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Sample records for agonists potential utility

  1. Thrombopoietin levels in patients with disorders of platelet production: diagnostic potential and utility in predicting response to TPO receptor agonists.

    Science.gov (United States)

    Makar, Robert S; Zhukov, Olga S; Sahud, Mervyn A; Kuter, David J

    2013-12-01

    Thrombopoietin (TPO) is the major regulator of megakaryopoiesis. Measurement of serum TPO levels may help distinguish between various causes of thrombocytopenia and predict treatment response to TPO receptor agonists. Serum TPO levels from 118 healthy volunteers and 88 patients with abnormal platelet counts were measured using a quantitative ELISA assay. The mean (range) TPO level in healthy volunteers was 39 (7-99) pg/mL. TPO values were correlated with the patient's diagnosis, platelet count, and response to TPO receptor agonists. 88 patients with history of consumptive thrombocytopenia (39) or hypoproliferative thrombocytopenia (49) were analyzed. Median (interquartile range) TPO level for consumptive thrombocytopenia patients was 63 (48-98) pg/mL with a corresponding median (interquartile range) platelet count of 73 (28-146) × 10(9) /L. In contrast, hypoproliferative thrombocytopenia patients had platelet counts [59 (30-117) × 10(9) /L] comparable with consumptive thrombocytopenia patients, but significantly higher serum TPO levels [706 (358-1546) pg/mL, P TPO receptor agonists demonstrated that a TPO level >95 pg/mL was associated with lack of clinical response (P TPO levels may have diagnostic utility in discriminating between patients with hypoproliferative and consumptive thrombocytopenia. Elevated TPO levels in ITP patients may predict a poor clinical response to treatment with TPO receptor agonists. Copyright © 2013 Wiley Periodicals, Inc.

  2. Not utilized learning potentials

    DEFF Research Database (Denmark)

    Kragelund, Linda

    -conscious disjuncture, in development of the concept pseudo-everyday life activities and in a categorizing mo­del for and a theory about student nurses' learning processes. The theory includes relations between 4 types of  disjuncture, 3 types of content in the learning processes, and factors that provoke...... transformation from one type of disjuncture to another.      Students and mentors are not aware that students are in potential learning situations when they interact on their own with patients, and that it is non-routine for students to act with patients in pseudo-everyday life activities. It may be possible......  When the Danish Nursing Education in 2002 became a Bachelor Degree the clinical part of the education was reduced. Therefore, it was necessary to optimize learning in practice.       I made a qualitative investigation to describe student nurses' learning processes in non-routine situations where...

  3. PPAR Agonists: Potential as Therapeutics for Neovascular Retinopathies

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    Harrihar A. Pershadsingh

    2008-01-01

    Full Text Available The angiogenic, neovascular proliferative retinopathies, proliferative diabetic retinopathy (PDR, and age-dependent macular degeneration (AMD complicated by choroidal neovascularization (CNV, also termed exudative or “wet” AMD, are common causes of blindness. The antidiabetic thiazolidinediones (TZDs, rosiglitazone, and troglitazone are PPAR agonists with demonstrable antiproliferative, and anti-inflammatory effects, in vivo, were shown to ameliorate PDR and CNV in rodent models, implying the potential efficacy of TZDs for treating proliferative retinopathies in humans. Activation of the angiotensin II type 1 receptor (AT1-R propagates proinflammatory and proliferative pathogenic determinants underlying PDR and CNV. The antihypertensive dual AT1-R blocker (ARB, telmisartan, recently was shown to activate PPAR and improve glucose and lipid metabolism and to clinically improve PDR and CNV in rodent models. Therefore, the TZDs and telmisartan, clinically approved antidiabetic and antihypertensive drugs, respectively, may be efficacious for treating and attenuating PDR and CNV humans. Clinical trials are needed to test these possibilities.

  4. Neurotensin Agonist Attenuates Nicotine Potentiation to Cocaine Sensitization

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    Paul Fredrickson

    2014-01-01

    Full Text Available Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a “gateway drug”. Neurotensin (NT is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13 analog, blocks behavioral sensitization (an animal model for psychostimulant addiction to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.

  5. Chronic levodopa treatment alters basal and dopamine agonist-stimulated cerebral glucose utilization

    Energy Technology Data Exchange (ETDEWEB)

    Engber, T.M.; Susel, Z.; Kuo, S.; Chase, T.N. (National Institute of Neurological Disorders and Stroke, Bethesda, MD (USA))

    1990-12-01

    The effect of chronic levodopa administration on the functional activity of the basal ganglia and its output regions was evaluated by means of the 2-deoxyglucose (2-DG) autoradiographic technique in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The rates of local cerebral glucose utilization were studied under basal conditions as well as in response to challenge with a selective D1 or D2 dopamine-receptor agonist. Levodopa (100 mg/kg/d, i.p.) was administered for 19 d either continuously via infusion with an osmotic pump or intermittently by twice-daily injections. Following a 3-d washout, glucose utilization was found to be decreased by both levodopa regimens in the nucleus accumbens; intermittent levodopa also decreased glucose utilization in the entopeduncular nucleus, subthalamic nucleus, ventrolateral thalamus, ventromedial thalamus, ventroposterolateral thalamus, and lateral habenula. In control (lesioned and treated chronically with saline) rats, the D1 agonist SKF 38393 (5 mg/kg, i.v.) increased 2-DG uptake in the substantia nigra pars reticulata and entopeduncular nucleus ipsilateral to the lesion by 84% and 56%, respectively. Both continuous and intermittent levodopa blunted the SKF 38393-induced elevation in glucose metabolism in the substantia nigra pars reticulata, while intermittent levodopa also attenuated the increase in the entopeduncular nucleus. The D2 agonist quinpirole (0.4 mg/kg, i.v.) did not increase glucose utilization in any brain region in control animals; following intermittent levodopa treatment, however, quinpirole increased 2-DG uptake by 64% in the subthalamic nucleus and by 39% in the deep layers of the superior colliculus on the ipsilateral side.

  6. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    Energy Technology Data Exchange (ETDEWEB)

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi, E-mail: kumamote@cc.saga-u.ac.jp

    2013-04-26

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  7. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    International Nuclear Information System (INIS)

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-01-01

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC 50 values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC 50 = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other

  8. A novel nicotinic agonist facilitates induction of long-term potentiation in the rat hippocampus.

    Science.gov (United States)

    Hunter, B E; de Fiebre, C M; Papke, R L; Kem, W R; Meyer, E M

    1994-02-28

    Long-term potentiation (LTP) can be modulated by a number of neurotransmitter receptors including muscarinic and GABAergic receptor types. We have found that a novel nicotinic agonist, 2,4-dimethoxybenzylidene anabaseine (DMXB), facilitated the induction of LTP in the hippocampus in a dose-dependent and mecamylamine-sensitive manner. DMXB displaced high affinity nicotinic [125I]alpha-bungarotoxin and [3H]acetylcholine binding in rat brain. Xenopus oocyte studies demonstrated that DMXB has agonist activity at alpha 7 but not alpha 4/beta 2 nicotinic receptor subtypes. These results indicated that DMXB is a novel nicotinic agonist with apparent specificity for the alpha 7/alpha-bungarotoxin nicotinic receptor subtype and indicate that nicotinic receptor activation is capable of modulating the induction of long-term potentiation.

  9. Monoterpenoids induce agonist-specific desensitization of transient receptor potential vanilloid-3 (TRPV3) ion channels.

    Science.gov (United States)

    Sherkheli, Muhammad Azhar; Benecke, Heike; Doerner, Julia Franca; Kletke, Olaf; Vogt-Eisele, A K; Gisselmann, Guenter; Hatt, Hanns

    2009-01-01

    Transient receptor potential vanilloid-3 (TRPV3) is a thermo-sensitive ion channel expressed in skin keratinocytes and in a variety of neural cells. It is activated by warmth as well as monoterpenoids including camphor, menthol, dihydrocarveol and 1,8-cineol. TRPV3 is described as a putative nociceptor and previous studies revealed sensitization of the channel during repeated short-term stimulation with different agonists. In the present investigation TRPV3 was transiently expressed in either Xenopus oocytes or HEK293 cells. Whole-cell voltage-clamp techniques were used to characterize the behavior of TRPV3 when challenged with different agonists. Similarly, a human keratinocyte-derived cell line (HaCaT cells) was used to monitor the behavior of native TRPV3 when challenged with different agonists. We report here that prolonged exposure (5-15 minutes) of monoterpenoids results in agonist-specific desensitization of TRPV3. Long-term exposure to camphor and 1,8-cineol elicits desensitizing currents in TRPV3 expressing oocytes, whereas the non-terpenoid agonist 2-APB induces sustained currents. Agonist-specific desensitization of endogenous TRPV3 was also found in HaCaT cells, which may be taken as a representative for the native system. Terpenoids have a long history of use in therapeutics, pharmaceuticals and cosmetics but knowledge about underpinning molecular mechanisms is incomplete. Our finding on agonist-induced desensitization of TRPV3 by some monoterpenoids displays a novel mechanism through which TRP channels could be functionally modulated. Desensitization of TRPV3 channels might be the molecular basis of action for some of the medicinal properties of camphor and 1,8-cineol.

  10. Ingestion of transient receptor potential channel agonists attenuates exercise-induced muscle cramps.

    Science.gov (United States)

    Craighead, Daniel H; Shank, Sean W; Gottschall, Jinger S; Passe, Dennis H; Murray, Bob; Alexander, Lacy M; Kenney, W Larry

    2017-09-01

    Exercise-associated muscle cramping (EAMC) is a poorly understood problem that is neuromuscular in origin. Ingestion of transient receptor potential (TRP) channel agonists has been efficacious in attenuating electrically induced muscle cramps. This study examines the effect of TRP agonist ingestion on voluntarily induced EAMC and motor function. Study 1: Thirty-nine participants completed 2 trials after ingesting TRP agonist-containing active treatment (A), or vehicle (V) control. Cramping in the triceps surae muscle was induced via voluntary isometric contraction. Study 2: After ingesting A or V, 31 participants performed kinematic and psychomotor tests of manual dexterity. A increased precramp contraction duration (A, 36.9 ± 4.1 s; V, 27.8 ± 3.1 s), decreased cramp EMG area under the curve (A, 37.3 ± 7.7 %EMG max ·s; V, 77.2 ± 17.7 %EMG max ·s), increased contraction force to produce the cramp (A, 13.8 ± 1.8 kg; V, 9.9 ± 1.6 kg), and decreased postcramp soreness (A, 4.1 ± 0.3 arbitrary units (a.u.); V, 4.7 ± 0.3 a.u.). Kinematic and psychomotor tests were not affected. TRP agonist ingestion attenuated EAMC characteristics without affecting motor function. Muscle Nerve 56: 379-385, 2017. © 2017 Wiley Periodicals, Inc.

  11. Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay.

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    Yiyi Sun

    Full Text Available Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (--arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases.

  12. Control of Methicillin-Resistant Staphylococcus aureus Pneumonia Utilizing TLR2 Agonist Pam3CSK4.

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    Yi-Guo Chen

    Full Text Available The spread of methicillin-resistant Staphylococcus aureus (MRSA is a critical health issue that has drawn greater attention to the potential use of immunotherapy. Toll-like receptor 2 (TLR2, a pattern recognition receptor, is an essential component in host innate defense system against S. aureus infection. However, little is known about the innate immune response, specifically TLR2 activation, against MRSA infection. Here, we evaluate the protective effect and the mechanism of MRSA murine pneumonia after pretreatment with Pam3CSK4, a TLR2 agonist. We found that the MRSA-pneumonia mouse model, pretreated with Pam3CSK4, had reduced bacteria and mortality in comparison to control mice. As well, lower protein and mRNA levels of TNF-α, IL-1β and IL-6 were observed in lungs and bronchus of the Pam3CSK4 pretreatment group. Conversely, expression of anti-inflammatory cytokine IL-10, but not TGF-β, increased in Pam3CSK4-pretreated mice. Our additional studies showed that CXCL-2 and CXCL1, which are necessary for neutrophil recruitment, were less evident in the Pam3CSK4-pretreated group compared to control group, whereas the expression of Fcγ receptors (FcγⅠ/Ⅲ and complement receptors (CR1/3 increased in murine lungs. Furthermore, we found that increased survival and improved bacterial clearance were not a result of higher levels of neutrophil infiltration, but rather a result of enhanced phagocytosis and bactericidal activity of neutrophils in vitro and in vivo as well as increased robust oxidative activity and release of lactoferrin. Our cumulative findings suggest that Pam3CSK4 could be a novel immunotherapeutic candidate against MRSA pneumonia.

  13. Hydrogen utilization potential in subsurface sediments

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    Rishi Ram Adhikari

    2016-01-01

    Full Text Available Subsurface microbial communities undertake many terminal electron-accepting processes, often simultaneously. Using a tritium-based assay, we measured the potential hydrogen oxidation catalyzed by hydrogenase enzymes in several subsurface sedimentary environments (Lake Van, Barents Sea, Equatorial Pacific and Gulf of Mexico with different predominant electron-acceptors. Hydrogenases constitute a diverse family of enzymes expressed by microorganisms that utilize molecular hydrogen as a metabolic substrate, product or intermediate. The assay reveals the potential for utilizing molecular hydrogen and allows qualitative detection of microbial activity irrespective of the predominant electron-accepting process. Because the method only requires samples frozen immediately after recovery, the assay can be used for identifying microbial activity in subsurface ecosystems without the need to preserve live material.We measured potential hydrogen oxidation rates in all samples from multiple depths at several sites that collectively span a wide range of environmental conditions and biogeochemical zones. Potential activity normalized to total cell abundance ranges over five orders of magnitude and varies, dependent upon the predominant terminal electron acceptor. Lowest per-cell potential rates characterize the zone of nitrate reduction and highest per-cell potential rates occur in the methanogenic zone. Possible reasons for this relationship to predominant electron acceptor include (i increasing importance of fermentation in successively deeper biogeochemical zones and (ii adaptation of H2ases to successively higher concentrations of H2 in successively deeper zones.

  14. Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases

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    Laura Foucault-Fruchard

    2017-01-01

    Full Text Available Neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's diseases, are all characterized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. Several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluated in vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist.

  15. Middle East gas utilization and export potential

    International Nuclear Information System (INIS)

    Cornet-Gandolphe, S.

    1995-01-01

    There is huge gas supply potential in the Middle East, which possesses over one third of the world's natural gas reserves. However, marketed production represents only 6% of the world total, demonstrating that gas resources in the Middle East are under utilized. The value of these resources will be realized only if the gas finds a commercial outlet that guarantees proper return on investments for gas producers and the best possible use of this nonrenewable resource for governments. Apart from the chemical sector, which has provided a good outlet for natural gas, the development of natural gas resources in the region has been very limited historically, inhibited by many factors linked to the resource itself and to the characteristics of the region. However, natural gas in the Middle East is now at a crossroads, facing both major challenges and significant opportunities. The region, which currently plays only a marginal role on the world gas market, has the potential to become a leading world supplier, provided a number of political and economic conditions are fulfilled. This paper discusses some of the challenges that Middle Eastern countries face in trying to develop their natural gas resources. It reviews development potential for Middle Eastern gas reserves, whether for local use and/or exports, and it highlights future opportunities. (Author)

  16. Effects on energy utilization of a beta3-adrenergic agonist in rats fed on a cafeteria diet.

    Science.gov (United States)

    Berraondo, B; Bonafonte, A; Fernandez-Otero, M P; Martinez, J A

    1997-09-01

    The antiobesity potential of a new beta3-adrenergic agonist (Trecadrine) was assessed in a cafeteria model of obesity through body composition, thermogenesis and oxygen consumption indicators. Animals fed on a cafeteria diet for 75 days increased body weight and fat content, while muscle mass as a percentage of body weight was reduced in relation to control fed rats. In addition, in vitro brown adipose tissue (BAT) and white adipose tissue (WAT) oxygen consumption was increased in these obese animals as compared with controls. Trecadrine administration reduced weight gain, BAT and WAT stores as well as the respiratory quotient, which was accompanied by an increase in WAT and BAT oxygen consumption and rectal temperature. Moreover, muscle mass as a percentage of body weight maintained the same values as non-obese animals, while an increase in absolute muscle weight was found in Trecadrine-treated obese rats. However, liver weights and in vitro oxygen consumption remained unaltered after cafeteria feeding and Trecadrine administration. Since chronic administration of Trecadrine had no effect on food intake, the stimulation of thermogenesis and oxygen consumption by the beta3-adrenergic agonist in white and brown adipose tissue are apparently responsible for the rise in energy expenditure as well as for the lower weight gain and fat deposition in obese treated rats. Thus, Trecadrine exhibits some promise as a potential treatment for obesity.

  17. Sensory effects of transient receptor potential channel agonists on whole mouth saliva extensional rheology.

    Science.gov (United States)

    Houghton, Jack William; Hans, Joachim; Pesaro, Manuel; Ley, Jakob Peter; Carpenter, Guy Howard; Proctor, Gordon

    2017-08-01

    The extensional rheology (ER) of saliva is a property associated with its ability to coat surfaces and is important for the maintenance of a normal mouth feeling. Transient receptor potential (TRP) channels are expressed in the oral cavity and this study investigated how the sensory effects of TRP channel agonists modify the ER of saliva. Healthy volunteers rinsed with solutions containing a TRP agonist. Unstimulated whole mouth saliva (WMS) was collected prior to rinsing and WMS was collected during the first and second minutes after the mouth rinse. The Spinnbarkeit of the collected saliva was measured using a Neva Meter. The nonivamide (TRPV1) mouth rinse increased WMS ER from 37.0 (± 6.3) mm to 49.3 (± 5.1) mm when compared with the vehicle control, which itself had no effect on WMS ER. However, this effect was short-lived and ER of WMS was not increased in the second minute after the nonivamide mouth rinse. The menthol (TRPM8) mouth rinse resulted in an increase up to 57.8 (± 7.8) mm in WMS ER from the vehicle control and returned to control levels in the second minute. The cinnamaldehyde (TRPA1) mouth rinse resulted in no change in WMS ER. It can be concluded that nonivamide and menthol mouth rinsing has a short-term effect of increasing WMS ER, an effect not observed after cinnamaldehyde rinsing. We hypothesize that the activation of some TRP channels in the oral cavity results in changes in the salivary protein composition that in turn alters WMS ER. Identifying compounds that modify the physical properties of saliva in a desirable way is important in developing treatments for conditions associated with changes in the physical properties of saliva such as xerostomia (also known as dry mouth). Furthermore, understanding the rheology of saliva contributes to the elucidation of food oral processing which is of importance to food manufacturers. © 2017 Wiley Periodicals, Inc.

  18. The 5-HT(1F) receptor agonist lasmiditan as a potential treatment of migraine attacks

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer C; Olesen, Jes

    2012-01-01

    Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo...

  19. Trialkyltin rexinoid-X receptor agonists selectively potentiate thyroid hormone induced programs of xenopus laevis metamorphosis

    NARCIS (Netherlands)

    Mengeling, Brenda J.; Murk, Albertinka J.; Furlow, J.D.

    2016-01-01

    The trialkyltins tributyltin (TBT) and triphenyltin (TPT) can function as rexinoid-X receptor (RXR) agonists. We recently showed that RXR agonists can alter thyroid hormone (TH) signaling in a mammalian pituitary TH-responsive reporter cell line, GH3.TRE-Luc. The prevalence of TBT and TPT in the

  20. Agonist- and subunit-dependent potentiation of glutamate receptors by a nootropic drug aniracetam.

    Science.gov (United States)

    Tsuzuki, K; Takeuchi, T; Ozawa, S

    1992-11-01

    GluR1 and GluR2 cDNAs encoding non-NMDA subtypes of glutamate receptor were isolated from a rat brain cDNA library by Boulter et al. (Science, 249 (1990) 1033-1037). Functional receptors activated by kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and glutamate were expressed in Xenopus oocytes injected with GluR1, GluR2 or a mixture of GluR1 and GluR2 RNAs. In GluR1-expressed oocytes, 1 mM aniracetam potentiated AMPA-induced currents by 99 +/- 10% (mean +/- S.E.M., n = 5) and glutamate-induced currents by 140 +/- 8% (n = 4), but little affected kainate-induced currents. Aniracetam was effective from a concentration of 0.1 mM, and it exhibited more conspicuous effects with the increase of the dose. In oocytes injected with GluR1 plus GluR2 RNAs, aniracetam more markedly potentiated current responses to AMPA and glutamate than those in oocytes injected with GluR1 RNA alone. For example, 1 mM aniracetam potentiated AMPA-induced currents by 396 +/- 76% (n = 4) and glutamate-induced currents by 970 +/- 65% (n = 5) in oocytes injected with 10% GluR1 and 90% GluR2 RNAs. In these oocytes, however, the potentiation of kainate-induced currents by 1 mM aniracetam was only 8 +/- 5% (n = 4). Thus, we conclude that the potentiation of the AMPA/kainate receptor by aniracetam depends on both species of agonists and subunit composition of the receptor.

  1. Functionalized Ergot-alkaloids as potential dopamine D3 receptor agonists for treatment of schizophrenia

    Science.gov (United States)

    Ivanova, Bojidarka; Spiteller, Michael

    2012-12-01

    The relationship between the molecular structure and physical properties of functionalized naturally occurred Ergot-alkaloids as potential dopamine D3 receptor agonists is presented. The molecular modeling of the ergoline-skeleton is based on the comprehensive theoretical study of the binding affinity of the isolated chemicals towards the active sites of the D3 sub-type receptor (D3R) loops. The studied proton accepting ability under physiological conditions allows classifying four types of monocationics, characterizing with the different binding modes to D3R involving selected amino acid residues to the active sites. These results marked the pharmaceutical potential and clinical usage of the reported compounds as antipsychotic drugs for Schizophrenia treatment, since they allowed evaluating the highlights of the different hypothesizes of the biochemical causes the illness. The applied complex approach for theoretical and experimental elucidation, including quantum chemistry method, electrospray ionization (ESI) and matrix assisted laser desorption/ionization (MALDI) mass spectrometric (MS) methods, nuclear magnetic resonance and vibrational IR and Raman spectroscopy on the isolated fifteen novel derivatives (1)-(15) and their different protonated forms (1a)-(15a) evidenced a strong dependence of molecular conformation, physical properties and binding affinity. Thus, the semi-synthetic functionalization of the naturally occurred products (NPs), provided significant possibilities to further molecular drugs-design and development of novel derivatives with wanted biological function, using the established profile of selected classes/families of NPs. The work described chiefly the non-linear (NL) approach for the interpretation of the mass chromatograms on the performed hybrid high performance liquid chromatography (HPLC) tandem MS/MS and MS/MS/MS experiments, discussing the merits and great diversity of instrumentation flexibility, thus achieving fundamental

  2. Selective serotonin reuptake inhibitors potentiate the rapid antidepressant-like effects of serotonin4 receptor agonists in the rat.

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    Guillaume Lucas

    2010-02-01

    Full Text Available We have recently reported that serotonin(4 (5-HT(4 receptor agonists have a promising potential as fast-acting antidepressants. Here, we assess the extent to which this property may be optimized by the concomitant use of conventional antidepressants.We found that, in acute conditions, the 5-HT(4 agonist prucalopride was able to counteract the inhibitory effect of the selective serotonin reuptake inhibitors (SSRI fluvoxamine and citalopram on 5-HT neuron impulse flow, in Dorsal Raphé Nucleus (DRN cells selected for their high (>1.8 Hz basal discharge. The co-administration of both prucalopride and RS 67333 with citalopram for 3 days elicited an enhancement of DRN 5-HT neuron average firing rate, very similar to what was observed with either 5-HT(4 agonist alone. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT(1A receptors, that was two to three times stronger when the 5-HT(4 agonist was combined with citalopram. Similarly, co-administration of citalopram synergistically potentiated the enhancing effect of RS 67333 on CREB protein phosphorylation within the hippocampus. Finally, in the Forced Swimming Test, the combination of RS 67333 with various SSRIs (fluvoxamine, citalopram and fluoxetine was more effective to reduce time of immobility than the separate administration of each compound.These findings strongly suggest that the adjunction of an SSRI to a 5-HT(4 agonist may help to optimize the fast-acting antidepressant efficacy of the latter.

  3. Evaluation of potential agonist radioligands for imaging dopamine D2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, J.P.

    2015-01-01

    Imaging dopamine receptors with PET and SPECT can shed light on the nature of neuropsychiatric disorders which are characterized by disturbances in dopamine D2/3 receptor functioning. Agonist radioligands are considered superior to antagonists because they are more sensitive to detect dopamine

  4. Hydrogen utilization potential in subsurface sediments

    DEFF Research Database (Denmark)

    Adhikari, Rishi Ram; Glombitza, Clemens; Nickel, Julia

    2016-01-01

    Subsurface microbial communities undertake many terminal electron-accepting processes, often simultaneously. Using a tritium-based assay, we measured the potential hydrogen oxidation catalyzed by hydrogenase enzymes in several subsurface sedimentary environments (Lake Van, Barents Sea, Equatorial...

  5. Utilization, spending, and price trends for short- and long-acting Beta-agonists and inhaled corticosteroids in the medicaid program, 1991-2010.

    Science.gov (United States)

    Chiu, Shih-Feng; Kelton, Christina M L; Guo, Jeff Jianfei; Wigle, Patricia R; Lin, Alex C; Szeinbach, Sheryl L

    2011-05-01

    Asthma is a chronic respiratory disease that afflicts millions of people and accounts for substantial utilization of healthcare resources in most industrialized countries, including in the United States. However, the exact cost and utilization of anti-asthma medications in Medicaid in the past 2 decades have not been well studied. Considering the safety issues surrounding the long-acting beta-agonists, guideline updates, and the increase in asthma prevalence, understanding anti-asthma medication prescribing trends is important to payers and patients. The purpose of this study was to analyze the utilization and spending trends for anti-asthmatic agents in the US Medicaid program over the past 2 decades. This study was based on a retrospective, descriptive analysis of trends in utilization of and spending on anti-asthma medications, including short-acting beta-agonists, inhaled corticosteroids, long-acting beta-agonists, and inhaled corticosteroid/long-acting beta-agonist combinations. Quarterly utilization and expenditure data were obtained from the national Medicaid pharmacy files provided by the Centers for Medicare & Medicaid Services from quarter 1 of 1991 through quarter 2 of 2010. Average reimbursement per prescription was calculated each quarter as a proxy for drug price. The total number of prescriptions for the studied anti-asthma medications rose from 8.9 million in 1991 to 15.6 million in 2009, peaking at 20.8 million in 2005, the year before Medicare and Medicaid dual-eligible beneficiaries were moved to Medicare Part D. From 1991 to 2009, Medicaid spending on anti-asthma medications overall rose from $180.7 million to $1.3 billion, and spending on inhaled corticosteroid/long-acting beta-agonist combinations rose from $52.8 million in 2001-their first year on the market-to $411.7 million in 2009. The average price per prescription has risen in all the anti-asthma drug classes: overall, spending per prescription has increased 4-fold between 1991 and 2009

  6. Overcoming qEEG abnormalities and reward gene deficits during protracted abstinence in male psychostimulant and polydrug abusers utilizing putative dopamine D₂ agonist therapy: part 2.

    Science.gov (United States)

    Blum, Kenneth; Chen, Thomas J H; Morse, Siobhan; Giordano, John; Chen, Amanda Lih Chaun; Thompson, James; Allen, Cameron; Smolen, Andrew; Lubar, Joel; Stice, Eric; Downs, B William; Waite, Roger L; Madigan, Margaret A; Kerner, Mallory; Fornari, Frank; Braverman, Eric R

    2010-11-01

    It is well established that in both food- and drug-addicted individuals there is "dopamine resistance" associated with the DRD2 gene A1 allele. Based on earlier studies, evidence is emerging wherein the potential of utilizing a natural, nonaddicting, safe, putative D2 agonist may play a significant role in the recovery of individuals with reward deficiency syndrome, including those addicted to psychoactive chemicals. Positive outcomes demonstrated by quantitative electroencephalographic (qEEG) imaging in a randomized, triple-blind, placebo-controlled, crossover study involving oral Synaptose Complex KB220Z™ showed an increase of alpha waves and low beta wave activity in the parietal brain region. Using t statistics, significant differences observed between placebo and Synaptose Complex KB220Z™ consistently occurred in the frontal regions after week 1 and then again after week 2 of analyses (P = 0.03). This is the first report to demonstrate involvement of the prefrontal cortex in the qEEG response to a natural putative D2 agonist (Synaptose Complex KB220Z™), especially evident in dopamine D2 A1 allele subjects. Independently, we have further supported this finding with an additional study of 3 serious polydrug abusers undergoing protracted abstinence who carried the DRD2 A1 allele. Significant qEEG differences were found between those who received 1 dose of placebo compared with those who were administered Synaptose Complex KB220Z™. Synaptose Complex KB220Z™ induced positive regulation of the dysregulated electrical activity of the brain in these addicts. The results are indicative of a phase change from low amplitude or low power in the brain to a more regulated state by increasing an average of 6.169 mV(2) across the prefrontal cortical region. In the first experiment we found that while 50% of the subjects carried the DRD2 A1 allele, 100% carried ≥ 1 risk allele. Specifically, based on the proposed addiction risk score for these 14 subjects, 72% had

  7. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Østergaard, L; Frandsen, Christian S.; Madsbad, S

    2016-01-01

    Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases...... gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA....

  8. Analysis of Hydropower Potential Utilization of Watercourses in Slovakia

    Science.gov (United States)

    Gejguš, Mirko; Aschbacher, Christine; Sablik, Jozef

    2017-09-01

    This article analyzes the hydropower potential of watercourses in Slovakia, defining water as the most promising and most used renewable energy source. The hydro-energetic potential as a source of energy is determined by the calculation of the technically feasible potential of the watercourses, which is divided into exploited and unused. It also identifies the potential of utilizing the unused technical hydro-energetic potential.

  9. Sustainable utilization of biomass potentials; Nachhaltige Nutzung von Biomassepotenzialen

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2013-06-15

    The biomass potential and the efficiency of resource utilization can be increased by further progress of the following core areas: (1) Increase of the yields of crops for energy utilization and material utilization; (2) Reduced land use; (3) Exploration of unused land in accordance with other societal targets; (4) Enhanced utilization of residues and waste; (5) Increase of the resource efficiency by optimizing the conversion process; (6) Recycling in order to reduce the consumption of raw materials. A coverage of the primary energy demand from biomass under simultaneous consideration of the demand of raw materials is possible without additional imports of biomass and energy sources.

  10. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review.

    Science.gov (United States)

    Østergaard, L; Frandsen, Christian S; Madsbad, S

    2016-01-01

    Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP-1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA.

  11. Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches.

    Science.gov (United States)

    Vallée, Alexandre; Lecarpentier, Yves; Guillevin, Rémy; Vallée, Jean-Noël

    2018-04-16

    Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4⁺ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4⁺ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4⁺ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.

  12. Characterization of a Broadly Reactive Anti-CD40 Agonistic Monoclonal Antibody for Potential Use as an Adjuvant.

    Directory of Open Access Journals (Sweden)

    Cameron Martin

    Full Text Available Lack of safe and effective adjuvants is a major hindrance to the development of efficacious vaccines. Signaling via CD40 pathway leads to enhanced antigen processing and presentation, nitric oxide expression, pro-inflammatory cytokine expression by antigen presenting cells, and stimulation of B-cells to undergo somatic hypermutation, immunoglobulin class switching, and proliferation. Agonistic anti-CD40 antibodies have shown promising adjuvant qualities in human and mouse vaccine studies. An anti-CD40 monoclonal antibody (mAb, designated 2E4E4, was identified and shown to have strong agonistic effects on primary cells from multiple livestock species. The mAb recognize swine, bovine, caprine, and ovine CD40, and evoked 25-fold or greater proliferation of peripheral blood mononuclear cells (PBMCs from these species relative to cells incubated with an isotype control (p<0.001. In addition, the mAb induced significant nitric oxide (p<0.0001 release by bovine macrophages. Furthermore, the mAb upregulated the expression of MHC-II by PBMCs, and stimulated significant (p<0.0001 IL-1α, IL6, IL-8, and TNF-α expression by PBMCs. These results suggest that the mAb 2E4E4 can target and stimulate cells from multiple livestock species and thus, it is a potential candidate for adjuvant development. This is the first study to report an anti-swine CD40 agonistic mAb that is also broadly reactive against multiple species.

  13. In silico Analysis and Experimental Validation of Lignan Extracts from Kadsura longipedunculata for Potential 5-HT1AR Agonists.

    Directory of Open Access Journals (Sweden)

    Yaxin Zheng

    Full Text Available Kadsura longipedunculata (KL has been widely used for the treatment of insomnia in traditional Chinese medicine. The aim of this study was to explore the mechanism of the sedative and hypnotic effects of KL.The content of KL was evaluated by HPLC-TOF-MS, and a potential target was found and used to construct its 3D structure to screen for potential ligands among the compounds in KL by using bioinformatics analysis, including similarity ensemble approach (SEA docking, homology modeling, molecular docking and ligand-based pharmacophore. The PCPA-induced insomnia rat model was then applied to confirm the potential targets related to the sedative effects of KL by performing the forced swimming test (FST, the tail suspension test (TST and the measurement of target-related proteins using western blotting and immunofluorescence.Bioinformatics analysis showed that most of lignan compounds in KL were optimal ligands for the 5-HT1A receptor (5-HT1AR, and they were found to be potential targets related to sedative effects; the main lignan content of KL extracts was characterized by HPLC-TOF-MS, with 7 proposed lignans detected. Administration of KL could significantly reduce FST and TST immobility time in the PCPA-induced 5HT-depleted insomnia rat model. The expressions of proteins related to the 5-HT1AR pathway were regulated by extracts of KL in a concentration-dependent manner, indicating that extracts of KL had 5-HT1AR agonist-like effects.In silico analysis and experimental validation together demonstrated that lignan extracts from KL can target 5-HT1AR in insomniac rats, which could shed light on its use as a potential 5-HT1AR agonist drug.

  14. A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease.

    Directory of Open Access Journals (Sweden)

    Daniel Todd

    Full Text Available Huntington's disease (HD is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.

  15. In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1.

    Science.gov (United States)

    Pak, Y Anne; Long, Amanda J; Annes, William F; Witcher, Jennifer W; Knadler, Mary Pat; Ayan-Oshodi, Mosun A; Mitchell, Malcolm I; Leese, Phillip; Hillgren, Kathleen M

    2017-02-01

    Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with K m value of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC 50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter. Copyright © 2017 by The Author(s).

  16. Identification of potential hazards associated with tilapia utilization in ...

    African Journals Online (AJOL)

    Identification of potential hazards associated with the harvest, distribution and utilization of fresh Tilapia species in and around Minna metropolis was carried out using the Hazard Analysis and Critical Control Point (HACCP) principle. Fresh Tilapia fish samples were obtained from four (4) different locations within the period ...

  17. Potentiation of insulin secretion and improvement of glucose intolerance by combining a novel G protein-coupled receptor 40 agonist DS-1558 with glucagon-like peptide-1 receptor agonists.

    Science.gov (United States)

    Nakashima, Ryutaro; Yano, Tatsuya; Ogawa, Junko; Tanaka, Naomi; Toda, Narihiro; Yoshida, Masao; Takano, Rieko; Inoue, Masahiro; Honda, Takeshi; Kume, Shoen; Matsumoto, Koji

    2014-08-15

    G protein-coupled receptor 40 (GPR40) is a Gq-coupled receptor for free fatty acids predominantly expressed in pancreatic β-cells. In recent years, GPR40 agonists have been investigated for use as novel therapeutic agents in the treatment of type 2 diabetes. We discovered a novel small molecule GPR40 agonist, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (DS-1558). The GPR40-mediated effects of DS-1558 on glucose-stimulated insulin secretion were evaluated in isolated islets from GPR40 knock-out and wild-type (littermate) mice. The GPR40-mediated effects on glucose tolerance and insulin secretion were also confirmed by an oral glucose tolerance test in these mice. Furthermore, oral administration of DS-1558 (0.03, 0.1 and 0.3mg/kg) significantly and dose-dependently improved hyperglycemia and increased insulin secretion during the oral glucose tolerance test in Zucker fatty rats, the model of insulin resistance and glucose intolerance. Next, we examined the combination effects of DS-1558 with glucagon like peptide-1 (GLP-1). DS-1558 not only increased the glucose-stimulated insulin secretion by GLP-1 but also potentiated the maximum insulinogenic effects of GLP-1 after an intravenous glucose injection in normal Sprague Dawley rats. Furthermore, the glucose lowering effects of exendin-4, a GLP-1 receptor agonist, were markedly potentiated by the DS-1558 (3mg/kg) add-on in diabetic db/db mice during an intraperitoneal glucose tolerance test. In conclusion, our results indicate that add-on GPR40 agonists to GLP-1 related agents might be a potential treatment compared to single administration of these compounds. Therefore the combinations of these agents are a novel therapeutic option for type 2 diabetes. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Effects of glutamate receptor agonists on the P13 auditory evoked potential and startle response in the rat

    Directory of Open Access Journals (Sweden)

    Christen eSimon

    2011-01-01

    Full Text Available The P13 potential is the rodent equivalent of the P50 potential, which is an evoked response recorded at the vertex (Vx 50 msec following an auditory stimulus in humans. Both the P13 and P50 potentials are only present during waking and rapid eye movement (REM sleep, and are considered to be measures of level of arousal. The source of the P13 and P50 potentials appears to be the pedunculopontine nucleus (PPN, a brainstem nucleus with indirect ascending projections to the cortex through the intralaminar thalamus (ILT, mediating arousal, and descending inhibitory projections to the caudal pontine reticular formation (CPRF, which mediates the auditory startle response (SR. We tested the hypothesis that intracranial microinjection (ICM of glutamate (GLU or GLU receptor agonists will increase the activity of PPN neurons, resulting in an increased P13 potential response, and decreased SR due to inhibitory projections from the PPN to the CPRF, in freely moving animals. Cannulae were inserted into the PPN to inject neuroactive agents, screws were inserted into the Vx in order to record the P13 potential, and electrodes inserted into the dorsal nuchal muscle to record electromyograms (EMGs and SR amplitude. Our results showed that ICM of GLU into the PPN dose-dependently increased the amplitude of the P13 potential and decreased the amplitude of the SR. Similarly, ICM of NMDA or KA into the PPN increased the amplitude of the P13 potential. These findings indicate that glutamatergic input to the PPN plays a role in arousal control in vivo, and changes in glutamatergic input, or excitability of PPN neurons, could be implicated in a number of neuropsychiatric disorders with the common symptoms of hyperarousal and REM sleep dysregulation.

  19. Environmental Toxin Acrolein Alters Levels of Endogenous Lipids, Including TRP Agonists: A Potential Mechanism for Headache Driven by TRPA1 Activation.

    Science.gov (United States)

    Leishman, Emma; Kunkler, Phillip E; Manchanda, Meera; Sangani, Kishan; Stuart, Jordyn M; Oxford, Gerry S; Hurley, Joyce H; Bradshaw, Heather B

    2017-01-01

    Exposure to airborne toxins can trigger headaches, but the mechanisms are not well understood. Some environmental toxins, such as acrolein, activate transient receptor potential ankyrin 1 (TRPA1), a receptor involved in pain sensation that is highly expressed in the trigeminovascular system. It has been shown in rat models that repeated exposure to acrolein induces trigeminovascular sensitization to both TRPA1 and TRP vanilloid 1 (TRPV1) agonists, a phenomenon linked to headache. In this study, we test the hypothesis that the sensitization of trigeminovascular responses in rats after acrolein exposure via inhalation is associated with changes in levels of endogenous lipids, including TRPV1 agonists, in the trigeminal ganglia, trigeminal nucleus, and cerebellum. Lipidomics analysis of 80 lipids was performed on each tissue after acute acrolein, chronic acrolein, or room air control. Both acute and chronic acrolein exposure drove widespread alterations in lipid levels. After chronic acrolein exposure, levels of all 6 N -acyl ethanolamines in the screening library, including the endogenous cannabinoid and TRPV1 agonist, N -arachidonoyl ethanolamine, were elevated in trigeminal tissue and in the cerebellum. This increase in TRPV1 ligands by acrolein exposure may indicate further downstream signaling, in that we also show here that a combination of these TRPV1 endogenous agonists increases the potency of the individual ligands in TRPV1-HEK cells. In addition to these TRPV1 agonists, 3 TRPV3 antagonists, 4 TRPV4 agonists, and 25 orphan lipids were up and down regulated after acrolein exposure. These data support the hypothesis that lipid signaling may represent a mechanism by which repeated exposure to the TRPA1 agonist and environmental toxin, acrolein, drives trigeminovascular sensitization.

