage to USH2B locus. Indeed, linkage analysis disclosed the cosegregation of the USH2 phenotype with the USH2C locus markers, D5S428 and D5S618, whereas the ARRP perfectly segregates with PDE6B flanking markers D4S3360 and D4S2930. Molecular analysis revealed two new missense mutations, p.Y6044C and p.W807R, occurring in GPR98 and PDE6B genes, respectively. In conclusion, our results show that the USH2B locus at chromosome 3p23-24.2 does not exist, and we therefore withdraw this locus designation. The combination of molecular findings for GPR98 and PDE6B genes enable us to explain the phenotypic heterogeneity and particularly the severe ocular affection first observed in one USH2 patient. This report presents an illustration of how consanguinity could increase familial clustering of multiple hereditary diseases within the same family.

A coherent nonlinear theory of auroral Langmuir-Alfven-whistler (LAW) events in the planetary magnetosphere.

NASA Astrophysics Data System (ADS)

Lopes, S. R.; Chian, A. C.-L.

1996-01-01

A coherent nonlinear theory of three-wave coupling involving Langmuir, Alfven and whistler waves is formulated and applied to the observation of auroral LAW events in the planetary magnetosphere. The effects of pump depletion, dissipation and frequency mismatch in the nonlinear wave dynamics are analyzed. The relevance of this theory for understanding the fine structures of auroral whistler-mode emissions and amplitude modulations of auroral Langmuir waves is discussed.

Fully Nonlinear Modeling and Analysis of Precision Membranes

NASA Technical Reports Server (NTRS)

Pai, P. Frank; Young, Leyland G.

2003-01-01

High precision membranes are used in many current space applications. This paper presents a fully nonlinear membrane theory with forward and inverse analyses of high precision membrane structures. The fully nonlinear membrane theory is derived from Jaumann strains and stresses, exact coordinate transformations, the concept of local relative displacements, and orthogonal virtual rotations. In this theory, energy and Newtonian formulations are fully correlated, and every structural term can be interpreted in terms of vectors. Fully nonlinear ordinary differential equations (ODES) governing the large static deformations of known axisymmetric membranes under known axisymmetric loading (i.e., forward problems) are presented as first-order ODES, and a method for obtaining numerically exact solutions using the multiple shooting procedure is shown. A method for obtaining the undeformed geometry of any axisymmetric membrane with a known inflated geometry and a known internal pressure (i.e., inverse problems) is also derived. Numerical results from forward analysis are verified using results in the literature, and results from inverse analysis are verified using known exact solutions and solutions from the forward analysis. Results show that the membrane theory and the proposed numerical methods for solving nonlinear forward and inverse membrane problems are accurate.

On the regularization for nonlinear tomographic absorption spectroscopy

NASA Astrophysics Data System (ADS)

Dai, Jinghang; Yu, Tao; Xu, Lijun; Cai, Weiwei

2018-02-01

Tomographic absorption spectroscopy (TAS) has attracted increased research efforts recently due to the development in both hardware and new imaging concepts such as nonlinear tomography and compressed sensing. Nonlinear TAS is one of the emerging modality that bases on the concept of nonlinear tomography and has been successfully demonstrated both numerically and experimentally. However, all the previous demonstrations were realized using only two orthogonal projections simply for ease of implementation. In this work, we examine the performance of nonlinear TAS using other beam arrangements and test the effectiveness of the beam optimization technique that has been developed for linear TAS. In addition, so far only smoothness prior has been adopted and applied in nonlinear TAS. Nevertheless, there are also other useful priors such as sparseness and model-based prior which have not been investigated yet. This work aims to show how these priors can be implemented and included in the reconstruction process. Regularization through Bayesian formulation will be introduced specifically for this purpose, and a method for the determination of a proper regularization factor will be proposed. The comparative studies performed with different beam arrangements and regularization schemes on a few representative phantoms suggest that the beam optimization method developed for linear TAS also works for the nonlinear counterpart and the regularization scheme should be selected properly according to the available a priori information under specific application scenarios so as to achieve the best reconstruction fidelity. Though this work is conducted under the context of nonlinear TAS, it can also provide useful insights for other tomographic modalities.

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.

What's Cooler Than Being Cool? Ice-Sheet Models Using a Fluidity-Based FOSLS Approach to Nonlinear-Stokes Flow

NASA Astrophysics Data System (ADS)

Allen, Jeffery M.

This research involves a few First-Order System Least Squares (FOSLS) formulations of a nonlinear-Stokes flow model for ice sheets. In Glen's flow law, a commonly used constitutive equation for ice rheology, the viscosity becomes infinite as the velocity gradients approach zero. This typically occurs near the ice surface or where there is basal sliding. The computational difficulties associated with the infinite viscosity are often overcome by an arbitrary modification of Glen's law that bounds the maximum viscosity. The FOSLS formulations developed in this thesis are designed to overcome this difficulty. The first FOSLS formulation is just the first-order representation of the standard nonlinear, full-Stokes and is known as the viscosity formulation and suffers from the problem above. To overcome the problem of infinite viscosity, two new formulation exploit the fact that the deviatoric stress, the product of viscosity and strain-rate, approaches zero as the viscosity goes to infinity. Using the deviatoric stress as the basis for a first-order system results in the the basic fluidity system. Augmenting the basic fluidity system with a curl-type equation results in the augmented fluidity system, which is more amenable to the iterative solver, Algebraic MultiGrid (AMG). A Nested Iteration (NI) Newton-FOSLS-AMG approach is used to solve the nonlinear-Stokes problems. Several test problems from the ISMIP set of benchmarks is examined to test the effectiveness of the various formulations. These test show that the viscosity based method is more expensive and less accurate. The basic fluidity system shows optimal finite-element convergence. However, there is not yet an efficient iterative solver for this type of system and this is the topic of future research. Alternatively, AMG performs better on the augmented fluidity system when using specific scaling. Unfortunately, this scaling results in reduced finite-element convergence.

Protective effects of phosphodiesterase-1 (PDE1) and ATP sensitive potassium (KATP) channel modulators against 3-nitropropionic acid induced behavioral and biochemical toxicities in experimental Huntington׳s disease.

PubMed

Gupta, Surbhi; Sharma, Bhupesh

2014-06-05

Huntington׳s disease (HD), a devastating neurodegenerative disorder, is characterized by weight loss, impairment of motor function, cognitive dysfunction, neuropsychiatric disturbances and striatal damage. Phosphodiesterase-1 (PDE1) has been implicated in various neurological diseases. Mitochondrial potassium channels in the brain take part in neuroprotection. This study has been structured to investigate the role of vinpocetine, a selective PDE1 inhibitor as well as nicorandil, selective ATP sensitive potassium (KATP) channel opener in 3-nitropropionic acid (3-NP) induced HD symptoms in rats. Systemic administration of 3-NP significantly, reduced body weight, impaired locomotion, grip strength and impaired cognition. 3-NP elicited marked oxidative stress in the brain (enhanced malondialdehyde-MDA, reduced glutathione-GSH content, superoxide dismutase-SOD and catalase-CAT), elevated brain acetylcholinesterase activity and inflammation (myeloperoxidase-MPO), with marked nitrosative stress (nitrite/nitrate) in the brain. 3-NP has also induced mitochondrial dysfunction (impaired mitochondrial NADH dehydrogenase-complex I, succinate dehydrogenase-complex II and cytochrome oxidase-complex IV) activities in the striatum of the rat. Tetrabenazine was used as a positive control. Treatment with vinpocetine, nicorandil and tetrabenazine ameliorated 3-NP induced reduction in body weight, impaired locomotion, grip strength and impaired cognition. Treatment with these drugs reduced brain striatum oxidative (MDA, GSH, SOD and CAT) and nitrosative (nitrite/nitrate) stress, acetylcholinesterase activity, inflammation and mitochondrial dysfunctions. These results indicate that vinpocetine, a selective PDE1 inhibitor and nicorandil, a KATP channel opener have attenuated 3-NP induced experimental HD. Hence, pharmacological modulation of PDE1 as well as KATP channels may be considered as potential research targets for mitigation of HD. Copyright © 2014 Elsevier B.V. All rights

Rational solitons in deep nonlinear optical Bragg grating.

PubMed

Alatas, H; Iskandar, A A; Tjia, M O; Valkering, T P

2006-06-01

We have examined the rational solitons in the Generalized Coupled Mode model for a deep nonlinear Bragg grating. These solitons are the degenerate forms of the ordinary solitons and appear at the transition lines in the parameter plane. A simple formulation is presented for the investigation of the bifurcations induced by detuning the carrier wave frequency. The analysis yields among others the appearance of in-gap dark and antidark rational solitons unknown in the nonlinear shallow grating. The exact expressions for the corresponding rational solitons are also derived in the process, which are characterized by rational algebraic functions. It is further demonstrated that certain effects in the soliton energy variations are to be expected when the frequency is varied across the values where the rational solitons appear.

Nonlinear Inference in Partially Observed Physical Systems and Deep Neural Networks

NASA Astrophysics Data System (ADS)

Rozdeba, Paul J.

The problem of model state and parameter estimation is a significant challenge in nonlinear systems. Due to practical considerations of experimental design, it is often the case that physical systems are partially observed, meaning that data is only available for a subset of the degrees of freedom required to fully model the observed system's behaviors and, ultimately, predict future observations. Estimation in this context is highly complicated by the presence of chaos, stochasticity, and measurement noise in dynamical systems. One of the aims of this dissertation is to simultaneously analyze state and parameter estimation in as a regularized inverse problem, where the introduction of a model makes it possible to reverse the forward problem of partial, noisy observation; and as a statistical inference problem using data assimilation to transfer information from measurements to the model states and parameters. Ultimately these two formulations achieve the same goal. Similar aspects that appear in both are highlighted as a means for better understanding the structure of the nonlinear inference problem. An alternative approach to data assimilation that uses model reduction is then examined as a way to eliminate unresolved nonlinear gating variables from neuron models. In this formulation, only measured variables enter into the model, and the resulting errors are themselves modeled by nonlinear stochastic processes with memory. Finally, variational annealing, a data assimilation method previously applied to dynamical systems, is introduced as a potentially useful tool for understanding deep neural network training in machine learning by exploiting similarities between the two problems.

Nonlinear probabilistic finite element models of laminated composite shells

NASA Technical Reports Server (NTRS)

Engelstad, S. P.; Reddy, J. N.

