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

PubMed

Holcman, David; Korenbrot, Juan I

2005-06-01

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

Detonation Propagation Through Ducts in a Pulsed Detonation Engine

DTIC Science & Technology

2011-03-01

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

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

PubMed

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

2017-02-01

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

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

PubMed

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

2010-06-01

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

White lupin cluster root acclimation to phosphorus deficiency and root hair development involve unique glycerophosphodiester phosphodiesterases

USDA-ARS?s Scientific Manuscript database

White lupin (Lupinus albus L.) is a phosphate (Pi) deficiency tolerant legume which develops short, densely clustered tertiary lateral roots (cluster/proteoid roots) in response to Pi limitation. In this report we characterize two glycerophosphodiester phosphodiesterase (GPX-PDE) genes (GPX-PDE1 and...

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

On locally and nonlocally related potential systems

NASA Astrophysics Data System (ADS)

Cheviakov, Alexei F.; Bluman, George W.

2010-07-01

For any partial differential equation (PDE) system, a local conservation law yields potential equations in terms of some potential variable, which normally is a nonlocal variable. The current paper examines situations when such a potential variable is a local variable, i.e., is a function of the independent and dependent variables of a given PDE system, and their derivatives. In the case of two independent variables, a simple necessary and sufficient condition is presented for the locality of such a potential variable, and this is illustrated by several examples. As a particular example, two-dimensional reductions of equilibrium equations for fluid and plasma dynamics are considered. It is shown that such reductions with respect to helical, axial, and translational symmetries have conservation laws which yield local potential variables. This leads to showing that the well-known Johnson-Frieman-Kruskal-Oberman (JFKO) and Bragg-Hawthorne (Grad-Shafranov) equations are locally related to the corresponding helically and axially symmetric PDE systems of fluid/plasma dynamics. For the axially symmetric case, local symmetry classifications and arising invariant solutions are compared for the original PDE system and the Bragg-Hawthorne (potential) equation. The potential equation is shown to have additional symmetries, denoted as restricted symmetries. Restricted symmetries leave invariant a family of solutions of a given PDE system but not the whole solution manifold, and hence are not symmetries of the given PDE system. Corresponding reductions are shown to yield solutions, which are not obtained as invariant solutions from local symmetry reduction.

Medicare part D data: major changes on the horizon.

PubMed

Greenwald, Leslie M

2007-10-01

The 3 primary administrative data sets developed by the Centers for Medicare and Medicaid services (CMS) to support the Medicare Part D program implementation represent a valuable source of data for health services researchers. This paper describes the structure of the Medicare Part D program and the related databases, and discusses their utilization for research purposes. The Medicare Part D administrative data include information on plan benefits (integrated into the Health Plan Management System), beneficiary enrollment files, and prescription drug event (PDE) claims-type data. The enrollment data may be of use in investigating the benefits and plan types that appeal to beneficiaries, but their application is limited by the fact that, although individual beneficiaries' enrollment choices are recorded, only summary enrollment data are currently publicly available. PDE data are likely to be of most interest to researchers as they are detailed (including beneficiary identifiers, contract identifiers pharmacy provider information on drugs provided, drug cost, and insurance status), beneficiary-specific (allowing them to be linked to beneficiary characteristics), and an unusual output for a program reimbursed under a capitation-based system. Because PDE data are highly sensitive, only summary data on the number of Part D prescriptions filled are publicly available. Although the data collected in relation to the Medicare Part D program could be applied to many questions of interest to health services researchers, their utility is limited by the sensitive natures of many of these data, making it difficult currently to obtain access for research purposes.

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.

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

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

NASA Astrophysics Data System (ADS)

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

2017-11-01

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

Combination therapy for erectile dysfunction: an update review.

PubMed

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

2011-05-01

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

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

PubMed

Röhrig, Teresa; Liesenfeld, David; Richling, Elke

2017-05-17

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

Off-Target Effect of Sildenafil on Postsurgical Erectile Dysfunction: Alternate Pathways and Localized Delivery System.

PubMed

Salmasi, Amirali; Lee, Geun Taek; Patel, Neal; Goyal, Ritu; Dinizo, Michael; Kwon, Young Suk; Modi, Part K; Faiena, Izak; Kim, Hee-Jin; Lee, Nara; Hannan, Johanna L; Kohn, Joachim; Kim, Isaac Yi

2016-12-01

There is no consensus on the best oral phosphodiesterase type 5 inhibitor (PDE5I) for patients undergoing penile rehabilitation after surgical nerve injury. To determine the mechanism of PDE5I on cultured neuronal cells and the effectiveness of local drug delivery using nanospheres (NSPs) to sites of nerve injury in a rat model of bilateral cavernous nerve injury (BCNI). The effects of sildenafil, tadalafil, and vardenafil on cyclic adenosine monophosphate, cyclic guanosine monophosphate, and cell survival after exposure to hypoxia and H 2 O 2 were measured in PC12, SH-SY5Y, and NTERA-2 (NT2) cell cultures. The effects of phosphodiesterase type 4 inhibitor (PDE4I) and PDE5I on neuronal cell survival were evaluated. Male rats underwent BCNI and were untreated (BCNI), immediately treated with application of empty NSPs (BCNI + NSP), NSPs containing sildenafil (Sild + NSP), or NSPs containing rolipram (Rol + NSP). Viability of neuronal cells was measured. Intracavernous pressure changes after cavernous nerve electrostimulation and expression of neurofilament, nitric oxide synthase, and actin in mid-shaft of penis were analyzed 14 days after injury. Sildenafil and rolipram significantly decreased cell death after exposure to H 2 O 2 and hypoxia in PC12, SH-SY5Y, and NT2 cells. PC12 cells did not express PDE5 and knockdown of PDE4 significantly increased cell viability in PC12, SH-SY5Y, and NT2 cells exposed to hypoxia. The ratio of intracavernous pressure to mean arterial pressure and expression of penile neurofilament, nitric oxide synthase, and actin were significantly higher in the Sild + NSP and Rol + NSP groups than in the BCNI and BCNI + NSP groups. Limitations included analysis in only two PDE families using only a single dose. Sildenafil showed the most profound neuroprotective effect compared with tadalafil and vardenafil. Sildenafil- or rolipram-loaded NSP delivery to the site of nerve injury prevented erectile dysfunction and led to increased neurofilament, nitric oxide synthase, smooth muscle content in rat penile tissue after BCNI. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

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…

Efficacy of a novel phosphodiesterase inhibitor, E6005, in patients with atopic dermatitis: An investigator-blinded, vehicle-controlled study.

PubMed

Ohba, Fuminori; Matsuki, Shunji; Imayama, Shuhei; Matsuguma, Kyoko; Hojo, Seiichiro; Nomoto, Maiko; Akama, Hideto

2016-10-01

Phosphodiesterase type 4 (PDE4) inhibition is a well-known anti-inflammatory mechanism. However, the clinical use of PDE4 inhibitors has been compromised by the occurrence of mechanism-associated adverse reactions, which often limit the maximum tolerated dose. To minimize systemic exposure, a topically active PDE4 inhibitor with low transdermal bioavailability could be clinically useful. The purpose of this study was to evaluate the efficacy of a novel topical PDE4 inhibitor, E6005, in patients with atopic dermatitis. This randomized, investigator-blinded, vehicle-controlled, multiple ascending dose study included 40 adult male patients with atopic dermatitis, who were randomly assigned to 10 days of treatment with either E6005 ointment (0.01, 0.03, 0.1 or 0.2%) or vehicle ointment. Of 81 patients screened, 40 who had typical lesions on their posterior trunk were randomized into the study. One patient receiving 0.03% E6005 treatment discontinued because of acute gout and one receiving vehicle treatment discontinued because of progression of atopic dermatitis. The targeted lesion severity scores decreased in a concentration-dependent manner in patients treated with E6005. This drop was significant in the 0.2% E6005 ointment treatment group (mean percent change: -54.30%, p = 0.007). E6005 ointment showed anti-inflammatory efficacy in adult patients with atopic dermatitis.

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.

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.

Phosphodiesterase Type 5 Inhibitors, Sport and Doping.

PubMed

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

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

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.

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.

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

Transient Heat Transfer Properties in a Pulse Detonation Combustor

DTIC Science & Technology

2011-03-01

strategies for future systems. 15. NUMBER OF PAGES 89 14. SUBJECT TERMS Pulse Detonation Engines, PDE , Heat Transfer 16. PRICE CODE 17. SECURITY...GUI Graphical User Interface NPS Naval Postgraduate School PDC Pulse Detonation Combustion PDE Pulse Detonation Engine RPL Rocket...a tactical missile with a Pulse Detonation Engine ( PDE ) and provide greater range for the same amount of fuel as compared to other current

Investigation of Sustained Detonation Devices: the Pulse Detonation Engine-Crossover System and the Rotating Detonation Engine System

NASA Astrophysics Data System (ADS)

Driscoll, Robert B.

An experimental study is conducted on a Pulse Detonation Engine-Crossover System to investigate the feasibility of repeated, shock-initiated combustion and characterize the initiation performance. A PDE-crossover system can decrease deflagration-to-detonation transition length while employing a single spark source to initiate a multi-PDE system. Visualization of a transferred shock wave propagating through a clear channel reveals a complex shock train behind the leading shock. Shock wave Mach number and decay rate remains constant for varying crossover tube geometries and operational frequencies. A temperature gradient forms within the crossover tube due to forward flow of high temperature ionized gas into the crossover tube from the driver PDE and backward flow of ionized gas into the crossover tube from the driven PDE, which can cause intermittent auto-ignition of the driver PDE. Initiation performance in the driven PDE is strongly dependent on initial driven PDE skin temperature in the shock wave reflection region. An array of detonation tubes connected with crossover tubes is developed using optimized parameters and successful operation utilizing shock-initiated combustion through shock wave reflection is achieved and sustained. Finally, an air-breathing, PDE-Crossover System is developed to characterize the feasibility of shock-initiated combustion within an air-breathing pulse detonation engine. The initiation effectiveness of shock-initiated combustion is compared to spark discharge and detonation injection through a pre-detonator. In all cases, shock-initiated combustion produces improved initiation performance over spark discharge and comparable detonation transition run-up lengths relative to pre-detonator initiation. A computational study characterizes the mixing processes and injection flow field within a rotating detonation engine. Injection parameters including reactant flow rate, reactant injection area, placement of the fuel injection, and fuel injection distribution are varied to assess the impact on mixing. Decreasing reactant injection areas improves fuel penetration into the cross-flowing air stream, enhances turbulent diffusion of the fuel within the annulus, and increases local equivalence ratio and fluid mixedness. Staggering fuel injection holes produces a decrease in mixing when compared to collinear fuel injection. Finally, emulating nozzle integration by increasing annulus back-pressure increases local equivalence ratio in the injection region due to increased convection residence time.

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.

Aging has the opposite effect on cAMP and cGMP circadian variations in rat Leydig cells.

PubMed

Baburski, Aleksandar Z; Sokanovic, Srdjan J; Andric, Silvana A; Kostic, Tatjana S

2017-05-01

The Leydig cell physiology displays a circadian rhythm driven by a complex interaction of the reproductive axis hormones and circadian system. The final output of this regulatory process is circadian pattern of steroidogenic genes expression and testosterone production. Aging gradually decreases robustness of rhythmic testosterone secretion without change in pattern of LH secretion. Here, we analyzed effect of aging on circadian variation of cAMP and cGMP signaling in Leydig cells. Results showed opposite effect of aging on cAMP and cGMP daily variation. Reduced amplitude of cAMP circadian oscillation was probably associated with changed expression of genes involved in cAMP production (increased circadian pattern of Adcy7, Adcy9, Adcy10 and decreased Adcy3); cAMP degradation (increased Pde4a, decreased Pde8b, canceled rhythm of Pde4d, completely reversed circadian pattern of Pde7b and Pde8a); and circadian expression of protein kinase A subunits (Prkac/PRKAC and Prkar2a). Aging stimulates expression of genes responsible for cGMP production (Nos2, Gucy1a3 and Gucy1b3/GUCYB3) and degradation (Pde5a, Pde6a and Pde6h) but the overall net effect is elevation of cGMP circadian oscillations in Leydig cells. In addition, the expression of cGMP-dependent kinase, Prkg1/PRKG1 is up-regulated. It seems that aging potentiate cGMP- and reduce cAMP-signaling in Leydig cells. Since both signaling pathways affect testosterone production and clockwork in the cells, further insights into these signaling pathways will help to unravel disorders linked to the circadian timing system, aging and reproduction.

Initiation Mechanisms of Low-loss Swept-ramp Obstacles for Deflagration to Detonation Transition in Pulse Detonation Combustors

DTIC Science & Technology

2009-12-01

minimal pressure losses. 15. NUMBER OF PAGES 113 14. SUBJECT TERMS Pulse Detonation Combustors, PDC, Pulse Detonation Engines, PDE , PDE ...Postgraduate School PDC Pulse Detonation Combustor PDE Pulse Detonation Engine RAM Random Access Memory RDT Research, Design and Test RPL...inhibiting the implementation of this advanced propulsion system. The primary advantage offered by pulse detonation engines ( PDEs ) is the high efficiency

Treatment of psoriasis with crisaborole.

PubMed

Lee, Erica B; Lebwohl, Mark G; Wu, Jashin J

2018-06-08

Crisaborole, a topical phosphodiesterase-4 (PDE4) inhibitor, is effective in patients with atopic dermatitis. As systemic PDE4 inhibition has also been used with success in psoriasis, clinical trials are underway to determine the utility of topical PDE4 inhibitors in these patients. However, there is no current literature documenting use of crisaborole for psoriasis. Here, we present two cases in which patients with psoriasis were treated successfully with crisaborole.

Thrust Augmentation Measurements Using a Pulse Detonation Engine Ejector

NASA Technical Reports Server (NTRS)

Santoro, Robert J.; Pal, Sibtosh

2003-01-01

The present NASA GRC-funded three-year research project is focused on studying PDE driven ejectors applicable to a hybrid Pulse Detonation/Turbofan Engine. The objective of the study is to characterize the PDE-ejector thrust augmentation. A PDE-ejector system has been designed to provide critical experimental data for assessing the performance enhancements possible with this technology. Completed tasks include demonstration of a thrust stand for measuring average thrust for detonation tube multi-cycle operation, and design of a 72-in.-long, 2.25-in.-diameter (ID) detonation tube and modular ejector assembly. This assembly will allow testing of both straight and contoured ejector geometries. Initial ejectors that have been fabricated are 72-in.-long-constant-diameter tubes (4-, 5-, and 6-in.-diameter) instrumented with high-frequency pressure transducers. The assembly has been designed such that the detonation tube exit can be positioned at various locations within the ejector tube. PDE-ejector system experiments with gaseous ethylene/ nitrogen/oxygen propellants will commence in the very near future. The program benefits from collaborations with Prof. Merkle of University of Tennessee whose PDE-ejector analysis helps guide the experiments. The present research effort will increase the TRL of PDE-ejectors from its current level of 2 to a level of 3.

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

PubMed

Zhu, Bing; Strada, Samuel J

2007-01-01

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

Faculty Planning, Development, and Evaluation System: Washtenaw Community College.

ERIC Educational Resources Information Center

Altieri, Guy; And Others

Between 1989 and 1991, the Planning, Development and Evaluation (PDE) Committee of Washtenaw Community College (Michigan) designed a faculty assessment process focusing on professional development and academic planning. It is an approach in which all educators (faculty and administrators) work together, using the PDE system to continually define…

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 therapy. Factors like education level, ED severity, and ED duration were associated with persistence and adherence; additional study is warranted to investigate the predictive value of these factors.

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

PubMed

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

2016-09-01

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

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

PubMed

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

2008-11-01

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

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

Pilot Assessment of the Repeatability of Indocyanine Green Fluorescence Imaging and Correlation with Traditional Foot Perfusion Assessments.

PubMed

Venermo, M; Settembre, N; Albäck, A; Vikatmaa, P; Aho, P-S; Lepäntalo, M; Inoue, Y; Terasaki, H

2016-10-01

Ankle brachial index (ABI), toe pressures (TP), and transcutaneous oxygen pressure (TcPO 2 ) are traditionally used in the assessment of critical limb ischemia (CLI). Indocyanine green (ICG) fluorescence imaging can be used to evaluate local circulation in the foot and to evaluate the severity of ischemia. This prospective study analyzed the suitability of a fluorescence imaging system (photodynamic eye [PDE]) in CLI. Forty-one patients with CLI were included. Of the patients, 66% had diabetes and there was an ischemic tissue lesion in 70% of the limbs. ABI, toe pressures, TcPO 2 and ICG-fluorescence imaging (ICG-FI) were measured in each leg. To study the repeatability of the ICG-FI, each patient underwent the study twice. After the procedure, foot circulation was measured using a time-intensity curve, where T1/2 (the time needed to achieve half of the maximum fluorescence intensity) and PDE10 (increase of the intensity during the first 10 s) were determined. A time-intensity curve was plotted using the same areas as for the TcPO 2 probes (n=123). The mean ABI was 0.43, TP 21 mmHg, TcPO 2 23 mmHg, T1/2 38 s, and PDE10 19 AU. Time-intensity curves were repeatable. In a Bland-Altman scatter plot, the 95% limits of agreement of PDE10 was 9.9 AU and the corresponding value of T1/2 was 14 s. Correlation between ABI and TP was significant (R=.73, p<.001), and it was weaker in diabetic patients (R=.47, p=.048) compared with non-diabetic patients (R=.89, p=.002). Correlations between ABI and TcPO 2 and TP and TcPO 2 were weak (R=.37, p=.05 and R=.43, p=.037, respectively). Correlation between TcPO 2 and PDE10 was strong in diabetic patients (R=.70, p=.003). According to this pilot study, ICG-FI with PDE can be used in the assessment of blood supply in the ischemic foot. Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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

2015-04-01

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

University Capstone Project: Enhanced Initiation Techniques for Thermochemical Energy Conversion

DTIC Science & Technology

2013-03-01

technologies such as scramjets, gas turbine engines (relight and afterburner ignition), and pulsed detonation engines ( PDEs ) because of the limited...events in a flow tube were recorded, and the PDE engine was fired while monitoring ignition time and wave speed throughout the detonation process...long steel tube fitted with a 36” long, 2” x 2” square polycarbonate test section is used in place of the instrumented detonation tube. The PDE

Inhibitors of cyclic nucleotide phosphodiesterase 3 and 5 as therapeutic agents in heart failure.

PubMed

Stehlik, Josef; Movsesian, Matthew A

2006-07-01

Cyclic nucleotide phosphodiesterases (PDE) 3 and 5 regulate cAMP and cGMP signalling in cardiac and smooth muscle myocytes. Important advances in the understanding of the roles of these enzymes have recently been made. PDE3 inhibitors have inotropic and vasodilatory properties, and although they acutely improve haemodynamics in patients with heart failure, they do not improve long-term morbidity and mortality. Although combination therapy with beta-adrenergic receptor antagonists or selective inhibition of specific PDE3 isoforms might result in a more favourable long-term outcome, more clinical data are needed to test this proposition. The role of PDE5 inhibitors in the treatment of cardiac disease is evolving. PDE5 inhibitors cause pulmonary and systemic vasodilation. How these drugs will compare with other vasodilators in terms of long-term outcomes in patients with heart failure is unknown. Recent studies also suggest that PDE5 inhibitors may have antihypertropic effects, exerted through increased myocardial cGMP signalling, that could be of additional benefit in patients with heart failure.

Application of dry elixir system to oriental traditional medicine: taste masking of peonjahwan by coated dry elixir.

PubMed

Choi, H G; Kim, C K

2000-02-01

Peonjahwan, an oriental traditional medicine composed of crude herbal drugs and animal tissues is bitter and poorly water-soluble. To mask the bitterness of peonjahwan and enhance the release of bilirubin, one of the crude active ingredients of peonjahwan, peonja dry elixir (PDE), was prepared using a spray-dryer after extracting the crude materials in ethanol-water solution. Coated peonja dry elixir (CPDE) was then prepared by coating the PDE with Eudragit acrylic resin. Panel assessed bitterness and release test of bilirubin from PDE and CPDE were carried out and compared with peonjahwan alone. PDE was found to have little effect upon the reduction of the bitterness of peonjahwan. However, the bitterness of CPDE was found to reduce to 1/4 of that of peonjahwan due to the encapsulation of crude active ingredients by the dextrin and Eudragit shell (P<0.05). The release rate of bilirubin from PDE and CPDE for 60 min increased about 3.5- and 2.5- fold, respectively, compared to peonjahwan at pH 1.2. It is concluded that CPDE, which masked the bitterness of peonjahwan and enhanced the release of bilirubin, is a preferable delivery system for peonjahwan.

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

PubMed Central

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

2008-01-01

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

Ca(2+)/calmodulin-activated phosphodiesterase 1A is highly expressed in rabbit cardiac sinoatrial nodal cells and regulates pacemaker function.

PubMed

Lukyanenko, Yevgeniya O; Younes, Antoine; Lyashkov, Alexey E; Tarasov, Kirill V; Riordon, Daniel R; Lee, Joonho; Sirenko, Syevda G; Kobrinsky, Evgeny; Ziman, Bruce; Tarasova, Yelena S; Juhaszova, Magdalena; Sollott, Steven J; Graham, David R; Lakatta, Edward G

2016-09-01

Constitutive Ca(2+)/calmodulin (CaM)-activation of adenylyl cyclases (ACs) types 1 and 8 in sinoatrial nodal cells (SANC) generates cAMP within lipid-raft-rich microdomains to initiate cAMP-protein kinase A (PKA) signaling, that regulates basal state rhythmic action potential firing of these cells. Mounting evidence in other cell types points to a balance between Ca(2+)-activated counteracting enzymes, ACs and phosphodiesterases (PDEs) within these cells. We hypothesized that the expression and activity of Ca(2+)/CaM-activated PDE Type 1A is higher in SANC than in other cardiac cell types. We found that PDE1A protein expression was 5-fold higher in sinoatrial nodal tissue than in left ventricle, and its mRNA expression was 12-fold greater in the corresponding isolated cells. PDE1 activity (nimodipine-sensitive) accounted for 39% of the total PDE activity in SANC lysates, compared to only 4% in left ventricular cardiomyocytes (LVC). Additionally, total PDE activity in SANC lysates was lowest (10%) in lipid-raft-rich and highest (76%) in lipid-raft-poor fractions (equilibrium sedimentation on a sucrose density gradient). In intact cells PDE1A immunolabeling was not localized to the cell surface membrane (structured illumination microscopy imaging), but located approximately within about 150nm inside of immunolabeling of hyperpolarization-activated cyclic nucleotide-gated potassium channels (HCN4), which reside within lipid-raft-rich microenvironments. In permeabilized SANC, in which surface membrane ion channels are not functional, nimodipine increased spontaneous SR Ca(2+) cycling. PDE1A mRNA silencing in HL-1 cells increased the spontaneous beating rate, reduced the cAMP, and increased cGMP levels in response to IBMX, a broad spectrum PDE inhibitor (detected via fluorescence resonance energy transfer microscopy). We conclude that signaling via cAMP generated by Ca(2+)/CaM-activated AC in SANC lipid raft domains is limited by cAMP degradation by Ca(2+)/CaM-activated PDE1A in non-lipid raft domains. This suggests that local gradients of [Ca(2+)]-CaM or different AC and PDE1A affinity regulate both cAMP production and its degradation, and this balance determines the intensity of Ca(2+)-AC-cAMP-PKA signaling that drives SANC pacemaker function. Copyright © 2016. Published by Elsevier Ltd.

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.

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.

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.

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

PubMed

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

2014-07-09

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

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

PubMed

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

2010-03-01

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

Experimental Study of a Pulse Detonation Engine Driven Ejector

NASA Technical Reports Server (NTRS)

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

2005-01-01

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

Identification of New Signaling Components in the Sensory Epithelium of Human Saccule

PubMed Central

Degerman, Eva; Rauch, Uwe; Göransson, Olga; Lindberg, Sven; Hultgårdh, Anna; Magnusson, Måns

2011-01-01

Objective: To locate components and target proteins of relevance for the cAMP and cGMP signaling networks including cAMP and cGMP phosphodiesterases (PDEs), salt-inducible kinases (SIKs), subunits of Na+, K+-ATPases, and aquaporins (AQPs) in the human saccule. Methods: The human saccule was dissected out during the removal of vestibular schwannoma via the translabyrinthine approach and immediately fixed. Immunohistochemistry was performed using PDE, SIK, Na+, K+-ATPase, and AQP antibodies. Results: PDEs selective for cAMP (PDE4A, PDE4D, and PDE8A) and cGMP (PDE9A) as well a dual specificity PDE (PDE10A) were detected in the sensory epithelium of the saccule. Furthermore, AQP2, 4, and 9, SIK1 and the α-1 subunit of the Na+, K+-ATPase were detected. Conclusion: cAMP and cGMP are important regulators of ion and water homeostasis in the inner ear. The identification of PDEs and SIK1 in the vestibular system offers new treatment targets for endolymphatic hydrops. Exactly how the PDEs are connected to SIK1 and the SIK1 substrate Na+, K+-ATPase and to AQPs 2, 4, 9 remains to be elucidated. The dissection of the signaling networks utilizing these components and evaluating their roles will add new basic knowledge regarding inner ear physiology. PMID:21886636

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.

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

NASA Astrophysics Data System (ADS)

Zheng, Dianfeng

2016-11-01

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

LC-ESI-MS/MS analysis of phosphodiesterase-5 inhibitors and their analogues in foods and dietary supplements in Korea.

PubMed

Jeong, Ji Hye; Lee, Ji Hyun; Kim, Hyung Joo; Park, Hyoung Joon; Hwang, In Sun; Han, Kyoung Moon; Yoon, Chang-Yong; Cho, Sooyeul; Kim, Woo Seong

2016-01-01

A number of 188 food and dietary supplement samples were collected from 2009 to the first half of 2013 in Korean online and offline stores. A method to identify phosphodiesterase-5 (PDE-5) inhibitors and their analogues using liquid chromatography-electrospray ionisation-mass spectrometry/mass spectrometry (LC-ESI-MS/MS) was validated. Limit of detection and limit of quantitation of liquid-type and solid-type negative samples ranged from 0.05 to 3.33 ng/mL or ng/g and from 0.15 to 10.00 ng/mL or ng/g, respectively. Recoveries ranged from 83% to 112%. Nineteen PDE-5 inhibitors and their analogues were detected, with tadalafil group compounds being the most frequently observed (53.0%), followed by the sildenafil group (42.5%). Tadalafil concentrations ranged from 0.08 to 138.69 mg/g. Compounds were most frequently detected in capsules (in 40 of 80 adulterated samples). To protect public health and food safety, appropriate monitoring of PDE-5 inhibitors and their analogues in foods and dietary supplements is recommended.

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.

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.

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.

Multi-vortex crystal lattices in Bose-Einstein condensates with a rotating trap.

PubMed

Xie, Shuangquan; Kevrekidis, Panayotis G; Kolokolnikov, Theodore

2018-05-01

We consider vortex dynamics in the context of Bose-Einstein condensates (BECs) with a rotating trap, with or without anisotropy. Starting with the Gross-Pitaevskii (GP) partial differential equation (PDE), we derive a novel reduced system of ordinary differential equations (ODEs) that describes stable configurations of multiple co-rotating vortices (vortex crystals). This description is found to be quite accurate quantitatively especially in the case of multiple vortices. In the limit of many vortices, BECs are known to form vortex crystal structures, whereby vortices tend to arrange themselves in a hexagonal-like spatial configuration. Using our asymptotic reduction, we derive the effective vortex crystal density and its radius. We also obtain an asymptotic estimate for the maximum number of vortices as a function of rotation rate. We extend considerations to the anisotropic trap case, confirming that a pair of vortices lying on the long (short) axis is linearly stable (unstable), corroborating the ODE reduction results with full PDE simulations. We then further investigate the many-vortex limit in the case of strong anisotropic potential. In this limit, the vortices tend to align themselves along the long axis, and we compute the effective one-dimensional vortex density, as well as the maximum admissible number of vortices. Detailed numerical simulations of the GP equation are used to confirm our analytical predictions.

The development and testing of pulsed detonation engine ground demonstrators

NASA Astrophysics Data System (ADS)

Panicker, Philip Koshy

2008-10-01

The successful implementation of a PDE running on fuel and air mixtures will require fast-acting fuel-air injection and mixing techniques, detonation initiation techniques such as DDT enhancing devices or a pre-detonator, an effective ignition system that can sustain repeated firing at high rates and a fast and capable, closed-loop control system. The control system requires high-speed transducers for real-time monitoring of the PDE and the detection of the detonation wave speed. It is widely accepted that the detonation properties predicted by C-J detonation relations are fairly accurate in comparison to experimental values. The post-detonation flow properties can also be expressed as a function of wave speed or Mach number. Therefore, the PDE control system can use C-J relations to predict the post-detonation flow properties based on measured initial conditions and compare the values with those obtained from using the wave speed. The controller can then vary the initial conditions within the combustor for the subsequent cycle, by modulating the frequency and duty cycle of the valves, to obtain optimum air and fuel flow rates, as well as modulate the energy and timing of the ignition to achieve the required detonation properties. Five different PDE ground demonstrators were designed, built and tested to study a number of the required sub-systems. This work presents a review of all the systems that were tested, along with suggestions for their improvement. The PDE setups, ranged from a compact PDE with a 19 mm (3/4 in.) i.d., to two 25 mm (1 in.) i.d. setups, to a 101 mm (4 in.) i.d. dual-stage PDE setup with a pre-detonator. Propane-oxygen mixtures were used in the smaller PDEs. In the dual-stage PDE, propane-oxygen was used in the pre-detonator, while propane-air mixtures were used in the main combustor. Both rotary valves and solenoid valve injectors were studied. The rotary valves setups were tested at 10 Hz, while the solenoid valves were tested at up to 30 Hz on a 25 mm i.d. PDE. The dual-stage PDE was run at both 1 Hz and 10 Hz using solenoid valves. The two types of valves have their drawbacks and advantages which are discussed, along with ways to enhance their functionality. Rotary valves with stepper motor drives are recommended to be used for air flow control, while an array of solenoid injectors may be used for liquid or gaseous fuel injection. Various DDT enhancing devices were tested, including Shchelkin spirals (with varying thicknesses, lengths and pitches), grooved sleeves and converging-diverging nozzles. The Shchelkin spirals are found to be the most effective of all, at blockage ratios in the region of 50 to 55%. To improve the durability of Shchelkin spirals, it is recommended that they be grooved into the inside of tubes or inserted as replaceable sleeves. Orifice plates with high blockage ratios, in the region of 50 to 80%, are also recommended due to their simple and rugged design. All these devices along with the PDE combustor will require a strong cooling system to prevent damage from the extreme detonation temperatures. High energy (HE) and low energy (LE) ignition systems were tested and compared along with various designs of igniters and automotive spark plugs. It is concluded that while HE ignition may help unsensitized fuel-air mixtures to achieve detonations faster than LE systems, the former have severe drawbacks. The HE igniters get damaged quickly, and require large and heavy power supplies. While the HE ignition is able to reduce ignition delay in a propane-oxygen pre-detonator, it did not show a significant improvement in bringing about DDT in the main combustor using propane-air mixtures. The compact pre-detonator design with a gradual area change transitioning to a larger combustor is found to be effective for detonation initiation, but the pre-detonator concept is recommended for high-speed applications only, since higher speeds requires more sensitive, easily detonable fuels that have short ignition delays and DDT run-up distances. Dynamic pressure transducers, ion detectors and photo-detectors were compared for the diagnostics of the detonation wave. The ion detector is found to be a safe, cheap and effective choice for obtaining detonation or flame velocities, and better than the optical detector, which is not practical for long-duration PDE operations. The piezoelectric dynamic pressure transducer has problems with heating and requires an effective cooling system to enable it to function in a PDE. Other diagnostics studied include thrust measurement and mass flow rate measurement techniques. Additionally, fuel sensitizing techniques, such as hydrogen blending, along with the DDT devices can ensure that detonations are produced successfully.

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

Lyapunov-based control of limit cycle oscillations in uncertain aircraft systems

NASA Astrophysics Data System (ADS)

Bialy, Brendan

Store-induced limit cycle oscillations (LCO) affect several fighter aircraft and is expected to remain an issue for next generation fighters. LCO arises from the interaction of aerodynamic and structural forces, however the primary contributor to the phenomenon is still unclear. The practical concerns regarding this phenomenon include whether or not ordnance can be safely released and the ability of the aircrew to perform mission-related tasks while in an LCO condition. The focus of this dissertation is the development of control strategies to suppress LCO in aircraft systems. The first contribution of this work (Chapter 2) is the development of a controller consisting of a continuous Robust Integral of the Sign of the Error (RISE) feedback term with a neural network (NN) feedforward term to suppress LCO behavior in an uncertain airfoil system. The second contribution of this work (Chapter 3) is the extension of the development in Chapter 2 to include actuator saturation. Suppression of LCO behavior is achieved through the implementation of an auxiliary error system that features hyperbolic functions and a saturated RISE feedback control structure. Due to the lack of clarity regarding the driving mechanism behind LCO, common practice in literature and in Chapters 2 and 3 is to replicate the symptoms of LCO by including nonlinearities in the wing structure, typically a nonlinear torsional stiffness. To improve the accuracy of the system model a partial differential equation (PDE) model of a flexible wing is derived (see Appendix F) using Hamilton's principle. Chapters 4 and 5 are focused on developing boundary control strategies for regulating the bending and twisting deformations of the derived model. The contribution of Chapter 4 is the construction of a backstepping-based boundary control strategy for a linear PDE model of an aircraft wing. The backstepping-based strategy transforms the original system to a exponentially stable system. A Lyapunov-based stability analysis is then used to show boundedness of the wing bending dynamics. A Lyapunov-based boundary control strategy for an uncertain nonlinear PDE model of an aircraft wing is developed in Chapter 5. In this chapter, a proportional feedback term is coupled with an gradient-based adaptive update law to ensure asymptotic regulation of the flexible states.

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.

Thrust Augmentation Measurements Using a Pulse Detonation Engine Ejector

NASA Technical Reports Server (NTRS)

Santoro, Robert J.; Pal, Sibtosh

2005-01-01

Results of an experimental effort on pulse detonation driven ejectors are presented and discussed. The experiments were conducted using a pulse detonation engine (PDE)/ejector setup that was specifically designed for the study and operated at frequencies up to 50 Hz. The results of various experiments designed to probe different aspects of the PDE/ejector setup are reported. The baseline PDE was operated using ethylene (C2H4) as the fuel and an oxygen/nitrogen O2 + N2) mixture at an equivalence ratio of one. The PDE only experiments included propellant mixture characterization using a laser absorption technique, high fidelity thrust measurements using an integrated spring-damper system, and shadowgraph imaging of the detonation/shock wave structure emanating from the tube. The baseline PDE thrust measurement results at each desired frequency agree with experimental and modeling results reported in the literature. These PDE setup results were then used as a basis for quantifying thrust augmentation for various PDE/ejector setups with constant diameter ejector tubes and various ejector lengths, the radius of curvature for the ejector inlets and various detonation tube/ejector tube overlap distances. For the studied experimental matrix, the results showed a maximum thrust augmentation of 106% at an operational frequency of 30 Hz. The thrust augmentation results are complemented by shadowgraph imaging of the flowfield in the ejector tube inlet area and high frequency pressure transducer measurements along the length of the ejector tube.

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

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.

Case Studies of Five Teacher Supervision/Evaluation Systems.

ERIC Educational Resources Information Center

Patrick, Edward M.; Dawson, Judith A.

In the 1984-85 school year, the Pennsylvania Department of Education (PDE) began to actively encourage Pennsylvania school districts to reform their teacher supervision/evaluation (TS/E) procedures. To obtain data necessary for developing TS/E models, the PDE commissioned Research for Better Schools (RBS) to conduct a study of five school…

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

Approach to the Highly Sensitized Kidney Transplant Candidate

PubMed Central

Vranic, Gayle M.

2016-01-01

For patients with ESRD, kidney transplant offers significant survival and quality-of-life advantages compared with dialysis. But for patients seeking transplant who are highly sensitized, wait times have traditionally been long and options limited. The approach to the highly sensitized candidate for kidney transplant has changed substantially over time owing to new advances in desensitization, options for paired donor exchange (PDE), and changes to the deceased-donor allocation system. Initial evaluation should focus on determining living-donor availability because a compatible living donor is always the best option. However, for most highly sensitized candidates this scenario is unlikely. For candidates with an incompatible donor, PDE can improve the prospects of finding a compatible living donor but for many highly sensitized patients the probability of finding a match in the relatively small pools of donors in PDE programs is limited. Desensitization of a living donor/recipient pair with low levels of incompatibility is another reasonable approach. But for pairs with high levels of pathologic HLA antibodies, outcomes after desensitization for the patient and allograft are less optimal. Determining the degree of sensitization by calculated panel-reactive antibody (cPRA) is critical in counseling the highly sensitized patient on expected wait times to deceased-donor transplant. For candidates with a high likelihood of finding a compatible deceased donor in a reasonable time frame, waiting for a kidney is a good strategy. For the candidate without a living donor and with a low probability of finding a deceased-donor match, desensitization on the waiting list can be considered. The approach to the highly sensitized kidney transplant candidate must be individualized and requires careful discussion among the transplant center, patient, and referring nephrologist. PMID:26915916

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.

Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.

PubMed

Aversa, A; Fittipaldi, S; Bimonte, V M; Wannenes, F; Papa, V; Francomano, D; Greco, E A; Lenzi, A; Migliaccio, S

2016-02-01

Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD). Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression. Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation. Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

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

PubMed

Granovsky, A E; Artemyev, N O

2001-06-15

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

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

PubMed

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

2012-08-01

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

Optical properties of materials at low temperature and their application to optical detection

NASA Technical Reports Server (NTRS)

Hartwig, W. H.; Tarchi, A. A.

1972-01-01

A lumped model to represent the photodielectric effect is developed. An analog simulation for a sample in a microwave cavity with a static magnetic field is developed. A system to measure continuously the PDE is analyzed. A performance factor to compared PD detectors versus ac photoconductors is computed. The operating conditions are defined for the appropriate noise conditions. The detectivity of the detector is found to be limited by the semiconductor sample noise.

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

PubMed

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

2002-03-26

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

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

PubMed

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

2018-06-06

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

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

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

PubMed

Du, Haixia; Qin, Hong

2007-01-01

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

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

Solving Partial Differential Equations in a data-driven multiprocessor environment

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

Gaudiot, J.L.; Lin, C.M.; Hosseiniyar, M.

1988-12-31

Partial differential equations can be found in a host of engineering and scientific problems. The emergence of new parallel architectures has spurred research in the definition of parallel PDE solvers. Concurrently, highly programmable systems such as data-how architectures have been proposed for the exploitation of large scale parallelism. The implementation of some Partial Differential Equation solvers (such as the Jacobi method) on a tagged token data-flow graph is demonstrated here. Asynchronous methods (chaotic relaxation) are studied and new scheduling approaches (the Token No-Labeling scheme) are introduced in order to support the implementation of the asychronous methods in a data-driven environment.more » New high-level data-flow language program constructs are introduced in order to handle chaotic operations. Finally, the performance of the program graphs is demonstrated by a deterministic simulation of a message passing data-flow multiprocessor. An analysis of the overhead in the data-flow graphs is undertaken to demonstrate the limits of parallel operations in dataflow PDE program graphs.« less

SOP conservative (medical and mechanical) treatment of erectile dysfunction.

PubMed

Porst, Hartmut; Burnett, Arthur; Brock, Gerald; Ghanem, Hussein; Giuliano, Francois; Glina, Sidney; Hellstrom, Wayne; Martin-Morales, Antonio; Salonia, Andrea; Sharlip, Ira

2013-01-01

Erectile dysfunction (ED) is the most frequently treated male sexual dysfunction worldwide. ED is a chronic condition that exerts a negative impact on male self-esteem and nearly all life domains including interpersonal, family, and business relationships. The aim of this study is to provide an updated overview on currently used and available conservative treatment options for ED with a special focus on their efficacy, tolerability, safety, merits, and limitations including the role of combination therapies for monotherapy failures. The methods used were PubMed and MEDLINE searches using the following keywords: ED, phosphodiesterase type 5 (PDE5) inhibitors, oral drug therapy, intracavernosal injection therapy, transurethral therapy, topical therapy, and vacuum-erection therapy/constriction devices. Additionally, expert opinions by the authors of this article are included. Level 1 evidence exists that changes in sedentary lifestyle with weight loss and optimal treatment of concomitant diseases/risk factors (e.g., diabetes, hypertension, and dyslipidemia) can either improve ED or add to the efficacy of ED-specific therapies, e.g., PDE5 inhibitors. Level 1 evidence also exists that treatment of hypogonadism with total testosterone < 300 ng/dL (10.4 nmol/L) can either improve ED or add to the efficacy of PDE5 inhibitors. There is level 1 evidence regarding the efficacy and safety of the following monotherapies in a spectrum-wide range of ED populations: PDE5 inhibitors, intracavernosal injection therapy with prostaglandin E1 (PGE1, synonymous alprostadil) or vasoactive intestinal peptide (VIP)/phentolamine, and transurethral PGE1 therapy. There is level 2 evidence regarding the efficacy and safety of the following ED treatments: vacuum-erection therapy in a wide range of ED populations, oral L-arginine (3-5 g), topical PGE1 in special ED populations, intracavernosal injection therapy with papaverine/phentolamine (bimix), or papaverine/phentolamine/PGE1 (trimix) combination mixtures. There is level 3 evidence regarding the efficacy and safety of oral yohimbine in nonorganic ED. There is level 3 evidence that combination therapies of PDE5 inhibitors + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone. There is level 4 evidence showing enhanced efficacy with the combination of vacuum-erection therapy + either PDE5 inhibitor or transurethral PGE1 or intracavernosal injection therapy. There is level 5 evidence (expert opinion) that combination therapy of PDE5 inhibitors + L-arginine or daily dosing of tadalafil + short-acting PDE5 inhibitors pro re nata may rescue PDE5 inhibitor monotherapy failures. There is level 5 evidence (expert opinion) that adding either PDE5 inhibitors or transurethral PGE1 may improve outcome of penile prosthetic surgery regarding soft (cold) glans syndrome. There is level 5 evidence (expert opinion) that the combination of PDE5 inhibitors and dapoxetine is effective and safe in patients suffering from both ED and premature ejaculation. © 2013 International Society for Sexual Medicine.

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.

Estimating varying coefficients for partial differential equation models.