  20. Environmental toxin acrolein alters levels of endogenous lipids, including TRP agonists: A potential mechanism for headache driven by TRPA1 activation

    Directory of Open Access Journals (Sweden)

    Emma Leishman

    2017-01-01

    Full Text Available Exposure to airborne toxins can trigger headaches, but the mechanisms are not well understood. Some environmental toxins, such as acrolein, activate transient receptor potential ankyrin 1 (TRPA1, a receptor involved in pain sensation that is highly expressed in the trigeminovascular system. It has been shown in rat models that repeated exposure to acrolein induces trigeminovascular sensitization to both TRPA1 and TRP vanilloid 1 (TRPV1 agonists, a phenomenon linked to headache. In this study, we test the hypothesis that the sensitization of trigeminovascular responses in rats after acrolein exposure via inhalation is associated with changes in levels of endogenous lipids, including TRPV1 agonists, in the trigeminal ganglia, trigeminal nucleus, and cerebellum. Lipidomics analysis of 80 lipids was performed on each tissue after acute acrolein, chronic acrolein, or room air control. Both acute and chronic acrolein exposure drove widespread alterations in lipid levels. After chronic acrolein exposure, levels of all 6 N-acyl ethanolamines in the screening library, including the endogenous cannabinoid and TRPV1 agonist, N-arachidonoyl ethanolamine, were elevated in trigeminal tissue and in the cerebellum. This increase in TRPV1 ligands by acrolein exposure may indicate further downstream signaling, in that we also show here that a combination of these TRPV1 endogenous agonists increases the potency of the individual ligands in TRPV1-HEK cells. In addition to these TRPV1 agonists, 3 TRPV3 antagonists, 4 TRPV4 agonists, and 25 orphan lipids were up and down regulated after acrolein exposure. These data support the hypothesis that lipid signaling may represent a mechanism by which repeated exposure to the TRPA1 agonist and environmental toxin, acrolein, drives trigeminovascular sensitization. Keywords: Lipidomics, Endogenous cannabinoid, TRPA1, TRPV1, Lipoamine, Acrolein, Migraine

  1. On the hypothetical utilization of atmospheric potential energy

    Directory of Open Access Journals (Sweden)

    Thomas Frisius

    2014-09-01

    Full Text Available Atmospheric potential energy is typically divided into an available and a nonavailable part. In this article a hypothetical utilization of a fraction of the nonavailable potential energy is described. This part stems from the water vapor that can be converted into the liquid phase. An energy gain results when the potential energy of the condensate relative to a reference height exceeds the energy necessary to condensate the water vapor. It is shown that this can be the case in a saturated atmosphere without convective available potential energy. Finally, simulations with the numerical cloud model HURMOD are performed to estimate the usability of the device in practice. Indeed, a positive energy output results in a simulation with immediate gathering of the condensate. On the contrary, potential energy gained falls significantly short of the necessary energy for forming the condensate when a realistic cloud microphysical scheme allowing re-evaporation of condensate is applied. Taken together it can be concluded that, a utilization of atmospheric potential energy is hypothetically possible but the practical realization is probably not feasible.

  2. Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease

    Energy Technology Data Exchange (ETDEWEB)

    Stachel, Shawn J.; Zerbinatti, Celina; Rudd, Michael T.; Cosden, Mali; Suon, Sokreine; Nanda, Kausik K.; Wessner, Keith; DiMuzio, Jillian; Maxwell, Jill; Wu, Zhenhua; Uslaner, Jason M.; Michener, Maria S.; Szczerba, Peter; Brnardic, Edward; Rada, Vanessa; Kim, Yuntae; Meissner, Robert; Wuelfing, Peter; Yuan, Yang; Ballard, Jeanine; Holahan, Marie; Klein, Daniel J.; Lu, Jun; Fradera, Xavier; Parthasarathy, Gopal; Uebele, Victor N.; Chen, Zhongguo; Li, Yingjie; Li, Jian; Cooke, Andrew J.; Bennett, D. Jonathan; Bilodeau, Mark T.; Renger, John (Merck); (WuXi App Tec)

    2016-04-14

    Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.

  3. Preclinical evaluation of the abuse potential of Pitolisant, a histamine H3 receptor inverse agonist/antagonist compared with Modafinil

    Science.gov (United States)

    Uguen, M; Perrin, D; Belliard, S; Ligneau, X; Beardsley, PM; Lecomte, JM; Schwartz, JC

    2013-01-01

    Background and Purpose Pitolisant, a histamine H3 receptor inverse agonist/antagonist is currently under Phase III clinical trials for treatment of excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse potential was investigated using in vivo models in rodents and monkeys and compared with those of Modafinil, a psychostimulant currently used in the same indications. Experimental Approach Effects of Pitolisant on dopamine release in the nucleus accumbens, on spontaneous and cocaine-induced locomotion, locomotor sensitization were monitored. It was also tested in three standard drug abuse tests i.e. conditioned place preference in rats, self-administration in monkeys and cocaine discrimination in mice as well as in a physical dependence model. Key Results Pitolisant did not elicit any significant changes in dopaminergic indices in rat nucleus accumbens whereas Modafinil increased dopamine release. In rodents, Pitolisant was without any effect on locomotion and reduced the cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no conditioned hyperlocomotion were evidenced with this compound in rats whereas significant effects were elicited by Modafinil. Finally, Pitolisant was devoid of any significant effects in the three standard drug abuse tests (including self-administration in monkeys) and in the physical dependence model. Conclusions and Implications No potential drug abuse liability for Pitolisant was evidenced in various in vivo rodent and primate models, whereas the same does not seem so clear in the case of Modafinil. PMID:23472741

  4. The PPARα/γ Agonist, Tesaglitazar, Improves Insulin Mediated Switching of Tissue Glucose and Free Fatty Acid Utilization In Vivo in the Obese Zucker Rat

    Directory of Open Access Journals (Sweden)

    Kristina Wallenius

    2013-01-01

    Full Text Available Metabolic flexibility was assessed in male Zucker rats: lean controls, obese controls, and obese rats treated with the dual peroxisome proliferator activated receptor (PPAR agonist, tesaglitazar, 3 μmol/kg/day for 3 weeks. Whole body glucose disposal rate ( and hepatic glucose output (HGO were assessed under basal fasting and hyperinsulinemic isoglycemic clamp conditions using [3,3H]glucose. Indices of tissue specific glucose utilization ( were measured at basal, physiological, and supraphysiological levels of insulinemia using 2-deoxy-D-[2,6-3H]glucose. Finally, whole body and tissue specific FFA and glucose utilization and metabolic fate were evaluated under basal and hyperinsulinemic conditions using a combination of [U-13C]glucose, 2-deoxy-D-[U-14C]glucose, [U-14C]palmitate, and [9,10-3H]-(R-bromopalmitate. Tesaglitazar improved whole body insulin action by greater suppression of HGO and stimulation of compared to obese controls. This involved increased insulin stimulation of in fat and skeletal muscle as well as increased glycogen synthesis. Tesaglitazar dramatically improved insulin mediated suppression of plasma FFA level, whole body turnover (, and muscle, liver, and fat utilization. At basal insulin levels, tesaglitazar failed to lower HGO or compared to obese controls. In conclusion, the results demonstrate that tesaglitazar has a remarkable ability to improve insulin mediated control of glucose and FFA fluxes in obese Zucker rats.

  5. Membrane potential responses to ionophoretically applied alpha-adrenoceptor agonists in the mouse anococcygeus muscle.

    Science.gov (United States)

    Large, W. A.

    1983-01-01

    1 Noradrenaline phenylephrine, naphazoline and oxymetazoline were applied by ionophoresis to the mouse anococcygeus muscle and the membrane potential was recorded with an intracellular microelectrode. 2 The ionophoretic application of noradrenaline and phenylephrine produced dose-related depolarizations in 96% of the cells tested; in contrast, naphazoline and oxymetazoline depolarized only 62% of the cells although contraction was always seen. 3 The depolarizations produced by all four drugs had similar characteristics in shape and time course except that the latency of responses induced by the imidazoline-related drugs was significantly longer than the value obtained with the phenylethanolamines. This discrepancy was not due to the difference in susceptibility to neuronal uptake of the two groups of drugs. 4 The time to peak depolarization for naphazoline and oxymetazoline was longer than that for noradrenaline and phenylephrine but was not sufficient to account for the considerably slower contraction produced by the former drugs. 5 At room temperature the sensitivity of the mouse anococcygeus to ionophoretically applied naphazoline and oxymetazoline was significantly lower than that to noradrenaline and phenylephrine but at 35 degrees C the sensitivity was similar for all drugs. 6 These results suggest that there might be two subclasses of alpha 1-adrenoceptor in the mouse anococcygeus; stimulation of one type leads to depolarization and contraction and activation of the other class produces contraction with no change in membrane potential. PMID:6135476

  6. A snapshot of geothermal energy potential and utilization in Turkey

    International Nuclear Information System (INIS)

    Erdogdu, Erkan

    2009-01-01

    Turkey is one of the countries with significant potential in geothermal energy. It is estimated that if Turkey utilizes all of her geothermal potential, she can meet 14% of her total energy need (heat and electricity) from geothermal sources. Therefore, today geothermal energy is an attractive option in Turkey to replace fossil fuels. Besides, increase in negative effects of fossil fuels on the environment has forced many countries, including Turkey, to use renewable energy sources. Also, Turkey is an energy importing country; more than two-thirds of her energy requirement is supplied by imports. In this context, geothermal energy appears to be one of the most efficient and effective solutions for sustainable energy development and environmental pollution prevention in Turkey. Since geothermal energy will be used more and more in the future, its current potential, usage, and assessment in Turkey is the focus of the present study. The paper not only presents a review of the potential and utilization of the geothermal energy in Turkey but also provides some guidelines for policy makers. (author)

  7. Assessment of Global Wind Energy Resource Utilization Potential

    Science.gov (United States)

    Ma, M.; He, B.; Guan, Y.; Zhang, H.; Song, S.

    2017-09-01

    Development of wind energy resource (WER) is a key to deal with climate change and energy structure adjustment. A crucial issue is to obtain the distribution and variability of WER, and mine the suitable location to exploit it. In this paper, a multicriteria evaluation (MCE) model is constructed by integrating resource richness and stability, utilization value and trend of resource, natural environment with weights. The global resource richness is assessed through wind power density (WPD) and multi-level wind speed. The utilizable value of resource is assessed by the frequency of effective wind. The resource stability is assessed by the coefficient of variation of WPD and the frequency of prevailing wind direction. Regression slope of long time series WPD is used to assess the trend of WER. All of the resource evaluation indicators are derived from the atmospheric reanalysis data ERA-Interim with spatial resolution 0.125°. The natural environment factors mainly refer to slope and land-use suitability, which are derived from multi-resolution terrain elevation data 2010 (GMTED 2010) and GlobalCover2009. Besides, the global WER utilization potential map is produced, which shows most high potential regions are located in north of Africa. Additionally, by verifying that 22.22 % and 48.8 9% operational wind farms fall on medium-high and high potential regions respectively, the result can provide a basis for the macroscopic siting of wind farm.

  8. Role of methylglyoxal as a transient receptor potential ankyrin 1 agonist in colon motility disturbances associated with diabetes

    Directory of Open Access Journals (Sweden)

    Abdulmohsen Assiri

    2017-01-01

    Full Text Available Introduction: Evidence has been found to suggest that methylglyoxal (MG plays a mediating role in diabetes-related gastrointestinal conditions, and a possible mechanism relating to these conditions could be revealed by determining MG as a transient receptor potential ankyrin 1 (TRPA1 channel agonist. Methods: Muscle strips from the distal colon of male Wistar rats were used, and organ bath was employed to gain insight into the impact of MG + TRPA1 antagonist (HC-030031. Results: Considerable rise of spontaneous contractions for longitudinal muscle strips subjected to pre-treatment with MG were observed. The potentiation of the contractile response of control longitudinal muscle strips to electric field stimulation (EFS took place as a consequence of pre-treatment with 10 mM MG, and maximum response values displayed a rise from 2.16 g ± 0.323 to 3.64 g ± 0.421. 10 μM HC-030031 was observed to block the improvement of EFS responses by MG, and regarding circular muscle strips, a considerable decline in the maximum relaxation response was facilitated by 10 mM MG. Specifically, this was achieved at 20 Hz from 0.26 g ± 0.036 to 0.055 g ± 0.046. Conclusion: MG has been found to directly contract the distal colons of Wistar rats while enhancing the responses initiated as a result of carbachol and EFS. After blockading the impacts using HC-030031, evidence was found to suggest that the mediation of the impacts takes place through the activation of the TRPA1 channel, which occurs from the excretion of excitatory neurotransmitters. The findings also implicate MG in the blocking of inhibitory neurotransmission.

  9. Salvinorin A, a kappa-opioid receptor (KOP-r agonist hallucinogen: Pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Eduardo eButelman

    2015-09-01

    Full Text Available Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins in higher functions, including cognition, and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A- containing products have undergone frequent non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and drug reinforcers (including drugs of abuse. KOPr activation (including by salvinorin A can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike all other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects, with a reduced burden of undesirable effects associated with salvinorin A.

  10. Antipruritic Effect of Cold-induced and Transient Receptor Potential-agonist-induced Counter-irritation on Histaminergic Itch in Humans

    DEFF Research Database (Denmark)

    Andersen, Hjalte H.; Melholt, Camilla; Hilborg, Sigurd D.

    2017-01-01

    A frequent empirical observation is that cold-induced counter-irritation may attenuate itch. The aim of this randomized, single-blinded, exploratory study was to evaluate the counter-irritation effects of cold-stimulation and topical application of transient receptor potential TRPA1/M8-agonists...... and trans-cinnamaldehyde had antipruritic efficacy similar to doxepin (p Cold-induced counter-irritation had an inhibitory effect on histaminergic itch, suggesting that agonists of cold transduction receptors could be of potential antipruritic value....... (measured by laser-speckle perfusion-imaging). Homotopic thermal counter-irritation was performed with 6 temperatures, ranging from 4°C to 37°C, using a 3 × 3-cm thermal stimulator. Chemical “cold-like” counter-irritation was conducted with 40% L-menthol and 10% trans-cinnamaldehyde, while 5% doxepin...

  11. Space Resource Utilization: Technologies and Potential Synergism with Terrestrial Mining

    Science.gov (United States)

    Sanders, Gerald B.

    2015-01-01

    Space Resources and Their Uses: The idea of using resources in space to support human exploration and settlement or for economic development and profit beyond the surface of Earth has been proposed and discussed for decades. Work on developing a method to extract oxygen from lunar regolith started even before humans set foot on the Moon for the first time. The use of space resources, commonly referred to as In Situ Resource Utilization (ISRU), involves the processes and operations to harness and utilize resources in space (both natural and discarded) to create products for subsequent use. Potential space resources include water, solar wind implanted volatiles (hydrogen, helium, carbon, nitrogen, etc.), vast quantities of metals and minerals in extraterrestrial soils, atmospheric constituents, unlimited solar energy, regions of permanent light and darkness, the vacuum and zero-gravity of space itself, trash and waste from human crew activities, and discarded hardware that has completed its primary purpose. ISRU covers a wide variety of concepts, technical disciplines, technologies, and processes. When considering all aspects of ISRU, there are 5 main areas that are relevant to human space exploration and the commercialization of space: 1. Resource Characterization and Mapping, 2. In Situ Consumables Production, 3. Civil Engineering and Construction, 4. In Situ Energy Production and Storage, and 5. In Situ Manufacturing.

  12. Potential of utilizing solar cooling in The University of Jordan

    International Nuclear Information System (INIS)

    Fasfous, A.; Asfar, J.; Al-Salaymeh, A.; Sakhrieh, A.; Al-Hamamre, Z.; Al-bawwab, A.; Hamdan, M.

    2013-01-01

    Highlights: ► Potential of utilizing a solar cooling system in Jordan is investigated. ► The suggested system will be used for cooling a 41 m 2 laboratory. ► Solar collectors of 196 m 2 are required for an 8 kW solar air-conditioning system. ► The estimated payback period of the solar cooling system exceeds the project life time of the project. - Abstract: In this paper, the potential of utilizing a solar cooling system to improve the indoor air quality is investigated. The analysis is performed for a 41 m 2 with a 3.65 m height laboratory located at Mango Center for Scientific Research – University of Jordan in Amman. The hourly ambient temperatures and the monthly solar radiation in Amman are recorded. The calculations of the cooling demand were done using two methods, i.e. manual calculations and block load software. For the analysis, the internal loads of lightning, computer, etc. and the building envelope (e.g. double glass, no shading) were considered. The results show that proposed solar collectors of 40 m 2 area can provide solar heat for an 8 kW solar air-conditioning system. Moreover, domestic hot water (solar fraction up to 100%) and solar heating (approx. 15–25% solar fraction) could be also provided, with the solar air-conditioning system, for the centre. An economic study was also carried, which showed that the estimated payback period of the solar cooling system, exceeds that of project life time of the project, which is assumed to be 24 years unless the government of Jordan issues a new law for renewable energy that grants incentives, exemptions and subsidizes projects that invest in solar energy applications by about 40% of initial investment cost of the system.

  13. The μ opioid agonist morphine modulates potentiation of capsaicin-evoked TRPV1 responses through a cyclic AMP-dependent protein kinase A pathway

    Directory of Open Access Journals (Sweden)

    Roberts-Thomson Sarah J

    2006-07-01

    Full Text Available Abstract Background The vanilloid receptor 1 (TRPV1 is critical in the development of inflammatory hyperalgesia. Several receptors including G-protein coupled prostaglandin receptors have been reported to functionally interact with the TRPV1 through a cAMP-dependent protein kinase A (PKA pathway to potentiate TRPV1-mediated capsaicin responses. Such regulation may have significance in inflammatory pain. However, few functional receptor interactions that inhibit PKA-mediated potentiation of TRPV1 responses have been described. Results In the present studies we investigated the hypothesis that the μ opioid receptor (MOP agonist morphine can modulate forskolin-potentiated capsaicin responses through a cAMP-dependent PKA pathway. HEK293 cells were stably transfected with TRPV1 and MOP, and calcium (Ca2+ responses to injection of the TRPV1 agonist capsaicin were monitored in Fluo-3-loaded cells. Pre-treatment with morphine did not inhibit unpotentiated capsaicin-induced Ca2+ responses but significantly altered capsaicin responses potentiated by forskolin. TRPV1-mediated Ca2+ responses potentiated by the direct PKA activator 8-Br-cAMP and the PKC activator Phorbol-12-myristate-13-acetatewere not modulated by morphine. Immunohistochemical studies confirmed that the TRPV1 and MOP are co-expressed on cultured Dorsal Root Ganglion neurones, pointing towards the existence of a functional relationship between the G-protein coupled MOP and nociceptive TRPV1. Conclusion The results presented here indicate that the opioid receptor agonist morphine acts via inhibition of adenylate cyclase to inhibit PKA-potentiated TRPV1 responses. Targeting of peripheral opioid receptors may therefore have therapeutic potential as an intervention to prevent potentiation of TRPV1 responses through the PKA pathway in inflammation.

  14. Non-glycaemic effects mediated via GLP-1 receptor agonists and the potential for exploiting these for therapeutic benefit

    DEFF Research Database (Denmark)

    Vilsbøll, T; Garber, A J

    2012-01-01

    The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and exenatide can improve glycaemic control by stimulating insulin release through pancreatic β-cells in a glucose-dependent manner. GLP-1 receptors are not restricted to the pancreas; therefore, GLP-1 RAs cause additional non-...... for GLP-1 RAs in the cardiovascular and central nervous systems has been suggested from animal studies and short-term clinical trials. These effects and other safety aspects of GLP-1 therapy are currently being investigated in ongoing long-term clinical studies.......The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and exenatide can improve glycaemic control by stimulating insulin release through pancreatic β-cells in a glucose-dependent manner. GLP-1 receptors are not restricted to the pancreas; therefore, GLP-1 RAs cause additional non...

  15. Evaluating Utility Gloves as a Potential Reservoir for Pathogenic Bacteria.

    Science.gov (United States)

    Grant, Kathy L; Naber, E Donald; Halteman, William A

    2015-08-01

    This pilot study sought to determine the rate and degree to which gram-negative Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa and gram-positive Staphylococcus aureus occurred on the inside of utility gloves used at University of Maine at Augusta, Dental Health Programs' dental hygiene clinic. Five steam autoclave utility gloves were randomly selected to serve as control and a convenience sample of 10 used utility gloves were selected from the sterilization area. A sample was collected from a predetermined surface area from the inside of each steam autoclave utility glove and used utility glove. Each sample was used to inoculate a Petri plate containing 2 types of culture media. Samples were incubated at 37° C for 30 to 36 hours in aerobic conditions. Colony forming units (CFU) were counted. Confidence intervals (CI) estimated the rate of contamination with gram-negative K. pneumoniae, E. coli and P. aeruginosa on the inside of steam autoclave utility gloves to be n=33 95% CL [0.000, 0.049], used utility gloves to be n=70, 95% CL [0.000, 0.0303]. Data estimated the rate of contamination with gram-positive S. aureus on the inside of steam autoclave utility gloves to be n=35, 95% CL [0.233, 0.530], used utility gloves to be n=70, 95% CL [0.2730, 0.4975]. Culture media expressed a wide range of CFU from 0 to over 200. The risk of utility glove contamination with gram-negative bacteria is likely low. The expressed growth of S. aureus from steam autoclave utility gloves controls raises questions about the effectiveness and safety of generally accepted sterilization standards for the governmentally mandated use of utility gloves. Copyright © 2015 The American Dental Hygienists’ Association.

  16. Studies To Examine Potential Tolerability Differences between the 5-HT2C Receptor Selective Agonists Lorcaserin and CP-809101.

    Science.gov (United States)

    Higgins, Guy A; Silenieks, Leonardo B; Patrick, Amy; De Lannoy, Ines A M; Fletcher, Paul J; Parker, Linda A; MacLusky, Neil J; Sullivan, Laura C; Chavera, Teresa A; Berg, Kelly A

    2017-05-17

    Lorcaserin (LOR) is a selective 5-HT 2C receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT 2C agonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT 2C agonists having better tolerability, the present studies were designed to further investigate this apparent difference. In a conditioned gaping model, a rodent test of nausea, LOR produced significantly higher gapes compared to CP consistent with it having higher emetogenic properties. Subsequent studies were designed to identify features of each drug that may account for such differences. In rats trained to discriminate CP-809101 from saline, both CP and LOR produced full generalization suggesting a similar interoceptive cue. In vitro tests of functional selectivity designed to examine signaling pathways activated by both drugs in CHO (Chinese hamster ovary) cells expressing h5-HT 2C receptors failed to identify evidence for biased signaling differences between LOR and CP. Thus, both drugs showed similar profiles across PLC, PLA 2 , and ERK signaling pathways. In studies designed to examine pharmacokinetic differences between LOR and CP, while drug plasma levels correlated with increasing dose, CSF levels did not. CSF levels of LOR increased proportionally with dose; however CSF levels of CP plateaued from 6 to 12 mg/kg. Thus, the apparently improved tolerability of CP likely reflects a limit to CNS levels attained at relatively high doses.

  17. Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents.

    Science.gov (United States)

    Cheng, Jianjun; Giguère, Patrick M; Onajole, Oluseye K; Lv, Wei; Gaisin, Arsen; Gunosewoyo, Hendra; Schmerberg, Claire M; Pogorelov, Vladimir M; Rodriguiz, Ramona M; Vistoli, Giulio; Wetsel, William C; Roth, Bryan L; Kozikowski, Alan P

    2015-02-26

    The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic receptor and 5-HT2B receptor.

  18. Waste heat utilization. Potentials, savings, alternatives; Restwarmtebenutting. Potentielen, besparing, alternatieven

    Energy Technology Data Exchange (ETDEWEB)

    Daniels, B.W.; Wemmers, A.K.; Tigchelaar, C.; Wetzels, W. [ECN Beleidsstudies, Petten (Netherlands)

    2011-11-15

    This report provides an inventory of potential and costs for waste heat utilization in the Netherlands for low temperature application in households, services and greenhouse horticulture towards 2020. Despite large amounts of available waste heat, the amount that makes sense to be used in heat distribution for households, offices and greenhouses is relatively limited: an estimated 20 to 45 PJ. Deployment of this waste heat would result in an estimated 10-25 PJ saving of primary energy. The main cause for this apparent discrepancy between a large supply of waste heat and limited possibilities for using it, is the poor match between supply and demand: heat is often not available at the right temperature level, the right time and the right place. Moreover, alternatives for deployment of waste heat on the supply side and alternative heat sources on the demand side, may be more attractive in terms of savings, emission reductions and costs. The quantitative results that are shown represent indications of effects on energy use, emissions and costs, but do not reflect specific cases. [Dutch] Benutting van restwarmte van elektriciteitscentrales en industrie kan energiebesparing en CO2-emissreducties opleveren. Uit deze studie blijkt dat het deel dat praktisch en zinvol te benutten is voor warmtedistributie in Nederland relatief beperkt is, ondanks een grote beschikbaarheid van restwarmte. Zinvolle benutting betekent hier dat de restwarmtebenutting daadwerkelijk energie bespaart en/of CO2-emissies reduceert, dat de kosten acceptabel zijn, en dat er geen alternatieven zijn die goedkoper of makkelijker ongeveer dezelfde energiebesparing of emissiereductie kunnen opleveren. Dit praktisch en zinvol te benutten deel ligt tot 2020 naar schatting tussen de 25 en 45 PJ. Inzet hiervan bespaart 10 tot 25 PJ aan fossiele brandstof. De netto CO2-emissiereductie die dit oplevert is 0,6 tot 1,3 Mton. Deze netto emissiereductie bestaat uit een toename van de emissies bij de warmteproducent

  19. Is Kratom the New 'Legal High' on the Block?: The Case of an Emerging Opioid Receptor Agonist with Substance Abuse Potential.

    Science.gov (United States)

    Chang-Chien, George C; Odonkor, Charles A; Amorapanth, Prin

    2017-01-01

    Kratom is an unscheduled opioid receptor agonist that comes in the form of dietary supplements currently being abused by chronic pain patients on prescription opioids. Active alkaloids isolated from kratom such as mitragynine and 7-hydroxymitragynine are thought to act on mu- and delta-opioid receptors as well as alpha-2 adrenergic and 5-HT2A receptors. Animal studies suggest that kratom may be more potent than morphine. Consequently, kratom consumption produces analgesic and euphoric feelings among users. In particular, some chronic pain patients on opioids take kratom to counteract the effects of opioid withdrawal. Although the Food and Drug Administration has banned its use as a dietary supplement, kratom continues to be widely available and easily accessible on the Internet at much less expensive rates than some opioid replacement therapies like buprenorphine. There are no federal regulations monitoring the sale and distribution of this drug, yet kratom has been associated with severe signs and symptoms such as hallucinations, delusions, depressions, myalgias, chills, nausea/vomiting, respiratory hepatoxicity, seizures, coma, and death. A search of the pain literature shows past research has not described the use and potential deleterious effects of this drug. Many pain physicians are not familiar with kratom and as providers who take care of high-risk chronic pain patients using prescribed opioids, knowledge of current unregulated opioid receptor agonists with abuse potential is of paramount importance. The goal of this article is to introduce kratom to pain specialists and to spur a conversation on how pain physicians may take the lead to help curb the opioid abuse and overdose epidemic. Further studies may be required to help better understand the clinical and long-term effects of kratom use among chronic pain patients.Key words: Opioid receptor agonist, Kratom, Mitragynine, opioid overdose, chronic pain, substance abuse.

  20. Antipruritic Effect of Cold-induced and Transient Receptor Potential-agonist-induced Counter-irritation on Histaminergic Itch in Humans.

    Science.gov (United States)

    Andersen, Hjalte H; Melholt, Camilla; Hilborg, Sigurd D; Jerwiarz, Anne; Randers, Amalie; Simoni, Amalie; Elberling, Jesper; Arendt-Nielsen, Lars

    2017-01-04

    A frequent empirical observation is that cold-induced counter-irritation may attenuate itch. The aim of this randomized, single-blinded, exploratory study was to evaluate the counter-irritation effects of cold-stimulation and topical application of transient receptor potential TRPA1/M8-agonists (trans-cinnamaldehyde/L-menthol, respectively), on histamine-induced itch, wheals and neurogenic inflammation in 13 healthy volunteers. Histamine 1% was applied to the volar forearms using skin prick-test lancets. Recorded outcome-parameters were itch intensity, wheal reactions, and neurogenic inflammation (measured by laser-speckle perfusion-imaging). Homotopic thermal counter-irritation was performed with 6 temperatures, ranging from 4°C to 37°C, using a 3 × 3-cm thermal stimulator. Chemical "cold-like" counter-irritation was conducted with 40% L-menthol and 10% trans-cinnamaldehyde, while 5% doxepin was used as a positive antipruritic control/comparator. Cold counter-irritation stimuli from 4°C to 22°C inhibited itch in a stimulus-intensity-dependent manner (p cold-like" counter-irritation with both L-menthol and trans-cinnamaldehyde had antipruritic efficacy similar to doxepin (p Cold-induced counter-irritation had an inhibitory effect on histaminergic itch, suggesting that agonists of cold transduction receptors could be of potential antipruritic value.

  1. Nuclear Education and Training Programs of Potential Interest to Utilities.

    Science.gov (United States)

    Atomic Energy Commission, Washington, DC.

    This compilation of education and training programs related to nuclear applications in electric power generation covers programs conducted by nuclear reactor vendors, public utilities, universities, technical institutes, and community colleges, which were available in December 1968. Several training-program consultant services are also included.…

  2. The Potential Utility of Pharmacogenetic Testing in Psychiatry

    Directory of Open Access Journals (Sweden)

    Kathryn R. Gardner

    2014-01-01

    Full Text Available Over the last decade, pharmacogenetics has become increasingly significant to clinical practice. Psychiatric patients, in particular, may benefit from pharmacogenetic testing as many of the psychotropic medications prescribed in practice lead to varied response rates and a wide range of side effects. The use of pharmacogenetic testing can help tailor psychotropic treatment and inform personalized treatment plans with the highest likelihood of success. Recently, many studies have been published demonstrating improved patient outcomes and decreased healthcare costs for psychiatric patients who utilize genetic testing. This review will describe evidence supporting the clinical utility of genetic testing in psychiatry, present several case studies to demonstrate use in everyday practice, and explore current patient and clinician opinions of genetic testing.

  3. Market potential of heat utilization of modular HTR in Japan

    International Nuclear Information System (INIS)

    Ide, Akira; Tasaka, Kanji.

    1993-01-01

    HTR is considered to be the most suitable reactor type to use in the field other than power generation. So it is useful to know market potential of this type of reactor in Japan to justify its development. This potential was estimated to be about 400 200MWt modular HTR reactors. This number will be double if the market of hydrogen is developed. (J.P.N.)

  4. Utility Potential of Parthenium hysterophorus for Its Strategic Management

    Directory of Open Access Journals (Sweden)

    Anita Saini

    2014-01-01

    Full Text Available Parthenium hysterophorus, one of the world’s most dangerous weeds, is responsible for huge losses to the biodiversity, agriculture, economy, and health of livestock and human beings. High competitive success rate and adaptability of the species enable it to dominate diverse types of habitats. Various weed control strategies are being used globally to reduce its population to manageable levels. But owing to many limitations associated with the conventional methods, management of Parthenium still remains a challenge. Recently large scale utilization has been taken up as a holistic approach for the control of weeds. Parthenium hysterophorus can be managed by exploiting this weed in diverse fields. In agriculture, it can be used either as green manure or after composting. Industrially it can be used for producing various value added products. The weed also exhibits many environmental applications. Chemical constituents of Parthenium show extensive range of pharmacological activities suggesting its role as a chemotherapeutic agent. This review briefly discusses the problem of Parthenium and enlists its possible utilities which can open new avenues for effective management of this violent weed.

  5. Harnessing the incretin system beyond glucose control: potential cardiovascular benefits of GLP-1 receptor agonists in type 2 diabetes.

    Science.gov (United States)

    Cariou, B

    2012-10-01

    The management of type 2 diabetes continues to evolve as new data emerge. Although glycaemic control is still important, other risk factors--such as hypertension, dyslipidaemia and obesity--must also be addressed in order to reduce the long-term risks of cardiovascular complications and mortality. In this context, targeting the incretin system, and glucagon-like peptide-1 (GLP-1) in particular, has generated much interest. GLP-1 is released from the gut in response to food ingestion and plays a crucial role in glucose homeostasis. GLP-1 receptors are expressed in the heart and vasculature, prompting evaluation of their physiological role and pharmacological stimulation, both in healthy and disease states. These studies indicate that GLP-1 and GLP-1-based therapies appear to have direct, beneficial effects on the cardiovascular system, in addition to their glucose-lowering properties, such as modulation of blood pressure, endothelial function, and myocardial contractility. Intriguingly, some of these effects appear to be independent of GLP-1 receptor signalling. Data from clinical studies of the GLP-1 receptor agonists, exenatide and liraglutide on cardiovascular risk factors, in patients with type 2 diabetes are also promising and the results from prospective studies to assess cardiovascular outcomes are eagerly awaited. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  6. The benzodiazepine diazepam potentiates responses of α1β2γ2 γ-aminobutyric acid type A receptors activated by either γ-aminobutyric acid or allosteric agonists

    Science.gov (United States)

    Li, Ping; Eaton, Megan M.; Steinbach, Joe Henry; Akk, Gustav

    2013-01-01

    Background The γ-aminobutyric acid type A receptor is target for several anesthetics, anticonvulsants, anxiolytics and sedatives. Neurosteroids, barbiturates and etomidate both potentiate responses to γ-aminobutyric acid (GABA) and allosterically activate the receptor. We examined the ability of a benzodiazepine, diazepam, to potentiate responses to allosteric agonists. Methods The γ-aminobutyric acid type A receptors were expressed in human embryonic kidney 293 cells, and studied using whole-cell and single-channel patch clamp. The receptors were activated by the orthosteric agonist GABA, and allosteric agonists pentobarbital, etomidate and alfaxalone. Results Diazepam is equally potent at enhancing responses to orthosteric and allosteric agonists. Diazepam EC50s were 25±4, 26±6, 33±6, and 26±3 nM for receptors activated by GABA, pentobarbital, etomidate, and alfaxalone, respectively (mean±S.D., 5–6 cells at each condition). Mutations to the benzodiazepine-binding site (α1(H101C), γ2(R144C), γ2(R197C)) reduced or removed potentiation for all agonists, and an inverse agonist at the benzodiazepine site reduced responses to all agonists. Single-channel data elicited by GABA demonstrate that in the presence of 1 μM diazepam the prevalence of the longest open-time component is increased from 13±7 (mean±S.D., n=5 patches) to 27±8 % (n=3 patches) and the rate of channel closing is decreased from 129±28 s−1 to 47±6 s−1 (mean±S.D.) Conclusions We conclude that benzodiazepines do not act by enhancing affinity of the orthosteric site for GABA but rather by increasing channel gating efficacy. The results also demonstrate the presence of significant interactions between allosteric activators and potentiators, raising a possibility of effects on dosage requirements or changes in side effects. PMID:23407108

  7. Potential utility of the thematic mapper for surface mine monitoring

    International Nuclear Information System (INIS)

    Irons, J.R.; Lachowski, H.M.

    1981-01-01

    One of many potential applications of the thematic mapper (TM) is surface mine monitoring. To assess this potential, data acquired by an aircraft multispectral scanner over Pennsylvania surface mines were preprocessed to simulate the anticipated spectral, spatial, and radiometric characteristics of TM data. False color imagery and thematic maps were derived from the simulated data and compared to imagery and maps derived from LANDSAT multispectral scanner subsystems data. On the basis of this comparison, TM data should definitely increase the detail and accuracy of remotely acquired surface mine information and may enable the remote determination of compliance with reclamation regulations

  8. Potential industrial utilization of starches extracted from new yellow ...

    African Journals Online (AJOL)

    In this study, starches of some improved cassava varieties were analyzed in order to detect those revealing potentialities and aptitude for industrial exploitation. ... All starches showed very strong water absorption capacity with the strong value recorded by V53 (122.52 ± 1.57 %) and the lowest by V63 (104.84 ± 0.55 %) and ...

  9. Utilization of leaf litter as a potential feed source

    Science.gov (United States)

    Proximate analysis and In-situ nylon bag ruminal dry matter degradation of fall dropped Liriodendron tulipifera (tulip poplar) and Quercus alba (white oak) leaves were used to determine their potential use as a feed source for ruminant livestock animals. Ash content was 8.24 and 4.69 ...

  10. Energy Saving Potential by Utilizing Natural Ventilation under Warm Conditions

    DEFF Research Database (Denmark)

    Oropeza-Perez, Ivan; Østergaard, Poul Alberg

    2014-01-01

    –airflow simulations of 27 common cases of dwellings (considered as one thermal zone) based on the combination of specific features of the building design, occupancy and climate conditions. The energy saving potential is assessed then by the use of a new assessment method suitable for large-scale scenarios using......The objective of this article is to show the potential of natural ventilation as a passive cooling method within the residential sector of countries which are located in warm conditions using Mexico as a case study. The method is proposed as performing, with a simplified ventilation model, thermal...... the actual number of air-conditioned dwellings distributed among the 27 cases. Thereby, the energy saving is presented as the difference in the cooling demand of the dwelling during one year without and with natural ventilation, respectively. Results indicate that for hot-dry conditions, buildings with high...

  11. FGF21-based pharmacotherapy--potential utility for metabolic disorders.

    Science.gov (United States)

    Gimeno, Ruth E; Moller, David E

    2014-06-01

    Currently available therapies for diabetes or obesity produce modest efficacy and are usually used in combination with agents targeting cardiovascular risk factors. Fibroblast growth factor 21 (FGF21) is a circulating protein with pleiotropic metabolic actions; pharmacological doses of FGF21 produce anti-diabetic, lipid-lowering, and weight-reducing effects in rodents. Several potential benefits have translated to non-human primates and obese humans with type 2 diabetes (T2D). Accumulating results point to a specific receptor complex and actions in adipose tissue, liver, and brain; several pathways lead to enhanced fatty acid oxidation, increased insulin sensitivity, and augmented energy expenditure. A range of strategies are being explored to derive potent, safe, and convenient therapies which could potentially represent novel approaches to prevent and treat a variety of metabolic disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Environmental characteristics and utilization potential of metallurgical slag: Chapter 19

    Science.gov (United States)

    Piatak, Nadine; De Vivo, Benedetto; Belkin, Harvey E.; Lima, Annamaria

    2018-01-01

    Slag, an abundant byproduct from the pyrometallurgical processing of ores, can be an environmental liability or a valuable resource. The most common environmental impact of slag is from the leaching of potentially toxic elements, acidity, or alkalinity that may impact nearby soils and surface water and groundwater. Factors that influence its environmental behavior include physical characteristics, such as grain size and porosity, chemical composition with some slag being enriched in certain elements, the mineralogy and partitioning of elements in more or less reactive phases, water-slag interactions, and site conditions. Many of these same factors also influence its resource potential. For example, crystalline ferrous slag is most commonly used as construction aggregate, whereas glassy (i.e., granulated) slag is used in cement. Also, the calcium minerals found in ferrous slag result in useful applications in water treatment. In contrast, the high trace-element content of some base-metal slags makes the slags economically attractive for extraction of residual elements. An evaluation tool is used to help categorize a particular slag as an environmental hazard or valuable byproduct. Results for one type of slag, legacy steelmaking slag from the Chicago area in the USA, suggest the material has potential to be used for treating phosphate-rich or acidic waters; however, the pH and trace-element content of resulting solutions may warrant further examination.