1993-01-01

A probabilistic finite element analysis procedure for laminated composite shells has been developed. A total Lagrangian finite element formulation, employing a degenerated 3-D laminated composite shell with the full Green-Lagrange strains and first-order shear deformable kinematics, forms the modeling foundation. The first-order second-moment technique for probabilistic finite element analysis of random fields is employed and results are presented in the form of mean and variance of the structural response. The effects of material nonlinearity are included through the use of a rate-independent anisotropic plasticity formulation with the macroscopic point of view. Both ply-level and micromechanics-level random variables can be selected, the latter by means of the Aboudi micromechanics model. A number of sample problems are solved to verify the accuracy of the procedures developed and to quantify the variability of certain material type/structure combinations. Experimental data is compared in many cases, and the Monte Carlo simulation method is used to check the probabilistic results. In general, the procedure is quite effective in modeling the mean and variance response of the linear and nonlinear behavior of laminated composite shells.

On Mixed Data and Event Driven Design for Adaptive-Critic-Based Nonlinear $H_{\\infty}$ Control.

PubMed

Wang, Ding; Mu, Chaoxu; Liu, Derong; Ma, Hongwen

2018-04-01

In this paper, based on the adaptive critic learning technique, the control for a class of unknown nonlinear dynamic systems is investigated by adopting a mixed data and event driven design approach. The nonlinear control problem is formulated as a two-player zero-sum differential game and the adaptive critic method is employed to cope with the data-based optimization. The novelty lies in that the data driven learning identifier is combined with the event driven design formulation, in order to develop the adaptive critic controller, thereby accomplishing the nonlinear control. The event driven optimal control law and the time driven worst case disturbance law are approximated by constructing and tuning a critic neural network. Applying the event driven feedback control, the closed-loop system is built with stability analysis. Simulation studies are conducted to verify the theoretical results and illustrate the control performance. It is significant to observe that the present research provides a new avenue of integrating data-based control and event-triggering mechanism into establishing advanced adaptive critic systems.

Geometrical optics analysis of the structural imperfection of retroreflection corner cubes with a nonlinear conjugate gradient method.

PubMed

Kim, Hwi; Min, Sung-Wook; Lee, Byoungho

2008-12-01

Geometrical optics analysis of the structural imperfection of retroreflection corner cubes is described. In the analysis, a geometrical optics model of six-beam reflection patterns generated by an imperfect retroreflection corner cube is developed, and its structural error extraction is formulated as a nonlinear optimization problem. The nonlinear conjugate gradient method is employed for solving the nonlinear optimization problem, and its detailed implementation is described. The proposed method of analysis is a mathematical basis for the nondestructive optical inspection of imperfectly fabricated retroreflection corner cubes.

Asymptotically exact parabolic solutions of the generalized nonlinear Schrödinger equation with varying parameters

NASA Astrophysics Data System (ADS)

Kruglov, Vladimir I.; Harvey, John D.

2006-12-01

We present exact asymptotic similariton solutions of the generalized nonlinear Schrödinger equation (NLSE) with gain or loss terms for a normal-dispersion fiber amplifier with dispersion, nonlinearity, and gain profiles that depend on the propagation distance. Our treatment is based on the mapping of the NLSE with varying parameters to the NLSE with constant dispersion and nonlinearity coefficients and an arbitrary varying gain function. We formulate an effective procedure that leads directly, under appropriate conditions, to a wide range of exact asymptotic similariton solutions of NLSE demonstrating self-similar propagating regimes with linear chirp.

Convergence of Galerkin approximations for operator Riccati equations: A nonlinear evolution equation approach

NASA Technical Reports Server (NTRS)

Rosen, I. G.

1988-01-01

An approximation and convergence theory was developed for Galerkin approximations to infinite dimensional operator Riccati differential equations formulated in the space of Hilbert-Schmidt operators on a separable Hilbert space. The Riccati equation was treated as a nonlinear evolution equation with dynamics described by a nonlinear monotone perturbation of a strongly coercive linear operator. A generic approximation result was proven for quasi-autonomous nonlinear evolution system involving accretive operators which was then used to demonstrate the Hilbert-Schmidt norm convergence of Galerkin approximations to the solution of the Riccati equation. The application of the results was illustrated in the context of a linear quadratic optimal control problem for a one dimensional heat equation.

A geometrically exact formulation for three-dimensional numerical simulation of the umbilical cable in a deep-sea ROV system

NASA Astrophysics Data System (ADS)

Quan, Wei-cai; Zhang, Zhu-ying; Zhang, Ai-qun; Zhang, Qi-feng; Tian, Yu

2015-04-01

This paper proposes a geometrically exact formulation for three-dimensional static and dynamic analyses of the umbilical cable in a deep-sea remotely operated vehicle (ROV) system. The presented formulation takes account of the geometric nonlinearities of large displacement, effects of axial load and bending stiffness for modeling of slack cables. The resulting nonlinear second-order governing equations are discretized spatially by the finite element method and solved temporally by the generalized- α implicit time integration algorithm, which is adapted to the case of varying coefficient matrices. The ability to consider three-dimensional union action of ocean current and ship heave motion upon the umbilical cable is the key feature of this analysis. The presented formulation is firstly validated, and then three numerical examples for the umbilical cable in a deep-sea ROV system are demonstrated and discussed, including the steady configurations only under the action of depth-dependent ocean current, the dynamic responses in the case of the only ship heave motion, and in the case of the combined action of the ship heave motion and ocean current.

Multiple-mode nonlinear free and forced vibrations of beams using finite element method

NASA Technical Reports Server (NTRS)

Mei, Chuh; Decha-Umphai, Kamolphan

1987-01-01

Multiple-mode nonlinear free and forced vibration of a beam is analyzed by the finite element method. The geometric nonlinearity is investigated. Inplane displacement and inertia (IDI) are also considered in the formulation. Harmonic force matrix is derived and explained. Nonlinear free vibration can be simply treated as a special case of the general forced vibration by setting the harmonic force matrix equal to zero. The effect of the higher modes is more pronouced for the clamped supported beam than the simply supported one. Beams without IDI yield more effect of the higher modes than the one with IDI. The effects of IDI are to reduce nonlinearity. For beams with end supports restrained from axial movement (immovable cases), only the hardening type nonlinearity is observed. However, beams of small slenderness ratio (L/R = 20) with movable end supports, the softening type nonlinearity is found. The concentrated force case yields a more severe response than the uniformly distributed force case. Finite element results are in good agreement with the solution of simple elliptic response, harmonic balance method, and Runge-Kutte method and experiment.

In vivo assessment and dosimetry of 2 novel PDE10A PET radiotracers in humans: 18F-MNI-659 and 18F-MNI-654.

PubMed

Barret, Olivier; Thomae, David; Tavares, Adriana; Alagille, David; Papin, Caroline; Waterhouse, Rikki; McCarthy, Timothy; Jennings, Danna; Marek, Ken; Russell, David; Seibyl, John; Tamagnan, Gilles

2014-08-01

Phosphodiesterase (PDE) 10A is an enzyme involved in the regulation of cyclic adenosine monophosphate and cyclic guanosine monophosphate and is highly expressed in medium-sized spiny neurons of the striatum, making it an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function. Potential ligands for PET imaging of PDE10A have been reported. Here, we report the first-in-human characterization of 2 new PDE10A radioligands, 2-(2-(3-(1-(2-fluoroethyl)-1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ((18)F-MNI-654) and 2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ((18)F-MNI-659), with the goal of selecting the best one for use in future studies interrogating pathophysiologic changes in neuropsychiatric disorders and aiding pharmaceutical development targeting PDE10A. Eleven healthy volunteers participated in this study ((18)F-MNI-654 test-retest, 2 men; (18)F-MNI-659 test-retest, 4 men and 1 woman; (18)F-MNI-659 dosimetry, 2 men and 2 women). Brain PET images were acquired over 5.5 h for (18)F-MNI-654 and over 3.5 h for (18)F-MNI-659, and pharmacokinetic modeling with plasma- and reference-region (cerebellar cortex)-based methods was performed. Whole-body PET images were acquired over 6 h for (18)F-MNI-659 and radiation dosimetry estimated with OLINDA. Both radiotracers were similarly metabolized, with about 20% of intact parent remaining at 120 min after injection. PET time-activity data demonstrated that (18)F-MNI-654 kinetics were much slower than (18)F-MNI-659 kinetics. For (18)F-MNI-659, there was good agreement between the Logan and simplified reference tissue models for nondisplaceable binding potential (BPND), supporting noninvasive quantification, with test-retest variability less than 10% and intraclass correlation greater than 0.9. The (18)F-MNI-659 effective dose was

Phenotypic Variability in a Family with Acrodysostosis Type 2 Caused by a Novel PDE4D Mutation Affecting the Serine Target of Protein Kinase-A Phosphorylation

PubMed Central

Hoppmann, Julia; Gesing, Julia; Silve, Caroline; Leroy, Chrystel; Bertsche, Astrid; Hirsch, Franz Wolfgang; Kiess, Wieland; Pfäffle, Roland; Schuster, Volker

2017-01-01

Acrodysostosis is a very rare congenital multisystem condition characterized by skeletal dysplasia with severe brachydactyly, midfacial hypoplasia, and short stature, varying degrees of intellectual disability, and possible resistance to multiple G protein-coupled receptor signalling hormones. Two distinct subtypes are differentiated: acrodysostosis type 1 resulting from defects in protein kinase type 1-α regulatory subunit and acrodysostosis type 2 caused by mutations in phosphodiesterase 4D (PDE4D). Most cases are sporadic. We report on a rare multigenerational familial case of acrodysostosis type 2 due to a novel autosomal dominantly inherited PDE4D mutation. A 3.5-year-old boy presented with short stature, midfacial hypoplasia, severe brachydactyly, developmental delay, and behavioural problems. Laboratory investigations revealed mild thyrotropin resistance. His mother shared some characteristic features, such as midfacial hypoplasia and severe brachydactyly, but did not show short stature, intellectual disability or hormonal resistance. Genetic analysis identified the identical, novel heterozygous missense mutation of the PDE4D gene c.569C>T (p.Ser190Phe) in both patients. This case illustrates the significant phenotypic variability of acrodysostosis even within one family with identical mutations. Hence, a specific clinical diagnosis of acrodysostosis remains challenging because of great interindividual variability and a substantial overlap of the two subtypes as well as with other related Gsα-cAMP-signalling-linked disorders. PMID:28515031

Heat and mass transfer of Williamson nanofluid flow yield by an inclined Lorentz force over a nonlinear stretching sheet

NASA Astrophysics Data System (ADS)

Khan, Mair; Malik, M. Y.; Salahuddin, T.; Hussian, Arif.