PubMed

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

2017-09-01

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

AKAP3 Selectively Binds PDE4A Isoforms in Bovine Spermatozoa1

PubMed Central

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

2006-01-01

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

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

PubMed

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

2015-09-15

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

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2014-08-01

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

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

PubMed

Granovsky, A E; Artemyev, N O

2001-11-06

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

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

PubMed Central

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

2015-01-01

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

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2014-10-20

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

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

PubMed Central

Kelly, Michy P.

2017-01-01

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

Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24-month follow-up.

PubMed

Hooijmans, M T; Doorenweerd, N; Baligand, C; Verschuuren, J J G M; Ronen, I; Niks, E H; Webb, A G; Kan, H E

2017-01-01

To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5-15.4 years) and 12 age-matched healthy controls (range: 5-14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets. PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR. The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients.

Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24–month follow-up

PubMed Central

Doorenweerd, N.; Baligand, C.; Verschuuren, J. J. G. M.; Ronen, I.; Niks, E. H.; Webb, A. G.; Kan, H. E.

2017-01-01

Objectives To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. Methods Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5–15.4 years) and 12 age-matched healthy controls (range: 5–14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets. Results PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR. Discussion and conclusion The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients. PMID:28763477

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

PubMed

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

2014-05-01

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

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

PubMed

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

2013-05-01

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

Ideal cycle analysis of a regenerative pulse detonation engine for power production

NASA Astrophysics Data System (ADS)

Bellini, Rafaela

Over the last few decades, considerable research has been focused on pulse detonation engines (PDEs) as a promising replacement for existing propulsion systems with potential applications in aircraft ranging from the subsonic to the lower hypersonic regimes. On the other hand, very little attention has been given to applying detonation for electric power production. One method for assessing the performance of a PDE is through thermodynamic cycle analysis. Earlier works have adopted a thermodynamic cycle for the PDE that was based on the assumption that the detonation process could be approximated by a constant volume process, called the Humphrey cycle. The Fickett-Jacob cycle, which uses the one--dimensional Chapman--Jouguet (CJ) theory of detonation, has also been used to model the PDE cycle. However, an ideal PDE cycle must include a detonation based compression and heat release processes with a finite chemical reaction rate that is accounted for in the Zeldovich -- von Neumann -- Doring model of detonation where the shock is considered a discontinuous jump and is followed by a finite exothermic reaction zone. This work presents a thermodynamic cycle analysis for an ideal PDE cycle for power production. A code has been written that takes only one input value, namely the heat of reaction of a fuel-oxidizer mixture, based on which the program computes all the points on the ZND cycle (both p--v and T--s plots), including the von Neumann spike and the CJ point along with all the non-dimensionalized state properties at each point. In addition, the program computes the points on the Humphrey and Brayton cycles for the same input value. Thus, the thermal efficiencies of the various cycles can be calculated and compared. The heat release of combustion is presented in a generic form to make the program usable with a wide variety of fuels and oxidizers and also allows for its use in a system for the real time monitoring and control of a PDE in which the heat of reaction can be obtained as a function of fuel-oxidizer ratio. The Humphrey and ZND cycles are studied in comparison with the Brayton cycle for different fuel-air mixtures such as methane, propane and hydrogen. The validity and limitations of the ZND and Humphrey cycles related to the detonation process are discussed and the criteria for the selection of the best model for the PDE cycle are explained. It is seen that the ZND cycle is a more appropriate representation of the PDE cycle. Next, the thermal and electrical power generation efficiencies for the PDE are compared with those of the deflagration based Brayton cycle. While the Brayton cycle shows an efficiency of 0 at a compressor pressure ratio of 1, the thermal efficiency for the ZND cycle starts out at 42% for hydrogen--air and then climbs to a peak of 66% at a compression ratio of 7 before falling slowly for higher compression ratios. The Brayton cycle efficiency rises above the PDEs for compression ratios above 23. This finding supports the theoretical advantage of PDEs over the gas turbines because PDEs only require a fan or only a few compressor stages, thereby eliminating the need for heavy compressor machinery, making the PDEs less complex and therefore more cost effective than other engines. Lastly, a regeneration study is presented to analyze how the use of exhaust gases can improve the performance of the system. The thermal efficiencies for the regenerative ZND cycle are compared with the efficiencies for the non--regenerative cycle. For a hydrogen--air mixture the thermal efficiency increases from 52%, for a cycle without regeneration, to 78%, for the regenerative cycle. The efficiency is compared with the Carnot efficiency of 84% which is the maximum possible theoretical efficiency of the cycle. When compared to the Brayton cycle thermal efficiencies, the regenerative cycle shows efficiencies that are always higher for the pressure ratio studied of 5 ≤ pic ≤ 25, where pi c the compressor pressure ratio of the cycle. This observation strengthens the idea of using regeneration on PDEs.

Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships.

PubMed

Zhou, Zhong-Zhen; Ge, Bing-Chen; Chen, Yu-Fang; Shi, Xiu-Dong; Yang, Xue-Mei; Xu, Jiang-Ping

2015-11-15

In this study, a series of catechol-based amides (8a-n) with different amide linkers linking the catecholic moiety to the terminal phenyl ring was designed and synthesized as potent phosphodiesterase (PDE) 4D inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4B1 and PDE4D7 enzymes, and other PDE family members. The results indicated the majority of compounds 8a-n displayed moderate to good inhibitory activities against PDE4CAT. Among these compounds, compound 8 j with a short amide linker (-CONHCH2-) displayed comparable PDE4CAT inhibitory activity (IC50=410 nM) with rolipram. More interestingly, compound 8 g, a potent and selective PDE4D inhibitor (IC50=94 nM), exhibited a 10-fold selectivity over the PDE4B subtypes and an over 1000-fold selectivity against other PDE family members. Docking simulations suggested that 8 g forms three extra H-bonds with the N-H of residue Asn487 and two water molecules. Copyright © 2015 Elsevier Ltd. All rights reserved.

Myocardial Response to Milrinone in Single Right Ventricle Heart Disease.

PubMed

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

2016-07-01

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

Thrust Augmentation Measurements for a Pulse Detonation Engine Driven Ejector

NASA Technical Reports Server (NTRS)

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

2005-01-01

Thrust augmentation results of an ongoing study of pulse detonation engine driven ejectors are presented and discussed. The experiments were conducted using a pulse detonation engine (PDE) setup with various ejector configurations. The PDE used in these experiments utilizes ethylene (C2H4) as the fuel, and an equi-molar mixture of oxygen and nitrogen as the oxidizer at an equivalence ratio of one. High fidelity thrust measurements were made using an integrated spring damper system. The baseline thrust of the PDE engine was first measured and agrees with experimental and modeling results found in the literature. Thrust augmentation measurements were then made for constant diameter ejectors. The parameter space for the study included ejector length, PDE tube exit to ejector tube inlet overlap distance, and straight versus rounded ejector inlets. The relationship between the thrust augmentation results and various physical phenomena is described. To further understand the flow dynamics, shadow graph images of the exiting shock wave front from the PDE were also made. For the studied parameter space, the results showed a maximum augmentation of 40%. Further increase in augmentation is possible if the geometry of the ejector is tailored, a topic currently studied by numerous groups in the field.

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.

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.

Moving finite elements in 2-D

NASA Technical Reports Server (NTRS)

Gelinas, R. J.; Doss, S. K.; Vajk, J. P.; Djomehri, J.; Miller, K.

1983-01-01

The mathematical background regarding the moving finite element (MFE) method of Miller and Miller (1981) is discussed, taking into account a general system of partial differential equations (PDE) and the amenability of the MFE method in two dimensions to code modularization and to semiautomatic user-construction of numerous PDE systems for both Dirichlet and zero-Neumann boundary conditions. A description of test problem results is presented, giving attention to aspects of single square wave propagation, and a solution of the heat equation.

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.

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

PubMed Central

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

2009-01-01

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

MYOCARDIAL RESPONSE TO MILRINONE IN SINGLE RIGHT VENTRICLE HEART DISEASE

PubMed Central

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

2016-01-01

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

A simple robust and accurate a posteriori sub-cell finite volume limiter for the discontinuous Galerkin method on unstructured meshes

NASA Astrophysics Data System (ADS)

Dumbser, Michael; Loubère, Raphaël

2016-08-01

In this paper we propose a simple, robust and accurate nonlinear a posteriori stabilization of the Discontinuous Galerkin (DG) finite element method for the solution of nonlinear hyperbolic PDE systems on unstructured triangular and tetrahedral meshes in two and three space dimensions. This novel a posteriori limiter, which has been recently proposed for the simple Cartesian grid case in [62], is able to resolve discontinuities at a sub-grid scale and is substantially extended here to general unstructured simplex meshes in 2D and 3D. It can be summarized as follows: At the beginning of each time step, an approximation of the local minimum and maximum of the discrete solution is computed for each cell, taking into account also the vertex neighbors of an element. Then, an unlimited discontinuous Galerkin scheme of approximation degree N is run for one time step to produce a so-called candidate solution. Subsequently, an a posteriori detection step checks the unlimited candidate solution at time t n + 1 for positivity, absence of floating point errors and whether the discrete solution has remained within or at least very close to the bounds given by the local minimum and maximum computed in the first step. Elements that do not satisfy all the previously mentioned detection criteria are flagged as troubled cells. For these troubled cells, the candidate solution is discarded as inappropriate and consequently needs to be recomputed. Within these troubled cells the old discrete solution at the previous time tn is scattered onto small sub-cells (Ns = 2 N + 1 sub-cells per element edge), in order to obtain a set of sub-cell averages at time tn. Then, a more robust second order TVD finite volume scheme is applied to update the sub-cell averages within the troubled DG cells from time tn to time t n + 1. The new sub-grid data at time t n + 1 are finally gathered back into a valid cell-centered DG polynomial of degree N by using a classical conservative and higher order accurate finite volume reconstruction technique. Consequently, if the number Ns is sufficiently large (Ns ≥ N + 1), the subscale resolution capability of the DG scheme is fully maintained, while preserving at the same time an essentially non-oscillatory behavior of the solution at discontinuities. Many standard DG limiters only adjust the discrete solution in troubled cells, based on the limiting of higher order moments or by applying a nonlinear WENO/HWENO reconstruction on the data at the new time t n + 1. Instead, our new DG limiter entirely recomputes the troubled cells by solving the governing PDE system again starting from valid data at the old time level tn, but using this time a more robust scheme on the sub-grid level. In other words, the piecewise polynomials produced by the new limiter are the result of a more robust solution of the PDE system itself, while most standard DG limiters are simply based on a mere nonlinear data post-processing of the discrete solution. Technically speaking, the new method corresponds to an element-wise checkpointing and restarting of the solver, using a lower order scheme on the sub-grid. As a result, the present DG limiter is even able to cure floating point errors like NaN values that have occurred after divisions by zero or after the computation of roots from negative numbers. This is a unique feature of our new algorithm among existing DG limiters. The new a posteriori sub-cell stabilization approach is developed within a high order accurate one-step ADER-DG framework on multidimensional unstructured meshes for hyperbolic systems of conservation laws as well as for hyperbolic PDE with non-conservative products. The method is applied to the Euler equations of compressible gas dynamics, to the ideal magneto-hydrodynamics equations (MHD) as well as to the seven-equation Baer-Nunziato model of compressible multi-phase flows. A large set of standard test problems is solved in order to assess the accuracy and robustness of the new limiter.

Performance and environmental impact assessment of pulse detonation based engine systems

NASA Astrophysics Data System (ADS)

Glaser, Aaron J.

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

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

NASA Astrophysics Data System (ADS)

Martelloni, Gianluca; Bagnoli, Franco; Guarino, Alessio

2017-09-01

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

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

Homology modeling, docking studies and molecular dynamic simulations using graphical processing unit architecture to probe the type-11 phosphodiesterase catalytic site: a computational approach for the rational design of selective inhibitors.

PubMed

Cichero, Elena; D'Ursi, Pasqualina; Moscatelli, Marco; Bruno, Olga; Orro, Alessandro; Rotolo, Chiara; Milanesi, Luciano; Fossa, Paola

2013-12-01

Phosphodiesterase 11 (PDE11) is the latest isoform of the PDEs family to be identified, acting on both cyclic adenosine monophosphate and cyclic guanosine monophosphate. The initial reports of PDE11 found evidence for PDE11 expression in skeletal muscle, prostate, testis, and salivary glands; however, the tissue distribution of PDE11 still remains a topic of active study and some controversy. Given the sequence similarity between PDE11 and PDE5, several PDE5 inhibitors have been shown to cross-react with PDE11. Accordingly, many non-selective inhibitors, such as IBMX, zaprinast, sildenafil, and dipyridamole, have been documented to inhibit PDE11. Only recently, a series of dihydrothieno[3,2-d]pyrimidin-4(3H)-one derivatives proved to be selective toward the PDE11 isoform. In the absence of experimental data about PDE11 X-ray structures, we found interesting to gain a better understanding of the enzyme-inhibitor interactions using in silico simulations. In this work, we describe a computational approach based on homology modeling, docking, and molecular dynamics simulation to derive a predictive 3D model of PDE11. Using a Graphical Processing Unit architecture, it is possible to perform long simulations, find stable interactions involved in the complex, and finally to suggest guideline for the identification and synthesis of potent and selective inhibitors. © 2013 John Wiley & Sons A/S.

Atopic dermatitis: a review of topical nonsteroid therapy

PubMed Central

Papier, Ariana

2018-01-01

Background Atopic dermatitis is a chronic inflammatory skin condition that affects up to 20% of children and 3% of adults globally. Although topical corticosteroids are considered to be the first-line agents, they can be associated with cutaneous and systemic adverse effects. Since the early 2000s, two new classes of nonsteroid topical therapies, topical calcineurin inhibitors and phosphodiesterase 4 (PDE4) inhibitors, have been introduced and provide a safe treatment alternative. Method We performed a search and review of clinical trials that examined the safety and efficacy of topical calcineurin inhibitors and PDE4 inhibitors. The search was conducted using the PubMed database as well as preselected keywords and filters. This review focuses on the safety and efficacy of each therapy. Results Sixty-nine clinical trials identified in this study have demonstrated the efficacy and safety of topical calcineurin and a single novel PDE4 inhibitor in the treatment of atopic dermatitis. Topical calcineurin inhibitors have been shown to be effective in both achieving lesion clearance as well as reducing relapse when used long-term and proactively. Similarly, in clinical trials the PDE4 inhibitor showed success in lesion clearance and symptom management. All three therapies (pimecrolimus, tacrolimus, crisaborole) are associated with low systemic absorption. No clinical trials to date have shown an increased risk of systemic adverse events or malignancy such as lymphoma. The most commonly reported treatment-related adverse event across all three therapies was application-site discomfort, pain or pruritus. It is important to note that long-term studies are not yet available for the novel PDE4 inhibitor. Discussion Topical calcineurin inhibitors provide a safe and effective alternative to topical corticosteroid use in the treatment of atopic dermatitis. Although the US Food and Drug Administration (FDA) black box warning for topical calcineurin inhibitors remains, studies have not shown an increased risk of malignancy. These warnings have caused a decline in use in favor of topical steroids. A novel PDE4 inhibitor has shown efficacy and safety in studies up to one year. Further long-term safety data is needed. PMID:29632548

Atopic dermatitis: a review of topical nonsteroid therapy.

PubMed

Papier, Ariana; Strowd, Lindsay C

2018-01-01

Atopic dermatitis is a chronic inflammatory skin condition that affects up to 20% of children and 3% of adults globally. Although topical corticosteroids are considered to be the first-line agents, they can be associated with cutaneous and systemic adverse effects. Since the early 2000s, two new classes of nonsteroid topical therapies, topical calcineurin inhibitors and phosphodiesterase 4 (PDE4) inhibitors, have been introduced and provide a safe treatment alternative. We performed a search and review of clinical trials that examined the safety and efficacy of topical calcineurin inhibitors and PDE4 inhibitors. The search was conducted using the PubMed database as well as preselected keywords and filters. This review focuses on the safety and efficacy of each therapy. Sixty-nine clinical trials identified in this study have demonstrated the efficacy and safety of topical calcineurin and a single novel PDE4 inhibitor in the treatment of atopic dermatitis. Topical calcineurin inhibitors have been shown to be effective in both achieving lesion clearance as well as reducing relapse when used long-term and proactively. Similarly, in clinical trials the PDE4 inhibitor showed success in lesion clearance and symptom management. All three therapies (pimecrolimus, tacrolimus, crisaborole) are associated with low systemic absorption. No clinical trials to date have shown an increased risk of systemic adverse events or malignancy such as lymphoma. The most commonly reported treatment-related adverse event across all three therapies was application-site discomfort, pain or pruritus. It is important to note that long-term studies are not yet available for the novel PDE4 inhibitor. Topical calcineurin inhibitors provide a safe and effective alternative to topical corticosteroid use in the treatment of atopic dermatitis. Although the US Food and Drug Administration (FDA) black box warning for topical calcineurin inhibitors remains, studies have not shown an increased risk of malignancy. These warnings have caused a decline in use in favor of topical steroids. A novel PDE4 inhibitor has shown efficacy and safety in studies up to one year. Further long-term safety data is needed.

Phosphodiesterase inhibitors for persistent pulmonary hypertension of the newborn: a review.

PubMed

Travadi, J N; Patole, S K

2003-12-01

Persistent pulmonary hypertension of the newborn (PPHN) is a complex syndrome with multiple causes, with an incidence of 0.43-6.8/1,000 live births and a mortality of 10-20%. Survivors have high morbidity in the forms of neurodevelopmental and audiological impairment, cognitive delays, hearing loss, and a high rate of rehospitalization. The optimal approach to the management of PPHN remains controversial. Inhaled nitric oxide (iNO) is currently regarded as the gold standard therapy, but with as many as 30% of cases failing to respond, has not proven to be the single magic bullet. Given the complex pathophysiology of the disease, any such magic bullet is unlikely. A number of recent studies have suggested a role for specific phosphodiesterase (PDE) inhibitors in the management of PPHN. Sildenafil, a specific PDE5 inhibitor, appears the most promising of such agents. We aim to review the current status and limitations of iNO and the potential of PDE inhibitors in the management of PPHN. The reasons why caution is warranted before specific PDE5 inhibitors like sildenafil are labelled as potential magic bullets for PPHN will be discussed. The need for randomized-controlled trials to determine the safety, efficacy, and long-term outcome following treatment with sildenafil in PPHN is emphasized. Copyright 2003 Wiley-Liss, Inc.

Review: UK medicines likely to be affected by the proposed European Medicines Agency's guidelines on phthalates.

PubMed

Jamieson, Lisa; McCully, William

2015-06-13

Phthalates are excipients in drug formulations. However, concerns have been raised about the effects of particular phthalates on reproduction and development. As a result the EMA has introduced guidelines for permitted daily exposure (PDE) limits for certain phthalates. Therefore, the objective of this study was to identify UK licensed medicines that contain the relevant phthalates and determine if they fall within the recommended PDE. The eMC was used to identify which UK licensed medicines contain the phthalates in question. Companies were then contacted for information on the phthalate levels in their products, which was compared with the PDE recommended by the EMA. The eMC search revealed that 54 medicines contained at least one of the phthalates in question. However, only six medicines, namely Asacol 800 mg MR (Warner Chilcott UK), Epilim 200 Gastro-resistant tablets (Sanofi), Prednisolone 2.5 mg and 5 mg Gastro-resistant tablets (Actavis UK), Vivotif (Crucell Italy S.r.l), and Zentiva 200 mg Gastro-resistant tablets (Winthrop Pharmaceuticals UK), were identified as containing levels that exceeded the recommended PDE. These findings indicate that very few UK licensed medicines will be affected by the proposed EMA guidelines. For those medicines identified as exceeding recommendations, these findings highlight the need to instigate a risk-benefit review.

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

PubMed

Mitra, Jyotirmoy; Bhattacharyya, Debasish

2014-09-01

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

Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF.

PubMed

Puerta, Elena; Hervias, Isabel; Barros-Miñones, Lucía; Jordan, Joaquin; Ricobaraza, Ana; Cuadrado-Tejedor, Mar; García-Osta, Ana; Aguirre, Norberto

2010-05-01

In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD. Copyright 2010 Elsevier Inc. All rights reserved.

A Real-Time Near-Infrared Fluorescence Imaging Method for the Detection of Oral Cancers in Mice Using an Indocyanine Green-Labeled Podoplanin Antibody.

PubMed

Ito, Akihiro; Ohta, Mitsuhiko; Kato, Yukinari; Inada, Shunko; Kato, Toshio; Nakata, Susumu; Yatabe, Yasushi; Goto, Mitsuo; Kaneda, Norio; Kurita, Kenichi; Nakanishi, Hayao; Yoshida, Kenji

2018-01-01

Podoplanin is distinctively overexpressed in oral squamous cell carcinoma than oral benign neoplasms and plays a crucial role in the pathogenesis and metastasis of oral squamous cell carcinoma but its diagnostic application is quite limited. Here, we report a new near-infrared fluorescence imaging method using an indocyanine green (ICG)-labeled anti-podoplanin antibody and a desktop/a handheld ICG detection device for the visualization of oral squamous cell carcinoma-xenografted tumors in nude mice. Both near-infrared imaging methods using a desktop (in vivo imaging system: IVIS) and a handheld device (photodynamic eye: PDE) successfully detected oral squamous cell carcinoma tumors in nude mice in a podoplanin expression-dependent manner with comparable sensitivity. Of these 2 devices, only near-infrared imaging methods using a handheld device visualized oral squamous cell carcinoma xenografts in mice in real time. Furthermore, near-infrared imaging methods using the handheld device (PDE) could detect smaller podoplanin-positive oral squamous cell carcinoma tumors than a non-near-infrared, autofluorescence-based imaging method. Based on these results, a near-infrared imaging method using an ICG-labeled anti-podoplanin antibody and a handheld detection device (PDE) allows the sensitive, semiquantitative, and real-time imaging of oral squamous cell carcinoma tumors and therefore represents a useful tool for the detection and subsequent monitoring of malignant oral neoplasms in both preclinical and some clinical settings.

A Real-Time Near-Infrared Fluorescence Imaging Method for the Detection of Oral Cancers in Mice Using an Indocyanine Green–Labeled Podoplanin Antibody

PubMed Central

Ito, Akihiro; Ohta, Mitsuhiko; Kato, Yukinari; Inada, Shunko; Kato, Toshio; Nakata, Susumu; Yatabe, Yasushi; Goto, Mitsuo; Kaneda, Norio; Kurita, Kenichi; Nakanishi, Hayao; Yoshida, Kenji

2018-01-01

Podoplanin is distinctively overexpressed in oral squamous cell carcinoma than oral benign neoplasms and plays a crucial role in the pathogenesis and metastasis of oral squamous cell carcinoma but its diagnostic application is quite limited. Here, we report a new near-infrared fluorescence imaging method using an indocyanine green (ICG)–labeled anti-podoplanin antibody and a desktop/a handheld ICG detection device for the visualization of oral squamous cell carcinoma–xenografted tumors in nude mice. Both near-infrared imaging methods using a desktop (in vivo imaging system: IVIS) and a handheld device (photodynamic eye: PDE) successfully detected oral squamous cell carcinoma tumors in nude mice in a podoplanin expression–dependent manner with comparable sensitivity. Of these 2 devices, only near-infrared imaging methods using a handheld device visualized oral squamous cell carcinoma xenografts in mice in real time. Furthermore, near-infrared imaging methods using the handheld device (PDE) could detect smaller podoplanin-positive oral squamous cell carcinoma tumors than a non-near-infrared, autofluorescence-based imaging method. Based on these results, a near-infrared imaging method using an ICG-labeled anti-podoplanin antibody and a handheld detection device (PDE) allows the sensitive, semiquantitative, and real-time imaging of oral squamous cell carcinoma tumors and therefore represents a useful tool for the detection and subsequent monitoring of malignant oral neoplasms in both preclinical and some clinical settings. PMID:29649929

The Geometric Nature of the Flaschka Transformation

NASA Astrophysics Data System (ADS)

Bloch, Anthony M.; Gay-Balmaz, François; Ratiu, Tudor S.

2017-06-01

We show that the Flaschka map, originally introduced to analyze the dynamics of the integrable Toda lattice system, is the inverse of a momentum map. We discuss the geometrical setting of the map and apply it to the generalized Toda lattice systems on semisimple Lie algebras, the rigid body system on Toda orbits, and to coadjoint orbits of semidirect products groups. In addition, we develop an infinite-dimensional generalization for the group of area preserving diffeomorphisms of the annulus and apply it to the analysis of the dispersionless Toda lattice PDE and the solvable rigid body PDE.

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

PubMed

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

2010-05-01

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

Defining the Phosphodiesterase Superfamily Members in Rat Brain Microvessels

PubMed Central

2011-01-01

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

Dose received by occupationally exposed workers at a nuclear medicine department

NASA Astrophysics Data System (ADS)

Ávila, O.; Sánchez-Uribe, N. A.; Rodríguez-Laguna, A.; Medina, L. A.; Estrada, E.; Buenfil, A. E.; Brandan, M. E.

2012-10-01

Personal Dose Equivalent (PDE) values were determined for occupational exposed workers (OEW) at the Nuclear Medicine Department (NMD) of "Instituto Nacional de Cancerología" (INCan), Mexico, using TLD-100 thermoluminescent dosemeters. OEW at NMD, INCan make use of radiopharmaceuticals for diagnosis and treatment of diseases. Radionuclides associated to a pharmaceutical compound used at this Department are 131I, 18F, 68Ga, 99mTc, 111In and 11C with main gamma emission energies between 140 and 511 keV. Dosemeter calibration was performed at the metrology department of "Instituto Nacional de Investigaciones Nucleares" (ININ), Mexico. Every occupational worker used dark containers with three dosimeters which were replaced monthly for a total of 5 periods. Additionally, control dosemeters were also placed at a site free of radioactive sources in order to determine the background radiation. Results were adjusted to find PDE/day and estimating annual PDE values in the range between 2 mSv (background) and 9 mSv. The mean annual value is 3.51 mSv and the standard deviation SD is 0.78 mSv. Four of the 16 OEW received annual doses higher than the average +1 SD (4.29 mSv). Results depend on OEW daily activities and were consistent for each OEW for the 5 studied periods as well as with PDE values reported by the firm that performs the monthly service. All obtained values are well within the established annual OEW dose limit stated in the "Reglamento General de Seguridad Radiológica", México (50 mSv), as well as within the lower limit recommended by the "International Commission on Radiation Protection" (ICRP), report no.60 (20 mSv). These results verify the adequate compliance of the NMD at INCan, Mexico with the norms given by the national regulatory commission.

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

PubMed

Talaei, Behzad; Jagannathan, Sarangapani; Singler, John

2018-04-01

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

Sildenafil reduces respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy.

PubMed

Percival, Justin M; Whitehead, Nicholas P; Adams, Marvin E; Adamo, Candace M; Beavo, Joseph A; Froehner, Stanley C

2012-09-01

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy caused by mutations in the dystrophin gene. Loss of dystrophin initiates a progressive decline in skeletal muscle integrity and contractile capacity which weakens respiratory muscles including the diaphragm, culminating in respiratory failure, the leading cause of morbidity and mortality in DMD patients. At present, corticosteroid treatment is the primary pharmacological intervention in DMD, but has limited efficacy and adverse side effects. Thus, there is an urgent need for new safe, cost-effective, and rapidly implementable treatments that slow disease progression. One promising new approach is the amplification of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signalling pathways with phosphodiesterase 5 (PDE5) inhibitors. PDE5 inhibitors serve to amplify NO signalling that is attenuated in many neuromuscular diseases including DMD. We report here that a 14-week treatment of the mdx mouse model of DMD with the PDE5 inhibitor sildenafil (Viagra(®), Revatio(®)) significantly reduced mdx diaphragm muscle weakness without impacting fatigue resistance. In addition to enhancing respiratory muscle contractility, sildenafil also promoted normal extracellular matrix organization. PDE5 inhibition slowed the establishment of mdx diaphragm fibrosis and reduced matrix metalloproteinase-13 (MMP-13) expression. Sildenafil also normalized the expression of the pro-fibrotic (and pro-inflammatory) cytokine tumour necrosis factor α (TNFα). Sildenafil-treated mdx diaphragms accumulated significantly less Evans Blue tracer dye than untreated controls, which is also indicative of improved diaphragm muscle health. We conclude that sildenafil-mediated PDE5 inhibition significantly reduces diaphragm respiratory muscle dysfunction and pathology in the mdx mouse model of Duchenne muscular dystrophy. This study provides new insights into the therapeutic utility of targeting defects in NO-cGMP signalling with PDE5 inhibitors in dystrophin-deficient muscle. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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

PubMed Central

Punzalan, Florencio Rusty; Kunieda, Yoshitoshi; Amano, Akira

2015-01-01

Clinical and experimental studies involving human hearts can have certain limitations. Methods such as computer simulations can be an important alternative or supplemental tool. Physiological simulation at the tissue or organ level typically involves the handling of partial differential equations (PDEs). Boundary conditions and distributed parameters, such as those used in pharmacokinetics simulation, add to the complexity of the PDE solution. These factors can tailor PDE solutions and their corresponding program code to specific problems. Boundary condition and parameter changes in the customized code are usually prone to errors and time-consuming. We propose a general approach for handling PDEs and boundary conditions in computational models using a replacement scheme for discretization. This study is an extension of a program generator that we introduced in a previous publication. The program generator can generate code for multi-cell simulations of cardiac electrophysiology. Improvements to the system allow it to handle simultaneous equations in the biological function model as well as implicit PDE numerical schemes. The replacement scheme involves substituting all partial differential terms with numerical solution equations. Once the model and boundary equations are discretized with the numerical solution scheme, instances of the equations are generated to undergo dependency analysis. The result of the dependency analysis is then used to generate the program code. The resulting program code are in Java or C programming language. To validate the automatic handling of boundary conditions in the program code generator, we generated simulation code using the FHN, Luo-Rudy 1, and Hund-Rudy cell models and run cell-to-cell coupling and action potential propagation simulations. One of the simulations is based on a published experiment and simulation results are compared with the experimental data. We conclude that the proposed program code generator can be used to generate code for physiological simulations and provides a tool for studying cardiac electrophysiology. PMID:26356082

10-Year analysis of adverse event reports to the Food and Drug Administration for phosphodiesterase type-5 inhibitors.

PubMed

Lowe, Gregory; Costabile, Raymond A

2012-01-01

To ensure public safety all Food and Drug Administration (FDA)-approved medications undergo postapproval safety analysis. Phosphodiesterase type-5 inhibitors (PDE5-i) are generally regarded as safe and effective. We performed a nonindustry-sponsored analysis of FDA reports for sildenafil, tadalafil, and vardenafil to evaluate the reported cardiovascular and mortality events over the past 10 years. Summarized reports of adverse events (AEs) for each PDE5-i were requested from the Center for Drug Evaluation and Research within the FDA. These data are available under the Freedom of Information Act and document industry and nonindustry reports of AEs entered into the computerized system maintained by the Office of Surveillance and Epidemiology. The data were analyzed for the number of AE reports, number of objective cardiovascular events, and reported deaths. Overall, 14,818 AEs were reported for sildenafil. There were 1,824 (12.3%) reported deaths, and reports of cardiovascular AEs numbered 2,406 (16.2%). Tadalafil was associated with 5,548 AEs and 236 deaths were reported. Vardenafil was associated with 6,085 AEs and 121 reports of deaths. The percentage of reported severe cardiovascular disorders has stabilized at 10% to 15% of all AE reports for sildenafil and tadalafil and 5% to 10% for vardenafil. Only 10% of AE reports sent to the FDA for PDE5-i were from pharmaceutical manufacturers. Reports of deaths associated with PDE5-i remain around 5% of total reported events. Despite inherent limitations from evaluating FDA reports of AEs, it is important that these reports be reviewed outside pharmaceutical industry support in order to provide due diligence and transparency. Lowe G and Costabile RA. 10-year analysis of adverse event reports to the Food and Drug Administration for phosphodiesterase type-5 inhibitors. J Sex Med 2012;9:265-270. © 2011 International Society for Sexual Medicine.

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

PubMed

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

2012-05-15

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

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

PubMed Central

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

1996-01-01

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

Partial differential equation transform — Variational formulation and Fourier analysis

PubMed Central

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

2011-01-01

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

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

PubMed Central

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

2012-01-01

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

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

PubMed Central

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

2016-01-01

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

A pathophysiological role of PDE3 in allergic airway inflammation

PubMed Central

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

2018-01-01

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

A multiscale approach to modelling electrochemical processes occurring across the cell membrane with application to transmission of action potentials.

PubMed

Richardson, G

2009-09-01

By application of matched asymptotic expansions, a simplified partial differential equation (PDE) model for the dynamic electrochemical processes occurring in the vicinity of a membrane, as ions selectively permeate across it, is formally derived from the Poisson-Nernst-Planck equations of electrochemistry. It is demonstrated that this simplified model reduces itself, in the limit of a long thin axon, to the cable equation used by Hodgkin and Huxley to describe the propagation of action potentials in the unmyelinated squid giant axon. The asymptotic reduction from the simplified PDE model to the cable equation leads to insights that are not otherwise apparent; these include an explanation of why the squid giant axon attains a diameter in the region of 1 mm. The simplified PDE model has more general application than the Hodgkin-Huxley cable equation and can, e.g. be used to describe action potential propagation in myelinated axons and neuronal cell bodies.

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

PubMed

Brinks, Ralph; Landwehr, Sandra

2015-01-01

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

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

PubMed Central

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

2009-01-01

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

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

PubMed

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

2017-06-01

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

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.

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

PubMed Central

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

1993-01-01

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

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.

Performance Impact of Deflagration to Detonation Transition Enhancing Obstacles

NASA Technical Reports Server (NTRS)

Paxson, Daniel E.; Schauer, Frederick; Hopper, David

2012-01-01

A sub-model is developed to account for the drag and heat transfer enhancement resulting from deflagration-to-detonation (DDT) inducing obstacles commonly used in pulse detonation engines (PDE). The sub-model is incorporated as a source term in a time-accurate, quasi-onedimensional, CFD-based PDE simulation. The simulation and sub-model are then validated through comparison with a particular experiment in which limited DDT obstacle parameters were varied. The simulation is then used to examine the relative contributions from drag and heat transfer to the reduced thrust which is observed. It is found that heat transfer is far more significant than aerodynamic drag in this particular experiment.

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.

Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.

PubMed

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

2017-04-27

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

Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival.

PubMed

Medina-Rodríguez, E M; Arenzana, F J; Pastor, J; Redondo, M; Palomo, V; García de Sola, R; Gil, C; Martínez, A; Bribián, A; de Castro, F

2013-09-01

During the development of the central nervous system (CNS), oligodendrocyte precursors (OPCs) are generated in specific sites within the neural tube and then migrate to colonize the entire CNS, where they differentiate into myelin-forming oligodendrocytes. Demyelinating diseases such as multiple sclerosis (MS) are characterized by the death of these cells. The CNS reacts to demyelination and by promoting spontaneous remyelination, an effect mediated by endogenous OPCs, cells that represent approximately 5-7 % of the cells in the adult brain. Numerous factors influence oligodendrogliogenesis and oligodendrocyte differentiation, including morphogens, growth factors, chemotropic molecules, extracellular matrix proteins, and intracellular cAMP levels. Here, we show that during development and in early adulthood, OPCs in the murine cerebral cortex contain phosphodiesterase-7 (PDE7) that metabolizes cAMP. We investigated the effects of different PDE7 inhibitors (the well-known BRL-50481 and two new ones, TC3.6 and VP1.15) on OPC proliferation, survival, and differentiation. While none of the PDE7 inhibitors analyzed altered OPC proliferation, TC3.6 and VP1.15 enhanced OPC survival and differentiation, processes in which ERK intracellular signaling played a key role. PDE7 expression was also observed in OPCs isolated from adult human brains and the differentiation of these OPCs into more mature oligodendroglial phenotypes was accelerated by treatment with both new PDE7 inhibitors. These findings reveal new roles for PDE7 in regulating OPC survival and differentiation during brain development and in adulthood, and they may further our understanding of myelination and facilitate the development of therapeutic remyelination strategies for the treatment of MS.

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.

Geometry of PDE's. IV

NASA Astrophysics Data System (ADS)

Prástaro, Agostino

2008-02-01

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

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.

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 relaxation limit, and compare the numerical results with exact or numerical reference solutions obtained for the Euler and Navier-Stokes equations. Numerical convergence results are also provided. To show the universality of the HPR model, the paper is rounded-off with an application to wave propagation in elastic solids, for which one only needs to switch off the strain relaxation source term in the governing PDE system. We provide various examples showing that for the purpose of flow visualization, the distortion tensor A seems to be particularly useful.

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

PubMed

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

2017-02-22

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

Comparative efficacy of tadalafil once daily in men with erectile dysfunction who demonstrated previous partial responses to as-needed sildenafil, tadalafil, or vardenafil.

PubMed

Kim, Edward; Seftel, Allen; Goldfischer, Evan; Baygani, Simin; Burns, Patrick

2015-02-01

Phosphodiesterase type-5 inhibitors (PDE5Is) are first-line therapies for erectile dysfunction (ED). Sildenafil (SIL) and vardenafil (VAR) are approved for as-needed (PRN) dosing; tadalafil (TAD) is approved for both PRN and once-a-day (OaD) dosing for ED. Recent evidence suggests that TAD-OaD may be effective as therapy in men with an incomplete response to PRN-PDE5I therapy. This study evaluated whether TAD-OaD provides similar efficacy in men with ED who had previously demonstrated a partial response to PRN-PDE5I therapy. In this randomized, double-blind, placebo-controlled trial, men with a ≥3 month ED history received SIL 100 mg, TAD 20 mg, or VAR 20 mg during a 4 week open-label lead-in period. Those with International Index of Erectile Function - Erectile Function (IIEF-EF) domain scores <26 following lead-in treatment completed a 4 week washout period, then randomized to TAD 2.5 mg up-titrated to 5 mg, TAD 5 mg, or placebo (PBO) OaD for 12 weeks. MAIN OUTCOME MEASURES obtained from patients treated with TAD-OaD were compared to PBO-treated patients. Additionally, results of treatment with TAD-OaD were compared to results obtained from 4 week PRN-PDE5I therapy to determine whether OaD and PRN regimens provided comparable efficacy. NCT01130532. International Index of Erectile Function (IIEF) domain scores; Sexual Encounter Profile (SEP) questions 2-5. Endpoint data was obtained from 590 men (391 TAD; 199 PBO). RESULTS for all IIEF and SEP measures were significantly better for TAD-OaD (p < 0.001 for all) compared to PBO and were comparable to those observed during PRN-PDE5I treatment. TAD 2.5 mg and TAD 5 mg OaD therapy were safe and generally well tolerated. Tadalafil once daily is a viable alternative to as-needed PDE5I therapy in men with ED. Key limitations include the lack of a PRN PDE5I study group during the double-blind period, and that many more patients took tadalafil than sildenafil or vardenafil during the PRN period.

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

Crisaborole: Phosphodiesterase inhibitor for treatment of atopic dermatitis.

PubMed

Paton, D M

2017-04-01

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

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.

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.

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

PubMed

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

2016-06-13

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

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

PubMed

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

2016-12-01

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

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

PubMed Central

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

2016-01-01

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

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

PubMed

Richter, Wito; Conti, Marco

2004-07-16

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

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2017-08-01

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

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

PubMed Central

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

2016-01-01

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

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.

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 proposed model is that the propagation speeds of all physical processes, including dissipative processes, are finite. The model is discretized using high order accurate ADER discontinuous Galerkin (DG) finite element schemes with a posteriori subcell finite volume limiter and using high order ADER-WENO finite volume schemes. We show numerical test problems that explore a rather large parameter space of the model ranging from ideal MHD, viscous and resistive MHD over pure electro-dynamics to moving dielectric elastic solids in a magnetic field.

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.

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

PubMed

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

2016-07-01

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

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

PubMed

Strahm, Emmanuel; Rane, Anders; Ekström, Lena

2014-01-01

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

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

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

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

Use of Indocyanine Green for Sentinel Lymph Node Biopsy: Case Series and Methods Comparison.

PubMed

McGregor, Andrew; Pavri, Sabrina N; Tsay, Cynthia; Kim, Samuel; Narayan, Deepak

2017-11-01

Sentinel lymph node biopsy is indicated for patients with biopsy-proven thickness melanoma greater than 1.0 mm. Use of lymphoscintigraphy along with vital blue dyes is the gold standard for identifying sentinel lymph nodes intraoperatively. Indocyanine green (ICG) has recently been used as a method of identifying sentinel lymph nodes. We herein describe a case series of patients who have successfully undergone ICG-assisted sentinel lymph node biopsy for melanoma. We compare 2 imaging systems that are used for ICG-assisted sentinel lymph node biopsy. Fourteen patients underwent ICG-assisted sentinel lymph node biopsy for melanoma using the SPY Elite system (Novadaq, Mississigua, Canada) and the Hamamatsu PDE-Neo probe system (Mitaka USA, Park City, Utah). We analyzed costs for 2 systems that utilize ICG for sentinel lymph node biopsies. Intraoperative use of ICG for sentinel lymph node biopsies was successful in correctly identifying sentinel lymph nodes. There was no difference between the Hamamatsu PDE-Neo probe and SPY Elite systems in the ability to detect sentinel lymph nodes; however, the former was associated with a lower operating cost and ease of use compared with the latter. ICG-assisted sentinel lymph biopsy using the SPY Elite or the Hamamatsu PDE-Neo probe systems for melanoma are comparable in terms of sentinel node detection. The Neo probe system delivers pertinent clinical data with the advantages of lower cost and ease of operation.

Innovative Airbreathing Propulsion Concepts for High-speed Applications

NASA Technical Reports Server (NTRS)

Whitlow, Woodrow, Jr.