  13. Potential Utility of Non-Cognitive Constructs in Graduate Admissions

    Science.gov (United States)

    Miller, Casey

    2015-03-01

    It is becoming clear that the methods employed by many graduate admissions committees need updating. Regarding outcomes, we cannot select students that will actually graduate much better than would a coin toss. Further, the GRE is often misused. For example, the most recent GRE general test data (2006-2007) shows that for US citizens in the physical sciences, a cut-off score of ~64th percentile (700/155 on old/new test) would eliminate from eligibility: 63% of women vs 42% of men; 76% of all under-represented minorities vs 38% of Asian and 47% of White applicants. Fortunately, Organizational Psychologists have identified and validated several ``non-cognitive constructs'' for admissions: aspects of personality (conscientiousness); and self-management factors. Some intriguing facts about these parameters: they are measurable with the help of social scientists; they do not show race/ethnicity/gender performance differences; they are orthogonal to cognitive metrics measured by GPA and tests scores. These are proven to enhance both validity and diversity in admissions. My goals for this talk are to overview the non-cognitive constructs with the most potential for being used in physics graduate admissions, and to suggest example admissions protocols. Supported by the National Science Foundation.

  14. [Potential utility of ceftaroline fosamil in osteoarticular infections].

    Science.gov (United States)

    Reinoso, Javier Cobo; Cardenal, Javier Ariza

    2014-03-01

    Osteoarticular infections (OAI) include a wide-usually complex-spectrum of clinical scenarios. The approach is usually medical-surgical. In addition to this complexity, there is a low grade of evidence in the medical literature on these infections. Nevertheless, it is possible-and necessary-to integrate microbiological, pharmacological, experimental and clinical information to achieve the best possible clinical results. The most appropriate choice of antibiotic therapy largely depends on the clinical scenario and, obviously, on the microorganisms involved. Given the protagonism of staphylococci in OAI, it is appropriate to elucidate the role that could be played by a new antistaphylococcic agent in these infections. For clinicians who manage OAI, the incorporation of ceftaroline represents the recovery of a beta-lactam to treat methicillin-resistant staphylococci. This perspective can be used to guide the potential role of this new antibiotic for the management of OAI in various scenarios and the clinical research required for its introduction in clinical practice. Copyright © 2014 Elsevier España, S.L. All rights reserved.

  15. FTBMT, a Novel and Selective GPR52 Agonist, Demonstrates Antipsychotic-Like and Procognitive Effects in Rodents, Revealing a Potential Therapeutic Agent for Schizophrenia.

    Science.gov (United States)

    Nishiyama, Keiji; Suzuki, Hirobumi; Harasawa, Toshiya; Suzuki, Noriko; Kurimoto, Emi; Kawai, Takayuki; Maruyama, Minoru; Komatsu, Hidetoshi; Sakuma, Kensuke; Shimizu, Yuji; Shimojo, Masato

    2017-11-01

    GPR52 is a Gs-coupled G protein-coupled receptor that is predominantly expressed in the striatum and nucleus accumbens (NAc) and was recently proposed as a potential therapeutic target for schizophrenia. In the current study, we investigated the in vitro and in vivo pharmacologic activities of a novel GPR52 agonist, 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-1 H -1,2,4-triazol-1-yl)-2-methylbenzamide (FTBMT). FTBMT functioned as a selective GPR52 agonist in vitro and in vivo, as demonstrated by the activation of Camp signaling in striatal neurons. FTBMT inhibited MK-801-induced hyperactivity, an animal model for acute psychosis, without causing catalepsy in mice. The c-fos expression also revealed that FTBMT preferentially induced neuronal activation in the shell of the Nac compared with the striatum, thereby supporting its antipsychotic-like activity with less catalepsy. Furthermore, FTBMT improved recognition memory in a novel object-recognition test and attenuated MK-801-induced working memory deficits in a radial arm maze test in rats. These recognitive effects were supported by the results of FTBMT-induced c-fos expression in the brain regions related to cognition, including the medial prefrontal cortex, entorhinal cortex, and hippocampus. Taken together, these findings suggest that FTBMT shows antipsychotic and recognitive properties without causing catalepsy in rodents. Given its unique pharmacologic profile, which differs from that of current antipsychotics, FTBMT may provide a new therapeutic option for the treatment of positive and cognitive symptoms of schizophrenia. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  16. Environmental potential of carbon dioxide utilization in the polyurethane supply chain.

    Science.gov (United States)

    von der Assen, Niklas; Sternberg, André; Kätelhön, Arne; Bardow, André

    2015-01-01

    Potential environmental benefits have been identified for the utilization of carbon dioxide (CO2) as a feedstock for polyurethanes (PUR). CO2 can be utilized in the PUR supply chain in a wide variety of ways ranging from direct CO2 utilization for polyols as a PUR precursor, to indirect CO2 utilization for basic chemicals in the PUR supply chain. In this paper, we present a systematic exploration and environmental evaluation of all direct and indirect CO2 utilization options for flexible and rigid PUR foams. The analysis is based on an LCA-based PUR supply chain optimization model using linear programming to identify PUR production with minimal environmental impacts. The direct utilization of CO2 for polyols allows for large specific impact reductions of up to 4 kg CO2-eq. and 2 kg oil-eq. per kg CO2 utilized, but the amounts of CO2 that can be utilized are limited to 0.30 kg CO2 per kg PUR. The amount of CO2 utilized can be increased to up to 1.7 kg CO2 per kg PUR by indirect CO2 utilization in the PUR supply chain. Indirect CO2 utilization requires hydrogen (H2). The environmental impacts of H2 production strongly affect the impact of indirect CO2 utilization in PUR. To achieve optimal environmental performance under the current fossil-based H2 generation, PUR production can only utilize much less CO2 than theoretically possible. Thus, utilizing as much CO2 in the PUR supply chain as possible is not always environmentally optimal. Clean H2 production is required to exploit the full CO2 utilization potential for environmental impact reduction in PUR production.

  17. Synthesis and in vitro evaluation of [18F]FECIMBI-36: A potential agonist PET ligand for 5-HT2A/2C receptors.

    Science.gov (United States)

    Prabhakaran, Jaya; Underwood, Mark D; Kumar, J S Dileep; Simpson, Norman R; Kassir, Suham A; Bakalian, Mihran J; Mann, J John; Arango, Victoria

    2015-09-15

    Radiosynthesis and in vitro evaluation of [(18)F]-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([(18)F]FECIMBI-36) or ([(18)F]1), a potential agonist PET imaging agent for 5-HT2A/2C receptors is described. Syntheses of reference standard 1 and the corresponding des-fluoroethyl radiolabeling precursor (2) were achieved with 75% and 65% yields, respectively. In vitro pharmacology assay of FECIMBI-36 by [(3)H]-ketanserin competition binding assay obtained from NIMH-PDSP showed high affinities to 5-HT2AR (Ki = 1nM) and 5-HT2CR (Ki=1.7 nM). Radiolabeling of FECIMBI-36 was achieved from the boc-protected precursor 2 using [(18)F]-fluoroethyltosylate in presence of Cs2CO3 in DMSO followed by removal of the protective group. [(18)F]1 was isolated using RP-HPLC in 25 ± 5% yield, purity > 95% and specific activity 1-2Ci/μmol (N = 6). In vitro autoradiography studies demonstrate that [(18)F]1 selectively label 5-HT2A and 5-HT2C receptors in slide-mounted sections of postmortem human brain using phosphor imaging. Our results indicate the potential of [(18)F]1 for imaging 5-HT2A/2C receptors in the high affinity state in vivo using PET imaging. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive–Compulsive Disorder

    Directory of Open Access Journals (Sweden)

    Michelle M. Rodriguez

    2017-05-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are the only effective pharmacological treatments for obsessive–compulsive disorder (OCD. Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C receptor agonist ((3S-3-Methyl-1-[4-(trifluoromethyl-7-benzofuranyl]-piperazine (CPD 1 with high potency and full efficacy at 5-HT2C receptors and less potency and partial agonism at 5-HT2A and 5-HT2B receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats and non-consummatory behaviors (marble-burying and nestlet-shredding in mice that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia. The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C receptor antagonist SB242084. The 5-HT2C receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors

  19. Study on the Potential Development of Rainwater Utilization in the Hilly City of Southern China

    Science.gov (United States)

    Fu, Xiaoran; Liu, Jiahong; Shao, Weiwei; Zhang, Haixing

    2017-12-01

    Aimed at the current flood problems and the contradiction between supply and demand of water resources in the southern cities of China, the comprehensive utilization of Urban Rainwater Resources (URRs) is a significant solution. At present, the research on the comprehensive utilization system of urban rainwater resources in China is still immature, especially the lack of a comprehensive method for the comprehensive utilization of the rainwater and flood resources in the south. Based on the current mode for utilization of URRs at home and abroad, Fenghuang County in Hunan Province was taken as a case of study, which is a typical mountainous city in the southern China. And the potential development of URRs was simulated and evaluated with a comparison of before and after the exploitation and utilization of URRs in this paper. The reduction effect of flood and waterlogging on the ancient city area is analyzed from SWMM. The simulation results show that the potential of exploitation and utilization of URRs in Fenghuang county is remarkable under the mode of exploitation and utilization which is given priority to flood prevention and control, and the annual development potential is 4.865×105 m3. The rainwater utilization measures of flood control effect is obvious with this mode, and the relevant research results can provide theoretical and technical support for enhancing urban water security capability, water conservation capacity, and disaster mitigation of urban flood.

  20. Evaluation of TLR agonists as potential mucosal adjuvants for HIV gp140 and tetanus toxoid in mice.

    Directory of Open Access Journals (Sweden)

    Viviana Buffa

    Full Text Available In the present study we investigate the impact of a range of TLR ligands and chitosan as potential adjuvants for different routes of mucosal immunisation (sublingual (SL, intranasal (IN, intravaginal (IVag and a parenteral route (subcutaneous (SC in the murine model. We assess their ability to enhance antibody responses to HIV-1 CN54gp140 (gp140 and Tetanus toxoid (TT in systemic and vaginal compartments. A number of trends were observed by route of administration. For non-adjuvanted antigen, SC>SL>IN immunisation with respect to systemic IgG responses, where endpoint titres were greater for TT than for gp140. In general, co-administration with adjuvants increased specific IgG responses where IN = SC>SL, while in the vaginal compartment IN>SL>SC for specific IgA. In contrast, for systemic and mucosal IgA responses to antigen alone SL>IN = SC. A number of adjuvants increased specific systemic IgA responses where in general IN>SL>SC immunisation, while for mucosal responses IN = SL>SC. In contrast, direct intravaginal immunisation failed to induce any detectable systemic or mucosal responses to gp140 even in the presence of adjuvant. However, significant systemic IgG responses to TT were induced by intravaginal immunisation with or without adjuvant, and detectable mucosal responses IgG and IgA were observed when TT was administered with FSL-1 or Poly I∶C. Interestingly some TLRs displayed differential activity dependent upon the route of administration. MPLA (TLR4 suppressed systemic responses to SL immunisation while enhancing responses to IN or SC immunisation. CpG B enhanced SL and IN responses, while having little or no impact on SC immunisation. These data demonstrate important route, antigen and adjuvant effects that need to be considered in the design of mucosal vaccine strategies.

  1. Analysis of Water Resource Utilization Potential for Jiangsu Coastal Area ' in Nantong City

    Science.gov (United States)

    Ren, Li; Liu, Jin-Tao; Ni, Jian-Jun

    2015-04-01

    Along with the advance of the growth of population and social economy, requirements for water quality and quantity in coastal areas is getting higher and higher, but due to the uneven distribution of rainfall years and water exploitation, use and management level, the influence of the shortage of water resources is increasingly prominent, seriously restricting the social and economic sustainable development in this region. Accordingly, water resource utilization potential in Jiangsu coastal region is vital for water security in the region. Taking Nantong City as the study area, the regional water resources development and utilization status were evaluated. In this paper, the meaning of water resources, water resources development and utilization, and water resources development and utilization of the three stages of concepts such as system were discussed. Then the development and utilization of regional water resource evaluation were carried out, and the significance of regional society, economy, resources and environment and its development status quo of water resources were exploited. According to conditions and area source, an evaluation index system for development and utilization of water resources of Nantong was built up. The index layer was composed of 16 indicators. In this study, analytic hierarchy process (AHP) was used to determine of weights of indicators at all levels in the index system. Multistage fuzzy comprehensive evaluation model was selected to evaluate the water resources development and utilization status of Nantong, and then water resource utilization potential of Nantong was analyzed.

  2. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  3. Synthesis, radiofluorination, and preliminary evaluation of the potential 5-HT2A receptor agonists [18 F]Cimbi-92 and [18 F]Cimbi-150

    DEFF Research Database (Denmark)

    Edgar, Fraser Graeme; Hansen, Hanne D; Leth-Petersen, Sebastian

    2017-01-01

    An agonist PET tracer is of key interest for the imaging of the 5-HT2A receptor, as exemplified by the previously reported success of [11 C]Cimbi-36. Fluorine-18 holds several advantages over carbon-11, making it the radionuclide of choice for clinical purposes. In this respect, an 18 F......-labelled agonist 5-HT2A receptor (5-HT2A R) tracer is highly sought after. Herein, we report a 2-step, 1-pot labelling methodology of 2 tracer candidates. Both ligands display high in vitro affinities for the 5-HT2A R. The compounds were synthesised from easily accessible labelling precursors, and radiolabelled...

  4. Advance reactor and fuel-cycle systems--potentials and limitations for United States utilities

    International Nuclear Information System (INIS)

    Zebroski, E.L.; Williams, R.F.

    1979-01-01

    This paper reviews the potential benefits and limitations of advance reactor and fuel-cycle systems for United States utilities. The results of the review of advanced technologies show that for the near and midterm, the only advance reactor and fuel-cycle system with significant potential for United States utilities is the current LWR, and evolutionary, not revolutionary, enhancements. For the long term, the liquid-metal breeder reactor continues to be the most promising advance nuclear option. The major factors leading to this conclusion are summarized

  5. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  6. Discovery of Potent and Selective Agonists for the Free Fatty Acid Receptor 1 (FFA1/GPR40), a Potential Target for the Treatment of Type II Diabetes

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Urban, Christian; Merten, Nicole

    2008-01-01

    A series of 4-phenethynyldihydrocinnamic acid agonists of the free fatty acid receptor 1 (FFA 1) has been discovered and explored. The preferred compound 20 (TUG-424, EC 50 = 32 nM) significantly increased glucose-stimulated insulin secretion at 100 nM and may serve to explore the role of FFA 1 i...... in metabolic diseases such as diabetes or obesity....

  7. Electrocardiographic Characteristics of Potential Organ Donors and Associations with Cardiac Allograft Utilization

    Science.gov (United States)

    Khush, Kiran K.; Menza, Rebecca; Nguyen, John; Goldstein, Benjamin A.; Zaroff, Jonathan G.; Drew, Barbara J.

    2012-01-01

    Background Current regulations require that all cardiac allograft offers for transplantation must include an interpreted 12-lead electrocardiogram (ECG). However, little is known about the expected ECG findings in potential organ donors, or the clinical significance of any identified abnormalities in terms of cardiac allograft function and suitability for transplantation. Methods and Results A single experienced reviewer interpreted the first ECG obtained after brainstem herniation in 980 potential organ donors managed by the California Transplant Donor Network from 2002-2007. ECG abnormalities were summarized, and associations between specific ECG findings and cardiac allograft utilization for transplantation were studied. ECG abnormalities were present in 51% of all cases reviewed. The most common abnormalities included voltage criteria for left ventricular hypertrophy (LVH), prolongation of the corrected QT interval (QTc), and repolarization changes (ST/T wave abnormalities). Fifty seven percent of potential cardiac allografts in this cohort were accepted for transplantation. LVH on ECG was a strong predictor of allograft non-utilization. No significant associations were seen between QTc prolongation, repolarization changes and allograft utilization for transplantation, after adjusting for donor clinical variables and echocardiographic findings. Conclusions We have performed the first comprehensive study of ECG findings in potential donors for cardiac transplantation. Many of the common ECG abnormalities seen in organ donors may result from the heightened state of sympathetic activation that occurs after brainstem herniation, and are not associated with allograft utilization for transplantation. PMID:22615333

  8. Power plant reject heat utilization: an assessment of the potential for wide-scale implementation

    Energy Technology Data Exchange (ETDEWEB)

    Olszewski, M.

    1977-12-01

    An assessment of the relative economic and heat utilization merits of plant reject heat utilization systems was made in an effort to indicate those technologies that show the greatest potential for wide-scale implementation in the power generating industry. The heat utilization systems were designed to accommodate the yearly cooling needs of a 1000-MW(e) power plant. Thus, for the purposes of this study, it was assumed that these systems replaced the cooling tower as the primary condenser cooling water heat dissipation system. Implementation potential and user incentive considerations were used in assessing the technologies. Assessment of the implementation potential included economic, marketing, and power plant performance criteria. The user incentive assessment essentially viewed the use of reject heat from the user's perspective. Heat costs and performance characteristics of the heat utilization system were the criteria used in this assessment. The two analyses were combined in the overall assessment. The overall assessment indicated that extensive pond aquaculture offered the greatest potential for wide-scale implementation. This was followed by animal rearing, algal pond, greenhouse, intensive aquaculture and undersoil heating systems. Based on this assessment, it is recommended that extensive pond aquaculture should receive top research priority. Animal rearing, algal pond and greenhouse research should also be vigorously pursued. It appears that intensive aquaculture can be investigated in certain locations but undersoil heating should not be pursued.

  9. Utilization potential evaluation of plant resources in the dry-hot valley of Jinsha River

    Science.gov (United States)

    Xi, Rong; Xu, Naizhong; Liu, Shengxiang; Ren, Tingyan

    2017-08-01

    Plant resources in the dry-hot valley of Jinsha River are endemic to a class of district. The article adopts the analytic hierarchy process method to evaluate the exploitation and utilization potential of plant resources of thirty typical plant resources on the basis of their characteristics in the dry-hot valley of Jinsha River, which provide scientific evidence for quantitative evaluation of regional plant resources, and we also suggest pathways offering protection and development.

  10. Clinical Utility and Limitations of Intraoperative Monitoring of Visual Evoked Potentials

    OpenAIRE

    Luo, Yeda; Regli, Luca; Bozinov, Oliver; Sarnthein, Johannes

    2015-01-01

    OBJECTIVES During surgeries that put the visual pathway at risk of injury, continuous monitoring of the visual function is desirable. However, the intraoperative monitoring of the visual evoked potential (VEP) is not yet widely used. We evaluate here the clinical utility of intraoperative VEP monitoring. METHODS We analyzed retrospectively 46 consecutive surgeries in 2011-2013. High luminance stimulating devices delivered flash stimuli on the closed eyelid during intravenous anesthesia. We...

  11. Point-of-Care Ultrasound Utility and Potential for High Altitude Crew Recovery Missions.

    Science.gov (United States)

    Galdamez, Laura A; Clark, Jonathan B; Antonsen, Erik L

    2017-02-01

    Flights to high altitude can lead to exposure and unique pathology not seen in normal commercial aviation. This paper assesses the potential for point-of-care ultrasound to aid in management and disposition of injured crewmembers from a high altitude incident. This was accomplished through a systematic literature review regarding current diagnostic and therapeutic uses of ultrasound for injuries expected in high altitude free fall and parachuting. While current research supports its utility in diagnostics, therapeutic procedures, and triage decisions, little research has been done regarding its utility in high altitude specific pathology, but its potential has been demonstrated. An algorithm was created for use in high altitude missions, in the event of an emergency descent and traumatic landing for an unconscious and hypotensive pilot, to rule out most life threatening causes. Each endpoint includes disposition, allowing concise decision-making.Galdamez LA, Clark JB, Antonsen EL. Point-of-care ultrasound utility and potential for high altitude crew recovery missions. Aerosp Med Hum Perform. 2017; 88(2):128-136.

  12. Potential for increased wind-generated electricity utilization using heat pumps in urban areas

    International Nuclear Information System (INIS)

    Waite, Michael; Modi, Vijay

    2014-01-01

    Highlights: • Large-scale wind power and increased electric heat pumps were evaluated. • A deterministic model of wind power and electricity demand was developed. • Sub-models for space heating and domestic hot water demand were developed. • Increased use of heat pumps can improve the viability of large-scale wind power. • Larger wind power capacity can meet a target utilization rate with more heat pumps. - Abstract: The U.S. has substantial wind power potential, but given wind’s intermittent availability and misalignment with electricity demand profiles, large-scale deployment of wind turbines could result in high electricity costs due to energy storage requirements or low utilization rates. While fuel switching and heat pumps have been proposed as greenhouse gas (GHG) emissions and energy reduction strategies at the building scale, this paper shows that heat pump adoption could have additional system-wide benefits by increasing the utilization of wind-generated electricity. A model was developed to evaluate the effects of coupling large-scale wind power installations in New York State with increased use of electric heat pumps to meet a portion of space heating and domestic hot water (DHW) demands in New York City. The analysis showed significant increases in wind-generated electricity utilization with increased use of heat pumps, allowing for higher installed capacity of wind power. One scenario indicates that 78.5% annual wind-generated electricity utilization can be achieved with 3 GW of installed wind power capacity generated electricity equal to 20% of existing NYC annual electricity demand; if 20% of space heating and DHW demands are provided by heat pumps, the 78.5% utilization rate can be achieved with an increase of total wind power capacity to 5 GW. Therefore, this integrated supply–demand approach could provide additional system-wide emissions reductions

  13. Resource potential of bamboo, challenges and future directions towards sustainable management and utilization in Ethiopia

    Directory of Open Access Journals (Sweden)

    Getachew Desalegn

    2014-08-01

    Full Text Available Aim of study: Bamboo, the fastest growing and high yielding perennial plant of the world has more than 1500 species and 1500 versatile socio-economic uses and ecological services. Ethiopia has two indigenous bamboo species namely Yushania alpina and Oxytenantheria abyssinica, covering about one million ha with a wide distribution. The objective of this paper is to highlight the potential of bamboo resources, challenges including biodeterioration damage, opportunities and future research directions towards its sustainable management and rational utilization.Area of study: Bamboo resources of EthiopiaMaterial and Methods: Reconnaissance survey was done to some parts of the bamboo growing potential areas in Ethiopia besides the literature review. Main results: The bamboo resource, despite its socio-economic and environmental benefits, currently, in most areas has been under high pressure due to land use changes, bamboo mass- flowering, poor processing with low value addition, and damage by biodeteriorating agents (termites, beetles and fungi. The preservative tests on Ethiopian bamboos revealed low natural durability and highlighted the paramount importance of appropriate protection measures such as Tanalith and vehicles used motor oil to increase durability, service life and rational utilization of bamboo-based products and structures as potential alternative construction and furniture material.Research highlights: Therefore, integrated research and development interventions involving different propagation and managements techniques, harvesting season, processing, value addition including proper seasoning and preservation technologies and marketing are recommended to fill the information and technological gaps on sustainable management and rational utilization of this fast growing and multipurpose bamboo resources in Ethiopia.Key words: Bamboo; challenges; management; socio-economic and environmental significance; utilization.

  14. Synthesis, radiofluorination, and preliminary evaluation of the potential 5-HT2Areceptor agonists [18F]Cimbi-92 and [18F]Cimbi-150.

    Science.gov (United States)

    Edgar, Fraser Graeme; Hansen, Hanne D; Leth-Petersen, Sebastian; Ettrup, Anders; Kristensen, Jesper L; Knudsen, Gitte M; Herth, Matthias M

    2017-10-01

    An agonist PET tracer is of key interest for the imaging of the 5-HT 2A receptor, as exemplified by the previously reported success of [ 11 C]Cimbi-36. Fluorine-18 holds several advantages over carbon-11, making it the radionuclide of choice for clinical purposes. In this respect, an 18 F-labelled agonist 5-HT 2A receptor (5-HT 2A R) tracer is highly sought after. Herein, we report a 2-step, 1-pot labelling methodology of 2 tracer candidates. Both ligands display high in vitro affinities for the 5-HT 2A R. The compounds were synthesised from easily accessible labelling precursors, and radiolabelled in acceptable radiochemical yields, sufficient for in vivo studies in domestic pigs. PET images partially conformed to the expected brain distribution of the 5-HT 2A R; a notable exception however being significant uptake in the striatum and thalamus. Additionally, a within-scan displacement challenge with a 5-HT 2A R antagonist was unsuccessful, indicating that the tracers cannot be considered optimal for neuroimaging of the 5-HT 2A R. Copyright © 2017 John Wiley & Sons, Ltd.

  15. POTENTIAL OF GREENHOUSE GASES REDUCTION BY FUEL CROP CULTIVATION UTILIZING SEWAGE SLUDGE IN JAPAN

    Science.gov (United States)

    Honda, Ryo; Fukushi, Kensuke

    Potential of greenhouse gases (GHG) reduction was estimated and compared in six scenarios of fuel crop cultivation by utilizing sewage sludge in Japan. Bioethanol from corn and biodiesel fuel from soybean was selected as biofuel produced. When all the sludge discharged from sewage treatment plants in 18 major cities was utilized for soybean cultivation and subsequent biodiesel fuel production, produced biofuel corresponded to 4.0% of GHG emitted from sewage treatment in Japan. On the other hand, cultivation area for fuel crop cultivation was found to be the regulating factor. When fuel crop was cultivated only in abandoned agricultural fields, produced biofuel corresponded to 0.60% and 0.62%, respectively, in the case that corn and soybean was cultivated. Production of biodiesel fuel from soybean was estimated to have more net reduction potential than bioehanol production from corn when sludge production is limited, because required sewage sludge compost was 2.5-times larger in corn although reduction potential per crop area was 2-times larger in bioethanol production from corn.

  16. Chaparral vegetation reflectance and its potential utility for assessment of fire hazard

    Science.gov (United States)

    Cohen, Warren B.

    1991-01-01

    Current methods for assessment of ignition potential often fail to alert wildland managers to the severity of drought-induced fire hazard at remote locations and over large geographic areas. After the severe fires of 1988 in the western United States, the need was heightened for improved fire hazard assessment techniques. Chaparral vegetation is particularly receptive to recurring drought-related episodes of extreme fire hazard and was thus chosen for study here. Demonstrated herein is that chaparral vegetation has considerably different reflecting properties at different levels of drought stress. As such, remote sensing may have utility for fire hazard assessment in this vegetation type.

  17. Biotechnological route for sustainable succinate production utilizing oil palm frond and kenaf as potential carbon sources.

    Science.gov (United States)

    Luthfi, Abdullah Amru Indera; Manaf, Shareena Fairuz Abdul; Illias, Rosli Md; Harun, Shuhaida; Mohammad, Abdul Wahab; Jahim, Jamaliah Md

    2017-04-01

    Due to the world's dwindling energy supplies, greater thrust has been placed on the utilization of renewable resources for global succinate production. Exploration of such biotechnological route could be seen as an act of counterbalance to the continued fossil fuel dominance. Malaysia being a tropical country stands out among many other nations for its plenty of resources in the form of lignocellulosic biomass. To date, oil palm frond (OPF) contributes to the largest fraction of agricultural residues in Malaysia, while kenaf, a newly introduced fiber crop with relatively high growth rate, holds great potential for developing sustainable succinate production, apart from OPF. Utilization of non-food, inexhaustible, and low-cost derived biomass in the form of OPF and kenaf for bio-based succinate production remains largely untapped. Owing to the richness of carbohydrates in OPF and kenaf, bio-succinate commercialization using these sources appears as an attractive proposition for future sustainable developments. The aim of this paper was to review some research efforts in developing a biorefinery system based on OPF and kenaf as processing inputs. It presents the importance of the current progress in bio-succinate commercialization, in addition to describing the potential use of different succinate production hosts and various pretreatments-saccharifications under development for OPF and kenaf. Evaluations on the feasibility of OPF and kenaf as fermentation substrates are also discussed.

  18. The market potential for SMES in electric utility applications. Final report

    Energy Technology Data Exchange (ETDEWEB)

    1994-06-01

    Superconducting magnetic energy storage (SMES) is an emerging technology with features that are potentially attractive in electric utility applications. This study evaluates the potential for SMES technology in the generation, transmission, distribution, and use of electric energy; the time frame of the assessment is through the year 2030. Comparisons are made with other technology options, including both commercially available and advanced systems such as various peaking generation technologies, transmission stability improvement technologies, and power quality enhancement devices. The methodology used for this study focused on the needs of the market place, the capabilities of S and the characteristics of the competing technologies. There is widespread interest within utilities for the development of SMES technology, but there is no general consensus regarding the most attractive size. Considerable uncertainty exists regarding the eventual costs and benefits of commercial SMES systems, but general trends have been developed based on current industry knowledge. Results of this analysis indicate that as storage capacity increases, cost increases at a rate faster than benefits. Transmission system applications requiring dynamic storage appear to have the most attractive economics. Customer service applications may be economic in the near term, but improved ride-through capability of end-use equipment may limit the size of this market over time. Other applications requiring greater storage capacity appear to be only marginally economic at best.

  19. Design novel dual agonists for treating type-2 diabetes by targeting peroxisome proliferator-activated receptors with core hopping approach.

    Directory of Open Access Journals (Sweden)

    Ying Ma

    Full Text Available Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones, the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful "core hopping" and "glide docking" techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the "core hopping" technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses.

  20. Potential utility of MRI in the evaluation of children at risk of renal scarring

    International Nuclear Information System (INIS)

    Chan Yuleung; Chan Kamwing; Roebuck, D.J.; Chu, W.C.W.; Metreweli, C.; Yeung Chungkwong; Lee Kimhung

    1999-01-01

    Background. Gadolinium-enhanced MRI has recently been employed in the diagnosis of acute pyelonephritis. Its potential utility in the diagnosis of renal scars in children is unknown. Objective. To evaluate the potential utility of MRI using fat-saturated T1-weighted (T1-W) and post-gadolinium, short-tau inversion-recovery (STIR) sequences in detecting renal scarring by comparison with technetium dimercaptosuccinic acid ( 99 m Tc-DMSA) renal scintigraphy in children at risk of renal scarring. Materials and methods. A group of 24 children with spina bifida and neurogenic bladder or anorectal anomaly was studied. No patient had a history of acute pyelonephritis. Documented urinary tract infection (UTI) was present in 10 children (42 %). The remaining 14 (58 %) children had a history of asymptomatic bacteriuria. None had clinical signs or symptoms of acute UTI at the time of the study. 99 m Tc-DMSA and MRI were performed to detect renal scarring. 99 m Tc-DMSA scans were supplemented with pinhole imaging. MRI of the kidneys employed a fat-saturated T1-W sequence and a post-gadolinium STIR sequence employing a short echo time. Results. Of the kidneys studied, 33 % (n = 16) had evidence of a renal parenchymal defect suggestive of scarring on 99 m Tc-DMSA. The concordance in the detection of a scarred kidney by post-gadolinium STIR sequence and 99 m Tc-DMSA is 94 %; that by fat-saturated T1-W sequence and 99 m Tc-DMSA is 82 %; that by both sequences (positive result on either sequence) and 99 m Tc-DMSA is 100 %. Using 99 m Tc-DMSA as the gold standard, MRI had a sensitivity of 100 % and a specificity of 78 % in the diagnosis of a scarred kidney. The concordance in the detection of a scarred zone by post-gadolinium STIR sequence and 99 m Tc-DMSA is 68 %; that by fat-saturated T1-W sequence and DMSA is 44 %; that by both sequences (positive result on either sequence) and 99 m Tc-DMSA is 84 %. MRI had a sensitivity of 84 % and a specificity of 86 % in the diagnosis of a

  1. The Era of International Space Station Utilization Begins: Research Strategy, International Collaboration, and Realized Potential

    Science.gov (United States)

    Thumm, Tracy; Robinson, Julie A.; Ruttley, Tara; Johnson-Green, Perry; Karabadzhak, George; Nakamura, Tai; Sorokin, Igor V.; Zell, Martin; Jean, Sabbagh

    2010-01-01

    With the assembly of the International Space Station (ISS) nearing completion and the support of a full-time crew of six, a new era of utilization for research is beginning. For more than 15 years, the ISS international partnership has weathered financial, technical and political challenges proving that nations can work together to complete assembly of the largest space vehicle in history. And while the ISS partners can be proud of having completed one of the most ambitious engineering projects ever conceived, the challenge of successfully using the platform remains. During the ISS assembly phase, the potential benefits of space-based research and development were demonstrated; including the advancement of scientific knowledge based on experiments conducted in space, development and testing of new technologies, and derivation of Earth applications from new understanding. The configurability and human-tended capabilities of the ISS provide a unique platform. The international utilization strategy is based on research ranging from physical sciences, biology, medicine, psychology, to Earth observation, human exploration preparation and technology demonstration. The ability to complete follow-on investigations in a period of months allows researchers to make rapid advances based on new knowledge gained from ISS activities. During the utilization phase, the ISS partners are working together to track the objectives, accomplishments, and the applications of the new knowledge gained. This presentation will summarize the consolidated international results of these tracking activities and approaches. Areas of current research on ISS with strong international cooperation will be highlighted including cardiovascular studies, cell and plant biology studies, radiation, physics of matter, and advanced alloys. Scientific knowledge and new technologies derived from research on the ISS will be realized through improving quality of life on Earth and future spaceflight endeavours

  2. Interrogation of Chesapeake Bay sediment microbial communities for intrinsic alkane-utilizing potential under anaerobic conditions.

    Science.gov (United States)

    Johnson, Jamie M; Wawrik, Boris; Isom, Catherine; Boling, Wilford B; Callaghan, Amy V

    2015-02-01

    Based on the transient exposure of Chesapeake Bay sediments to hydrocarbons and the metabolic versatility of known anaerobic alkane-degrading microorganisms, it was hypothesized that distinct Bay sediment communities, governed by geochemical gradients, would have intrinsic alkane-utilizing potential under sulfate-reducing and/or methanogenic conditions. Sediment cores were collected along a transect of the Bay. Community DNA was interrogated via pyrosequencing of 16S rRNA genes, PCR of anaerobic hydrocarbon activation genes, and qPCR of 16S rRNA genes and genes involved in sulfate reduction/methanogenesis. Site sediments were used to establish microcosms amended with n-hexadecane under sulfate-reducing and methanogenic conditions. Sequencing of 16S rRNA genes indicated that sediments associated with hypoxic water columns contained significantly greater proportions of Bacteria and Archaea consistent with syntrophic degradation of organic matter and methanogenesis compared to less reduced sediments. Microbial taxa frequently associated with hydrocarbon-degrading communities were found throughout the Bay, and the genetic potential for hydrocarbon metabolism was demonstrated via the detection of benzyl-(bssA) and alkylsuccinate synthase (assA) genes. Although microcosm studies did not indicate sulfidogenic alkane degradation, the data suggested that methanogenic conversion of alkanes was occurring. These findings highlight the potential role that anaerobic microorganisms could play in the bioremediation of hydrocarbons in the Bay. © FEMS 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. Sports doping: emerging designer and therapeutic β2-agonists.

    Science.gov (United States)

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future. © 2013.

  4. A potential of utilizing renewable energy sources and the state support in Slovakia

    Directory of Open Access Journals (Sweden)

    Lívia Bodonská

    2007-04-01

    Full Text Available The renewable energy sources are domestic sources of energy that help to enhance the safety of energy supplies and the diversification of energy sources. The utilization of such sources complies with the environmental acceptability requirement and leads to a reduction in greenhouse gas emissions. The renewable energy is proved to be commercially viable for a growing list of consumers and uses. The renewable energy technologies provide many benefits that go well beyond the energy alone. More and more, the renewable energies contribute to the three pillars of the sustainable development in the economy, environment and the society.Several renewable energy technologies are established in world markets, building global industries and infrastructures. Other renewables become competitive in growing markets, and some are widely recognised as the lowest cost option for stand-alone and offgrid applications. An increased utilization of renewable energy sources in the heat and electricity generation is one of priority tasks of the Slovak Republic to boost the use of domestic energy potential and thus to decrease the Slovakia’s dependence on imported fossil fuels.

  5. Solar thermal technologies - Potential benefits to U.S. utilities and industry

    Science.gov (United States)

    Terasawa, K. L.; Gates, W. R.

    1983-01-01

    Solar energy systems were investigated which complement nuclear and coal technologies as a means of reducing the U.S. dependence on imported petroleum. Solar Thermal Energy Systems (STES) represents an important category of solar energy technologies. STES can be utilized in a broad range of applications servicing a variety of economic sectors, and they can be deployed in both near-term and long-term markets. The net present value of the energy cost savings attributable to electric utility and IPH applications of STES were estimated for a variety of future energy cost scenarios and levels of R&D success. This analysis indicated that the expected net benefits of developing an STES option are significantly greater than the expected costs of completing the required R&D. In addition, transportable fuels and chemical feedstocks represent a substantial future potential market for STES. Due to the basic nature of this R&D activity, however, it is currently impossible to estimate the value of STES in these markets. Despite this fact, private investment in STES R&D is not anticipated due to the high level of uncertainty characterizing the expected payoffs. Previously announced in STAR as N83-10547

  6. Adaptation policies to increase terrestrial ecosystem resilience. Potential utility of a multicriteria approach

    Energy Technology Data Exchange (ETDEWEB)

    de Bremond, Ariane [Univ. of Maryland, College Park, MD (United States); Joint Global Change Research Inst., College Park, MD (United States); Engle, Nathan L. [World Bank, Washington, DC (United States)

    2014-01-30

    Climate change is rapidly undermining terrestrial ecosystem resilience and capacity to continue providing their services to the benefit of humanity and nature. Because of the importance of terrestrial ecosystems to human well-being and supporting services, decision makers throughout the world are busy creating policy responses that secure multiple development and conservation objectives- including that of supporting terrestrial ecosystem resilience in the context of climate change. This article aims to advance analyses on climate policy evaluation and planning in the area of terrestrial ecosystem resilience by discussing adaptation policy options within the ecology-economy-social nexus. The paper evaluates these decisions in the realm of terrestrial ecosystem resilience and evaluates the utility of a set of criteria, indicators, and assessment methods, proposed by a new conceptual multi-criteria framework for pro-development climate policy and planning developed by the United Nations Environment Programme. Potential applications of a multicriteria approach to climate policy vis-A -vis terrestrial ecosystems are then explored through two hypothetical case study examples. The paper closes with a brief discussion of the utility of the multi-criteria approach in the context of other climate policy evaluation approaches, considers lessons learned as a result efforts to evaluate climate policy in the realm of terrestrial ecosystems, and reiterates the role of ecosystem resilience in creating sound policies and actions that support the integration of climate change and development goals.

  7. Solar thermal technologies - Potential benefits to U.S. utilities and industry

    Science.gov (United States)

    Terasawa, K. L.; Gates, W. R.