2018-03-01

The present analysis is devoted to explore the computational solution of the problem addressing the variable viscosity and inclined Lorentz force effects on Williamson nanofluid over a stretching sheet. Variable viscosity is assumed to vary as a linear function of temperature. The basic mathematical modelled problem i.e. system of PDE's is converted nonlinear into ODE's via applying suitable transformations. Computational solutions of the problem is also achieved via efficient numerical technique shooting. Characteristics of controlling parameters i.e. stretching index, inclined angle, Hartmann number, Weissenberg number, variable viscosity parameter, mixed convention parameter, Brownian motion parameter, Prandtl number, Lewis number, thermophoresis parameter and chemical reactive species on concentration, temperature and velocity gradient. Additionally, friction factor coefficient, Nusselt number and Sherwood number are describe with the help of graphics as well as tables verses flow controlling parameters.

Lagrangian formulation for penny-shaped and Perkins-Kern geometry models

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

Lee, W.S.

1989-09-01

This paper discusses basic theories for vertical penny-shaped and Perkins-Kern (PK) geometry models developed with a Lagrangian formulation combined with a virtual-work analysis. The Lagrangian formulation yields a pair of nonlinear equations in R/sub f/ or L/sub f/ and b/sub f/, the fracture radius or length and half-width. By introduction of a virtual-work analysis, a simple equation is obtained that can be solved numerically. This equation is written in a form that can be used to determine fracture geometry when the fluid-loss coefficient of the fracturing fluid is known. Also, this equation, coupled with a material-balance equation after shut-in, canmore » be used to analyze pressure-decline data after shut-in to determine the effective fluid-loss coefficient and fracture geometry.« less

Muscle MRS detects elevated PDE/ATP ratios prior to fatty infiltration in Becker muscular dystrophy.

PubMed

Wokke, B H; Hooijmans, M T; van den Bergen, J C; Webb, A G; Verschuuren, J J; Kan, H E

2014-11-01

Becker muscular dystrophy (BMD) is characterized by progressive muscle weakness. Muscles show structural changes (fatty infiltration, fibrosis) and metabolic changes, both of which can be assessed using MRI and MRS. It is unknown at what stage of the disease process metabolic changes arise and how this might vary for different metabolites. In this study we assessed metabolic changes in skeletal muscles of Becker patients, both with and without fatty infiltration, quantified via Dixon MRI and (31) P MRS. MRI and (31) P MRS scans were obtained from 25 Becker patients and 14 healthy controls using a 7 T MR scanner. Five lower-leg muscles were individually assessed for fat and muscle metabolite levels. In the peroneus, soleus and anterior tibialis muscles with non-increased fat levels, PDE/ATP ratios were higher (P < 0.02) compared with controls, whereas in all muscles with increased fat levels PDE/ATP ratios were higher compared with healthy controls (P ≤ 0.05). The Pi /ATP ratio in the peroneus muscles was higher in muscles with increased fat fractions (P = 0.005), and the PCr/ATP ratio was lower in the anterior tibialis muscles with increased fat fractions (P = 0.005). There were no other significant changes in metabolites, but an increase in tissue pH was found in all muscles of the total group of BMD patients in comparison with healthy controls (P < 0.05). These findings suggest that (31) P MRS can be used to detect early changes in individual muscles of BMD patients, which are present before the onset of fatty infiltration. Copyright © 2014 John Wiley & Sons, Ltd.

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.

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

Nonlinear forcing in the resolvent analysis of wall-turbulence

NASA Astrophysics Data System (ADS)

Rosenberg, Kevin; Lozano Duran, Adrian; Towne, Aaron; McKeon, Beverley

2016-11-01

The resolvent analysis of McKeon and Sharma formulates the Navier-Stokes equations as an input/output system in which the nonlinearity is treated as a forcing that acts upon the linear dynamics to yield a velocity response across wavenumber/frequency space. DNS data for a low Reynolds number turbulent channel (Reτ = 180) is used to investigate the structure of the nonlinear forcing directly. Specifically, we explore the spatio-temporal scales where the forcing is active and analyze its interplay with the linear amplification mechanisms present in the resolvent operator. This work could provide insight into self-sustaining processes in wall-turbulence and inform the modeling of scale interactions in large eddy simulations. We gratefully acknowledge Stanford's Center for Turbulence Research for support of this work.

Nonlinear guided wave propagation in prestressed plates.

PubMed

Pau, Annamaria; Lanza di Scalea, Francesco

2015-03-01

The measurement of stress in a structure presents considerable interest in many fields of engineering. In this paper, the diagnostic potential of nonlinear elastic guided waves in a prestressed plate is investigated. To do so, an analytical model is formulated accounting for different aspects involved in the phenomenon. The fact that the initial strains can be finite is considered using the Green Lagrange strain tensor, and initial and final configurations are not merged, as it would be assumed in the infinitesimal strain theory. Moreover, an appropriate third-order expression of the strain energy of the hyperelastic body is adopted to account for the material nonlinearities. The model obtained enables to investigate both the linearized case, which gives the variation of phase and group velocity as a function of the initial stress, and the nonlinear case, involving second-harmonic generation as a function of the initial state of stress. The analysis is limited to Rayleigh-Lamb waves propagating in a plate. Three cases of initial prestress are considered, including prestress in the direction of the wave propagation, prestress orthogonal to the direction of wave propagation, and plane isotropic stress.

Pharmacokinetic analysis of modified-release metoprolol formulations: An interspecies comparison.

PubMed

De Thaye, Elien; Vervaeck, Anouk; Marostica, Eleonora; Remon, Jean Paul; Van Bocxlaer, Jan; Vervaet, Chris; Vermeulen, An

2017-01-15

In the current study, we investigated the metoprolol absorption kinetics of an in-house produced oral sustained-release formulation, matrices manufactured via prilling, and two commercially available formulations, ZOK-ZID ® (reservoir) and Slow-Lopresor ® (matrix) in both New Zealand White rabbits and Beagle dogs, using a population pharmacokinetic analysis approach. The aim of this study was to compare the in vivo pharmacokinetic (PK) profiles of different formulations based on metoprolol, a selective adrenergic β 1 -receptor antagonist, in dogs and rabbits and to contrast the observed differences. To that end, metoprolol (50 to 200mg) was administered to 6 Beagle dogs and 6 New Zealand White rabbits as a single intravenous (IV) bolus injection and to 8 dogs and 6 rabbits as an oral modified release formulation. To derive pharmacokinetic parameters from the data, a non-linear mixed-effects model was developed using NONMEM ® where the contribution of observations below the limit of detection (BDL, below detection limit) to the parameter estimates was taken into account in the parameter estimation procedure. In both species and for the three modified release formulations, different absorption models were tested to describe the PK of metoprolol following oral dosing. In Beagle dogs, plasma concentration-time profiles were best described using a sequential zero- and first-order absorption model. In rabbits though, the absorption phase was best described using a first-order process only. In both species, the reservoir formulation ZOK-ZID ® was behaving quite similarly. In contrast, the absorption properties of both matrix formulations were rather different between species. This study indicates that the PK of the reservoir formulation is similar in both species, even after accounting for the almost completely missed absorption phase in rabbits. The insights gained further illustrate that rabbits are not very well suited to study the PK of the current matrix

Equivalent linearization for fatigue life estimates of a nonlinear structure

NASA Technical Reports Server (NTRS)

Miles, R. N.

1989-01-01

An analysis is presented of the suitability of the method of equivalent linearization for estimating the fatigue life of a nonlinear structure. Comparisons are made of the fatigue life of a nonlinear plate as predicted using conventional equivalent linearization and three other more accurate methods. The excitation of the plate is assumed to be Gaussian white noise and the plate response is modeled using a single resonant mode. The methods used for comparison consist of numerical simulation, a probabalistic formulation, and a modification of equivalent linearization which avoids the usual assumption that the response process is Gaussian. Remarkably close agreement is obtained between all four methods, even for cases where the response is significantly linear.

On the conditions for nonlinear growth in magnetospheric chorus and triggered emissions

NASA Astrophysics Data System (ADS)

Gołkowski, Mark; Gibby, Andrew R.

2017-09-01

The nonlinear whistler mode instability associated with magnetospheric chorus and VLF triggered emissions continues to be poorly understood. Following up on formulations of other authors, an analytical exploration of the stability of the phenomenon from a new vantage point is given. This exploration derives an additional requirement on the anisotropy of the energetic electron distribution relative to the linear treatment of the instability, and shows that the nonlinear instability is most favorable to increasing growth rate when electrons become initially trapped in the wave potential of a constant frequency wave. These results imply that the initiation of the nonlinear instability at the equator requires a positive frequency sweep rate, while the initiation of the instability by a constant frequency triggering wave must occur at a location downstream of the geomagnetic equator.

Nonlinear equations for dynamics of pretwisted beams undergoing small strains and large rotations

NASA Technical Reports Server (NTRS)

Hodges, D. H.

1985-01-01

Nonlinear beam kinematics are developed and applied to the dynamic analysis of a pretwisted, rotating beam element. The common practice of assuming moderate rotations caused by structural deformation in geometric nonlinear analyses of rotating beams was abandoned in the present analysis. The kinematic relations that described the orientation of the cross section during deformation are simplified by systematically ignoring the extensional strain compared to unity in those relations. Open cross section effects such as warping rigidity and dynamics are ignored, but other influences of warp are retained. The beam cross section is not allowed to deform in its own plane. Various means of implementation are discussed, including a finite element formulation. Numerical results obtained for nonlinear static problems show remarkable agreement with experiment.

Development of two fluorine-18 labeled PET radioligands targeting PDE10A and in vivo PET evaluation in nonhuman primates.

PubMed

Stepanov, Vladimir; Takano, Akihiro; Nakao, Ryuji; Amini, Nahid; Miura, Shotaro; Hasui, Tomoaki; Kimura, Haruhide; Taniguchi, Takahiko; Halldin, Christer

2018-02-01

Phosphodiesterase 10A (PDE10A) is a member of the PDE enzyme family that degrades cyclic adenosine and guanosine monophosphates (cAMP and cGMP). Based on the successful development of [ 11 C]T-773 as PDE10A positron emission tomography (PET) radioligand, in this study our aim was to develop and evaluate fluorine-18 analogs of [ 11 C]T-773. [ 18 F]FM-T-773-d 2 and [ 18 F]FE-T-773-d 4 were synthesized from the same precursor used for 11 C-labeling of T-773 in a two-step approach via 18 F-fluoromethylation and 18 F-fluoroethylation, respectively, using corresponding deuterated synthons. A total of 12 PET measurements were performed in seven non-human primates. First, baseline PET measurements were performed using High Resolution Research Tomograph system with both [ 18 F]FM-T-773-d 2 and [ 18 F]FE-T-773-d 4 ; the uptake in whole brain and separate brain regions, as well as the specific binding and tissue ratio between putamen and cerebellum, was examined. Second, baseline and pretreatment PET measurements using MP-10 as the blocker were performed for [ 18 F]FM-T-773-d 2 including arterial blood sampling with radiometabolite analysis in four NHPs. Both [ 18 F]FM-T-773-d 2 and [ 18 F]FE-T-773-d 4 were successfully radiolabeled with an average molar activity of 293 ± 114 GBq/μmol (n=8) for [ 18 F]FM-T-773-d 2 and 209 ± 26 GBq/μmol (n=4) for [ 18 F]FE-T-773-d 4 , and a radiochemical yield of 10% (EOB, n=12, range 3%-16%). Both radioligands displayed high brain uptake (~5.5% of injected radioactivity for [ 18 F]FM-T-773-d 2 and ~3.5% for [ 18 F]FE-T-773-d 4 at the peak) and a fast washout. Specific binding reached maximum within 30 min for [ 18 F]FM-T-773-d 2 and after approximately 45 min for [ 18 F]FE-T-773-d 4 . [ 18 F]FM-T-773-d 2 data fitted well with kinetic compartment models. BP ND values obtained indirectly through compartment models were correlated well with those obtained by SRTM. BP ND calculated with SRTM was 1.0-1.7 in the putamen. The occupancy with 1

Taming the nonlinearity of the Einstein equation.