2002-01-01

The current cost to launch payloads to low earth orbit (LEO) is approximately loo00 U.S. dollars ($) per pound ($22000 per kilogram). This high cost limits our ability to pursue space science and hinders the development of new markets and a productive space enterprise. This enterprise includes NASA's space launch needs and those of industry, universities, the military, and other U.S. government agencies. NASA's Advanced Space Transportation Program (ASTP) proposes a vision of the future where space travel is as routine as in today's commercial air transportation systems. Dramatically lower launch costs will be required to make this vision a reality. In order to provide more affordable access to space, NASA has established new goals in its Aeronautics and Space Transportation plan. These goals target a reduction in the cost of launching payloads to LEO to $lo00 per pound ($2200 per kilogram) by 2007 and to $100' per pound by 2025 while increasing safety by orders of magnitude. Several programs within NASA are addressing innovative propulsion systems that offer potential for reducing launch costs. Various air-breathing propulsion systems currently are being investigated under these programs. The NASA Aerospace Propulsion and Power Base Research and Technology Program supports long-term fundamental research and is managed at GLenn Research Center. Currently funded areas relevant to space transportation include hybrid hyperspeed propulsion (HHP) and pulse detonation engine (PDE) research. The HHP Program currently is addressing rocket-based combined cycle and turbine-based combined cycle systems. The PDE research program has the goal of demonstrating the feasibility of PDE-based hybrid-cycle and combined cycle propulsion systems that meet NASA's aviation and access-to-space goals. The ASTP also is part of the Base Research and Technology Program and is managed at the Marshall Space Flight Center. As technologies developed under the Aerospace Propulsion and Power Base Research and Technology Program mature, they are incorporated into ASTP. One example of this is rocket-based combined cycle systems that are being considered as part of ASTP. The NASA Ultra Efficient Engine Technology (UEET) Program has the goal of developing propulsion system component technology that is relevant to a wide range of vehicle missions. In addition to subsonic and supersonic speed regimes, it includes the hypersonic speed regime. More specifically, component technologies for turbine-based combined cycle engines are being developed as part of UEET.

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.

Computationally efficient statistical differential equation modeling using homogenization

USGS Publications Warehouse

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

2013-01-01

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

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

Dose received by occupationally exposed workers at a nuclear medicine department

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

Avila, O.; Sanchez-Uribe, N. A.; Rodriguez-Laguna, A.

2012-10-23

Personal Dose Equivalent (PDE) values were determined for occupational exposed workers (OEW) at the Nuclear Medicine Department (NMD) of 'Instituto Nacional de Cancerologia' (INCan), Mexico, using TLD-100 thermoluminescent dosemeters. OEW at NMD, INCan make use of radiopharmaceuticals for diagnosis and treatment of diseases. Radionuclides associated to a pharmaceutical compound used at this Department are {sup 131}I, {sup 18}F, {sup 68}Ga, {sup 99m}Tc, {sup 111}In and {sup 11}C with main gamma emission energies between 140 and 511 keV. Dosemeter calibration was performed at the metrology department of 'Instituto Nacional de Investigaciones Nucleares' (ININ), Mexico. Every occupational worker used dark containers withmore » three dosimeters which were replaced monthly for a total of 5 periods. Additionally, control dosemeters were also placed at a site free of radioactive sources in order to determine the background radiation. Results were adjusted to find PDE/day and estimating annual PDE values in the range between 2 mSv (background) and 9 mSv. The mean annual value is 3.51 mSv and the standard deviation SD is 0.78 mSv. Four of the 16 OEW received annual doses higher than the average +1 SD (4.29 mSv). Results depend on OEW daily activities and were consistent for each OEW for the 5 studied periods as well as with PDE values reported by the firm that performs the monthly service. All obtained values are well within the established annual OEW dose limit stated in the {sup R}eglamento General de Seguridad Radiologica{sup ,} Mexico (50 mSv), as well as within the lower limit recommended by the 'International Commission on Radiation Protection' (ICRP), report no.60 (20 mSv). These results verify the adequate compliance of the NMD at INCan, Mexico with the norms given by the national regulatory commission.« less

Effect of phosphodiesterase inhibitors in the bladder.

PubMed

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

2015-01-01

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

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.

Biomolecular surface construction by PDE transform

PubMed Central

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

2011-01-01

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

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

PubMed

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

2014-04-01

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

A synthetic cGMP-sensitive gene switch providing Viagra(®)-controlled gene expression in mammalian cells and mice.

PubMed

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

2015-05-01

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

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

PubMed

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

2015-01-01

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

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

PubMed

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

2015-07-01

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

Chiral discrimination of the Japanese beetle sex pheromone and a behavioral antagonist by a pheromone-degrading enzyme.

PubMed

Ishida, Yuko; Leal, Walter S

2008-07-01

The sophistication of the insect olfactory system is elegantly demonstrated by the reception of sex pheromone by the Japanese beetle. In this insect, two olfactory receptor neurons housed in antennal sensilla placodea are highly sensitive. One neuron specifically detects the sex pheromone produced by conspecific females (R,Z)-5-(-)-(1-decenyl)oxacyclopentan-2-one [(R)-japonilure]. The other neuron is tuned to (S)-japonilure, a sex pheromone from a closely related species and a behavioral antagonist for the Japanese beetle. These chemical signals are enzymatically terminated by antennal esterases that open the lactone rings to form physiologically inactive hydroxyacids. We have isolated a pheromone-degrading enzyme, PjapPDE, from >100,000 antennae of the Japanese beetle. PjapPDE was demonstrated to be expressed only in the antennal tissues housing the pheromone-detecting sensilla placodea. Baculovirus expression generated recombinant PjapPDE with likely the same posttranslational modifications as the native enzyme. Kinetic studies with pure native and recombinant PjapPDE showed a clear substrate preference, with an estimated half-life in vivo for the sex pheromone and a behavioral antagonist of approximately 30 and approximately 90 ms, respectively.

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.

Efficient Implementation of Multigrid Solvers on Message-Passing Parrallel Systems

NASA Technical Reports Server (NTRS)

Lou, John

1994-01-01

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

Intraoperative Identification of the Parathyroid Gland with a Fluorescence Detection System.

PubMed

Shinden, Yoshiaki; Nakajo, Akihiro; Arima, Hideo; Tanoue, Kiyonori; Hirata, Munetsugu; Kijima, Yuko; Maemura, Kosei; Natsugoe, Shoji

2017-06-01

Intraoperative identification of the difficult-to-spot parathyroid gland is critical during surgery for thyroid and parathyroid disease. Recently, intrinsic fluorescence of the parathyroid gland was identified, and a new method was developed for intraoperative detection of the parathyroid with an original fluorescent detection apparatus. Here, we describe a method for intraoperative detection of the parathyroid using a ready-made photodynamic eye (PDE) system without any fluorescent dye or contrast agents. Seventeen patients who underwent surgical treatment for thyroid or parathyroid disease at Kagoshima University Hospital were enrolled in this study. Intrinsic fluorescence of various tissues was detected with the PDE system. Intraoperative in vivo and ex vivo intrinsic fluorescence of the parathyroid, thyroid, lymph nodes and fat tissues was measured and analyzed. The parathyroid gland had a significantly higher fluorescence intensity than the other tissues, including the thyroid glands, lymph nodes and fat tissues, and we could identify them during surgery using the fluorescence-guided method. Our method could be applicable for two intraoperative clinical procedures: ex vivo tissue identification of parathyroid tissue and in vivo identification of the location of the parathyroid gland, including ectopic glands. The PDE system may be an easy and highly feasible method to identify the parathyroid gland during surgery.

Treatment of Skin Inflammation with Benzoxaborole Phosphodiesterase Inhibitors: Selectivity, Cellular Activity, and Effect on Cytokines Associated with Skin Inflammation and Skin Architecture Changes.

PubMed

Dong, Chen; Virtucio, Charlotte; Zemska, Olga; Baltazar, Grober; Zhou, Yasheen; Baia, Diogo; Jones-Iatauro, Shannon; Sexton, Holly; Martin, Shamra; Dee, Joshua; Mak, Yvonne; Meewan, Maliwan; Rock, Fernando; Akama, Tsutomu; Jarnagin, Kurt

2016-09-01

Psoriasis and atopic dermatitis are skin diseases affecting millions of patients. Here, we characterize benzoxaborole phosphodiesterase (PDE)-4 inhibitors, a new topical class that has demonstrated therapeutic benefit for psoriasis and atopic dermatitis in phase 2 or phase 3 studies. Crisaborole [AN2728, 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile], compd2 [2-ethoxy-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)nicotinonitrile], compd3 [6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-(2-isopropoxyethoxy)nicotinonitrile], and compd4 [5-chloro-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-((4-oxopentyl)oxy)nicotinonitrile] are potent PDE4 inhibitors with similar affinity for PDE4 isoforms and equivalent inhibition on the catalytic domain and the full-length enzyme. These benzoxaboroles are less active on other PDE isozymes. Compd4 binds to the catalytic domain of PDE4B2 with the oxaborole group chelating the catalytic bimetal and overlapping with the phosphate in cAMP during substrate hydrolysis, and the interaction extends into the adenine pocket. In cell culture, benzoxaborole PDE4 inhibitors suppress the release of tumor necrosis factor-α, interleukin (IL)-23, IL-17, interferon-γ, IL-4, IL-5, IL-13, and IL-22, and these cytokines contribute to the pathologic changes in skin structure and barrier functions as well as immune dysregulation in atopic dermatitis and psoriasis. Treatment with compd3 or N(6),2'-O-dibutyryladenosine 3',5'-cyclic monophosphate increases cAMP response element binding protein phosphorylation in human monocytes and decreases extracellular signal-regulated kinase phosphorylation in human T cells; these changes lead to reduced cytokine production and are among the mechanisms by which compd3 blocks cytokine release. Topical compd3 penetrates the skin and suppresses phorbol myristate acetate-induced IL-13, IL-22, IL-17F, and IL-23 transcription and calcipotriol-induced thymic stromal lymphopoietin expression in mouse skin. Skin thinning is a major dose-limiting side effect of glucocorticoids. By contrast, repeated application of compd3 did not thin mouse skin. These findings show the potential benefits and safety of benzoxaborole PDE4 inhibitors for the treatment of psoriasis and atopic dermatitis. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Applications of Laser Diagnostics

DTIC Science & Technology

2005-03-01

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

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.

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

NASA Technical Reports Server (NTRS)

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

2002-01-01

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

Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair

PubMed Central

Knott, Eric P.; Assi, Mazen; Rao, Sudheendra N. R.; Ghosh, Mousumi; Pearse, Damien D.

2017-01-01

A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies. The only known negative regulators of cyclic nucleotides are a family of enzymes called phosphodiesterases (PDEs) that hydrolyze cyclic nucleotides into adenosine monophosphate (AMP) or guanylate monophosphate (GMP). Herein, we discuss the structure and physiological function as well as the roles PDEs play in pathological processes of the diseased or injured CNS. Further we review the approaches that have been employed therapeutically in experimental paradigms to block PDE expression or activity and in turn elevate cyclic nucleotide levels to mediate neuroprotection or neurorepair as well as discuss both the translational pathway and current limitations in moving new PDE-targeted therapies to the clinic. PMID:28338622

Correspondence between discrete and continuous models of excitable media: trigger waves

NASA Technical Reports Server (NTRS)

Chernyak, Y. B.; Feldman, A. B.; Cohen, R. J.

1997-01-01

We present a theoretical framework for relating continuous partial differential equation (PDE) models of excitable media to discrete cellular automata (CA) models on a randomized lattice. These relations establish a quantitative link between the CA model and the specific physical system under study. We derive expressions for the CA model's plane wave speed, critical curvature, and effective diffusion constant in terms of the model's internal parameters (the interaction radius, excitation threshold, and time step). We then equate these expressions to the corresponding quantities obtained from solution of the PDEs (for a fixed excitability). This yields a set of coupled equations with a unique solution for the required CA parameter values. Here we restrict our analysis to "trigger" wave solutions obtained in the limiting case of a two-dimensional excitable medium with no recovery processes. We tested the correspondence between our CA model and two PDE models (the FitzHugh-Nagumo medium and a medium with a "sawtooth" nonlinear reaction source) and found good agreement with the numerical solutions of the PDEs. Our results suggest that the behavior of trigger waves is actually controlled by a small number of parameters.

Spatial evolutionary games with weak selection.

PubMed

Nanda, Mridu; Durrett, Richard

2017-06-06

Recently, a rigorous mathematical theory has been developed for spatial games with weak selection, i.e., when the payoff differences between strategies are small. The key to the analysis is that when space and time are suitably rescaled, the spatial model converges to the solution of a partial differential equation (PDE). This approach can be used to analyze all [Formula: see text] games, but there are a number of [Formula: see text] games for which the behavior of the limiting PDE is not known. In this paper, we give rules for determining the behavior of a large class of [Formula: see text] games and check their validity using simulation. In words, the effect of space is equivalent to making changes in the payoff matrix, and once this is done, the behavior of the spatial game can be predicted from the behavior of the replicator equation for the modified game. We say predicted here because in some cases the behavior of the spatial game is different from that of the replicator equation for the modified game. For example, if a rock-paper-scissors game has a replicator equation that spirals out to the boundary, space stabilizes the system and produces an equilibrium.

Spatial evolutionary games with weak selection

PubMed Central

Nanda, Mridu; Durrett, Richard

2017-01-01

Recently, a rigorous mathematical theory has been developed for spatial games with weak selection, i.e., when the payoff differences between strategies are small. The key to the analysis is that when space and time are suitably rescaled, the spatial model converges to the solution of a partial differential equation (PDE). This approach can be used to analyze all 2×2 games, but there are a number of 3×3 games for which the behavior of the limiting PDE is not known. In this paper, we give rules for determining the behavior of a large class of 3×3 games and check their validity using simulation. In words, the effect of space is equivalent to making changes in the payoff matrix, and once this is done, the behavior of the spatial game can be predicted from the behavior of the replicator equation for the modified game. We say predicted here because in some cases the behavior of the spatial game is different from that of the replicator equation for the modified game. For example, if a rock–paper–scissors game has a replicator equation that spirals out to the boundary, space stabilizes the system and produces an equilibrium. PMID:28533405

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

PubMed

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

2016-08-01

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

COMPUTATION OF ℛ IN AGE-STRUCTURED EPIDEMIOLOGICAL MODELS WITH MATERNAL AND TEMPORARY IMMUNITY.

PubMed

Feng, Zhilan; Han, Qing; Qiu, Zhipeng; Hill, Andrew N; Glasser, John W

2016-03-01

For infectious diseases such as pertussis, susceptibility is determined by immunity, which is chronological age-dependent. We consider an age-structured epidemiological model that accounts for both passively acquired maternal antibodies that decay and active immunity that wanes, permitting reinfection. The model is a 6-dimensional system of partial differential equations (PDE). By assuming constant rates within each age-group, the PDE system can be reduced to an ordinary differential equation (ODE) system with aging from one age-group to the next. We derive formulae for the effective reproduction number ℛ and provide their biological interpretation in some special cases. We show that the disease-free equilibrium is stable when ℛ < 1 and unstable if ℛ > 1.

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

NASA Astrophysics Data System (ADS)

Cao, Fangfei; Liu, Jinkun

2018-05-01

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

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

NASA Astrophysics Data System (ADS)

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

2016-12-01

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

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

NASA Astrophysics Data System (ADS)

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

2011-08-01

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

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

PubMed Central

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

1991-01-01

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

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

PubMed

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

2016-08-24

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

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

PubMed Central

Pauwelyn, Vicky; Lefebvre, Romain A.

2018-01-01

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

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

PubMed

Sugita, Minoru; Miyakawa, Michiko

2010-07-01

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

Novel Therapeutic Targets for Phosphodiesterase 5 Inhibitors: current state-of-the-art on systemic arterial hypertension and atherosclerosis.

PubMed

Vasquez, Elisardo C; Gava, Agata L; Graceli, Jones B; Balarini, Camille M; Campagnaro, Bianca P; Pereira, Thiago Melo C; Meyrelles, Silvana S

2016-01-01

The usefulness of selective inhibitors of phosphodiesterase 5 (PDE5) is well known, first for the treatment of male erectile dysfunction and more recently for pulmonary hypertension. The discovery that PDE5 is present in the systemic artery endothelium and smooth muscle cells led investigators to test the extra sexual effects of sildenafil, the first and most investigated PDE5 inhibitor, in diseases affecting the systemic arteries. Cumulative data from experimental and clinical studies have revealed beneficial effects of sildenafil on systemic arterial hypertension and its target organs, such as the heart, kidneys and vasculature. An important effect of sildenafil is reduction of hypertension and improvement of endothelial function in experimental models of hypertension and hypertensive subjects. Interestingly, in angiotensin-dependent hypertension, its beneficial effects on endothelial and kidney dysfunctions seem to at least in part be caused by its ability to decrease the levels of angiotensin II and increase angiotensin 1-7, in addition to improving nitric oxide bioavailability and diminishing reactive oxygen species. Another remarkable finding on the effects of sildenafil comes from studies in apolipoprotein E knockout mice, a model of atherosclerosis that closely resembles human atherosclerotic disease. In this review, we focus on the promising beneficial effects of sildenafil for treating systemic high blood pressure, especially resistant hypertension, and the endothelial dysfunction that is present in hypertension and atherosclerosis.

Partial regularity of weak solutions to a PDE system with cubic nonlinearity

NASA Astrophysics Data System (ADS)

Liu, Jian-Guo; Xu, Xiangsheng

2018-04-01

In this paper we investigate regularity properties of weak solutions to a PDE system that arises in the study of biological transport networks. The system consists of a possibly singular elliptic equation for the scalar pressure of the underlying biological network coupled to a diffusion equation for the conductance vector of the network. There are several different types of nonlinearities in the system. Of particular mathematical interest is a term that is a polynomial function of solutions and their partial derivatives and this polynomial function has degree three. That is, the system contains a cubic nonlinearity. Only weak solutions to the system have been shown to exist. The regularity theory for the system remains fundamentally incomplete. In particular, it is not known whether or not weak solutions develop singularities. In this paper we obtain a partial regularity theorem, which gives an estimate for the parabolic Hausdorff dimension of the set of possible singular points.

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

PubMed

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

2008-11-15

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

Biomolecular surface construction by PDE transform.

PubMed

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

2012-03-01

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

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

PubMed

Yates, Christian A; Flegg, Mark B

2015-05-06

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

Crisaborole Topical Ointment, 2% in Patients Ages 2 to 17 Years with Atopic Dermatitis: A Phase 1b, Open-Label, Maximal-Use Systemic Exposure Study.

PubMed

Zane, Lee T; Kircik, Leon; Call, Robert; Tschen, Eduardo; Draelos, Zoe Diana; Chanda, Sanjay; Van Syoc, Merrie; Hebert, Adelaide A

2016-07-01

Phosphodiesterase-4 (PDE4) is a promising target in atopic dermatitis (AD) treatment. The pharmacokinetics (PK), safety, and efficacy of crisaborole topical ointment, 2% (formerly AN2728) (Anacor Pharmaceuticals, Palo Alto, CA), a boron-based benzoxaborole PDE4 inhibitor, were evaluated in children with mild to moderate AD. This phase 1b, open-label, maximal-use study of crisaborole topical ointment, 2% applied twice daily (dose 3 mg/cm(2) ) for 28 days enrolled patients ages 2 to 17 years with extensive AD involving 25% or more or 35% or more treatable body surface area, depending on age. Primary PK and safety assessments included systemic exposure to crisaborole and its metabolites after 7 days of treatment and the incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy assessments included change from baseline in Investigator Static Global Assessment (ISGA), treatment success (ISGA score ≤1 with a two-grade or greater improvement from baseline), and improvement in five AD signs and symptoms. Of 34 patients enrolled, 31 completed the study. Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8. Twenty-three of 34 patients reported one or more TEAEs; 95% were mild or moderate and one patient discontinued because of a TEAE. Mean ISGA scores declined from 2.65 at baseline to 1.15 at day 29, 47.1% of patients achieved treatment success, and 64.7% of patients achieved ISGA scores of clear (0) or almost clear . Mean severity scores for AD signs and symptoms declined throughout the study. This open-label study provides evidence that crisaborole topical ointment, 2% was well tolerated, with limited systemic exposure under maximal-use conditions in patients ages 2 years and older. © 2016 The Authors. Pediatric Dermatology Published by Wiley Periodicals, Inc.

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

DTIC Science & Technology

2009-01-01

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

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

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.

Prenatal drug exposure, behavioral problems and drug experimentation among African American urban adolescents

PubMed Central

Wang, Yan; Buckingham-Howes, Stacy; Nair, Prasanna; Zhu, Shijun; Magder, Larry; Black, Maureen M.

2014-01-01

Purpose To examine how prenatal heroin/cocaine exposure (PDE) and behavioral problems relate to adolescent drug experimentation. Methods The sample included African American adolescents (mean age=14.2 yr, SD=1.2) with PDE (n=73) and a non-exposed community comparison (n=61). PDE status was determined at delivery through toxicology analysis and maternal-report. Internalizing/externalizing problems were assessed during adolescence with the Behavior Assessment System for Children, Second Edition. Drug experimentation was assessed by adolescent-report and urine analysis. Logistic regression evaluated the likelihood of drug experimentation related to PDE and behavioral problems, adjusting for age, gender, prenatal tobacco/alcohol exposure, perceived peer drug use and caregiver drug use. Interaction terms examined gender modification. Results 67 (50%) used drugs. 25 (19%) used tobacco/alcohol only and 42 (31%) used marijuana/illegal drugs. 94 (70%) perceived peer drug use. PDE significantly increased the risk of tobacco/alcohol experimentation (OR=3.07, 95% CI: 1.09–8.66, p=0.034), but not after covariate adjustment (aOR=1.31, 95% CI: 0.39–4.36, p>0.05). PDE was not related to overall or marijuana/illegal drug experimentation. The likelihood of overall drug experimentation was doubled per Standard Deviation (SD) increase in externalizing problems (aOR=2.28, 95% CI: 1.33–3.91, p=0.003) and, among girls, 2.82 times greater (aOR=2.82, 95% CI: 1.34–5.94, p=0.006) per SD increase in internalizing problems. Age and perceived peer drug use were significant covariates. Conclusions Drug experimentation was relatively common (50%), especially in the context of externalizing problems, internalizing problems (girls only), age, and perceived peer drug use. Findings support Problem Behavior Theory and suggest that adolescent drug prevention address behavioral problems and promote prosocial peer groups. PMID:24768161

Pulsed Ejector Wave Propogation Test Program

NASA Technical Reports Server (NTRS)

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

2003-01-01

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

Do vardenafil and tadalafil have advantages over sildenafil in the treatment of erectile dysfunction?

PubMed

Doggrell, S

2007-01-01

Erectile dysfunction (ED) affects up to 50% of men between the ages of 40 and 70 years of age. Sildenafil, vardenafil and tadalafil have all been shown to be similarly effective in the treatment of men with ED of vary etiologies, to have similar adverse effects profiles, and to improve quality-of-life by similar amounts. As these phosphodiesterase 5 (PDE5) inhibitors all increase the hypotensive effects of nitrates, they are not suitable for use in patients taking nitrates for the treatment of ischaemic heart disease. All three inhibitors must be used with caution in patients taking alpha(1)-adrenoceptors antagonists for benign prostatic hyperplasia. Although nonarteritic anterior ischaemic neuropathy has been reported in some users of the PDE5 inhibitors, there is no conclusive evidence that PDE5 inhibitors cause this rare effect. Tadalafil has a longer half-life than sildenafil or vardenafil, and a longer duration of action than sildenafil and vardenafil. Most preference studies have shown tadalafil to be preferred, but there are serious limitations to some of these studies. One approach to treatment is to give each patient a short- and long-acting agent, and for individuals to decide their preference.

Novel therapy for pyridoxine dependent epilepsy due to ALDH7A1 genetic defect: L-arginine supplementation alternative to lysine-restricted diet.

PubMed

Mercimek-Mahmutoglu, Saadet; Cordeiro, Dawn; Cruz, Vivian; Hyland, Keith; Struys, Eduard A; Kyriakopoulou, Lianna; Mamak, Eva

2014-11-01

Pyridoxine dependent epilepsy (PDE) due to mutations in the ALDH7A1 gene (PDE-ALDH7A1) is caused by α-aminoadipic-semialdehyde-dehydrogenase enzyme deficiency in the lysine pathway resulting in the accumulation of α-aminoadipic acid semialdehyde (α-AASA). Classical presentation is neonatal intractable seizures with a dramatic response to pyridoxine. Pyridoxine therapy does not prevent developmental delays in the majority of the patients. We hypothesized that L-arginine supplementation will decrease accumulation of α-AASA by competitive inhibition of lysine transport into the central nervous system and improve neurodevelopmental and neurocognitive functions in PDE-ALDH7A1. A 12-year-old male with PDE-ALDH7A1 was treated with l-arginine supplementation as an innovative therapy. Treatment outcome was monitored by cerebral-spinal-fluid (CSF) α-AASA measurements at baseline, 6th and 12th months of therapy. Neuropsychological assessments were performed at baseline and 12th months of therapy. L-arginine therapy was well tolerated without side effects. CSF α-AASA was decreased 57% at 12th months of therapy. Neuropsychological assessments revealed improvements in general abilities index from 108 to 116 and improvements in verbal and motor functioning at 12th months of therapy. The short-term treatment outcome of this novel L-arginine supplementation therapy for PDE-ALDH7A1 was successful for biochemical and neurocognitive improvements. Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

2'-phosphodiesterase and 2',5'-oligoadenylate synthetase activities in the lowest metazoans, sponge [porifera].

PubMed

Saby, Emilie; Poulsen, Jesper Buchhave; Justesen, Just; Kelve, Merike; Uriz, Maria Jesus

2009-01-01

Sponges [porifera], the most ancient metazoans, contain modules related to the vertebrate immune system, including the 2',5'-oligoadenylate synthetase (OAS). The components of the antiviral 2',5'-oligoadenylate (2-5A) system (OAS, 2'-Phosphodiesterase (2'-PDE) and RNAse L) of vertebrates have not all been identified in sponges. Here, we demonstrate for the first time that in addition to the OAS activity, sponges possess a 2'-PDE activity, which highlights the probable existence of a premature 2-5A system. Indeed, Suberites domuncula and Crella elegans exhibited this 2-5A degrading activity. Upon this finding, two out of three elements forming the 2-5A system have been found in sponges, only a endoribonuclease, RNAse L or similar, has to be found. We suspect the existence of a complex immune system in sponges, besides the self/non-self recognition system and the use of phagocytosis and secondary metabolites against pathogens.

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

PubMed

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

2017-03-01

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

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

PubMed Central

Schwarz, Simon; Ravens, Ursula; Knaut, Michael

2016-01-01

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

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

PubMed

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

2017-09-22

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

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 properties.

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

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

PubMed

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

2016-11-01

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

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

PubMed Central

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

2014-01-01

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

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

PubMed Central

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

2009-01-01

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

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

PubMed Central

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

2018-01-01

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

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.

A PDE-based methodology for modeling, parameter estimation and feedback control in structural and structural acoustic systems

NASA Technical Reports Server (NTRS)

Banks, H. T.; Brown, D. E.; Metcalf, Vern L.; Silcox, R. J.; Smith, Ralph C.; Wang, Yun

1994-01-01

A problem of continued interest concerns the control of vibrations in a flexible structure and the related problem of reducing structure-borne noise in structural acoustic systems. In both cases, piezoceramic patches bonded to the structures have been successfully used as control actuators. Through the application of a controlling voltage, the patches can be used to reduce structural vibrations which in turn lead to methods for reducing structure-borne noise. A PDE-based methodology for modeling, estimating physical parameters, and implementing a feedback control scheme for problems of this type is discussed. While the illustrating example is a circular plate, the methodology is sufficiently general so as to be applicable in a variety of structural and structural acoustic systems.

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

PubMed Central

2015-01-01

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

Multiscale Modeling of Angiogenesis and Predictive Capacity

NASA Astrophysics Data System (ADS)

Pillay, Samara; Byrne, Helen; Maini, Philip

Tumors induce the growth of new blood vessels from existing vasculature through angiogenesis. Using an agent-based approach, we model the behavior of individual endothelial cells during angiogenesis. We incorporate crowding effects through volume exclusion, motility of cells through biased random walks, and include birth and death-like processes. We use the transition probabilities associated with the discrete model and a discrete conservation equation for cell occupancy to determine collective cell behavior, in terms of partial differential equations (PDEs). We derive three PDE models incorporating single, multi-species and no volume exclusion. By fitting the parameters in our PDE models and other well-established continuum models to agent-based simulations during a specific time period, and then comparing the outputs from the PDE models and agent-based model at later times, we aim to determine how well the PDE models predict the future behavior of the agent-based model. We also determine whether predictions differ across PDE models and the significance of those differences. This may impact drug development strategies based on PDE models.

Phosphodiesterases regulate airway smooth muscle function in health and disease.

PubMed

Krymskaya, Vera P; Panettieri, Reynold A

2007-01-01

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

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

PubMed

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

2015-01-01

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

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

PubMed Central

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

2008-01-01

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

PDE and cognitive processing: beyond the memory domain.

PubMed

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

2015-03-01

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

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

PubMed

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

2016-12-01

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

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

PubMed

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

1994-06-15

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

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

PubMed Central

Balhadère, Pascale V.; Talbot, Nicholas J.

2001-01-01

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

UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy.

PubMed

Wang, Li; Burmeister, Brian T; Johnson, Keven R; Baillie, George S; Karginov, Andrei V; Skidgel, Randal A; O'Bryan, John P; Carnegie, Graeme K

2015-05-01

Hypertrophy increases the risk of heart failure and arrhythmia. Prevention or reversal of the maladaptive hypertrophic phenotype has thus been proposed to treat heart failure. Chronic β-adrenergic receptor (β-AR) stimulation induces cardiomyocyte hypertrophy by elevating 3',5'-cyclic adenosine monophosphate (cAMP) levels and activating downstream effectors such protein kinase A (PKA). Conversely, hydrolysis of cAMP by phosphodiesterases (PDEs) spatiotemporally restricts cAMP signaling. Here, we demonstrate that PDE4, but not PDE3, is critical in regulating cardiomyocyte hypertrophy, and may represent a potential target for preventing maladaptive hypertrophy. We identify a sequence within the upstream conserved region 1 of PDE4D, termed UCR1C, as a novel activator of PDE4 long isoforms. UCR1C activates PDE4 in complex with A-kinase anchoring protein (AKAP)-Lbc resulting in decreased PKA signaling facilitated by AKAP-Lbc. Expression of UCR1C in cardiomyocytes inhibits hypertrophy in response to chronic β-AR stimulation. This effect is partially due to inhibition of nuclear PKA activity, which decreases phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In conclusion, PDE4 activation by UCR1C attenuates cardiomyocyte hypertrophy by specifically inhibiting nuclear PKA activity. Published by Elsevier Inc.

Addressing the immunopathogenesis of atopic dermatitis: advances in topical and systemic treatment.

PubMed

Eichenfield, Lawrence F; Stein Gold, Linda F

2017-03-01

Several immunologic mediators-phosphodiesterase (PDE), interleukin (IL), small molecules, and Janus kinase-have been implicated in the pathogenesis of atopic dermatitis, and evidence has shown that blocking these mediators can help modify the disease process. Several new topical medications have been developed that target the enzyme PDE; crisaborole was recently approved by the US Food and Drug Administration (FDA) for the treatment of atopic dermatitis, and phase II studies have been completed on OPA-15406. The phase III clinical trial results of the systemic medication dupilumab, an inhibitor of the IL-4 receptor α subunit (which inhibits both IL-4 and IL-13 signaling), are currently being reviewed by the FDA. ©2017 Frontline Medical Communications.

PDE3, but not PDE4, reduces β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

PubMed Central

Molenaar, Peter; Christ, Torsten; Hussain, Rizwan I; Engel, Andreas; Berk, Emanuel; Gillette, Katherine T; Chen, Lu; Galindo-Tovar, Alejandro; Krobert, Kurt A; Ravens, Ursula; Levy, Finn Olav; Kaumann, Alberto J

2013-01-01

Background and Purpose PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3–1 μM) or PDE4 inhibitor rolipram (1–10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. Experimental Approach Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β1 adrenoceptors (β2 adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2 adrenoceptors (β1 adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from –logEC50s. Key Results Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. Conclusions and Implications Metoprolol induces a control by PDE3 of ventricular effects mediated through both β1 and β2 adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β2 adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle. Linked Article This article is commented on by Eschenhagen, pp 524–527 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12168 PMID:23489141

CHBPR: Decreased cGMP level contributes to increased contraction in arteries from hypertensive rats: role of PDE1

PubMed Central

Giachini, Fernanda R.; Lima, Victor V.; Carneiro, Fernando S.; Tostes, Rita C.; Webb, R. Clinton

2011-01-01

Recent evidence suggests that angiotensin II (Ang II) upregulates phosphodiesterase (PDE)-1A expression. We hypothesized that Ang II augmented PDE1 activation, decreasing the bioavailability of cyclic cyclic guanosine 3', 5'-monophosphate (cGMP), contributing to increased vascular contractility. Male Sprague-Dawley rats received mini-osmotic pumps with Ang II (60 ng.min−1) or saline for 14 days. PE-induced contractions were increased in aorta (Emax168±8 vs. 136±4%) and small-mesenteric arteries [(SMA), Emax170±6 vs. 143±3%] from Ang II infused rats compared to control. PDE1 inhibition with vinpocetine (10µM) reduced PE-induced contraction in aortas from Ang II rats (Emax94±12%) but not in control (154±7%). Vinpocetine decreased the sensitivity to PE in SMA from Ang II rats compared to vehicle (pD2 5.1±0.1 vs. 5.9±0.06), but not in control (6.0±0.03 vs. 6.1±0.04). Sildenafil (10µM), a PDE5 inhibitor reduced PE-induced maximal contraction similarly in Ang II and control rats. Arteries were contracted with PE (1µM) and concentration-dependent relaxation to vinpocetine and sildenafil was evaluated. Aortas from Ang II rats displayed increased relaxation to vinpocetine compared to control (Emax82±12 vs. 44±5%). SMA from Ang II rats showed greater sensitivity during vinpocetine-induced relaxation, compared to control (pD2 6.1±0.3 vs. 5.3±0.1). No differences in sildenafil-induced relaxation were observed. PDE1A and PDE1C expressions in aorta and PDE1A expression in SMA were increased in Ang II rats. cGMP production, which is decreased in arteries from Ang II rats, was restored after PDE1 blockade. We conclude that PDE1 activation reduces cGMP bioavailability in arteries from ANG II, contributing to increased contractile responsiveness. PMID:21282562

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 reserved.

Equation-free and variable free modeling for complex/multiscale systems. Coarse-grained computation in science and engineering using fine-grained models

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

Kevrekidis, Ioannis G.

The work explored the linking of modern developing machine learning techniques (manifold learning and in particular diffusion maps) with traditional PDE modeling/discretization/scientific computation techniques via the equation-free methodology developed by the PI. The result (in addition to several PhD degrees, two of them by CSGF Fellows) was a sequence of strong developments - in part on the algorithmic side, linking data mining with scientific computing, and in part on applications, ranging from PDE discretizations to molecular dynamics and complex network dynamics.

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.

Cyanidin-3-glucoside suppresses B[a]PDE-induced cyclooxygenase-2 expression by directly inhibiting Fyn kinase activity.

PubMed

Lim, Tae-Gyu; Kwon, Jung Yeon; Kim, Jiyoung; Song, Nu Ry; Lee, Kyung Mi; Heo, Yong-Seok; Lee, Hyong Joo; Lee, Ki Won

2011-07-15

Benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE) is a well-known carcinogen that is associated with skin cancer. Abnormal expression of cyclooxygenase-2 (COX-2) is an important mediator in inflammation and tumor promotion. We investigated the inhibitory effect of cyanidin-3-glucoside (C3G), an anthocyanin present in fruits, on B[a]PDE-induced COX-2 expression in mouse epidermal JB6 P+ cells. Pretreatment with C3G resulted in the reduction of B[a]PDE-induced expression of COX-2 and COX-2 promoter activity. The activation of activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) induced by B[a]PDE was also attenuated by C3G. C3G attenuated the B[a]PDE-induced phosphorylation of MEK, MKK4, Akt, and mitogen-activated protein kinases (MAPKs), but no effect on the phosphorylation of the upstream MAPK regulator Fyn. However, kinase assays demonstrated that C3G suppressed Fyn kinase activity and C3G directly binds Fyn kinase noncompetitively with ATP. By using PP2, a pharmacological inhibitor for SFKs, we showed that Fyn kinase regulates B[a]PDE-induced COX-2 expression by activating MAPKs, AP-1 and NF-κB. These results suggest that C3G suppresses B[a]PDE-induced COX-2 expression mainly by blocking the activation of the Fyn signaling pathway, which may contribute to its chemopreventive potential. Copyright © 2011 Elsevier Inc. All rights reserved.

Regulation of Phosphodiesterase 3 in the Pulmonary Arteries During the Perinatal Period in Sheep

PubMed Central

Chen, Bernadette; Lakshminrusimha, Satyan; Czech, Lyubov; Groh, Beezly S.; Gugino, Sylvia F.; Russell, James A.; Farrow, Kathryn N.; Steinhorn, Robin H.

2009-01-01

The role of cAMP in the pulmonary vasculature during the transition from intrauterine to extrauterine life is poorly understood. We hypothesized that cAMP levels are regulated by alterations in phosphodiesterase 3 (PDE3), which hydrolyzes cAMP. PDE3 protein expression and hydrolytic activity were increased in resistance pulmonary arteries (PA) from spontaneously breathing one-day-old (1dSB) lambs relative to equivalent-gestation fetuses. This was accompanied by a decrease in steady-state cAMP. Ventilation with 21% O2 and 100% O2 for 24h disrupted the normal transition, whereas ventilation with 100% O2+inhaled NO (iNO) for 24h restored both PDE3 activity and cAMP to 1dSB levels. Consistent with these findings, relaxation to milrinone, a PDE3 inhibitor, was greater in PA isolated from 1dSB and 100% O2+iNO lambs, relative to fetal, 21% O2, and 100% O2 lambs. In conclusion, PDE3 expression and activity in PA dramatically increase after birth, with a concomitant decrease in steady-state cAMP. Ventilation with either 21% O2 or 100% O2 blunts this PDE3 increase, whereas iNO restores PDE3 activity to levels equivalent to 1dSB lambs. The vasodilatory effects of milrinone were most pronounced in vessels from lambs with the highest PDE3 activity, i.e. 1dSB and 100% O2+iNO lambs. Thus, milrinone may be most beneficial when used in conjunction with iNO. PMID:19707176

Inhibition of Cyclic Adenosine Monophosphate-Specific Phosphodiesterase by Various Food Plant-Derived Phytotherapeutic Agents

PubMed Central

Pacjuk, Olga; Hernández-Huguet, Silvia; Körner, Johanna; Scherer, Katharina; Richling, Elke

2017-01-01

Background: Phosphodiesterases (PDEs) play a major role in the regulation of cyclic adenosine monophosphate (cAMP)- and cyclic guanosine monophosphate (cGMP)-mediated pathways. Their inhibitors exhibit anti-inflammatory, vasodilatory and antithrombotic effects. Therefore, consumption of foods with PDE-inhibiting potential may possess beneficial influence on the risk of cardiovascular diseases. Methods: Four plant extracts (Arbutus unedo, Camellia sinensis, Cynara scolymus, Zingiber officinale) with promising ingredient profiles and physiological effects were tested for their ability to inhibit cAMP-specific PDE in vitro in a radioactive assay. Results: Strawberry tree fruit (Arbutus unedo) and tea (Camellia sinensis) extracts did not inhibit PDE markedly. Alternatively, artichoke (Cynara scolymus) extract had a significant inhibitory influence on PDE activity (IC50 = 0.9 ± 0.1 mg/mL) as well as its flavone luteolin (IC50 = 41 ± 10 μM) and 3,4-dicaffeoylquinic acid (IC50 > 1.0 mM). Additionally, the ginger (Zingiber officinale) extract and one of its constituents, [6]-gingerol, significantly inhibited PDE (IC50 = 1.7 ± 0.2 mg/mL and IC50 > 1.7 mM, respectively). Crude fractionation of ginger extract showed that substances responsible for PDE inhibition were in the lipoid fraction (IC50 = 455 ± 19 μg/mL). Conclusions: A PDE-inhibitory effect was shown for artichoke and ginger extract. Whether PDE inhibition in vivo can be achieved through ingestion of artichoke or ginger extracts leading to physiological effects concerning cardiovascular health should be addressed in future research. PMID:29113064

PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer.

PubMed

Das, Anindita; Durrant, David; Salloum, Fadi N; Xi, Lei; Kukreja, Rakesh C

2015-03-01

The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement of stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and anti-cancer benefits. Despite mixed results of these clinical trials, there is a continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Airbreathing Pulse Detonation Engine Performance

NASA Technical Reports Server (NTRS)

Povinelli, Louis A.; Yungster, Shaye

2002-01-01

This paper presents performance results for pulse detonation engines (PDE) taking into account the effects of dissociation and recombination. The amount of sensible heat recovered through recombination in the PDE chamber and exhaust process was found to be significant. These results have an impact on the specific thrust, impulse and fuel consumption of the PDE.

Stability analysis of coupled torsional vibration and pressure in oilwell drillstring system

NASA Astrophysics Data System (ADS)

Toumi, S.; Beji, L.; Mlayeh, R.; Abichou, A.

2018-01-01

To address security issues in oilwell drillstring system, the drilling operation handling which is in generally not autonomous but ensured by an operator may be drill bit destructive or fatal for the machine. To control of stick-slip phenomenon, the drillstring control at the right speed taking only the drillstring vibration is not sufficient as the mud dynamics and the pressure change around the drill pipes cannot be neglected. A coupled torsional vibration and pressure model is presented, and the well-posedness problem is addressed. As a Partial Differential Equation-Ordinary Differential Equation (PDE-ODE) coupled system, and in order to maintain a non destructive downhole pressure, we investigate the control stability with and without the damping term in the wave PDE. In terms of, the torsional variable, the downhole pressure, and the annulus pressure, the coupled system equilibrium is shown to be exponentially stable.

The safety of phosphodiesterase type 5 inhibitors for erectile dysfunction.

PubMed

Ventimiglia, Eugenio; Capogrosso, Paolo; Montorsi, Francesco; Salonia, Andrea

2016-01-01

Phosphodiesterase type 5 inhibitors (PDE5Is) are the leading drugs for the treatment of erectile dysfunction (ED), being recommended as a first line treatment by both the European and US urological guidelines. PDE5Is are highly effective as compared to placebo, well tolerated and have a very low, though not negligible, rate of severe treatment-related adverse events. This paper reviews the safety profile of currently available PDE5Is, comparing them in a broad spectrum ED population and outlining a number of real-life aspects of importance in the real-life everyday clinical setting. Guidelines unanimously agree in considering PDE5Is as first line treatments for ED when well-tolerated and not contraindicated. Despite the fact that no high-grade evidence comparing the efficacy and the safety for PDE5Is is currently available, published data seem to suggest that there are no major differences in their safety profiles. Moreover, although oral PDE5Is were shown to cause more AEs than placebo, they were generally mild and well tolerated.

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.