    1983-08-01

    Solar energy systems were investigated which complement nuclear and coal technologies as a means of reducing the U.S. dependence on imported petroleum. Solar Thermal Energy Systems (STES) represents an important category of solar energy technologies. STES can be utilized in a broad range of applications servicing a variety of economic sectors, and they can be deployed in both near-term and long-term markets. The net present value of the energy cost savings attributable to electric utility and IPH applications of STES were estimated for a variety of future energy cost scenarios and levels of R&D success. This analysis indicated that the expected net benefits of developing an STES option are significantly greater than the expected costs of completing the required R&D. In addition, transportable fuels and chemical feedstocks represent a substantial future potential market for STES. Due to the basic nature of this R&D activity, however, it is currently impossible to estimate the value of STES in these markets. Despite this fact, private investment in STES R&D is not anticipated due to the high level of uncertainty characterizing the expected payoffs. Previously announced in STAR as N83-10547

  8. Extracellular vesicles from parasitic helminths and their potential utility as vaccines.

    Science.gov (United States)

    Mekonnen, Gebeyaw Getnet; Pearson, Mark; Loukas, Alex; Sotillo, Javier

    2018-03-01

    Helminths are multicellular parasites affecting nearly three billion people worldwide. To orchestrate a parasitic existence, helminths secrete different molecules, either in soluble form or contained within extracellular vesicles (EVs). EVs are secreted by most cell types and organisms, and have varied roles in intercellular communication, including immune modulation and pathogenesis. Areas covered: In this review, we describe the nucleic acid and proteomic composition of EVs from helminths, with a focus on the protein vaccine candidates present on the EV surface membrane, and discuss the potential utility of helminth EVs and their constituent proteins in the fight against helminth infections. Expert commentary: A significant number of proteins present in helminth-secreted EVs are known vaccine candidates. The characterization of helminth EV proteomes will shed light on host-pathogen interactions, facilitate the discovery of new diagnostic biomarkers, and provide a novel approach for the development of new control measures against helminth infections.

  9. Use of Pregabalin - A Nationwide Pharmacoepidemiological Drug Utilization Study with Focus on Abuse Potential

    DEFF Research Database (Denmark)

    Schjerning, O; Pottegård, A; Damkier, P

    2016-01-01

    INTRODUCTION: Pregabalin is currently approved for the treatment of epilepsy, generalized anxiety disorder and neuropathic pain with a licensed dosage range of 150 mg to 600 mg/day. Growing concern about the abuse potential of pregabalin is partly based on reports of pregabalin being used...... in dosages that exceed the approved therapeutic range. METHODS: To identify predictors of pregabalin use above recommended dosage, we conducted a pharmacoepidemological drug utilization study using the Danish nationwide registers. We deployed 4 measures of abuse: high use (≥600 mg/day) or very high use (≥1...... 200 mg/day) over a 6- or 12-month period, respectively. Multiple logistic regression was used to identify patient and treatment characteristics that were associated with either abuse marker. RESULTS: Out of 42 520 pregabalin users 4 090 (9.6%) were treated with more than 600 mg/day for 6 months and 2...

  10. Physicochemical Analysis And Mineralogical Composition Of Enugu Coal In Nigeria For Potential Utilization

    Directory of Open Access Journals (Sweden)

    Nwoko Christopher Ikpeamadi

    2017-01-01

    Full Text Available The abundance of coal in certain regions of Nigeria had been described as an alternative energy solution. The potential information obtained from the physicochemical and mineralogical characterization of coal samples in such regions has enabled scientist and government to make well informed decisions. Coal samples were obtained from Okpara Mine in Enugu state Nigeria and subjected to proximate ultimate and mineralogical analyses. The results showed that the coal had uneven particle distribution with higher content of fixed carbon and lower amount of hydrogen and volatile matter. The mineral analyses showed that the coal was rich in silicon and aluminum. The rank was bituminous coal that can be utilized for power generation steel industry glass manufacturing and thermite process.

  11. A combined α7 nicotinic acetylcholine receptor agonist and monoamine reuptake inhibitor, NS9775, represents a novel profile with potential benefits in emotional and cognitive disturbances

    DEFF Research Database (Denmark)

    Andreasen, Jesper T; Redrobe, John P; Nielsen, Elsebet Ø

    2013-01-01

    also improve by nicotinic acetylcholine receptor (nAChR) activation. Preclinical studies have corroborated this and also demonstrated a synergistic antidepressant-like action when nAChR agonists and MRIs are combined. Here, we present the in vitro and in vivo profile of NS9775, a combined full α7 nAChR......-induced deficits in a modified Y-maze and MK-801-induced learning deficits in 5-trial inhibitory avoidance. Swim distance in the forced swim test was increased by 30 mg/kg NS9775, and 10 and 30 mg/kg NS9775 reduced digging behaviour in the marble burying paradigm and increased the number of punished crossings...... in the four plate test. This pro-cognitive, antidepressant-like and anxiolytic-like effect of NS9775 suggests that combining α7 nAChR agonism and triple monoamine reuptake inhibition could be a step in the evolution of pharmacological treatments of affective and/or cognitive disturbances....

  12. Evaluation of a natural speech based informational inquiry system as a potential means to increase transit utilization.

    Science.gov (United States)

    2013-05-01

    This project proposed to explore the potential of a user friendly, natural speech based : information inquiry application as one means of increasing public transit utilization. It suggested : that a key challenge to expanding transit ridership isto e...

  13. The Potential for Electrofuels Production in Sweden Utilizing Fossil and Biogenic CO2 Point Sources

    International Nuclear Information System (INIS)

    Hansson, Julia; Hackl, Roman; Taljegard, Maria; Brynolf, Selma; Grahn, Maria

    2017-01-01

    This paper maps, categorizes, and quantifies all major point sources of carbon dioxide (CO 2 ) emissions from industrial and combustion processes in Sweden. The paper also estimates the Swedish technical potential for electrofuels (power-to-gas/fuels) based on carbon capture and utilization. With our bottom-up approach using European databases, we find that Sweden emits approximately 50 million metric tons of CO 2 per year from different types of point sources, with 65% (or about 32 million tons) from biogenic sources. The major sources are the pulp and paper industry (46%), heat and power production (23%), and waste treatment and incineration (8%). Most of the CO 2 is emitted at low concentrations (<15%) from sources in the southern part of Sweden where power demand generally exceeds in-region supply. The potentially recoverable emissions from all the included point sources amount to 45 million tons. If all the recoverable CO 2 were used to produce electrofuels, the yield would correspond to 2–3 times the current Swedish demand for transportation fuels. The electricity required would correspond to about 3 times the current Swedish electricity supply. The current relatively few emission sources with high concentrations of CO 2 (>90%, biofuel operations) would yield electrofuels corresponding to approximately 2% of the current demand for transportation fuels (corresponding to 1.5–2 TWh/year). In a 2030 scenario with large-scale biofuels operations based on lignocellulosic feedstocks, the potential for electrofuels production from high-concentration sources increases to 8–11 TWh/year. Finally, renewable electricity and production costs, rather than CO 2 supply, limit the potential for production of electrofuels in Sweden.

  14. Chronic administration of the dopamine D2/3 agonist ropinirole invigorates performance of a rodent slot machine task, potentially indicative of less distractible or compulsive-like gambling behaviour.

    Science.gov (United States)

    Cocker, Paul J; Tremblay, M; Kaur, S; Winstanley, Catharine A

    2017-01-01

    Whilst dopamine agonist therapies can successfully manage the symptoms of diseases such as Parkinson's disease (PD), fibromyalgia and restless leg syndrome, they can also cause impulse control and addiction disorders such as gambling disorder (GD). These compulsive behaviours seriously undermine the utility of such treatments. The objective of the study was to model this phenomenon using a rodent slot machine task (rSMT) in order to investigate the neurobiological basis underlying such behavioural changes. Male Long Evans rats were trained to perform the rSMT. The D 2 -like agonist ropinirole, or saline, was then delivered continuously for 28 days via osmotic mini-pump. The effects of ropinirole on baseline rSMT performance, as well as extinction and reinstatement sessions, were determined during this time. Brain samples from key frontostriatal regions implicated in GD and PD were then harvested immediately or after a 4-week washout period during which behaviour returned to pre-drug baseline. Ropinirole invigorated task performance, in that drug treatment resulted in a robust and sustained increase in the number of trials completed. Ex vivo analyses revealed that chronic ropinirole treatment led to a pattern of changes indicative of upregulation within the β-arrestin-AKT-GSK3β intracellular cascade, recently theorised to dominate D 2 -mediated signalling under hyperdopaminergic conditions, in the dorsal striatum, rather than the canonical PKA-dependent signalling pathway associated with D 2 receptor activation. Such findings provide novel insight into the role of dopamine signalling in mediating compulsive-like gambling behaviour and may inform more directed pharmacotherapies for the treatment of both idiopathic and iatrogenic GD.

  15. Evaluation of present thermal barrier coatings for potential service in electric utility gas turbines

    Science.gov (United States)

    Bratton, R. J.; Lau, S. K.; Lee, S. Y.

    1982-01-01

    The resistance of present-day thermal barrier coatings to combustion gases found in electric utility turbines was assessed. The plasma sprayed coatings, both duplex and graded types, were primarily zirconia-based, although a calcium silicate was also evaluated. Both atmospheric burner rig tests and high pressure tests (135 psig) showed that several present-day thermal barrier coatings have a high potential for service in gas turbines burning the relatively clean GT No. 2 fuel. However, coating improvements are needed for use in turbines burning lower grade fuel such as residual oil. The duplex ZrO2.8Y2O3/NiCrA1Y coating was ranked highest and selected for near-term field testing, with Ca2SiO4/NiCrA1Y ranked second. Graded coatings show potential for corrosive turbine operating conditions and warrant further development. The coating degradation mechanisms for each coating system subjected to the various environmental conditions are also described.

  16. Neurotensin agonists block the prepulse inhibition deficits produced by a 5-HT2A and an alpha1 agonist.

    Science.gov (United States)

    Shilling, P D; Melendez, G; Priebe, K; Richelson, E; Feifel, D

    2004-09-01

    Neurotensin (NT) agonists have been proposed as potential antipsychotics based exclusively upon their ability to inhibit dopamine-2 (D2) receptor transmission. Several other pharmacological mechanisms have been implicated in enhancing the antipsychotic profile produced by D2 inhibition alone. These include inhibition of 5-HT2A and alpha1-adrenoceptors. Recently, we reported that systemic administration of the neurotensin agonist PD149163 blocks deficits in prepulse inhibition (PPI) of the startle reflex produced by the 5-HT2A receptor agonist DOI. This suggested that NT agonists could inhibit 5-HT2A modulation of neurotransmission. To determine if other peripherally administered NT agonists shared this effect, we examined the effects of NT69L, another NT agonist, on DOI-induced PPI deficits. In addition, to determine if NT agonists also inhibit alpha1-adrenoceptor neurotransmission, we examined the effects of PD149163 and NT69L on PPI deficits induced by the alpha1-adrenoceptor agonist, cirazoline. In the NT69L/DOI study, rats received subcutaneous (SC) injections of NT69L (0, 0.1, 1, or 2 mg/kg) followed 30 min later by SC saline or DOI (0.5 mg/kg). In the NT agonist/cirazoline studies, animals received SC injections of either PD149163 (0, 0.01, 0.1, or 1 mg/kg) or NT69L (0, 0.01, 0.1, or 1 mg/kg) followed 30 min later by SC saline or cirazoline (0.7 mg/kg). Animals were tested in startle chambers 20 min later. In all three experiments the PPI disruption produced by DOI and cirazoline was blocked by the NT agonists. These findings provide strong evidence that NT agonists inhibit 5-HT2A and alpha1-adrenoceptor modulation of neurotransmission, pharmacological effects that, in conjunction with their known inhibition of dopamine transmission, strengthen the antipsychotic potential of NT agonists.

  17. Potential utility of MRI in the evaluation of children at risk of renal scarring

    Energy Technology Data Exchange (ETDEWEB)

    Chan Yuleung; Chan Kamwing; Roebuck, D.J.; Chu, W.C.W.; Metreweli, C. [Dept. of Diagnostic Radiology and Organ Imaging, Chinese Univ. of Hong Kong, Shatin (China); Yeung Chungkwong; Lee Kimhung [Dept. of Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (China)

    1999-11-01

    Background. Gadolinium-enhanced MRI has recently been employed in the diagnosis of acute pyelonephritis. Its potential utility in the diagnosis of renal scars in children is unknown. Objective. To evaluate the potential utility of MRI using fat-saturated T1-weighted (T1-W) and post-gadolinium, short-tau inversion-recovery (STIR) sequences in detecting renal scarring by comparison with technetium dimercaptosuccinic acid ({sup 99} {sup m}Tc-DMSA) renal scintigraphy in children at risk of renal scarring. Materials and methods. A group of 24 children with spina bifida and neurogenic bladder or anorectal anomaly was studied. No patient had a history of acute pyelonephritis. Documented urinary tract infection (UTI) was present in 10 children (42 %). The remaining 14 (58 %) children had a history of asymptomatic bacteriuria. None had clinical signs or symptoms of acute UTI at the time of the study. {sup 99} {sup m}Tc-DMSA and MRI were performed to detect renal scarring. {sup 99} {sup m}Tc-DMSA scans were supplemented with pinhole imaging. MRI of the kidneys employed a fat-saturated T1-W sequence and a post-gadolinium STIR sequence employing a short echo time. Results. Of the kidneys studied, 33 % (n = 16) had evidence of a renal parenchymal defect suggestive of scarring on {sup 99} {sup m}Tc-DMSA. The concordance in the detection of a scarred kidney by post-gadolinium STIR sequence and {sup 99} {sup m}Tc-DMSA is 94 %; that by fat-saturated T1-W sequence and {sup 99} {sup m}Tc-DMSA is 82 %; that by both sequences (positive result on either sequence) and {sup 99} {sup m}Tc-DMSA is 100 %. Using {sup 99} {sup m}Tc-DMSA as the gold standard, MRI had a sensitivity of 100 % and a specificity of 78 % in the diagnosis of a scarred kidney. The concordance in the detection of a scarred zone by post-gadolinium STIR sequence and {sup 99} {sup m}Tc-DMSA is 68 %; that by fat-saturated T1-W sequence and DMSA is 44 %; that by both sequences (positive result on either sequence) and {sup 99

  18. Evaluating Potential Human Health Risks Associated with the Development of Utility-Scale Solar Energy Facilities on Contaminated Sites

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, J. -J. [Argonne National Lab. (ANL), Argonne, IL (United States); Chang, Y. -S. [Argonne National Lab. (ANL), Argonne, IL (United States); Hartmann, H. [Argonne National Lab. (ANL), Argonne, IL (United States); Wescott, K. [Argonne National Lab. (ANL), Argonne, IL (United States); Kygeris, C. [Indiana Univ. of Pennsylvania, PA (United States)

    2013-09-01

    This report presents a general methodology for obtaining preliminary estimates of the potential human health risks associated with developing a utility-scale solar energy facility on a contaminated site, based on potential exposures to contaminants in soils (including transport of those contaminants into the air).

  19. Isihlambezo: utilization patterns and potential health effects of pregnancy-related traditional herbal medicine.

    Science.gov (United States)

    Varga, C A; Veale, D J

    1997-04-01

    Isihlambezo is a herbal decoction used by many Zulu women in South Africa as a preventative health tonic during pregnancy. Though the practice is cited by ethnographers and medical practitioners, few studies have focused on specific elements of isihlambezo use and preparation. Moreover, though some evidence exists suggesting negative effects of its ingestion, the maternal-fetal health impact and toxicity of isihlambezo have not been adequately studied. We examined two aspects of this traditional antenatal health practice: (1) the potential impact of urbanization and access to Western clinic-based care on popularity and utilization patterns of isihlambezo, and (2) the potential maternal-fetal health effects of its use. Interviews were conducted among rural and urban women in clinic and non-clinic settings regarding socio-behavioral aspects of isihlambezo use. The pharmacology of certain plant ingredients of isihlambezo was investigated through laboratory assays, literature review, and interviews with traditional healers. There were significant differences by area of interview in nearly all aspects of isihlambezo use examined. Though isihlambezo was most popular among urbanites and clinic non-attenders, it was considered an important antenatal health care alternative by the majority of women surveyed. Mixing traditional and clinic-based antenatal care was also strongly advocated. Pharmacological analysis suggested the possibility of both therapeutic and harmful consequences of isihlambezo. It was suggested that the following factors might contribute the popularity of isihlambezo among urban women: high cost and inferior quality of clinic care, use of isihlambezo as a means of adapting to urbanization-related stress, and socio-cultural transition.

  20. Potential harmful effects on agricultural environments of sewage sludge utilization as a fertilizer

    International Nuclear Information System (INIS)

    Suess, A.

    1997-01-01

    There can be harmful effects of sewage-sludge utilization in agriculture. However, these can be overcome by treatment of the sludge and by appropriate farm-management practices. Sewage sludge is of increasing potential importance to farmers because of its value as a fertilizer. But some compounds in sludge can be harmful for plants, animals and man. Heavy metals may be taken up by plants, and the higher the content in the soil, the greater the uptake. There are substantial differences in heavy-metal accumulation and tolerance among plant species. With respect to pathogens (for example Salmonella) in sludge, recent developments in decontamination processes can provide greater guarantee of preservation of the environment. Gamma-radiation treatment at a dose of 3 kGy has been proven effective. The use of sewage sludge in agriculture is attractive from the economical and environmental points of view. It is therefore important that farmers are provided not only with more information about the nutrient effects, but also about risks, if any, of leaching of heavy metals and microbial condition to groundwater. To achieve this, there must be close co-operation between farmers and the authorities responsible for disposal of sewage sludge. (author)

  1. Economic problems of utilization of hydroenergetic potential of the Slovak Republic and possibilities for their solution

    International Nuclear Information System (INIS)

    Dusicka, M.

    1997-01-01

    The aim of this paper is to clarify basic inputs into economic calculations of hydro power projects which then can drastically affect efficiency of these projects in different ways as there are no distinct economic and legal regulations in the Slovak Republic as the hydroelectric potential (HEP utilization is concerned. In 1995, the share of individual resources of electrical system (ES) in production in the Slovak Republic was as follows: nuclear plants - 41.86%, steam power plants - 24,93%, hydroelectrical power plants (HPP) - 18.93%, factory power plants - 9.09%, and import - 5.19%. However, in the same year, the individual resources of ES in the Slovak Republic shared in a balance of installed capacity - 7.114 MW as follows: nuclear power plants - 24.7%, steam power plants - 32.0%, HPP -33.4%, and factory power plants - 10.9%. Financing of the building of HPP -power engineering and water management ones (the Ministry of National Economy and the Ministry of Agriculture at present) is discussed. 1 ref

  2. Complex-scaling of screened Coulomb potentials for resonance calculations utilizing the modified Bessel functions

    Science.gov (United States)

    Jiao, Li-Guang; Ho, Yew Kam

    2014-05-01

    The screened Coulomb potential (SCP) has been extensively used in atomic physics, nuclear physics, quantum chemistry and plasma physics. However, an accurate calculation for atomic resonances under SCP is still a challenging task for various methods. Within the complex-scaling computational scheme, we have developed a method utilizing the modified Bessel functions to calculate doubly-excited resonances in two-electron atomic systems with configuration interaction-type basis. To test the validity of our method, we have calculated S- and P-wave resonance states of the helium atom with various screening strengths, and have found good agreement with earlier calculations using different methods. Our present method can be applied to calculate high-lying resonances associated with high excitation thresholds of the He+ ion, and with high-angular-momentum states. The derivation and calculation details of our present investigation together with new results of high-angular-momentum states will be presented at the meeting. Supported by NSC of Taiwan.

  3. Evaluation of Universitas Indonesia’s Recharge Pond Performance and Potential Utilization for Raw Water Source

    Directory of Open Access Journals (Sweden)

    Nyoman Suwartha

    2012-05-01

    Full Text Available The UI recharge pond has been constructed 5 years ago. However, monitoring and evaluation activities on its performances are very lack. Aims of this study are to understand the recharge rate, and to evaluate existing quantity and water quality of the pond during dry and rainy season. Measurement of water depth, rainfall intensity, and evaporation is conducted to determine water availability, recharge rate, and water balance of the recharge pond. Amount of surface water is collected from recharge pond and river at three sampling point to determine existing water quality of the pond. The results showed that recharge rate of the pond between dry season (3.2 mm/day and wet season (6.1 mm/day are considered as insignificant different. The water balance of the recharge pond shows an excessive rate. Various physics and chemical parameters (turbidity, color, TDS, pH, and  Cl are found to have concentration lower than the water quality standard. The results suggest that the pond surface water is remain suitable to be recharged into aquifer zone so that sustaining ground water conservation campaign, and it is potential to be utilized as an additional  raw water source for domestic water demand of UI Campus Depok.

  4. The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Luis F Razgado-Hernandez

    Full Text Available The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson's disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old, immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy

  5. [Cardiovascular effects of GLP-1 receptor agonist treatment: focus on liraglutide].

    Science.gov (United States)

    Haluzík, Martin; Trachta, Pavel; Mráz, Miloš

    2015-01-01

    Cardiovascular risk reduction is the major aim of type 2 diabetes mellitus treatment. The effects of various antidiabetics on the cardiovascular complications are currently under careful scrutiny. Incretin-based therapy that utilizes the effects of glucagon-like peptide 1 (GLP-1) or stimulation of its receptor by GLP-1 receptor agonists represents one of the most promising approaches from the potential cardiovascular risk reduction point of view. Experimental studies have shown that the GLP-1 and GLP-1 agonists treatment improves endothelial function, decrease blood pressure and protects myocardium during experimentally-induced ischemia. Clinical studies with GLP-1 receptor agonists consistently show that, in addition to good antidiabetic efficacy, its long-term administration decreases blood pressure, body weight and improves circulating lipid levels while slightly increasing heart rate. In this paper, we focus on the cardiovascular effects of GLP-1 receptor agonist liraglutide. Preliminary analyses of cardiovascular complications in phase III trials with liraglutide indicate its good cardiovascular safety. A possibility of cardioprotective effects of liraglutide remains still open and is currently studied within a prospective cardiovascular trial LEADER.

  6. The most important structures utilizing primary and secondary hydroenergetic potential for electric energy production

    International Nuclear Information System (INIS)

    Zacharovsky, M.

    1997-01-01

    In this paper the construction, technological parameters and operation of Gabcikovo (primary hydro energy power) and Cierny Vah (secondary hydro energy power) are described. Construction of the hydroelectric power plant (HPP) Gabcikovo started in 1978 as a part of a system of hydro power projects Gabcikovo-Nagymaros. Basic technical data are: installed capacity 8 x 90 MW, production in an average aqueous year 2.650 GWh, number of hydroelectric generating sets (HGS) 8, turbine flow 8 x 413-636 m 3 /s, head 12.9-24 m.The Gabcikovo plant produced 9.163 GWh of electricity from the beginning of its operation till the end of 1966. The construction of the pumped storage plant (PSP) Cierny Vah started in 1976 and it was put into operation at the end of 1980. The main goal of the PSP Cierny Vah is to meet the control functions of an electrification system of the Slovak Republic, a substitute function in the cases of unexpected power outages and a planned electricity production from re-pumping. Technological parts are: six re-pumping vertical HGS in a three machine arrangement - a motor-generator, a turbine, a pump - are located in three double-blocks. Basic technical data: installed capacity 6 x 122.4 MW + 0.768 MW, yearly production 1,281 GWh, number of HGS 6, number of domestic hydroelectric generating sets 1, turbine flow 3 x 30 m / s, pump flow 6 x 22 m 3 /s, upper reservoir volume 3.7 mil. m 3 , max. head 434 m, peak time 5.71 hour, pumping time 7.78 hour, re-pumping cycle efficiency 74.36%. From putting the PSP into operation till the end of 1996, the HGS in operation 145,269 hours in total, including 53,332 hours in a turbine mode of operation, 70,293 hours in a pumping mode operation and 21,644 hours in a compensation mode operation. Whereas they supplied 5,346 GWh in the mains and the consumed 6,933 GWh of electricity for pumping. Hydroenergetic potential is a primary source of energy which is recyclable, i.e. unexhaustible and also ecologically the most tolerable

  7. Diversity of ABC transporter genes across the plant kingdom and their potential utility in biotechnology.

    Science.gov (United States)

    Lane, Thomas S; Rempe, Caroline S; Davitt, Jack; Staton, Margaret E; Peng, Yanhui; Soltis, Douglas Edward; Melkonian, Michael; Deyholos, Michael; Leebens-Mack, James H; Chase, Mark; Rothfels, Carl J; Stevenson, Dennis; Graham, Sean W; Yu, Jun; Liu, Tao; Pires, J Chris; Edger, Patrick P; Zhang, Yong; Xie, Yinlong; Zhu, Ying; Carpenter, Eric; Wong, Gane Ka-Shu; Stewart, C Neal

    2016-05-31

    The ATP-binding cassette (ABC) transporter gene superfamily is ubiquitous among extant organisms and prominently represented in plants. ABC transporters act to transport compounds across cellular membranes and are involved in a diverse range of biological processes. Thus, the applicability to biotechnology is vast, including cancer resistance in humans, drug resistance among vertebrates, and herbicide and other xenobiotic resistance in plants. In addition, plants appear to harbor the highest diversity of ABC transporter genes compared with any other group of organisms. This study applied transcriptome analysis to survey the kingdom-wide ABC transporter diversity in plants and suggest biotechnology applications of this diversity. We utilized sequence similarity-based informatics techniques to infer the identity of ABC transporter gene candidates from 1295 phylogenetically-diverse plant transcriptomes. A total of 97,149 putative (approximately 25 % were full-length) ABC transporter gene members were identified; each RNA-Seq library (plant sample) had 88 ± 30 gene members. As expected, simpler organisms, such as algae, had fewer unique members than vascular land plants. Differences were also noted in the richness of certain ABC transporter subfamilies. Land plants had more unique ABCB, ABCC, and ABCG transporter gene members on average (p plant groups (p plant groups. An increase in the number of gene family members present in the ABCB, ABCC, and ABCD transporter subfamilies may indicate an expansion of the ABC transporter superfamily among green land plants, which include all crop species. The striking difference between the number of ABCA subfamily transporter gene members between ferns and other plant taxa is surprising and merits further investigation. Discussed is the potential exploitation of ABC transporters in plant biotechnology, with an emphasis on crops.

  8. Clinical utility and limitations of intraoperative monitoring of visual evoked potentials.

    Science.gov (United States)

    Luo, Yeda; Regli, Luca; Bozinov, Oliver; Sarnthein, Johannes

    2015-01-01

    During surgeries that put the visual pathway at risk of injury, continuous monitoring of the visual function is desirable. However, the intraoperative monitoring of the visual evoked potential (VEP) is not yet widely used. We evaluate here the clinical utility of intraoperative VEP monitoring. We analyzed retrospectively 46 consecutive surgeries in 2011-2013. High luminance stimulating devices delivered flash stimuli on the closed eyelid during intravenous anesthesia. We monitored VEP features N75 and P100 and took patients' preoperative and postoperative visual function from patient charts. Postoperative ophthalmologic workup was performed in 25 (54%) patients and preoperatively in 28 (61%) patients. VEP recordings were feasible in 62 of 85 eyes (73%) in 46 patients. All 23 eyes without VEP had impaired vision. During surgery, VEPs remained stable throughout surgery in 50 eyes. In 44 of these, visual function did not deteriorate and three patients (6 eyes) developed hemianopia. VEP decreased transiently in 10 eyes and visual function of all was preserved. VEPs were lost permanently in 2 eyes in two patients without new postoperative visual impairment. Satisfactory intraoperative VEP monitoring was feasible in all patients except in those with severe visual impairment. Preservation of VEPs predicted preserved visual function. During resection of lesions in the visual cortex, VEP monitoring could not detect new major visual field defects due to injury in the posterior visual pathway. Intraoperative VEPs were sensitive enough to detect vascular damage during aneurysm clipping and mechanical manipulation of the anterior visual pathway in an early reversible stage. Intraoperative VEP monitoring influenced surgical decisions in selected patients and proved to be a useful supplement to the toolbox of intraoperative neurophysiological monitoring.

  9. Clinical utility and limitations of intraoperative monitoring of visual evoked potentials.

    Directory of Open Access Journals (Sweden)

    Yeda Luo

    Full Text Available During surgeries that put the visual pathway at risk of injury, continuous monitoring of the visual function is desirable. However, the intraoperative monitoring of the visual evoked potential (VEP is not yet widely used. We evaluate here the clinical utility of intraoperative VEP monitoring.We analyzed retrospectively 46 consecutive surgeries in 2011-2013. High luminance stimulating devices delivered flash stimuli on the closed eyelid during intravenous anesthesia. We monitored VEP features N75 and P100 and took patients' preoperative and postoperative visual function from patient charts. Postoperative ophthalmologic workup was performed in 25 (54% patients and preoperatively in 28 (61% patients.VEP recordings were feasible in 62 of 85 eyes (73% in 46 patients. All 23 eyes without VEP had impaired vision. During surgery, VEPs remained stable throughout surgery in 50 eyes. In 44 of these, visual function did not deteriorate and three patients (6 eyes developed hemianopia. VEP decreased transiently in 10 eyes and visual function of all was preserved. VEPs were lost permanently in 2 eyes in two patients without new postoperative visual impairment.Satisfactory intraoperative VEP monitoring was feasible in all patients except in those with severe visual impairment. Preservation of VEPs predicted preserved visual function. During resection of lesions in the visual cortex, VEP monitoring could not detect new major visual field defects due to injury in the posterior visual pathway. Intraoperative VEPs were sensitive enough to detect vascular damage during aneurysm clipping and mechanical manipulation of the anterior visual pathway in an early reversible stage. Intraoperative VEP monitoring influenced surgical decisions in selected patients and proved to be a useful supplement to the toolbox of intraoperative neurophysiological monitoring.

  10. Antioxidant and Antibacterial Potential of Silver Nanoparticles: Biogenic Synthesis Utilizing Apple Extract

    Directory of Open Access Journals (Sweden)

    Upendra Nagaich

    2016-01-01

    Full Text Available The advancement of the biological production of nanoparticles using herbal extracts performs a significant role in nanotechnology discipline as it is green and does not engage harsh chemicals. The objective of the present investigation was to extract flavonoids in the mode of apple extract and synthesize its silver nanoparticles and ultimately nanoparticles loading into hydrogels. The presence of flavonoids in apple extract was characterized by preliminary testing like dil. ammonia test and confirmatory test by magnesium ribbon test. The synthesized silver nanoparticles were characterized using UV spectroscopy, particle size and surface morphology, and zeta potential. Silver nanoparticles loaded hydrogels were evaluated for physical appearance, pH, viscosity, spreadability, porosity, in vitro release, ex vivo permeation, and antibacterial (E. coli and S. aureus and antioxidant studies (DPPH radical scavenging assay. Well dispersed silver nanoparticles below were observed in scanning electron microscope image. Hydrogels displayed in vitro release of 98.01%  ±  0.37% up to 24 h and ex vivo permeation of 98.81  ±  0.24% up to 24 h. Hydrogel effectively inhibited the growth of both microorganism indicating good antibacterial properties. The value of percent radical inhibition was 75.16%  ±  0.04 revealing its high antioxidant properties. As an outcome, it can be concluded that antioxidant and antiageing traits of flavonoids in apple extract plus biocidal feature of silver nanoparticles can be synergistically and successfully utilized in the form of hydrogel.

  11. Developing Multiple Diverse Potential Designs for Heat Transfer Utilizing Graph Based Evolutionary Algorithms

    Energy Technology Data Exchange (ETDEWEB)

    David J. Muth Jr.

    2006-09-01

    This paper examines the use of graph based evolutionary algorithms (GBEAs) to find multiple acceptable solutions for heat transfer in engineering systems during the optimization process. GBEAs are a type of evolutionary algorithm (EA) in which a topology, or geography, is imposed on an evolving population of solutions. The rates at which solutions can spread within the population are controlled by the choice of topology. As in nature geography can be used to develop and sustain diversity within the solution population. Altering the choice of graph can create a more or less diverse population of potential solutions. The choice of graph can also affect the convergence rate for the EA and the number of mating events required for convergence. The engineering system examined in this paper is a biomass fueled cookstove used in developing nations for household cooking. In this cookstove wood is combusted in a small combustion chamber and the resulting hot gases are utilized to heat the stove’s cooking surface. The spatial temperature profile of the cooking surface is determined by a series of baffles that direct the flow of hot gases. The optimization goal is to find baffle configurations that provide an even temperature distribution on the cooking surface. Often in engineering, the goal of optimization is not to find the single optimum solution but rather to identify a number of good solutions that can be used as a starting point for detailed engineering design. Because of this a key aspect of evolutionary optimization is the diversity of the solutions found. The key conclusion in this paper is that GBEA’s can be used to create multiple good solutions needed to support engineering design.

  12. Policies related to opioid agonist therapy for opioid use disorders: The evolution of state policies from 2004 to 2013.

    Science.gov (United States)

    Burns, Rachel M; Pacula, Rosalie L; Bauhoff, Sebastian; Gordon, Adam J; Hendrikson, Hollie; Leslie, Douglas L; Stein, Bradley D

    2016-01-01

    State Medicaid policies play an important role in Medicaid enrollees' access to and use of opioid agonists, such as methadone and buprenorphine, in the treatment of opioid use disorders. Little information is available, however, regarding the evolution of state policies facilitating or hindering access to opioid agonists among Medicaid enrollees. During 2013-2014, we surveyed state Medicaid officials and other designated state substance abuse treatment specialists about their state's recent history of Medicaid coverage and policies pertaining to methadone and buprenorphine. We describe the evolution of such coverage and policies and present an overview of the Medicaid policy environment with respect to opioid agonist therapy from 2004 to 2013. Among our sample of 45 states with information on buprenorphine and methadone coverage, we found a gradual trend toward adoption of coverage for opioid agonist therapies in state Medicaid agencies. In 2013, only 11% of states in our sample (n = 5) had Medicaid policies that excluded coverage for methadone and buprenorphine, whereas 71% (n = 32) had adopted or maintained policies to cover both buprenorphine and methadone among Medicaid enrollees. We also noted an increase in policies over the time period that may have hindered access to buprenorphine and/or methadone. There appears to be a trend for states to enact policies increasing Medicaid coverage of opioid agonist therapies, while in recent years also enacting policies, such as prior authorization requirements, that potentially serve as barriers to opioid agonist therapy utilization. Greater empirical information about the potential benefits and potential unintended consequences of such policies can provide policymakers and others with a more informed understanding of their policy decisions.

  13. Estimating potential stranded commitments for U.S. investor-owned electric utilities

    Energy Technology Data Exchange (ETDEWEB)

    Baxter, L.; Hirst, E.

    1995-01-01

    New technologies, low natural gas prices, and federal and state utility regions are restructuring the electricity industry. Yesterday`s vertically integrated utility with a retail monopoly franchise may be a very different organization in a few years. Conferences, regulatory-commission hearings, and other industry fora are dominated by debates over the extent and form of utility deintegration, wholesale competition, and retail wheeling. A key obstacle to restructuring the electricity industry is stranded commitments. Past investments, power-purchase contracts, and public-policy-driven programs that made sense in an era of cost-of-service regulation may not be cost-effective in a competitive power market. Regulators, utilities, and other parties face tough decisions concerning the mitigation and allocation of these stranded commitments. The authors developed and applied a simple method to calculate the amount of stranded commitments facing US investor-owned electric utilities. The results obtained with this method depend strongly on a few key assumptions: (1) the fraction of utility sales that is at risk with respect to competition, (2) the market price of electric generation, and (3) the number of years during which the utility would lose money because of differences between its embedded cost of production and the market price.

  14. Estimating potential stranded commitments for U.S. investor-owned electric utilities

    International Nuclear Information System (INIS)

    Baxter, L.; Hirst, E.

    1995-01-01

    New technologies, low natural gas prices, and federal and state utility regions are restructuring the electricity industry. Yesterday's vertically integrated utility with a retail monopoly franchise may be a very different organization in a few years. Conferences, regulatory-commission hearings, and other industry fora are dominated by debates over the extent and form of utility deintegration, wholesale competition, and retail wheeling. A key obstacle to restructuring the electricity industry is stranded commitments. Past investments, power-purchase contracts, and public-policy-driven programs that made sense in an era of cost-of-service regulation may not be cost-effective in a competitive power market. Regulators, utilities, and other parties face tough decisions concerning the mitigation and allocation of these stranded commitments. The authors developed and applied a simple method to calculate the amount of stranded commitments facing US investor-owned electric utilities. The results obtained with this method depend strongly on a few key assumptions: (1) the fraction of utility sales that is at risk with respect to competition, (2) the market price of electric generation, and (3) the number of years during which the utility would lose money because of differences between its embedded cost of production and the market price

  15. Utilization of Used Nuclear Fuel in a Potential Future US Fuel Cycle Scenario - 13499

    International Nuclear Information System (INIS)

    Worrall, Andrew

    2013-01-01

    from the FRs due to time in the core, cooling time, reprocessing, and re-fabrication time is built into the analysis, along with impacts in delays and other key assumptions and sensitivities have been investigated. The results of this assessment highlight how the UNF from future reactors (LWRs and FRs) and the resulting fissile materials (U and Pu) from reprocessing can be effectively utilized, and show that the timings of future nuclear programs are key considerations (both for reactors and fuel cycle facilities). The analysis also highlights how the timings are relevant to managing the UNF and how such an analysis can therefore assist in informing the potential future R and D strategy and needs of the US fuel cycle programs and reactor technology. (authors)

  16. Transcriptomic and phenotypic profiling in developing zebrafish exposed to thyroid hormone receptor agonists

    Energy Technology Data Exchange (ETDEWEB)

    Haggard, Derik E.; Noyes, Pamela D.; Waters, Katrina M.; Tanguay, Robert L.

    2018-04-01

    There is a need to develop novel, high-throughput screening and prioritization methods to identify chemicals with adverse estrogen, androgen, and thyroid activity to protect human health and the environment and is of interest to the Endocrine Disruptor Screening Program. The current aim is to explore the utility of zebrafish as a testing paradigm to classify endocrine activity using phenotypically anchored transcriptome profiling. Transcriptome analysis was conducted on embryos exposed to 25 estrogen-, androgen-, or thyroid-active chemicals at a concentration that elicited adverse malformations or mortality at 120 hours post-fertilization in 80% of the animals exposed. Analysis of the top 1000 significant differentially expressed transcripts across all treatments identified a unique transcriptional and phenotypic profile for thyroid hormone receptor agonists, which can be used as a biomarker screen for potential thyroid hormone agonists.

  17. Study of potential utility of new radiopharmaceuticals based on technetium-99m labeled derivative of glucose

    Science.gov (United States)

    Zeltchan, R.; Medvedeva, A.; Sinilkin, I.; Chernov, V.; Stasyuk, E.; Rogov, A.; Il'ina, E.; Larionova, L.; Skuridin, V.

    2016-08-01

    Purpose: to study the potential utility of 1-thio-D-glucose labeled with 99mTc for cancer imaging in laboratory animals. Materials and method: the study was carried out in cell cultures of normal CHO (Chinese hamster ovary cells CHO) and malignant tissues MCF-7 (human breast adenocarcinoma MCF-7). To evaluate the uptake of 99mTc-1-thio-D-glucose in normal and tumor tissue cells, 25 MBq of 1-thio-D-glucose labeled with 99mTc was added to the vials with 3 million cells and incubated for 30 min at room temperature. After centrifugation of the vials with cells, the supernatant was removed. The radioactivity in vials with normal and tumor cells was then measured. In addition, the study included 40 mice of C57B1/6j lines with tumor lesion of the right femur. For neoplastic lesions, Lewis lung carcinoma model was used. Following anesthesia, mice were injected intravenously with 25 MBq of 99mTc-1-thio-D-glucose. Planar scintigraphy was performed 15 minutes later in a matrix of 512x512 pixels for 5 min. Results: when measuring the radioactivity of normal and malignant cells after incubation with 99mTc-1-thio-D-glucose, it was found that the radioactivity of malignant cells was higher than that of normal cells. The mean values of radioactivity levels in normal and malignant cells were 0.3 ± 0.15 MBq and 1.07 ± 0.6 MBq, respectively. All examined animals had increased accumulation of 99mTc-1-thio-D-glucose at the tumor site. The accumulation of 99mTc-1-thio-D-glucose in the tumor was on average twice as high as compared to the symmetric region. Conclusion: The present study demonstrated that 99mTc-1-thio-D-glucose is a prospective radiopharmaceutical for cancer visualization. In addition, high accumulation of 99mTc-1-thio-D-glucose in the culture of cancer cells and in tumor tissue of animals demonstrates tumor tropism of the radiopharmaceutical.