PubMed

Harte, Abraham I

2014-12-31

Many of the technical complications associated with the general theory of relativity ultimately stem from the nonlinearity of Einstein's equation. It is shown here that an appropriate choice of dynamical variables may be used to eliminate all such nonlinearities beyond a particular order: Both Landau-Lifshitz and tetrad formulations of Einstein's equation are obtained that involve only finite products of the unknowns and their derivatives. Considerable additional simplifications arise in physically interesting cases where metrics become approximately Kerr or, e.g., plane waves, suggesting that the variables described here can be used to efficiently reformulate perturbation theory in a variety of contexts. In all cases, these variables are shown to have simple geometrical interpretations that directly relate the local causal structure associated with the metric of interest to the causal structure associated with a prescribed background. A new method to search for exact solutions is outlined as well.

Slave finite elements: The temporal element approach to nonlinear analysis

NASA Technical Reports Server (NTRS)

Gellin, S.

1984-01-01

A formulation method for finite elements in space and time incorporating nonlinear geometric and material behavior is presented. The method uses interpolation polynomials for approximating the behavior of various quantities over the element domain, and only explicit integration over space and time. While applications are general, the plate and shell elements that are currently being programmed are appropriate to model turbine blades, vanes, and combustor liners.

Determination of Nonlinear Stiffness Coefficients for Finite Element Models with Application to the Random Vibration Problem

NASA Technical Reports Server (NTRS)

Muravyov, Alexander A.

1999-01-01

In this paper, a method for obtaining nonlinear stiffness coefficients in modal coordinates for geometrically nonlinear finite-element models is developed. The method requires application of a finite-element program with a geometrically non- linear static capability. The MSC/NASTRAN code is employed for this purpose. The equations of motion of a MDOF system are formulated in modal coordinates. A set of linear eigenvectors is used to approximate the solution of the nonlinear problem. The random vibration problem of the MDOF nonlinear system is then considered. The solutions obtained by application of two different versions of a stochastic linearization technique are compared with linear and exact (analytical) solutions in terms of root-mean-square (RMS) displacements and strains for a beam structure.

Computational Methods for Design, Estimation and Real-Time Control of PDE Systems with Applications to Mobile Sensor Networks

DTIC Science & Technology

2013-08-14

TIME CONTROL OF PDE SYSTEMS WITH APPLICATIONS TO MOBILE SENSOR NETWORKS Finall Report: AFOSR Grant...linear time invariant (LTI) control problem. If the control is a linear function of the states, then the closed loop system then takes the form[ żr u̇...Ar2 A r 3 0T 0 ] − [ Br 1 ] K ) ︸ ︷︷ ︸ Ac [ zr u ] . (3) As the purpose of the control law is to stabilize the system , it is desired to have

Enhancement of linear/nonlinear optical responses of molecular vibrations using metal nanoantennas

NASA Astrophysics Data System (ADS)

Morichika, Ikki; Kusa, Fumiya; Takegami, Akinobu; Ashihara, Satoshi

2017-04-01

Plasmonic enhancements of optical near-fields with metal nanostructures offer extensive potential for amplifying lightmatter interactions. We analytically formulate the enhancement of linear and nonlinear optical responses of molecular vibrations through resonant nanoantennas, based on a coupled-dipole model. We apply the formulae to evaluation of signal enhancement factors in the antenna-enhanced vibrational spectroscopy.

[Effectiveness of low-intensity extracorporeal shock wave therapy on patients with Erectile Dysfunction (ED) who have failed to respond to PDE5i therapy. A pilot study].

PubMed

Bechara, Amado; Casabé, Adolfo; De Bonis, Walter; Nazar, Julián

2015-03-01

Low-intensity extracorporeal shock wave therapy (LIESWT) of the penis has recently emerged as a promising modality in the treatment of ED. The objective of this paper is to assess the effectiveness and safety of LIESWT on patients with ED who have failed to respond to PDE5i treatment. Open label, prospective, longitudinal observational study. The study involved an uncontrolled population of 25 patients. The treatment consisted in applying 20,000 shock waves during a period of four weeks. In each session the patient received 5000 shock waves of 0.09 mJ/mm2: 1800 were applied on the penis (900 on each corpus cavernosum), and 3200 were applied on the perineum (1600 on each crus). During the active treatment and follow-up phases, all patients remained on their regular high on demand or once-a-day dose PDE5i schedules. Effectiveness was assessed by IIEF-6, SEP2, SEP3 and GAQ. Patients were considered to be responders whenever they improved on all three erection assessment parameters and respond positively to the GAQ at three months post-treatment. Adverse events were recorded. Statistical variables were applied and findings were considered to be statistically significant whenever the P value was<0.05. Eighty percent (median age 63) of the patients (20/25) completed the study. Five patients were lost to follow-up and were excluded from the analysis. Sixty percent (60%) of the patients responded to the treatment, improved the 3 efficacy evaluating parameters and responded positively to the GAQ. The increase in mean IIEF-6 score was of 9 points after the third post-treatment month. There were no patients reporting treatment-related adverse events. LIESWT for men with ED and that are PDE5i non-responders was safe and effective and restoring PDE5i response in more than 50% of patients.A large-scale multicenter study is required to determine the benefits of this treatment for ED.

Control of nonlinear flexible space structures

NASA Astrophysics Data System (ADS)

Shi, Jianjun

With the advances made in computer technology and efficiency of numerical algorithms over last decade, the MPC strategies have become quite popular among control community. However, application of MPC or GPC to flexible space structure control has not been explored adequately in the literature. The work presented in this thesis primarily focuses on application of GPC to control of nonlinear flexible space structures. This thesis is particularly devoted to the development of various approximate dynamic models, design and assessment of candidate controllers, and extensive numerical simulations for a realistic multibody flexible spacecraft, namely, Jupiter Icy Moons Orbiter (JIMO)---a Prometheus class of spacecraft proposed by NASA for deep space exploratory missions. A stable GPC algorithm is developed for Multi-Input-Multi-Output (MIMO) systems. An end-point weighting (penalty) is used in the GPC cost function to guarantee the nominal stability of the closed-loop system. A method is given to compute the desired end-point state from the desired output trajectory. The methodologies based on Fake Algebraic Riccati Equation (FARE) and constrained nonlinear optimization, are developed for synthesis of state weighting matrix. This makes this formulation more practical. A stable reconfigurable GPC architecture is presented and its effectiveness is demonstrated on both aircraft as well as spacecraft model. A representative in-orbit maneuver is used for assessing the performance of various control strategies using various design models. Different approximate dynamic models used for analysis include linear single body flexible structure, nonlinear single body flexible structure, and nonlinear multibody flexible structure. The control laws evaluated include traditional GPC, feedback linearization-based GPC (FLGPC), reconfigurable GPC, and nonlinear dissipative control. These various control schemes are evaluated for robust stability and robust performance in the presence of

Isogeometric Kirchhoff-Love shell formulations for biological membranes

PubMed Central

Tepole, Adrián Buganza; Kabaria, Hardik; Bletzinger, Kai-Uwe; Kuhl, Ellen

2015-01-01

Computational modeling of thin biological membranes can aid the design of better medical devices. Remarkable biological membranes include skin, alveoli, blood vessels, and heart valves. Isogeometric analysis is ideally suited for biological membranes since it inherently satisfies the C1-requirement for Kirchhoff-Love kinematics. Yet, current isogeometric shell formulations are mainly focused on linear isotropic materials, while biological tissues are characterized by a nonlinear anisotropic stress-strain response. Here we present a thin shell formulation for thin biological membranes. We derive the equilibrium equations using curvilinear convective coordinates on NURBS tensor product surface patches. We linearize the weak form of the generic linear momentum balance without a particular choice of a constitutive law. We then incorporate the constitutive equations that have been designed specifically for collagenous tissues. We explore three common anisotropic material models: Mooney-Rivlin, May Newmann-Yin, and Gasser-Ogden-Holzapfel. Our work will allow scientists in biomechanics and mechanobiology to adopt the constitutive equations that have been developed for solid three-dimensional soft tissues within the framework of isogeometric thin shell analysis. PMID:26251556

Distributed Coordinated Control of Large-Scale Nonlinear Networks

DOE PAGES

Kundu, Soumya; Anghel, Marian

2015-11-08

We provide a distributed coordinated approach to the stability analysis and control design of largescale nonlinear dynamical systems by using a vector Lyapunov functions approach. In this formulation the large-scale system is decomposed into a network of interacting subsystems and the stability of the system is analyzed through a comparison system. However finding such comparison system is not trivial. In this work, we propose a sum-of-squares based completely decentralized approach for computing the comparison systems for networks of nonlinear systems. Moreover, based on the comparison systems, we introduce a distributed optimal control strategy in which the individual subsystems (agents) coordinatemore » with their immediate neighbors to design local control policies that can exponentially stabilize the full system under initial disturbances.We illustrate the control algorithm on a network of interacting Van der Pol systems.« less

Nonlinear Dispersive Elastic Waves in Solids: Exact, Approximate, and Numerical Solutions

NASA Astrophysics Data System (ADS)