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

[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 function, desire, satisfaction during intercourse, overall satisfaction, and even the quality of life when it was studied. However, very few patients were included. Little data are available on the use of PDE5 inhibitors in schizophrenic patients. The 6 studies included few patients which reduces the power and the scope of their conclusions. There is also an important bias due to the use of self-questionnaires. The methodologies of the studies differ in many aspects which limits the comparability. Inclusion and exclusion criteria, drugs used and scales varied among the studies. However, the management of erectile disorder seems to be a consistent target in an integrative approach for the overall well-being of schizophrenic patients. PDE-5 inhibitors appear to be safe and could improve erectile function in schizophrenic patients. In total, the current data suggest efficiency and good tolerance of the use of PDE-5 inhibitors in schizophrenic patients with erectile dysfunction. However, further studies focusing on PDE-5 inhibitors are needed to more deeply assess their efficacy and safety in patients with schizophrenia. Copyright © 2016 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Pulse Detonation Engines for High Speed Flight

NASA Technical Reports Server (NTRS)

Povinelli, Louis A.

2002-01-01

Revolutionary concepts in propulsion are required in order to achieve high-speed cruise capability in the atmosphere and for low cost reliable systems for earth to orbit missions. One of the advanced concepts under study is the air-breathing pulse detonation engine. Additional work remains in order to establish the role and performance of a PDE in flight applications, either as a stand-alone device or as part of a combined cycle system. In this paper, we shall offer a few remarks on some of these remaining issues, i.e., combined cycle systems, nozzles and exhaust systems and thrust per unit frontal area limitations. Currently, an intensive experimental and numerical effort is underway in order to quantify the propulsion performance characteristics of this device. In this paper, we shall highlight our recent efforts to elucidate the propulsion potential of pulse detonation engines and their possible application to high-speed or hypersonic systems.

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish.

PubMed

Viringipurampeer, I A; Shan, X; Gregory-Evans, K; Zhang, J P; Mohammadi, Z; Gregory-Evans, C Y

2014-05-01

Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c(w59) mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c(w59) embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed. Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c(w59) mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

Nebivolol potentiates the efficacy of PDE5 inhibitors to relax corpus cavernosum and penile arteries from diabetic patients by enhancing the NO/cGMP pathway.

PubMed

Martínez-Salamanca, Juan I; La Fuente, José M; Cardoso, José; Fernández, Argentina; Cuevas, Pedro; Wright, Harold M; Angulo, Javier

2014-05-01

The efficacy of oral pharmacotherapy for erectile dysfunction (ED) (i.e., type 5 phosphodiesterase[PDE5] inhibitors) is significantly reduced in diabetic patients. Nebivolol is a selective β1-blocker used for treatinghy pertension that has been shown to increase the efficacy of sildenafil to reverse ED in diabetic rats. To evaluate the effects of nebivolol on the efficacy of the PDE5 inhibitors, sildenafil, tadalafil, and vardenafil to relax human corpus cavernosum (HCC) and vasodilate human penile resistance arteries (HPRA) from diabetic patients with ED (DMED). The influence of nebivolol on the capacity of these three PDE5 inhibitors to stimulate cyclic guanosine monophosphate (cGMP) production in HCC was also evaluated. HCC and HPRA were obtained from organ donors without ED (NEND; n = 18) or patients with diabetes undergoing penile prosthesis implantation (DMED; n = 19). Relaxations of HCC strips and HPRA to sildenafil,tadalafil, and vardenafil were evaluated in organ chambers and wire myographs. cGMP content in HCC was determined by ether extraction and quantification by ELISA. Effects of nebivolol on PDE5 inhibitor-induced relaxation of HCC, vasodilation ofHPRA and cGMP accumulation in HCC. Treatment with nebivolol (1 μM) significantly potentiated sildenafil-, tadalafil- and vardenafil-induced relaxations of HCC and vasodilations of HPRA from both NEND and DMED. Enhancement of relaxant capacity by nebivolol resulted in reversion of the impairment of PDE5 inhibition-induced responses in DMED and it was accompanied by enhancing the ability of PDE5 inhibitors to increase cGMP in HCC restoring reduced cGMP levelsin HCC from DMED. Nebivolol potentiated the capacity of PDE5 inhibitors to relax vascular structures of erectile tissue from diabetic patients by enhancing the nitric oxide (NO)/cGMP pathway in these tissues. These effects suggest a potential therapeutic utility of nebivolol as an adjunct to PDE5 inhibitors for the treatment of ED associated with diabetes.

Characterization of particulate cyclic nucleotide phosphodiesterases from bovine brain: Purification of a distinct cGMP-stimulated isoenzyme

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

Murashima, Seiko; Tanaka, Takayuki; Hockman, S.

1990-06-05

In the absence of detergent, {approx}80-85% of the total cGMP-stimulated phosphodiesterase (PDE) activity in bovine brain was associated with washed particulate fractions; {approx}85-90% of the calmodulin-sensitive PDE was soluble. Particulate cGMP-stimulated PDE was higher in cerebral cortical gray matter than in other regions. Homogenization of the brain particulate fraction in 1% Lubrol increased cGMP-stimulated activity {approx}100% and calmodulin-stimulated {approx}400-500%. Although 1% Lubrol readily solubilized these PDE activities, {approx}75% of the cAMP PDE activity (0.5 {mu}M ({sup 3}H)cAMP) that was not affected by cGMP was not solubilized. This cAMP PDE activity was very sensitive to inhibition by Rolipram but not cilostamide.more » Thus, three different PDE types, i.e., cGMP stimulated, calmodulin sensitive, and Rolipram inhibited, are associated in different ways with crude bovine brain particulate fractions. The brain enzyme exhibited a slightly greater subunit M{sub r} than did soluble forms from calf liver or bovine brain, as evidenced by protein staining or immunoblotting after polyacrylamide gel electrophoresis under denaturing conditions. Incubation of brain particulate and liver soluble cGMP-stimulated PDEs with V{sub 8} protease produced several peptides of similar size, as well as at least two distinct fragments of {approx}27 kDa from the brain and {approx}23 kDa from the liver enzyme. After photolabeling in the presence of ({sup 32}P)cGMP and digestion with V{sub 8} protease, ({sup 32}P)cGMP in each PDE was predominantly recovered with a peptide of {approx}14 kDa. All of these observations are consistent with the existence of at least two discrete forms (isoenzymes) of cGMP-stimulated PDE.« less

Does educational status affect a patient's behavior toward erectile dysfunction?

PubMed

Salonia, Andrea; Abdollah, Firas; Gallina, Andrea; Pellucchi, Federico; Castillejos Molina, Ricardo Alonso; Maccagnano, Carmen; Rocchini, Lorenzo; Zanni, Giuseppe; Rigatti, Patrizio; Montorsi, Francesco

2008-08-01

Educational status has been investigated rarely as a potential factor affecting the behavior of patients with new onset erectile dysfunction (ED) toward seeking first medical help and subsequent compliance with prescribed phosphodiesterase type 5 inhibitor (PDE5) therapy. To test whether the educational status of patients with new onset ED and naïve to PDE5 therapy may have a significant impact on the delay before seeking first medical help (DSH) and compliance with the suggested PDE5. Assessing DSH and compliance with PDE5 in new onset ED patients according to their educational status by means of detailed logistic regression analyses. Data from 302 consecutive patients with new onset ED and naïve to PDE5s were comprehensively analyzed. Patients were segregated according to their educational status into low (elementary and/or secondary school education) and high (high school and/or university degrees) educational levels. Complete data were available for 231 assessable patients. Univariate (UVA) and multivariate (MVA) logistic regression analyses addressed the association between educational status and DSH after adjusting for age, relationship status, and Sexual Health Inventory for Men score. Likewise, UVA and MVA were performed to test the association between educational status and patient compliance with PDE5 at the 9-month median follow-up. Median DSH was 24 months (range 1-350; mean 38.1 +/- 42.8). The lower the educational status, the shorter the DSH (P = 0.03). In contrast, a significantly (P < 0.0001) greater proportion of patients with a higher educational status showed compliance with the suggested PDE5 at the 9-month follow-up. Overall, educational status was not an independent predictor of either DSH or patient compliance with PDE5 therapy. After adjusting for other variables, our findings suggest that in new onset ED patients, educational status does not independently affect the DSH and patient compliance with PDE5 therapy.

[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.

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

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

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

2007-01-01

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

The multiscale expansions of difference equations in the small lattice spacing regime, and a vicinity and integrability test: I

NASA Astrophysics Data System (ADS)

Santini, Paolo Maria

2010-01-01

We propose an algorithmic procedure (i) to study the 'distance' between an integrable PDE and any discretization of it, in the small lattice spacing epsilon regime, and, at the same time, (ii) to test the (asymptotic) integrability properties of such discretization. This method should provide, in particular, useful and concrete information on how good is any numerical scheme used to integrate a given integrable PDE. The procedure, illustrated on a fairly general ten-parameter family of discretizations of the nonlinear Schrödinger equation, consists of the following three steps: (i) the construction of the continuous multiscale expansion of a generic solution of the discrete system at all orders in epsilon, following Degasperis et al (1997 Physica D 100 187-211) (ii) the application, to such an expansion, of the Degasperis-Procesi (DP) integrability test (Degasperis A and Procesi M 1999 Asymptotic integrability Symmetry and Perturbation Theory, SPT98, ed A Degasperis and G Gaeta (Singapore: World Scientific) pp 23-37 Degasperis A 2001 Multiscale expansion and integrability of dispersive wave equations Lectures given at the Euro Summer School: 'What is integrability?' (Isaac Newton Institute, Cambridge, UK, 13-24 August); Integrability (Lecture Notes in Physics vol 767) ed A Mikhailov (Berlin: Springer)), to test the asymptotic integrability properties of the discrete system and its 'distance' from its continuous limit; (iii) the use of the main output of the DP test to construct infinitely many approximate symmetries and constants of motion of the discrete system, through novel and simple formulas.

Effects of the approximations of light propagation on quantitative photoacoustic tomography using two-dimensional photon diffusion equation and linearization

NASA Astrophysics Data System (ADS)

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

2017-12-01

Quantitative photoacoustic tomography (QPAT) employing a light propagation model will play an important role in medical diagnoses by quantifying the concentration of hemoglobin or a contrast agent. However, QPAT by the light propagation model with the three-dimensional (3D) radiative transfer equation (RTE) requires a huge computational load in the iterative forward calculations involved in the updating process to reconstruct the absorption coefficient. The approximations of the light propagation improve the efficiency of the image reconstruction for the QPAT. In this study, we compared the 3D/two-dimensional (2D) photon diffusion equation (PDE) approximating 3D RTE with the Monte Carlo simulation based on 3D RTE. Then, the errors in a 2D PDE-based linearized image reconstruction caused by the approximations were quantitatively demonstrated and discussed in the numerical simulations. It was clearly observed that the approximations affected the reconstructed absorption coefficient. The 2D PDE-based linearized algorithm succeeded in the image reconstruction of the region with a large absorption coefficient in the 3D phantom. The value reconstructed in the phantom experiment agreed with that in the numerical simulation, so that it was validated that the numerical simulation of the image reconstruction predicted the relationship between the true absorption coefficient of the target in the 3D medium and the reconstructed value with the 2D PDE-based linearized algorithm. Moreover, the the true absorption coefficient in 3D medium was estimated from the 2D reconstructed image on the basis of the prediction by the numerical simulation. The estimation was successful in the phantom experiment, although some limitations were revealed.

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.

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.

Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman Primate

PubMed Central

Li, Junfeng; Zhang, Xiang; Jin, Hongjun; Fan, Jinda; Flores, Hubert; Perlmutter, Joel S.; Tu, Zhude

2015-01-01

A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [11C]MP-10. Twenty of the 22 new analogues had high potency and selectivity for PDE10A: 18a–j, 19d–j, 20a–b, and 21b had IC50 values <5 nM for PDE10A. Seven F-18 labeled compounds [18F]18a–e, [18F]18g, and [18F]20a were radiosynthesized by 18F-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed ~2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [18F]18a–d and [18F]20a. Micro-PET studies of [18F]18d and [18F]20a in nonhuman primates provided clear visualization of striatum with suitable equilibrium kinetics and favorable metabolic stability. These results suggest this strategy may identify a 18F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington’s disease and schizophrenia. PMID:26430878

Genetic deletion and pharmacological inhibition of phosphodiesterase 10A protects mice from diet-induced obesity and insulin resistance.

PubMed

Nawrocki, Andrea R; Rodriguez, Carlos G; Toolan, Dawn M; Price, Olga; Henry, Melanie; Forrest, Gail; Szeto, Daphne; Keohane, Carol Ann; Pan, Yie; Smith, Karen M; Raheem, Izzat T; Cox, Christopher D; Hwa, Joyce; Renger, John J; Smith, Sean M

2014-01-01

Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report a novel role of PDE10A in the regulation of caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) and associated metabolic disturbances. Inhibition of weight gain is due to hypophagia after mice are fed a highly palatable diet rich in fats and sugar but not a standard diet. PDE10A deficiency produces a decrease in caloric intake without affecting meal frequency, daytime versus nighttime feeding behavior, or locomotor activity. We tested THPP-6, a small molecule PDE10A inhibitor, in DIO mice. THPP-6 treatment resulted in decreased food intake, body weight loss, and reduced adiposity at doses that produced antipsychotic efficacy in behavioral models. We show that PDE10A inhibition increased whole-body energy expenditure in DIO mice fed a Western-style diet, achieving weight loss and reducing adiposity beyond the extent seen with food restriction alone. Therefore, chronic THPP-6 treatment conferred improved insulin sensitivity and reversed hyperinsulinemia. These data demonstrate that PDE10A inhibition represents a novel antipsychotic target that may have additional metabolic benefits over current medications for schizophrenia by suppressing food intake, alleviating weight gain, and reducing the risk for the development of diabetes.

A phosphodiesterase 4B-dependent interplay between tumor cells and the microenvironment regulates angiogenesis in B-cell lymphoma

PubMed Central

Suhasini, Avvaru N.; Lin, An-Ping; Bhatnagar, Harshita; Kim, Sang-Woo; Moritz, August W.; Aguiar, Ricardo C. T.

2015-01-01

Angiogenesis associates with poor outcome in diffuse large B-cell lymphoma (DLBCL), but the contribution of the lymphoma cells to this process remains unclear. Addressing this knowledge gap may uncover unsuspecting proangiogenic signaling nodes and highlight alternative antiangiogenic therapies. Here we identify the second messenger cyclic-AMP (cAMP) and the enzyme that terminates its activity, phosphodiesterase 4B (PDE4B), as regulators of B-cell lymphoma angiogenesis. We first show that cAMP, in a PDE4B-dependent manner, suppresses PI3K/AKT signals to down-modulate VEGF secretion and vessel formation in vitro. Next, we create a novel mouse model that combines the lymphomagenic Myc transgene with germline deletion of Pde4b. We show that lymphomas developing in a Pde4b-null background display significantly lower microvessel density in association with lower VEGF levels and PI3K/AKT activity. We recapitulate these observations by treating lymphoma-bearing mice with the FDA-approved PDE4 inhibitor Roflumilast. Lastly, we show that primary human DLBCLs with high PDE4B expression display significantly higher microvessel density. Here, we defined an unsuspected signaling circuitry in which the cAMP generated in lymphoma cells downmodulates PI3K/AKT and VEGF secretion to negatively influence vessel development in the microenvironment. These data identify PDE4 as an actionable antiangiogenic target in DLBCL. PMID:26503641

New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment.

PubMed

Brullo, Chiara; Ricciarelli, Roberta; Prickaerts, Jos; Arancio, Ottavio; Massa, Matteo; Rotolo, Chiara; Romussi, Alessia; Rebosio, Claudia; Marengo, Barbara; Pronzato, Maria Adelaide; van Hagen, Britt T J; van Goethem, Nick P; D'Ursi, Pasqualina; Orro, Alessandro; Milanesi, Luciano; Guariento, Sara; Cichero, Elena; Fossa, Paola; Fedele, Ernesto; Bruno, Olga

2016-11-29

Phosphodiesterase type 4D (PDE4D) has been indicated as a promising target for treating neurodegenerative pathologies such as Alzheimer's Disease (AD). By preventing cAMP hydrolysis, PDE4 inhibitors (PDE4Is) increase the cAMP response element-binding protein (CREB) phosphorylation, synaptic plasticity and long-term memory formation. Pharmacological and behavioral studies on our hit GEBR-7b demonstrated that selective PDE4DIs could improve memory without causing emesis and sedation. The hit development led to new molecule series, herein reported, characterized by a catechol structure bonded to five member heterocycles. Molecular modeling studies highlighted the pivotal role of a polar alkyl chain in conferring selective enzyme interaction. Compound 8a showed PDE4D3 selective inhibition and was able to increase intracellular cAMP levels in neuronal cells, as well as in the hippocampus of freely moving rats. Furthermore, 8a was able to readily cross the blood-brain barrier and enhanced memory performance in mice without causing any emetic-like behavior. These data support the view that PDE4D is an adequate molecular target to restore memory deficits in different neuropathologies, including AD, and also indicate compound 8a as a promising candidate for further preclinical development. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Current Status and Clinical Studies of Oriental Herbs in Sexual Medicine in Korea

PubMed Central

Shin, Yu Seob; Zhao, Chen; Zhang, Li Tao

2015-01-01

Erectile dysfunction (ED) is one of the most common diseases among aging men. Although previous studies have shown that type 5 phosphodiesterase inhibitors (PDE5-Is) are very effective for the treatment of ED, many researchers are currently attempting to identify therapeutic agents from natural sources with comparable or better effects than PDE5-Is. Herbal medicine is thought to be advantageous because it is natural; moreover, it not only treats isolated symptoms, but also maintains general well-being. Furthermore, since newly created chemical compound libraries have limited structural diversity with regard to pharmaceutical agents, more attention has recently been paid to the ability of oriental herbs to enhance physical health, including sexual function. Herein, we review the current status of Korean preclinical or clinical studies of the application of oriental herbs to sexual medicine. PMID:26331122

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.

Elevated leukocyte phosphodiesterase as a basis for depressed cyclic adenosine monophosphate responses in the Basenji greyhound dog model of asthma

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

Chan, S.C.; Hanifin, J.M.; Holden, C.A.

1985-08-01

The BG dog manifests various characteristics of human asthma, including airway hyperreactivity to low concentrations of methacholine. Studies have suggested that airway hyperreactivity in asthma is related to inadequate intracellular cAMP responses. The authors studied cAMP characteristics in MNL from 19 BG and 14 mongrel dogs. beta-Adrenergic receptors were assessed by /sup 125/I CYP in the presence and absence of propranolol. The responses of cAMP to ISO were measured by radioimmunoassay. Adenylate cyclase activity was determined in homogenized MNL preparations by cAMP generation. PDE activity was quantitated by radioenzyme assay. Mongrel dog leukocyte ISO-stimulated cAMP levels doubled, whereas there weremore » negligible increases in MNL from BG dogs. Basal PDE levels were higher in BG dogs than in mongrel dogs. The PDE inhibitor Ro 20-1724 restored ISO-stimulated cAMP responses in MNL of BG dogs. Adenylate cyclase activity was not lower in MNL homogenates from BG dogs than in mongrel dogs. Cells from both BG and mongrel dogs demonstrated similar receptor numbers and affinities of saturable, specific beta-adrenergic binding over a 10 pM to 400 pM range. The results suggest that depressed cAMP responses in BG dogs are due to high PDE activity rather than to a defect in the beta-adrenergic receptor adenylate cyclase system.« less

Measuring personal exposure from 900MHz mobile phone base stations in Australia and Belgium using a novel personal distributed exposimeter.

PubMed

Bhatt, Chhavi Raj; Thielens, Arno; Redmayne, Mary; Abramson, Michael J; Billah, Baki; Sim, Malcolm R; Vermeulen, Roel; Martens, Luc; Joseph, Wout; Benke, Geza

2016-01-01

The aims of this study were to: i) measure personal exposure in the Global System for Mobile communications (GSM) 900MHz downlink (DL) frequency band with two systems of exposimeters, a personal distributed exposimeter (PDE) and a pair of ExpoM-RFs, ii) compare the GSM 900MHz DL exposures across various microenvironments in Australia and Belgium, and iii) evaluate the correlation between the PDE and ExpoM-RFs measurements. Personal exposure data were collected using the PDE and two ExpoM-RFs simultaneously across 34 microenvironments (17 each in Australia and Belgium) located in urban, suburban and rural areas. Summary statistics of the electric field strengths (V/m) were computed and compared across similar microenvironments in Australia and Belgium. The personal exposures across urban microenvironments were higher than those in the rural or suburban microenvironments. Likewise, the exposure levels across the outdoor were higher than those for indoor microenvironments. The five highest median exposure levels were: city centre (0.248V/m), bus (0.124V/m), railway station (0.105V/m), mountain/forest (rural) (0.057V/m), and train (0.055V/m) [Australia]; and bicycle (urban) (0.238V/m), tram station (0.238V/m), city centre (0.156V/m), residential outdoor (urban) (0.139V/m) and park (0.124V/m) [Belgium]. Exposures in the GSM900 MHz frequency band across most of the microenvironments in Australia were significantly lower than the exposures across the microenvironments in Belgium. Overall correlations between the PDE and the ExpoM-RFs measurements were high. The measured exposure levels were far below the general public reference levels recommended in the guidelines of the ICNIRP and the ARPANSA. Copyright © 2016 Elsevier Ltd. All rights reserved.

New Insights into the Cyclic Di-adenosine Monophosphate (c-di-AMP) Degradation Pathway and the Requirement of the Cyclic Dinucleotide for Acid Stress Resistance in Staphylococcus aureus.

PubMed

Bowman, Lisa; Zeden, Merve S; Schuster, Christopher F; Kaever, Volkhard; Gründling, Angelika

2016-12-30

Nucleotide signaling networks are key to facilitate alterations in gene expression, protein function, and enzyme activity in response to diverse stimuli. Cyclic di-adenosine monophosphate (c-di-AMP) is an important secondary messenger molecule produced by the human pathogen Staphylococcus aureus and is involved in regulating a number of physiological processes including potassium transport. S. aureus must ensure tight control over its cellular levels as both high levels of the dinucleotide and its absence result in a number of detrimental phenotypes. Here we show that in addition to the membrane-bound Asp-His-His and Asp-His-His-associated (DHH/DHHA1) domain-containing phosphodiesterase (PDE) GdpP, S. aureus produces a second cytoplasmic DHH/DHHA1 PDE Pde2. Although capable of hydrolyzing c-di-AMP, Pde2 preferentially converts linear 5'-phosphadenylyl-adenosine (pApA) to AMP. Using a pde2 mutant strain, pApA was detected for the first time in S. aureus, leading us to speculate that this dinucleotide may have a regulatory role under certain conditions. Moreover, pApA is involved in a feedback inhibition loop that limits GdpP-dependent c-di-AMP hydrolysis. Another protein linked to the regulation of c-di-AMP levels in bacteria is the predicted regulator protein YbbR. Here, it is shown that a ybbR mutant S. aureus strain has increased acid sensitivity that can be bypassed by the acquisition of mutations in a number of genes, including the gene coding for the diadenylate cyclase DacA. We further show that c-di-AMP levels are slightly elevated in the ybbR suppressor strains tested as compared with the wild-type strain. With this, we not only identified a new role for YbbR in acid stress resistance in S. aureus but also provide further insight into how c-di-AMP levels impact acid tolerance in this organism. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

New Insights into the Cyclic Di-adenosine Monophosphate (c-di-AMP) Degradation Pathway and the Requirement of the Cyclic Dinucleotide for Acid Stress Resistance in Staphylococcus aureus*

PubMed Central

Bowman, Lisa; Zeden, Merve S.; Kaever, Volkhard

2016-01-01

Nucleotide signaling networks are key to facilitate alterations in gene expression, protein function, and enzyme activity in response to diverse stimuli. Cyclic di-adenosine monophosphate (c-di-AMP) is an important secondary messenger molecule produced by the human pathogen Staphylococcus aureus and is involved in regulating a number of physiological processes including potassium transport. S. aureus must ensure tight control over its cellular levels as both high levels of the dinucleotide and its absence result in a number of detrimental phenotypes. Here we show that in addition to the membrane-bound Asp-His-His and Asp-His-His-associated (DHH/DHHA1) domain-containing phosphodiesterase (PDE) GdpP, S. aureus produces a second cytoplasmic DHH/DHHA1 PDE Pde2. Although capable of hydrolyzing c-di-AMP, Pde2 preferentially converts linear 5′-phosphadenylyl-adenosine (pApA) to AMP. Using a pde2 mutant strain, pApA was detected for the first time in S. aureus, leading us to speculate that this dinucleotide may have a regulatory role under certain conditions. Moreover, pApA is involved in a feedback inhibition loop that limits GdpP-dependent c-di-AMP hydrolysis. Another protein linked to the regulation of c-di-AMP levels in bacteria is the predicted regulator protein YbbR. Here, it is shown that a ybbR mutant S. aureus strain has increased acid sensitivity that can be bypassed by the acquisition of mutations in a number of genes, including the gene coding for the diadenylate cyclase DacA. We further show that c-di-AMP levels are slightly elevated in the ybbR suppressor strains tested as compared with the wild-type strain. With this, we not only identified a new role for YbbR in acid stress resistance in S. aureus but also provide further insight into how c-di-AMP levels impact acid tolerance in this organism. PMID:27834680

Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction: Pharmacology and Clinical Impact of the Sildenafil Citrate Orodispersible Tablet Formulation.

PubMed

Scaglione, Francesco; Donde, Shaantanu; Hassan, Tarek A; Jannini, Emmanuele A

2017-02-01

The purpose of this review is to provide an overview of the pharmacology, tolerability, and efficacy of the different phosphodiesterase type 5 (PDE5) inhibitors available for the treatment of erectile dysfunction (ED), with a special focus on the sildenafil orodispersible tablet (ODT) formulation. A literature search was performed in PubMed, EMBASE, and Cochrane Reviews using the terms erectile dysfunction, patient preference, sildenafil, and PDE5 inhibitors to identify articles published in English between May 1, 2006, and November 18, 2016. A total of 29 studies were included in this review. There are substantial data in the literature on the use of PDE5 inhibitors for the treatment of ED. Oral PDE5 inhibitors have been found to be efficacious in the treatment of ED based on results from standard tools used to assess treatment outcomes, such as the Global Assessment Questionnaire 1. In addition, PDE5 inhibitors are defined as well tolerated because of the low occurrence of serious adverse effects or discomfort. Mild adverse reactions, compared with a placebo, include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash. Both the film-coated tablet and ODT formulations of sildenafil with or without water have equivalent systemic exposure. However, use of a sildenafil ODT formulation offers a convenient alternative method of administration that would be advantageous for patients with ED. According to the published literature, the PDE5 inhibitors are considered an effective and well-tolerated option for the treatment of ED as determined by data generated from standard instruments used in the assessment of treatment outcomes in ED and reported types and severity of adverse effects. The sildenafil ODT formulation, which disintegrates rapidly in the mouth, is an alternative to the solid film-coated tablet formulation that offers administration benefit with the potential to improve treatment adherence, thereby enhancing the sexual health and sense of psychological well-being of patients and their partners. Copyright © 2017. Published by Elsevier Inc.

PDE 5 inhibitor improves insulin sensitivity by enhancing mitochondrial function in adipocytes.

PubMed

Yu, Hea Min; Chung, Hyo Kyun; Kim, Koon Soon; Lee, Jae Min; Hong, Jun Hwa; Park, Kang Seo

2017-11-04

Adipocytes are involved in many metabolic disorders. It was recently reported that phosphodiesterase type 5 (PDE5) is expressed in human adipose tissue. In addition, PDE5 inhibitors have been shown to improve insulin sensitivity in humans. However, the mechanism underlying the role of PDE5 inhibitors as an insulin sensitizer remains largely unknown. The present study was undertaken to investigate the role of the PDE5 inhibitor udenafil in insulin signaling in adipocytes and whether this is mediated through the regulation of mitochondrial function. To study the mechanism underlying the insulin sensitizing action of PDE5 inhibitors, we evaluated quantitative changes in protein or mRNA levels of mitochondrial oxidative phosphorylation (OxPhos) complex, oxygen consumption rate (OCR), and fatty acid oxidation with varying udenafil concentrations in 3T3-L1 cells. Our cell study suggested that udenafil enhanced the insulin signaling pathway in 3T3-L1 cells. Following udenafil treatment, basal mitochondrial OCR, maximal OxPhos capacity, and OxPhos gene expression significantly increased. Finally, we examined whether udenafil can affect the fatty acid oxidation process. Treatment of 3T3-L1 cells with udenafil (10 and 20 μM) significantly increased fatty acid oxidation rate in a dose-dependent manner. In addition, the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) significantly increased. We demonstrated that the PDE5 inhibitor udenafil enhances insulin sensitivity by improving mitochondrial function in 3T3-L1 cells. This might be the mechanism underlying the PDE5 inhibitor-enhanced insulin signaling in adipocytes. This also suggests that udenafil may provide benefit in the treatment of type 2 diabetes and other related cardiovascular diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

The multinational Men's Attitudes to Life Events and Sexuality (MALES) Study Phase II: understanding PDE5 inhibitor treatment seeking patterns, among men with erectile dysfunction.

PubMed

Fisher, William A; Rosen, Raymond C; Eardley, Ian; Niederberger, Craig; Nadel, Andrea; Kaufman, Joel; Sand, Michael

2004-09-01

The aim of Phase II of the Men's Attitudes to Life Events and Sexuality (MALES) Study is to explore PDE5 inhibitor treatment seeking among men with erectile dysfunction (ED). Phase II of the MALES study involved 2,912 men, aged 20-75 years, from 8 countries (U.S., U.K., Germany, France, Italy, Spain, Mexico, and Brazil), who reported ED. Participants were recruited from the MALES Phase I sample [1] and via booster methods (e.g., physician referral, street interception), and completed self-report questionnaires concerning the characteristics of their ED, their efforts to seek PDE5 inhibitor treatment for their sexual dysfunction, and attitudinal and referent influences that potentially affect treatment-seeking. Statistical analyses focus on identification of correlates of PDE5 inhibitor treatment seeking. PDE5 inhibitor utilization is strongly associated with ED sufferers' assessment of the severity of their sexual dysfunction, with their belief that medication for ED is dangerous, and with their perceptions of whether physicians, other professionals, and spouses or family members are supportive of their seeking treatment. ED sufferers who evaluate their sexual dysfunction as severe, who believe that medication for ED is not dangerous, and who perceive support for treatment seeking from referent others, are more likely to utilize PDE5 inhibitor treatment. Findings indicate that perceived ED severity, beliefs about ED medication, and referent influences are strongly correlated with utilization of PDE5 inhibitor therapy. These findings aid our understanding of factors that may incline men with ED to seek-or to avoid-PDE5 inhibitor therapy for their sexual dysfunction, and provide a basis for clinical and educational interventions to assist men with ED to seek appropriate treatment.

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

Targeting the Dopamine 1 Receptor or its Downstream Signalling by Inhibiting Phosphodiesterase-1 Improves Cognitive Performance.

PubMed

Pekcec, Anton; Schülert, Niklas; Stierstorfer, Birgit; Deiana, Serena; Dorner-Ciossek, Cornelia; Rosenbrock, Holger

2018-05-03

Insufficient prefrontal dopamine 1 (D1) receptor signalling has been linked to cognitive dysfunction in several psychiatric conditions. Because the phosphodiesterase-1 (PDE1) isoform B (PDE1B) is postulated to regulate D1 receptor-dependent signal transduction, this study intended to elucidate the role of PDE1 for cognitive processes reliant on D1 receptor function. Cognitive performance of the D1 receptor agonist, SKF38393, was studied in the T-maze continuous alternation task and the 5-Choice Serial Reaction Time Task. D1 receptor/ PDE1B double-immunohistochemistry was performed using human and rat prefrontal brain sections. Pharmacological activity of the PDE1 inhibitor, ITI-214, was assessed by measuring the increase of cAMP/ cGMP in prefrontal brain tissue and its effect on working memory performance. Mechanistic studies on modulation of prefrontal neuronal transmission by SKF38393 and ITI-214 were performed using extracellular recordings in brain slices. SKF38393 improved working memory and attentional performance in rodents. D1 receptor/ PDE1B co-expression was verified in both, human and rat prefrontal brain sections. The pharmacological activity of ITI-214 on its target was demonstrated by increased prefrontal cAMP/ cGMP upon administration. In addition, ITI-214 improved working memory performance. SKF38393 and ITI-214 facilitated neuronal transmission in prefrontal brain slices. We hypothesise that PDE1 inhibition may improve working memory performance by increasing prefrontal synaptic transmission and/or postsynaptic D1 receptor signalling, by modulating prefrontal downstream second messenger levels. These data may therefore support the use of PDE1 inhibitors as a potential approach for the treatment of cognitive dysfunction. This article is protected by copyright. All rights reserved.

Genome-wide Association Analysis Identifies PDE4D as an Asthma-Susceptibility Gene

PubMed Central

Himes, Blanca E.; Hunninghake, Gary M.; Baurley, James W.; Rafaels, Nicholas M.; Sleiman, Patrick; Strachan, David P.; Wilk, Jemma B.; Willis-Owen, Saffron A.G.; Klanderman, Barbara; Lasky-Su, Jessica; Lazarus, Ross; Murphy, Amy J.; Soto-Quiros, Manuel E.; Avila, Lydiana; Beaty, Terri; Mathias, Rasika A.; Ruczinski, Ingo; Barnes, Kathleen C.; Celedón, Juan C.; Cookson, William O.C.; Gauderman, W. James; Gilliland, Frank D.; Hakonarson, Hakon; Lange, Christoph; Moffatt, Miriam F.; O'Connor, George T.; Raby, Benjamin A.; Silverman, Edwin K.; Weiss, Scott T.

2009-01-01

Asthma, a chronic airway disease with known heritability, affects more than 300 million people around the world. A genome-wide association (GWA) study of asthma with 359 cases from the Childhood Asthma Management Program (CAMP) and 846 genetically matched controls from the Illumina ICONdb public resource was performed. The strongest region of association seen was on chromosome 5q12 in PDE4D. The phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila) gene (PDE4D) is a regulator of airway smooth-muscle contractility, and PDE4 inhibitors have been developed as medications for asthma. Allelic p values for top SNPs in this region were 4.3 × 10−07 for rs1588265 and 9.7 × 10−07 for rs1544791. Replications were investigated in ten independent populations with different ethnicities, study designs, and definitions of asthma. In seven white and Hispanic replication populations, two PDE4D SNPs had significant results with p values less than 0.05, and five had results in the same direction as the original population but had p values greater than 0.05. Combined p values for 18,891 white and Hispanic individuals (4,342 cases) in our replication populations were 4.1 × 10−04 for rs1588265 and 9.2 × 10−04 for rs1544791. In three black replication populations, which had different linkage disequilibrium patterns than the other populations, original findings were not replicated. Further study of PDE4D variants might lead to improved understanding of the role of PDE4D in asthma pathophysiology and the efficacy of PDE4 inhibitor medications. PMID:19426955

Pinus densiflora extract protects human skin fibroblasts against UVB-induced photoaging by inhibiting the expression of MMPs and increasing type I procollagen expression.

PubMed

Jung, Hoe-Yune; Shin, Jae-Cheon; Park, Seon-Min; Kim, Na-Ri; Kwak, Wonjung; Choi, Bo-Hwa

2014-01-01

Exposure to ultraviolet (UV) light can cause skin photoaging, which is associated with upregulation of matrix metalloproteinases (MMPs) and downregulation of collagen synthesis. It has been reported that MMPs, especially MMP-1, MMP-3 and MMP-9, decrease the elasticity of the dermis by degrading collagen. In this study, we assessed the effects of Pinus densiflora extract (PDE) on photoaging and investigated its mechanism of action in human skin fibroblast (Hs68) cells after UVB exposure using real-time polymerase chain reaction, Western blot analysis, and enzymatic activity assays. PDE exhibited an antioxidant activity and inhibited elastase activities in vitro. We also found that PDE inhibited UVB-induced cytotoxicity, MMP-1 production and expression of MMP-1, -3 and -9 mRNA in Hs68 cells. In addition, PDE decreased UVB-induced MMP-2 activity and MMP-2 mRNA expression. Moreover, PDE prevented the decrease of type I procollagen mediated by exposure to UVB irradiation, an effect that is linked to the upregulation and downregulation of Smad3 and Smad7, respectively. Another effect of UV irradiation is to stimulate activator protein 1 (AP-1) activity via overexpression of c-Jun/c-Fos, which, in turn, upregulates MMP-1, -3, and -9. In this study, we found that PDE suppressed UV-induced c-Jun and c-Fos mRNA expression. Taken together, these results demonstrate that PDE regulates UVB-induced expression of MMPs and type I procollagen synthesis by inhibiting AP-1 activity and restoring impaired Smad signaling, suggesting that PDE may be useful as an effective anti-photoaging agent.

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

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

Dumbser, Michael, E-mail: michael.dumbser@unitn.it; Peshkov, Ilya, E-mail: peshkov@math.nsc.ru; Romenski, Evgeniy, E-mail: evrom@math.nsc.ru

Highlights: • High order schemes for a unified first order hyperbolic formulation of continuum mechanics. • The mathematical model applies simultaneously to fluid mechanics and solid mechanics. • Viscous fluids are treated in the frame of hyper-elasticity as generalized visco-plastic solids. • Formal asymptotic analysis reveals the connection with the Navier–Stokes equations. • The distortion tensor A in the model appears to be well-suited for flow visualization. - Abstract: 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. Inmore » 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 relaxation limit, and compare the numerical results with exact or numerical reference solutions obtained for the Euler and Navier–Stokes equations. Numerical convergence results are also provided. To show the universality of the HPR model, the paper is rounded-off with an application to wave propagation in elastic solids, for which one only needs to switch off the strain relaxation source term in the governing PDE system. We provide various examples showing that for the purpose of flow visualization, the distortion tensor A seems to be particularly useful.« less

Performance Characterization of Swept Ramp Obstacle Fields in Pulse Detonation Applications

DTIC Science & Technology

2010-03-01

field of practical obstacle geometries. 15. NUMBER OF PAGES 97 14. SUBJECT TERMS Pulse Detonation , PDE , Transient Plasma Ignition, TPI, Swept... Detonation Transition NI - National Instruments NPS - Naval Postgraduate School PDC - Pulse Detonation Combustor PDE - Pulse Detonation Engine...with incredible grace. xvi THIS PAGE INTENTIONALLY LEFT BLANK 1 I. INTRODUCTION Pulse detonation engines ( PDE ) continue to be explored due to

How Schools and Students Respond to School Improvement Programs: The Case of Brazil's PDE

ERIC Educational Resources Information Center

Carnoy, Martin; Gove, Amber K.; Loeb, Susanna; Marshall, Jeffrey H.; Socias, Miguel

2008-01-01

This study uses rich empirical data from Brazil to assess how a government program (PDE) that decentralizes school management decisions changes what goes on in schools and how these changes affect student outcomes. It appears that the PDE resulted in some improvements in management and learning materials, but little change in other areas including…

N Termini of apPDE4 Isoforms Are Responsible for Targeting the Isoforms to Different Cellular Membranes

ERIC Educational Resources Information Center

Jang, Deok-Jin; Park, Soo-Won; Lee, Jin-A; Lee, Changhoon; Chae, Yeon-Su; Park, Hyungju; Kim, Min-Jeong; Choi, Sun-Lim; Lee, Nuribalhae; Kim, Hyoung; Kaang, Bong-Kiun

2010-01-01

Phosphodiesterases (PDEs) are known to play a key role in the compartmentalization of cAMP signaling; however, the molecular mechanisms underlying intracellular localization of different PDE isoforms are not understood. In this study, we have found that each of the supershort, short, and long forms of apPDE4 showed distinct localization in the…

Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility.

PubMed

Rzasa, Robert M; Frohn, Michael J; Andrews, Kristin L; Chmait, Samer; Chen, Ning; Clarine, Jeffrey G; Davis, Carl; Eastwood, Heather A; Horne, Daniel B; Hu, Essa; Jones, Adrie D; Kaller, Matthew R; Kunz, Roxanne K; Miller, Silke; Monenschein, Holger; Nguyen, Thomas; Pickrell, Alexander J; Porter, Amy; Reichelt, Andreas; Zhao, Xiaoning; Treanor, James J S; Allen, Jennifer R

2014-12-01

We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.

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

PubMed

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

2015-12-01

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

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

PubMed

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

2018-01-21

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

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.

Phosphodiesterase 4B plays a role in benzophenone-3-induced phototoxicity in normal human keratinocytes.

PubMed

Kim, Hyoung-June; Lee, Eunyoung; Lee, Moonyoung; Ahn, Sungjin; Kim, Jungmin; Liu, Jingjing; Jin, Sun Hee; Ha, Jaehyoun; Bae, Il Hong; Lee, Tae Ryong; Noh, Minsoo

2018-01-01

Benzophenone-3 (BP-3), which is extensively used in organic sunscreen, has phototoxic potential in human skin. Phosphodiesterase 4B (PDE4B) has a well-established role in inflammatory responses in immune cells. Currently, it is unknown if PDE4B is associated with BP-3-induced phototoxicity in normal human keratinocytes (NHKs). We found that BP-3 significantly increased PDE4B expression in ultraviolet B (UVB)-irradiated NHKs. Notably, BP-8, a sunscreen agent that shares the 2-hydroxy-4-methoxyphenyl methanone moiety with BP-3, also upregulated PDE4B expression in NHKs. Upon UVB irradiation, BP-3 upregulated the expression of pro-inflammatory factors, such as prostaglandin endoperoxide synthase 2, tumor necrosis factor α, interleukin 8, and S100A7, and downregulated the level of cornified envelope associated proteins, which are important in the development of the epidermal permeability barrier. The additive effects of UVB-activated BP-3 on the expression of both pro-inflammatory mediators and cornified envelope associated proteins were antagonized by treatment with the PDE4 inhibitor rolipram. The BP-3 and UVB co-stimulation-induced PDE4B upregulation and its association with the upregulation of pro-inflammatory mediators and the downregulation of epidermal differentiation markers were confirmed in a reconstituted three dimensional human epidermis model. Therefore, PDE4B has a role in the mechanism of BP-3-induced phototoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

Early Alcohol Exposure Disrupts Visual Cortex Plasticity in Mice

PubMed Central

Lantz, Crystal L.; Wang, Weili; Medina, Alexandre E.