  18. Study of potential utility of new radiopharmaceuticals based on technetium-99m labeled derivative of glucose

    Energy Technology Data Exchange (ETDEWEB)

    Zeltchan, R., E-mail: r.zelchan@yandex.ru; Medvedeva, A.; Sinilkin, I.; Chernov, V. [Tomsk Cancer Research Institute, Tomsk, 634050 (Russian Federation); Tomsk Polytechnic University, Tomsk, 634050 (Russian Federation); Stasyuk, E.; Rogov, A.; Il’ina, E.; Larionova, L.; Skuridin, V. [Tomsk Polytechnic University, Tomsk, 634050 (Russian Federation)

    2016-08-02

    Purpose: to study the potential utility of 1-thio-D-glucose labeled with {sup 99m}Tc for cancer imaging in laboratory animals. Materials and method: the study was carried out in cell cultures of normal CHO (Chinese hamster ovary cells CHO) and malignant tissues MCF-7 (human breast adenocarcinoma MCF-7). To evaluate the uptake of {sup 99m}Tc-1-thio-D-glucose in normal and tumor tissue cells, 25 MBq of 1-thio-D-glucose labeled with {sup 99m}Tc was added to the vials with 3 million cells and incubated for 30 min at room temperature. After centrifugation of the vials with cells, the supernatant was removed. The radioactivity in vials with normal and tumor cells was then measured. In addition, the study included 40 mice of C57B1/6j lines with tumor lesion of the right femur. For neoplastic lesions, Lewis lung carcinoma model was used. Following anesthesia, mice were injected intravenously with 25 MBq of {sup 99m}Tc-1-thio-D-glucose. Planar scintigraphy was performed 15 minutes later in a matrix of 512x512 pixels for 5 min. Results: when measuring the radioactivity of normal and malignant cells after incubation with {sup 99m}Tc-1-thio-D-glucose, it was found that the radioactivity of malignant cells was higher than that of normal cells. The mean values of radioactivity levels in normal and malignant cells were 0.3 ± 0.15 MBq and 1.07 ± 0.6 MBq, respectively. All examined animals had increased accumulation of {sup 99m}Tc-1-thio-D-glucose at the tumor site. The accumulation of {sup 99m}Tc-1-thio-D-glucose in the tumor was on average twice as high as compared to the symmetric region. Conclusion: The present study demonstrated that {sup 99m}Tc-1-thio-D-glucose is a prospective radiopharmaceutical for cancer visualization. In addition, high accumulation of {sup 99m}Tc-1-thio-D-glucose in the culture of cancer cells and in tumor tissue of animals demonstrates tumor tropism of the radiopharmaceutical.

  19. Improving the optimized shea butter quality: a great potential of utilization for common consumers and industrials.

    Science.gov (United States)

    Megnanou, Rose-Monde; Niamke, Sébastien

    2015-01-01

    Industrials interest in fats as raw material, resides in their exceptional quality and potentialities of exploitation in several fields. This study aimed to exalt the optimized shea butter quality and present its wide potentialities of utilization. Hence, the characteristics of beige and yellow optimized shea butters were determined. Both samples recorded very weak acid (0.280 ± 0.001 and 0.140 ± 0.001 mgKOH/g) and peroxide (0.960 ± 0.001 and 1.010 ± 0.001 mEgO2/kg) indexes, when the iodine indexes (52.64 ± 0.20 and 53.06 ± 0.20 gI2/100 g) and the unsaponifiable matters (17.61 ± 0.01 and 17.27 ± 0.01 %) were considerable. The refractive indexes (1.454 ± 0.00 and 1.453 ± 0.00) and the pH (6.50 ± 0.30 and 6.78 ± 0.30) were statistically similar; but the specific gravity (0.915 ± 0.01-0.79 ± 0.01 and 0.94 ± 0.01-0.83 ± 0.01) and the viscosity (90.41 ± 0.20-20.02 ± 0.20 and 125.37 ± 0.20-23.55 ± 0.20 MPas) differed and decreased exponentially with the temperature increasing (35-65 °C), except for the specific gravity of the yellow butter which decreased linearly. The UV-Vis spectrum showed a high peak at 300 nm and a rapid decrease from 300 to 500 nm when the near infra-red one, revealed peaks at 450, 1200, 1400, 1725 and 2150 nm for all the samples. The chromatographic profile identified palmitic (16.42 and 26.36 %), stearic (32.39 and 36.36 %), oleic (38.12 and 29.09 %), linoleic (9.72 and 5.92 %) and arachidic (1.84 and 1.59 %) acids, and also exaltolide compound (1.51 and 0.68 %). The samples also contained essential minerals (Calcium, magnesium, zinc, iron, etc.) carotene (550 ± 50 and 544 ± 50 ppm), vitamins A (0.065 ± 0.001 and 0.032 ± 0.001 µg/g) and E (2992.09 ± 1.90 and 3788.44 ± 1.90 ppm) in relatively important amounts; neither microbiological germs nor heavy were detected. All these valorizing characteristics would confer to the optimized shea butters good

  20. Utilizing the Potential of the Affected Population and Prevalent Mobile Technology during Disaster Response : Propositions for a Literature Survey

    NARCIS (Netherlands)

    Gunawan, L.T.; Fitrianie, S.; Brinkman, W.P.; Neerincx, M.A.

    2012-01-01

    Despite the growing awareness of the untapped potential of the affected population in a disaster situation, their inclusion in a disaster management is extremely limited. This study aims to survey the literature to see whether utilizing the affected people and prevalent mobile technology can be used

  1. Utilizing the potential of the affected population and prevalent mobile technology during disaster response : Propositions from a literature survey

    NARCIS (Netherlands)

    Gunawan, L.T.; Fitrianie, S.; Brinkman, W.P.; Neerincx, M.A.

    2012-01-01

    Despite the growing awareness of the untapped potential of the affected population in a disaster situation, their inclusion in a disaster management is extremely limited. This study aims to survey the literature to see whether utilizing the affected people and prevalent mobile technology can be used

  2. A Review of Thorium Utilization as an option for Advanced Fuel Cycle-Potential Option for Brazil in the Future

    International Nuclear Information System (INIS)

    Maiorino, J.R.; Carluccio, T.

    2004-01-01

    Since the beginning of Nuclear Energy Development, Thorium was considered as a potential fuel, mainly due to the potential to produce fissile uranium 233. Several Th/U fuel cycles, using thermal and fast reactors were proposed, such as the Radkwoski once through fuel cycle for PWR and VVER, the thorium fuel cycles for CANDU Reactors, the utilization in Molten Salt Reactors, the utilization of thorium in thermal (AHWR), and fast reactors (FBTR) in India, and more recently in innovative reactors, mainly Accelerator Driven System, in a double strata fuel cycle. All these concepts besides the increase in natural nuclear resources are justified by non proliferation issues (plutonium constrain) and the waste radiological toxicity reduction. The paper intended to summarize these developments, with an emphasis in the Th/U double strata fuel cycle using ADS. Brazil has one of the biggest natural reserves of thorium, estimated in 1.2 millions of tons of ThO 2 , as will be reviewed in this paper, and therefore RandD programs would be of strategically national interest. In fact, in the past there was some projects to utilize Thorium in Reactors, as the ''Instinto/Toruna'' Project, in cooperation with France, to utilize Thorium in Pressurized Heavy Water Reactor, in the mid of sixties to mid of seventies, and the thorium utilization in PWR, in cooperation with German, from 1979-1988. The paper will review these initiatives in Brazil, and will propose to continue in Brazil activities related with Th/U fuel cycle

  3. Identification, definition and evaluation of potential impacts facing the US electric utility industry over the next decade. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Grainger, J.J.; Lee, S.S.H.

    1993-11-26

    There are numerous conditions of the generation system that may ultimately develop into system states affecting system reliability and security. Such generation system conditions should also be considered when evaluating the potential impacts on system operations. The following five issues have been identified to impact system reliability and security to the greatest extent: transmission access/retail wheeling; non-utility generators and independent power producers; integration of dispersed storage and generation into utility distribution systems; EMF and right-of-way limitations; Clean Air Act Amendments. Strictly speaking, some issues are interrelated and one issue cannot be completely dissociated from the others. However, this report addresses individual issues separately in order to determine all major aspects of bulk power system operations affected by each issue. The impacts of the five issues on power system reliability and security are summarized. This report examines the five critical issues that the US electric utility industry will be facing over the next decade. The investigation of their impacts on utility industry will be facing over the next decade. The investigation of their impacts on utility system reliability and security is limited to the system operation viewpoint. Those five issues will undoubtedly influence various planning aspects of the bulk transmission system. However, those subjects are beyond the scope of this report. While the issues will also influence the restructure and business of the utility industry politically, sociologically, environmentally, and economically, all discussion included in the report are focused only on technical ramifications.

  4. Possibilities of further utilization of hydroenergetic potential of the Slovak Republic

    International Nuclear Information System (INIS)

    Tarbajovsky, L.

    1997-01-01

    This entry deals with a description of possibilities of energetic utilization of so far not used sections of main streams, it does not cover possibilities of construction of hydroelectric power plans on border streams (rivers Vah, Hron, and Orava) and less important streams in the eastern part of the Slovak Republic

  5. Evaluating forest biomass utilization in the Appalachians: A review of potential impacts and guidelines for management

    Science.gov (United States)

    Michael R. Vanderberg; Mary Beth Adams; Mark S. Wiseman

    2012-01-01

    Forests are important economic and ecological resources for both the Appalachian hardwood forest region and the country. Increased demand for woody biomass can be met, at least in part, by improved utilization of these resources. However, concerns exist about the impacts of increased intensity of woody biomass removal on the sustainability of forest ecosystems....

  6. Enhancement of the potential to utilize octopine in the nonfluorescent Pseudomonas sp. strain 92

    International Nuclear Information System (INIS)

    Gill, S.S.; Boivin, R.; Dion, P.

    1991-01-01

    The nonfluorescent Pseudomonas sp. strain 92 requires the presence of a supplementary carbon source for growth on octopine, whereas the spontaneous mutant RB100 has acquired the capacity to utilize this opine as the sole carbon and nitrogen source. Insertional mutagenesis of RB100 with transposon Tn5 generated mutants which were unable to grow on octopine and others which grew slowly on this substrate. Both types of mutants yielded revertants that had regained the ability to utilize octopine. Some of the revertants had lost the transposon, whereas in others the transposon was retained but with rearrangements of the insertion site. Genes of octopine catabolism from strain 92 were cloned on a cosmid vector to generate pK3. The clone pK3 conferred the ability to utilize octopine as the sole carbon and nitrogen source on the host Pseudomonas putida KT2440. Although they conferred an equivalent growth phenotype, the mutant genes carried by RB100 and the cloned genes on pK3 differed in their regulation. Utilization of [ 14 C]octopine was inducible by octopine in RB100 and was constitutive in KT2440(pK3)

  7. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists have become available for the treatment of type 2 diabetes. These agents exploit the physiological effects of GLP-1, which is able to address several of the pathophysiological features of type 2 diabetes. GLP-1R agonists...... presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide...... and liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  8. Problematic gambling on dopamine agonists: Not such a rarity.

    Science.gov (United States)

    Grosset, Katherine A; Macphee, Graeme; Pal, Guru; Stewart, David; Watt, Andrew; Davie, Jim; Grosset, D G

    2006-12-01

    Excessive gambling is recognized with dopamine agonist therapy, but the prevalence is unknown. We assessed the prevalence of excess gambling by specific prospective enquiry in Parkinson's disease patients attending six West Scotland movement disorder clinics. Of 388 patients taking anti-Parkinson medication, 17 (4.4%) developed pathological gambling, all of whom were prescribed dopamine agonists. Thus, 8% of patients taking dopamine agonists had pathological gambling. Pathological gambling is not uncommon, and patients should be made aware of this potential adverse effect. Copyright 2006 Movement Disorder Society.

  9. Gonadotropin releasing hormone agonists: Expanding vistas

    Directory of Open Access Journals (Sweden)

    Navneet Magon

    2011-01-01

    Full Text Available Gonadotropin-releasing hormone (GnRH agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women′s healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

  10. Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

    Directory of Open Access Journals (Sweden)

    Monica Marzagalli

    2016-10-01

    Full Text Available Cutaneous melanoma is an aggressive tumor with its incidence increasing faster than any other cancer in the past decades. Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways. The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade. However, treatment resistance and side effects are common events of these therapeutic strategies.Increasing evidence supports that melanoma is a hormone-related cancer. Melanoma incidence is higher in males than in females and females have a significant survival advantage over men. Estrogens exert their effects through estrogen receptors (ER and ERβ that exert opposite effects on cancer growth: ER is associated with a proliferative action and ERβ with an anticancer effect. ERβ is the predominant estrogen receptor in melanoma and its expression decreases in melanoma progression, supporting its role as a tumor suppressor. Thus, ERβ is now considered as an effective molecular target for melanoma treatment. 17β-estradiol was reported to inhibit melanoma cells proliferation. However, clinical trials did not provide the expected survival benefits. In vitro studies demonstrate that ERβ ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF mutation, suggesting that ERβ activation might impair melanoma development through the inhibition of the PI3K/Akt pathway. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas. In an era of personalized medicine, pretreatment evaluation of the expression of ER isoforms together with the concurrent oncogenic mutations should be considered before selecting the most appropriate therapeutic intervention

  11. Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

    Science.gov (United States)

    Marzagalli, Monica; Montagnani Marelli, Marina; Casati, Lavinia; Fontana, Fabrizio; Moretti, Roberta Manuela; Limonta, Patrizia

    2016-01-01

    Cutaneous melanoma is an aggressive tumor; its incidence has been reported to increase fast in the past decades. Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways. The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade. However, treatment resistance and side effects are common events of these therapeutic strategies. Increasing evidence supports that melanoma is a hormone-related cancer. Melanoma incidence is higher in males than in females, and females have a significant survival advantage over men. Estrogens exert their effects through estrogen receptors (ERα and ERβ) that affect cancer growth in an opposite way: ERα is associated with a proliferative action and ERβ with an anticancer effect. ERβ is the predominant ER in melanoma, and its expression decreases in melanoma progression, supporting its role as a tumor suppressor. Thus, ERβ is now considered as an effective molecular target for melanoma treatment. 17β-estradiol was reported to inhibit melanoma cells proliferation; however, clinical trials did not provide the expected survival benefits. In vitro studies demonstrate that ERβ ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF) mutation, suggesting that ERβ activation might impair melanoma development through the inhibition of the PI3K/Akt pathway. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas. In an era of personalized medicine, pretreatment evaluation of the expression of ER isoforms together with the concurrent oncogenic mutations should be considered before selecting the most appropriate therapeutic intervention. Natural compounds that specifically bind to

  12. Agribusiness geothermal energy utilization potential of Klamath and Western Snake River Basins, Oregon. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Lienau, P.J.

    1978-03-01

    Resource assessment and methods of direct utilization for existing and prospective food processing plants have been determined in two geothermal resource areas in Oregon. Ore-Ida Foods, Inc. and Amalgamated Sugar Company in the Snake River Basin; Western Polymer Corporation (potato starch extraction) and three prospective industries--vegetable dehydration, alfalfa drying and greenhouses--in the Klamath Basin have been analyzed for direct utilization of geothermal fluids. Existing geologic knowledge has been integrated to indicate locations, depth, quality, and estimated productivity of the geothermal reservoirs. Energy-economic needs and balances, along with cost and energy savings associated with field development, delivery systems, in-plant applications and fluid disposal have been calculated for interested industrial representatives.

  13. Performance potential of combined cycles integrated with low-Btu gasifiers for future electric utility applications

    Science.gov (United States)

    Nainiger, J. J.; Burns, R. K.

    1977-01-01

    A comparison and an assessment of 10 advanced utility power systems on a consistent basis and to a common level of detail were analyzed. Substantial emphasis was given to a combined cycle systems integrated with low-Btu gasifiers. Performance and cost results from that study were presented for these combined cycle systems, together with a comparative evaluation. The effect of the gasifier type and performance and the interface between the gasifier and the power system were discussed.

  14. Treatment with a corticotrophin releasing factor 2 receptor agonist modulates skeletal muscle mass and force production in aged and chronically ill animals

    Directory of Open Access Journals (Sweden)

    Ferreira Leonardo F

    2011-01-01

    Full Text Available Abstract Background Muscle weakness is associated with a variety of chronic disorders such as emphysema (EMP and congestive heart failure (CHF as well as aging. Therapies to treat muscle weakness associated with chronic disease or aging are lacking. Corticotrophin releasing factor 2 receptor (CRF2R agonists have been shown to maintain skeletal muscle mass and force production in a variety of acute conditions that lead to skeletal muscle wasting. Hypothesis We hypothesize that treating animals with a CRF2R agonist will maintain skeletal muscle mass and force production in animals with chronic disease and in aged animals. Methods We utilized animal models of aging, CHF and EMP to evaluate the potential of CRF2R agonist treatment to maintain skeletal muscle mass and force production in aged animals and animals with CHF and EMP. Results In aged rats, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater extensor digitorum longus (EDL force production, EDL mass, soleus mass and soleus force production compared to age matched untreated animals. In the hamster EMP model, we demonstrate that treatment with a CRF2R agonist for up to 5 months results in greater EDL force production in EMP hamsters when compared to vehicle treated EMP hamsters and greater EDL mass and force in normal hamsters when compared to vehicle treated normal hamsters. In the rat CHF model, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater EDL and soleus muscle mass and force production in CHF rats and normal rats when compared to the corresponding vehicle treated animals. Conclusions These data demonstrate that the underlying physiological conditions associated with chronic diseases such as CHF and emphysema in addition to aging do not reduce the potential of CRF2R agonists to maintain skeletal muscle mass and force production.

  15. Simulation Suggests that medical group mergers won't undermine the potential utility of health information exchanges.

    Science.gov (United States)

    Rudin, Robert S; Schneider, Eric C; Volk, Lynn A; Szolovits, Peter; Salzberg, Claudia A; Simon, Steven R; Bates, David W

    2012-03-01

    Federal and state agencies are investing substantial resources in the creation of community health information exchanges, which are consortia that enable independent health care organizations to exchange clinical data. However, under pressure to form accountable care organizations, medical groups may merge and support private health information exchanges. Such activity could reduce the potential utility of community exchanges-that is, the exchanges' capacity to share patient data across hospitals and physician practices that are independent. Simulations of care transitions based on data from ten Massachusetts communities suggest that there would have to be many such mergers to undermine the potential utility of health information exchanges. At the same time, because hospitals and the largest medical groups account for only 10-20 percent of care transitions in a community, information exchanges will still need to recruit a large proportion of the medical groups in a given community for the exchanges to maintain their usefulness in fostering information exchange across independent providers.

  16. Simulation Suggests That Medical Group Mergers Won’t Undermine The Potential Utility Of Health Information Exchanges

    Science.gov (United States)

    Schneider, Eric C.; Volk, Lynn A.; Szolovits, Peter; Salzberg, Claudia A.; Simon, Steven R.; Bates, David W.

    2013-01-01

    Substantial resources are being invested in health information exchanges (HIE), community-based consortia that enable independent health-care organizations to exchange clinical data. However, under pressure to form accountable care organizations, medical groups may merge and support private HIE, reducing the potential utility of community HIEs. Simulations of “care transitions” based on data from 10 Massachusetts communities suggest that mergers would have to be considerable to substantially reduce the potential utility of an HIE. Nonetheless, simulations also suggest that HIEs will need to recruit a large proportion of the medical groups in a community, as hospitals and the largest groups account for only 10 to 20% of care transitions in communities. PMID:22392665

  17. A safe potential juice clarifying pectinase from Trichoderma viride EF-8 utilizing Egyptian onion skins

    OpenAIRE

    Abdel-Mohsen S. Ismail; Heba I. Abo-Elmagd; Manal M. Housseiny

    2016-01-01

    The production of a notable, safe and highly active pectinase by the local fungal strain Trichoderma viride EF-8 utilizing the abundant pigmented Egyptian onion (Allium cepa L.) skins (6.5%, w/v) was achieved in 4 days submerged fermentation (SMF) cultures, at temperature and pH of 30 °C and 4.0, respectively. The indigenously produced pectinase was partially purified by 50% batch ethanol precipitation and its general properties were studied following the standard procedures. The lyophilized ...

  18. Use of transglutaminases in foods and potential utilization of plants as a transglutaminase source – Review

    Directory of Open Access Journals (Sweden)

    Fernando Bittencourt Luciano

    2012-09-01

    Full Text Available http://dx.doi.org/10.5007/2175-7925.2012v25n4p1   Transglutaminases (TGases are enzymes able to catalyze acyl-transfer reactions introducing covalent cross-links between proteins, peptides and primary amines. Animal TGases were the first studied and are divided in nine different groups of isoenzymes. They have a wide range of functions in the metabolism of most animal cells, and share the characteristic of being Ca2+-dependent. Microbial and plant TGases were also identified, and there is a vast heterogeneity among their amino acid sequences. Interestingly, it seems that all transglutaminases share a specific amino acid triad of Cys-His-Asp in their catalytic site, which can be found in all tertiary structures of the enzymes yet studied so far. Microbial TGases are the most widely used for food modification due to lower costs and high yields involved with their extraction and purification when compared to mammal sources. TGases are ubiquitously found in a variety of plants, and their utilization for food transformation has been proposed. However, there is only a single attempt using vegetal TGase in food systems, where apple pomace was used to improve the quality of pork meat. The transference of mammalian TGase genes to plants has also been considered and they were found to be successfully expressed in rice and tobacco leaves. These results lead to a new approach, where TGases could be literally farmed for food utilization.

  19. Use of transglutaminases in foods and potential utilization of plants as a transglutaminase source – Review

    Directory of Open Access Journals (Sweden)

    Fernando B. Luciano

    2012-11-01

    Full Text Available Transglutaminases (TGases are enzymes able to catalyze acyl-transfer reactions introducing covalent cross-links between proteins, peptides and primary amines. Animal TGases were the first studied and are divided in nine different groups of isoenzymes. They have a wide range of functions in the metabolism of most animal cells, and share the characteristic of being Ca2+-dependent. Microbial and plant TGases were also identified, and here is a vast heterogeneity among their amino acid sequences. Interestingly, it seems that all transglutaminases share a specific amino acid triad of Cys-His-Asp in their catalytic site, which can be found in all tertiary structures of the enzymes yet studied so far. Microbial TGases are the most widely used for food modification due to lower costs and high yields involved with their extraction and purification when compared to mammal sources. TGases are ubiquitously found in a variety of plants, and their utilization for food transformation has been proposed. However, there is only a single attempt using vegetal TGase in food systems, where apple pomace was used to improve the quality of pork meat. The transference of mammalian TGase genes to plants has also been considered and they were found to be successfully expressed in rice and tobacco leaves. These results lead to a new approach, where TGases could be literally farmed for food utilization.

  20. Potential utility of SumbandilaSat imagery for monitoring indigenous forest health

    CSIR Research Space (South Africa)

    Cho, Moses A

    2010-09-01

    Full Text Available various applications. We investigated the potential of SumbandilaSat sensor for providing information on forest canopy stress for the Dukuduku indigenous forest (28o25’S, 32o17’E) situated in the northern part of KwaZulu-Natal, South Africa. Airborne...

  1. Characterization of structurally novel G protein biased CB1 agonists: Implications for drug development.

    Science.gov (United States)

    Ford, Benjamin M; Franks, Lirit N; Tai, Sherrica; Fantegrossi, William E; Stahl, Edward L; Berquist, Michael D; Cabanlong, Christian V; Wilson, Catheryn D; Penthala, Narsimha R; Crooks, Peter A; Prather, Paul L

    2017-11-01

    The human cannabinoid subtype 1 receptor (hCB 1 R) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant-derived and synthetic cannabinoids. Unfortunately, acute use of hCB 1 R agonists produces unwanted psychotropic effects and chronic administration results in development of tolerance and dependence, limiting the potential clinical use of these ligands. Studies in β-arrestin knockout mice suggest that interaction of certain GPCRs, including μ-, δ-, κ-opioid and hCB 1 Rs, with β-arrestins might be responsible for several adverse effects produced by agonists acting at these receptors. Indeed, agonists that bias opioid receptor activation toward G-protein, relative to β-arrestin signaling, produce less severe adverse effects. These observations indicate that therapeutic utility of agonists acting at hCB 1 Rs might be improved by development of G-protein biased hCB 1 R agonists. Our laboratory recently reported a novel class of indole quinulidinone (IQD) compounds that bind cannabinoid receptors with relatively high affinity and act with varying efficacy. The purpose of this study was to determine whether agonists in this novel cannabinoid class exhibit ligand bias at hCB 1 receptors. Our studies found that a novel IQD-derived hCB 1 receptor agonist PNR-4-20 elicits robust G protein-dependent signaling, with transduction ratios similar to the non-biased hCB 1 R agonist CP-55,940. In marked contrast to CP-55,940, PNR-4-20 produces little to no β-arrestin 2 recruitment. Quantitative calculation of bias factors indicates that PNR-4-20 exhibits from 5.4-fold to 29.5-fold bias for G protein, relative to β-arrestin 2 signaling (when compared to G protein activation or inhibition of forskolin-stimulated cAMP accumulation, respectively). Importantly, as expected due to reduced β-arrestin 2 recruitment, chronic exposure of cells to PNR-4-20 results in significantly less desensitization and down-regulation of hCB 1

  2. Revealing the potential pathogenesis of glioma by utilizing a glioma associated protein-protein interaction network.

    Science.gov (United States)

    Pan, Weiran; Li, Gang; Yang, Xiaoxiao; Miao, Jinming

    2015-04-01

    This study aims to explore the potential mechanism of glioma through bioinformatic approaches. The gene expression profile (GSE4290) of glioma tumor and non-tumor samples was downloaded from Gene Expression Omnibus database. A total of 180 samples were available, including 23 non-tumor and 157 tumor samples. Then the raw data were preprocessed using robust multiarray analysis, and 8,890 differentially expressed genes (DEGs) were identified by using t-test (false discovery rate What' more, for the top 10 sub-networks, Gene Ontology (GO) enrichment analysis (p value tissue-specific genes were calculated (p value = 1.0, 1.0, and 0.00014, respectively) and visualized by Venn Diagram package in R. About 61% of human tissue-specific genes were DEGs as well. This research shed new light on the pathogenesis of glioma based on DEGs and GAPN, and our findings might provide potential targets for clinical glioma treatment.

  3. Recovery of fission products from waste solutions utilizing controlled cathodic potential electrolysis

    International Nuclear Information System (INIS)

    Carlin, W.W.; Darlington, W.B.

    1975-01-01

    Fission products, e.g., palladium, rhodium and technetium, are recovered from aqueous waste solutions thereof, e.g., aged Purex alkaline waste solutions. The metal values from the waste solutions are extracted by ion exchange techniques. The metals adsorbed by the ion exchange resin are eluted and selectively recovered by controlled cathodic potential electrolysis. The metal values deposited on the cathode are recovered and, if desired, further purified

  4. Nitrogen Utilization and Environmental Losses from Organic Farming and Biochar's Potential to Improve N Efficiency.

    Science.gov (United States)

    Pereira, E. I.; SIX, J. W. U. A.

    2014-12-01

    The response of plant performance and nitrogen (N) dynamics to biochar amendments were studied across various levels of N input for two growing seasons in mesocosms representing an organic lettuce production systems. A silt loam soil was amended with pine chip (PC) and walnut shell (WS) biochar (10 t ha-1) in combination with five organic N fertilization rates 0%, 25%, 50%, 75%, and 100% of 225 kg N ha-1. N output through harvest, leachate, and nitrous oxide (N2O) emissions were determined to assess N utilization and environmental losses of biochar-amended soils. Analysis of plant performance indicate that PC and WS biochar did not provide any increases in plant biomass in soils that received less than business-as-usual fertilization rates. At 100% N fertilization rate, biochar amendments (both PC and WS) improved lettuce biomass production, which resulted in significant increases in NUE with no effects on N2O emissions. Furthermore, N losses via leaching were decreased by PC biochar at 100% N fertilization rates. Thus, due to increases in plant biomass and decreases in N losses via leachate, PC biochar significantly decreased the ratio of N lost over N exported in biomass. Findings from this study suggest that biochar can provide some beneficial effects to organic farming systems, however, not in all circumstances, given the effects seem to vary with biochar type and fertilization level.

  5. A safe potential juice clarifying pectinase from Trichoderma viride EF-8 utilizing Egyptian onion skins

    Directory of Open Access Journals (Sweden)

    Abdel-Mohsen S. Ismail

    2016-06-01

    Full Text Available The production of a notable, safe and highly active pectinase by the local fungal strain Trichoderma viride EF-8 utilizing the abundant pigmented Egyptian onion (Allium cepa L. skins (6.5%, w/v was achieved in 4 days submerged fermentation (SMF cultures, at temperature and pH of 30 °C and 4.0, respectively. The indigenously produced pectinase was partially purified by 50% batch ethanol precipitation and its general properties were studied following the standard procedures. The lyophilized enzyme preparation was free of any ochra or aflatoxins. The optimum conditions for the partially purified enzyme form were 2 mg/mL and 1% (w/v enzyme protein and substrate (citrus pectin concentrations, reaction pH and temperature of 7.0 and 40 °C, respectively. The results presented the low cost onion skins waste as the major substrate for the fungal pectinase production and its subsequent use in perfect fruit (apple, lemon and orange juices clarification with remarkable stability during and after this process, which certainly enhance fruit juices processing in the tropics.

  6. Comparative Phytonutrient Analysis of Broccoli By-Products: The Potentials for Broccoli By-Product Utilization

    Directory of Open Access Journals (Sweden)

    Mengpei Liu

    2018-04-01

    Full Text Available The phytonutrient concentrations of broccoli (Brassica oleracea var. italica florets, stems, and leaves were compared to evaluate the value of stem and leaf by-products as a source of valuable nutrients. Primary metabolites, including amino acids, organic acids, and sugars, as well as glucosinolates, carotenoids, chlorophylls, vitamins E and K, essential mineral elements, total phenolic content, antioxidant activity, and expression of glucosinolate biosynthesis and hydrolysis genes were quantified from the different broccoli tissues. Broccoli florets had higher concentrations of amino acids, glucoraphanin, and neoglucobrassicin compared to other tissues, whereas leaves were higher in carotenoids, chlorophylls, vitamins E and K, total phenolic content, and antioxidant activity. Leaves were also good sources of calcium and manganese compared to other tissues. Stems had the lowest nitrile formation from glucosinolate. Each tissue exhibited specific core gene expression profiles supporting glucosinolate metabolism, with different gene homologs expressed in florets, stems, and leaves, which suggests that tissue-specific pathways function to support primary and secondary metabolic pathways in broccoli. This comprehensive nutrient and bioactive compound profile represents a useful resource for the evaluation of broccoli by-product utilization in the human diet, and as feedstocks for bioactive compounds for industry.

  7. Achieving the economic potential for industrial cogeneration in Ontario: A financial perspective on electric utility policy

    International Nuclear Information System (INIS)

    Diemer, S.G.; Cain, S.R.

    1993-01-01

    The impact of private vs public ownership regimes on the magnitude of achievable industrial cogeneration capacity in Ontario is assessed. Estimates of technical and economic potential are presented for several industrial subsectors and heat demand categories, showing that nearly all of the technically feasible 7,600 MW is also economically efficient given a value of power of at least 4 cents/kWh in 1991 dollars. Using financial data and investment criteria specific to the two forms of ownership, the project evaluation model points to a significantly larger quantum of financial (achievable) potential with public rather than private development of industrial cogeneration. At avoided costs and associated buyback rates of 4 and 5 cents/kWh, the achievable cogeneration capacities are ca 2,400 and 7,600 MW under public ownership and 132 and 3,000 MW under private ownership. Ratepayer savings are significant: the full economic potential can be achieved through public ownership at a buyback rate of 5 cents/kWh; under private ownership, a comparable capacity requires a 6 cents buyback rate, reflecting additional ratepayer costs of nearly $600 million annually. 1 fig., 4 tabs

  8. Utilization of renewable energy potential in Pakistan - a goal oriented approach through industry-cum-academia linkage

    International Nuclear Information System (INIS)

    Khalil, M.S.

    2011-01-01

    Due to the recent power crisis in Pakistan, it is essential to utilize the god gifted renewable energy potentials in the form of hydro-power, solar, wind etc. With recent developments in emerging technologies globally, it is the basic need for indigenous development of renewable energy resources. It can be done through research and development by bridging the gaps between industries and technical institutions. In the world, this approach is being carried out not only for the development but for sustain ability of the R and D in the field of renewable energies. Local industries can play a vital role in using latest computational techniques in the research and development areas with the utilization of technical and engineering institutions. For sustainable development of renewable energy resources in the country, local industry have to come forward and contribute toward the betterment of the country. (author)

  9. Utility and potential of rapid epidemic intelligence from internet-based sources.

    Science.gov (United States)

    Yan, S J; Chughtai, A A; Macintyre, C R

    2017-10-01

    Rapid epidemic detection is an important objective of surveillance to enable timely intervention, but traditional validated surveillance data may not be available in the required timeframe for acute epidemic control. Increasing volumes of data on the Internet have prompted interest in methods that could use unstructured sources to enhance traditional disease surveillance and gain rapid epidemic intelligence. We aimed to summarise Internet-based methods that use freely-accessible, unstructured data for epidemic surveillance and explore their timeliness and accuracy outcomes. Steps outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist were used to guide a systematic review of research related to the use of informal or unstructured data by Internet-based intelligence methods for surveillance. We identified 84 articles published between 2006-2016 relating to Internet-based public health surveillance methods. Studies used search queries, social media posts and approaches derived from existing Internet-based systems for early epidemic alerts and real-time monitoring. Most studies noted improved timeliness compared to official reporting, such as in the 2014 Ebola epidemic where epidemic alerts were generated first from ProMED-mail. Internet-based methods showed variable correlation strength with official datasets, with some methods showing reasonable accuracy. The proliferation of publicly available information on the Internet provided a new avenue for epidemic intelligence. Methodologies have been developed to collect Internet data and some systems are already used to enhance the timeliness of traditional surveillance systems. To improve the utility of Internet-based systems, the key attributes of timeliness and data accuracy should be included in future evaluations of surveillance systems. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  10. The potential of bioash for utilization in road construction in eastern Croatia

    Science.gov (United States)

    Zagvozda, Martina; Dimter, Sanja; Rukavina, Tatjana

    2017-12-01

    In recent years usage of biomass as energy source has intensified in eastern Croatia. Newly built biomass power plants generate great amounts of bioash that is being disposed at landfills. Due to its favorable properties bioashes could be reused as alternative materials in road construction or road fundation. Therefore, research on application of bioashes in construction industry is being conducted at Faculty of Civil Engineering in Osijek. The main motivation behind this research, in a form of biomass and bioash production in eastern Croatia as well as international research on potential application of this types of bioashes, is show in this paper.

  11. Screw engine used as an expander in ORC for low-potential heat utilization

    Science.gov (United States)

    Richter, Lukáš

    2017-09-01

    This paper deals with a screw motor that is used as an expander in an ORC (Organic Rankin Cycle) system, whose organic working substance allows the transformation of low-potential heat (waste heat, solar and geothermal energy) into electrical energy. The article describes the specific properties of an organic substance and a screw motor that must be considered when designing and assembling a complete power unit. Screw machines are not commonly used as expansion devices, so it is necessary to perform an analysis that makes it possible to adapt the screw machine to the expansion process in terms of profiling and design.

  12. Utilization of potentially inappropriate medications in elderly patients in a tertiary care teaching hospital in India

    Directory of Open Access Journals (Sweden)

    Binit N Jhaveri

    2014-01-01

    Full Text Available Aim: To evaluate the use of potentially inappropriate medicines in elderly inpatients in a tertiary care teaching hospital. Materials and Methods: Retrospective analysis was performed for cases of elderly patients admitted between January 2010 and December 2010. Data on age, gender, diagnosis, duration of hospital stay, treatment, and outcome were collected. Prescriptions were assessed for the use of potentially inappropriate medications in geriatric patients by using American Geriatric Society Beer′s criteria (2012 and PRISCUS list (2010. Results: A total of 676 geriatric patients (52.12% females were admitted in the medicine ward. The average age of geriatric patients was 72.69 years. According to Beer′s criteria, at least one inappropriate medicine was prescribed in 590 (87.3% patients. Metoclopramide (54.3%, alprazolam (9%, diazepam (8%, digoxin > 0.125 mg/day (5%, and diclofenac (3.7% were the commonly used inappropriate medications. Use of nonsteroidal anti-inflammatory drugs (NSAIDs in heart and renal failure patients was the commonly identified drug-disease interaction. According to PRISCUS list, at least one inappropriate medication was prescribed in 210 (31.06% patients. Conclusion: Use of inappropriate medicines is highly prevalent in elderly patients.

  13. Potential utilization of biodiesel as alternative fuel for compression ignition engine in Malaysia

    Science.gov (United States)

    Wahab, M. A.; Ma'arof, M. I. N.; Ahmad, I. N.; Husain, H.

    2017-10-01

    Biodiesel is a type of fuel which is derived from various sources of vegetable plants and waste fuels. Today, numerous biodiesels have been engineered to be at par or even better in term of performance in comparison to pure diesel. Therefore, biodiesel has shown a promising sign as one of the best candidate in overcoming total dependency on pure diesel. This paper gives review on various tests and experiments conducted on biodiesel in order to highlight the potentials given by this particular fuel. In addition, providing the supporting evidences to further endorse for a mass usage of biodiesel in Malaysia - simultaneously, driving the country to become a potential global biodiesel producer in the near future. The reviewed studies were obtained mainly via indexed journals and online libraries. Conclusively, every test and study for every blend of biodiesel had shown consistent positive results in regards to performance and in overcoming emission related issues. Thus, providing the evidence that biodiesel is highly reliable. Malaysia as a semi-agricultural nation could take the advantage in becoming one of the leading global biodiesel producers. Nevertheless, this will requires total cooperation of every concerned government bodies and authorities.

  14. Microbial Biofilm Community Variation in Flowing Habitats: Potential Utility as Bioindicators of Postmortem Submersion Intervals

    Directory of Open Access Journals (Sweden)

    Jennifer M. Lang

    2016-01-01

    Full Text Available Biofilms are a ubiquitous formation of microbial communities found on surfaces in aqueous environments. These structures have been investigated as biomonitoring indicators for stream heath, and here were used for the potential use in forensic sciences. Biofilm successional development has been proposed as a method to determine the postmortem submersion interval (PMSI of remains because there are no standard methods for estimating the PMSI and biofilms are ubiquitous in aquatic habitats. We sought to compare the development of epinecrotic (biofilms on Sus scrofa domesticus carcasses and epilithic (biofilms on unglazed ceramic tiles communities in two small streams using bacterial automated ribosomal intergenic spacer analysis. Epinecrotic communities were significantly different from epilithic communities even though environmental factors associated with each stream location also had a significant influence on biofilm structure. All communities at both locations exhibited significant succession suggesting that changing communities throughout time is a general characteristic of stream biofilm communities. The implications resulting from this work are that epinecrotic communities have distinctive shifts at the first and second weeks, and therefore the potential to be used in forensic applications by associating successional changes with submersion time to estimate a PMSI. The influence of environmental factors, however, indicates the lack of a successional pattern with the same organisms and a focus on functional diversity may be more applicable in a forensic context.

  15. A novel synthesis and pharmacological evaluation of a potential dopamine D-1/D-2 agonist : 1-Propyl-1,2,3,4,4a,5,10,10-aoctahydrobenzo[g]quinoline-6,7-diol

    NARCIS (Netherlands)

    Liu, Danyang; Dijkstra, Durk; de Vries, Jan B.; Wikstrom, Hakan V.