Khajehtourian, Romik

Wave motion lies at the heart of many disciplines in the physical sciences and engineering. For example, problems and applications involving light, sound, heat, or fluid flow are all likely to involve wave dynamics at some level. A particular class of problems is concerned with the propagation of elastic waves in a solid medium, such as a fiber-reinforced composite material responding to vibratory excitations, or soil and rock admitting seismic waves moments after the onset of an earthquake, or phonon transport in a semiconducting crystal like silicon. Regardless of the type of wave, the dispersion relation provides a fundamental characterization of the elastodynamic properties of the medium. The first part of the dissertation examines the propagation of a large-amplitude elastic wave in a one-dimensional homogeneous medium with a focus on the effects of inherent nonlinearities on the dispersion relation. Considering a thin rod, where the thickness is small compared to the wavelength, an exact, closed-form formulation is presented for the treatment of two types of nonlinearity in the strain-displacement gradient relation: Green-Lagrange and Hencky. The derived relation is then verified by direct time-domain simulations, examining both instantaneous dispersion (by direct observation) and short-term, pre-breaking dispersion (by Fourier transformation). A high-order perturbation analysis is also conducted yielding an explicit analytical space-time solution, which is shown to be spectrally accurate. The results establish a perfect match between theory and simulation and reveal that regardless of the strength of the nonlinearity, the dispersion relation fully embodies all information pertaining to the nonlinear harmonic generation mechanism that unfolds as an arbitrary-profiled wave evolves in the medium. In the second part of the dissertation, the analysis is extended to a continuous periodic thin rod exhibiting multiple phases or embedded local resonators. The

High order ADER schemes for a unified first order hyperbolic formulation of Newtonian continuum mechanics coupled with electro-dynamics

NASA Astrophysics Data System (ADS)

Dumbser, Michael; Peshkov, Ilya; Romenski, Evgeniy; Zanotti, Olindo

2017-11-01

In this paper, we propose a new unified first order hyperbolic model of Newtonian continuum mechanics coupled with electro-dynamics. The model is able to describe the behavior of moving elasto-plastic dielectric solids as well as viscous and inviscid fluids in the presence of electro-magnetic fields. It is actually a very peculiar feature of the proposed PDE system that viscous fluids are treated just as a special case of elasto-plastic solids. This is achieved by introducing a strain relaxation mechanism in the evolution equations of the distortion matrix A, which in the case of purely elastic solids maps the current configuration to the reference configuration. The model also contains a hyperbolic formulation of heat conduction as well as a dissipative source term in the evolution equations for the electric field given by Ohm's law. Via formal asymptotic analysis we show that in the stiff limit, the governing first order hyperbolic PDE system with relaxation source terms tends asymptotically to the well-known viscous and resistive magnetohydrodynamics (MHD) equations. Furthermore, a rigorous derivation of the model from variational principles is presented, together with the transformation of the Euler-Lagrange differential equations associated with the underlying variational problem from Lagrangian coordinates to Eulerian coordinates in a fixed laboratory frame. The present paper hence extends the unified first order hyperbolic model of Newtonian continuum mechanics recently proposed in [110,42] to the more general case where the continuum is coupled with electro-magnetic fields. The governing PDE system is symmetric hyperbolic and satisfies the first and second principle of thermodynamics, hence it belongs to the so-called class of symmetric hyperbolic thermodynamically compatible systems (SHTC), which have been studied for the first time by Godunov in 1961 [61] and later in a series of papers by Godunov and Romenski [67,69,119]. An important feature of the

Linear analysis using secants for materials with temperature dependent nonlinear elastic modulus and thermal expansion properties

NASA Astrophysics Data System (ADS)

Pepi, John W.

2017-08-01

Thermally induced stress is readily calculated for linear elastic material properties using Hooke's law in which, for situations where expansion is constrained, stress is proportional to the product of the material elastic modulus and its thermal strain. When material behavior is nonlinear, one needs to make use of nonlinear theory. However, we can avoid that complexity in some situations. For situations in which both elastic modulus and coefficient of thermal expansion vary with temperature, solutions can be formulated using secant properties. A theoretical approach is thus presented to calculate stresses for nonlinear, neo-Hookean, materials. This is important for high acuity optical systems undergoing large temperature extremes.

COPS: Large-scale nonlinearly constrained optimization problems

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

Bondarenko, A.S.; Bortz, D.M.; More, J.J.

2000-02-10

The authors have started the development of COPS, a collection of large-scale nonlinearly Constrained Optimization Problems. The primary purpose of this collection is to provide difficult test cases for optimization software. Problems in the current version of the collection come from fluid dynamics, population dynamics, optimal design, and optimal control. For each problem they provide a short description of the problem, notes on the formulation of the problem, and results of computational experiments with general optimization solvers. They currently have results for DONLP2, LANCELOT, MINOS, SNOPT, and LOQO.

PDK1/Akt/PDE4D axis identified as a target for asthma remedy synergistic with β2 AR agonists by a natural agent arctigenin.

PubMed

Fang, R; Cui, Q; Sun, J; Duan, X; Ma, X; Wang, W; Cheng, B; Liu, Y; Hou, Y; Bai, G

2015-12-01

Asthma is a heterogenetic disorder characterized by chronic inflammation with variable airflow obstruction and airway hyper-responsiveness. As the most potent and popular bronchodilators, β2 adrenergic receptor (β2 AR) agonists bind to the β2 ARs that are coupled via a stimulatory G protein to adenylyl cyclase, thereby improving cAMP accumulation and resulting in airway smooth muscle relaxation. We previously demonstrated arctigenin had a synergistic function with the β2 AR agonist, but the target for this remained elusive. Chemical proteomics capturing was used to enrich and uncover the target of arctigenin in human bronchial smooth muscle cells, and reverse docking and molecular dynamic stimulation were performed to evaluate the binding of arctigenin and its target. In vitro enzyme activities and protein levels were demonstrated with special kits and Western blotting. Finally, guinea pig tracheal muscle segregation and ex vivo function were analysed. Arctigenin bound to PDK1 with an ideal binding free energy -25.45 kcal/mol and inhibited PDK1 kinase activity without changing its protein level. Additionally, arctigenin reduced PKB/Akt-induced phosphorylation of PDE4D, which was first identified in this study. Attenuation of PDE4D resulted in cAMP accumulation in human bronchial smooth muscle. The inhibition of PDK1 showed a synergistic function with β2 AR agonists and relaxed the constriction of segregated guinea pig tracheal muscle. The PDK1/Akt/PDE4D axis serves as a novel asthma target, which may benefit airflow obstruction. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

A geometrical approach to control and controllability of nonlinear dynamical networks

PubMed Central

Wang, Le-Zhi; Su, Ri-Qi; Huang, Zi-Gang; Wang, Xiao; Wang, Wen-Xu; Grebogi, Celso; Lai, Ying-Cheng

2016-01-01

In spite of the recent interest and advances in linear controllability of complex networks, controlling nonlinear network dynamics remains an outstanding problem. Here we develop an experimentally feasible control framework for nonlinear dynamical networks that exhibit multistability. The control objective is to apply parameter perturbation to drive the system from one attractor to another, assuming that the former is undesired and the latter is desired. To make our framework practically meaningful, we consider restricted parameter perturbation by imposing two constraints: it must be experimentally realizable and applied only temporarily. We introduce the concept of attractor network, which allows us to formulate a quantifiable controllability framework for nonlinear dynamical networks: a network is more controllable if the attractor network is more strongly connected. We test our control framework using examples from various models of experimental gene regulatory networks and demonstrate the beneficial role of noise in facilitating control. PMID:27076273

Modelling formulations using gene expression programming--a comparative analysis with artificial neural networks.

PubMed

Colbourn, E A; Roskilly, S J; Rowe, R C; York, P

2011-10-09

This study has investigated the utility and potential advantages of gene expression programming (GEP)--a new development in evolutionary computing for modelling data and automatically generating equations that describe the cause-and-effect relationships in a system--to four types of pharmaceutical formulation and compared the models with those generated by neural networks, a technique now widely used in the formulation development. Both methods were capable of discovering subtle and non-linear relationships within the data, with no requirement from the user to specify the functional forms that should be used. Although the neural networks rapidly developed models with higher values for the ANOVA R(2) these were black box and provided little insight into the key relationships. However, GEP, although significantly slower at developing models, generated relatively simple equations describing the relationships that could be interpreted directly. The results indicate that GEP can be considered an effective and efficient modelling technique for formulation data. Copyright © 2011 Elsevier B.V. All rights reserved.

Pseudo-time methods for constrained optimization problems governed by PDE

NASA Technical Reports Server (NTRS)

Taasan, Shlomo

1995-01-01

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

On the correct representation of bending and axial deformation in the absolute nodal coordinate formulation with an elastic line approach

NASA Astrophysics Data System (ADS)

Gerstmayr, Johannes; Irschik, Hans

2008-12-01

In finite element methods that are based on position and slope coordinates, a representation of axial and bending deformation by means of an elastic line approach has become popular. Such beam and plate formulations based on the so-called absolute nodal coordinate formulation have not yet been verified sufficiently enough with respect to analytical results or classical nonlinear rod theories. Examining the existing planar absolute nodal coordinate element, which uses a curvature proportional bending strain expression, it turns out that the deformation does not fully agree with the solution of the geometrically exact theory and, even more serious, the normal force is incorrect. A correction based on the classical ideas of the extensible elastica and geometrically exact theories is applied and a consistent strain energy and bending moment relations are derived. The strain energy of the solid finite element formulation of the absolute nodal coordinate beam is based on the St. Venant-Kirchhoff material: therefore, the strain energy is derived for the latter case and compared to classical nonlinear rod theories. The error in the original absolute nodal coordinate formulation is documented by numerical examples. The numerical example of a large deformation cantilever beam shows that the normal force is incorrect when using the previous approach, while a perfect agreement between the absolute nodal coordinate formulation and the extensible elastica can be gained when applying the proposed modifications. The numerical examples show a very good agreement of reference analytical and numerical solutions with the solutions of the proposed beam formulation for the case of large deformation pre-curved static and dynamic problems, including buckling and eigenvalue analysis. The resulting beam formulation does not employ rotational degrees of freedom and therefore has advantages compared to classical beam elements regarding energy-momentum conservation.

Non-linear osmosis

PubMed Central

Diamond, Jared M.