2012-01-01

There is growing evidence that deficits in neuronal plasticity underlie the cognitive problems seen in fetal alcohol spectrum disorders (FASD). However, the mechanisms behind these deficits are not clear. Here we test the effects of early alcohol exposure on ocular dominance plasticity (ODP) in mice and the reversibility of these effects by phosphodiesterase (PDE) inhibitors. Mouse pups were exposed to 5 g/kg of 25% ethanol i.p. on postnatal days (P) 5, 7 and 9. This type of alcohol exposure mimics binge drinking during the third trimester equivalent of human gestation. To assess ocular dominance plasticity animals were monocularly deprived at P21 for 10 days, and tested using optical imaging of intrinsic signals. During the period of monocular deprivation animals were treated with vinpocetine (20mg/kg; PDE1 inhibitor), rolipram (1.25 mg/Kg; PDE4 inhibitor), vardenafil (3 mg/Kg; PDE5 inhibitor) or vehicle solution. Monocular deprivation resulted in the expected shift in ocular dominance of the binocular zone in saline controls but not in the ethanol group. While vinpocetine successfully restored ODP in the ethanol group, rolipram and vardenafil did not. However, when rolipram and vardenafil were given simultaneously ODP was restored. PDE4 and PDE5 are specific to cAMP and cGMP respectively, while PDE1 acts on both of these nucleotides. Our findings suggest that the combined activation of the cAMP and cGMP cascades may be a good approach to improve neuronal plasticity in FASD models. PMID:22617459

Identification, characterization and subcellular localization of TcPDE1, a novel cAMP-specific phosphodiesterase from Trypanosoma cruzi.

PubMed Central

D'Angelo, Maximiliano A; Sanguineti, Santiago; Reece, Jeffrey M; Birnbaumer, Lutz; Torres, Héctor N; Flawiá, Mirtha M

2004-01-01

Compartmentalization of cAMP phosphodiesterases plays a key role in the regulation of cAMP signalling in mammals. In the present paper, we report the characterization and subcellular localization of TcPDE1, the first cAMP-specific phosphodiesterase to be identified from Trypanosoma cruzi. TcPDE1 is part of a small gene family and encodes a 929-amino-acid protein that can complement a heat-shock-sensitive yeast mutant deficient in phospho-diesterase genes. Recombinant TcPDE1 strongly associates with membranes and cannot be released with NaCl or sodium cholate, suggesting that it is an integral membrane protein. This enzyme is specific for cAMP and its activity is not affected by cGMP, Ca2+, calmodulin or fenotiazinic inhibitors. TcPDE1 is sensitive to the phosphodiesterase inhibitor dipyridamole but is resistant to 3-isobutyl-1-methylxanthine, theophylline, rolipram and zaprinast. Papaverine, erythro-9-(2-hydroxy-3-nonyl)-adenine hydrochloride, and vinpocetine are poor inhibitors of this enzyme. Confocal laser scanning of T. cruzi epimastigotes showed that TcPDE1 is associated with the plasma membrane and concentrated in the flagellum of the parasite. The association of TcPDE1 with this organelle was confirmed by subcellular fractionation and cell-disruption treatments. The localization of this enzyme is a unique feature that distinguishes it from all the trypanosomatid phosphodiesterases described so far and indicates that compartmentalization of cAMP phosphodiesterases could also be important in these parasites. PMID:14556647

A comparative review of the options for treatment of erectile dysfunction: which treatment for which patient?

PubMed

Hatzimouratidis, Konstantinos; Hatzichristou, Dimitrios G

2005-01-01

The field of erectile dysfunction (ED) has been revolutionised over the last two decades. Several treatment options are available today, most of which are associated with high efficacy rates and favourable safety profiles. A MEDLINE search was undertaken in order to evaluate all currently available data on treatment modalities for ED. Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil) are currently the first-choice of most physicians and patients for the treatment of ED. PDE5 inhibitors have differences in their pharmacological profiles, the most obvious being the long duration of action of tadalafil, but there are no data supporting superiority for any one of them in terms of efficacy or safety. Sublingual apomorphine has limited efficacy compared with the PDE5 inhibitors, and its use is limited to patients with mild ED. Treatment failures with oral drugs may be due to medication, clinician and patient issues. The physician needs to address all of these issues in order to identify true treatment failures. Patients who are truly unresponsive to oral drugs may be offered other treatment options.Intracavernous injections of alprostadil alone, or in combination with other vasoactive agents (papaverine and phentolamine), remain an excellent treatment option, with proven efficacy and safety over time. Topical pharmacotherapy is appealing in nature, but currently available formulations have limited efficacy. Vacuum constriction devices may be offered mainly to elderly patients with occasional intercourse attempts, as younger patients show limited preference because of the unnatural erection that is associated with this treatment modality. Penile prostheses are generally the last treatment option offered, because of invasiveness, cost and non-reversibility; however, they are associated with high satisfaction rates in properly selected patients. All treatment options are associated with particular strengths and weaknesses. A patient-centred approach based on patient needs and expectations is necessary for the management of ED. The clinician must educate the patient and provide a supportive environment for shared decision making. The management strategy must be supplemented by careful follow-up in order to identify changes in patient health and relationship/emotional status that may necessitate treatment optimisation.

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.

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

Comparative Analysis of a High Bypass Turbofan Using a Pulsed Detonation Combustor

DTIC Science & Technology

2007-03-01

Thrust Specific Fuel Consumption . . . . . . . . . . . . . 67 xiii List of Abbreviations Abbreviation Page PDE Pulsed Detonation Engine...past ten years to develop pulsed det- onation engines ( PDE ) as a means of aircraft propulsion. Detonation combustion holds the promise of a more...aviation engine, and detonation creates more of it than previous aircraft engines. It is hoped that a marriage of the PDE with traditional

Role of selective cyclic GMP phosphodiesterase inhibition in the myorelaxant actions of M&B 22,948, MY-5445, vinpocetine and 1-methyl-3-isobutyl-8-(methylamino)xanthine.

PubMed Central

Souness, J. E.; Brazdil, R.; Diocee, B. K.; Jordan, R.

1989-01-01

1. The mechanism by which M&B 22,948, MY-5445, vinpocetine and 1-methyl-3-isobutyl-8-(methylamino)xanthine (MIMAX), which have been described as selective cyclic GMP phosphodiesterase (PDE) inhibitors, relax rat aorta was investigated. 2. Three cyclic nucleotide PDEs were identified in the soluble fraction of rat aorta; a Ca2+-insensitive form exhibiting substrate selectivity for cyclic GMP (cGMP PDE), a Ca2+/calmodulin-stimulated form which also preferentially hydrolyzed cyclic GMP (Ca2+ PDE), and a form demonstrating substrate selectivity for cyclic AMP (cAMP PDE). 3. M&B 22,948 and MIMAX inhibited cGMP PDE (Ki = 0.16 microM and 0.43 microM, respectively) and Ca2+ PDE (Ki = 9.9 microM and 0.55 microM, respectively), but exhibited weak activity against cAMP PDE (Ki = 249 microM and 42 microM, respectively). MY-5445 selectivity inhibited cGMP PDE (Ki = 1.3 microM) and vinpocetine selectively inhibited Ca2+ PDE (Ki = 14 microM). 4. M&B 22,948 and MIMAX induced dose-dependent increases in the accumulation of cyclic GMP, but not cyclic AMP, in rat aorta pieces. These effects were greatly reduced by endothelial denudation and by methylene blue (5 microM) which blocks the actions of endothelium-derived relaxant factor. MY-5445 and vinpocetine had no effect on rat aorta cyclic GMP or cyclic AMP accumulation. 5. All four compounds caused dose-related relaxation of 5-hydroxytryptamine (10 microM) contracted, endothelium-intact rat aorta, the effects of M&B 22,948 and MIMAX being greatly reduced by methylene blue (5 microM). Methylene blue also caused 10 fold and 100 fold rightward shifts in the dose-response curves of MY-5445 and vinpocetine, respectively. 6. The results are consistent with the smooth muscle relaxant actions of M&B 22,948 and MIMAX, but not vinpocetine and MY-5445, being mediated through a mechanism involving inhibition of cyclic GMP hydrolysis. PMID:2480168

The Association Between Phosphodiesterase Type 5 Inhibitor Use and Risk of Non-Arteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Meta-Analysis.

PubMed

Liu, Bing; Zhu, Linxin; Zhong, Jingxiang; Zeng, Guohua; Deng, Tuo

2018-06-05

Phosphodiesterase type 5 inhibitors (PDE5-Is) are first-line drugs for erectile dysfunction. Non-arteritic anterior ischemic optic neuropathy (NAION) has been linked with PDE5-I use. However, no meta-analysis or conclusive review has explored the association between NAION and PDE5-I use. To investigate the association between PDE5-I use and risk of NAION. A comprehensive literature search was conducted using online databases in October 2017 to obtain studies researching the association between PDE5-I application and occurrence of NAION. Summarized unadjusted risk ratios (RRs) with 95% CIs were calculated for the strength of this association. This study was conducted in accordance to Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and registered in PROSPERO under number CRD42017080865. The strength of association between PDE5-I use and risk of NAION was assessed through pooled unadjusted RRs and 95% CIs. 5 original articles with 6 clinical observations were included in the meta-analysis. No significant higher risk of NAION was observed after the use of PDE5-Is within a 1-month period (RR = 1.16, 95% CI = 0.98-1.39, P = .09). Subgroup analyses indicated 2 PDE5-Is were significantly related to NAION (tadalafil: RR = 2.14, 95% CI = 1.20-3.84, P = .01; sildenafil: RR = 2.25, 95% CI = 1.29-3.94, P = .004). Although we found no association between NAION and PDE5-I use, our results should be interpreted cautiously because we included only observational studies and could not control for potential confounders. Because NAION is a rare ocular disease and difficult to diagnose, this association should be confirmed in prospective comparative studies with larger samples and more rigorous designs. Liu B, Zhu L, Zhong J, et al. The Association Between Phosphodiesterase Type 5 Inhibitor Use and Risk of Non-Arteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Meta-Analysis. Sex Med 2018;X:XXX-XXX. Copyright © 2018. Published by Elsevier Inc.

Master equations and the theory of stochastic path integrals

NASA Astrophysics Data System (ADS)

Weber, Markus F.; Frey, Erwin

2017-04-01

This review provides a pedagogic and self-contained introduction to master equations and to their representation by path integrals. Since the 1930s, master equations have served as a fundamental tool to understand the role of fluctuations in complex biological, chemical, and physical systems. Despite their simple appearance, analyses of master equations most often rely on low-noise approximations such as the Kramers-Moyal or the system size expansion, or require ad-hoc closure schemes for the derivation of low-order moment equations. We focus on numerical and analytical methods going beyond the low-noise limit and provide a unified framework for the study of master equations. After deriving the forward and backward master equations from the Chapman-Kolmogorov equation, we show how the two master equations can be cast into either of four linear partial differential equations (PDEs). Three of these PDEs are discussed in detail. The first PDE governs the time evolution of a generalized probability generating function whose basis depends on the stochastic process under consideration. Spectral methods, WKB approximations, and a variational approach have been proposed for the analysis of the PDE. The second PDE is novel and is obeyed by a distribution that is marginalized over an initial state. It proves useful for the computation of mean extinction times. The third PDE describes the time evolution of a ‘generating functional’, which generalizes the so-called Poisson representation. Subsequently, the solutions of the PDEs are expressed in terms of two path integrals: a ‘forward’ and a ‘backward’ path integral. Combined with inverse transformations, one obtains two distinct path integral representations of the conditional probability distribution solving the master equations. We exemplify both path integrals in analysing elementary chemical reactions. Moreover, we show how a well-known path integral representation of averaged observables can be recovered from them. Upon expanding the forward and the backward path integrals around stationary paths, we then discuss and extend a recent method for the computation of rare event probabilities. Besides, we also derive path integral representations for processes with continuous state spaces whose forward and backward master equations admit Kramers-Moyal expansions. A truncation of the backward expansion at the level of a diffusion approximation recovers a classic path integral representation of the (backward) Fokker-Planck equation. One can rewrite this path integral in terms of an Onsager-Machlup function and, for purely diffusive Brownian motion, it simplifies to the path integral of Wiener. To make this review accessible to a broad community, we have used the language of probability theory rather than quantum (field) theory and do not assume any knowledge of the latter. The probabilistic structures underpinning various technical concepts, such as coherent states, the Doi-shift, and normal-ordered observables, are thereby made explicit.

Master equations and the theory of stochastic path integrals.

PubMed

Weber, Markus F; Frey, Erwin

2017-04-01

This review provides a pedagogic and self-contained introduction to master equations and to their representation by path integrals. Since the 1930s, master equations have served as a fundamental tool to understand the role of fluctuations in complex biological, chemical, and physical systems. Despite their simple appearance, analyses of master equations most often rely on low-noise approximations such as the Kramers-Moyal or the system size expansion, or require ad-hoc closure schemes for the derivation of low-order moment equations. We focus on numerical and analytical methods going beyond the low-noise limit and provide a unified framework for the study of master equations. After deriving the forward and backward master equations from the Chapman-Kolmogorov equation, we show how the two master equations can be cast into either of four linear partial differential equations (PDEs). Three of these PDEs are discussed in detail. The first PDE governs the time evolution of a generalized probability generating function whose basis depends on the stochastic process under consideration. Spectral methods, WKB approximations, and a variational approach have been proposed for the analysis of the PDE. The second PDE is novel and is obeyed by a distribution that is marginalized over an initial state. It proves useful for the computation of mean extinction times. The third PDE describes the time evolution of a 'generating functional', which generalizes the so-called Poisson representation. Subsequently, the solutions of the PDEs are expressed in terms of two path integrals: a 'forward' and a 'backward' path integral. Combined with inverse transformations, one obtains two distinct path integral representations of the conditional probability distribution solving the master equations. We exemplify both path integrals in analysing elementary chemical reactions. Moreover, we show how a well-known path integral representation of averaged observables can be recovered from them. Upon expanding the forward and the backward path integrals around stationary paths, we then discuss and extend a recent method for the computation of rare event probabilities. Besides, we also derive path integral representations for processes with continuous state spaces whose forward and backward master equations admit Kramers-Moyal expansions. A truncation of the backward expansion at the level of a diffusion approximation recovers a classic path integral representation of the (backward) Fokker-Planck equation. One can rewrite this path integral in terms of an Onsager-Machlup function and, for purely diffusive Brownian motion, it simplifies to the path integral of Wiener. To make this review accessible to a broad community, we have used the language of probability theory rather than quantum (field) theory and do not assume any knowledge of the latter. The probabilistic structures underpinning various technical concepts, such as coherent states, the Doi-shift, and normal-ordered observables, are thereby made explicit.

A computer-assisted study of pulse dynamics in anisotropic media

NASA Astrophysics Data System (ADS)

Krishnan, J.; Engelborghs, K.; Bär, M.; Lust, K.; Roose, D.; Kevrekidis, I. G.

2001-06-01

This study focuses on the computer-assisted stability analysis of travelling pulse-like structures in spatially periodic heterogeneous reaction-diffusion media. The physical motivation comes from pulse propagation in thin annular domains on a diffusionally anisotropic catalytic surface. The study was performed by computing the travelling pulse-like structures as limit cycles of the spatially discretized PDE, which in turn is performed in two ways: a Newton method based on a pseudospectral discretization of the PDE, and a Newton-Picard method based on a finite difference discretization. Details about the spectra of these modulated pulse-like structures are discussed, including how they may be compared with the spectra of pulses in homogeneous media. The effects of anisotropy on the dynamics of pulses and pulse pairs are studied. Beyond shifting the location of bifurcations present in homogeneous media, anisotropy can also introduce certain new instabilities.

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.

Second-order oriented partial-differential equations for denoising in electronic-speckle-pattern interferometry fringes.

PubMed

Tang, Chen; Han, Lin; Ren, Hongwei; Zhou, Dongjian; Chang, Yiming; Wang, Xiaohang; Cui, Xiaolong

2008-10-01

We derive the second-order oriented partial-differential equations (PDEs) for denoising in electronic-speckle-pattern interferometry fringe patterns from two points of view. The first is based on variational methods, and the second is based on controlling diffusion direction. Our oriented PDE models make the diffusion along only the fringe orientation. The main advantage of our filtering method, based on oriented PDE models, is that it is very easy to implement compared with the published filtering methods along the fringe orientation. We demonstrate the performance of our oriented PDE models via application to two computer-simulated and experimentally obtained speckle fringes and compare with related PDE models.

Pharmacology of the lower urinary tract

PubMed Central

Hennenberg, Martin; Stief, Christian G.; Gratzke, Christian

2014-01-01

Pharmacology of the lower urinary tract provides the basis for medical treatment of lower urinary tract symptoms (LUTS). Therapy of LUTS addresses obstructive symptoms (frequently explained by increased prostate smooth muscle tone and prostate enlargement) in patients with benign prostate hyperplasia (BPH) and storage symptoms in patients with overactive bladder (OAB). Targets for medical treatment include G protein-coupled receptors (α1-adrenoceptors, muscarinic acetylcholine receptors, β3-adrenoceptors) or intracellular enzymes (5α-reductase; phosphodiesterase-5, PDE5). Established therapies of obstructive symptoms aim to induce prostate smooth muscle relaxation by α1-blockers or PDE5 inhibitors, or to reduce prostate growth and volume with 5α-reductase inhibitors. Available options for treatment of OAB comprise anitmuscarinics, β3-adrenoceptor agonists, and botulinum toxin A, which improve storage symptoms by inhibition of bladder smooth muscle contraction. With the recent approval of β3-antagonists, PDE inhibitors, and silodosin for therapy of LUTS, progress from basic research of lower urinary tract pharmacology was translated into new clinical applications. Further targets are in preclinical stages of examination, including modulators of the endocannabinoid system and transient receptor potential (TRP) channels. PMID:24744518

[Cardiovascular disease and sexuality].

PubMed

Pfister, Otmar

2010-03-01

Sexual activity corresponds to light to moderate physical exercise and entails no significant risk to the majority of patients with cardiovascular disease. In patients suffering from severe angina or chronic heart failure, however, sexual activity might trigger coital angina or cardiac decompensation necessitating hospitalization. Nevertheless, even for patients with coronary artery disease the absolute risk of having a heart attack or fatal event during sexual activity is extremely low. Due to systemic atherosclerosis and concomitant endothelial dysfunction the prevalence of sexual dysfunction is higher in patients with cardiovascular disease as compared to the general population. PDE-5 inhibitors can be safely used by many patients suffering from both, cardiovascular disease and sexual dysfunction as long as no concomitant medication with nitrates exists. The concomitant use of PDE-5 inhibitors and nitrates is strictly contraindicated because of the risk of life-threatening hypotension. It is therefore of utmost importance to ask patients presenting with coital angina about PDE-5 inhibitor intake before the administration of nitrate-based anti-ischemic therapies. The recommendations of the Princeton Consensus Conference provide a useful framework for risk stratification and counseling of patients with cardiovascular disease regarding sexual activity.

Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies.

PubMed

Hu, Essa; Chen, Ning; Kunz, Roxanne K; Hwang, Dah-Ren; Michelsen, Klaus; Davis, Carl; Ma, Ji; Shi, Jianxia; Lester-Zeiner, Dianna; Hungate, Randall; Treanor, James; Chen, Hang; Allen, Jennifer R

2016-07-14

We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding potential (BPND) in NHP than our previously reported tracer 1, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washout rate in vivo. Five candidates (2-6) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines (2, 3) and one keto-benzimidazole (5) exhibited PDE10A target specificity and brain uptake comparable to or better than 1 in the in vivo LC-MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [(18)F]-5 produced a significantly improved BPND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies.

Phosphodiesterase inhibitors in clinical urology.

PubMed

Ückert, Stefan; Kuczyk, Markus A; Oelke, Matthias

2013-05-01

To date, benign diseases of the male and female lower urinary and genital tract, such as erectile dysfunction, bladder overactivity, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and symptoms of female sexual dysfunction (including arousal and orgasmic disorders), can be therapeutically approached by influencing the function of the smooth musculature of the respective tissues. The use of isoenzyme-selective phosphodiesterase (PDE) inhibitors is considered a great opportunity to treat various diseases of the human urogenital tract. PDE inhibitors, in particular the PDE5 (cyclic GMP PDE) inhibitors avanafil, lodenafil, sildenafil, tadalafil, udenafil and vardenafil, are regarded as efficacious, having a fast onset of drug action and an improved effect-to-adverse event ratio, combining a high response rate with the advantage of an on-demand intake. The purpose of this review is to summarize recent as well as potential future indications, namely, erectile dysfunction, Peyronie's disease, overactive bladder, urinary stone disease, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and premature ejaculation, for the use of PDE inhibitors in clinical urology.

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.

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.

Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma.

PubMed

Ge, Xuecai; Milenkovic, Ljiljana; Suyama, Kaye; Hartl, Tom; Purzner, Teresa; Winans, Amy; Meyer, Tobias; Scott, Matthew P

2015-09-15

Alterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic targets. Here we show that phosphodiesterase 4D (PDE4D) acts downstream of Neuropilins to control Hh transduction and medulloblastoma growth. PDE4D interacts directly with Neuropilins, positive regulators of Hh pathway. The Neuropilin ligand Semaphorin3 enhances this interaction, promoting PDE4D translocation to the plasma membrane and cAMP degradation. The consequent inhibition of protein kinase A (PKA) enhances Hh transduction. In the developing cerebellum, genetic removal of Neuropilins reduces Hh signaling activity and suppresses proliferation of granule neuron precursors. In mouse medulloblastoma allografts, PDE4D inhibitors suppress Hh transduction and inhibit tumor growth. Our findings reveal a new regulatory mechanism of Hh transduction, and highlight PDE4D as a promising target to treat Hh-related tumors.

Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents.

PubMed

Zagórska, Agnieszka; Bucki, Adam; Kołaczkowski, Marcin; Siwek, Agata; Głuch-Lutwin, Monika; Starowicz, Gabriela; Kazek, Grzegorz; Partyka, Anna; Wesołowska, Anna; Słoczyńska, Karolina; Pękala, Elżbieta; Pawłowski, Maciej

2016-01-01

A series of 2-fluoro and 3-trifluoromethylphenylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (4-21) were synthesized and evaluated for their serotonin (5-HT 1A /5-HT 7 ) receptor affinity and phosphodiesterase (PDE4B and PDE10A) inhibitor activity. The study enabled the identification of potent 5-HT 1A , 5-HT 7 and mixed 5-HT 1A /5-HT 7 receptor ligands with weak inhibitory potencies for PDE4B and PDE10A. The tests have been completed with the determination of lipophilicity and metabolic stability using micellar electrokinetic chromatography (MEKC) system and human liver microsomes (HLM) model. In preliminary pharmacological in vivo studies, selected compound 8-(5-(4-(2-fluorophenyl)piperazin-1-yl)pentyl)-1,3,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (9) behaved as a potential antidepressant in forced swim test (FST) in mice. Moreover, potency of antianxiety effects evoked by 9 (2.5 mg/kg) is greater than that of the reference anxiolytic drug, diazepam. Molecular modeling revealed that fluorinated arylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione have major significance for the provision of lead compounds for antidepressant and/or anxiolytic application.

Branch Detonation of a Pulse Detonation Engine With Flash Vaporized JP-8

DTIC Science & Technology

2006-12-01

Mark F. Reeder (Member) date iii Abstract Pulse Detonation Engines ( PDE ) operating on liquid hydrocarbon fuels are... Detonation Transition FF – Fill Fraction FN – Flow Number NPT – National Pipe Thread OH – Hydroxyl PDE – Pulse Detonation Engine PF – Purge...Introduction Motivation Research on Pulsed Detonation Engines ( PDE ) has increased over the past ten years due to the potential for increased

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.

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.

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

PubMed

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

2014-12-09

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

Preservation of nitric oxide-induced relaxation of porcine coronary artery: roles of the dimers of soluble guanylyl cyclase, phosphodiesterase type 5, and cGMP-dependent protein kinase.

PubMed

Liu, Juan; Chen, Zhengju; Ye, Liping; Liu, Huixia; Dou, Dou; Liu, Limei; Yu, Xiaoxing; Gao, Yuansheng

2014-10-01

Soluble guanylyl cyclase (sGC), phosphodiesterase type 5 (PDE5), and guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (PKG) are all dimeric. The present study was to determine the role of their dimeric status in nitric oxide-induced vasodilatation. In isolated porcine coronary arteries, after 20 h incubation with serum-free medium, serum-containing medium, or phosphate-buffered saline solution, the protein levels of the dimers of sGC, PDE5, and PKG were diminished while the monomer levels remained unchanged, associated with reduced cGMP elevation in response to DETA NONOate and decreased PDE5 activity; the activity of PKG was not significantly altered. DETA NONOate caused a greater relaxation in arteries incubated for 20 vs. 2 h. The relaxant response was largely abolished by 1H-[1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one, an sGC inhibitor. Zaprinast, a PDE5 inhibitor, had no effect on relaxation caused by DETA NONOate of arteries incubated for 20 h but augmented the response incubated for 2 h. A greater relaxation to 8-bromo-guanosine 3'5'-cyclic monophosphate occurred in arteries incubated for 20 than for 2 h. The protein level of the dimers but not monomers of PDE5 was reduced by dithiothreitol and unaffected by hydrogen peroxide, accompanied with decreased PDE5 activity and reduced response to DETA NONOate. These results demonstrate that the dimeric but not monomeric status of sGC and PDE5 of coronary arteries are closely related to their activities. The preserved vasodilator response after 20 h incubation may result in part from a synchronous reduction of the dimer levels of sGC and PDE5 as well as an augmented response to cGMP.

Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes

PubMed Central

Hackett, Geoffrey; Jones, Peter W; Strange, Richard C; Ramachandran, Sudarshan

2017-01-01

AIM To determine how statins, testosterone (T) replacement therapy (TRT) and phosphodiesterase 5-inhibitors (PDE5I) influence age related mortality in diabetic men. METHODS We studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual. RESULTS Age was associated with mortality (logistic regression, OR = 1.10, 95%CI: 1.08-1.13, P < 0.001). With all factors included, age (OR = 1.08, 95%CI: 1.06-1.11, P < 0.001), Low T/treated (OR = 0.38, 95%CI: 0.15-0.92, P = 0.033), PDE5I/treated (OR = 0.17, 95%CI: 0.053-0.56, P = 0.004) and statin/treated (OR = 0.59, 95%CI: 0.36-0.97, P = 0.038) were associated with lower mortality. Age related mortality was as described by Gompertz, r2 = 0.881 when Ln (mortality) was plotted against age. The probability of mortality and 95%CI (from logistic regression) of individuals, treated/untreated with the drugs, alone and in combination was plotted against age. Overlap of 95%CI lines was evident with statins and TRT. No overlap was evident with PDE5I alone and with statins and TRT, this suggesting a change in the relationship between age and mortality. CONCLUSION We show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men. PMID:28344753

[Anti-B[a]PDE-DNA formation in lymphomonocytes of humans environmentally exposed to polycyclic aromatic hydrocarbons].

PubMed

Pavanello, S; Pulliero, A; Lai, A; Gaiardo, A; Mastrangelo, G; Clonfero, E

2005-01-01

[Anti-B[a]PDE-DNA formation in lymphomonocytes of humans environmentally exposed to polycyclic aromatic hydrocarbons] We are currently evaluating anti-benzo[a]pyrenediolepoxide-(B[a]PDE)-DNA adduct levels in lymphomonocytes of humans exposed to polycyclic aromatic hydrocarbons (PAHs) to validate this indicator of biologically effective dose in a surrogate tissue. The study protocol (October 2002-June 2005) implies: (a) a signed informed consent by each participant; (b) recruitment of 600 Padua municipal workers during visits at our outpatient clinic; (c) administration of a questionnaire regarding non occupational sources of PAH (B[a]P) exposure; (d) collection of blood (15 ml) and urine (200 ml) samples. Anti-B[a]PDE-DNA adduct levels in lymphomonocytes are detected by HPLC-fluorescence analysis. To date, 438 subjects have been examined (age range 20-62 years; 52% males). We found that: (i) anti-B[a]PDE-DNA adduct levels are significantly lower than those we previously found in coke-oven workers (N=95) occupationally exposed to high levels of PAHs (1.51 +/- 2.68 versus 4.07 +/- 3.78 anti-B[a]PDE-adduct/10(8) nucleotides, p < 0.001; 37% versus 97% positive subjects with > or =1 adduct/10(8) nucleotides; p < 0.001); (ii) smokers (23%) have significantly higher adduct levels than non smokers (p < 0.001); iii) non smokers who consume PAH-rich meals > or =52 times/year (142 subjects, 42%) have significantly increased adduct levels than those <52 times/year (p < 0.01). Dietary and smoking habits did not influence the occupationally-induced adduct levels in coke-oven workers. This is the first study that examines anti-B[a]PDE-DNA adduct levels in a large cohort showing that anti-B[a]PDE-DNA adducts can be detected in humans environmentally exposed to low doses of PAH (B[a]P and are modulated by smoke and dietary habits.

Intraperitoneal Vancomycin Concentrations During Peritoneal Dialysis–Associated Peritonitis: Correlation with Serum Levels

PubMed Central

Fish, Richard; Nipah, Robert; Jones, Chris; Finney, Hazel; Fan, Stanley L.S.

2012-01-01

♦ Background: For the treatment of peritoneal dialysis–associated peritonitis (PDP), it has been suggested that serum concentrations of vancomycin be kept above 12 mg/L – 15 mg/L. However, studies correlating vancomycin concentrations in serum and peritoneal dialysate effluent (PDE) during active infection are sparse. We undertook the present study to investigate this issue and to determine whether achieving the recommended serum level of vancomycin results in therapeutic levels intraperitoneally. ♦ Methods: We studied patients treated with intraperitoneal (IP) vancomycin for non-gram-negative PDP. We gave a single dose (approximately 30 mg/kg) at presentation, and we subsequently measured vancomycin levels in PDE on day 5; we wanted to determine if efflux of vancomycin from serum to PDE during a 4-hour dwell was consistent and resulted in therapeutic levels. ♦ Results: Of the 48 episodes of PDP studied, serum vancomycin concentrations exceeding 12 mg/L were achieved in 98% of patients, but in 11 patients (23%), a PDE vancomycin level below 4 mg/L—the minimal inhibitory concentration (MIC) of many gram-positive organisms—was observed at the end of a 4-hour dwell on day 5. The correlation between the concentrations of vancomycin in serum and PDE (from efflux of antibiotic over 4 hours) was statistically significant, but poor (R2 = 0.18). ♦ Conclusions: Our data support the International Society for Peritoneal Dialysis statement that adequate serum vancomycin concentrations can be achieved with intermittent dosing (single dose every 5 days), but cannot guarantee therapeutic PDE levels in the treatment of PDP. Intermittent dosing of vancomycin may not consistently result in PDE concentrations markedly greater than MIC of many important pathogens. Although the clinical significance of this finding remains to be determined, it may be preferable to give smaller but more frequent doses of PDE vancomycin (continuous dosing) for adults with PDP (as is currently recommended for children). PMID:22045102

[Adenoviral short hairpin RNA targeting phosphodiesterase 5 attenuates cardiac remodeling and cardiac dysfunction following myocardial infarction in mice].

PubMed

Zhang, Jian; Jin, Zhe; Li, Longhu; Gang, Li; Yu, Qin; Wang, Meilan; Song, Ailin; Hong, Bingzhe

2014-04-01

To observe the impact of PDE5shRNA on cardiac remodeling and heart function following myocardial infarction in mice. Myocardial infarction (MI) was induced in mice by left coronary artery ligation. Mice were randomly assigned to sham group (n = 6), PDE5shRNA group (n = 12), common adenovirus group (n = 15) and DMEM group (n = 8). Four weeks post-MI, the survival rate was evaluated. Cardiac function was examined by echocardiography. HE staining and Masson staining were used to evaluate the myocardial infarction size and fibrosis. The number of blood vessels was evaluated by immunohistochemistry, PDE5 protein expression in the left ventricular was detected using Western blot, level of cGMP or PKG activity in the left ventricle was evaluated with ELISA. Four weeks post-MI, all mice survived in the sham group, 3(37%) mice died in the DMEM group, 1 (8%) died in the PDE5shRNA group and 5 died in the common adenovirus group (33%). Infarct size was significantly reduced in PDE5shRNA group compared with the common adenovirus group and DMEM group [(25.4 ± 2.9)% vs. (42.0 ± 3.2)% and (43.4 ± 2.6) %, P < 0.05]. Cardiac function was significantly improved in PDE5shRNA group compared to common adenovirus group and DMEM group[LVFS: (21.1 ± 3.7)% vs. (14.2 ± 2.9)% and (14.22 ± 2.91)%, all P < 0.05; LVEF: (48.2 ± 7.1)% vs. (34.6 ± 6.2)% and (38.1 ± 2.8)%, all P < 0.05; LVESD: (3.87 ± 0.45) mm vs.(4.91 ± 0.62) mm and (4.63 ± 0.37) mm, all P < 0.05]. The blood vessel density was also higher in PDE5shRNA group compared with common adenovirus group (infarct area:14.3 ± 2.0 vs. 6.6 ± 1.2, P < 0.05; periinfarct area: 23.6 ± 2.1 vs. 13.7 ± 2.4, P < 0.05). Compared with common adenovirus group, level of PDE5 was significantly downregulated and level of cGMP or PKG was significantly upregulated in PDE5shRNA group (all P < 0.05). Present study suggests PDE5shRNA improves cardiac function and attenuates cardiac remodeling through reducing infarction size and cardiac fibrosis and these beneficial effects are possibly mediated by activating cGMP/PKG signaling pathway.

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.

Modelling Root Systems Using Oriented Density Distributions

NASA Astrophysics Data System (ADS)

Dupuy, Lionel X.

2011-09-01

Root architectural models are essential tools to understand how plants access and utilize soil resources during their development. However, root architectural models use complex geometrical descriptions of the root system and this has limitations to model interactions with the soil. This paper presents the development of continuous models based on the concept of oriented density distribution function. The growth of the root system is built as a hierarchical system of partial differential equations (PDEs) that incorporate single root growth parameters such as elongation rate, gravitropism and branching rate which appear explicitly as coefficients of the PDE. Acquisition and transport of nutrients are then modelled by extending Darcy's law to oriented density distribution functions. This framework was applied to build a model of the growth and water uptake of barley root system. This study shows that simplified and computer effective continuous models of the root system development can be constructed. Such models will allow application of root growth models at field scale.

Direct Initiation Through Detonation Branching in a Pulsed Detonation Engine

DTIC Science & Technology

2008-03-01

important features noted ................................. 33  Figure 20. GM Quad 4 engine head used as the PDE research engine with the detonation tube...Deflagration to Detonation Transition EF – Engine Frequency FF – Fill Fraction NPT – National Pipe Thread MPT – Male National Pipe Thread PDE – Pulsed... Detonation Engines ( PDE ) has increased greatly in recent years due in part to the potential for increased thermal efficiency derived from constant

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.

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.

Erectile Dysfunction Medication Use in Veterans Eligible for Medicare Part D.

PubMed

Spencer, Samantha H; Suda, Katie J; Smith, Bridget M; Huo, Zhiping; Bailey, Lauren; Stroupe, Kevin T

2016-07-01

Erectile dysfunction (ED) medications are therapeutically effective and associated with satisfaction. Medicare Part D included ED medications on the formulary during 2006 and inadvertently in 2007-2008. To characterize phosphodiesterase-5 inhibitor (PDE-5) medication use among veterans who were dually eligible for Veterans Affairs (VA) and Medicare Part D benefits. Veterans aged > 66 years who received PDE-5 inhibitors between 2005 and 2009 were included. Veterans were categorized by PDE-5 inhibitor claims: VA-only, Part D-only, or dual users of VA and Part D-reimbursed pharmacies. T-tests and chi-square tests were applied as appropriate. From 2005 to 2009, the majority (85.2%) of veterans used VA benefits exclusively for their PDE-5 inhibitors; 11.4% used Medicare Part D exclusively; and 3.4% were dual users. The Part D-only group was older, more frequently not black, had a VA copay, and had a higher income (P < 0.03). The VA group was more likely to have comorbidities, smoke, and have a history of substance abuse (P < 0.001). With the inception of Medicare Part D in 2006, the number of patients filling prescriptions for PDE-5 inhibitors (-68%) and total number of PDE-5 inhibitor 30-day equivalents dispensed (-86.7%) from the VA decreased. Part D prescriptions increased through 2006 (full coverage period) and 2007 (accidental partial coverage) and decreased in 2008. While Part D accounted for only 10% of PDE-5 inhibitor 30-day equivalents, it equaled 29.2% of dispensed tablets. In October 2007, VA PDE-5 inhibitor use returned to 2005 levels. Implementation of Medicare Part D reduced VA PDE-5 inhibitor acquisition. However, after removal of PDE-5 inhibitors from the Part D formulary, use of VA pharmacies for PDE-5 inhibitors resumed. Medication policies outside the VA can affect medication use. Veterans with access to non-VA health care may obtain medications from the private sector because of VA restrictions. This may be especially true for nonformulary and lifestyle medications. The authors received funding support for this research project from the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service as grant IIR 07-165-2. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or Health Services Research and Development Service. Study concept and design were contributed by Smith and Stroupe, assisted by the other authors. Huo, Bailey, and Stroupe took the lead in data collection, assisted by the other authors. Data interpretation was performed by Spencer and Suda, along with Smith and Stroupe and assisted by Huo and Bailey. The manuscript was primarily written by Spencer and Suda, with assistance from the other authors, and revised by Spencer, along with the other authors.

Pharmacokinetic Profile, Safety, and Tolerability of Crisaborole Topical Ointment, 2% in Adolescents with Atopic Dermatitis: An Open-Label Phase 2a Study.

PubMed

Tom, Wynnis L; Van Syoc, Merrie; Chanda, Sanjay; Zane, Lee T

2016-01-01

Phosphodiesterase-4 (PDE4) is an emerging target in treating inflammatory skin diseases. Crisaborole topical ointment, 2% is a novel, boron-based, topical PDE4 inhibitor under investigation for treatment of mild to moderate atopic dermatitis (AD). Adolescent patients aged 12 to 17 years with treatable AD lesions involving ≥ 10% to ≤ 35% body surface area (BSA) were enrolled into a phase 2a, open-label study comprising pharmacokinetic (PK), safety, tolerability, and efficacy assessments. Crisaborole topical ointment, 2% was applied twice daily to affected areas for 28 days, with dosage based on baseline treatable BSA. PK blood samples were collected on days 1, 2, 4, 6, 8, and 9. Safety assessments included adverse events (AEs), laboratory parameters, and vital signs. Efficacy assessments included the Investigator's Static Global Assessment (ISGA) score and severity of AD signs and symptoms. Twenty-three patients were enrolled; 22 completed the study (1 patient discontinued due to an AE [application site dermatitis]). PK analysis demonstrated limited exposure to crisaborole topical ointment, 2% after 8 days of dosing. Ten patients reported a total of 19 AEs, most commonly application site pain and nasopharyngitis (3 patients each). There were no clinically meaningful changes in laboratory or vital sign parameters. Efficacy was demonstrated by reductions in mean ISGA and AD sign and symptom severity scores. At day 29, eight patients (35%) had achieved an ISGA score ≤ 1 with ≥ 2-grade improvement. Mean treatable BSA declined from 17.6% to 8.2%. These results provide preliminary evidence for the limited systemic exposure, safety, and effectiveness of crisaborole topical ointment, 2% in adolescents with mild to moderate AD. © 2016 Wiley Periodicals, Inc.

A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement

PubMed Central

Taylor, Peter N; Panicker, Vijay; Sayers, Adrian; Shields, Beverley; Iqbal, Ahmed; Bremner, Alexandra P; Beilby, John P; Leedman, Peter J; Hattersley, Andrew T; Vaidya, Bijay; Frayling, Timothy; Evans, Jonathan; Tobias, Jonathan H; Timpson, Nicholas J; Walsh, John P; Dayan, Colin M

2011-01-01

Objective Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T4). Design Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T4). Methods Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T3), and T4 levels. Results Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64×10−10 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T4 (P=0.023, −0.07 s.d./allele, 95% CI −0.137, −0.01), no association was seen with free T3 (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T4 in 1981 (−0.068 s.d./allele, 95% CI −0.167, 0.031) and 1994 (−0.07 s.d./allele, 95% CI −0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T4. Conclusion Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T4 levels that are consistent over time and lost in individuals on l-T4. These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid. PMID:21317282

How does pre-dialysis education need to change? Findings from a qualitative study with staff and patients.

PubMed

Combes, Gill; Sein, Kim; Allen, Kerry

2017-11-23

Pre-dialysis education (PDE) is provided to thousands of patients every year, helping them decide which renal replacement therapy (RRT) to choose. However, its effectiveness is largely unknown, with relatively little previous research into patients' views about PDE, and no research into staff views. This study reports findings relevant to PDE from a larger mixed methods study, providing insights into what staff and patients think needs to improve. Semi-structured interviews in four hospitals with 96 clinical and managerial staff and 93 dialysis patients, exploring experiences of and views about PDE, and analysed using thematic framework analysis. Most patients found PDE helpful and staff valued its role in supporting patient decision-making. However, patients wanted to see teaching methods and materials improve and biases eliminated. Staff were less aware than patients of how informal staff-patient conversations can influence patients' treatment decision-making. Many staff felt ill equipped to talk about all treatment options in a balanced and unbiased way. Patient decision-making was found to be complex and patients' abilities to make treatment decisions were adversely affected in the pre-dialysis period by emotional distress. Suggested improvements to teaching methods and educational materials are in line with previous studies and current clinical guidelines. All staff, irrespective of their role, need to be trained about all treatment options so that informal conversations with patients are not biased. The study argues for a more individualised approach to PDE which is more like counselling than education and would demand a higher level of skill and training for specialist PDE staff. The study concludes that even if these improvements are made to PDE, not all patients will benefit, because some find decision-making in the pre-dialysis period too complex or are unable to engage with education due to illness or emotional distress. It is therefore recommended that pre-dialysis treatment decisions are temporary, and that PDE is replaced with on-going RRT education which provides opportunities for personalised education and on-going review of patients' treatment choices. Emotional support to help overcome the distress of the transition to end-stage renal disease will also be essential to ensure all patients can benefit from RRT education.

Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn

PubMed Central

Lakshminrusimha, Satyan; Wedgwood, Stephen; Czech, Lyubov; Gugino, Sylvia F.; Russell, James A.; Farrow, Kathryn N.; Steinhorn, Robin H.