    2008-01-01

    Previously, we have demonstrated that enone prodrugs of dopaminergic catecholamines represent a new type of dopamine (DA) agonist. Trans-1-propyl-1,2, 3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (TL-334), the active form

  16. QMQSAR: utilization of a semiempirical probe potential in a field-based QSAR method.

    Science.gov (United States)

    Dixon, Steve; Merz, Kenneth M; Lauri, Giorgio; Ianni, James C

    2005-01-15

    A semiempirical quantum mechanical approach is described for the creation of molecular field-based QSAR models from a set of aligned ligand structures. Each ligand is characterized by a set of probe interaction energy (PIE) values computed at various grid points located near the surface of the ligand. Single-point PM3 calculations afford these PIE values, which represents a pool of independent variables from which multilinear regression models of activity are built. The best n-variable fit is determined by constructing an initial regression using standard forward stepwise selection, followed by refinement using a simulated annealing technique. The resulting fit provides an easily interpreted 3D physical model of ligand binding affinity. Validation against three literature datasets demonstrates the ability of the semiempirical potential to model critical binding interactions in diverse systems.

  17. Potential Utilization of Renewable Energy Resources for Electicity Generation in Bosnia and Herzegovina

    Directory of Open Access Journals (Sweden)

    Fajik Begić

    2005-12-01

    Full Text Available Along with the current processes of restructuring of Energy power system of Bosnia and Herzegovina, liberalisation of the electricity market, and modernisation of the existing power plants, Bosnia and Herzegovina must turn to the utilisation of renewable resources in reasonable dynamics as well. Respecting this policy, the initial evaluation of the potential of renewable energy resources in Bosnia and Herzegovina is performed. The methodology of evaluation of wind energy utilisation is presented in this paper, as well as some other aspects of utilisation of the renewable energy resources in Bosnia and Herzegovina. Implementation of selected projects should improve sustainability of energy power production in Bosnia and Herzegovina, by reducing the total emission of carbon dioxide originated from energy power system of Bosnia and Herzegovina.

  18. Bioremediation potential of hydrocarbon-utilizing fungi from select marine niches of India.

    Science.gov (United States)

    Barnes, Natasha Maria; Khodse, Vishwas B; Lotlikar, Nikita P; Meena, Ram Murti; Damare, Samir R

    2018-01-01

    Ten fungal isolates with an ability to degrade crude oil were isolated from select marine substrates, such as mangrove sediments, Arabian Sea sediments, and tarballs. Out of the ten isolates, six belonged to Aspergillus , two to Fusarium and one each to Penicillium and Acremonium as identified using ITS rDNA sequencing. The selected ten fungal isolates were found to degrade the long-chain n -alkanes as opposed to short-chain n -alkanes from the crude oil. Mangrove fungus #NIOSN-M126 ( Penicillium citrinum ) was found to be highly efficient in biodegradation of crude oil, reducing the total crude oil content by 77% and the individual n -alkane fraction by an average of 95.37%, indicating it to be a potential candidate for the development into a bioremediation agent.

  19. Utilization of intrinsic boron isotopes as co-migrating tracers for identifying potential nitrate contamination sources

    International Nuclear Information System (INIS)

    Leenhouts, J.M.; Bassett, R.L.; Maddock, T. III.

    1998-01-01

    The stable isotopes of the conservative element boron, 11B and 10B, have been employed as co-migrating isotopic tracers to trace potential sources of nitrate observed in ground water pumped from a large capacity 0.167 m3/s irrigation well in the Avra Valley of southeastern Arizona. The isotopic ratios provided an identifying signature for two nitrogen carrying source waters: municipal waste water and agricultural return flow. Additional chemical parameters were also examined to corroborate the isotopic indications. Boron isotopes provided a superior delineation of mixing processes in the system compared to the general inorganic chemical parameters. Findings of this investigation indicate that the water pumped by the study well at the beginning of the 1993 irrigation season was composed of a mixture of approximately 25% municipal waste water and 75% background ground water. As the irrigation season progressed, an increasing proportion of water was contributed by irrigation return flow from neighboring agricultural fields

  20. A GIS based national assessment of algal bio-oil production potential through flue gas and wastewater co-utilization

    International Nuclear Information System (INIS)

    Orfield, Nolan D.; Keoleian, Gregory A.; Love, Nancy G.

    2014-01-01

    The high theoretical productivity of microalgae makes it a promising energy crop, but economically viable large-scale production facilities have yet to emerge. Coupling algae cultivation ponds with flue gas emissions from power utilities to provide carbon dioxide and municipal wastewater to provide nutrients has been recommended as a solution. This flue gas and wastewater co-utilization (FWC) strategy not only reduces the upstream impacts and costs associated with providing inputs, but also provides a credit for wastewater treatment, a service currently required to reduce production costs to a viable level. This study provides the first national assessment of the potential for producing algal bio-oil in the United States using FWC. Spatial-temporal algae growth was simulated using solar radiation and temperature data to calculate the average annual algae yield for any location, which significantly impacts feasibility. The results of this model were integrated into a geospatial analysis which establishes the economically viable bio-oil production potential of FWC by accounting for the relative abundance of the input resources and their proximity. At most, 1.7 billion liters of bio-oil could be produced annually in a manner economically competitive with crude oil prices of $80 per barrel. The amount of nutrients in wastewater limits yields to 20.5 L of bio-oil per capita annually, and climatic constraints further reduce this potential by nearly 60%. Carbon dioxide constraints play a negligible role. Although the bio-oil production potential of FWC is relatively small, it does provide an opportunity to increase national biofuel output while providing a needed service. - Highlights: • Spatial-temporal algae growth was simulated using historical climate data. • A geospatial overlay analysis was used to assess national production potential. • Nutrient availability in wastewater is most limiting. • At most, 1.7 billion liters of algal biofuel per year could be

  1. Chinese perceptions of the utility of nuclear weapons. Prospects and potential problems in disarmament

    Energy Technology Data Exchange (ETDEWEB)

    Jing-dong, Yuan

    2010-07-01

    deployment of the long-anticipated DF- 31 and DF-31A long-range ballistic missiles and the Jin-class ballistic missile submarines. In addition, China is also developing anti-space weapons and missile defense, as well as cruise missile capabilities. The qualitative as well as quantitative improvements of the Chinese nuclear arsenal raise important questions for the global nuclear balance in 2025 as the United States and Russia implement their nuclear disarmament commitments, further cutting down their nuclear arsenals. But the more critical question to ask is how Beijing views the utility of nuclear weapons and how and to what extent such perspectives influence China's attitudes toward and participation in multilateral nuclear disarmament. This paper begins with a detailed analysis of Chinese positions on the role of nuclear weapons and of its arms control and disarmament policies. This is followed by a preliminary discussion of Chinese responses to the nuclear-free world initiative. Finally, the paper concludes by offering some recommendations on what needs to take place to remove the obstacles and concerns that may prohibit Beijing from endorsing and participating in efforts toward eliminating nuclear weapons. (author)

  2. Chinese perceptions of the utility of nuclear weapons. Prospects and potential problems in disarmament

    International Nuclear Information System (INIS)

    Jing-dong, Yuan

    2010-01-01

    -anticipated DF- 31 and DF-31A long-range ballistic missiles and the Jin-class ballistic missile submarines. In addition, China is also developing anti-space weapons and missile defense, as well as cruise missile capabilities. The qualitative as well as quantitative improvements of the Chinese nuclear arsenal raise important questions for the global nuclear balance in 2025 as the United States and Russia implement their nuclear disarmament commitments, further cutting down their nuclear arsenals. But the more critical question to ask is how Beijing views the utility of nuclear weapons and how and to what extent such perspectives influence China's attitudes toward and participation in multilateral nuclear disarmament. This paper begins with a detailed analysis of Chinese positions on the role of nuclear weapons and of its arms control and disarmament policies. This is followed by a preliminary discussion of Chinese responses to the nuclear-free world initiative. Finally, the paper concludes by offering some recommendations on what needs to take place to remove the obstacles and concerns that may prohibit Beijing from endorsing and participating in efforts toward eliminating nuclear weapons. (author)

  3. Drug utilization, prescription errors and potential drug-drug interactions: an experience in rural Sri Lanka.

    Science.gov (United States)

    Rathish, Devarajan; Bahini, Sivaswamy; Sivakumar, Thanikai; Thiranagama, Thilani; Abarajithan, Tharmarajah; Wijerathne, Buddhika; Jayasumana, Channa; Siribaddana, Sisira

    2016-06-25

    Prescription writing is a process which transfers the therapeutic message from the prescriber to the patient through the pharmacist. Prescribing errors, drug duplication and potential drug-drug interactions (pDDI) in prescriptions lead to medication error. Assessment of the above was made in prescriptions dispensed at State Pharmaceutical Corporation (SPC), Anuradhapura, Sri Lanka. A cross sectional study was conducted. Drugs were classified according to the WHO anatomical, therapeutic chemical classification system. A three point Likert scale, a checklist and Medscape online drug interaction checker were used to assess legibility, completeness and pDDIs respectively. Thousand prescriptions were collected. Majority were hand written (99.8 %) and from the private sector (73 %). The most frequently prescribed substance and subgroup were atorvastatin (4 %, n = 3668) and proton pump inhibitors (7 %, n = 3668) respectively. Out of the substances prescribed from the government and private sectors, 59 and 50 % respectively were available in the national list of essential medicines, Sri Lanka. Patients address (5 %), Sri Lanka Medical Council (SLMC) registration number (35 %), route (7 %), generic name (16 %), treatment symbol (48 %), diagnosis (41 %) and refill information (6 %) were seen in less than half of the prescriptions. Most were legible with effort (65 %) and illegibility was seen in 9 %. There was significant difference in omission and/or errors of generic name (P = 0.000), dose (P = 0.000), SLMC registration number (P = 0.000), and in evidence of pDDI (P = 0.009) with regards to the sector of prescribing. The commonest subgroup involved in duplication was non-steroidal anti-inflammatory drugs (NSAIDs) (43 %; 56/130). There were 1376 potential drug interactions (466/887 prescriptions). Most common pair causing pDDI was aspirin with losartan (4 %, n = 1376). Atorvastatin was the most frequently prescribed substance

  4. Potential lignocellulose resources and their utilization by ruminants in tropical regions

    International Nuclear Information System (INIS)

    Sansoucy, R.; Mahadevan, P.

    1983-01-01

    The nature and estimated quantities of potential lignocellulose resources in tropical regions are described. The most abundant sources of these materials are the natural grasslands, crop residues and by-products, e.g. sugar cane, cereals and fruits, and, to a limited extent, cultivated grasses, e.g. guinea and elephant grass. The availability of these resources to livestock is limited by a variety of environmental and logistic factors, e.g. seasonality of production and problems of collection and transport. Additionally, the nutritive value of pastures and fodders in the tropics is relatively lower than in temperate regions owing to their higher fibre and lower N and P content, with consequent lowering of intake and digestibility. Crop residues also have low N and high lignin contents and are generally deficient in fermentable energy, fermentable N, protein and micronutrients. The possibilities for improving the nutritive value of tropical feeds are discussed; these include supplementation with urea, molasses and minerals, good quality forage, and/or ''by-pass'' nutrients, e.g. oil cakes, and treatment by various physical, chemical or biological methods. (author)

  5. Topical lotions utilized in outpatient rehabilitation clinics as a potential source of bacterial contamination.

    Science.gov (United States)

    Spratt, Henry G; Levine, David; Bage, Julie; Giles, David K; Collier, A Grace

    2018-02-26

    Soft tissue mobilization and massage requiring lotions or creams are commonly used interventions in outpatient rehabilitation clinics. For at least 50 years hand creams used in healthcare settings have been found to be contaminated by bacteria. The purpose of this study was to determine the current state of bacterial contamination of lotions used in clinics and to determine the efficacy of lotion preservatives to kill bacteria. Unopened containers of lotions were studied, along with 81 lotion containers used in 22 outpatient clinics in southeast Tennessee and northwest Georgia. Three sites on each container were sampled using sterile swabs. At a microbiology lab, bacterial growth media was inoculated and incubated. Of the 81 containers sampled, 16 supported bacterial growth (19.8%). Container threads displayed the highest contamination compared with other container locations (p < 0.01). No bacteria were found in unopened lotion containers, although when challenged with live bacterial cultures lotion preservatives did not kill bacteria tested. Enrichment cultures using lotions studied here supported the growth of several bacterial species. These findings suggest the need for standardized protocols to help reduce potential healthcare-associated infections due to use of lotions. Improved efficacy of preservatives added to lotions should be a priority.

  6. Evaluation of Fertilizer Potential of Different K Compounds Prepared Utilizing Sea Bittern as Feed Stock

    Directory of Open Access Journals (Sweden)

    Khanjan Trivedi

    2017-09-01

    Full Text Available Aim: Many countries import potassic fertilizers due to dearth of K-mineral deposits. Therefore processes to obtain K-nutrient sources from sea bittern were developed by our Institute. The present investigation evaluated the fertilizer potential of three different sea bittern-derived (SBD potassium forms developed viz., potassium schoenite, potassium nitrate and potassium ammonium sulfate on maize productivity in two cropping seasons.Methods: The pot and field experiments consisted of four treatments, wherein the three K forms were applied at the recommended rate of 40 kg K2O ha−1 and were compared with commercially used sulfate of potash. The effect of these fertilizers on different parameters of plant and soil were evaluated.Results: The application of SBD-potassic fertilizers led to enhancement in growth, productivity and quality of maize which related well with higher photosynthesis, nutrient uptake and soil quality parameters. On an average all the three forms of sea bittern-derived potash enhanced yield of maize over control by 22.3 and 23.8%, respectively, in pot and field trials. The best performance was under SBD-KNO3, which also recorded the highest benefit: cost ratio of 1.76.Conclusion: The K-fertilizers derived from sea-bittern—a waste product of salt industry—can thus be economically used to improve crop production sustainably.

  7. Toward brain-computer interface based wheelchair control utilizing tactually-evoked event-related potentials

    Science.gov (United States)

    2014-01-01

    Background People with severe disabilities, e.g. due to neurodegenerative disease, depend on technology that allows for accurate wheelchair control. For those who cannot operate a wheelchair with a joystick, brain-computer interfaces (BCI) may offer a valuable option. Technology depending on visual or auditory input may not be feasible as these modalities are dedicated to processing of environmental stimuli (e.g. recognition of obstacles, ambient noise). Herein we thus validated the feasibility of a BCI based on tactually-evoked event-related potentials (ERP) for wheelchair control. Furthermore, we investigated use of a dynamic stopping method to improve speed of the tactile BCI system. Methods Positions of four tactile stimulators represented navigation directions (left thigh: move left; right thigh: move right; abdomen: move forward; lower neck: move backward) and N = 15 participants delivered navigation commands by focusing their attention on the desired tactile stimulus in an oddball-paradigm. Results Participants navigated a virtual wheelchair through a building and eleven participants successfully completed the task of reaching 4 checkpoints in the building. The virtual wheelchair was equipped with simulated shared-control sensors (collision avoidance), yet these sensors were rarely needed. Conclusion We conclude that most participants achieved tactile ERP-BCI control sufficient to reliably operate a wheelchair and dynamic stopping was of high value for tactile ERP classification. Finally, this paper discusses feasibility of tactile ERPs for BCI based wheelchair control. PMID:24428900

  8. Utilization of industrial dairy waste as microalgae cultivation medium : a potential study for sustainable energy resources

    Science.gov (United States)

    Nurmayani, S.; Sugiarti, Y.; Putra, R. H.

    2016-04-01

    Microalgae is one of biodiesel resources and call as third generation biofuel. Biodiesel is one alternative energy that being developed. So study about resource of biodiesel need a development, for the example is development the basic material such as microalgae. In this paper we explain the potential use of dairy waste from industry as a cultivation medium of microalgae for biodiesel production. Dairy waste from dairy industry contains 34.98% protein, 4.42% lactose, 9.77% fiber, 11.04% fat, 2.33% calcium, 1.05% phosfor, and 0.4 % magnesium, meaning that the dairy waste from dairy industry has a relatively high nutrient content and complete from a source of carbon, nitrogen and phosphorus as macro nutrients. The method in this paper is literature review to resulting a new conclusion about the potency of waste water from dairy industry as microalgae cultivation medium. Based on the study, the dairy waste from dairy industry has potency to be used as cultivation medium of Botryococcus braunii in the production of biodiesel, replacing the conventional cultivation medium.

  9. Potential utilization of Citrullus lanatus var. Colocynthoides waste as a novel source of pectin.

    Science.gov (United States)

    Korish, Mohamed

    2015-04-01

    The Citrullus lanatus var. Colocynthoides is an ancestor type of watermelon. It was investigated as a new source of pectin. It was cultivated in Egypt for seeds only, while the remaining fruits are discarded as waste. Effect of different extraction conditions such as pH, solid: liquid ratio, temperature and extraction time on pectin yield of Citrullus lanatus var. Colocynthoides waste was investigated in the present study. The highest yield (19.75 % w/w) was achieved at pH 2, solid: liquid ratio1:15 and 85 °C, for 60 min. Methylation degree and galacturonic acid content of extracted pectin were 55.25 %, w/w and 76.84 %, w/w. The main neutral sugars were galactose followed by arabinose and rhamnose. In addition, glucose, xylose and mannose existed as constituents in the pectin hydrolysate. The results indicated that Citrullus lanatus var. Colocynthoide waste is a potential new source of pectin.

  10. Utilization potential of wood clones of Eucalyptus urophylla in the production of wood-cement panels

    Directory of Open Access Journals (Sweden)

    Lourival Marin Mendes

    2011-03-01

    Full Text Available The objective of this study was to evaluate the potential of using clones of Eucalyptus urophylla in the production of wood-cement panels. The study used six clones of Eucalyptus urophylla with 8 years of age, from the Companhia Mineira de Metais, located in Paracatu - MG. For the formation of the panels it was used Portland cement CP V - ARI / Plus, possessing high initial resistance to mineral binder and calcium chloride (CaCl2 as accelerator for the cement curing. The panels were produced with the following parameters: dimensions of 49.5 x 49.5 x 1.5 cm, nominal density of 1.2 g/cm ³, relation wood: cement (1:2.5 and relation water: cement (1:1.5. The results can showed that: (1 for thickness swelling in two and twenty-four hours, only clones 19.28 and 58 attended the specifications, (2 for water absorption, clone 62 showed the best results, (3 to internal bond, only clone 58 didn`t attend specifications, (4 for the compression, clones 19.36 and 58 showed the best results, (5 for MOE and MOR, none of the clones presented values compatible to the bison process. It is suggested the continuation of this line of research, including the manipulation of variables of production, so that all properties be compatible to the minimum required standards.

  11. Potential to cofire high-sulfur coal and MSW/RDF in Illinois utility boilers: A survey and analysis

    International Nuclear Information System (INIS)

    South, D.W.

    1993-01-01

    The disposal of refuse is of ever-increasing concern for municipalities and other organizations and agencies throughout the United States. Disposal in landfills is becoming more costly, and new landfills are more difficult to site because of stricter environmental regulations. Mass burning incinerators for municipal solid wastes (MSW) have also met with increased public resistance due to excessive emissions. Nevertheless, increased awareness of the need for alternative disposal techniques has led to a new interest in cofiring MSW with coal. In addition to solid waste concerns, the requirements to reduce SO 2 and NO x emissions from coal-fired utility boilers in the Clean Air Act Amendments of 1990, present an opportunity to cofire MSW/RDF with coal as an emission control measure. These issues were the impetus for a 1992 study (conducted by ANL for the Illinois Clean Coal Institute) to examine the potential to cofire coal with MSW/RDF in Illinois utility boilers. This paper will provide a synopsis of the ANL/ICCI report. It will summarize (1) the combustibility and emission characteristics of high-sulfur coal and MSW/RDF; (2) the facilities firing RDF and/or producing/selling RDF, together with their combustion and emissions experience; (3) the applicable emissions regulations in Illinois; and (4) the analysis of candidate utility boilers in Illinois capable of cofiring, together with the effect on coal consumption and SO 2 and NO x emissions that would result from 20% cofiring with RDF/MSW

  12. Dopamine agonists and Othello's syndrome

    Science.gov (United States)

    Graff-Radford, Jonathan; Ahlskog, J Eric.; Bower, James H.; Josephs, Keith A.

    2014-01-01

    Background Othello's syndrome (OS) is a delusion of infidelity. We describe seven cases of OS in Parkinson's disease (iPD) patients using dopamine agonists. Methods We searched the Mayo Clinic Medical Records System to identify all patients with OS. Clinical data abstracted include sex, age of onset of iPD, age of onset of OS, medications, effect of discontinuing the dopamine agonist, neuroimaging, and comorbidities. Results Seven non-demented iPD patients with dopamine agonist implementation time locked to the development and resolution of OS are reported. The average age of iPD onset was 46.6 years (Standard deviation: 5.0 years), and OS onset was 53.7 years (7.1 years). All seven patients had significant marital conflict as a result of the delusions. Conclusions OS can be associated with dopamine agonist use and can lead to serious consequences. Dopamine agonist cessation eliminates the delusion of infidelity and should be the first treatment option. PMID:20829092

  13. Workshop on the role of enhancement of utilization of primary and secondary hydro potential in the context of environmental protection. Part II

    International Nuclear Information System (INIS)

    1997-01-01

    The publication has been set up as proceedings of the workshop on the role of enhancement of utilization of primary and secondary hydro potential in the context of environmental protection. The proceedings consist of the following chapters: (1) Use of a part and a secondary hydroenergetic potential of the Slovak Republic for electric energy production and its impact on the environment; (2) Economic problems of utilization of hydroenergetic potential of the Slovak Republic and possibilities for their solution; (3) Modernization of control systems of primary and secondary hydro energetic sources of electricity from the point of view of their fulfillment of important functions in operation of a power engineering system in the Slovak Republic; (4) The most important structures utilizing primary and secondary hydroenergetic potential for electric energy production; (5) Progressive technologies, modernization of hydro power projects aimed at rationalization in a use of hydroenergetic potential and environment protection; (6) Possibilities of further utilization of hydroenergetic potential of the Slovak Republic

  14. Biomaterials Approaches for Utilizing the Regenerative Potential of the Peripheral Nerve Injury Microenvironment

    Science.gov (United States)

    Wrobel, Melissa Renee

    following classical activation (M1/pro-inflammatory) with lipopolysaccharide (LPS; 1microg/mL) and would accelerate the transformation of Schwann cells from an immature state fol-lowing injury to a mature/pro-myelinating one. Cell phenotypes were functionally assessed using quantified reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence, and sandwich-ELISA based antibody arrays to measure changes in mRNA expression, mor-phology, and cytokine release, respectively. Macrophages cultured with the SCM and HA fibers had significantly reduced M1 gene expression, released lower levels of M1 cytokines (IL-1a, RANTES and TFN-a) and assumed an elongated morphology indicative of M2. These cues also induced changes in the Schwann cells including significantly reduced area, increased elongation, decreased expression of immature genes (GFAP) and increased expression of mature genes (Krox20 and Oct6). These results suggest that the SCM and HA nanofibers could trigger non-neuronal cells towards regenerative programs more quickly than traditional PNI interventions. Changes induced by biomaterials have distinct benefits over the use of immunomodulatory cy-tokines and would be a novel approach to direct repair. Our collective studies offer improved in-sight into the endogenous potential of the injured peripheral nerve and offer ways to incorporate intrinsic repair cues into a biomaterial system for treating large gaps.

  15. Potential utility of environmental DNA for early detection of Eurasian watermilfoil (Myriophyllum spicatum)

    Science.gov (United States)

    Newton, Jeremy; Sepulveda, Adam; Sylvester, K; Thum, Ryan

    2016-01-01

    EWM invasions have negative impacts on native biodiversity, recreational boating, fishing, and other types of aquatic tourism (e.g., Eiswerth et al. 2000). On a broader scale, EWM can also be harmful to man-made aquatic infrastructure, such as hydroelectric dams. If an EWM invasion can be detected in an early stage where eradication is still a possibility, many of these negative consequences can be limited or prevented altogether (e.g., Madsen et al. 2002). The purpose of this research was to develop and validate a traditional polymerase chain reaction (PCR) assay for the detection of pure and hybridized EWM DNA using both laboratory and field experiments. We performed a pilot experiment in outdoor tanks to determine the basic functionality and sensitivity of the assay. Following this initial test, we collected field samples from Michigan and Montana lakes with and without known EWM populations. Taken together, our findings suggest that eDNA techniques have potential to be a useful strategy for the early detection of EWM.

  16. Capacity and levels of utilization of tourism potentials of Yankari and Cross River National Parks – implications for optimistic ecotourism development in Nigeria

    Directory of Open Access Journals (Sweden)

    PC Ngoka

    2013-01-01

    Full Text Available Development of sustainable tourism constitutes an essential component of Nigeria’s agenda for attaining sustainable development by the year 2020. The level of utilization of existing tourism capacities of national parks can affect the attainment of this goal. The present study examined capacity and levels of utilization of tourism potentials of Yankari National Park (YNP and Cross River National Park (CRNP. Mean visitor holding capacity (MVHC of each park over the period 2002 – 2006 was determined. Further, mean visitation of the parks during the study period was obtained from records of tourism visitation of the parks. From these, capacity utilizations were determined. Cross sectional survey of levels of utilization of attractions in each park was conducted using questionnaire. YNP recorded 49.3% capacity utilization; while CRNP had 3.5%. Both parks witnessed varying levels of utilization of their existing potentials. In YNP, game viewing and warm spring bathing had high levels of utilization (91% and 64% respectively. Old iron smelting sites and Dukkey Wells recorded low levels of utilization (1.0% each. In CRNP, rainforest experience and cave adventure had high utilization levels (93.3% and 68.3% respectively. Neither park had optimum use of its potentials. Updating of parks’ tourism infrastructure and creation of better awareness of the parks as tourist destinations were recommended for beefing up capacity and levels of utilization of the parks.

  17. The Pharmacology of TUG-891, a Potent and Selective Agonist of the Free Fatty Acid Receptor 4 (FFA4/GPR120), Demonstrates Both Potential Opportunity and Possible Challenges to Therapeutic Agonism

    DEFF Research Database (Denmark)

    Hudson, Brian D; Shimpukade, Bharat; Mackenzie, Amanda E

    2013-01-01

    TUG-891 [3-(4-((4-fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoic acid] was recently described as a potent and selective agonist for the long chain free fatty acid (LCFA) receptor 4 (FFA4; previously G protein-coupled receptor 120, or GPR120). Herein, we have used TUG-891 to further......, β-arrestin-1 and β-arrestin-2 recruitment, and extracellular signal-regulated kinase phosphorylation. Activation of human FFA4 by TUG-891 also resulted in rapid phosphorylation and internalization of the receptor. While these latter events were associated with desensitization of the FFA4 signaling...... response, removal of TUG-891 allowed both rapid recycling of FFA4 back to the cell surface and resensitization of the FFA4 Ca(2+) signaling response. TUG-891 was also a potent agonist of mouse FFA4, but it showed only limited selectivity over mouse FFA1, complicating its use in vivo in this species...

  18. Potential Effect and Analysis of High Residential Solar Photovoltaic (PV Systems Penetration to an Electric Distribution Utility (DU

    Directory of Open Access Journals (Sweden)

    Jeffrey Tamba Dellosa

    2016-11-01

    Full Text Available The Renewable Energy Act of 2008 in the Philippines provided an impetus for residential owners to explore solar PV installations at their own rooftops through the Net-Metering policy. The Net-Metering implementation through the law however presented some concerns with inexperienced electric DU on the potential effect of high residential solar PV system installations. It was not known how a high degree of solar integration to the grid can possibly affect the operations of the electric DU in terms of energy load management. The primary objective of this study was to help the local electric DU in the analysis of the potential effect of high residential solar PV system penetration to the supply and demand load profile in an electric distribution utility (DU grid in the province of Agusan del Norte, Philippines. The energy consumption profiles in the year 2015 were obtained from the electric DU operating in the area. An average daily energy demand load profile was obtained from 0-hr to the 24th hour of the day based from the figures provided by the electric DU. The assessment part of the potential effect of high solar PV system integration assumed four potential total capacities from 10 Mega Watts (MW to 40 MW generated by all subscribers in the area under study at a 10 MW interval. The effect of these capacities were measured and analyzed with respect to the average daily load profile of the DU. Results of this study showed that a combined installations beyond 20 MWp coming from all subscribers is not viable for the local electric DU based on their current energy demand or load profile. Based from the results obtained, the electric DU can make better decisions in the management of high capacity penetration of solar PV systems in the future, including investment in storage systems when extra capacities are generated. Article History: Received July 15th 2016; Received in revised form Sept 23rd 2016; Accepted Oct 1st 2016; Available online How to Cite

  19. Not utilized learning potentials

    DEFF Research Database (Denmark)

    Kragelund, Linda

    -conscious disjuncture, in development of the concept pseudo-everyday life activities and in a categorizing mo­del for and a theory about student nurses' learning processes. The theory includes relations between 4 types of  disjuncture, 3 types of content in the learning processes, and factors that provoke......  When the Danish Nursing Education in 2002 became a Bachelor Degree the clinical part of the education was reduced. Therefore, it was necessary to optimize learning in practice.       I made a qualitative investigation to describe student nurses' learning processes in non-routine situations where...... they interact with psychiatric patients. The theoretical framework includes primarily P. Jarvis' concept disjuncture and A. Heller's theory about everyday life. The empirical part of the study is primarily based on qualitative semi-structured interviews with, observations of and obser-views with a volunteer...

  20. Hormones and β-Agonists

    NARCIS (Netherlands)

    Ginkel, van L.A.; Bovee, T.F.H.; Blokland, M.H.; Sterk, S.S.; Smits, N.G.E.; Pleadin, Jelka; Vulić, Ana

    2016-01-01

    This chapter provides some updated information on contemporary methods for hormone and β-agonist analyses. It deals with the classical approaches for the effective detection and identification of exogenous hormones. The chapter examines specific problems related to control strategies for natural

  1. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    and liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  2. An Estimation of the Potential Utilization in Iranian Pharmaceutical Industry Involved in the Stock Exchange, 2008-2012

    Science.gov (United States)

    Annabi, Majid; Kebriaeezadeh, Abbas; Mohammadi, Timor; Marashi Shoshtari, Seyed Nasrolah; Abedin Dorkoosh, Farid; Pourreza, Abolghasem; Heydari, Hassan

    2017-01-01

    The aim of this study was to measure the potential of production and the capacity used in the pharmaceutical industry. Capacity use is the actual production rate to the potential output, which reflects the gap between actual production and production capacity. Through econometric methods, translog cost function in the short run along with functions of share cost of production factors is estimated through seemingly unrelated repeated regression (SURE) as a multivariate regression analysis provided by zeller. During the study the capacity used is decreasing. The capacity used, which calculated by weighted average, also decreased and the amount during the study period is much less than the simple average of the industry. Average capacity utilization in the industry over five years of study is equal to 57% while the average capacity used calculated by the weighted of industry average is 37%. To enhance the economic potential requires a proper use of resources, creation of favorable economic structure and productivity of the industry. Due to the large amount of unused capacity in the pharmaceutical industry there is no need to invest anymore unless in new grounds and it is obvious that more investment will change using capacity. PMID:29552074

  3. Theoretical Calculations on the Feasibility of Microalgal Biofuels: Utilization of Marine Resources Could Help Realizing the Potential of Microalgae.

    Science.gov (United States)

    Park, Hanwool; Lee, Choul-Gyun

    2016-11-01

    Microalgae have long been considered as one of most promising feedstocks with better characteristics for biofuels production over conventional energy crops. There have been a wide range of estimations on the feasibility of microalgal biofuels based on various productivity assumptions and data from different scales. The theoretical maximum algal biofuel productivity, however, can be calculated by the amount of solar irradiance and photosynthetic efficiency (PE), assuming other conditions are within the optimal range. Using the actual surface solar irradiance data around the world and PE of algal culture systems, maximum algal biomass and biofuel productivities were calculated, and feasibility of algal biofuel were assessed with the estimation. The results revealed that biofuel production would not easily meet the economic break-even point and may not be sustainable at a large-scale with the current algal biotechnology. Substantial reductions in the production cost, improvements in lipid productivity, recycling of resources, and utilization of non-conventional resources will be necessary for feasible mass production of algal biofuel. Among the emerging technologies, cultivation of microalgae in the ocean shows great potentials to meet the resource requirements and economic feasibility in algal biofuel production by utilizing various marine resources. © 2016 The Authors. Biotechnology Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Pro-arrhythmic potential of oral antihistamines (H1): combining adverse event reports with drug utilization data across Europe.

    Science.gov (United States)

    Poluzzi, Elisabetta; Raschi, Emanuel; Godman, Brian; Koci, Ariola; Moretti, Ugo; Kalaba, Marija; Wettermark, Bjorn; Sturkenboom, Miriam; De Ponti, Fabrizio

    2015-01-01

    There is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in '90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines. To investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries. We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance. Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible. Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and

  5. The Potential for Electrofuels Production in Sweden Utilizing Fossil and Biogenic CO{sub 2} Point Sources

    Energy Technology Data Exchange (ETDEWEB)

    Hansson, Julia, E-mail: julia.hansson@ivl.se [Climate and Sustainable Cities, IVL Swedish Environmental Research Institute, Stockholm (Sweden); Division of Physical Resource Theory, Department of Energy and Environment, Chalmers University of Technology, Göteborg (Sweden); Hackl, Roman [Climate and Sustainable Cities, IVL Swedish Environmental Research Institute, Stockholm (Sweden); Taljegard, Maria [Division of Energy Technology, Department of Energy and Environment, Chalmers University of Technology, Göteborg (Sweden); Brynolf, Selma; Grahn, Maria [Division of Physical Resource Theory, Department of Energy and Environment, Chalmers University of Technology, Göteborg (Sweden)

    2017-03-13

    This paper maps, categorizes, and quantifies all major point sources of carbon dioxide (CO{sub 2}) emissions from industrial and combustion processes in Sweden. The paper also estimates the Swedish technical potential for electrofuels (power-to-gas/fuels) based on carbon capture and utilization. With our bottom-up approach using European databases, we find that Sweden emits approximately 50 million metric tons of CO{sub 2} per year from different types of point sources, with 65% (or about 32 million tons) from biogenic sources. The major sources are the pulp and paper industry (46%), heat and power production (23%), and waste treatment and incineration (8%). Most of the CO{sub 2} is emitted at low concentrations (<15%) from sources in the southern part of Sweden where power demand generally exceeds in-region supply. The potentially recoverable emissions from all the included point sources amount to 45 million tons. If all the recoverable CO{sub 2} were used to produce electrofuels, the yield would correspond to 2–3 times the current Swedish demand for transportation fuels. The electricity required would correspond to about 3 times the current Swedish electricity supply. The current relatively few emission sources with high concentrations of CO{sub 2} (>90%, biofuel operations) would yield electrofuels corresponding to approximately 2% of the current demand for transportation fuels (corresponding to 1.5–2 TWh/year). In a 2030 scenario with large-scale biofuels operations based on lignocellulosic feedstocks, the potential for electrofuels production from high-concentration sources increases to 8–11 TWh/year. Finally, renewable electricity and production costs, rather than CO{sub 2} supply, limit the potential for production of electrofuels in Sweden.

  6. Inhibition of protein tyrosine phosphatases unmasks vasoconstriction and potentiates calcium signalling in rat aorta smooth muscle cells in response to an agonist of 5-HT2B receptors BW723C86

    OpenAIRE

    Mironova, G. Y.; Avdonin, P. P.; Goncharov, Nikolay V.; Jenkins, R. O.; Avdonin, P. V.

    2016-01-01

    The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. In blood vessels, serotonin 5-HT2B receptors mainly mediate relaxation, although their activation by the selective agonist BW723C86 is known to exert contraction of aorta in deoxycorticosterone acetate (DOCA)-salt and N(omega)-nitro-L-arginine (L-NAME) hypertensive rats [Russel et al., 2002; Banes et al., 2003] and in mice with type 2 diabetes ...

  7. Transcriptional profiling of peripheral blood mononuclear cells in pancreatic cancer patients identifies novel genes with potential diagnostic utility.

    Directory of Open Access Journals (Sweden)

    Michael J Baine

    2011-02-01

    Full Text Available It is well known that many malignancies, including pancreatic cancer (PC, possess the ability to evade the immune system by indirectly downregulating the mononuclear cell machinery necessary to launch an effective immune response. This knowledge, in conjunction with the fact that the trancriptome of peripheral blood mononuclear cells has been shown to be altered in the context of many diseases, including renal cell carcinoma, lead us to study if any such alteration in gene expression exists in PC as it may have diagnostic utility.PBMC samples from 26 PC patients and 33 matched healthy controls were analyzed by whole genome cDNA microarray. Three hundred eighty-three genes were found to be significantly different between PC and healthy controls, with 65 having at least a 1.5 fold change in expression. Pathway analysis revealed that many of these genes fell into pathways responsible for hematopoietic differentiation, cytokine signaling, and natural killer (NK cell and CD8+ T-cell cytotoxic response. Unsupervised hierarchical clustering analysis identified an eight-gene predictor set, consisting of SSBP2, Ube2b-rs1, CA5B, F5, TBC1D8, ANXA3, ARG1, and ADAMTS20, that could distinguish PC patients from healthy controls with an accuracy of 79% in a blinded subset of samples from treatment naïve patients, giving a sensitivity of 83% and a specificity of 75%.In summary, we report the first in-depth comparison of global gene expression profiles of PBMCs between PC patients and healthy controls. We have also identified a gene predictor set that can potentially be developed further for use in diagnostic algorithms in PC. Future directions of this research should include analysis of PBMC expression profiles in patients with chronic pancreatitis as well as increasing the number of early-stage patients to assess the utility of PBMCs in the early diagnosis of PC.

  8. Modeling, Synthesis and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Novel Analogs of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethynyl]benzoic Acid (Bexarotene)

    Science.gov (United States)

    Wagner, Carl E.; Jurutka, Peter W.; Marshall, Pamela A.; Groy, Thomas L.; van der Vaart, Arjan; Ziller, Joseph W.; Furmick, Julie K.; Graeber, Mark E.; Matro, Erik; Miguel, Belinda V.; Tran, Ivy T.; Kwon, Jeng Eun S.; Tedeschi, Jamie N.; Moosavi, Shahram; Danishyar, Amina; Philp, Joshua S.; Khamees, Reina O.; Jackson, Jevon N.; Grupe, Darci K.; Badshah, Syed L.; Hart, Justin W.

    2009-01-01

    This report describes the synthesis of analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid-X-receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogs in the present study have been evaluated for RXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay, and for their ability to induce apoptosis, as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of 3 analogs that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable Ki and EC50 values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties. PMID:19791803

  9. Modeling, synthesis and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene).

    Science.gov (United States)

    Wagner, Carl E; Jurutka, Peter W; Marshall, Pamela A; Groy, Thomas L; van der Vaart, Arjan; Ziller, Joseph W; Furmick, Julie K; Graeber, Mark E; Matro, Erik; Miguel, Belinda V; Tran, Ivy T; Kwon, Jungeun; Tedeschi, Jamie N; Moosavi, Shahram; Danishyar, Amina; Philp, Joshua S; Khamees, Reina O; Jackson, Jevon N; Grupe, Darci K; Badshah, Syed L; Hart, Justin W

    2009-10-08

    This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated for RXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable K(i) and EC(50) values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.

  10. Pro-arrhythmic potential of oral antihistamines (H1: combining adverse event reports with drug utilization data across Europe.

    Directory of Open Access Journals (Sweden)

    Elisabetta Poluzzi

    Full Text Available There is appreciable utilisation of antihistamines (H1 in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in '90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines.To investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS with drug utilization data from 13 European Countries.We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP, QT abnormalities (QTabn, ventricular arrhythmia (VA and sudden cardiac death/cardiac arrest (SCD/CA. Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance.Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine. Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden and in most European countries their use was negligible.Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators

  11. Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: potential utility as antipsychotic medications.