1966-01-01

1. The relation between osmotic gradient and rate of osmotic water flow has been measured in rabbit gall-bladder by a gravimetric procedure and by a rapid method based on streaming potentials. Streaming potentials were directly proportional to gravimetrically measured water fluxes. 2. As in many other tissues, water flow was found to vary with gradient in a markedly non-linear fashion. There was no consistent relation between the water permeability and either the direction or the rate of water flow. 3. Water flow in response to a given gradient decreased at higher osmolarities. The resistance to water flow increased linearly with osmolarity over the range 186-825 m-osM. 4. The resistance to water flow was the same when the gall-bladder separated any two bathing solutions with the same average osmolarity, regardless of the magnitude of the gradient. In other words, the rate of water flow is given by the expression (Om — Os)/[Ro′ + ½k′ (Om + Os)], where Ro′ and k′ are constants and Om and Os are the bathing solution osmolarities. 5. Of the theories advanced to explain non-linear osmosis in other tissues, flow-induced membrane deformations, unstirred layers, asymmetrical series-membrane effects, and non-osmotic effects of solutes could not explain the results. However, experimental measurements of water permeability as a function of osmolarity permitted quantitative reconstruction of the observed water flow—osmotic gradient curves. Hence non-linear osmosis in rabbit gall-bladder is due to a decrease in water permeability with increasing osmolarity. 6. The results suggest that aqueous channels in the cell membrane behave as osmometers, shrinking in concentrated solutions of impermeant molecules and thereby increasing membrane resistance to water flow. A mathematical formulation of such a membrane structure is offered. PMID:5945254

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

Nonlinear Prediction Model for Hydrologic Time Series Based on Wavelet Decomposition

NASA Astrophysics Data System (ADS)

Kwon, H.; Khalil, A.; Brown, C.; Lall, U.; Ahn, H.; Moon, Y.

2005-12-01

Traditionally forecasting and characterizations of hydrologic systems is performed utilizing many techniques. Stochastic linear methods such as AR and ARIMA and nonlinear ones such as statistical learning theory based tools have been extensively used. The common difficulty to all methods is the determination of sufficient and necessary information and predictors for a successful prediction. Relationships between hydrologic variables are often highly nonlinear and interrelated across the temporal scale. A new hybrid approach is proposed for the simulation of hydrologic time series combining both the wavelet transform and the nonlinear model. The present model employs some merits of wavelet transform and nonlinear time series model. The Wavelet Transform is adopted to decompose a hydrologic nonlinear process into a set of mono-component signals, which are simulated by nonlinear model. The hybrid methodology is formulated in a manner to improve the accuracy of a long term forecasting. The proposed hybrid model yields much better results in terms of capturing and reproducing the time-frequency properties of the system at hand. Prediction results are promising when compared to traditional univariate time series models. An application of the plausibility of the proposed methodology is provided and the results conclude that wavelet based time series model can be utilized for simulating and forecasting of hydrologic variable reasonably well. This will ultimately serve the purpose of integrated water resources planning and management.

A triangular thin shell finite element: Nonlinear analysis. [structural analysis

NASA Technical Reports Server (NTRS)

Thomas, G. R.; Gallagher, R. H.

1975-01-01

Aspects of the formulation of a triangular thin shell finite element which pertain to geometrically nonlinear (small strain, finite displacement) behavior are described. The procedure for solution of the resulting nonlinear algebraic equations combines a one-step incremental (tangent stiffness) approach with one iteration in the Newton-Raphson mode. A method is presented which permits a rational estimation of step size in this procedure. Limit points are calculated by means of a superposition scheme coupled to the incremental side of the solution procedure while bifurcation points are calculated through a process of interpolation of the determinants of the tangent-stiffness matrix. Numerical results are obtained for a flat plate and two curved shell problems and are compared with alternative solutions.

Component mode synthesis and large deflection vibration of complex structures. Volume 3: Multiple-mode nonlinear free and forced vibrations of beams using finite element method

NASA Technical Reports Server (NTRS)

Mei, Chuh; Shen, Mo-How

1987-01-01

Multiple-mode nonlinear forced vibration of a beam was analyzed by the finite element method. Inplane (longitudinal) displacement and inertia (IDI) are considered in the formulation. By combining the finite element method and nonlinear theory, more realistic models of structural response are obtained more easily and faster.

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.

Nonlinear analysis of 0-3 polarized PLZT microplate based on the new modified couple stress theory

NASA Astrophysics Data System (ADS)

Wang, Liming; Zheng, Shijie

2018-02-01

In this study, based on the new modified couple stress theory, the size- dependent model for nonlinear bending analysis of a pure 0-3 polarized PLZT plate is developed for the first time. The equilibrium equations are derived from a variational formulation based on the potential energy principle and the new modified couple stress theory. The Galerkin method is adopted to derive the nonlinear algebraic equations from governing differential equations. And then the nonlinear algebraic equations are solved by using Newton-Raphson method. After simplification, the new model includes only a material length scale parameter. In addition, numerical examples are carried out to study the effect of material length scale parameter on the nonlinear bending of a simply supported pure 0-3 polarized PLZT plate subjected to light illumination and uniform distributed load. The results indicate the new model is able to capture the size effect and geometric nonlinearity.

An introduction to optimal power flow: Theory, formulation, and examples

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

Frank, Stephen; Rebennack, Steffen

The set of optimization problems in electric power systems engineering known collectively as Optimal Power Flow (OPF) is one of the most practically important and well-researched subfields of constrained nonlinear optimization. OPF has enjoyed a rich history of research, innovation, and publication since its debut five decades ago. Nevertheless, entry into OPF research is a daunting task for the uninitiated--both due to the sheer volume of literature and because OPF's ubiquity within the electric power systems community has led authors to assume a great deal of prior knowledge that readers unfamiliar with electric power systems may not possess. This articlemore » provides an introduction to OPF from an operations research perspective; it describes a complete and concise basis of knowledge for beginning OPF research. The discussion is tailored for the operations researcher who has experience with nonlinear optimization but little knowledge of electrical engineering. Topics covered include power systems modeling, the power flow equations, typical OPF formulations, and common OPF extensions.« less

Numerical study of nonlinear full wave acoustic propagation

NASA Astrophysics Data System (ADS)

Velasco-Segura, Roberto; Rendon, Pablo L.

2013-11-01

With the aim of describing nonlinear acoustic phenomena, a form of the conservation equations for fluid dynamics is presented, deduced using slightly less restrictive hypothesis than those necessary to obtain the well known Westervelt equation. This formulation accounts for full wave diffraction, nonlinearity, and thermoviscous dissipative effects. A CLAWPACK based, 2D finite-volume method using Roe's linearization has been implemented to obtain numerically the solution of the proposed equations. In order to validate the code, two different tests have been performed: one against a special Taylor shock-like analytic solution, the other against published results on a HIFU system, both with satisfactory results. The code is written for parallel execution on a GPU and improves performance by a factor of over 50 when compared to the standard CLAWPACK Fortran code. This code can be used to describe moderate nonlinear phenomena, at low Mach numbers, in domains as large as 100 wave lengths. Applications range from modest models of diagnostic and therapeutic HIFU, parametric acoustic arrays, to acoustic wave guides. A couple of examples will be presented showing shock formation and oblique interaction. DGAPA PAPIIT IN110411, PAEP UNAM 2013.

The Swift-Hohenberg equation with a nonlocal nonlinearity

NASA Astrophysics Data System (ADS)

Morgan, David; Dawes, Jonathan H. P.

2014-03-01

It is well known that aspects of the formation of localised states in a one-dimensional Swift-Hohenberg equation can be described by Ginzburg-Landau-type envelope equations. This paper extends these multiple scales analyses to cases where an additional nonlinear integral term, in the form of a convolution, is present. The presence of a kernel function introduces a new lengthscale into the problem, and this results in additional complexity in both the derivation of envelope equations and in the bifurcation structure. When the kernel is short-range, weakly nonlinear analysis results in envelope equations of standard type but whose coefficients are modified in complicated ways by the nonlinear nonlocal term. Nevertheless, these computations can be formulated quite generally in terms of properties of the Fourier transform of the kernel function. When the lengthscale associated with the kernel is longer, our method leads naturally to the derivation of two different, novel, envelope equations that describe aspects of the dynamics in these new regimes. The first of these contains additional bifurcations, and unexpected loops in the bifurcation diagram. The second of these captures the stretched-out nature of the homoclinic snaking curves that arises due to the nonlocal term.

Restoration of vision in the pde6β-deficient dog, a large animal model of rod-cone dystrophy.

PubMed

Petit, Lolita; Lhériteau, Elsa; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Guihal, Caroline; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

2012-11-01

Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment.

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.

Notes on the ExactPack Implementation of the DSD Explosive Arc Solver

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

Kaul, Ann; Doebling, Scott William

It has been shown above that the discretization scheme implemented in the ExactPack solver for the DSD Explosive Arc equation is consistent with the Explosive Arc PDE. In addition, a stability analysis has provided a CFL condition for a stable time step. Together, consistency and stability imply convergence of the scheme, which is expected to be close to first-order in time and second-order in space. It is understood that the nonlinearity of the underlying PDE will affect this rate somewhat.

Poly (amidoamine) dendrimer-mediated hybrid formulation for combination therapy of ramipril and hydrochlorothiazide.

PubMed

Singh, Mayank Kumar; Pooja, Deep; Kulhari, Hitesh; Jain, Sanjay Kumar; Sistla, Ramakrishna; Chauhan, Abhay Singh

2017-01-01

We present a dendrimer-based hybrid formulation strategy to explore the potential of poly (amidoamine) PAMAM dendrimers to be used as drug carriers for combination therapy of an anti-hypertensive drug ramipril (RAPL) and a diuretic hydrochlorothiazide (HCTZ). The drug-dendrimer complexes were prepared by phase-equilibration method. The results showed that the solubility of RAPL and HCTZ was dependent on dendrimer concentration and pH of dendrimer solution. The solubility profile of both RAPL and HCTZ dendrimer complexes illustrated a non-linear relationship with dendrimer concentration. At 0.8% (w/v) dendrimer concentration, solubility of RAPL was increased 4.91 folds with amine-terminated while for HCTZ, solubility enhancement was highest (3.72 folds) with carboxy-terminated. The complexes were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance analysis and high performance liquid chromatography. In-vitro drug dissolution performance of pure drugs, individual drug loaded dendrimer formulations and hybrid formulations was studied in USP dissolution medium (pH7.0) and in simulated gastric fluid (pH1.2). Dendrimer mediated formulations showed faster and complete dissolution compared to pure RAPL or HCTZ. Surprisingly, similar pattern of dissolution profile was established with hybrid formulations as compared to individual drug loaded dendrimers. The dendrimer-based hybrid formulations were found to be stable at dark and refrigerated conditions up to 5weeks. Conclusively, the proposed formulation strategy establishes a novel multitasking platform using dendrimer for simultaneous loading and delivery of multiple drugs for pharmaceutical applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Passive simulation of the nonlinear port-Hamiltonian modeling of a Rhodes Piano

NASA Astrophysics Data System (ADS)

Falaize, Antoine; Hélie, Thomas

2017-03-01

This paper deals with the time-domain simulation of an electro-mechanical piano: the Fender Rhodes. A simplified description of this multi-physical system is considered. It is composed of a hammer (nonlinear mechanical component), a cantilever beam (linear damped vibrating component) and a pickup (nonlinear magneto-electronic transducer). The approach is to propose a power-balanced formulation of the complete system, from which a guaranteed-passive simulation is derived to generate physically-based realistic sound synthesis. Theses issues are addressed in four steps. First, a class of Port-Hamiltonian Systems is introduced: these input-to-output systems fulfill a power balance that can be decomposed into conservative, dissipative and source parts. Second, physical models are proposed for each component and are recast in the port-Hamiltonian formulation. In particular, a finite-dimensional model of the cantilever beam is derived, based on a standard modal decomposition applied to the Euler-Bernoulli model. Third, these systems are interconnected, providing a nonlinear finite-dimensional Port-Hamiltonian System of the piano. Fourth, a passive-guaranteed numerical method is proposed. This method is built to preserve the power balance in the discrete-time domain, and more precisely, its decomposition structured into conservative, dissipative and source parts. Finally, simulations are performed for a set of physical parameters, based on empirical but realistic values. They provide a variety of audio signals which are perceptively relevant and qualitatively similar to some signals measured on a real instrument.

Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance.

PubMed

Xia, Wenmin; Pessentheiner, Ariane R; Hofer, Dina C; Amor, Melina; Schreiber, Renate; Schoiswohl, Gabriele; Eichmann, Thomas O; Walenta, Evelyn; Itariu, Bianca; Prager, Gerhard; Hackl, Hubert; Stulnig, Thomas; Kratky, Dagmar; Rülicke, Thomas; Bogner-Strauss, Juliane G

2018-05-15

Elevated circulating fatty acids (FAs) contribute to obesity-associated metabolic complications, but the mechanisms by which insulin suppresses lipolysis are poorly understood. We show that α/β-hydrolase domain-containing 15 (ABHD15) is required for the anti-lipolytic action of insulin in white adipose tissue (WAT). Neither insulin nor glucose treatments can suppress FA mobilization in global and conditional Abhd15-knockout (KO) mice. Accordingly, insulin signaling is impaired in Abhd15-KO adipocytes, as indicated by reduced AKT phosphorylation, glucose uptake, and de novo lipogenesis. In vitro data reveal that ABHD15 associates with and stabilizes phosphodiesterase 3B (PDE3B). Accordingly, PDE3B expression is decreased in the WAT of Abhd15-KO mice, mechanistically explaining increased protein kinase A (PKA) activity, hormone-sensitive lipase (HSL) phosphorylation, and undiminished FA release upon insulin signaling. Ultimately, Abhd15-KO mice develop insulin resistance. Notably, ABHD15 expression is decreased in humans with obesity and diabetes compared to humans with obesity and normal glucose tolerance, identifying ABHD15 as a potential therapeutic target to mitigate insulin resistance. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Influence of combined fundamental potentials in a nonlinear vibration energy harvester

NASA Astrophysics Data System (ADS)

Podder, Pranay; Mallick, Dhiman; Amann, Andreas; Roy, Saibal

2016-11-01

Ambient mechanical vibrations have emerged as a viable energy source for low-power wireless sensor nodes aiming the upcoming era of the ‘Internet of Things’. Recently, purposefully induced dynamical nonlinearities have been exploited to widen the frequency spectrum of vibration energy harvesters. Here we investigate some critical inconsistencies between the theoretical formulation and applications of the bistable Duffing nonlinearity in vibration energy harvesting. A novel nonlinear vibration energy harvesting device with the capability to switch amidst individually tunable bistable-quadratic, monostable-quartic and bistable-quartic potentials has been designed and characterized. Our study highlights the fundamentally different large deflection behaviors of the theoretical bistable-quartic Duffing oscillator and the experimentally adapted bistable-quadratic systems, and underlines their implications in the respective spectral responses. The results suggest enhanced performance in the bistable-quartic potential in comparison to others, primarily due to lower potential barrier and higher restoring forces facilitating large amplitude inter-well motion at relatively lower accelerations.

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.

A new impedance accounting for short- and long-range effects in mixed substructured formulations of nonlinear problems

NASA Astrophysics Data System (ADS)

Negrello, Camille; Gosselet, Pierre; Rey, Christian

2018-05-01

An efficient method for solving large nonlinear problems combines Newton solvers and Domain Decomposition Methods (DDM). In the DDM framework, the boundary conditions can be chosen to be primal, dual or mixed. The mixed approach presents the advantage to be eligible for the research of an optimal interface parameter (often called impedance) which can increase the convergence rate. The optimal value for this parameter is often too expensive to be computed exactly in practice: an approximate version has to be sought for, along with a compromise between efficiency and computational cost. In the context of parallel algorithms for solving nonlinear structural mechanical problems, we propose a new heuristic for the impedance which combines short and long range effects at a low computational cost.

Nonlinear spectral singularities for confined nonlinearities.

PubMed

Mostafazadeh, Ali

2013-06-28

We introduce a notion of spectral singularity that applies for a general class of nonlinear Schrödinger operators involving a confined nonlinearity. The presence of the nonlinearity does not break the parity-reflection symmetry of spectral singularities but makes them amplitude dependent. Nonlinear spectral singularities are, therefore, associated with a resonance effect that produces amplified waves with a specific amplitude-wavelength profile. We explore the consequences of this phenomenon for a complex δ-function potential that is subject to a general confined nonlinearity.

Micronuclei related to anti-B[a]PDE-DNA adduct in peripheral blood lymphocytes of heavily polycyclic aromatic hydrocarbon-exposed nonsmoking coke-oven workers and controls.

PubMed

Pavanello, Sofia; Kapka, Lucyna; Siwinska, Ewa; Mielzyñska, Danuta; Bolognesi, Claudia; Clonfero, Erminio

2008-10-01

Micronuclei (MN) frequency associated to biologically effective dose of polycyclic aromatic hydrocarbons [PAH; anti-benzo[a]pyrene diolepoxide (B[a]PDE)-DNA] within the same subjects' peripheral blood lymphocytes (PBL) was evaluated. Study subjects were nonsmoking male Polish coke-oven workers (n=49) and matched controls (n=45) verified for PAH exposure by urinary 1-pyrenol. We found that coke-oven workers, heavily exposed to PAHs (80% workers exceeded the urinary 1-pyrenol biological exposure index value), presented significantly higher MN frequency in PBLs than controls (P<0.01). Substantial difference was also found for adduct levels in PBLs (P<0.01). Increase in MN levels was significantly related to anti-B[a]PDE-DNA formation, key adduct of the ultimate carcinogenic metabolite of B[a]P (n=94; r=0.47; P<0.001). The dose-response relationship was improved when subjects with adduct levels above the 3rd tertile (>or=4.35 adducts/10(8) nucleotides) were excluded (n=61; r=0.69; P<0.001). Saturation of adduct/MN formation at high levels may disturb the underlying relationship. Linear multiple regression analysis, without subjects of 3rd tertile adduct level (n=61), revealed that adduct formation (t=4.61; P<0.001), but not 1-pyrenol, was the significant determinant in increasing MN. In conclusion, the increase in MN frequency is mainly related to the specific anti-B[a]PDE-DNA formation within PBLs of the same subject. Our results substantiate, with the use of an early indicator of biological effect as well, that workers are at higher cancer risk than controls.

Darcy-Forchheimer Three-Dimensional Flow of Williamson Nanofluid over a Convectively Heated Nonlinear Stretching Surface

NASA Astrophysics Data System (ADS)

Hayat, Tasawar; Aziz, Arsalan; Muhammad, Taseer; Alsaedi, Ahmed

2017-09-01

The present study elaborates three-dimensional flow of Williamson nanoliquid over a nonlinear stretchable surface. Fluid flow obeys Darcy-Forchheimer porous medium. A bidirectional nonlinear stretching surface generates the flow. Convective surface condition of heat transfer is taken into consideration. Further the zero nanoparticles mass flux condition is imposed at the boundary. Effects of thermophoresis and Brownian diffusion are considered. Assumption of boundary layer has been employed in the problem formulation. Convergent series solutions for the nonlinear governing system are established through the optimal homotopy analysis method (OHAM). Graphs have been sketched in order to analyze that how the velocity, temperature and concentration distributions are affected by distinct emerging flow parameters. Skin friction coefficients and local Nusselt number are also computed and discussed.

PDE5 inhibitors enhance the lethality of pemetrexed through inhibition of multiple chaperone proteins and via the actions of cyclic GMP and nitric oxide

PubMed Central

Booth, Laurence; Roberts, Jane L.; Poklepovic, Andrew; Gordon, Sarah; Dent, Paul

2017-01-01

Phosphodiesterase 5 (PDE5) inhibitors prevent the breakdown of cGMP that results in prolonged protein kinase G activation and the generation of nitric oxide. PDE5 inhibitors enhanced the anti-NSCLC cell effects of the NSCLC therapeutic pemetrexed. [Pemetrexed + sildenafil] activated an eIF2α – ATF4 – CHOP – Beclin1 pathway causing formation of toxic autophagosomes; activated a protective IRE1 – XBP-1 – chaperone induction pathway; and activated a toxic eIF2α – CHOP – DR4 / DR5 / CD95 induction pathway. [Pemetrexed + sildenafil] reduced the expression of c-FLIP-s, MCL-1 and BCL-XL that was blocked in a cell-type -dependent fashion by either over-expression of HSP90 / GRP78 / HSP70 / HSP27 or by blockade of eIF2α-CHOP signaling. Knock down of PKGI/II abolished the ability of sildenafil to enhance pemetrexed toxicity whereas pan-inhibition of NOS using L-NAME or knock down of [iNOS + eNOS] only partially reduced the lethal drug interaction. Pemetrexed reduced the ATPase activities of HSP90 and HSP70 in an ATM-AMPK-dependent fashion that was enhanced by sildenafil signaling via PKGI/II. The drug combination activated an ATM-AMPK-TSC2 pathway that was associated with reduced mTOR S2448 and ULK-1 S757 phosphorylation and increased ULK-1 S317 and ATG13 S318 phosphorylation. These effects were prevented by chaperone over-expression or by expression of an activated form of mTOR that prevented autophagosome formation and reduced cell killing. In two models of NSCLC, sildenafil enhanced the ability of pemetrexed to suppress tumor growth. Collectively we argue that the combination of [pemetrexed + PDE5 inhibitor] should be explored in a new NSCLC phase I trial. PMID:27903966

Identifying the nonlinear mechanical behaviour of micro-speakers from their quasi-linear electrical response

NASA Astrophysics Data System (ADS)

Zilletti, Michele; Marker, Arthur; Elliott, Stephen John; Holland, Keith

2017-05-01

In this study model identification of the nonlinear dynamics of a micro-speaker is carried out by purely electrical measurements, avoiding any explicit vibration measurements. It is shown that a dynamic model of the micro-speaker, which takes into account the nonlinear damping characteristic of the device, can be identified by measuring the response between the voltage input and the current flowing into the coil. An analytical formulation of the quasi-linear model of the micro-speaker is first derived and an optimisation method is then used to identify a polynomial function which describes the mechanical damping behaviour of the micro-speaker. The analytical results of the quasi-linear model are compared with numerical results. This study potentially opens up the possibility of efficiently implementing nonlinear echo cancellers.