2012-01-01

In the pulmonary vasculature, cGMP levels are regulated by soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). We previously reported that lambs with persistent pulmonary hypertension of the newborn (PPHN) demonstrate increased reactive oxygen species (ROS) and altered sGC and PDE5 activity, with resultant decreased cGMP. The objective of this study was to evaluate the effects of hydrocortisone on pulmonary vascular function, ROS, and cGMP in the ovine ductal ligation model of PPHN. PPHN lambs were ventilated with 100% O2 for 24 h. Six lambs received 5 mg/kg hydrocortisone every 8 h times three doses (PPHN-hiHC), five lambs received 3 mg/kg hydrocortisone followed by 1 mg·kg−1·dose−1 times two doses (PPHN-loHC), and six lambs were ventilated with O2 alone (PPHN). All groups were compared with healthy 1-day spontaneously breathing lambs (1DSB). O2 ventilation of PPHN lambs decreased sGC activity, increased PDE5 activity, and increased ROS vs. 1DSB lambs. Both hydrocortisone doses significantly improved arterial-to-alveolar ratios relative to PPHN lambs, decreased PDE5 activity, and increased cGMP relative to PPHN lambs. High-dose hydrocortisone also increased sGC activity, decreased PDE5 expression, decreased ROS, and increased total vascular SOD activity vs. PPHN lambs. These data suggest that hydrocortisone treatment in clinically relevant doses improves oxygenation and decreases hyperoxia-induced changes in sGC and PDE5 activity, increasing cGMP levels. Hydrocortisone reduces ROS levels in part by increasing SOD activity in PPHN lambs ventilated with 100% O2. We speculate that hydrocortisone increases cGMP by direct effects on sGC and PDE5 expression and by attenuating abnormalities induced by oxidant stress. PMID:22198909

Systematic review and meta-analysis on phosphodiesterase 5 inhibitors and α-adrenoceptor antagonists used alone or combined for treatment of LUTS due to BPH

PubMed Central

Wang, Xing-Huan; Wang, Xiao; Shi, Ming-Jun; Li, Sheng; Liu, Tao; Zhang, Xin-Hua

2015-01-01

The aim of this systematic review is to determine the comparative effectiveness and safety of phosphodiesterase 5 inhibitors (PDE5-Is) and α-blockers used alone or combined for the treatment of lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). An electronic search of PubMed, Cochrane Library and Embase up to January 2014 was performed to identify randomized controlled trials comparing the efficacy and safety of PDE5-Is and α-blockers for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia, which assessed IPSS score, maximum flow rate, postvoided residual urine, quality of life and Erectile Function (IIEF) score as outcomes. Data were analyzed by fixed or random effect models using Cochrane Collaboration review manager software. A total of 12 studies were included. Our novel data demonstrated that there was a trend that α-blockers were more efficacious than PDE5-Is on decreasing IPSS score and increasing maximum flow rate. α-blockers were significantly more effective than PDE5-Is on reduction of postvoided residual urine with a mean difference of 3.67 (95% CI 1.56 to 5.77, P = 0.0006) and PDE5-Is showed greater effect than α-blockers on increasing IIEF score with a mean difference of 9.82 (95% CI 3.80 to 15.85, P = 0.001). In conclusion, our novel data demonstrated that PDE5-Is plus ABs ranked the highest on the improvement of LUTS/BPH. PDE5-Is monotherapy was also effective in this kind of disorder except less reduction of PVR than ABs. In addition, both combined- or mono-therapy were safe. PMID:25994648

Elevated Cyclic AMP Levels in T Lymphocytes Transformed by Human T-Cell Lymphotropic Virus Type 1▿

PubMed Central

Kress, Andrea K.; Schneider, Grit; Pichler, Klemens; Kalmer, Martina; Fleckenstein, Bernhard; Grassmann, Ralph

2010-01-01

Human T-cell lymphotropic virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), transforms CD4+ T cells to permanent growth through its transactivator Tax. HTLV-1-transformed cells share phenotypic properties with memory and regulatory T cells (T-reg). Murine T-reg-mediated suppression employs elevated cyclic AMP (cAMP) levels as a key regulator. This led us to determine cAMP levels in HTLV-1-transformed cells. We found elevated cAMP concentrations as a consistent feature of all HTLV-1-transformed cell lines, including in vitro-HTLV-1-transformed, Tax-transformed, and patient-derived cells. In transformed cells with conditional Tax expression, high cAMP levels coincided with the presence of Tax but were lost without it. However, transient ectopic expression of Tax alone was not sufficient to induce cAMP. We found specific downregulation of the cAMP-degrading phosphodiesterase 3B (PDE3B) in HTLV-1-transformed cells, which was independent of Tax in transient expression experiments. This is in line with the notion that PDE3B transcripts and cAMP levels are inversely correlated. Overexpression of PDE3B led to a decrease of cAMP in HTLV-1-transformed cells. Decreased expression of PDE3B was associated with inhibitory histone modifications at the PDE3B promoter and the PDE3B locus. In summary, Tax transformation and its continuous expression contribute to elevated cAMP levels, which may be regulated through PDE3B suppression. This shows that HTLV-1-transformed cells assume biological features of long-lived T-cell populations that potentially contribute to viral persistence. PMID:20573814

Low-Intensity Extracorporeal Shockwave Therapy Can Improve Erectile Function in Patients Who Failed to Respond to Phosphodiesterase Type 5 Inhibitors

PubMed Central

Tsai, Chia-Chun; Wang, Chii-Jye; Lee, Yung-Chin; Kuo, Yen-Ting; Lin, Hsiao-Hua; Li, Ching-Chia; Wu, Wen-Jeng; Liu, Chia-Chu

2017-01-01

Managing patients with erectile dysfunction (ED) who failed to respond to phosphodiesterase type 5 inhibitors (PDE5is) is a challenging task. Recently, low-intensity extracorporeal shockwave therapy (LI-ESWT) was reported to improve ED by enhancing perfusion of the penis. The current study was performed to evaluate whether combined treatment with LI-ESWT and PDE5is can restore erectile function in patients who failed to respond to PDE5is alone. This was an open-label single-arm prospective study. ED patients with an erection hardness score (EHS) ≦2 under a maximal dosage of PDE5is were enrolled. Sociodemographic information and detailed medical history were recorded. LI-ESWT treatment consisted of 3,000 shockwaves once weekly for 12 weeks. All patients continued their regular PDE5is use. The EHS and the 5-item version of the International Index of Erectile Function (IIEF-5) were used to evaluate the change in erectile function 1 and 3 months after LI-ESWT. A total of 52 patients were enrolled. After LI-ESWT treatment, 35 of the 52 patients (67.3%) could achieve an erection hard enough for intercourse (EHS ≧ 3) under PDE5is use at the 1-month follow-up. Initial severity of ED was the only significant predictor of a successful response (EHS1: 35.7% vs. EHS2: 78.9%, p = .005). Thirty-three of the 35 (94.3%) subjects who responded to LI-ESWT could still maintain their erectile function at the 3-month follow-up. LI-ESWT can serve as a salvage therapy for ED patients who failed to respond to PDE5is. Initial severity of ED was an important predictor of a successful response. PMID:28884638

Inhibition of Adrenergic and Non-Adrenergic Smooth Muscle Contraction in the Human Prostate by the Phosphodiesterase 10-Selective Inhibitor TC-E 5005.

PubMed

Hennenberg, Martin; Schott, Melanie; Kan, Aysenur; Keller, Patrick; Tamalunas, Alexander; Ciotkowska, Anna; Rutz, Beata; Wang, Yiming; Strittmatter, Frank; Herlemann, Annika; Yu, Qingfeng; Stief, Christian G; Gratzke, Christian

2016-11-01

The phosphodiesterase (PDE) 5 inhibitor tadalafil is available for treatment of male lower urinary tract symptoms (LUTS), while the role of other PDE isoforms for prostate smooth muscle tone is still unknown. Here, we examined effects of the PDE10-selective inhibitor TC-E 5005 on smooth muscle contraction in human prostate tissue. Prostate samples were obtained from patients undergoing radical prostatectomy. Expression of PDE10 was addressed by RT-PCR, Western blot, and fluorescence staining with different markers. Effects of TC-E 5005 and tadalafil on contraction, and relaxation of prostate strips were studied via organ bath. PDE10A was detectable by RT-PCR, Western blot, and fluorescence staining in prostate tissues. Colocalization with markers suggested expression of PDE10A in smooth muscle cells and catecholaminergic nerves. Norepinephrine, the α1 -adrenergic agonist phenylephrine, the thromboxane A2 analogue U46619, and endothelins 1-3 induced concentration-dependent contractions of prostate strips, while electric field stimulation (EFS) induced frequence-dependent contractions. Application of TC-E 5005 (500 nM) caused significant inhibition of norepinephrine-, phenylephrine-, and endothelin-3-induced contractions. Inhibition of EFS-induced contractions by TC-E 5005 ranged around 50%, resembling inhibition of EFS-induced contractions by tadalafil (10 μM). The prostacyclin analog treprostinil and the nitric oxide donor DEA NONOate induced relaxations of precontracted prostate strips, which were significantly amplified by TCE 5005. The PDE10-selective inhibitor TC-E 5005 inhibits adrenergic and neurogenic smooth muscle contractions in the human prostate. TC-E 5005 inhibits neurogenic contractions with similar efficacy than tadalafil, so that urodynamic effects in vivo appear possible. Prostate 76:1364-1374, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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.

Dextran Sulfate Sodium-Induced Colonic Histopathology, but not Altered Epithelial Ion Transport, Is Reduced by Inhibition of Phosphodiesterase Activity

PubMed Central

Diaz-Granados, Natalia; Howe, Kathryn; Lu, Jun; McKay, Derek M.

2000-01-01

Inhibition of phosphodiesterase (PDE) activity is beneficial in models of arthritis and airway inflammation. Here we assessed the ability of PDE inhibitors to modulate colitis by exposing mice to 4% (w/v) dextran sulfate sodium (DSS) drinking water for 5 days with or without rolipram, an inhibitor of PDE type 4, or the nonselective PDE inhibitor, pentoxifylline (both at 5 mg/kg, i.p., twice daily). Controls received saline, vehicle, or drug only. Colonic histology, myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels, and epithelial ion transport (baseline and stimulated by electrical nerve stimulation, carbachol, and forskolin) were examined. DSS-treated mice displayed a variable diarrhea, significant histopathology in the mid-distal colon, elevated MPO activity, and reduced (>50%) responses to all three pro-secretory stimuli. Treatment with rolipram, and to a lesser extent pentoxifylline, significantly reduced the severity of the colonic histopathology and MPO levels. Neither PDE inhibitor had any affect on the diminished ion transport events caused by DSS-induced colitis. However, although stimulated ion transport events were still reduced 3 days after DSS treatment, colonic segments from DSS + rolipram-treated mice displayed enhanced recovery in their secretory responsiveness, particularly to carbachol. These findings indicate that specific PDE4 inhibition can significantly reduce the tissue damage that accompanies colitis and enhance recovery of normal colonic function. PMID:10854237

Inhibition of phosphodiesterase-4 decreases ethanol intake in mice.

PubMed

Hu, Wei; Lu, Tina; Chen, Alan; Huang, Ying; Hansen, Rolf; Chandler, L Judson; Zhang, Han-Ting

2011-11-01

Cyclic AMP (cAMP)-protein kinase A signaling has been implicated in the regulation of ethanol consumption. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cAMP and plays a critical role in controlling intracellular cAMP levels in the brain. However, the role of PDE4 in ethanol consumption remains unknown. The objective of this study is to examine whether PDE4 was involved in regulating ethanol intake. The two-bottle choice paradigm was used to assess intake of ethanol, sucrose, and quinine in C57BL/6J mice treated with the selective PDE4 inhibitor rolipram or Ro 20-1724; locomotor activity was also monitored using the open-field test in mice treated with rolipram. Administration (i.p.) of either rolipram (0.25 and 0.5 mg/kg) or Ro 20-1724 (10 mg/kg) reduced ethanol intake and preference by 60-80%, but did not alter total fluid intake. In contrast, rolipram even at the higher dose of 0.5 mg/kg was not able to affect intake of sucrose or quinine, alcohol-induced sedation, or blood ethanol elimination. At 0.5 mg/kg, rolipram did decrease locomotor activity, but the effect only lasted for approximately 40 min, which did not likely affect behavior of ethanol drinking. These results suggest that PDE4 is a novel target for drugs that reduce ethanol intake; PDE4 inhibitors may be used for treatment of alcohol dependence.

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.

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.

Is PDE4 too difficult a drug target?

PubMed

Higgs, Gerry

2010-05-01

The search for selective inhibitors of PDE4 as novel anti-inflammatory drugs has continued for more than 30 years. Although several compounds have demonstrated therapeutic effects in diseases such as asthma, COPD, atopic dermatitis and psoriasis, none have reached the market. A persistent challenge in the development of PDE4 inhibitors has been drug-induced gastrointestinal adverse effects, such as nausea. However, extensive clinical trials with well-tolerated doses of roflumilast (Daxas; Nycomed/Mitsubishi Tanabe Pharma Corp/Forest Laboratories Inc) in COPD, a disease that is generally unresponsive to existing therapies, have demonstrated significant therapeutic improvements. In addition, GlaxoSmithKline plc is developing 256066, an inhaled formulation of a PDE4 inhibitor that has demonstrated efficacy in trials in asthma, and apremilast from Celgene Corp has been reported to be effective for the treatment of psoriasis. Despite the challenges and complications that have been encountered during the development of PDE4 inhibitors, these drugs may provide a genuinely novel class of anti-inflammatory agents, and there are several compounds in development that could fulfill that promise.

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.

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.

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

Tian, Yuanyuan; Cui, Wenjun; Huang, Manna

Cyclic nucleotide phosphodiesterases (PDEs) decompose second messengers cAMP and cGMP that play critical roles in many physiological processes. PDE1 of Saccharomyces cerevisiae has been subcloned and expressed in Escherichia coli. Recombinant yPDE1 has a K M of 110 μM and a k cat of 16.9 s⁻¹ for cAMP and a K M of 105 μM and a k cat of 11.8 s₅⁻¹ for cGMP. Thus, the specificity constant (k cat/K McAMP)/(k cat/K M cGMP) of 1.4 indicates a dual specificity of yPDE1 for hydrolysis of both cAMP and cGMP. The crystal structures of unliganded yPDE1 and its complex with GMPmore » at 1.31 Å resolution reveal a new structural folding that is different from those of human PDEs but is partially similar to that of some other metalloenzymes such as metallo-β-lactamase. In spite of their different structures and divalent metals, yPDE1 and human PDEs may share a common mechanism for hydrolysis of cAMP and cGMP.« less

Using CLIPS in the domain of knowledge-based massively parallel programming

NASA Technical Reports Server (NTRS)

Dvorak, Jiri J.

1994-01-01

The Program Development Environment (PDE) is a tool for massively parallel programming of distributed-memory architectures. Adopting a knowledge-based approach, the PDE eliminates the complexity introduced by parallel hardware with distributed memory and offers complete transparency in respect of parallelism exploitation. The knowledge-based part of the PDE is realized in CLIPS. Its principal task is to find an efficient parallel realization of the application specified by the user in a comfortable, abstract, domain-oriented formalism. A large collection of fine-grain parallel algorithmic skeletons, represented as COOL objects in a tree hierarchy, contains the algorithmic knowledge. A hybrid knowledge base with rule modules and procedural parts, encoding expertise about application domain, parallel programming, software engineering, and parallel hardware, enables a high degree of automation in the software development process. In this paper, important aspects of the implementation of the PDE using CLIPS and COOL are shown, including the embedding of CLIPS with C++-based parts of the PDE. The appropriateness of the chosen approach and of the CLIPS language for knowledge-based software engineering are discussed.

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

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

Yu, Juan; Beltran, Chris J., E-mail: beltran.chris@mayo.edu; Herman, Michael G.

Purpose: To quantitatively and systematically assess dosimetric effects induced by spot positioning error as a function of spot spacing (SS) on intensity-modulated proton therapy (IMPT) plan quality and to facilitate evaluation of safety tolerance limits on spot position. Methods: Spot position errors (PE) ranging from 1 to 2 mm were simulated. Simple plans were created on a water phantom, and IMPT plans were calculated on two pediatric patients with a brain tumor of 28 and 3 cc, respectively, using a commercial planning system. For the phantom, a uniform dose was delivered to targets located at different depths from 10 tomore » 20 cm with various field sizes from 2{sup 2} to 15{sup 2} cm{sup 2}. Two nominal spot sizes, 4.0 and 6.6 mm of 1 σ in water at isocenter, were used for treatment planning. The SS ranged from 0.5 σ to 1.5 σ, which is 2–6 mm for the small spot size and 3.3–9.9 mm for the large spot size. Various perturbation scenarios of a single spot error and systematic and random multiple spot errors were studied. To quantify the dosimetric effects, percent dose error (PDE) depth profiles and the value of percent dose error at the maximum dose difference (PDE [ΔDmax]) were used for evaluation. Results: A pair of hot and cold spots was created per spot shift. PDE[ΔDmax] is found to be a complex function of PE, SS, spot size, depth, and global spot distribution that can be well defined in simple models. For volumetric targets, the PDE [ΔDmax] is not noticeably affected by the change of field size or target volume within the studied ranges. In general, reducing SS decreased the dose error. For the facility studied, given a single spot error with a PE of 1.2 mm and for both spot sizes, a SS of 1σ resulted in a 2% maximum dose error; a SS larger than 1.25 σ substantially increased the dose error and its sensitivity to PE. A similar trend was observed in multiple spot errors (both systematic and random errors). Systematic PE can lead to noticeable hot spots along the field edges, which may be near critical structures. However, random PE showed minimal dose error. Conclusions: Dose error dependence for PE was quantitatively and systematically characterized and an analytic tool was built to simulate systematic and random errors for patient-specific IMPT. This information facilitates the determination of facility specific spot position error thresholds.« less

Hesperetin-5,7,3'-O-triacetate suppresses airway hyperresponsiveness in ovalbumin-sensitized and challenged mice without reversing xylazine/ketamine-induced anesthesia in normal mice.

PubMed

Yang, You-Lan; Chen, Chi-Li; Chen, Chi-Ming; Ko, Wun-Chang

2017-05-30

We recently reported that hesperetin-5,7,3'-O-triacetate (HTA) dually inhibited phosphodiesterase (PDE)3/4 with a therapeutic ratio of 20.8. The application and development of PDE4 inhibitors for treating asthma or COPD are limited by their side effects, such as nausea, vomiting and gastric hypersecretion. PDE4 inhibitors were reported to reverse xylazine/ketamine-induced anesthesia in rats and triggered vomiting in ferrets. Thus the reversing effect of HTA on xylazine/ketamine-induced anesthesia in mice was studied to assess emetic effect of HTA. The aim of this study was to prove the therapeutic effect of HTA without vomiting effect at an effective dose for treating COPD. Ten female BALB/c mice in each group were sensitized by ovalbumin (OVA) on days 0 and 14. On day 21, these mice were emphasized the sensitization by Freund's complete adjuvant. Mice were challenged by 1% OVA nebulization on days 28, 29, and 30. Airway hyperresponsiveness (AHR) was assessed on day 32 in each group, using the FlexiVent system to determine airway resistance (R L ) and lung dynamic compliance (C dyn ) in anesthetized ovalbumin (OVA)-sensitized and challenged mice. Each group was orally administered HTA (10 ~ 100 μmol/kg), roflumilast (1 and 5 mg/kg) or vehicles (controls) 2 h before and 6 and 24 h after OVA provocation. For comparison, sham-treated mice were challenged with saline instead of 1% OVA. The ability to reverse xylazine/ketamine-induced anesthesia by HTA or roflumilast for 3 h was determined in normal mice. We used roflumilast, a selective PDE4 inhibitor and bronchodilator for severe COPD approved by the US Food and Drug Administration, as a reference drug. In the results, HTA (100 μmol/kg, p.o.) or roflumilast (5 mg/kg, p.o.) significantly suppressed all R L values of MCh at 0.78 ~ 25 mg/mL and enhanced C dyn values of MCh at 3.125 ~ 25 mg/mL compared to OVA-sensitized and -challenged control mice. Orally administered 1, 3 or 10 mg/kg roflumilast, but not 30 or 100 μmol/kg HTA, significantly reversed xylazine/ketamine-induced anesthesia. In contrast to roflumilast, HTA may ameliorate COPD but induce few side effects of nausea, vomiting and gastric hypersecretion at an effective dose for treating COPD, because HTA did not reverse xylazine/ketamine-induced anesthesia in mice.

Bringing Planetary Data into Learning Environments: A Community Effort

NASA Astrophysics Data System (ADS)

Shipp, S.; Higbie, M.; Lowes, L.

2005-12-01

Recognizing the need to communicate scientific findings, and the power of using real planetary data in educational settings to engage students in Earth and space science in meaningful ways, the South Central Organization of Researchers and Educators and the Solar System Exploration Education Forum, part of NASA's Science Mission Directorate's Support Network, have established the Planetary Data in Education (PDE) Initiative. The Initiative strives to: 1) Establish a collaborative community of educators, education specialists, curriculum developers, tool developers, learning technologists, scientists, and data providers to design and develop educationally appropriate products; 2) Build awareness in the broader educational and scientific community of existing programs, products, and resources; 3) Address issues hindering the effective use of planetary data in formal and informal educational settings; and 4) Encourage partnerships that leverage the community's expertise The PDE community has hosted two conferences exploring issues in using data in educational settings. The community recognizes that data are available through venues such as the Planetary Data Systems (PDS), but not in a format that the end-user in a formal or informal educational setting can digest; these data are intended for the scientific audience. Development of meaningful educational programs using planetary data requires design of appropriate learner interfaces and involvement of data providers, product developers, learning technologists, scientists, and educators. The PDE community will participate in the development of Earth Exploration Toolbooks during the DLESE Data Services Workshop and will host a workshop in the summer of 2006 to bring together small groups of educators, data providers, and learning technologists, and scientists to design and develop products that bring planetary data into educational settings. In addition, the PDE community hosts a Web site that presents elements identified as needed by the community, including examples of planetary data use in education, recommendations for program development, links to data providers, opportunities for collaboration, pertinent research, and a Web portal to access educational resources using planetary data on the DLESE Web site.

Backstepping-based boundary control design for a fractional reaction diffusion system with a space-dependent diffusion coefficient.

PubMed

Chen, Juan; Cui, Baotong; Chen, YangQuan

2018-06-11

This paper presents a boundary feedback control design for a fractional reaction diffusion (FRD) system with a space-dependent (non-constant) diffusion coefficient via the backstepping method. The contribution of this paper is to generalize the results of backstepping-based boundary feedback control for a FRD system with a space-independent (constant) diffusion coefficient to the case of space-dependent diffusivity. For the boundary stabilization problem of this case, a designed integral transformation treats it as a problem of solving a hyperbolic partial differential equation (PDE) of transformation's kernel, then the well posedness of the kernel PDE is solved for the plant with non-constant diffusivity. Furthermore, by the fractional Lyapunov stability (Mittag-Leffler stability) theory and the backstepping-based boundary feedback controller, the Mittag-Leffler stability of the closed-loop FRD system with non-constant diffusivity is proved. Finally, an extensive numerical example for this closed-loop FRD system with non-constant diffusivity is presented to verify the effectiveness of our proposed controller. Copyright © 2018 ISA. Published by Elsevier Ltd. All rights reserved.

Tryptophan W207 in transducin T alpha is the fluorescence sensor of the G protein activation switch and is involved in the effector binding.

PubMed Central

Faurobert, E; Otto-Bruc, A; Chardin, P; Chabre, M

1993-01-01

We have produced a recombinant transducin alpha subunit (rT alpha) in sf9 cells, using a baculovirus system. Deletion of the myristoylation site near the N-terminal increased the solubility and allowed the purification of rT alpha. When reconstituted with excess T beta gamma on retinal membrane, rT alpha displayed functional characteristics of wild-type T alpha vis à vis its coupled receptor, rhodopsin and its effector, cGMP phosphodiesterase (PDE). We further mutated a tryptophan, W207, which is conserved in all G proteins and is suspected to elicit the fluorescence change correlated to their activation upon GDP/GTP exchange or aluminofluoride (AlFx) binding. [W207F]T alpha mutant displayed high affinity receptor binding and underwent a conformational switch upon receptor-catalysed GTP gamma S binding or upon AlFx binding, but this did not elicit any fluorescence change. Thus W207 is the only fluorescence sensor of the switch. Upon the switch the mutant remained unable to activate the PDE. To characterize better its effector-activating interaction we measured the affinity of [W207F]T alpha GDP-AlFx for PDE gamma, the effector subunit that binds most tightly to T alpha. [W207F]T alpha still bound in an activation-dependent way to PDE gamma, but with a 100-fold lower affinity than rT alpha. This suggests that W207 contributes to the G protein effector binding. Images PMID:8223434

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

PubMed

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

2012-02-28

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

The 1D Richards' equation in two layered soils: a Filippov approach to treat discontinuities

NASA Astrophysics Data System (ADS)

Berardi, Marco; Difonzo, Fabio; Vurro, Michele; Lopez, Luciano

2018-05-01

The infiltration process into the soil is generally modeled by the Richards' partial differential equation (PDE). In this paper a new approach for modeling the infiltration process through the interface of two different soils is proposed, where the interface is seen as a discontinuity surface defined by suitable state variables. Thus, the original 1D Richards' PDE, enriched by a particular choice of the boundary conditions, is first approximated by means of a time semidiscretization, that is by means of the transversal method of lines (TMOL). In such a way a sequence of discontinuous initial value problems, described by a sequence of second order differential systems in the space variable, is derived. Then, Filippov theory on discontinuous dynamical systems may be applied in order to study the relevant dynamics of the problem. The numerical integration of the semidiscretized differential system will be performed by using a one-step method, which employs an event driven procedure to locate the discontinuity surface and to adequately change the vector field.

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.

Reverse engineering of aircraft wing data using a partial differential equation surface model

NASA Astrophysics Data System (ADS)

Huband, Jacalyn Mann

Reverse engineering is a multi-step process used in industry to determine a production representation of an existing physical object. This representation is in the form of mathematical equations that are compatible with computer-aided design and computer-aided manufacturing (CAD/CAM) equipment. The four basic steps to the reverse engineering process are data acquisition, data separation, surface or curve fitting, and CAD/CAM production. The surface fitting step determines the design representation of the object, and thus is critical to the success or failure of the reverse engineering process. Although surface fitting methods described in the literature are used to model a variety of surfaces, they are not suitable for reversing aircraft wings. In this dissertation, we develop and demonstrate a new strategy for reversing a mathematical representation of an aircraft wing. The basis of our strategy is to take an aircraft design model and determine if an inverse model can be derived. A candidate design model for this research is the partial differential equation (PDE) surface model, proposed by Bloor and Wilson and used in the Rapid Airplane Parameter Input Design (RAPID) tool at the NASA-LaRC Geolab. There are several basic mathematical problems involved in reversing the PDE surface model: (i) deriving a computational approximation of the surface function; (ii) determining a radial parametrization of the wing; (iii) choosing mathematical models or classes of functions for representation of the boundary functions; (iv) fitting the boundary data points by the chosen boundary functions; and (v) simultaneously solving for the axial parameterization and the derivative boundary functions. The study of the techniques to solve the above mathematical problems has culminated in a reverse PDE surface model and two reverse PDE surface algorithms. One reverse PDE surface algorithm recovers engineering design parameters for the RAPID tool from aircraft wing data and the other generates a PDE surface model with spline boundary functions from an arbitrary set of grid points. Our numerical tests show that the reverse PDE surface model and the reverse PDE surface algorithms can be used for the reverse engineering of aircraft wing data.

OPC-13013, a cyclic nucleotide phosphodiesterase type III, inhibitor, inhibits cell proliferation and transdifferentiation of cultured rat hepatic stellate cells.

PubMed

Shimizu, E; Kobayashi, Y; Oki, Y; Kawasaki, T; Yoshimi, T; Nakamura, H

1999-01-01

Activated hepatic stellate cells (HSC; lipocytes; Ito cells) proliferate and are responsible for extracellular matrix synthesis during hepatic fibrogenesis. During activation, HSC undergo transdifferentiation into myofibroblasts expressing alpha-smooth muscle actin (alpha-SMA). Adenosine 3', 5'-cyclic monophosphate (cyclic AMP) is an ubiquitous intracellular signaling molecule, and is upregulated by the activation of adenylate cyclase and downregulated via hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). Recently, increased intracellular cyclic AMP has been shown to inhibit HSC activation. The aim of the current study was to determine the effects of inhibition of PDEs on cell proliferation and transdifferentiation in cultured rat HSC. Cell proliferation was determined by [3H]thymidine incorporation, and Western blot analysis was performed for detection of alpha-SMA, a phenotypic marker of transdifferentiation into myofibroblast. When the cells were exposed to 3-isobutyl-1-methylxanthine (IBMX; 50-1000 microM), a nonselective PDE inhibitor, serum-stimulated [3H]thymidine incorporation was suppressed in a dose-dependent manner with a maximum inhibition of 66% at a concentration of 500 microM OPC-13013 (1-60 microM), a selective PDE III isoenzyme inhibitor, induced a dose-dependent inhibitory effect on serum-stimulated DNA synthesis that reached a maximum inhibition of 95% at a concentration of 60 microM, while neither 8-methoxymethyl-3-isobutyl-1-methylxanthine (8-MMX), a PDE I isoenzyme inhibitor, nor Ro-20-1724, a PDE IV isoenzyme inhibitor, had an inhibitory effect. Western blot analysis revealed that IBMX or OPC-13013 decreased alpha-SMA expression, while other selective PDE isoenzyme inhibitors did not have a suppressive effect. IBMX, OPC-13013 or Ro-20-1724, but not 8-MMX augmented forskolin-induced increase in intracellular cyclic AMP levels although cyclic AMP levels were not affected by treatment with any of these PDE inhibitors alone. These data indicate that inhibition of PDEs, especially PDE III isoenzyme, can produce an inhibitory effect on HSC activation. The PDE III isoenzyme may contribute to the regulation of HSC activation during fibrogenesis. In addition, OPC-13013 may have the potential to inhibit initiation and progression of hepatic fibrosis by interfering with HSC activation.

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 desensitization of cardiac βARs under hormonal stimulation, which is associated with impaired cardiac function during the development of pathophysiological conditions. PMID:28339772

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 βARs under hormonal stimulation, which is associated with impaired cardiac function during the development of pathophysiological conditions. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

Adherence to Phosphodiesterase Type 5 Inhibitors in the Treatment of Erectile Dysfunction in Long-Term Users: How Do Men Use the Inhibitors?

PubMed Central

Carvalheira, Ana; Forjaz, Vera; Pereira, Nuno Monteiro

2014-01-01

Introduction The high effectiveness of phosphodiesterase type 5 inhibitors (PDE5-i) in the treatment of erectile dysfunction (ED) has been demonstrated. However, previous research shows that PDE5-i treatments have high discontinuation rates. Aim The main goals of this study were to (i) characterize the way men use PDE5-i and (ii) analyze the adherence to treatment, identifying the factors that influence PDE5-i use. Methods A total of 148 men with clinical diagnosis for ED who maintained the treatment with PDE5-i for over 3 years were interviewed. Interviews concerning their ongoing treatment were carried out using a standardized questionnaire with quantitative and qualitative items. Main Outcome Measures Physiological measures included the intracavernous alprostadil injection test, associated with penile rigidometry and penile Doppler ultrasound. The qualitative measure included two questions: “Do you use the drug in every sexual intercourse?” and “How do you use the inhibitor?” Results ED causes were classified as venogenic (31%), arteriogenic (23%), psychogenic (18%), iatrogenic (13%), neurogenic (8%), and diabetic (7%). Participation rate was 71.8%. Of the 148 patients studied, 75% claimed not to use PDE5-i in every intercourse. Most used tadalafil (66%), followed by sildenafil (20%), vardenafil (10%), and 4% alternated the type of medicine. Four main categories emerged concerning the factors that determine the intake of PDE5-i in some intercourse situations and not in others: (i) psychological factors; (ii) medication-related factors; (iii) circumstantial factors; and (iv) relational factors. Conclusion The analysis of men's narratives revealed a combination of factors that influence the adherence to PDE5-i. The psychological and medication-related factors were the most prevalent. This study highlighted the importance of taking these factors into account, both at the time of prescription and during the follow-up in order to improve adherence. Carvalheira A, Forjaz V, and Pereira NM. Adherence to phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction in long-term users: How do men use the inhibitors? Sex Med 2014;2:96–102. PMID:25356304

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 treatment expectations were identified. Our analyses have described key characteristics, such as self- and partner perceptions, sexual attitudes, and treatment expectations in relation to the patients' country and prescribed treatment, which might guide treatment decisions in MENA and LA men with ED.

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

NASA Astrophysics Data System (ADS)

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

2018-02-01

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

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.

Hybrid approaches for multiple-species stochastic reaction-diffusion models

NASA Astrophysics Data System (ADS)

Spill, Fabian; Guerrero, Pilar; Alarcon, Tomas; Maini, Philip K.; Byrne, Helen

2015-10-01

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

Hybrid approaches for multiple-species stochastic reaction-diffusion models.

PubMed

Spill, Fabian; Guerrero, Pilar; Alarcon, Tomas; Maini, Philip K; Byrne, Helen

2015-10-15

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

Hybrid approaches for multiple-species stochastic reaction–diffusion models

PubMed Central

Spill, Fabian; Guerrero, Pilar; Alarcon, Tomas; Maini, Philip K.; Byrne, Helen

2015-01-01

Reaction–diffusion models are used to describe systems in fields as diverse as physics, chemistry, ecology and biology. The fundamental quantities in such models are individual entities such as atoms and molecules, bacteria, cells or animals, which move and/or react in a stochastic manner. If the number of entities is large, accounting for each individual is inefficient, and often partial differential equation (PDE) models are used in which the stochastic behaviour of individuals is replaced by a description of the averaged, or mean behaviour of the system. In some situations the number of individuals is large in certain regions and small in others. In such cases, a stochastic model may be inefficient in one region, and a PDE model inaccurate in another. To overcome this problem, we develop a scheme which couples a stochastic reaction–diffusion system in one part of the domain with its mean field analogue, i.e. a discretised PDE model, in the other part of the domain. The interface in between the two domains occupies exactly one lattice site and is chosen such that the mean field description is still accurate there. In this way errors due to the flux between the domains are small. Our scheme can account for multiple dynamic interfaces separating multiple stochastic and deterministic domains, and the coupling between the domains conserves the total number of particles. The method preserves stochastic features such as extinction not observable in the mean field description, and is significantly faster to simulate on a computer than the pure stochastic model. PMID:26478601

Relation of phosphodiesterase type 5 inhibitors and malignant melanoma: a meta-analysis and systematic review.

PubMed

Wang, Jie; Shen, Yigen; Wang, Jiaoni; Xue, Yangjing; Liao, Lianming; Thapa, Saroj; Ji, Kangting

2017-07-11

Data on the association between using PDE5 inhibitors and malignant melanoma are conflicting. To estimate the relation of using PDE5 inhibitors with risk of malignant melanoma, Medline (Ovid) and Embase (Ovid) databases were searched up to February 2017, and a random effects model was used to calculate the summary risk estimates. Five observational studies were included. Five studies reports encompassed a total of 15,979 melanoma cases occurring among 1, 188,414 participants. The pooled multivariable-adjusted RR of melanoma in patients with using PDE5 inhibitors was 1.12 (95% CI: 1.03-1.21, I2 = 0.48). Findings from this systematic review support that PDE5 inhibitor use is associated with increased risk of melanoma in ED patients, the result remains inclusive and warrants further study in the future.

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.

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.

Functional characterization of the human phosphodiesterase 7A1 promoter.

PubMed Central

Torras-Llort, Mònica; Azorín, Fernando

2003-01-01

In this paper, the human phosphodiesterase 7A1 (h PDE7A1 ) promoter region was identified and functionally characterized. Transient transfection experiments indicated that a 2.9 kb fragment of the h PDE7A1 5'-flanking region, to position -2907, has strong promoter activity in Jurkat T-cells. Deletion analysis showed that the proximal region, up to position -988, contains major cis -regulatory elements of the h PDE7A1 promoter. This minimal promoter region contains a regulatory CpG island which is essential for promoter activity. The CpG island contains three potential cAMP-response-element-binding protein (CREB)-binding sites that, as judged by in vivo dimethyl sulphate (DMS) footprinting, are occupied in Jurkat T-cells. Moreover, over-expression of CREB results in increased promoter activity, but, on the other hand, promoter activity decreases when a dominant-negative form of CREB (KCREB) is over-expressed. In vivo DMS footprinting strongly indicates that other transcription factors, such Ets-2, nuclear factor of activated T-cells 1 (NFAT-1) and nuclear factor kappaB (NF-kappaB), might also contribute to the regulation of h PDE7A1 promoter. Finally, h PDE7A1 promoter was found to be induced by treatment with PMA, but not by treatment with dibutyryl cAMP or forskolin. These results provide insights into the factors and mechanisms that regulate expression of the h PDE7A gene. PMID:12737631

Patterns of age related changes for phosphodiesterase type-10A in comparison with dopamine D2/3 receptors and sub-cortical volumes in the human basal ganglia: A PET study with 18F-MNI-659 and 11C-raclopride with correction for partial volume effect.

PubMed

Fazio, Patrik; Schain, Martin; Mrzljak, Ladislav; Amini, Nahid; Nag, Sangram; Al-Tawil, Nabil; Fitzer-Attas, Cheryl J; Bronzova, Juliana; Landwehrmeyer, Bernhard; Sampaio, Cristina; Halldin, Christer; Varrone, Andrea

2017-05-15

Phosphodiesterase 10A enzyme (PDE10A) is an important striatal target that has been shown to be affected in patients with neurodegenerative disorders, particularly Huntington´s disease (HD). PDE10A is expressed on striatal neurones in basal ganglia where other known molecular targets are enriched such as dopamine D 2/3 receptors (D 2/3 R). The aim of this study was to examine the availability of PDE10A enzyme in relation with age and gender and to compare those changes with those related to D 2/3 R and volumes in different regions of the basal ganglia. As a secondary objective we examined the relative distribution of D 2/3 R and PDE10A enzyme in the striatum and globus pallidus. Forty control subjects (20F/20M; age: 44±11y, age range 27-69) from an ongoing positron emission tomography (PET) study in HD gene expansion carriers were included. Subjects were examined with PET using the high-resolution research tomograph (HRRT) and with 3T magnetic resonance imaging (MRI). The PDE10A radioligand 18 F-MNI-659 and D 2/3 R radioligand 11 C-raclopride were used. The outcome measure was the binding potential (BP ND ) estimated with the two-tissue compartment model ( 18 F-MNI-659) and the simplified reference tissue model ( 11 C-raclopride) using the cerebellum as reference region. The PET data were corrected for partial volume effects. In the striatum, PDE10A availability showed a significant age-related decline that was larger compared to the age-related decline of D 2/3 R availability and to the age-related decline of volumes measured with MRI. In the globus pallidus, a less pronounced decline of PDE10A availability was observed, whereas D 2/3 R availability and volumes seemed to be rather stable with aging. The distribution of the PDE10A enzyme was different from the distribution of D 2/3 R, with higher availability in the globus pallidus. These results indicate that aging is associated with a considerable physiological reduction of the availability of PDE10A enzyme in the striatum. Moreover as result of the analysis, in the striatum for both the molecular targets, we observed a gender effect with higher BP ND the female group. Copyright © 2017 Elsevier Inc. All rights reserved.

Preliminary results for the design, fabrication, and performance of a backside-illuminated avalanche drift detector

NASA Astrophysics Data System (ADS)

Qiao, Yun; Liang, Kun; Chen, Wen-Fei; Han, De-Jun

2013-10-01

The detection of low-level light is a key technology in various experimental scientific studies. As a photon detector, the silicon photomultiplier (SiPM) has gradually become an alternative to the photomultiplier tube (PMT) in many applications in high-energy physics, astroparticle physics, and medical imaging because of its high photon detection efficiency (PDE), good resolution for single-photon detection, insensitivity to magnetic field, low operating voltage, compactness, and low cost. However, primarily because of the geometric fill factor, the PDE of most SiPMs is not very high; in particular, for those SiPMs with a high density of micro cells, the effective area is small, and the bandwidth of the light response is narrow. As a building block of the SiPM, the concept of the backside-illuminated avalanche drift detector (ADD) was first proposed by the Max Planck Institute of Germany eight years ago; the ADD is promising to have high PDE over the full energy range of optical photons, even ultraviolet light and X-ray light, and because the avalanche multiplication region is very small, the ADD is beneficial for the fabrication of large-area SiPMs. However, because of difficulties in design and fabrication, no significant progress had been made, and the concept had not yet been verified. In this paper, preliminary results in the design, fabrication, and performance of a backside-illuminated ADD are reported; the difficulties in and limitations to the backside-illuminated ADD are analyzed.

Targeting New Pharmacological Approaches for Alzheimer's Disease: Potential for Statins and Phosphodiesterase Inhibitors.

PubMed

Sallustio, Fabrizio; Studer, Valeria

2016-01-01

Alzheimer's disease (AD) is the most common cause of dementia among the elderly. It is pathologically characterized by diffused extracellular deposits, senile plaques, and intracellular neurofibrillary tangles in the brain, responsible for neuronal dysfunction and cell death. Memory, language and other cognitive functions can be affected to a limited extent in the initial stage called mild cognitive impairment (MCI) or in a more severe and daily life interfering manner in the later stage called dementia. Currently no effective disease-modifying treatment exists for the majority of neurodegenerative diseases. Failure of therapy aimed at affecting beta amyloid pathology has led research to investigate alternative approaches. Recent findings address statins and phosphodiesterase (PDE) inhibitors as compounds able to affect different mechanisms underlying AD. Statins could exert several effects based on their lipid-lowering and cerebral blood flow increasing abilities but also pleiotropic/antinflammatory and neuroprotective properties have been claimed. PDEs act as regulators of intracellular signaling cascades through the control of two second messengers, cyclic adenosine monophosphate and cyclic guanosine monophosphate. PDE inhibitors effects in animal models of AD have been promising and their proven safety in clinical use create high expectations for the treatment of AD. In this review, we will report main data and evidence on: 1. Current pathophysiological theories of AD in order to better understand which mechanisms lead to pathological changes and can be affected by therapies; 2. The use of statins and PDE inhibitors in animal models of AD and in humans, analyzing their mechanisms of action.

Toward the identification of the cardiac cGMP inhibited-phosphodiesterase catalytic site

NASA Astrophysics Data System (ADS)

Fossa, Paola; Boggia, Raffaella; Mosti, Luisa

1998-07-01

Cyclic nucleotide phosphodiesterases (PDEs) comprise a complex group of enzymes; five major PDE families or classes with distinctive properties have been identified. Among these a great deal of interest has recently been focused on the so called cGMP-inhibited low Km cAMP phosphodiesterase (cGI PDE) or PDE III. A number of positive inotropic agents, including the well-known milrinone, display a specific inhibition of PDE III as primary mechanism of action. Recent studies have been carried out to develop a pharmacophore model of the PDE III active site. We therefore performed molecular modelling and 3D-SAR studies so as to better define structural requirements for potent and selective enzymatic inhibition. The DISCO (DIStance COmparison) strategy has been applied on a set of compounds taken from literature and a milrinone analogue previously synthesized by us, all of which are characterized by a marked inotropic effect but with varying degrees of enzyme selectivity. A common pharmacophoric model was derived, validated and considered as starting point to perform a 3D-SAR study using the GRID force field and PCA (Principal Component Analysis) with the aim of rationally designing more selective inhibitors. This paper presents the results of this theoretical approach.