    Science.gov (United States)

    Morgan, Drake; Kondabolu, Krishnakanth; Kuipers, Allison; Sakhuja, Rajeev; Robertson, Kimberly L; Rowland, Neil E; Booth, Raymond G

    2013-09-01

    Desired serotonin 5HT2 receptor pharmacology for treatment of psychoses is 5HT2A antagonism and/or 5HT2C agonism. No selective 5HT2A antagonist has been approved for psychosis and the only approved 5HT2C agonist (for obesity) also activates 5HT2A and 5HT2B receptors, which can lead to clinical complications. Studies herein tested the hypothesis that a dual-function 5HT2A antagonist/5HT2C agonist that does not activate 5HT2B receptors would be suitable for development as an antipsychotic drug, without liability for weight gain. The novel compounds (+)- and (-)-trans-4-(4'-chlorophenyl)-N,N-dimethyl-2-aminotetralin (p-Cl-PAT) were synthesized, characterized in vitro for affinity and functional activity at human 5HT2 receptors, and administered by intraperitoneal (i.p.) and oral (gavage) routes to mice in behavioral paradigms that assessed antipsychotic efficacy and effects on feeding behavior. (+)- and (-)-p-Cl-PAT activated 5HT2C receptors, with (+)-p-Cl-PAT being 12-times more potent, consistent with its higher affinity across 5HT2 receptors. Neither p-Cl-PAT enantiomer activated 5HT2A or 5HT2B receptors at concentrations up to 300-times greater than their respective affinity (Ki), and (+)-p-Cl-PAT was shown to be a 5HT2A competitive antagonist. When administered i.p. or orally, (+)- and (-)-p-Cl-PAT attenuated the head-twitch response (HTR) in mice elicited by the 5HT2 agonist (-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and reduced intake of a highly palatable food in non-food-deprived mice, with (+)-p-Cl-PAT being more potent across behavioral assays. The novel in vitro pharmacology of (+)-p-Cl-PAT (5HT2A antagonism/5HT2C agonism without activation of 5HT2B) translated in vivo to an orally-active drug candidate with preclinical efficacy to treat psychoses without liability for weight gain. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Monitoring potential ecological impacts of a utility-scale photovoltaic panel facility on a creosote-bursage plant community

    Science.gov (United States)

    Apodaca, L.; Devitt, D. A.

    2016-12-01

    High energy demands and greater financial viability have propelled recent growth in the solar energy market. Southern Nevada is poised to become a major contributor of green energy through the commissioning of public and private lands for solar development, but there exists a pressing need to better understand the ecological consequences of these facilities as documentation of the impacts of large-scale solar operations on surrounding environments is severely lacking. The Copper Mountain 2 (CM2) solar facility in Eldorado Valley, Nevada, USA utilizes nearly 1.8 square kilometers of photovoltaic panels to generate enough energy to power about 50,000 homes and is situated within a predominately creosote (Larrea tridentata) and white bursage (Ambrosia dumosa) habitat. Currently, the potential impacts on the local environment related to this massive development are being studied from two perspectives: microclimate effects and alteration of surface hydrology. A series of meteorological towers and ibuttons are being used to monitor microclimate changes in the area of CM2 and the adjacent natural habitat as localized climate within the facility may be altering growing conditions in nearby desert plant communities. Because the placement of CM2 represents a major obstacle to established surface water flow, a transect of soil moisture probe access tubes have been placed in association with creosote plants along a downslope gradient from the facility to observe changes to soil water storage. Individual creosote and bursage plant physiologies are also being monitored to study any potential increase in plant stress influenced by the CM2 solar facility. Most measurements have been ongoing for at least one year. Greater details on the research infrastructure will be presented along with the latest observational data.

  13. Phosphorus(V)-corrole: synthesis, spectroscopic properties, theoretical calculations, and potential utility for in vivo applications in living cells.

    Science.gov (United States)

    Liang, Xu; Mack, John; Zheng, Li-Min; Shen, Zhen; Kobayashi, Nagao

    2014-03-17

    The synthesis and properties of phosphorus(V) 5,10,15-tris(4-methoxycarbonylphenyl)corrole (1) have been investigated, and its potential utility for bioimaging applications in living cells has been explored. As would normally be anticipated for corrole complexes, the intensity of the Q(0,0) bands of 1 is greater than those of comparable phosphorus(V) tetraphenylporphyrins, but the ΦF values (0.25 for 1) are found to be comparable. A detailed analysis of the electronic structure of the complex was carried out by comparing electronic absorption and MCD spectral data to the results of TD-DFT calculations. The meso-aryl substituents, which enhance the lipophilicity of 1 and hence result in its localization in intracellular membranes during HeLa cell experiments, are predicted to result in a narrowing of the HOMO-LUMO gap and hence a red shift of the Q(0,0) bands toward the optical window in biological tissues.

  14. Estimation of low-potential heat recuperation efficiency of smoke fumes in a condensation heat utilizer under various operation conditions of a boiler and a heating system

    Science.gov (United States)

    Ionkin, I. L.; Ragutkin, A. V.; Luning, B.; Zaichenko, M. N.

    2016-06-01

    For enhancement of the natural gas utilization efficiency in boilers, condensation heat utilizers of low-potential heat, which are constructed based on a contact heat exchanger, can be applied. A schematic of the contact heat exchanger with a humidifier for preheating and humidifying of air supplied in the boiler for combustion is given. Additional low-potential heat in this scheme is utilized for heating of the return delivery water supplied from a heating system. Preheating and humidifying of air supplied for combustion make it possible to use the condensation utilizer for heating of a heat-transfer agent to temperature exceeding the dewpoint temperature of water vapors contained in combustion products. The decision to mount the condensation heat utilizer on the boiler was taken based on the preliminary estimation of the additionally obtained heat. The operation efficiency of the condensation heat utilizer is determined by its structure and operation conditions of the boiler and the heating system. The software was developed for the thermal design of the condensation heat utilizer equipped by the humidifier. Computation investigations of its operation are carried out as a function of various operation parameters of the boiler and the heating system (temperature of the return delivery water and smoke fumes, air excess, air temperature at the inlet and outlet of the condensation heat utilizer, heating and humidifying of air in the humidifier, and portion of the circulating water). The heat recuperation efficiency is estimated for various operation conditions of the boiler and the condensation heat utilizer. Recommendations on the most effective application of the condensation heat utilizer are developed.

  15. Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling.

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E; Zarnke, Allison L; Laine, Muriel; Al Abosy, Rose; Chang, Ya-Fang; Dembo, Anna G; Schoenfelt, Kelly; Vadhi, Raga; Qiu, Xintao; Rao, Prakash; Santhamma, Bindu; Nair, Hareesh B; Nickisch, Klaus J; Long, Henry W; Becker, Lev; Brown, Myles; Greene, Geoffrey L

    2018-01-12

    Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR

  16. Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E.; Zarnke, Allison L.; Laine, Muriel; Al Abosy, Rose; Chang, Ya-Fang; Dembo, Anna G.; Schoenfelt, Kelly; Vadhi, Raga; Qiu, Xintao; Rao, Prakash; Santhamma, Bindu; Nair, Hareesh B.; Nickisch, Klaus J.; Long, Henry W.; Becker, Lev; Brown, Myles; Greene, Geoffrey L.

    2018-01-01

    Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR

  17. Aquatic Insects of New York Salt Marsh Associated with Mosquito Larval Habitat and their Potential Utility as Bioindicators

    Science.gov (United States)

    Rochlin, Ilia; Dempsey, Mary E.; Iwanejko, Tom; Ninivaggi, Dominick V.

    2011-01-01

    The aquatic insect fauna of salt marshes is poorly characterized, with the possible exception of biting Diptera. Aquatic insects play a vital role in salt marsh ecology, and have great potential importance as biological indicators for assessing marsh health. In addition, they may be impacted by measures to control mosquitoes such as changes to the marsh habitat, altered hydrology, or the application of pesticides. Given these concerns, the goals of this study were to conduct the first taxonomic survey of salt marsh aquatic insects on Long Island, New York, USA and to evaluate their utility for non-target pesticide impacts and environmental biomonitoring. A total of 18 species from 11 families and five orders were collected repeatedly during the five month study period. Diptera was the most diverse order with nine species from four families, followed by Coleoptera with four species from two families, Heteroptera with three species from three families, then Odonata and the hexapod Collembola with one species each. Water boatmen, Trichocorixa verticalis Fieber (Heteroptera: Corixidae) and a shore fly, Ephydra subopaca Loew (Diptera: Ephydridae), were the two most commonly encountered species. An additional six species; Anurida maritima Guérin-Méneville (Collembola: Neanuridae), Mesovelia mulsanti White (Heteroptera: Mesovelidae), Enochrus hamiltoni Horn (Coleoptera: Hydrophilidae), Tropisternus quadristriatus Horn (Coleoptera: Hydrophilidae), Dasyhelea pseudocincta Waugh and Wirth (Diptera: Ceratopogonidae), and Brachydeutera argentata Walker (Diptera: Ephydridae), were found regularly. Together with the less common Erythrodiplax berenice Drury (Odonata: Libellulidae), these nine species were identified as the most suitable candidates for pesticide and environmental impact monitoring due to abundance, position in the food chain, and extended seasonal occurrence. This study represents a first step towards developing an insectbased index of biological integrity for

  18. Utility of a low-cost wireless force platform as a potential clinical test of balance recovery after neuraxial anaesthesia.

    Science.gov (United States)

    Tweed, N; Williams, S; Williams, D; Dingley, J

    2014-08-01

    Recovery of balance after neuraxial anaesthesia can remain delayed after simple clinical tests have demonstrated motor recovery. Dynamic posturography tracks the small movements or sway of a person standing as still as possible on a force platform and has been investigated as an objective measure of the ability to walk following anaesthesia. These are expensive laboratory devices, limiting their clinical utility. One measured variable is path length, the cumulative distance travelled in the horizontal plane by the centre of pressure of a person standing on the platform over 1min. Path length might potentially be measured using the Nintendo® Wii-Fit Balance Board™. The feasibility of intercepting raw wireless data from a Wii-Fit Balance Board™ using custom software to calculate path length was explored. Subsequently, path lengths were measured using both this and a laboratory platform simultaneously. In a random order 20 volunteers (a) stood for 1min, feet together, eyes open (conventional baseline test); and (b) stood for 1min, feet together, eyes closed (simulating residual anaesthesia with increased sway). For each device, the ratio b:a was calculated as an index of performance reduction when eyes were closed. Path lengths ranged from 58.5 to 243cm, mean bias 9cm (Wii-FitWii-Fit>laboratory platform) and 95% confidence limits of 0.04 to -0.13. The path lengths were in close agreement and the Wii-Fit Balance Board™ may be worthy of further investigation as a tool to objectively assess readiness to ambulate following neuraxial anaesthesia. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Feasibility and potential utility of multicomponent exhaled breath analysis for predicting development of radiation pneumonitis after stereotactic ablative radiotherapy.

    Science.gov (United States)

    Moré, Jayaji M; Eclov, Neville C W; Chung, Melody P; Wynne, Jacob F; Shorter, Joanne H; Nelson, David D; Hanlon, Alexandra L; Burmeister, Robert; Banos, Peter; Maxim, Peter G; Loo, Billy W; Diehn, Maximilian

    2014-07-01

    In this prospective pilot study, we evaluated the feasibility and potential utility of measuring multiple exhaled gases as biomarkers of radiation pneumonitis (RP) in patients receiving stereotactic ablative radiotherapy (SABR) for lung tumors. Breath analysis was performed for 26 patients receiving SABR for lung tumors. Concentrations of exhaled nitric oxide (eNO), carbon monoxide (eCO), nitrous oxide (eN2O), and carbon dioxide (eCO2) were measured before and immediately after each fraction using real-time, infrared laser spectroscopy. RP development (CTCAE grade ≥2) was correlated with baseline gas concentrations, acute changes in gas concentrations after each SABR fraction, and dosimetric parameters. Exhaled breath analysis was successfully completed in 77% of patients. Five of 20 evaluable patients developed RP at a mean of 5.4 months after SABR. Acute changes in eNO and eCO concentrations, defined as percent changes between each pre-fraction and post-fraction measurement, were significantly smaller in RP versus non-RP cases (p = 0.022 and 0.015, respectively). In an exploratory analysis, a combined predictor of baseline eNO greater than 24 parts per billion and acute decrease in eCO less than 5.5% strongly correlated with RP incidence (p =0.0099). Neither eN2O nor eCO2 concentrations were significantly associated with RP development. Although generally higher in patients destined to develop RP, dosimetric parameters were not significantly associated with RP development. The majority of SABR patients in this pilot study were able to complete exhaled breath analysis. Baseline concentrations and acute changes in concentrations of exhaled breath components were associated with RP development after SABR. If our findings are validated, exhaled breath analysis may become a useful approach for noninvasive identification of patients at highest risk for developing RP after SABR.

  20. ADN-1184 a monoaminergic ligand with 5-HT(6/7) receptor antagonist activity: pharmacological profile and potential therapeutic utility.

    Science.gov (United States)

    Kołaczkowski, M; Mierzejewski, P; Bieńkowski, P; Wesołowska, A; Newman-Tancredi, A

    2014-02-01

    Many dementia patients exhibit behavioural and psychological symptoms (BPSD) that include psychosis, aggressivity, depression and anxiety. Antipsychotic drugs are frequently prescribed but fail to significantly attenuate mood deficits, may interfere with cognitive function and are associated with motor and cardiac side effects, which are problematic in elderly patients. A need therefore exists for drugs that are better suited for the treatment of BPSD. We used in vitro cellular and in vivo behavioural tests to characterize ADN-1184, a novel arylsulfonamide ligand with potential utility for treatment of BPSD. ADN-1184 exhibits substantial 5-HT6 /5-HT7 /5-HT2A /D2 receptor affinity and antagonist properties in vitro. In tests of antipsychotic-like activity, it reversed MK-801-induced hyperactivity and stereotypies and inhibited conditioned avoidance response (MED = 3 mg·kg(-1) i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg·kg(-1) i.p.; higher doses were not significantly active). Notably, up to 30 mg·kg(-1) ADN-1184 did not impair memory performance in the passive avoidance test or elicit significant catalepsy and only modestly inhibited spontaneous locomotor activity (MED = 30 mg·kg(-1) i.p.). ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is better than that of commonly used atypical antipsychotics tested under the same conditions and suggests that it is feasible to identify drugs that improve BPSD, without exacerbating cognitive deficit or movement impairment, which are of particular concern in patients with dementia. © 2013 The British Pharmacological Society.

  1. ADN-1184 a monoaminergic ligand with 5-HT6/7 receptor antagonist activity: pharmacological profile and potential therapeutic utility

    Science.gov (United States)

    Kołaczkowski, M; Mierzejewski, P; Bieńkowski, P; Wesołowska, A; Newman-Tancredi, A

    2014-01-01

    Background and Purpose Many dementia patients exhibit behavioural and psychological symptoms (BPSD) that include psychosis, aggressivity, depression and anxiety. Antipsychotic drugs are frequently prescribed but fail to significantly attenuate mood deficits, may interfere with cognitive function and are associated with motor and cardiac side effects, which are problematic in elderly patients. A need therefore exists for drugs that are better suited for the treatment of BPSD. Experimental Approach We used in vitro cellular and in vivo behavioural tests to characterize ADN-1184, a novel arylsulfonamide ligand with potential utility for treatment of BPSD. Key Results ADN-1184 exhibits substantial 5-HT6/5-HT7/5-HT2A/D2 receptor affinity and antagonist properties in vitro. In tests of antipsychotic-like activity, it reversed MK-801-induced hyperactivity and stereotypies and inhibited conditioned avoidance response (MED = 3 mg·kg−1 i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg·kg−1 i.p.; higher doses were not significantly active). Notably, up to 30 mg·kg−1 ADN-1184 did not impair memory performance in the passive avoidance test or elicit significant catalepsy and only modestly inhibited spontaneous locomotor activity (MED = 30 mg·kg−1 i.p.). Conclusions and Implications ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is better than that of commonly used atypical antipsychotics tested under the same conditions and suggests that it is feasible to identify drugs that improve BPSD, without exacerbating cognitive deficit or movement impairment, which are of particular concern in patients with dementia. PMID:24199650

  2. Aquatic insects of New York salt marsh associated with mosquito larval habitat and their potential utility as bioindicators.

    Science.gov (United States)

    Rochlin, Ilia; Dempsey, Mary E; Iwanejko, Tom; Ninivaggi, Dominick V

    2011-01-01

    The aquatic insect fauna of salt marshes is poorly characterized, with the possible exception of biting Diptera. Aquatic insects play a vital role in salt marsh ecology, and have great potential importance as biological indicators for assessing marsh health. In addition, they may be impacted by measures to control mosquitoes such as changes to the marsh habitat, altered hydrology, or the application of pesticides. Given these concerns, the goals of this study were to conduct the first taxonomic survey of salt marsh aquatic insects on Long Island, New York, USA and to evaluate their utility for non-target pesticide impacts and environmental biomonitoring. A total of 18 species from 11 families and five orders were collected repeatedly during the five month study period. Diptera was the most diverse order with nine species from four families, followed by Coleoptera with four species from two families, Heteroptera with three species from three families, then Odonata and the hexapod Collembola with one species each. Water boatmen, Trichocorixa verticalis Fieber (Heteroptera: Corixidae) and a shore fly, Ephydra subopaca Loew (Diptera: Ephydridae), were the two most commonly encountered species. An additional six species; Anurida maritima Guérin-Méneville (Collembola: Neanuridae), Mesovelia mulsanti White (Heteroptera: Mesovelidae), Enochrus hamiltoni Horn (Coleoptera: Hydrophilidae), Tropisternus quadristriatus Horn (Coleoptera: Hydrophilidae), Dasyhelea pseudocincta Waugh and Wirth (Diptera: Ceratopogonidae), and Brachydeutera argentata Walker (Diptera: Ephydridae), were found regularly. Together with the less common Erythrodiplax berenice Drury (Odonata: Libellulidae), these nine species were identified as the most suitable candidates for pesticide and environmental impact monitoring due to abundance, position in the food chain, and extended seasonal occurrence. This study represents a first step towards developing an insect-based index of biological integrity for

  3. Melatonin Receptor Agonists as the "Perioceutics" Agents for Periodontal Disease through Modulation of Porphyromonas gingivalis Virulence and Inflammatory Response.

    Science.gov (United States)

    Zhou, Wei; Zhang, Xuan; Zhu, Cai-Lian; He, Zhi-Yan; Liang, Jing-Ping; Song, Zhong-Chen

    2016-01-01

    "Perioceutics" including antimicrobial therapy and host modulatory therapy has emerged as a vital adjunctive treatment of periodontal disease. Melatonin level was significantly reduced in patients with periodontal diseases suggesting melatonin could be applied as a potential "perioceutics" treatment of periodontal diseases. This study aims to investigate the effects of melatonin receptor agonists (melatonin and ramelteon) on Porphyromonas gingivalis virulence and Porphyromonas gingivalis-derived lipopolysaccharide (Pg-LPS)-induced inflammation. Effects of melatonin receptor agonists on Porphyromonas gingivalis planktonic cultures were determined by microplate dilution assays. Formation, reduction, and viability of Porphyromonas gingivalis biofilms were detected by crystal violet staining and MTT assays, respectively. Meanwhile, biofilms formation was also observed by confocal laser scanning microscopy (CLSM). The effects on gingipains and hemolytic activities of Porphyromonas gingivalis were evaluated using chromogenic peptides and sheep erythrocytes. The mRNA expression of virulence and iron/heme utilization was assessed using RT-PCR. In addition, cell viability of melatonin receptor agonists on human gingival fibroblasts (HGFs) was evaluated by MTT assays. After pretreatment of melatonin receptor agonists, HGFs were stimulated with Pg-LPS and then release of cytokines (IL-6 and lL-8) was measured by enzyme-linked immunosorbent assay (ELISA). Melatonin and ramelteon did exhibit antimicrobial effects against planktonic culture. Importantly, they inhibited biofilm formation, reduced the established biofilms, and decreased biofilm viability of Porphyromonas gingivalis. Furthermore, they at sub-minimum inhibitory concentration (sub-MIC) concentrations markedly inhibited the proteinase activities of gingipains and hemolysis in a dose-dependent manner. They at sub-MIC concentrations significantly inhibited the mRNA expression of virulence factors (kgp, rgpA, rgpB, hag

  4. Melatonin Receptor Agonists as the "Perioceutics" Agents for Periodontal Disease through Modulation of Porphyromonas gingivalis Virulence and Inflammatory Response.

    Directory of Open Access Journals (Sweden)

    Wei Zhou

    Full Text Available "Perioceutics" including antimicrobial therapy and host modulatory therapy has emerged as a vital adjunctive treatment of periodontal disease. Melatonin level was significantly reduced in patients with periodontal diseases suggesting melatonin could be applied as a potential "perioceutics" treatment of periodontal diseases. This study aims to investigate the effects of melatonin receptor agonists (melatonin and ramelteon on Porphyromonas gingivalis virulence and Porphyromonas gingivalis-derived lipopolysaccharide (Pg-LPS-induced inflammation.Effects of melatonin receptor agonists on Porphyromonas gingivalis planktonic cultures were determined by microplate dilution assays. Formation, reduction, and viability of Porphyromonas gingivalis biofilms were detected by crystal violet staining and MTT assays, respectively. Meanwhile, biofilms formation was also observed by confocal laser scanning microscopy (CLSM. The effects on gingipains and hemolytic activities of Porphyromonas gingivalis were evaluated using chromogenic peptides and sheep erythrocytes. The mRNA expression of virulence and iron/heme utilization was assessed using RT-PCR. In addition, cell viability of melatonin receptor agonists on human gingival fibroblasts (HGFs was evaluated by MTT assays. After pretreatment of melatonin receptor agonists, HGFs were stimulated with Pg-LPS and then release of cytokines (IL-6 and lL-8 was measured by enzyme-linked immunosorbent assay (ELISA.Melatonin and ramelteon did exhibit antimicrobial effects against planktonic culture. Importantly, they inhibited biofilm formation, reduced the established biofilms, and decreased biofilm viability of Porphyromonas gingivalis. Furthermore, they at sub-minimum inhibitory concentration (sub-MIC concentrations markedly inhibited the proteinase activities of gingipains and hemolysis in a dose-dependent manner. They at sub-MIC concentrations significantly inhibited the mRNA expression of virulence factors (kgp, rgp

  5. Utilization of non-conventional systems for conversion of biomass to food components: Potential for utilization of algae in engineered foods

    Science.gov (United States)

    Karel, M.; Kamarei, A. R.; Nakhost, Z.

    1985-01-01

    The major nutritional components of the green algae (Scenedesmus obliquus) grown in a Constant Cell density Apparatus were determined. Suitable methodology to prepare proteins from which three major undesirable components of these cells (i.e., cell walls, nucleic acids, and pigments) were either removed or substantially reduced was developed. Results showed that processing of green algae to protein isolate enhances its potential nutritional and organoleptic acceptability as a diet component in a Controlled Ecological Life Support System.

  6. Using virtual reality to provide health care information to people with intellectual disabilities: acceptability, usability, and potential utility.

    Science.gov (United States)

    Hall, Valerie; Conboy-Hill, Suzanne; Taylor, Dave

    2011-11-14

    People with intellectual disabilities have poor access to health care, which may be further compromised by a lack of accessible health information. To be effective, health information must be easily understood and remembered. People with intellectual disabilities learn better from multimodal information sources, and virtual reality offers a 3-dimensional (3D) computer-generated environment that can be used for providing information and learning. To date, research into virtual reality experiences for people with intellectual disabilities has been limited to skill-based training and leisure opportunities within the young to mid age ranges. This study assessed the acceptability, usability, and potential utility of a virtual reality experience as a means of providing health care-related information to people with intellectual disabilities. We designed a prototype multimodal experience based on a hospital scenario and situated on an island in the Second Life 3D virtual world. We wanted to know how people of different ages and with varying levels of cognitive function would participate in the customized virtual environment, what they understood from being there, and what they remembered a week later. The study drew on qualitative data. We used a participatory research approach that involved working alongside people with intellectual disabilities and their supporters in a community setting. Cognitive function was assessed, using the Matrix Analogies Test and the British Picture Vocabulary Scale, to describe the sample. Participants, supported by facilitators, were video recorded accessing and engaging with the virtual environment. We assessed recall 1 week later, using a specialized interview technique. Data were downloaded into NVivo 8 and analyzed using the framework analysis technique. Study participants were 20 people aged between 20 and 80 years with mild to severe intellectual disabilities. All participants were able to access the environment and voluntarily stayed

  7. Association Between Benzodiazepine Receptor Agonists and Snoring Among Women in the Nurses' Health Study.

    Science.gov (United States)

    Lin, Brian M; Hu, Frank B; Curhan, Gary C

    2017-02-01

    Snoring is highly prevalent among adults. The use of benzodiazepine receptor agonists is also common, with higher prevalence of use with more advanced age. Benzodiazepine receptor agonists cause muscle relaxation, which may affect muscle tone and airway dynamics and thereby increase snoring. Previous studies examining the association between use of benzodiazepine receptor agonists and snoring were underpowered to detect clinically meaningful differences or did not report the magnitude of association. To investigate the association between use of benzodiazepine receptor agonists and snoring in women. Women aged 62 to 86 years provided information on snoring and covariates of interest in the 2008 survey of the Nurses' Health Study, a cross-sectional cohort study of female registered nurses in the United States. Potential effect modification of the association between use of benzodiazepine receptor agonists and snoring by age, body mass index, waist circumference, smoking, alcohol consumption, and physical activity was explored. Logistic regression was used to adjust for potential confounders. Data analysis was conducted from November 2015 to March 2016. Self-reported habitual snoring, defined as a few nights a week or more. Of 52 504 participants (mean [SD] age, 72.4 [6.7] years), 14 831 (28.2%) reported habitual snoring. There was a slightly higher prevalence of benzodiazepine receptor agonist use among habitual snorers (11.4%) compared with nonhabitual snorers (10.6%) (absolute difference, 0.8%; 95% CI, 0.2%-1.4%). After multivariable adjustment, use of benzodiazepine receptor agonists was not associated with snoring (odds ratio, 1.01; 95% CI, 0.95-1.07) compared with women who did not use benzodiazepine receptor agonists. Although there was no significant interaction with smoking, there were higher odds of snoring with use of benzodiazepine receptor agonists among current smokers (odds ratio, 1.34; 95% CI, 1.04-1.73). Use of benzodiazepine receptor agonists is

  8. Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells.

    Science.gov (United States)

    Pan, Shi; Sharma, Pawan; Shah, Sushrut D; Deshpande, Deepak A

    2017-07-01

    Airway remodeling, including increased airway smooth muscle (ASM) mass, is a hallmark feature of asthma and COPD. We previously identified the expression of bitter taste receptors (TAS2Rs) on human ASM cells and demonstrated that known TAS2R agonists could promote ASM relaxation and bronchodilation and inhibit mitogen-induced ASM growth. In this study, we explored cellular mechanisms mediating the antimitogenic effect of TAS2R agonists on human ASM cells. Pretreatment of ASM cells with TAS2R agonists chloroquine and quinine resulted in inhibition of cell survival, which was largely reversed by bafilomycin A1, an autophagy inhibitor. Transmission electron microscope studies demonstrated the presence of double-membrane autophagosomes and deformed mitochondria. In ASM cells, TAS2R agonists decreased mitochondrial membrane potential and increased mitochondrial ROS and mitochondrial fragmentation. Inhibiting dynamin-like protein 1 (DLP1) reversed TAS2R agonist-induced mitochondrial membrane potential change and attenuated mitochondrial fragmentation and cell death. Furthermore, the expression of mitochondrial protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) and mitochondrial localization of DLP1 were significantly upregulated by TAS2R agonists. More importantly, inhibiting Bnip3 mitochondrial localization by dominant-negative Bnip3 significantly attenuated cell death induced by TAS2R agonist. Collectively the TAS2R agonists chloroquine and quinine modulate mitochondrial structure and function, resulting in ASM cell death. Furthermore, Bnip3 plays a central role in TAS2R agonist-induced ASM functional changes via a mitochondrial pathway. These findings further establish the cellular mechanisms of antimitogenic effects of TAS2R agonists and identify a novel class of receptors and pathways that can be targeted to mitigate airway remodeling as well as bronchoconstriction in obstructive airway diseases. Copyright © 2017 the American Physiological

  9. Agonist activation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

    Science.gov (United States)

    Gill, JasKiran K.; Savolainen, Mari; Young, Gareth T.; Zwart, Ruud; Sher, Emanuele; Millar, Neil S.

    2011-01-01

    Conventional nicotinic acetylcholine receptor (nAChR) agonists, such as acetylcholine, act at an extracellular “orthosteric” binding site located at the interface between two adjacent subunits. Here, we present evidence of potent activation of α7 nAChRs via an allosteric transmembrane site. Previous studies have identified a series of nAChR-positive allosteric modulators (PAMs) that lack agonist activity but are able to potentiate responses to orthosteric agonists, such as acetylcholine. It has been shown, for example, that TQS acts as a conventional α7 nAChR PAM. In contrast, we have found that a compound with close chemical similarity to TQS (4BP-TQS) is a potent allosteric agonist of α7 nAChRs. Whereas the α7 nAChR antagonist metyllycaconitine acts competitively with conventional nicotinic agonists, metyllycaconitine is a noncompetitive antagonist of 4BP-TQS. Mutation of an amino acid (M253L), located in a transmembrane cavity that has been proposed as being the binding site for PAMs, completely blocks agonist activation by 4BP-TQS. In contrast, this mutation had no significant effect on agonist activation by acetylcholine. Conversely, mutation of an amino acid located within the known orthosteric binding site (W148F) has a profound effect on agonist potency of acetylcholine (resulting in a shift of ∼200-fold in the acetylcholine dose-response curve), but had little effect on the agonist dose-response curve for 4BP-TQS. Computer docking studies with an α7 homology model provides evidence that both TQS and 4BP-TQS bind within an intrasubunit transmembrane cavity. Taken together, these findings provide evidence that agonist activation of nAChRs can occur via an allosteric transmembrane site. PMID:21436053

  10. Beta-agonists and animal welfare

    Science.gov (United States)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  11. GnRH agonist triggering

    DEFF Research Database (Denmark)

    Kol, Shahar; Humaidan, Peter; Al Humaidan, Peter Samir Heskjær

    2013-01-01

    The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin (HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages......, including virtually complete prevention of ovarian hyperstimulation syndrome (OHSS), the introduction of a surge of FSH in addition to the LH surge and finally the possibility to individualize luteal-phase supplementation based on ovarian response to stimulation. We maintain that the automatic HCG...... triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients. Routinely, human chorionic gonadotrophin (HCG) is used to induce ovulation in fertility treatments. This approach deviates...

  12. Small Molecule Fluoride Toxicity Agonists

    Science.gov (United States)

    Nelson1, James W.; Plummer, Mark S.; Blount, Kenneth F.; Ames, Tyler D.; Breaker, Ronald R.

    2015-01-01

    SUMMARY Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch-reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. PMID:25910244

  13. Dopamine agonists and risk: impulse control disorders in Parkinson's disease.

    Science.gov (United States)

    Voon, Valerie; Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J; Hallett, Mark

    2011-05-01

    Impulse control disorders are common in Parkinson's disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a 'Sure' choice and a 'Gamble' choice of moderate risk. To commence each trial, in the 'Gain' condition, individuals started at $0 and in the 'Loss' condition individuals started at -$50 below the 'Sure' amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk ('Gamble Risk'). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the 'Gain' relative to the 'Loss' condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals.

  14. Dopamine agonists and risk: impulse control disorders in Parkinson's; disease

    Science.gov (United States)

    Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J.; Hallett, Mark

    2011-01-01

    Impulse control disorders are common in Parkinson's; disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's; disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a ‘Sure’ choice and a ‘Gamble’ choice of moderate risk. To commence each trial, in the ‘Gain’ condition, individuals started at $0 and in the ‘Loss’ condition individuals started at −$50 below the ‘Sure’ amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk (‘Gamble Risk’). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's; disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the ‘Gain’ relative to the ‘Loss’ condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's; disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's; disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals. PMID:21596771

  15. Nest-building behavior of Monk Parakeets and insights into potential mechanisms for reducing damage to utility poles

    Directory of Open Access Journals (Sweden)

    Kevin R. Burgio

    2014-09-01

    Full Text Available The Monk Parakeet (Myiopsitta monachus commonly uses utility poles as a substrate for building large, bulky nests. These nests often cause fires and electric power outages, creating public safety risks and increasing liability and maintenance costs for electric companies. Previous research has focused on lethal methods and chemical contraception to prevent nesting on utility poles and electrical substations. However, implementation of lethal methods has led to public protests and lawsuits, while chemical contraception may affect other than the targeted species, and must be continually reapplied for effectiveness. One non-lethal alternative, nest removal, is costly and may not be a sustainable measure if Monk Parakeet populations continue to grow. In order to identify cost-effective non-lethal solutions to problems caused by Monk Parakeet nesting, we studied their behavior as they built nests on utility poles. Monk Parakeets initiate nests by attaching sticks at the intersection of the pole and electric lines. We found that parakeets use the electric lines exclusively to gain access to the intersection of lines and pole during nest initiation, and continue to use the lines intensively throughout construction. Monk Parakeets also have more difficulty attaching sticks during the early stages of nest construction than when the nest is nearing completion. These findings suggest that intervention during the earlier stages of nest building, by excluding Monk Parakeets from electric lines adjacent to poles, may be an effective, non-lethal method of reducing or eliminating parakeets nesting on, and damaging, utility poles.

  16. Case Studies of Potential Facility-Scale and Utility-Scale Non-Hydro Renewable Energy Projects across Reclamation

    Energy Technology Data Exchange (ETDEWEB)

    Haase, S.; Burman, K.; Dahle, D.; Heimiller, D.; Jimenez, A.; Melius, J.; Stoltenberg, B.; VanGeet, O.

    2013-05-01

    This report summarizes the results of an assessment and analysis of renewable energy opportunities conducted for the U.S. Department of the Interior, Bureau of Reclamation by the National Renewable Energy Laboratory. Tasks included assessing the suitability for wind and solar on both a utility and facility scale.

  17. Food resource utilization by juvenile Baltic cod Gadus morhua : a mechanism potentially influencing recruitment success at the demersal juvenile stage?

    DEFF Research Database (Denmark)

    Hüssy, Karin; St. John, Michael; Böttcher, U.

    1997-01-01

    those reported to be consumed by juveniles in other areas. The apparent overlap in food resource utilization among the different size groups of demersal juveniles observed in this study suggests that in years with low prey abundance, or high abundance of pelagic juveniles, strong intra-specific...... competition for food. resources may affect the recruitment success of Baltic cod....

  18. Are They Paying Attention? Students' Lack of Motivation and Attention Potentially Threaten the Utility of Course Evaluations

    Science.gov (United States)

    Bassett, Jonathan; Cleveland, Amanda; Acorn, Deborah; Nix, Marie; Snyder, Timothy

    2017-01-01

    Student evaluations are a common source of information used by instructors and administrators, but their utility depends on students' motivation and attention. This paper presents evidence from two studies indicating that insufficient effort responding and lack of motivation may be problems in course evaluations. In the first study, approximately…

  19. Nest-building behavior of Monk Parakeets and insights into potential mechanisms for reducing damage to utility poles.

    Science.gov (United States)

    Burgio, Kevin R; Rubega, Margaret A; Sustaita, Diego

    2014-01-01

    The Monk Parakeet (Myiopsitta monachus) commonly uses utility poles as a substrate for building large, bulky nests. These nests often cause fires and electric power outages, creating public safety risks and increasing liability and maintenance costs for electric companies. Previous research has focused on lethal methods and chemical contraception to prevent nesting on utility poles and electrical substations. However, implementation of lethal methods has led to public protests and lawsuits, while chemical contraception may affect other than the targeted species, and must be continually reapplied for effectiveness. One non-lethal alternative, nest removal, is costly and may not be a sustainable measure if Monk Parakeet populations continue to grow. In order to identify cost-effective non-lethal solutions to problems caused by Monk Parakeet nesting, we studied their behavior as they built nests on utility poles. Monk Parakeets initiate nests by attaching sticks at the intersection of the pole and electric lines. We found that parakeets use the electric lines exclusively to gain access to the intersection of lines and pole during nest initiation, and continue to use the lines intensively throughout construction. Monk Parakeets also have more difficulty attaching sticks during the early stages of nest construction than when the nest is nearing completion. These findings suggest that intervention during the earlier stages of nest building, by excluding Monk Parakeets from electric lines adjacent to poles, may be an effective, non-lethal method of reducing or eliminating parakeets nesting on, and damaging, utility poles.

  20. Medical treatment in Cushing's syndrome: dopamine agonists and cabergoline.

    Science.gov (United States)

    Petrossians, Patrick; Thonnard, Anne-Sophie; Beckers, Albert

    2010-01-01

    Dopamine (DA) is a catecholamine with a wide range of functions and whose five subtype receptors are found in different organs where they exert a mainly inhibitory action. Since this action may also appear in a number of secretory tumors in various locations, DA agonists have elicited some interest as a medical treatment for hypercorticism. Non-iatrogenic Cushing's syndromes are due in 70% of the cases to a pituitary adrenocorticotropic hormone (ACTH)-producing adenoma, and, less frequently, to an adrenal adenoma or an ectopic ACTH secretion by a neuroendocrine tumor. First-line treatment in Cushing's syndrome consists of the surgical removal of the secreting tumor. However, surgery may not achieve a complete cure in a number of cases, hence emphasizing the potential benefit of a medical complementary treatment, which could also benefit patients as an alternative approach, either when waiting for, or when the patient is not eligible for surgery. Studies of corticotropic adenomas have shown that 80% of these tumors express D2 receptors. Clinical trials of DA agonists in Cushing's disease have shown an inhibitory effect of these drugs with an inhibition of ACTH secretion and/or a decrease of tumor size. There are only a few cases of documented use of DA agonists in ectopic ACTH secretion, but when the tumor expresses DA receptors, DA agonists may represent a useful complementary treatment. DA receptors are also expressed in normal and tumoral adrenals, suggesting a potential use of DA agonists in Cushing's syndrome secondary to adrenal tumors. However, clinical data regarding this specific situation are very scarce, maybe due to the relatively high rate of surgical cure of adrenal adenomas. In conclusion, DA agonists represent a potential preparatory or complementary treatment for endogenous Cushing's syndrome, especially in Cushing's disease. These compounds may be underused as suggested by the scarce number of publication and case reports in the literature. In the

  1. Pyrazolodiazepine derivatives with agonist activity toward Drosophila RYamide receptor.

    Science.gov (United States)

    Yoon, Yeu Kyung; Kim, Jung Ha; Kim, Jeong-Hyun; Kwon, Jae-Young; Kim, Yong-Chul; Kim, Young-Joon; Park, Zee-Yong

    2016-10-15

    The neuropeptide Y (NPY)-like signaling is conserved broadly in many animal species, and implicated in diverse biological functions, particularly those associated with feeding and metabolism. In Drosophila, three G protein coupled receptors (GPCRs) are closely related to the vertebrate NPY receptors: RYamide receptor (RYa-R) CG5811, neuropeptide F receptor (NPFR) CG1147 and short neuropeptide F receptor (sNPF-R) CG7395. Here, we screened 442 compounds of the pyrazolodiazepine analogs library, and identified four synthetic small compounds that activate the RYa-R, but not other two receptors. Their maximum activity is about 40% of the endogenous ligand, Drosophila RYamide-1, indicating they are partial agonists. Structural comparisons of these agonists identified an active core structure, characterized by phenylalanine and lysine fused pyrazolodiazepine skeletons, which can be utilized as a lead structure for further development of more potent drugs active on mammalian NPYRs. Identification of small compound agonists selective on RYa-R of the genetically amenable insect model will facilitate future efforts to understand biological functions of RYa-R, a GPCR conserved in many species. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Hierarchical Phosphorylation of δ-Opioid Receptor Regulates Agonist-induced Receptor Desensitization and Internalization*

    OpenAIRE

    Maestri-El Kouhen, Odile; Wang, Guilin; Solberg, Jonathan; Erickson, Laurie J.; Law, Ping-Yee; Loh, Horace H.