GPU-based acceleration of computations in nonlinear finite element deformation analysis.

PubMed

Mafi, Ramin; Sirouspour, Shahin

2014-03-01

The physics of deformation for biological soft-tissue is best described by nonlinear continuum mechanics-based models, which then can be discretized by the FEM for a numerical solution. However, computational complexity of such models have limited their use in applications requiring real-time or fast response. In this work, we propose a graphic processing unit-based implementation of the FEM using implicit time integration for dynamic nonlinear deformation analysis. This is the most general formulation of the deformation analysis. It is valid for large deformations and strains and can account for material nonlinearities. The data-parallel nature and the intense arithmetic computations of nonlinear FEM equations make it particularly suitable for implementation on a parallel computing platform such as graphic processing unit. In this work, we present and compare two different designs based on the matrix-free and conventional preconditioned conjugate gradients algorithms for solving the FEM equations arising in deformation analysis. The speedup achieved with the proposed parallel implementations of the algorithms will be instrumental in the development of advanced surgical simulators and medical image registration methods involving soft-tissue deformation. Copyright © 2013 John Wiley & Sons, Ltd.

Adaptive eigenspace method for inverse scattering problems in the frequency domain

NASA Astrophysics Data System (ADS)

Grote, Marcus J.; Kray, Marie; Nahum, Uri

2017-02-01

A nonlinear optimization method is proposed for the solution of inverse scattering problems in the frequency domain, when the scattered field is governed by the Helmholtz equation. The time-harmonic inverse medium problem is formulated as a PDE-constrained optimization problem and solved by an inexact truncated Newton-type iteration. Instead of a grid-based discrete representation, the unknown wave speed is projected to a particular finite-dimensional basis of eigenfunctions, which is iteratively adapted during the optimization. Truncating the adaptive eigenspace (AE) basis at a (small and slowly increasing) finite number of eigenfunctions effectively introduces regularization into the inversion and thus avoids the need for standard Tikhonov-type regularization. Both analytical and numerical evidence underpins the accuracy of the AE representation. Numerical experiments demonstrate the efficiency and robustness to missing or noisy data of the resulting adaptive eigenspace inversion method.

Thermoviscoplastic nonlinear constitutive relationships for structural analysis of high temperature metal matrix composites

NASA Technical Reports Server (NTRS)

Chamis, C. C.; Hopkins, D. A.

1985-01-01

A set of thermoviscoplastic nonlinear constitutive relationships (1VP-NCR) is presented. The set was developed for application to high temperature metal matrix composites (HT-MMC) and is applicable to thermal and mechanical properties. Formulation of the TVP-NCR is based at the micromechanics level. The TVP-NCR are of simple form and readily integrated into nonlinear composite structural analysis. It is shown that the set of TVP-NCR is computationally effective. The set directly predicts complex materials behavior at all levels of the composite simulation, from the constituent materials, through the several levels of composite mechanics, and up to the global response of complex HT-MMC structural components.

Globally convergent techniques in nonlinear Newton-Krylov

NASA Technical Reports Server (NTRS)

Brown, Peter N.; Saad, Youcef

1989-01-01

Some convergence theory is presented for nonlinear Krylov subspace methods. The basic idea of these methods is to use variants of Newton's iteration in conjunction with a Krylov subspace method for solving the Jacobian linear systems. These methods are variants of inexact Newton methods where the approximate Newton direction is taken from a subspace of small dimensions. The main focus is to analyze these methods when they are combined with global strategies such as linesearch techniques and model trust region algorithms. Most of the convergence results are formulated for projection onto general subspaces rather than just Krylov subspaces.

Nonlinear feedback guidance law for aero-assisted orbit transfer maneuvers

NASA Technical Reports Server (NTRS)

Menon, P. K. A.

1992-01-01

Aero-assisted orbit transfer vehicles have the potential for significantly reducing the fuel requirements in certain classes of orbit transfer operations. Development of a nonlinear feedback guidance law for performing aero-assisted maneuvers that accomplish simultaneous change of all the orbital elements with least vehicle acceleration magnitude is discussed. The analysis is based on a sixth order nonlinear point-mass vehicle model with lift, bank angle, thrust and drag modulation as the control variables. The guidance law uses detailed vehicle aerodynamic and the atmosphere models in the feedback loop. Higher-order gravitational harmonics, planetary atmosphere rotation and ambient winds are included in the formulation. Due to modest computational requirements, the guidance law is implementable on-board an orbit transfer vehicle. The guidance performance is illustrated for three sets of boundary conditions.

Simulations of heart valves by thin shells with non-linear material properties

NASA Astrophysics Data System (ADS)

Borazjani, Iman; Asgharzadeh, Hafez; Hedayat, Mohammadali

2016-11-01

The primary function of a heart valve is to allow blood to flow in only one direction through the heart. Triangular thin-shell finite element formulation is implemented, which considers only translational degrees of freedom, in three-dimensional domain to simulate heart valves undergoing large deformations. The formulation is based on the nonlinear Kirchhoff thin-shell theory. The developed method is intensively validated against numerical and analytical benchmarks. This method is added to previously developed membrane method to obtain more realistic results since ignoring bending forces can results in unrealistic wrinkling of heart valves. A nonlinear Fung-type constitutive relation, based on experimentally measured biaxial loading tests, is used to model the material properties for response of the in-plane motion in heart valves. Furthermore, the experimentally measured liner constitutive relation is used to model the material properties to capture the flexural motion of heart valves. The Fluid structure interaction solver adopts a strongly coupled partitioned approach that is stabilized with under-relaxation and the Aitken acceleration technique. This work was supported by American Heart Association (AHA) Grant 13SDG17220022 and the Center of Computational Research (CCR) of University at Buffalo.

First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430

PubMed Central

Waterhouse, Rikki N.; Nabulsi, Nabeel; Lin, Shu-Fei; Labaree, David; Ropchan, Jim; Tarabar, Sanela; DeMartinis, Nicholas; Ogden, Adam; Banerjee, Anindita; Huang, Yiyun; Carson, Richard E.

2016-01-01

This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand 18F-PF-05270430. The primary goals were to determine the appropriate tracer kinetic model to quantify brain uptake and to examine the within-subject test–retest variability. Methods: In advance of human studies, radiation dosimetry was determined in nonhuman primates. Six healthy male subjects participated in a test–retest protocol with dynamic scans and metabolite-corrected input functions. Nine brain regions of interest were studied, including the striatum, white matter, neocortical regions, and cerebellum. Multiple modeling methods were applied to calculate volume of distribution (VT) and binding potentials relative to the nondisplaceable tracer in tissue (BPND), concentration of tracer in plasma (BPP), and free tracer in tissue (BPF). The cerebellum was selected as a reference region to calculate binding potentials. Results: The dosimetry study provided an effective dose of less than 0.30 mSv/MBq, with the gallbladder as the critical organ; the human target dose was 185 MBq. There were no adverse events or clinically detectable pharmacologic effects reported. Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time–activity curves were well fit by multilinear analysis-1, and a 70-min scan duration was sufficient to quantify VT and the binding potentials. BPND, with mean values ranging from 0.3 to 0.8, showed the best intrasubject and intersubject variability and reliability. Test–retest variability in the whole brain (excluding the cerebellum) of VT, BPND, and BPP were 8%, 16%, and 17%, respectively. Conclusion: 18F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values. PMID:27103022

Pure connection formulation, twistors, and the chase for a twistor action for general relativity

NASA Astrophysics Data System (ADS)

Herfray, Yannick

2017-11-01

This paper establishes the relation between traditional results from the (Euclidean) twistor theory and chiral formulations of general relativity (GR), especially the pure connection formulation. Starting from an SU(2)-connection only, we show how to construct natural complex data on twistor space, mainly an almost Hermitian structure and a connection on some complex line bundle. Only when this almost Hermitian structure is integrable is the connection related to an anti-self-dual-Einstein metric and makes contact with the usual results. This leads to a new proof of the non-linear graviton theorem. Finally, we discuss what new strategies this "connection approach" to twistors suggests for constructing a twistor action for gravity. In Appendix A, we also review all known chiral Lagrangians for GR.

Influence of GSTM1 null and low repair XPC PAT+ on anti-B[a]PDE-DNA adduct in mononuclear white blood cells of subjects low exposed to PAHs through smoking and diet.

PubMed

Pavanello, Sofia; Pulliero, Alessandra; Clonfero, Erminio

2008-02-01

The influence of low-activity NER genotypes (XPC PAT-/+, XPA-A23G, XPD Asp312Asn, XPD Lys751Gln) and GSTM1 (active or null) was evaluated on anti-benzo[a]pyrene diol epoxide-(B[a]PDE)-DNA adduct formed in the lymphocyte plus monocyte fraction (LMF). The sample population consisted of 291 healthy subjects with low exposure to polycyclic aromatic hydrocarbons (PAHs) (B[a]P) through their smoking (n=126 smokers) or dietary habits (n=165 non-smokers with high (>or=52 times/year) consumption of charcoaled meat or pizza). The bulky anti-B[a]PDE-DNA adduct levels were detected by HPLC/fluorescence analysis and genotypes by PCR. Anti-B[a]PDE-DNA was present (>or=0.5 adducts/10(8) nucleotides) in 163 (56%) subjects (median (range) 0.77 (0.125-32.0) adducts/10(8) nucleotides), with smokers showing a significantly higher adduct level than non-smokers with high consumption of PAH-rich meals (P<0.01). Our exposed-sample population with unfavourable XPC PAT+/- or +/+ and GSTM1 null genotypes has the significantly highest adduct level (P<0.01). Taking into account tobacco smoke and diet as sources of exposure to B[a]P, low-activity XPC PAT+ shows a major role in smokers (P<0.05) and GSTM1 null in non-smokers with frequent consumption of PAH-rich meals (P<0.01). The modulation of anti-B[a]PDE-DNA adduct in the LMF by GSTM1 null and low-activity XPC PAT+ polymorphisms may be considered as potential genetic susceptibility factors that can modify individual responses to low PAH (B[a]P) genotoxic exposure, with the consequent risk of cancer in the general population.