Dual specificity and novel structural folding of yeast phosphodiesterase-1 for hydrolysis of second messengers cyclic adenosine and guanosine 3',5'-Monophosphate

DOE PAGES

Tian, Yuanyuan; Cui, Wenjun; Huang, Manna; ...

2014-08-05

Cyclic nucleotide phosphodiesterases (PDEs) decompose second messengers cAMP and cGMP that play critical roles in many physiological processes. PDE1 of Saccharomyces cerevisiae has been subcloned and expressed in Escherichia coli. Recombinant yPDE1 has a K M of 110 μM and a k cat of 16.9 s⁻¹ for cAMP and a K M of 105 μM and a k cat of 11.8 s₅⁻¹ for cGMP. Thus, the specificity constant (k cat/K McAMP)/(k cat/K M cGMP) of 1.4 indicates a dual specificity of yPDE1 for hydrolysis of both cAMP and cGMP. The crystal structures of unliganded yPDE1 and its complex with GMPmore » at 1.31 Å resolution reveal a new structural folding that is different from those of human PDEs but is partially similar to that of some other metalloenzymes such as metallo-β-lactamase. In spite of their different structures and divalent metals, yPDE1 and human PDEs may share a common mechanism for hydrolysis of cAMP and cGMP.« less

The application of quantitative methods for identifying and exploring the presence of bias in systematic reviews: PDE-5 inhibitors for erectile dysfunction.

PubMed

Bekkering, G E; Abou-Setta, A M; Kleijnen, J

2008-01-01

A systematic review of PDE-5 inhibitors for erectile dysfunction was performed to evaluate the utility of quantitative methods for identifying and exploring the influence of bias and study quality on pooled outcomes from meta-analyses. We included 123 randomized controlled trials (RCTs). Methodological quality was poorly reported. All three drugs appeared highly effective. Indirect adjusted analyses showed no differences between the three drugs. Funnel plots and statistical tests showed no evidence of small-study effects for sildenafil whereas there was evidence of such bias for tadalafil and vardenafil. Adjustment for missing studies using trim and fill techniques did not alter the pooled estimates substantially. The exclusion of previous sildenafil nonresponders was associated with larger treatment effects for tadalafil. This investigation was hampered by poor reporting of methodological quality, a low number of studies, heterogeneity and large effect sizes. Despite such limitations, a comprehensive assessment of biases should be a routine in systematic reviews.

A Temperature-Dependent Phase-Field Model for Phase Separation and Damage

NASA Astrophysics Data System (ADS)

Heinemann, Christian; Kraus, Christiane; Rocca, Elisabetta; Rossi, Riccarda

2017-07-01

In this paper we study a model for phase separation and damage in thermoviscoelastic materials. The main novelty of the paper consists in the fact that, in contrast with previous works in the literature concerning phase separation and damage processes in elastic media, in our model we encompass thermal processes, nonlinearly coupled with the damage, concentration and displacement evolutions. More particularly, we prove the existence of "entropic weak solutions", resorting to a solvability concept first introduced in Feireisl (Comput Math Appl 53:461-490, 2007) in the framework of Fourier-Navier-Stokes systems and then recently employed in Feireisl et al. (Math Methods Appl Sci 32:1345-1369, 2009) and Rocca and Rossi (Math Models Methods Appl Sci 24:1265-1341, 2014) for the study of PDE systems for phase transition and damage. Our global-in-time existence result is obtained by passing to the limit in a carefully devised time-discretization scheme.

[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.

Influence of erectile dysfunction course on its progress and efficacy of treatment with phosphodiesterase type 5 inhibitors.

PubMed

Liu, De-Feng; Jiang, Hui; Hong, Kai; Zhao, Lian-Ming; Tang, Wen-Hao; Ma, Lu-Lin

2010-11-01

Erectile dysfunction (ED) is a common impairment among older men, and the prevalence rates increase sharply after age of 60 years. Most studies have focused on the prevalence rate or dangerous factors. The aim of this study was to investigate the basic epidemiologic data about ED patients with different ED courses. The purpose of this research was to understand the therapeutic effect of phosphodiesterase type 5 inhibitor (PDE5-I) and see how and why the ED course impact the progress of ED and the therapeutic effect of PDE5-I treatment. From June 2008 to June 2009, 4252 questionnaires (Quality of Erection Questionnaire, QEQ) were gathered from 46 centers by urology or andrology doctors all around China. Patients with ED (age ≥ 20 years) filled in first half of the questionnaires when they came for the first time, and then completed the second half 4 weeks after PDE5-I therapy. ED courses of most patients were less than 5 years (< 5 years, 74.0%; 5 - 10 years 20.8%; > 10 years, 5.2%). As ED course increasing, the incidence of the risk factors of ED, such as smoking, drinking, hypertension, diabetes, heart disease and hyperlipidemia also increase (P ≤ 0.01). PDE5-I was effective in improving the quality of sexual activities (P ≤ 0.01). Administration of PDE5-I improves satisfaction, enjoyment and frequency of sexual activities. The longer the ED course, the worse the therapeutic effect (< 5 years, 96.1%; 5 - 10 years, 94.9%; > 10 years, 89.0%) (P ≤ 0.01). The ED course greatly affected the therapeutic effect of PDE5-1, the patients with ED should consult doctor at early stage of the disease. Administration of PDE5-I effectively improves the penile erection and the quality of sexual life of the patients hence should be considered as first-line medicine in the treatment of ED.

Calcium-dependent phosphodiesterase 1C inhibits renin release from isolated juxtaglomerular cells

PubMed Central

Ortiz-Capisano, M. Cecilia; Liao, Tang-Dong; Ortiz, Pablo A.

2009-01-01

Renin release from the juxtaglomerular (JG) cell is stimulated by the second messenger cAMP and inhibited by calcium. We previously showed JG cells contain a calcium sensing receptor (CaSR), which, when stimulated, decreases cAMP formation and inhibits renin release. We hypothesize CaSR activation decreases cAMP and renin release, in part, by stimulating a calcium calmodulin-activated phosphodiesterase 1 (PDE1). We incubated our primary culture of JG cells with two selective PDE1 inhibitors [8-methoxymethil-IBMX (8-MM-IBMX; 20 μM) and vinpocetine (40 μM)] and the calmodulin inhibitor W-7 (10 μM) and measured cAMP and renin release. Stimulation of the JG cell CaSR with the calcimimetic cinacalcet (1 μM) resulted in decreased cAMP from a basal of 1.13 ± 0.14 to 0.69 ± 0.08 pM/mg protein (P < 0.001) and in renin release from 0.89 ± 0.16 to 0.38 ± 0.08 μg ANG I/ml·h−1·mg protein−1 (P < 0.001). However, the addition of 8-MM-IBMX with cinacalcet returned both cAMP (1.10 ± 0.19 pM/mg protein) and renin (0.57 ± 0.16 μg ANG I/ml·h−1·mg protein−1) to basal levels. Similar results were obtained with vinpocetine, and also with W-7. Combining 8-MM-IBMX and W-7 had no additive effect. To determine which PDE1 isoform is involved, we performed Western blot analysis for PDE1A, B, and C. Only Western blot analysis for PDE1C showed a characteristic band apparent at 80 kDa. Immunofluorescence showed cytoplasmic distribution of PDE1C and renin in the JG cells. In conclusion, PDE1C is expressed in isolated JG cells, and contributes to calcium's inhibitory modulation of renin release from JG cells. PMID:19741056

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.

A cost-effective method to get insight into the peritoneal dialysate effluent proteome.

PubMed

Araújo, J E; Jorge, S; Teixeira E Costa, F; Ramos, A; Lodeiro, C; Santos, H M; Capelo, J L

2016-08-11

Protein depletion with acetonitrile and protein equalization with dithiothreitol have been assessed with success as proteomics tools for getting insight into the peritoneal dialysate effluent proteome. The methods proposed are cost-effective, fast and easy of handling, and they match the criteria of analytical minimalism: low sample volume and low reagent consumption. Using two-dimensional gel electrophoresis and peptide mass fingerprinting, a total of 72 unique proteins were identified. Acetonitrile depletes de PDE proteome from high-abundance proteins, such as albumin, and enriches the sample in apolipo-like proteins. Dithiothreitol equalizes the PDE proteome by diminishing the levels of albumin and enriching the extract in immunoglobulin-like proteins. The annotation per gene ontology term reveals the same biological paths being affected for patients undergoing peritoneal dialysis, namely that the largest number of proteins lost through peritoneal dialysate are extracellular proteins involved in regulation processes through binding. Renal failure is a growing problem worldwide, and particularly in Europe where the population is getting older. Up-to-date there is a focus of interest in peritoneal dialysis (PD), as it provides a better quality of life and autonomy of the patients than other renal replacement therapies such as haemodialysis. However, PD can only be used during a short period of years, as the peritoneum lost its permeability through time. Therefore to make a breakthrough in PD and consequently contribute to better healthcare system it is urgent to find a group of biomarkers of peritoneum degradation. Here we report on two cost-effective methods for protein depletion in peritoneal dialysate effluent (PDE). The use of ACN and DTT over PDE to deplete high abundant proteins or to equalize the concentration of proteins, respectively, performs well and with similar protein profiles than when the same chemicals are used in human plasma samples. ACN depletes de PDE proteome from large proteins, such as albumin, and enriches the sample in apolipoproteins. DTT equalizes the PDE proteome by diminishing the levels of large proteins such as albumin and enriching the extract in immunoglobulins. Although the number and type of proteins identified are different, the annotation per gene ontology term reveals the same biological paths being affected for patients undergoing peritoneal dialysate. Thus, the largest number of proteins lost through peritoneal dialysate belongs to the group of extracellular proteins involved in regulation processes through binding. As for the searching of biomarkers, DTT seems to be the most promising of the two methods because acts as an equalizer and it allows interrogating more proteins in the same sample.

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

NASA Astrophysics Data System (ADS)

Proedrou, Elisavet; Hocke, Klemens

2016-06-01

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

Thrust Measurements for a Pulse Detonation Engine Driven Ejector

NASA Technical Reports Server (NTRS)

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

2005-01-01

Results of an experimental effort on pulse detonation driven ejectors aimed at probing different aspects of PDE ejector processes, are presented and discussed. The PDE was operated using ethylene as the fuel and an equimolar oxygen/nitrogen mixture as the oxidizer at an equivalence ratio of one. The thrust measurements for the PDE alone are in excellent agreement with experimental and modeling results reported in the literature and serve as a Baseline for the ejector studies. These thrust measurements were then used as a basis for quantifying thrust augmentation for various PDE/ejector setups using constant diameter ejector tubes and various detonation tube/ejector tube overlap distances. The results show that for the geometries studied here, a maximum thrust augmentation of 24% is achieved. The thrust augmentation results are complemented by shadowgraph imaging of the flowfield in the ejector tube inlet area and high frequency pressure transducer measurements along the length of the ejector tube.

Fourth-order partial differential equation noise removal on welding images

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

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

2015-10-22

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

Review on factors affecting the performance of pulse detonation engine

NASA Astrophysics Data System (ADS)

Tripathi, Saurabh; Pandey, Krishna Murari

2018-04-01

Now a day's rocket engines (air-breathing type) are being used for aerospace purposes but the studies have shown that these are less efficient, so alternatives are being searched for these. Pulse Detonation Engine (PDE) is one such efficient engine which can replace the rocket engines. In this review paper, different researches have been cited. As can be observed from various researches, insertion of obstacles is better. Deflagration to Detonation(DDT) transition process is found to be most important factor. So a lot of researches are being done considering this DDT chamber. Also, the ignition chamber and ejector were found to improve the effectiveness of PDE. The PDE works with a range of Mach 0-4. Flame acceleration is also found to increase the DDT process. Use of valve and valveless engine has also been compared. Various other factors have been focused in this review paper which is found to boost PDE performance.

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.

Selective inhibition of phosphodiesterase 5 enhances glutamatergic synaptic plasticity and memory in mice.

PubMed

Uthayathas, Subramaniam; Parameshwaran, Kodeeswaran; Karuppagounder, Senthilkumar S; Ahuja, Manuj; Dhanasekaran, Muralikrishnan; Suppiramaniam, Vishnu

2013-11-01

Phosphodiesterases (PDEs) belong to a family of proteins that control metabolism of cyclic nucleotides. Targeting PDE5, for enhancing cellular function, is one of the therapeutic strategies for male erectile dysfunction. We have investigated whether in vivo inhibition of PDE5, which is expressed in several brain regions, will enhance memory and synaptic transmission in the hippocampus of healthy mice. We have found that acute administration of sildenafil, a specific PDE5 inhibitor, enhanced hippocampus-dependent memory tasks. To elucidate the underlying mechanism in the memory enhancement, effects of sildenafil on long-term potentiation (LTP) were measured. The level of LTP was significantly elevated, with concomitant increases in basal synaptic transmission, in mice treated with sildenafil (1 mg/kg/day) for 15 days compared to control mice. These results suggest that moderate PDE5 inhibition enhances memory by increasing synaptic plasticity and transmission in the hippocampus. Copyright © 2013 Wiley Periodicals, Inc.

Low doses of cyclic AMP-phosphodiesterase inhibitors rapidly evoke opioid receptor-mediated thermal hyperalgesia in naïve mice which is converted to prominent analgesia by cotreatment with ultra-low-dose naltrexone.

PubMed

Crain, Stanley M; Shen, Ke-Fei

2008-09-22

Systemic (s.c.) injection in naïve mice of cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitors, e.g. 3-isobutyl-1-methylxanthine [(IBMX) or caffeine, 10 mg/kg] or the more specific cAMP-PDE inhibitor, rolipram (1 mug/kg), rapidly evokes thermal hyperalgesia (lasting >5 h). These effects appear to be mediated by enhanced excitatory opioid receptor signaling, as occurs during withdrawal in opioid-dependent mice. Cotreatment of these mice with ultra-low-dose naltrexone (NTX, 0.1 ng/kg-1 pg/kg, s.c.) results in prominent opioid analgesia (lasting >4 h) even when the dose of rolipram is reduced to 1 pg/kg. Cotreatment of these cAMP-PDE inhibitors in naïve mice with an ultra-low-dose (0.1 ng/kg) of the kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI) or the mu-opioid receptor antagonist, beta-funaltrexamine (beta-FNA) also results in opioid analgesia. These excitatory effects of cAMP-PDE inhibitors in naïve mice may be mediated by enhanced release of small amounts of endogenous bimodally-acting (excitatory/inhibitory) opioid agonists by neurons in nociceptive networks. Ultra-low-dose NTX, nor-BNI or beta-FNA selectively antagonizes high-efficacy excitatory (hyperalgesic) Gs-coupled opioid receptor-mediated signaling in naïve mice and results in rapid conversion to inhibitory (analgesic) Gi/Go-coupled opioid receptor-mediated signaling which normally requires activation by much higher doses of opioid agonists. Cotreatment with a low subanalgesic dose of kelatorphan, an inhibitor of multiple endogenous opioid peptide-degrading enzymes, stabilizes endogenous opioid agonists released by cAMP-PDE inhibitors, resulting in conversion of the hyperalgesia to analgesia without requiring selective blockade of excitatory opioid receptor signaling. The present study provides a novel pharmacologic paradigm that may facilitate development of valuable non-narcotic clinical analgesics utilizing cotreatment with ultra-low-dose rolipram plus ultra-low-dose NTX or related agents.

Effect of Phosphodiesterase in Regulating the Activity of Lysosomes in the HeLa Cell Line.

PubMed

Hong, Eun-Seon; Kim, Bit-Na; Kim, Yang-Hoon; Min, Jiho

2017-02-28

The transport of lysosomal enzymes into the lysosomes depends on the phosphorylation of their chains and the binding of the phosphorylated residues to mannose-6-phosphate receptors. The efficiency of separation depends more on the phosphodiesterases (PDEs) than on the activity of the phosphorylation of mannose residues and can be determined in vitro. PDEs play important roles in regulation of the activation of lysosomes. The expression of proteins was confirmed by western blotting. All PDE4 series protein expression was reduced in high concentrations of rolipram. As a result of observing the fluorescence intensity after rolipram treatment, the lysosomal enzyme was activated at low concentrations and suppressed at high concentrations. High concentrations of rolipram recovered the original function. Antimicrobial activity was not shown in either 10 or 100 µ concentrations of rolipram in treated HeLa cells in vitro. However, the higher anticancer activity at lower rolipram concentration was shown in lysosomal enzyme treated with 10 µ of rolipram. The anticancer activity was confirmed through cathepsin B and D assay. Tranfection allowed examination of the relationship between PDE4 and lysosomal activity in more detail. Protein expression was confirmed to be reduced. Fluorescence intensity showed decreased activity of lysosomes and ROS in cells transfected with the antisense sequences of PDE4 A, B, C, and D. PDE4A showed anticancer activity, whereas lysosome from cells transfected with the antisense sequences of PDE4 B, C, and D had decreased anticancer activity. These results showed the PDE4 A, B, C, and D are conjunctly related with lysosomal activity.

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

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

PubMed Central

Wong, Kin-Yiu; Gao, Jiali

2011-01-01

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

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.

[Masturbation device (EGG) as a new penile rehabilitation tool: a pilot study].

PubMed

Sato, Yoshikazu; Tanda, Hitoshi; Nakajima, Hisao; Nitta, Toshikazu; Akagashi, Keigo; Hanzawa, Tatsuo; Tobe, Musashi; Haga, Kazunori; Uchida, Kosuke; Honma, Ichiya

2013-05-01

Erectile dysfunction following radical prostatectomy (RP) is still a significant burden as a post-operative morbidity, despite advances in nerve-sparing techniques and penile (erectile function) rehabilitation (PR) programs. We assessed the effects of stimulation with the masturbation device "EGG" on enhancement of erectile response along with administration of phospho diesterase type 5 inhibitor. We also studied the change of self-esteem and motivation for continuation of PR after stimulation with EGG. Eight nonresponders for PDE5-I who underwent retropubic RP were enrolled. Patients' median age was 71.5 years old. No patients received adjuvant therapy for prostate cancer. The patients' erectile response in the penile rehabilitation session (masturbation) with PDE5-I＋manual stimulation and PDE5-I＋stimulation with EGG were evaluated by erection hardness score (EHS). Changes of self-esteem and motivation for penile rehabilitation were assessed by the self-esteem subscale of the Self-Esteem and Relationship (SEAR) questionnaire and one original question, respectively. PDE5-I ＋ stimulation with EGG significantly enhanced EHS compared to PDE5-I＋manual stimulation in the eight patients (p＝0.027). Transformed score of self-esteem subscale score of SEAR questionnaire was significantly increased in the PR session with EGG compared to the PR session with manual stimulation (p＝0.043). Six patients who showed a better erectile response with EGG retained motivation for continuation of PR. PDE5-I＋stimulation with EGG improved the erectile response in post-RP patients. EGG as a masturbation device may have a potential for contribution to successful PR.

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.

The mediating role of phosphodiesterase type 4 in the dopaminergic modulation of motor impulsivity.

PubMed

Heckman, P R A; Blokland, A; Van Goethem, N P; Van Hagen, B T J; Prickaerts, J

2018-09-17

The current study investigated the mediating role of phosphodiesterase type 4 (PDE4) regulated cAMP in the dopaminergic modulation of premature responding (action restraint) in rats. Response inhibition, which includes action restraint, finds its neurobiological origin in cortico-striatal-thalamic circuitry and can be modulated by dopamine. Intracellularly, the effect of dopamine is largely mediated through the cAMP/PKA signaling cascade. Areas in the prefrontal cortex are very sensitive to their neurochemical environment, including catecholamine levels. As a result, we investigated the effects of intracellular modulation of the dopamine cascade by means of PDE4 inhibition by roflumilast on premature responding in a hypo, normal and hyper dopaminergic state of the brain. As a hypo dopaminergic model we induced a 6-OHDA lesion in the (rat) prefrontal cortex, more specifically the infralimbic cortex. For the hyper dopaminergic state we also turned to a well-established model of impaired action restraint, namely the systemic administration of d-amphetamine. In line with the notion of a U-shaped relation between dopamine and impulsive responding, we found that both increasing and decreasing dopamine levels resulted in an increase in premature responding in the choice serial reaction time task (CSRTT). The PDE4 inhibitor roflumilast increased premature responses in combination with d-amphetamine, whereas a decrease in premature responding after roflumilast treatment was found in the 6-OHDA lesioned animals. As a result, it would be interesting to test the effects of PDE4 inhibition in disorders affected by disrupted impulse control related to cortico-striatal-thalamic hypodopaminergia including attention deficit hyperactivity disorder (ADHD). Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

A method for solution of the Euler-Bernoulli beam equation in flexible-link robotic systems

NASA Technical Reports Server (NTRS)

Tzes, Anthony P.; Yurkovich, Stephen; Langer, F. Dieter

1989-01-01

An efficient numerical method for solving the partial differential equation (PDE) governing the flexible manipulator control dynamics is presented. A finite-dimensional model of the equation is obtained through discretization in both time and space coordinates by using finite-difference approximations to the PDE. An expert program written in the Macsyma symbolic language is utilized in order to embed the boundary conditions into the program, accounting for a mass carried at the tip of the manipulator. The advantages of the proposed algorithm are many, including the ability to (1) include any distributed actuation term in the partial differential equation, (2) provide distributed sensing of the beam displacement, (3) easily modify the boundary conditions through an expert program, and (4) modify the structure for running under a multiprocessor environment.

Effects of selective phosphodiesterases-4 inhibitors on learning and memory: a review of recent research.

PubMed

Peng, Sheng; Sun, Haiyan; Zhang, Xiaoqing; Liu, Gongjian; Wang, Guanglei

2014-09-01

Phosphodiesterase-4 (PDE-4) regulates the intracellular level of cyclic adenosine monophosphate. Recent studies demonstrated that PDE-4 inhibitors can counteract deficits in long-term memory caused by aging or increased expression of mutant forms of human amyloid precursor proteins, and can influence the process of memory function and cognitive enhancement. Therapeutics, such as ketamine, a drug used in clinical anesthesia, can also cause memory deficits as adverse effects. Targeting PDE-4 with selective inhibitors may offer a novel therapeutic strategy to prevent, slow the progress, and, eventually, treat memory deficits.

Cloning and expression of cDNA for a human low-K sub m , rolipram-sensitive cyclic AMP phosphodiesterase

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

Livi, G.P.; McHale, M.J.; Sathe, G.M.

1990-06-01

The authors have isolated cDNA clones representing cyclic AMP (cAMP)-specific phosphodiesterases (PDEases) from a human monocyte cDNA library. One cDNA clone (hPDE-1) defines a large open reading frame of ca. 2.1 kilobases, predicting a 686-amino-acid, ca. 77-kilodalton protein which contains significant homology to both rat brain and {ital Drosophila} cAMP PDEases, especially within an internal conserved domain of ca. 270 residues. Amino acid sequence divergence exists at the NH{sub 2} terminus and also within a 40- to 100-residue domain near the COOH-terminal end. hPDE-1 hybridizes to a major 4.8-kilobase mRNA transcript from both human monocytes and placenta. The coding regionmore » of hPDE-1 was engineered for expression in COS-1 cells, resulting in the overproduction of cAMP PDEase activity. The hPDE-1 recombinant gene product was identified as a low-{ital K{sub m}} cAMP phosphodiesterase on the basis of several biochemical properties including selective inhibition by the antidepressant drug rolipram. Known inhibitors of other PDEases (cGMP-specific PDEase, cGMP-inhibited PDEase) had little or no effect on the hPDE-1 recombinant gene product.« less

Hybrid approaches for multiple-species stochastic reaction–diffusion models

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

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

2015-10-15

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

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

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

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

2009-01-01

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

Roles of A-Kinase Anchoring Proteins and Phosphodiesterases in the Cardiovascular System

PubMed Central

Ercu, Maria; Klussmann, Enno

2018-01-01

A-kinase anchoring proteins (AKAPs) and cyclic nucleotide phosphodiesterases (PDEs) are essential enzymes in the cyclic adenosine 3′-5′ monophosphate (cAMP) signaling cascade. They establish local cAMP pools by controlling the intensity, duration and compartmentalization of cyclic nucleotide-dependent signaling. Various members of the AKAP and PDE families are expressed in the cardiovascular system and direct important processes maintaining homeostatic functioning of the heart and vasculature, e.g., the endothelial barrier function and excitation-contraction coupling. Dysregulation of AKAP and PDE function is associated with pathophysiological conditions in the cardiovascular system including heart failure, hypertension and atherosclerosis. A number of diseases, including autosomal dominant hypertension with brachydactyly (HTNB) and type I long-QT syndrome (LQT1), result from mutations in genes encoding for distinct members of the two classes of enzymes. This review provides an overview over the AKAPs and PDEs relevant for cAMP compartmentalization in the heart and vasculature and discusses their pathophysiological role as well as highlights the potential benefits of targeting these proteins and their protein-protein interactions for the treatment of cardiovascular diseases. PMID:29461511

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.

Comparison of phosphodiesterase 10A, dopamine receptors D1 and D2 and dopamine transporter ligand binding in the striatum of the R6/2 and BACHD mouse models of Huntington's disease.

PubMed

Miller, Silke; Hill Della Puppa, Geraldine; Reidling, Jack; Marcora, Edoardo; Thompson, Leslie M; Treanor, James

2014-01-01

Phosphodiesterase 10A (PDE10A) is expressed at high levels in the striatum and has been proposed both as a biomarker for Huntington's disease pathology and as a target for intervention. PDE10A radiotracers have been successfully used to measure changes in binding density in Huntington's disease patients, but little is known about PDE10A binding in mouse models that are used extensively to model pathology and test therapeutic interventions. Our study investigated changes in PDE10A binding using the selective tracer 3H-7980 at specific ages of two Huntington's disease transgenic mouse models: R6/2, a short-lived model carrying exon-1 of mutant HTT and BACHD, a longer-lived model carrying full-length mutant HTT. PDE10A binding was compared to binding of known markers of striatal atrophy in Huntington's disease, e.g. dopamine transporter (DAT) and dopamine receptors D1 and D2. We found that in the R6/2 model at 6 weeks of age, mice showed high variability of binding, however binding of all ligands was significantly decreased at 8 and 12 weeks of age. In contrast, no changes were detectable in the BACHD model at 8, 10 or 12 month of age. These findings suggest that radiotracer binding of PDE10A, DAT, D1 and D2 receptor in the R6/2 model may be a good indicator of striatal pathological changes that are observed in Huntington's disease patients, and that the first 12 months in the BACHD model may be more reflective of early stages of the disease.

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

Hand drawing of pencil electrodes on paper platforms for contactless conductivity detection of inorganic cations in human tear samples using electrophoresis chips.

PubMed

Chagas, Cyro L S; Costa Duarte, Lucas; Lobo-Júnior, Eulício O; Piccin, Evandro; Dossi, Nicolò; Coltro, Wendell K T

2015-08-01

This paper describes for the first time the fabrication of pencil drawn electrodes (PDE) on paper platforms for capacitively coupled contactless conductivity detection (C(4) D) on electrophoresis microchips. PDE-C(4) D devices were attached on PMMA electrophoresis chips and used for detection of K(+) and Na(+) in human tear samples. PDE-C(4) D devices were produced on office paper and chromatographic paper platforms and their performance were thoroughly investigated using a model mixture containing K(+) , Na(+) , and Li(+) . In comparison with chromatographic paper, PDE-C(4) D fabricated on office paper has exhibited better performance due to its higher electrical conductivity. Furthermore, the detector response was similar to that recorded with electrodes prepared with copper adhesive tape. The fabrication of PDE-C(4) D on office paper has offered great advantages including extremely low cost (< $ 0.004 per unit), reduced fabrication time (< 5 min), and minimal instrumentation (pencil and paper). The proposed electrodes demonstrated excellent analytical performance with good reproducibility. For an inter-PDE comparison (n = 7), the RSD values for migration time, peak area, and separation efficiency were lower than 2.5, 10.5, and 14%, respectively. The LOD's achieved for K(+) , Na(+) , and Li(+) were 4.9, 6.8, and 9.0 μM, respectively. The clinical feasibility of the proposed approach was successfully demonstrated with the quantitative analysis of K(+) and Na(+) in tear samples. The concentration levels found for K(+) and Na(+) were, respectively, 20.8 ± 0.1 mM and 101.2 ± 0.1 mM for sample #1, and 20.4 ± 0.1 mM and 111.4 ± 0.1 mM for sample #2. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Synergistic effect between 5-HT4 receptor agonist and phosphodiesterase 4-inhibitor in releasing acetylcholine in pig gastric circular muscle in vitro.

PubMed

Lefebvre, Romain A; Van Colen, Inge; Pauwelyn, Vicky; De Maeyer, Joris H

2016-06-15

5-HT4 receptor agonists have a gastroprokinetic effect by facilitating acetylcholine release from cholinergic nerves innervating gastrointestinal smooth muscle. The role of phosphodiesterase (PDE) 4 in the signal transduction pathway of the 5-HT4 receptors located on the cholinergic neurons towards the circular muscle layer in pig stomach was investigated by analysis of acetylcholine release. Circular muscle strips were prepared from pig proximal stomach and tritium outflow, induced by electrical field stimulation, was studied as a marker for acetylcholine release after incubation with [(3)H]-choline. The PDE4-inhibitor roflumilast concentration-dependently (0.1-1µM) enhanced the facilitating effect of a submaximally effective concentration of the 5-HT4 receptor agonist prucalopride (0.01µM) on electrically induced acetylcholine release. Roflumilast (0.3µM) enhanced acetylcholine release per se but in the combined presence of roflumilast and prucalopride, acetylcholine release was enhanced more than the sum of the effect of the 2 compounds alone. The 5-HT4 receptor agonist velusetrag concentration-dependently (0.01-0.1µM) enhanced acetylcholine release; the effect of the minimally effective concentration (0.01µM) was significantly enhanced by 1µM of the PDE4-inhibitor rolipram, again to a level higher than the sum of the effect of the 2 compounds alone. The synergistic effect between 5-HT4 receptor agonists and PDE4-inhibitors demonstrates that the intracellular pathway of the 5-HT4 receptors located on cholinergic neurons towards pig gastric circular muscle is controlled by PDE4. Combining a 5-HT4 receptor agonist with a PDE4-inhibitor might thus enhance its gastroprokinetic effect. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

Cardiac Hypertrophy Is Inhibited by a Local Pool of cAMP Regulated by Phosphodiesterase 2.

PubMed

Zoccarato, Anna; Surdo, Nicoletta C; Aronsen, Jan M; Fields, Laura A; Mancuso, Luisa; Dodoni, Giuliano; Stangherlin, Alessandra; Livie, Craig; Jiang, He; Sin, Yuan Yan; Gesellchen, Frank; Terrin, Anna; Baillie, George S; Nicklin, Stuart A; Graham, Delyth; Szabo-Fresnais, Nicolas; Krall, Judith; Vandeput, Fabrice; Movsesian, Matthew; Furlan, Leonardo; Corsetti, Veronica; Hamilton, Graham; Lefkimmiatis, Konstantinos; Sjaastad, Ivar; Zaccolo, Manuela

2015-09-25

Chronic elevation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodeling and cardiac hypertrophy. However, enhancement of particular aspects of cAMP/protein kinase A signaling seems to be beneficial for the failing heart. cAMP is a pleiotropic second messenger with the ability to generate multiple functional outcomes in response to different extracellular stimuli with strict fidelity, a feature that relies on the spatial segregation of the cAMP pathway components in signaling microdomains. How individual cAMP microdomains affect cardiac pathophysiology remains largely to be established. The cAMP-degrading enzymes phosphodiesterases (PDEs) play a key role in shaping local changes in cAMP. Here we investigated the effect of specific inhibition of selected PDEs on cardiac myocyte hypertrophic growth. Using pharmacological and genetic manipulation of PDE activity, we found that the rise in cAMP resulting from inhibition of PDE3 and PDE4 induces hypertrophy, whereas increasing cAMP levels via PDE2 inhibition is antihypertrophic. By real-time imaging of cAMP levels in intact myocytes and selective displacement of protein kinase A isoforms, we demonstrate that the antihypertrophic effect of PDE2 inhibition involves the generation of a local pool of cAMP and activation of a protein kinase A type II subset, leading to phosphorylation of the nuclear factor of activated T cells. Different cAMP pools have opposing effects on cardiac myocyte cell size. PDE2 emerges as a novel key regulator of cardiac hypertrophy in vitro and in vivo, and its inhibition may have therapeutic applications. © 2015 American Heart Association, 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.

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.

Synthetic phosphodiesterase-5-inhibitors use/abuse and interest of hair testing: reporting of a rape case.

PubMed

Duez, Mathieu; Etter, Matthieu; Klinger, Nadine; Cirimele, Vincent

2014-06-01

If classic phosphodiesterase-5 (PDE-5) inhibitors are well known, new synthetic PDE-5 analogues are of more recent introduction. Some of them have already been tested in dietary supplements. We describe here a rape case following the consumption of pills bought on the Internet and containing new synthetic PDE-5 inhibitors. The assailant declared that he lost control after ingesting these pills for the first time. Analyses of conventional matrices (blood, urine) don't allow us to highlight the intake of any substances in relation to this offence due to late sampling (5 days after the offence). Therefore, we have developed an analytical approach to test for PDE-5 inhibitors in hair including the two new synthetic PDE-5 inhibitors analogues - thiosildenafil and hydroxythiohomosildenafil - previously identified in the pills. This new method was validated and applied to the hair samples of the victim and the suspect. Analyses were conducted using a liquid/liquid extraction followed by liquid chromatography coupled with a mass spectrometer in multiple reaction monitoring mode detection. The 2-centimetre proximal hair section of the suspect revealed the presence of thiosildenafil (48 pg/mg), hydroxythiohomosildenafil (24 pg/mg), and sildenafil (7.5 pg/mg). To our knowledge, it is the first time that these two new synthetic PDE-5 inhibitors were detected in biological samples and especially in hair. Complementary investigations showed that a single pill taken by a volunteer provided similar levels in thiosildenafil (35 pg/mg), hydroxythiohomosildenafil (17 pg/mg), and sildenafil (8 pg/mg) to those found in the previous case described here. Copyright © 2014 John Wiley & Sons, Ltd.

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.

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

PubMed

Wong, Kin-Yiu; Gao, Jiali

2011-07-01

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

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 less than two minutes of measurement time is, in principle, sufficient to determine the dimensionless mixing free energy of a non-associating ternary mixture to within an integrated error norm of 0.003. These findings establish a quantitative framework for designing light scattering experiments to determine the Gibbs free energy of ternary liquid mixtures. PMID:22830693

Toward Understanding Business Student Professional Development Engagement

ERIC Educational Resources Information Center

Blau, Gary; Blessley, Misty; Kunkle, Matthew; Schirmer, Michael; Regan, Laureen

2017-01-01

Professional development engagement (PDE) is defined as the level of perceived undergraduate engagement in professional development activities. An 11-item measure of PDE exhibited a good reliability. Using a complete data sample of 467 graduating business undergraduates, four variable sets (student background or precollege variables,…

Approaches to Cycle Analysis and Performance Metrics

NASA Technical Reports Server (NTRS)

Parson, Daniel E.

2003-01-01

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

Genetic Variants Associated with Serum Thyroid Stimulating Hormone (TSH) Levels in European Americans and African Americans from the eMERGE Network

PubMed Central

Malinowski, Jennifer R.; Denny, Joshua C.; Bielinski, Suzette J.; Basford, Melissa A.; Bradford, Yuki; Peissig, Peggy L.; Carrell, David; Crosslin, David R.; Pathak, Jyotishman; Rasmussen, Luke; Pacheco, Jennifer; Kho, Abel; Newton, Katherine M.; Li, Rongling; Kullo, Iftikhar J.; Chute, Christopher G.; Chisholm, Rex L.; Jarvik, Gail P.; Larson, Eric B.; McCarty, Catherine A.; Masys, Daniel R.; Roden, Dan M.; de Andrade, Mariza; Ritchie, Marylyn D.; Crawford, Dana C.

2014-01-01

Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10−17, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10−6, β = −0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = −0.09), VEGFA (rs11755845 p = 0.01, β = −0.13), and NFIA (rs334699 p = 1.50×10−3, β = −0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations. PMID:25436638

Genetic variants associated with serum thyroid stimulating hormone (TSH) levels in European Americans and African Americans from the eMERGE Network.

PubMed

Malinowski, Jennifer R; Denny, Joshua C; Bielinski, Suzette J; Basford, Melissa A; Bradford, Yuki; Peissig, Peggy L; Carrell, David; Crosslin, David R; Pathak, Jyotishman; Rasmussen, Luke; Pacheco, Jennifer; Kho, Abel; Newton, Katherine M; Li, Rongling; Kullo, Iftikhar J; Chute, Christopher G; Chisholm, Rex L; Jarvik, Gail P; Larson, Eric B; McCarty, Catherine A; Masys, Daniel R; Roden, Dan M; de Andrade, Mariza; Ritchie, Marylyn D; Crawford, Dana C

2014-01-01

Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10-17, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10-6, β = -0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = -0.09), VEGFA (rs11755845 p = 0.01, β = -0.13), and NFIA (rs334699 p = 1.50×10-3, β = -0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations.

Systematic Review and Meta-Analysis of the Use of Phosphodiesterase Type 5 Inhibitors for Treatment of Erectile Dysfunction following Bilateral Nerve-Sparing Radical Prostatectomy

PubMed Central

Wang, Xiao; Wang, Xinghuan; Liu, Tao; He, Qianwen; Wang, Yipeng; Zhang, Xinhua

2014-01-01

Prostate cancer is relatively common cancer occurring in males. Radical prostatectomy (RP) is the most effective treatment for a localized tumor but erectile dysfunction (ED) is common complication, even when bilateral nerve-sparing RP (BNSRP) is performed. Clinical trials have shown varied effectiveness of phosphodiesterase type-5 inhibitors (PDE5-Is) for treatment of post-BNSRP ED, but there remains controversy over the application of this treatment and no formal systematic review and meta-analysis for the use of PDE5-Is for this condition has been conducted. This review was to systematically assess the efficacy and safety of oral PDE5-Is for post-BNSRP ED. A database search was conducted to identify randomized controlled trials (RCTs). The comparative efficacy of treatments was analyzed by fixed or random effect modeling. Erectile function was measured using the International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP) question-2, 3 and the Global Assessment Question (GAQ). The rate and incidence of adverse events (AEs) were determined. The quality of included studies was appraised using the Cochrane Collaboration bias appraisal tool. Eight RCTs were included in the analyses. PDE5-Is were effective for treating post-BNSRP ED compared to placebo when erectile function was determined using the IIEF score [mean difference (MD) 5.63, 95% confidence interval (CI) (4.26–6.99)], SEP-2 [relative risk (RR) 1.63, 95% CI (1.18–2.25) ], SEP-3 [RR 2.00, 95% CI (1.27–3.15) ] and GAQ [RR 3.35, 95% CI (2.68–4.67) ]. The subgroup analysis could find a trend that longer treatment duration, higher dosage, on-demand dosing, sildenafil and mild ED are associated with more responsiveness to PDE5-Is. PDE5-Is were overall well tolerated with headache being the most commonly reported AE. Our data provides compelling evidence for the use of PDE5-Is as a primary treatment for post-BNSRP ED. However, further studies are required to optomize usage parameters (such as dosage and duration of treatment). PMID:24618671

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 and Research, Inc. Published by Elsevier Inc. All rights reserved.

Course-, dose-, and stage-dependent toxic effects of prenatal dexamethasone exposure on fetal articular cartilage development.

PubMed

Chen, Ze; Zhao, Zhe; Li, Yunzepeng; Zhang, Xingyu; Li, Bin; Chen, Liaobin; Wang, Hui

2018-04-01

Dexamethasone, a synthetic long-acting glucocorticoid, is routinely used for treating mothers at risk for preterm delivery. However, intrauterine overexposure to glucocorticoids induces low birth weight and cartilage dysplasia in offspring. Also, the "critical window" and safe dose of this treatment are largely unknown. This study investigated the course-, dose-, and stage-dependent toxic effects and the possible mechanisms of prenatal dexamethasone exposure (PDE) on fetal development and articular cartilage development. Pregnant mice (C57BL/6) received subcutaneous injection of dexamethasone (0.8 mg/kg d) once on gestational day (GD) 15 or once a day from GD 15 to 17, or received various doses of dexamethasone (0, 0.2, 0.8, and 1.2 mg/kg d) on GD 15-17, or received dexamethasone (0.8 mg/kg d) at early stage (GD 12-14) or late stage of pregnancy (GD 15-17). Offspring's knee joints were harvested at birth for morphological analyses and detection of gene expression. Repeated PDE significantly suppressed fetal and articular cartilage development, which were characterized by decreased body weight and body length, coarse articular cartilage surfaces, and reduced gene and protein expression of Col2a1 and aggrecan. For those newborns treated with repeated PDE at different doses, the toxic effects on fetal and articular cartilage development were observed at doses of 0.8 and 1.2 mg/kg d, whereas no obvious toxic effects were observed at the dose of 0.2 mg/kg d. Moreover, PDE at 0.8 mg/kg d during the early embryonic stage induced stronger toxic effects on fetal and articular cartilage development, compared with PDE during the late embryonic stage. Detection of gene expression showed that the TGFβ signaling pathway in the articular cartilage was down-regulated after PDE. Taken together, PDE induces fetal developmental toxicity and articular cartilage developmental toxicity in a course-, dose-, and stage-dependent manner. Copyright © 2018 Elsevier B.V. All rights reserved.

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.

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 its comorbidities and increasing response rates to PDE5 inhibitors.

The U.S. Army Person-Event Data Environment: A Military-Civilian Big Data Enterprise.

PubMed

Vie, Loryana L; Scheier, Lawrence M; Lester, Paul B; Ho, Tiffany E; Labarthe, Darwin R; Seligman, Martin E P

2015-06-01

This report describes a groundbreaking military-civilian collaboration that benefits from an Army and Department of Defense (DoD) big data business intelligence platform called the Person-Event Data Environment (PDE). The PDE is a consolidated data repository that contains unclassified but sensitive manpower, training, financial, health, and medical records covering U.S. Army personnel (Active Duty, Reserve, and National Guard), civilian contractors, and military dependents. These unique data assets provide a veridical timeline capturing each soldier's military experience from entry to separation from the armed forces. The PDE was designed to afford unprecedented cost-efficiencies by bringing researchers and military scientists to a single computerized repository rather than porting vast data resources to individual laboratories. With funding from the Robert Wood Johnson Foundation, researchers from the University of Pennsylvania Positive Psychology Center joined forces with the U.S. Army Research Facilitation Laboratory, forming the scientific backbone of the military-civilian collaboration. This unparalleled opportunity was necessitated by a growing need to learn more about relations between psychological and health assets and health outcomes, including healthcare utilization and costs-issues of major importance for both military and civilian population health. The PDE represents more than 100 times the population size and many times the number of linked variables covered by the nation's leading sources of population health data (e.g., the National Health and Nutrition Examination Survey). Following extensive Army vetting procedures, civilian researchers can mine the PDE's trove of information using a suite of statistical packages made available in a Citrix Virtual Desktop. A SharePoint collaboration and governance management environment ensures user compliance with federal and DoD regulations concerning human subjects' protections and also provides a secure portal for multisite collaborations. Taking similarities and differences between military and civilian populations into account, PDE studies can provide much more detailed insight into health-related questions of broad societal concern. Finding ways to make the rich repository of digitized information in the PDE available through military-civilian collaboration can help solve critical medical and behavioral issues affecting the health and well-being of our nations' military and civilian populations.

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

NASA Astrophysics Data System (ADS)

Taranets, R.; Chugunova, M.

2018-03-01

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

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.

Adaptive wavelet collocation methods for initial value boundary problems of nonlinear PDE's

NASA Technical Reports Server (NTRS)

Cai, Wei; Wang, Jian-Zhong

1993-01-01

We have designed a cubic spline wavelet decomposition for the Sobolev space H(sup 2)(sub 0)(I) where I is a bounded interval. Based on a special 'point-wise orthogonality' of the wavelet basis functions, a fast Discrete Wavelet Transform (DWT) is constructed. This DWT transform will map discrete samples of a function to its wavelet expansion coefficients in O(N log N) operations. Using this transform, we propose a collocation method for the initial value boundary problem of nonlinear PDE's. Then, we test the efficiency of the DWT transform and apply the collocation method to solve linear and nonlinear PDE's.

A LAGRANGIAN GAUSS-NEWTON-KRYLOV SOLVER FOR MASS- AND INTENSITY-PRESERVING DIFFEOMORPHIC IMAGE REGISTRATION.

PubMed

Mang, Andreas; Ruthotto, Lars

2017-01-01

We present an efficient solver for diffeomorphic image registration problems in the framework of Large Deformations Diffeomorphic Metric Mappings (LDDMM). We use an optimal control formulation, in which the velocity field of a hyperbolic PDE needs to be found such that the distance between the final state of the system (the transformed/transported template image) and the observation (the reference image) is minimized. Our solver supports both stationary and non-stationary (i.e., transient or time-dependent) velocity fields. As transformation models, we consider both the transport equation (assuming intensities are preserved during the deformation) and the continuity equation (assuming mass-preservation). We consider the reduced form of the optimal control problem and solve the resulting unconstrained optimization problem using a discretize-then-optimize approach. A key contribution is the elimination of the PDE constraint using a Lagrangian hyperbolic PDE solver. Lagrangian methods rely on the concept of characteristic curves. We approximate these curves using a fourth-order Runge-Kutta method. We also present an efficient algorithm for computing the derivatives of the final state of the system with respect to the velocity field. This allows us to use fast Gauss-Newton based methods. We present quickly converging iterative linear solvers using spectral preconditioners that render the overall optimization efficient and scalable. Our method is embedded into the image registration framework FAIR and, thus, supports the most commonly used similarity measures and regularization functionals. We demonstrate the potential of our new approach using several synthetic and real world test problems with up to 14.7 million degrees of freedom.

Therapeutic pipeline for atopic dermatitis: End of the drought?

PubMed

Paller, Amy S; Kabashima, Kenji; Bieber, Thomas

2017-09-01

Until the past year, our therapeutic armamentarium for treating atopic dermatitis (AD) was still primarily topical corticosteroids and, for more severe disease, systemic immunosuppressants. The pipeline of more targeted topical and systemic therapies is expanding based on our growing understanding of the mechanism for AD and is particularly focused on suppressing the skewed immune activation. Most agents are in phase 2 clinical trials. Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, became available in late 2016 in the United States for mild-to-moderate AD, with other PDE4 inhibitors, an agonist of the aryl hydrocarbon receptor, Janus kinase inhibitors, and commensal organisms also in trials for topical application. The first highly effective mAb for AD, dupilumab, targets the IL-4/IL-13 receptor and was approved in early 2017 in the United States for moderate-to-severe adult AD. Other biologics similarly inhibit T H 2 cytokines (thymic stromal lymphopoietin, IL-4, IL-5, IL-13, and the itch-specific cytokine IL-31 and their receptors) or T H 22/T H 17 cytokines, levels of which are increased in lesional skin. Orally administered small-molecule inhibitors that suppress inflammation (targeting chemoattractant receptor-homologous molecules expressed on T H 2 lymphocytes, PDE4, the histamine 4 receptor, and Janus kinase) or specifically itching (eg, NK1R inhibitors) are also being studied. Comparing biomarkers with individual responses to experimental agents will help to determine subphenotypes within AD that predict prognosis and treatment responses. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Fully integrated free-running InGaAs/InP single-photon detector for accurate lidar applications.

PubMed

Yu, Chao; Shangguan, Mingjia; Xia, Haiyun; Zhang, Jun; Dou, Xiankang; Pan, Jian-Wei

2017-06-26

We present a fully integrated InGaAs/InP negative feedback avalanche diode (NFAD) based free-running single-photon detector (SPD) designed for accurate lidar applications. A free-piston Stirling cooler is used to cool down the NFAD with a large temperature range, and an active hold-off circuit implemented in a field programmable gate array is applied to further suppress the afterpulsing contribution. The key parameters of the free-running SPD including photon detection efficiency (PDE), dark count rate (DCR), afterpulse probability, and maximum count rate (MCR) are dedicatedly optimized for lidar application in practice. We then perform a field experiment using a Mie lidar system with 20 kHz pulse repetition frequency to compare the performance between the free-running InGaAs/InP SPD and a commercial superconducting nanowire single-photon detector (SNSPD). Our detector exhibits good performance with 1.6 Mcps MCR (0.6 μs hold-off time), 10% PDE, 950 cps DCR, and 18% afterpulse probability over 50 μs period. Such performance is worse than the SNSPD with 60% PDE and 300 cps DCR. However, after performing a specific algorithm that we have developed for afterpulse and count rate corrections, the lidar system performance in terms of range-corrected signal (Pr 2 ) distribution using our SPD agrees very well with the result using the SNSPD, with only a relative error of ∼2%. Due to the advantages of low-cost and small size of InGaAs/InP NFADs, such detector provides a practical solution for accurate lidar applications.

Influence of the PDE5 inhibitor tadalafil on redox status and antioxidant defense system in C2C12 skeletal muscle cells.

PubMed

Duranti, Guglielmo; Ceci, Roberta; Sgrò, Paolo; Sabatini, Stefania; Di Luigi, Luigi

2017-05-01

Phosphodiesterase type 5 inhibitors (PDE5Is), widely known for their beneficial effects onto male erectile dysfunction, seem to exert favorable effects onto metabolism as well. Tadalafil exposure increases oxidative metabolism of C2C12 skeletal muscle cells. A rise in fatty acid (FA) metabolism, requiring more oxygen, could induce a larger reactive oxygen species (ROS) release as a byproduct thus leading to a redox imbalance. The aim of this study was to determine how PDE5I tadalafil influences redox status in skeletal muscle cells to match the increasing oxidative metabolism. To this purpose, differentiated C2C12 skeletal muscle cells were treated with tadalafil and analyzed for total antioxidant capacity (TAC) and glutathione levels as marker of redox status; enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) engaged in antioxidant defense; and lipid peroxidation (TBARS) and protein carbonyls (PrCar) as markers of oxidative damage. Tadalafil increased total intracellular glutathione (tGSH), CAT, SOD, and GPx enzymatic activities while no changes were found in TAC. A perturbation of redox status, as showed by the decrease in the ratio between reduced/oxidized glutathione (GSH/GSSG), was observed. Nevertheless, it did not cause any change in TBARS and PrCar levels probably due to the enhancement in the antioxidant enzymatic network. Taken together, these data indicate that tadalafil, besides improving oxidative metabolism, may be beneficial to skeletal muscle cells by enhancing the enzymatic antioxidant system capacity.

Making Strides with Educational Data

ERIC Educational Resources Information Center

Golden, Michael

2005-01-01

The Pennsylvania Department of Education (PDE) is working with local education agencies throughout the Commonwealth to create a culture of teaching and learning in every school that is student-centered, data-informed, personalized, and results-focused. Each of these elements have been supported seamlessly by systems, resources, technology, and…

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

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.

A study of the management of erectile dysfunction in general practice.

PubMed

Griffiths, L; Bush, N; Mottram, D; Armstrong, D

2005-06-01

The Department of Health issued guidelines for the NHS treatment of erectile dysfunction (ED) with phosphodiesterase type 5 inhibitors (PDE 5 inhibitors) in 1999. There has been an increasing trend in the prescribing of PDE 5 inhibitors within Bebington and West Wirral Primary Care Trust (PCT) over the 3-year period from February 2001 to January 2004. The objective of the study was to investigate implementation of Government guidelines on prescribing of PDE 5 inhibitors for ED and the cost of prescribing outside these guidelines. Practice data were collected for all patients prescribed a PDE 5 inhibitor in 16 surgeries within Bebington and West Wirral Primary Care Trust, from November 2002 to December 2003. The data were evaluated with respect to adherence to UK Government guidelines. Analysis was made on the cost to the PCT with respect to treatment provided outside the guidelines. Prescribing for 78% of patients was within Government guidelines. With respect to frequency of prescribing, 89% of patients in the PCT received less than or equal to the recommended frequency of one tablet per week. The percentage range for practices was 67-100%. The cost to the PCT for PDE 5 inhibitor treatment provided outside the guidelines was 19,060 pounds sterling over the period of study. Prescribers generally follow Government guidelines, however, stricter adherence to guidelines could result in more efficient use of National Health Service resources.

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

A Hydrocarbon Fuel Flash Vaporization System for a Pulsed Detonation Engine

DTIC Science & Technology

2006-12-01

Experiments were performed in the Air Force Research Laboratory (AFRL) Pulsed Detonation Research Facility at Wright Patterson AFB, Ohio. The PDE ...AFRL-MN-EG-TP-2006-7420 A HYDROCARBON FUEL FLASH VAPORIZATION SYSTEM FOR A PULSED DETONATION ENGINE (PREPRINT) K. Colin Tucker...85,7<&/$66,),&$7,212) E7(/(3+21(180%(5 ,QFOXGHDUHDFRGH A Hydrocarbon Fuel Flash Vaporization System for a Pulsed Detonation Engine K

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

NASA Technical Reports Server (NTRS)

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

1999-01-01

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

Further Research on an Undergraduate Measure of Professional Development Engagement

ERIC Educational Resources Information Center

Blau, Gary; Pred, Robert; Andersson, Lynne; Lopez, Andrea B.

2015-01-01

Professional Development Engagement (PDE) refers to the level of undergraduate engagement in professional development. Professional Development (PD) involves activities designed to help students prepare for a successful college-to-work transition. This study tested a new 12-item measure of PDE for a complete-data sample of 246 undergraduate…

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…

Airbreathing Pulse Detonation Engine Performance

NASA Technical Reports Server (NTRS)

Povinelli, Louis A.; Yungster, Shaye

2002-01-01

This paper presents performance results for pulse detonation engines taking into account the effects of dissociation and recombination. The amount of sensible heat recovered through recombination in the PDE chamber and exhaust process was found to be significant. These results have an impact on the specific thrust, impulse and fuel consumption of the PDE.

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

Mechanism of tissue-selective drug action in the cardiovascular system.

PubMed

Barrett, Terrance D; Triggle, David J; Walker, Michael J A; Maurice, Donald H

2005-04-01

Analysis of the human genome project tells us that there may be as few as 3000 genes that are likely to be good drug targets. Although the number of targets is still very large, these data have been interpreted by some to mean that the pharmaceutical industry may someday run out of novel drug targets. Despite the doom and gloom of such analysis, there is considerable reason for optimism. Drugs may exhibit selectivity of action beyond that predicted by target expression alone. Drugs that act at a single molecular target may have very different pharmacology and, as a result, different therapeutic uses. Three well-characterized model systems are highlighted to illustrate this point. The first model system is exemplified by nifedipine and verapamil, both of which act on L-type calcium channels. Both drugs are used to treat hypertension, but only verapamil can be used to produce atrioventricular block in patients with atrial fibrillation. The second model system describes the therapeutic exploitation of unusual conditions that occur in the ischemic myocardium to produce drugs that are more effective for suppressing ischemia-induced arrhythmias. The third model system discusses the mechanisms through which phosphodiesterase-5 (PDE5) inhibitors act selectively to facilitate penile erection while having little effect in the non-penile vasculature that also expresses PDE5.

Characterization of antilipolytic action of polyamines in isolated rat adipocytes.

PubMed Central

Richelsen, B; Pedersen, S B; Hougaard, D M

1989-01-01

The interactions of polyamines with the lipolytic system were studied in isolated rat adipocytes. Spermine, spermidine and putrescine significantly inhibited adenosine deaminase-stimulated lipolysis. An antilipolytic effect of spermine was detectable at a concentration of 0.25 mM (P less than 0.05). At a concentration of 10 mM all three polyamines inhibited the stimulated lipolysis by 50-60% (P less than 0.001). In addition, spermine enhanced the antilipolytic sensitivity of insulin. Spermine (1 mM) decreased the half-maximal inhibitory concentration of insulin from 320 +/- 70 pM to 56 +/- 20 pM (P less than 0.01). The antilipolytic effects and the cyclic-AMP-lowering effects of the polyamines were almost completely prevented in the presence of different phosphodiesterase (PDE) inhibitors (3-isobutyl-1-methylxanthine and RO 20-1724) and, in addition, polyamines had no effect on lipolysis stimulated by dibutyryl cyclic AMP, indicating that polyamines may inhibit lipolysis by activating the PDE enzyme. This latter suggestion was confirmed by demonstrating that spermine (5 mM) significantly enhanced the low-Km PDE enzyme activity (P less than 0.01). Finally, the amounts of polyamines present in isolated adipocytes were measured, and the estimated cytoplasmic concentrations were 0.02 mM (putrescine), 0.86 mM (spermidine), and 1.0 mM (spermine). It is concluded that polyamines may possibly be involved in the physiological regulation of triacylglycerol mobilization in adipocytes. PMID:2476118

Possible Overlapping Time Frames of Acquisition and Consolidation Phases in Object Memory Processes: A Pharmacological Approach

ERIC Educational Resources Information Center

Akkerman, Sven; Blokland, Arjan; Prickaerts, Jos

2016-01-01

In previous studies, we have shown that acetylcholinesterase inhibitors and phosphodiesterase inhibitors (PDE-Is) are able to improve object memory by enhancing acquisition processes. On the other hand, only PDE-Is improve consolidation processes. Here we show that the cholinesterase inhibitor donepezil also improves memory performance when…

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

Pharmacological validation of Trypanosoma brucei phosphodiesterases B1 and B2 as druggable targets for African sleeping sickness.

PubMed

Bland, Nicholas D; Wang, Cuihua; Tallman, Craig; Gustafson, Alden E; Wang, Zhouxi; Ashton, Trent D; Ochiana, Stefan O; McAllister, Gregory; Cotter, Kristina; Fang, Anna P; Gechijian, Lara; Garceau, Norman; Gangurde, Rajiv; Ortenberg, Ron; Ondrechen, Mary Jo; Campbell, Robert K; Pollastri, Michael P

2011-12-08

Neglected tropical disease drug discovery requires application of pragmatic and efficient methods for development of new therapeutic agents. In this report, we describe our target repurposing efforts for the essential phosphodiesterase (PDE) enzymes TbrPDEB1 and TbrPDEB2 of Trypanosoma brucei , the causative agent for human African trypanosomiasis (HAT). We describe protein expression and purification, assay development, and benchmark screening of a collection of 20 established human PDE inhibitors. We disclose that the human PDE4 inhibitor piclamilast, and some of its analogues, show modest inhibition of TbrPDEB1 and B2 and quickly kill the bloodstream form of the subspecies T. brucei brucei . We also report the development of a homology model of TbrPDEB1 that is useful for understanding the compound-enzyme interactions and for comparing the parasitic and human enzymes. Our profiling and early medicinal chemistry results strongly suggest that human PDE4 chemotypes represent a better starting point for optimization of TbrPDEB inhibitors than those that target any other human PDEs.

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, solutions of the PDE converge strongly to weak solutions of the inviscid Burgers equation. We provide numerical evidence that this limit satisfies an entropy inequality for the inviscid Burgers equation. We demonstrate a Hamiltonian structure for the PDE.

Studies on the cardiac actions of flosequinan in vitro.

PubMed Central

Gristwood, R. W.; Beleta, J.; Bou, J.; Cardelús, I.; Fernández, A. G.; Llenas, J.; Berga, P.

1992-01-01

1. We have investigated the in vitro cardiac actions of flosequinan and of its major metabolite in man, BTS 53554. 2. Positive inotropic activity was seen with flosequinan in guinea-pig isolated ventricles, the threshold concentration for effect being less than 1 x 10(-5) M. BTS 53554 was approximately half as potent as the parent compound. 3. In guinea-pig working whole hearts flosequinan increased left ventricular dp/dtmax, indicating a positive inotropic action. This effect was accompanied by increases in heart rate, cardiac output and stroke volume. 4. The virtual complete inhibition of inotropic responses to flosequinan and BTS 53554 by carbachol suggests that these responses are adenosine 3':5'-cyclic monophosphate (cyclic AMP)-mediated. 5. Flosequinan was shown to increase calcium inward current in guinea-pig ventricle, an action consistent with a cyclic AMP involvement in the response. 6. The inotropic activity of flosequinan was not potentiated by the selective phosphodiesterase (PDE) III inhibitor SK&F 94120, a result which indicates that flosequinan does not increase cyclic AMP concentrations via stimulation of adenylate cyclase. 7. Flosequinan inotropic responses were potentiated by rolipram, a selective PDE IV inhibitor, a result consistent with flosequinan being itself a PDE III inhibitor. 8. Biochemical studies with purified enzymes confirmed that flosequinan and BTS 53554 are relatively selective inhibitors of PDE III. 9. A comparison of pharmacological and biochemical data for both flosequinan and BTS 53554 indicates that their PDE III inhibitory potency is sufficient to account for their inotropic activity. PMID:1324061

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

PubMed

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

2013-08-30

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

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

PubMed

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

2012-05-01

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

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.

Light adaption of the cyclic GMP phosphodiesterase of frog photoreceptor membranes mediated by ATP and calcium ions

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

Kawamura, S.; Bownds, M.D.

1981-05-01

The light-activated guanosine 3',5'-cyclic monophosphate (cyclic GMP) phosphodiesterase (PDE) of frog photoreceptor membranes has been assayed by measuring the evolution of protons that accompanies cyclic GMP hydrolysis. The validity of this assay has been confirmed by comparison with an isotope assay used in previous studies (Robinson et al. 1980. J. Gen. Physiol. 76: 631-645). The PDE activity elicited by either flash or continuous dim illumination is reduced if ATP is added to outer segment suspensions. This desensitization is most pronounced at low calcium levels. In 10(-9) M Ca/sup + +/, with 0.5 mM ATP and 0.5 mM GTP present, PDEmore » activity remains almost constant as dim illumination and rhodopsin bleaching continue. At intermediate Ca/sup + +/ levels (10-7-10-5M) the activity slowly increases during illumination. Finally, in 10(-4) and PDE activity is more a reflection of the total number of rhodopsin molecules bleached than of the rate of the rhodopsin bleaching. At intermediate or low calcium levels a short-lived inhibitory process is revealed by observing a nonlinear summation of responses of the enzyme to closely spaced flashes of light. Each flash makes PDE activity less responsive to successive flashes, and a steady state is obtained in which activation and inactivation are balanced. It is suggested that calcium and ATP regulation of PDE play a role in the normal light adaption processes of frog photoreceptor membranes.« 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.

In silico ordinary differential equation/partial differential equation hemodialysis model estimates methadone removal during dialysis.

PubMed

Linares, Oscar A; Schiesser, William E; Fudin, Jeffrey; Pham, Thien C; Bettinger, Jeffrey J; Mathew, Roy O; Daly, Annemarie L

2015-01-01

There is a need to have a model to study methadone's losses during hemodialysis to provide informed methadone dose recommendations for the practitioner. To build a one-dimensional (1-D), hollow-fiber geometry, ordinary differential equation (ODE) and partial differential equation (PDE) countercurrent hemodialyzer model (ODE/PDE model). We conducted a cross-sectional study in silico that evaluated eleven hemodialysis patients. Patients received a ceiling dose of methadone hydrochloride 30 mg/day. Outcome measures included: the total amount of methadone removed during dialysis; methadone's overall intradialytic mass transfer rate coefficient, km ; and, methadone's removal rate, j ME. Each metric was measured at dialysate flow rates of 250 mL/min and 800 mL/min. The ODE/PDE model revealed a significant increase in the change of methadone's mass transfer with increased dialysate flow rate, %Δkm =18.56, P=0.02, N=11. The total amount of methadone mass transferred across the dialyzer membrane with high dialysate flow rate significantly increased (0.042±0.016 versus 0.052±0.019 mg/kg, P=0.02, N=11). This was accompanied by a small significant increase in methadone's mass transfer rate (0.113±0.002 versus 0.014±0.002 mg/kg/h, P=0.02, N=11). The ODE/PDE model accurately predicted methadone's removal during dialysis. The absolute value of the prediction errors for methadone's extraction and throughput were less than 2%. ODE/PDE modeling of methadone's hemodialysis is a new approach to study methadone's removal, in particular, and opioid removal, in general, in patients with end-stage renal disease on hemodialysis. ODE/PDE modeling accurately quantified the fundamental phenomena of methadone's mass transfer during hemodialysis. This methodology may lead to development of optimally designed intradialytic opioid treatment protocols, and allow dynamic monitoring of outflow plasma opioid concentrations for model predictive control during dialysis in humans.

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.

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.

Negative feedback exerted by cAMP-dependent protein kinase and cAMP phosphodiesterase on subsarcolemmal cAMP signals in intact cardiac myocytes: an in vivo study using adenovirus-mediated expression of CNG channels.

PubMed

Rochais, Francesca; Vandecasteele, Grégoire; Lefebvre, Florence; Lugnier, Claire; Lum, Hazel; Mazet, Jean-Luc; Cooper, Dermot M F; Fischmeister, Rodolphe

2004-12-10

Intracardiac cAMP levels are modulated by hormones and neuromediators with specific effects on contractility and metabolism. To understand how the same second messenger conveys different information, mutants of the rat olfactory cyclic nucleotide-gated (CNG) channel alpha-subunit CNGA2, encoded into adenoviruses, were used to monitor cAMP in adult rat ventricular myocytes. CNGA2 was not found in native myocytes but was strongly expressed in infected cells. In whole cell patch-clamp experiments, the forskolin analogue L-858051 (L-85) elicited a non-selective, Mg2+ -sensitive current observed only in infected cells, which was thus identified as the CNG current (ICNG). The beta-adrenergic agonist isoprenaline (ISO) also activated ICNG, although the maximal efficiency was approximately 5 times lower than with L-85. However, ISO and L-85 exerted a similar maximal increase of the L-type Ca2+ current. The use of a CNGA2 mutant with a higher sensitivity for cAMP indicated that this difference is caused by the activation of a localized fraction of CNG channels by ISO. cAMP-dependent protein kinase (PKA) blockade with H89 or PKI, or phosphodiesterase (PDE) inhibition with IBMX, dramatically potentiated ISO- and L-85-stimulated ICNG. A similar potentiation of beta-adrenergic stimulation occurred when PDE4 was blocked, whereas PDE3 inhibition had a smaller effect (by 2-fold). ISO and L-85 increased total PDE3 and PDE4 activities in cardiomyocytes, although this effect was insensitive to H89. However, in the presence of IBMX, H89 had no effect on ISO stimulation of ICNG. This study demonstrates that subsarcolemmal cAMP levels are dynamically regulated by a negative feedback involving PKA stimulation of subsarcolemmal cAMP-PDE.

Prestack reverse time migration for tilted transversely isotropic media

NASA Astrophysics Data System (ADS)

Jang, Seonghyung; Hien, Doan Huy

2013-04-01

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

Venous leakage treatment revisited: pelvic venoablation using aethoxysclerol under air block technique and Valsalva maneuver.

PubMed

Herwig, Ralf; Sansalone, Salvatore

2015-03-31

We evaluated the effectiveness of pelvic vein embolization with aethoxysclerol in aero-block technique for the treatment of impotence due to venous leakage in men using sildenafil for intercourse. The aim of the procedure was to reduce the use of sildenafil. A total of 96 patients with veno-occlusive dysfunction, severe enough for the need of PDE5 inhibitors for vaginal penetration, underwent pelvic venoablation with aethoxysclerol. The mean patient age was 53.5 years. Venous leaks were identified by Color Doppler Ultrasound after intracavernous alprostadil injection. Under local anesthesia a 20-gauge needle was inserted into the deep dorsal penile vein. The pelvic venogram was obtained through deep dorsal venography. Aethoxysclerol 3% as sclerosing agent was injected after air-block under Valsalva manoeuver. Success was defined as the ability to achieve vaginal insertion without the aid of any drugs, vasoactive injections, penile prosthesis, or vacuum device. Additionally, a pre- and post- therapy IIEF score and a digital overnight spontaneous erections protocol (OSEP) with the NEVA™-system was performed. At 3 month follow-up 77 out of 96 patients (80.21%) reported to have erections sufficient for vaginal insertion without the use of any drug or additional device. Four (4.17%) patients did not report any improvement. Follow up with color Doppler ultrasound revealed a new or persistent venous leakage in 8 (8.33%) of the patients. No serious complications occurred. Our new pelvic venoablation technique using aethoxysclerol in air-block technique was effective, minimally invasive, and cost-effective. All patients were able to perform sexual intercourse without the previously used dosage of PDE5 inhibitor. This new method may help in patients with contra-indications against PDE5 inhibitors, in patients who cannot afford the frequent usage of expensive oral medication or those who do not fully respond to PDE5-inhibitors.

On the Exit Boundary Condition for One-Dimensional Calculations of Pulsed Detonation Engine Performance

NASA Technical Reports Server (NTRS)

Wilson, Jack; Paxson, Daniel E.

2002-01-01

In one-dimensional calculations of pulsed detonation engine (PDE) performance, the exit boundary condition is frequently taken to be a constant static pressure. In reality, for an isolated detonation tube, after the detonation wave arrives at the exit plane, there will be a region of high pressure, which will gradually return to ambient pressure as an almost spherical shock wave expands away from the exit, and weakens. Initially, the flow is supersonic, unaffected by external pressure, but later becomes subsonic. Previous authors have accounted for this situation either by assuming the subsonic pressure decay to be a relaxation phenomenon, or by running a two-dimensional calculation first, including a domain external to the detonation tube, and using the resulting exit pressure temporal distribution as the boundary condition for one-dimensional calculations. These calculations show that the increased pressure does affect the PDE performance. In the present work, a simple model of the exit process is used to estimate the pressure decay time. The planar shock wave emerging from the tube is assumed to transform into a spherical shock wave. The initial strength of the spherical shock wave is determined from comparison with experimental results. Its subsequent propagation, and resulting pressure at the tube exit, is given by a numerical blast wave calculation. The model agrees reasonably well with other, limited, results. Finally, the model was used as the exit boundary condition for a one-dimensional calculation of PDE performance to obtain the thrust wall pressure for a hydrogen-air detonation in tubes of length to diameter ratio (L/D) of 4, and 10, as well as for the original, constant pressure boundary condition. The modified boundary condition had no performance impact for values of L/D > 10, and moderate impact for L/D = 4.

A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.

PubMed

Porcu, Eleonora; Medici, Marco; Pistis, Giorgio; Volpato, Claudia B; Wilson, Scott G; Cappola, Anne R; Bos, Steffan D; Deelen, Joris; den Heijer, Martin; Freathy, Rachel M; Lahti, Jari; Liu, Chunyu; Lopez, Lorna M; Nolte, Ilja M; O'Connell, Jeffrey R; Tanaka, Toshiko; Trompet, Stella; Arnold, Alice; Bandinelli, Stefania; Beekman, Marian; Böhringer, Stefan; Brown, Suzanne J; Buckley, Brendan M; Camaschella, Clara; de Craen, Anton J M; Davies, Gail; de Visser, Marieke C H; Ford, Ian; Forsen, Tom; Frayling, Timothy M; Fugazzola, Laura; Gögele, Martin; Hattersley, Andrew T; Hermus, Ad R; Hofman, Albert; Houwing-Duistermaat, Jeanine J; Jensen, Richard A; Kajantie, Eero; Kloppenburg, Margreet; Lim, Ee M; Masciullo, Corrado; Mariotti, Stefano; Minelli, Cosetta; Mitchell, Braxton D; Nagaraja, Ramaiah; Netea-Maier, Romana T; Palotie, Aarno; Persani, Luca; Piras, Maria G; Psaty, Bruce M; Räikkönen, Katri; Richards, J Brent; Rivadeneira, Fernando; Sala, Cinzia; Sabra, Mona M; Sattar, Naveed; Shields, Beverley M; Soranzo, Nicole; Starr, John M; Stott, David J; Sweep, Fred C G J; Usala, Gianluca; van der Klauw, Melanie M; van Heemst, Diana; van Mullem, Alies; Vermeulen, Sita H; Visser, W Edward; Walsh, John P; Westendorp, Rudi G J; Widen, Elisabeth; Zhai, Guangju; Cucca, Francesco; Deary, Ian J; Eriksson, Johan G; Ferrucci, Luigi; Fox, Caroline S; Jukema, J Wouter; Kiemeney, Lambertus A; Pramstaller, Peter P; Schlessinger, David; Shuldiner, Alan R; Slagboom, Eline P; Uitterlinden, André G; Vaidya, Bijay; Visser, Theo J; Wolffenbuttel, Bruce H R; Meulenbelt, Ingrid; Rotter, Jerome I; Spector, Tim D; Hicks, Andrew A; Toniolo, Daniela; Sanna, Serena; Peeters, Robin P; Naitza, Silvia

2013-01-01

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

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 way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.

Approaches to optimal aquifer management and intelligent control in a multiresolutional decision support system

NASA Astrophysics Data System (ADS)

Orr, Shlomo; Meystel, Alexander M.

2005-03-01

Despite remarkable new developments in stochastic hydrology and adaptations of advanced methods from operations research, stochastic control, and artificial intelligence, solutions of complex real-world problems in hydrogeology have been quite limited. The main reason is the ultimate reliance on first-principle models that lead to complex, distributed-parameter partial differential equations (PDE) on a given scale. While the addition of uncertainty, and hence, stochasticity or randomness has increased insight and highlighted important relationships between uncertainty, reliability, risk, and their effect on the cost function, it has also (a) introduced additional complexity that results in prohibitive computer power even for just a single uncertain/random parameter; and (b) led to the recognition in our inability to assess the full uncertainty even when including all uncertain parameters. A paradigm shift is introduced: an adaptation of new methods of intelligent control that will relax the dependency on rigid, computer-intensive, stochastic PDE, and will shift the emphasis to a goal-oriented, flexible, adaptive, multiresolutional decision support system (MRDS) with strong unsupervised learning (oriented towards anticipation rather than prediction) and highly efficient optimization capability, which could provide the needed solutions of real-world aquifer management problems. The article highlights the links between past developments and future optimization/planning/control of hydrogeologic systems. Malgré de remarquables nouveaux développements en hydrologie stochastique ainsi que de remarquables adaptations de méthodes avancées pour les opérations de recherche, le contrôle stochastique, et l'intelligence artificielle, solutions pour les problèmes complexes en hydrogéologie sont restées assez limitées. La principale raison est l'ultime confiance en les modèles qui conduisent à des équations partielles complexes aux paramètres distribués (PDE) à une échelle donnée. Alors que l'accumulation d'incertitudes et, par conséquent, la stockasticité ou l'aléat a augmenté la perspicacité et amis en lumière d'importantes relations entre l'incertitude, la fiabilité, le risque, et leur effet sur les coûts de fonctionnement, il a également (a) introduit une complexité additionnelle qui résulte dans un pouvoir prohibitif des moyens de calcul informatique même pour une simple estimation de l'incertitude; et (b) a conduita une reconnaissance de notre manque d'aptitude à maîtriser l'incertitude totale même en introduisant tous les paramètres connus de l'incertitude. La représentation du changement est introduit: une adaptation de nouvelles méthodes de contrôle intelligent qui va relâcher la dépendance à la rigidité des algorithmes, aux calculs informatiques intensifs, à la PDE stockastique, et qui modifiera l'emphase entre les MRDS—systèmes interactifs d'aide à la décision de multiresolutionelle (flexibles, adaptables et orientables selon les objectifs)—avec un fort apprentissage non (orienté vers l'anticipation plutôt que la prédiction), et une capacité d'optimisation efficiente très élevée, qui pourrait apporter le besoin de solutions pour la modélisation des problèmes de management des aquifères réalistes. Cet article met en lumière les liens entre les développements passés et les futurs moyens d'optimisation, de gestion et de contrôle des systèmes hydrogéologiques. A pesar de nuevos avances notables en hidrología estocástica y las adaptaciones de métodos avanzados de investigación de operaciones, control estocástico, e inteligencia artificial, las soluciones de problemas complejos del mundo real en hidrogeología han sido bastante limitadas. La principal razón es la dependencia definitiva en modelos de primer-principio que conducen a ecuaciones parciales diferencias de parámetro distribuido complejas (PDE) a una escala dada. Mientras que la adición de incertidumbre, y por lo tanto, estocasticidad o aleatoriedad ha incrementado la profundidad y resaltado relaciones importantes entre la incertidumbre, confiabilidad, riesgo, y su efecto en la función de costo, la adición también ha permitido (a) introducir complejidad adicional que resulta en potencia computacional excesiva aún para un solo parámetro incierto/aleatorio; y (b) llevar a reconocer nuestra discapacidad para evaluar la incertidumbre completa aún cuando se incluyen todos los parámetros inciertos. Se introduce un cambio paradigmático: una adaptación de nuevos métodos de control de inteligencia que relajarála dependencia en PDE estocásticas, rígidas y de uso computacional intensivo, cambiando el énfasis hacia un sistema de apoyo de decisiones de propósitos múltiples (MRDS) adaptivo, flexible, y orientadoa objetivos con fuerte aprendizaje sin supervisión (orientado a la anticipación más que a la predicción) con fuerte capacidad de optimización eficiente, lo cual podría aportar las soluciones necesarias a los problemas de manejo reales con los acuíferos. El artículo resalta los vínculos entre desarrollos pasados y control/planificación/optimización futura de sistemas hidrogeológicos.

Stable finite element approximations of two-phase flow with soluble surfactant

NASA Astrophysics Data System (ADS)

Barrett, John W.; Garcke, Harald; Nürnberg, Robert

2015-09-01

A parametric finite element approximation of incompressible two-phase flow with soluble surfactants is presented. The Navier-Stokes equations are coupled to bulk and surfaces PDEs for the surfactant concentrations. At the interface adsorption, desorption and stress balances involving curvature effects and Marangoni forces have to be considered. A parametric finite element approximation for the advection of the interface, which maintains good mesh properties, is coupled to the evolving surface finite element method, which is used to discretize the surface PDE for the interface surfactant concentration. The resulting system is solved together with standard finite element approximations of the Navier-Stokes equations and of the bulk parabolic PDE for the surfactant concentration. Semidiscrete and fully discrete approximations are analyzed with respect to stability, conservation and existence/uniqueness issues. The approach is validated for simple test cases and for complex scenarios, including colliding drops in a shear flow, which are computed in two and three space dimensions.

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

PubMed

Li, Ben; Stenstrom, M K

2014-01-01

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

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

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

Kevrekidis, Ioannis

2017-03-22

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

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

PubMed Central

Povolotsky, Tatyana L.

2015-01-01

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

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

PubMed

Povolotsky, Tatyana L; Hengge, Regine

2016-01-01

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

ICASE Semiannual Report 1 October 1991 - 31 March 1992

DTIC Science & Technology

1992-05-01

who have resident appointments for limited periods of time as well as by visiting and resident consultants. Members of NASA’s research staff may also...performed showing that the full optimization problem can be solved with a computational cost which is only a few times more than that of solving the PDE...The goal is to obtain a solution of the optimization problem in a computational cost which is just a few times (2-3) that of the flow solver. Such a

Penile involvement in Systemic Sclerosis: New Diagnostic and Therapeutic Aspects

PubMed Central

Aversa, Antonio; Bruzziches, Roberto; Francomano, Davide; Rosato, Edoardo; Salsano, Felice; Spera, Giovanni

2010-01-01

Systemic Sclerosis (SSc) is a connective tissue disorder featuring vascular alterations and an immunological activation leading to a progressive and widespread fibrosis of several organs such as the skin, lung, gastrointestinal tract, heart, and kidney. Men with SSc are at increased risk of developing erectile dysfunction (ED) because of the evolution of early microvascular tissutal damage into corporeal fibrosis. The entity of penile vascular damage in SSc patients has been demonstrated by using Duplex ultrasonography and functional infra-red imaging and it is now clear that this is a true clinical entity invariably occurring irrespective of age and disease duration and constituting the ‘‘sclerodermic penis”. Once-daily phosphodiesterase type-5 (PDE5) inhibitors improve both sexual function and vascular measures of cavernous arteries by improving surrogate markers of endothelial dysfunction, that is, plasma endothelin-1 and adrenomedullin levels, which may play a potential role in preventing progression of penile fibrosis and ED. Also, the beneficial effect of long-term PDE5i add-on therapy to SSc therapy in the treatment of Raynaud's phenomenon is described. PMID:20981315

Analysis of a diffuse interface model of multispecies tumor growth

NASA Astrophysics Data System (ADS)

Dai, Mimi; Feireisl, Eduard; Rocca, Elisabetta; Schimperna, Giulio; Schonbek, Maria E.

2017-04-01

We consider a diffuse interface model for tumor growth recently proposed in Chen et al (2014 Int. J. Numer. Methods Biomed. Eng. 30 726-54). In this new approach sharp interfaces are replaced by narrow transition layers arising due to adhesive forces among the cell species. Hence, a continuum thermodynamically consistent model is introduced. The resulting PDE system couples four different types of equations: a Cahn-Hilliard type equation for the tumor cells (which include proliferating and dead cells), a Darcy law for the tissue velocity field, whose divergence may be different from 0 and depend on the other variables, a transport equation for the proliferating (viable) tumor cells, and a quasi-static reaction diffusion equation for the nutrient concentration. We establish existence of weak solutions for the PDE system coupled with suitable initial and boundary conditions. In particular, the proliferation function at the boundary is supposed to be nonnegative on the set where the velocity \\mathbf{u} satisfies \\mathbf{u}\\centerdot ν >0 , where ν is the outer normal to the boundary of the domain.

40 CFR 761.80 - Manufacturing, processing and distribution in commerce exemptions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 16823-0048 (PDE-41.2). (6) Radian Corp., Austin, TX 78766 (PDE-182.1). (7) Restek Corporation... petitioner(s) an exemption for 1 year to export PCBs for use in small quantities for research and development: (1) Accu-Standard, New Haven, CT. 06503. (2) ManTech, Research Triangle Park, NC 27709. (d) The...

40 CFR 761.80 - Manufacturing, processing and distribution in commerce exemptions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 16823-0048 (PDE-41.2). (6) Radian Corp., Austin, TX 78766 (PDE-182.1). (7) Restek Corporation... petitioner(s) an exemption for 1 year to export PCBs for use in small quantities for research and development: (1) Accu-Standard, New Haven, CT. 06503. (2) ManTech, Research Triangle Park, NC 27709. (d) The...

40 CFR 761.80 - Manufacturing, processing and distribution in commerce exemptions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 16823-0048 (PDE-41.2). (6) Radian Corp., Austin, TX 78766 (PDE-182.1). (7) Restek Corporation... petitioner(s) an exemption for 1 year to export PCBs for use in small quantities for research and development: (1) Accu-Standard, New Haven, CT. 06503. (2) ManTech, Research Triangle Park, NC 27709. (d) The...

40 CFR 761.80 - Manufacturing, processing and distribution in commerce exemptions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 16823-0048 (PDE-41.2). (6) Radian Corp., Austin, TX 78766 (PDE-182.1). (7) Restek Corporation... petitioner(s) an exemption for 1 year to export PCBs for use in small quantities for research and development: (1) Accu-Standard, New Haven, CT. 06503. (2) ManTech, Research Triangle Park, NC 27709. (d) The...

40 CFR 761.80 - Manufacturing, processing and distribution in commerce exemptions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 16823-0048 (PDE-41.2). (6) Radian Corp., Austin, TX 78766 (PDE-182.1). (7) Restek Corporation... petitioner(s) an exemption for 1 year to export PCBs for use in small quantities for research and development: (1) Accu-Standard, New Haven, CT. 06503. (2) ManTech, Research Triangle Park, NC 27709. (d) The...

Propulsion Systems Integration for a `Tractor Beam' Mercury Lightcraft: Liftoff Engine

NASA Astrophysics Data System (ADS)

Myrabo, L. N.

2003-05-01

Described herein is the concept and propulsion systems integration for a revolutionary beam-propelled shuttle called the ``Mercury'' lightcraft - emphasizing the liftoff engine mode. This one-person, ultra-energetic vehicle is designed to ride `tractor beams' into space, transmitted from a future network of satellite solar power stations. The objective is to create a safe, very low cost (e.g., 1000X below chemical rockets) space transportation system for human life, one that is completely `green' and independent of Earth's limited fossil fuel reserves. The lightcraft's airbreathing combined-cycle engine operates in a rotary pulsed detonation mode PDE for lift-offs and landings; at hypersonic speeds it transitions into a magnetohydrodynamic (MHD) slipstream accelerator mode. For the latter, the transatmospheric flight path is momentarily transformed into an extremely long, electromagnetic ``mass-driver'' channel with an effective `fuel' specific impulse in the range of 6000 to 16,000 seconds. These future single-stage-to-orbit, highly-reusuable vehicles will ride ``Highways of Light,'' accelerating at 3 Gs into space, with their throttles just barely beyond `idle' power.