    2000-01-01

    Treatment of HEK293 cells expressing the δ-opioid receptor with agonist [d-Pen2,5]enkephalin (DPDPE) resulted in the rapid phosphorylation of the receptor. We constructed several mutants of the potential phosphorylation sites (Ser/Thr) at the carboxyl tail of the receptor in order to delineate the receptor phosphorylation sites and the agonist-induced desensitization and internalization. The Ser and Thr were substituted to alanine, and the corresponding mutants were transiently and stably exp...

  3. The emergence of devastating impulse control disorders during dopamine agonist therapy of the restless legs syndrome.

    Science.gov (United States)

    Dang, Dien; Cunnington, David; Swieca, John

    2011-01-01

    The Restless Legs Syndrome is a common sensorimotor disorder, typically amenable to treatment with dopamine agonist therapy. Dopamine agonists have been associated with emergent impulse control disorders (ICDs) when used in patients with Parkinson disease, and ICDs have now been reported in individuals with RLS on dopamine agonist therapy. Our aim was to characterize cases of emergent ICDs in Australian patients with focus on the dopamine agonists implicated and the social significance of ICDs. A series of RLS patients on dopamine agonist therapy were identified with ICDs over a 2-year period. Additional cases of ICDs were found using a mailout questionnaire designed to capture those with high impulsivity. These patients were assessed using the Barratt Impulsiveness Scale, Version 11, and a modified Minnesota Impulse Disorders Interview. Case records and medication schedules were evaluated. Twelve cases of patients with de novo ICDs were found with a range of impulsive behaviors including pathological gambling, kleptomania, compulsive shopping, and hypersexuality. Criminality, suicidality, and marital discord also were featured. These occurred over a wide range of latencies and l-dopa exposures. This group of Australian RLS patients with ICDs display high levels of impulsivity and is the first to use the BIS-11 questionnaire in this setting. Impulse control disorders can occur over a wide range of dopamine agonist therapy types and dose exposures. Impulse control disorder tendencies may persist, despite withdrawal of dopamine agonists. The emergence of ICDs needs careful consideration in light of their potentially devastating financial, social, and marital consequences.

  4. TRPA1 agonist activity of probenecid desensitizes channel responses: consequences for screening.

    Science.gov (United States)

    McClenaghan, Conor; Zeng, Fanning; Verkuyl, Jan Martin

    2012-12-01

    The transient receptor potential channel subtype A member 1 (TRPA1) is a nonselective cation channel widely viewed as having therapeutic potential, particularly for pain-related indications. Realization of this potential will require potent, selective modulators; however, currently the pharmacology of TRPA1 is poorly defined. As TRPA1 is calcium permeable, calcium indicators offer a simple assay format for high-throughput screening. In this report, we show that probenecid, a uricosuric agent used experimentally in screening to increase loading of calcium-sensitive dyes, activates TRPA1. Prolonged probenecid incubation during the dye-loading process reduces agonist potency upon subsequent challenge. When Chinese Hamster Ovary (CHO)-hTRPA1 or STC-1 cells, which endogenously express TRPA1, were dye loaded in the presence of 2 mM probenecid TRPA1, agonists appeared less potent; EC(50) for allyl isothiocyante agonists in CHO-hTRPA1 was increased from 1.5±0.19 to 7.32±1.20 μM (P<0.01). No significant effect on antagonist potency was observed when using the agonist EC(80) concentration determined under the appropriate dye-loading conditions. We suggest an alternative protocol for calcium imaging using another blocker of anion transport, sulfinpyrazone. This blocker significantly augments indicator dye loading and the screening window, but is not a TRPA1 agonist and has no effect on agonist potency.

  5. The Potential to Forgo Social Welfare Gains through Over reliance on Cost Effectiveness/Cost Utility Analyses in the Evidence Base for Public Health

    International Nuclear Information System (INIS)

    Cohen, D.R.; Patel, N.

    2010-01-01

    Economic evaluations of clinical treatments most commonly take the form of cost effectiveness or cost utility analyses. This is appropriate since the main sometimes the only benefit of such interventions is increased health. The majority of economic evaluations in public health, however, have also been assessed using these techniques when arguably cost benefit analyses would in many cases have been more appropriate, given its ability to take account of non health benefits as well. An examination of the non health benefits from a sample of studies featured in a recent review of economic evaluations in public health illustrates how over focusing on cost effectiveness/cost utility analyses may lead to forgoing potential social welfare gains from programmes in public health. Prior to evaluation, programmes should be considered in terms of the potential importance of non health benefits and where these are considerable would be better evaluated by more inclusive economic evaluation techniques.

  6. Endogenous Receptor Agonists: Resolving Inflammation

    Directory of Open Access Journals (Sweden)

    Gerhard Bannenberg

    2007-01-01

    Full Text Available Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A comprehensive understanding of the cellular and molecular events that control the termination of acute inflammation is needed in molecular terms given the widely held view that aberrant inflammation underlies many common diseases. This review focuses on recent advances in the understanding of the role of arachidonic acid and ω-3 polyunsaturated fatty acids (PUFA–derived lipid mediators in regulating the resolution of inflammation. Using a functional lipidomic approach employing LC-MS-MS–based informatics, recent studies, reviewed herein, uncovered new families of local-acting chemical mediators actively biosynthesized during the resolution phase from the essential fatty acids eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA. These new families of local chemical mediators are generated endogenously in exudates collected during the resolution phase, and were coined resolvins and protectins because specific members of these novel chemical families control both the duration and magnitude of inflammation in animal models of complex diseases. Recent advances on the biosynthesis, receptors, and actions of these novel anti-inflammatory and proresolving lipid mediators are reviewed with the aim to bring to attention the important role of specific lipid mediators as endogenous agonists in inflammation resolution.

  7. Dopamine Agonists and Pathologic Behaviors

    Directory of Open Access Journals (Sweden)

    Brendan J. Kelley

    2012-01-01

    Full Text Available The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

  8. A Study of the Hazardous Glare Potential to Aviators from Utility-Scale Flat-Plate Photovoltaic Systems

    OpenAIRE

    Scott Olson; Evan Riley

    2011-01-01

    The potential flash glare a pilot could experience from a proposed 25-degree fixed-tilt flat-plate polycrystalline PV system located outside of Las Vegas, Nevada, was modeled for the purpose of hazard quantification. Hourly insolation data measured via satellite for the years 1998 to 2004 was used to perform the modeling. The theoretical glare was estimated using published ocular safety metrics which quantify the potential for a postflash glare after-image. This was then compared to the postf...

  9. Quantitative protein and fat metabolism in bull calves treated with beta-adrenergic agonist

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G

    1996-01-01

    Protein and energy utilization and quantitative retention of protein, fat and energy was investigated with 12 Red Danish bulls during two subsequent 6 weeks trials (Sections A and B) at a mean live weight of 195 and 335 kg respectively. Treatments were control (Group 1) and beta-agonist (L-644,96...

  10. Utilization of by-products from the tequila industry. Part 2: Potential value of Agave tequilana Weber azul leaves.

    Science.gov (United States)

    Iñiguez-Covarrubias, G; Díaz-Teres, R; Sanjuan-Dueñas, R; Anzaldo-Hernández, J; Rowell, R M

    2001-04-01

    The leaves of the agave plant are left in the field after harvesting the heads for tequila production. Different types of agave leaves were isolated, classified, and their content in the total plant determined. The usable fractions were collected and their properties determined. Of the total wet weight of the agave plant, 54% corresponds to the agave head, 32% corresponds to materials which could be usable for sugar and fiber production which leaves 14% of the wet plant without apparent utility. The fractions with higher total reducing sugars (TRS) content were the fresh fraction of partially dry leaves stuck to the head and the leaf bases with a TRS content of 16.1% and 13.1%, respectively. The highest TRS concentration (16-28%) is in the agave head which is used for tequila production. The leaves are 90-120 cm long and 8-12 cm wide and contain fiber bundles that are 23-52 cm long and 0.6-13 mm wide. The ultimate fiber length is approximately 1.6 mm with an average width of 25 microns. There are several types of leaf fibers that can be utilized depending on what part of the plant they come from and what product is desired. Agave leaf fibers were pulped using a soda pulping process and the pulp was hand formed into test sheets. Test sheets made from pulped agave leaf fibers had a breaking length comparable to paper made from both pine and eucalyptus fibers, but the tear index and burst index were lower than the other two papers.

  11. Growth patterns reflect response to antiretroviral therapy in HIV-positive infants: potential utility in resource-poor settings.

    Science.gov (United States)

    Benjamin, D K; Miller, W C; Ryder, R W; Weber, D J; Walter, E; McKinney, R E

    2004-01-01

    Laboratory monitoring of HIV-infected children is the current standard of care in the United States to guide the appropriate use of antiretroviral therapy (ART). Although ART is becoming a reality in some developing countries, laboratory monitoring of ART is costly, necessitating creative approaches to monitoring. As an initial step to guide monitoring of HIV progression in low resource settings, we assessed the utility of the physical examination to predict clinical progression of HIV. We conducted a retrospective cohort study of HIV-infected children using data from Pediatric AIDS Clinical Trials Group Protocol 300. We developed a clinical predictive model, and compared the utility of the clinical model to the change in HIV RNA viral load as diagnostic tests of ART failure. The clinical model incorporated treatment regimen, age, and height velocity: a three-level clinical predictive model provided likelihood ratios of 0.3, 3.9, and 14. For decline in RNA the likelihood ratios were 0.2 (> 1 log decline), 1.4, and 3.5 (> log increase). We developed a simple clinical predictive model that was able to predict clinical progression of HIV after initiation of new ART. The clinical model performed similarly to using changes in HIV RNA viral load. These data should be validated internationally and prospectively, because the test subjects were from a resource rich environment and growth patterns in undernourished children may be impacted differently by HIV and its treatment. The model was most pertinent to children 36 months of age or younger, and was conducted in children receiving monotherapy and dual therapy.

  12. Building generalized tree mass/volume component models for improved estimation of forest stocks and utilization potential

    Science.gov (United States)

    David W. MacFarlane

    2015-01-01

    Accurately assessing forest biomass potential is contingent upon having accurate tree biomass models to translate data from forest inventories. Building generality into these models is especially important when they are to be applied over large spatial domains, such as regional, national and international scales. Here, new, generalized whole-tree mass / volume...

  13. Energy saving potential of presence detection for lighting systems in utility buildings. Final report; Besparingspotentie aanwezigheidsdetectie voor verlichting in utiliteitsgebouwen

    Energy Technology Data Exchange (ETDEWEB)

    Van den Ham, E.R.; Nobel, K.C.J.

    2002-01-22

    A method to determine the energy saving potential of the title system is presented. [Dutch] Dit rapport geeft een methode voor het bepalen van de besparingpotentie van aanwezigheidsdetectie (AWD) op verlichtingsenergie in een gebouw of deel van een gebouw. Verder is een eenvoudige methode afgeleid om de besparing met AWD in te schatten.

  14. Assessment of the potential utility of different regions of Streptococcus uberis adhesion molecule (SUAM) for mastitis subunit vaccine development.

    Science.gov (United States)

    Perrig, Melina Soledad; Veaute, Carolina; Renna, María Sol; Pujato, Nazarena; Calvinho, Luis; Marcipar, Iván; Barbagelata, María Sol

    2017-04-01

    Streptococcus uberis is one of the most prevalent pathogens causing clinical and subclinical mastitis worldwide. Among bacterial factors involved in intramammary infections caused by this organism, S. uberis adhesion molecule (SUAM) is one of the main virulence factors identified. This molecule is involved in S. uberis internalization to mammary epithelial cells through lactoferrin (Lf) binding. The objective of this study was to evaluate SUAM properties as a potential subunit vaccine component for prevention of S. uberis mastitis. B epitope prediction analysis of SUAM sequence was used to identify potentially immunogenic regions. Since these regions were detected all along the gene, this criterion did not allow selecting a specific region as a potential immunogen. Hence, four fractions of SUAM (-1fr, 2fr, 3fr and 4fr), comprising most of the protein, were cloned and expressed. Every fraction elicited a humoral immune response in mice as predicted by bioinformatics analysis. SUAM-1fr generated antibodies with the highest recognition ability towards SUAM native protein. Moreover, antibodies against SUAM-1fr produced the highest proportion of internalization inhibition of S. uberis to mammary epithelial cells. In conclusion, SUAM immunogenic and functionally relevant regions were identified and allowed to propose SUAM-1fr as a potential candidate for a subunit vaccine for S. uberis mastitis prevention. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Utilizing Focus Groups with Potential Participants and Their Parents: An Approach to Inform Study Design in a Large Clinical Trial.

    Science.gov (United States)

    Kadimpati, Sandeep; McCormick, Jennifer B; Chiu, Yichen; Parker, Ashley B; Iftikhar, Aliya Z; Flick, Randall P; Warner, David O

    2014-01-01

    In the recent literature, there has been some evidence that exposure of children to anesthetic procedures during the first two years of life may impair cognitive function and learning in later life. We planned a clinical study to quantify this risk, a study involving testing 1,000 children for neurodevelopmental deficits. As a part of this planning, we conducted focus groups involving potential participants and their parents to elicit information regarding three issues: communications with the community and potential participants, recruitment and consent processes, and the return of neurodevelopmental testing results. Three focus groups were conducted with the parents of potential participants and one focus group was conducted with an 18-19 year old group; each group consisted of 6-10 participants. The moderated discussions had questions about recruitment, consenting issues, and expectations from the study about return of both overall trial findings and individual research test results. The focus group data gave us an insight on potential participants' views on recruitment, consenting, communications about the study, and expectations about return of both overall trial findings and individual research test results. The concerns expressed were largely addressable. In addition, the concern we had about some parents enrolling their children in the study solely for the sake of getting their child's cognitive function results was dispelled. We found that the individuals participating in our focus groups were generally enthusiastic about the large clinical study and could see the value in answering the study question. The data from the focus groups were used to inform changes to the recruitment and consent process. Focus group input was also instrumental in affirming the study design regarding return of results. Our experience suggests that the approach we used may serve as a model for other investigators to help inform the various elements of clinical study design, in

  16. Development of specific dopamine D-1 agonists and antagonists

    International Nuclear Information System (INIS)

    Sakolchai, S.

    1987-01-01

    To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo[a,d]cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo[1,2]cyclohepta[3,4,5d,e]isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC 50 of compound 11 for displacement of 3 H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of 3 H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor

  17. PPAR Agonists and Metabolic Syndrome: An Established Role?

    Directory of Open Access Journals (Sweden)

    Margherita Botta

    2018-04-01

    Full Text Available Therapeutic approaches to metabolic syndrome (MetS are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs, blood glucose, and abdominal adiposity. PPARs may be classified into the α, β/δ and γ subtypes. The PPAR-α agonists, mainly fibrates (including newer molecules such as pemafibrate and omega-3 fatty acids, are powerful TG-lowering agents. They mainly affect TG catabolism and, particularly with fibrates, raise the levels of high-density lipoprotein cholesterol (HDL-C. PPAR-γ agonists, mainly glitazones, show a smaller activity on TGs but are powerful glucose-lowering agents. Newer PPAR-α/δ agonists, e.g., elafibranor, have been designed to achieve single drugs with TG-lowering and HDL-C-raising effects, in addition to the insulin-sensitizing and antihyperglycemic effects of glitazones. They also hold promise for the treatment of non-alcoholic fatty liver disease (NAFLD which is closely associated with the MetS. The PPAR system thus offers an important hope in the management of atherogenic dyslipidemias, although concerns regarding potential adverse events such as the rise of plasma creatinine, gallstone formation, drug–drug interactions (i.e., gemfibrozil and myopathy should also be acknowledged.

  18. Potential of energetic utilization of grains residual biomass; Potencial de utilizacao energetica de biomassa residual de graos

    Energy Technology Data Exchange (ETDEWEB)

    Mourad, Anna L. [Instituto de Tecnologia de Alimentos (ITAL), Campinas, SP (Brazil). Centro de Tecnologia de Embalagem], e-mail: anna@ital.sp.gov.br; Ambrogi, Vinicius S.; Guerra, Sinclair M.G. [Universidade Estadual de Campinas (UNICAMP), SP (Brazil). Fac. de Engenharia Mecanica], e-mail: ambrogi@fem.unicamp.br, e-mail: sguerra@fem.unicamp.br

    2004-07-01

    The biomass resulting from the rejected parts of grains, as straw and peel of rice, corn, wheat, soy, all great cultivations in the country, has potential to be takes advantage as energy. It was considered that the contribution of this residual biomass is near of 167,8 million GJ/year, value that could be added to the use already established of the cane bagasse for energy purpose (658 million GJ, in 2001). This energy can be used for drying of these same grains (energy expense estimate of 67 million GJ), currently obtained from oil. It can also substitute the fuel oil used in the agricultural section, in the industries of food and beverage, ceramic and textile (sections that consumed 67.822 GJ in 2001). In Sao Paulo state the regions with greater potential to install biomass plants are located in Assis, Avare and Itapeva EDR (regional development office). (author)

  19. Aquatic Insects of New York Salt Marsh Associated with Mosquito Larval Habitat and their Potential Utility as Bioindicators

    OpenAIRE

    Rochlin, Ilia; Dempsey, Mary E.; Iwanejko, Tom; Ninivaggi, Dominick V.

    2011-01-01

    The aquatic insect fauna of salt marshes is poorly characterized, with the possible exception of biting Diptera. Aquatic insects play a vital role in salt marsh ecology, and have great potential importance as biological indicators for assessing marsh health. In addition, they may be impacted by measures to control mosquitoes such as changes to the marsh habitat, altered hydrology, or the application of pesticides. Given these concerns, the goals of this study were to conduct the first taxonom...

  20. Promotion Effect of Asian Dust on Phytoplankton Growth and Potential Dissolved Organic Phosphorus Utilization in the South China Sea

    Science.gov (United States)

    Chu, Qiang; Liu, Ying; Shi, Jie; Zhang, Chao; Gong, Xiang; Yao, Xiaohong; Guo, Xinyu; Gao, Huiwang

    2018-03-01

    Dust deposition is an important nutrient source to the South China Sea (SCS), but few in situ experiments were conducted on phytoplankton response to the deposition. We conducted onboard incubation experiments at three stations near Luzon Strait in the SCS, with addition of multiple dissolved inorganic nutrients, Asian dust, and rainwater. From our results, nitrogen and phosphorus were both urgently needed for phytoplankton growth in the SCS, indicated by the evident Chl a response to the addition of nitrogen and phosphorus together. Almost no evident response was observed by adding phosphorus or iron alone to incubation waters, although a delayed response of Chl a in mass concentration was observed by adding nitrogen alone. The latter implied a possible utilization of dissolved organic phosphorus because of insufficient dissolved inorganic phosphorus in incubation waters. Under such nutrient condition, Asian dust showed an apparent promotion effect on phytoplankton growth by providing sufficient amounts of nitrogen but low phosphorus. Meanwhile, it was found that large sized (> 5 μm) phytoplankton community showed different responses to dust addition at different stations. At stations A3 and A6, Chaetoceros spp. became the dominant species during the bloom period, while at station WG2, Nitzschia spp. became dominant. In combination with different initial nutrients and Chl a levels at the three stations, the different phytoplankton community evolution implied the response difference to external inputs between oligotrophic (stations A3 and A6) and ultraoligotrophic (station WG2) conditions in the SCS.

  1. The Potential Clinical Utility of Transdermal Alcohol Monitoring Data to Estimate the Number of Alcoholic Drinks Consumed.

    Science.gov (United States)

    Dougherty, Donald M; Hill-Kapturczak, Nathalie; Liang, Yuanyuan; Karns, Tara E; Lake, Sarah L; Cates, Sharon E; Roache, John D

    2015-09-01

    Transdermal alcohol monitoring is used extensively in forensic settings to identify whether individuals have violated court-ordered mandates to abstain from drinking. Despite widespread use in that setting, comparatively few studies have explored the clinical utility of transdermal alcohol monitoring. Furthermore, of the few studies conducted, most have relied on the forensically established conservative criteria to identify whether or not a drinking episode has occurred. Here, we explore how transdermal alcohol monitoring data can be used to estimate more clinically meaningful parameters relevant to clinical treatment programs. We developed a procedure to use transdermal data to objectively estimate the number of standardized drinks an individual has consumed. Participants included 46 men and women who consumed 1 to 5 beers within 2 hours in the laboratory on separate days while wearing devices to monitor transdermal alcohol concentrations (TAC). A mathematical model was derived to estimate the number of standardized alcohol drinks consumed, which included a number of variables (time-to-peak TAC, area under the TAC curve, and sex). The model was then validated by applying it to data from a separate study. Our results indicate that transdermal alcohol devices can be used to estimate the number of standard drinks consumed. Objective methods characterizing both the level of intoxication achieved and the number of drinks consumed, such as transdermal alcohol monitoring, could be useful in both research and treatment settings.

  2. Newspapers and Newspaper Ink Contain Agonists for the Ah Receptor

    Science.gov (United States)

    Bohonowych, Jessica E. S.; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T.; Denison, Michael S.

    2010-01-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [3H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed. PMID:18203687

  3. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond.

    Science.gov (United States)

    Xia, Yang; Kellems, Rodney E

    2013-06-21

    Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT₁) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT₁ agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT₁ agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT₁ agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT₁ agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT₁. These

  4. Regulation of p53 stability and apoptosis by a ROR agonist.

    Directory of Open Access Journals (Sweden)

    Yongjun Wang

    Full Text Available Activation of p53 function leading to cell-cycle arrest and/or apoptosis is a promising strategy for development of anti-cancer therapeutic agents. Here, we describe a novel mechanism for stabilization of p53 protein expression via activation of the orphan nuclear receptor, RORα. We demonstrate that treatment of cancer cells with a newly described synthetic ROR agonist, SR1078, leads to p53 stabilization and induction of apoptosis. These data suggest that synthetic ROR agonists may hold utility in the treatment of cancer.

  5. Sexual Preferences in Nutrient Utilization Regulate Oxygen Consumption and Reactive Oxygen Species Generation in Schistosoma mansoni: Potential Implications for Parasite Redox Biology.

    Science.gov (United States)

    Oliveira, Matheus P; Correa Soares, Juliana B R; Oliveira, Marcus F

    2016-01-01

    Schistosoma mansoni, one of the causative agents of human schistosomiasis, has a unique antioxidant network that is key to parasite survival and a valuable chemotherapeutic target. The ability to detoxify and tolerate reactive oxygen species increases along S. mansoni development in the vertebrate host, suggesting that adult parasites are more exposed to redox challenges than young stages. Indeed, adult parasites are exposed to multiple redox insults generated from blood digestion, activated immune cells, and, potentially, from their own parasitic aerobic metabolism. However, it remains unknown how reactive oxygen species are produced by S. mansoni metabolism, as well as their biological effects on adult worms. Here, we assessed the contribution of nutrients and parasite gender to oxygen utilization pathways, and reactive oxygen species generation in whole unpaired adult S. mansoni worms. We also determined the susceptibilities of both parasite sexes to a pro-oxidant challenge. We observed that glutamine and serum importantly contribute to both respiratory and non-respiratory oxygen utilization in adult worms, but with different proportions among parasite sexes. Analyses of oxygen utilization pathways revealed that respiratory rates were high in male worms, which contrast with high non-respiratory rates in females, regardless nutritional sources. Interestingly, mitochondrial complex I-III activity was higher than complex IV specifically in females. We also observed sexual preferences in substrate utilization to sustain hydrogen peroxide production towards glucose in females, and glutamine in male worms. Despite strikingly high oxidant levels and hydrogen peroxide production rates, female worms were more resistant to a pro-oxidant challenge than male parasites. The data presented here indicate that sexual preferences in nutrient metabolism in adult S. mansoni worms regulate oxygen utilization and reactive oxygen species production, which may differently contribute

  6. Theoretical potential for low energy consumption phase change memory utilizing electrostatically-induced structural phase transitions in 2D materials

    Science.gov (United States)

    Rehn, Daniel A.; Li, Yao; Pop, Eric; Reed, Evan J.

    2018-01-01

    Structural phase-change materials are of great importance for applications in information storage devices. Thermally driven structural phase transitions are employed in phase-change memory to achieve lower programming voltages and potentially lower energy consumption than mainstream nonvolatile memory technologies. However, the waste heat generated by such thermal mechanisms is often not optimized, and could present a limiting factor to widespread use. The potential for electrostatically driven structural phase transitions has recently been predicted and subsequently reported in some two-dimensional materials, providing an athermal mechanism to dynamically control properties of these materials in a nonvolatile fashion while achieving potentially lower energy consumption. In this work, we employ DFT-based calculations to make theoretical comparisons of the energy required to drive electrostatically-induced and thermally-induced phase transitions. Determining theoretical limits in monolayer MoTe2 and thin films of Ge2Sb2Te5, we find that the energy consumption per unit volume of the electrostatically driven phase transition in monolayer MoTe2 at room temperature is 9% of the adiabatic lower limit of the thermally driven phase transition in Ge2Sb2Te5. Furthermore, experimentally reported phase change energy consumption of Ge2Sb2Te5 is 100-10,000 times larger than the adiabatic lower limit due to waste heat flow out of the material, leaving the possibility for energy consumption in monolayer MoTe2-based devices to be orders of magnitude smaller than Ge2Sb2Te5-based devices.

  7. Tamarind (Tamarindus indica linn.) and Sweet Sorghum (Sorghum bicolor L.Moench): their Potential Utilization in Phytotherapy

    OpenAIRE

    Regina D Loria; Norman G. De Jesus; Filomena K. Reyes; Honorio M. Soriano Jr

    2015-01-01

    The use of botanical extracts and essential oil in skin care has been increasing due to greater demand on the part of consumers to use natural ingredients. Tamarind and Sweet Sorghum really have   big potentials  for reaching the public and showcasing its benefits , thus this study could encourage growers to raise more Tamarind and Sweet Sorghum in their areas not only as  food but as a raw material in the production of natural products which are for health and wellness. Both Tamarind and Swe...

  8. Camel Milk: Potential Utility as an Adjunctive Therapy to Peg-IFN/RBV in HCV-4 Infected Patients in Egypt.

    Science.gov (United States)

    Mohamed, Walid A; Schaalan, Mona F; El-Abhar, Hanan S

    2015-01-01

    The present prospective study aims to investigate the potential therapeutic effect and the underlying mechanisms of drinking camel milk for 60 days as an adjunctive therapy to the standard treatment PEG/RBV. Twenty-five hepatitis C virus (HCV)-infected Egyptian patients, with mild to moderate parenchymal affection to mild cirrhosis were enrolled in this study after proper history taking and clinical examination. Their biomarkers were evaluated before and after the addition of camel milk. The improving effect of camel milk was reflected on the marked inhibition of the serum levels of the proinflammatory markers, viz., tumor necrosis factor-α, monocyte chemotactic protein-1, hyaluronic acid, and TGF-β1, besides PCR, AST, ALT, GGT, bilirubin, prothrombin time, INR, and alpha-fetoprotein. In addition, camel milk elevated significantly (P camel milk on multiple parameters of inflammatory mediators, immunomodulators, antiapoptosis, and antioxidants, giving insight into the potential therapeutic benefit underlying the anti-HCV actions of camel milk. The limitations of the current study include the small sample size recruited and the failure to test it on cohorts with severe stages of hepatitis; like Child-Pugh stage C, and hepatocellular carcinoma.

  9. Pediatric Predispositional Genetic Risk Communication: Potential Utility for Prevention and Control of Melanoma Risk as an Exemplar.

    Science.gov (United States)

    Wu, Yelena P; Mays, Darren; Kohlmann, Wendy; Tercyak, Kenneth P

    2017-10-01

    Predispositional genetic testing among minor children is intensely debated due to the potential benefits and harms of providing this type of genetic information to children and their families. Existing guidelines on pediatric genetic testing state that predispositional testing could be appropriate for minors if preventive services exist that mitigate children's risk for or severity of the health condition in question. We use the example of hereditary melanoma to illustrate the rationale for and potential application of genetic risk communication for an adult-onset cancer to a pediatric population where childhood behaviors may reduce risk of disease later in life. We draw from the adult melanoma genetic risk communication and pediatric health behavior change literatures to suggest ways in which genetic test reporting and complementary education could be delivered to children who carry a hereditary risk for melanoma and their families in order to foster children's engagement in melanoma preventive behaviors. Genetic discoveries will continue to yield new opportunities to provide predispositional genetic risk information to unaffected individuals, including children, and could be delivered within programs that provide personalized and translational approaches to cancer prevention.

  10. Using program impact pathways to understand and improve program delivery, utilization, and potential for impact of Helen Keller International's homestead food production program in Cambodia.

    Science.gov (United States)

    Olney, Deanna K; Vicheka, Sao; Kro, Meng; Chakriya, Chhom; Kroeun, Hou; Hoing, Ly Sok; Talukder, Aminzzaman; Quinn, Victoria; Iannotti, Lora; Becker, Elisabeth; Roopnaraine, Terry

    2013-06-01

    Evidence of the impact of homestead food production programs on nutrition outcomes such as anemia and growth is scant. In the absence of information on program impact pathways, it is difficult to understand why these programs, which have been successful in increasing intake of micronutrient-rich foods, have had such limited documented impact on nutrition outcomes. To conduct a process evaluation of Helen Keller International's (HKI's) homestead food production program in Cambodia to assess whether the program was operating as planned (in terms of design, delivery, and utilization) and to identify ways in which the program might need to be strengthened in order to increase its potential for impact. A program theory framework, which laid out the primary components along the hypothesized program impact pathways, was developed in collaboration with HKI and used to design the research. Semistructured interviews and focus group discussions with program beneficiaries (n = 36 and 12, respectively), nonbeneficiaries (n = 12), and program implementers (n = 17 and 2, respectively) and observations of key program delivery points, including health and nutrition training sessions (n = 6), village model farms (n = 6), and household gardens of beneficiaries (n = 36) and nonbeneficiaries (n = 12), were conducted to assess the delivery and utilization of the primary program components along the impact pathways. The majority of program components were being delivered and utilized as planned. However, challenges with some of the key components posited to improve outcomes such as anemia and growth were noted. Among these were a gap in the expected pathway from poultry production to increased intake of eggs and poultry meat, and some weaknesses in the delivery of the health and nutrition training sessions and related improvements in knowledge among the village health volunteers and beneficiaries. Although the program has been successful in delivering the majority of the program

  11. Melatonin Receptor Agonists as the “Perioceutics” Agents for Periodontal Disease through Modulation of Porphyromonas gingivalis Virulence and Inflammatory Response

    Science.gov (United States)

    Zhu, Cai-Lian; He, Zhi-Yan; Liang, Jing-Ping; Song, Zhong-Chen

    2016-01-01

    Aim “Perioceutics” including antimicrobial therapy and host modulatory therapy has emerged as a vital adjunctive treatment of periodontal disease. Melatonin level was significantly reduced in patients with periodontal diseases suggesting melatonin could be applied as a potential “perioceutics” treatment of periodontal diseases. This study aims to investigate the effects of melatonin receptor agonists (melatonin and ramelteon) on Porphyromonas gingivalis virulence and Porphyromonas gingivalis-derived lipopolysaccharide (Pg-LPS)-induced inflammation. Methods Effects of melatonin receptor agonists on Porphyromonas gingivalis planktonic cultures were determined by microplate dilution assays. Formation, reduction, and viability of Porphyromonas gingivalis biofilms were detected by crystal violet staining and MTT assays, respectively. Meanwhile, biofilms formation was also observed by confocal laser scanning microscopy (CLSM). The effects on gingipains and hemolytic activities of Porphyromonas gingivalis were evaluated using chromogenic peptides and sheep erythrocytes. The mRNA expression of virulence and iron/heme utilization was assessed using RT-PCR. In addition, cell viability of melatonin receptor agonists on human gingival fibroblasts (HGFs) was evaluated by MTT assays. After pretreatment of melatonin receptor agonists, HGFs were stimulated with Pg-LPS and then release of cytokines (IL-6 and lL-8) was measured by enzyme-linked immunosorbent assay (ELISA). Results Melatonin and ramelteon did exhibit antimicrobial effects against planktonic culture. Importantly, they inhibited biofilm formation, reduced the established biofilms, and decreased biofilm viability of Porphyromonas gingivalis. Furthermore, they at sub-minimum inhibitory concentration (sub-MIC) concentrations markedly inhibited the proteinase activities of gingipains and hemolysis in a dose-dependent manner. They at sub-MIC concentrations significantly inhibited the mRNA expression of virulence

  12. Toxicological Evaluation of a Potential Immunosensitizer for Use as a Mucosal Adjuvant—Bacillus thuringiensis Cry1Ac Spore-Crystals: A Possible Inverse Agonist that Deserves Further Investigation

    Directory of Open Access Journals (Sweden)

    Bélin Poletto Mezzomo

    2015-12-01

    Full Text Available In addition to their applicability as biopesticides, Bacillus thuringiensis (Bt Cry1Ac spore-crystals are being researched in the immunology field for their potential as adjuvants in mucosal and parenteral immunizations. We aimed to investigate the hematotoxicity and genotoxicity of Bt spore-crystals genetically modified to express Cry1Ac individually, administered orally (p.o. or with a single intraperitoneal (i.p. injection 24 h before euthanasia, to simulate the routes of mucosal and parenteral immunizations in Swiss mice. Blood samples were used to perform hemogram, and bone marrow was used for the micronucleus test. Cry1Ac presented cytotoxic effects on erythroid lineage in both routes, being more severe in the i.p. route, which also showed genotoxic effects. The greater severity noted in this route, mainly at 6.75 mg/kg, as well as the intermediate effects at 13.5 mg/kg, and the very low hematotoxicity at 27 mg/kg, suggested a possible inverse agonism. The higher immunogenicity for the p.o. route, particularly at 27 mg/kg, suggested that at this dose, Cry 1Ac could potentially be used as a mucosal adjuvant (but not in parenteral immunizations, due to the genotoxic effects observed. This potential should be investigated further, including making an evaluation of the proposed inverse agonism and carrying out cytokine profiling.

  13. OX40 agonists and combination immunotherapy: putting the pedal to the metal

    Directory of Open Access Journals (Sweden)

    Stefanie N Linch

    2015-02-01

    Full Text Available Recent studies have highlighted the therapeutic efficacy of immunotherapy, a class of cancer treatments that utilize the patient’s own immune system to destroy cancerous cells. Within a tumor the presence of a family of negative regulatory molecules, collectively known as checkpoint inhibitors, can inhibit T cell function to suppress anti-tumor immunity. Checkpoint inhibitors, such as CTLA-4 and PD-1, attenuate T cell proliferation and cytokine production. Targeted blockade of CTLA-4 or PD-1 with antagonist monoclonal antibodies (mAb releases the brakes on T cells to boost anti-tumor immunity. Generating optimal killer CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including OX40 (CD134 and 4-1BB (CD137. OX40 is of particular interest as treatment with an activating (agonist anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors. When used as single agents, these drugs can induce potent clinical and immunologic responses in patients with metastatic disease. However, each of these agents only benefits a subset of patients, highlighting the critical need for more effective combinatorial therapeutic strategies. In this review, we will discuss our current understanding of the cellular and molecular mechanisms by which OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies.

  14. Spectral Doppler Waveforms for Diagnosis of Appendicitis: Potential Utility of Point Peak Systolic Velocity and Resistive Index Values.

    Science.gov (United States)

    Shin, Lewis K; Jeffrey, R Brooke; Berry, Gerald J; Olcott, Eric W

    2017-12-01

    Purpose To test the hypothesis that appendiceal spectral Doppler waveforms can distinguish patients with and patients without appendicitis. Materials and Methods In this retrospective study, Doppler waveforms were obtained from intramural appendiceal arteries identified with color Doppler imaging in 60% (93 of 155) of consecutive patients whose appendices were visualized at graded compression ultrasonography (US) performed for suspected appendicitis (53 male and 40 female; age, 1-56 years; mean, 14.5 years) over the 5-month period from November 2015 through March 2016. Point, non-angle-corrected peak systolic velocity (PSV) and resistive index (RI) values were compared between patients with and patients without appendicitis by utilizing histopathologically proven appendicitis and 6-week clinical follow-up as diagnostic reference standards. Data were assessed by using the Student t test, exact binomial distribution, two-sample test of proportions, and receiver operating characteristic analysis. Results Among the 93 patients, 36 (38.7%) had proven appendicitis (mean PSV, 19.7 cm/sec; mean RI, 0.69) and 57 patients (61.2%) did not (mean PSV, 7.1 cm/sec, P appendicitis was 0.97 (95% confidence interval [CI]: 0.95, 1.00) for PSV and 0.86 (95% CI: 0.78, 0.95; P = .011) for RI. Chosen discriminatory criteria of PSV greater than 10 cm/sec and RI greater than 0.65 yielded specificity for appendicitis of 94.7% and 96.5% with sensitivity of 88.9% and 63.9% (P = .013) and negative predictive value of 93.1% and 80.9% (P = .045), respectively. Original clinical graded compression US interpretations based on established US findings demonstrated specificity of 96.2% and sensitivity of 100.0%. Considering the subset of 20 patients whose maximum outer diameter measured 6-8 mm, the discriminatory criteria of PSV greater than 10 cm/sec and RI greater than 0.65 yielded specificity for appendicitis of 88.9% each, with sensitivity of 100.0% and 63.6% and negative predictive value of 100

  15. Protective effects of the angiotensin II ATreceptor agonist compound 21 in ischemic stroke

    DEFF Research Database (Denmark)

    Bennion, Douglas M; Jones, Chad H; Dang, Alex N

    2018-01-01

    ) and systemic administration, are unsuitable for translation into humans; in the latter case because AT2receptor agonists are blood-brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver......-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT2receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective...... in certain human central nervous system diseases, the N2B application of AT2receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients....

  16. A Novel Glucagon-like Peptide-1 (GLP-1)/Glucagon Hybrid Peptide with Triple-acting Agonist Activity at Glucose-dependent Insulinotropic Polypeptide, GLP-1, and Glucagon Receptors and Therapeutic Potential in High Fat-fed Mice*

    Science.gov (United States)

    Gault, Victor A.; Bhat, Vikas K.; Irwin, Nigel; Flatt, Peter R.

    2013-01-01

    Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion, and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [dA2]GLP-1/GcG, stimulated cAMP production in GIP, GLP-1, and glucagon receptor-transfected cells. Acute administration of [dA2]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [dA2]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high fat-fed mice. Twice daily administration of [dA2]GLP-1/GcG for 21 days decreased body weight and nonfasting plasma glucose and increased circulating plasma insulin concentrations in high fat-fed mice. Furthermore, [dA2]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [dA2]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knock-out mice confirmed the biological action of [dA2]GLP-1/GcG via multiple targets including GIP, GLP-1, and glucagon receptors. The data suggest significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity and diabetes. PMID:24165127

  17. A novel glucagon-like peptide-1 (GLP-1)/glucagon hybrid peptide with triple-acting agonist activity at glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors and therapeutic potential in high fat-fed mice.

    Science.gov (United States)

    Gault, Victor A; Bhat, Vikas K; Irwin, Nigel; Flatt, Peter R

    2013-12-06

    Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion, and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [dA(2)]GLP-1/GcG, stimulated cAMP production in GIP, GLP-1, and glucagon receptor-transfected cells. Acute administration of [dA(2)]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [dA(2)]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high fat-fed mice. Twice daily administration of [dA(2)]GLP-1/GcG for 21 days decreased body weight and nonfasting plasma glucose and increased circulating plasma insulin concentrations in high fat-fed mice. Furthermore, [dA(2)]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [dA(2)]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knock-out mice confirmed the biological action of [dA(2)]GLP-1/GcG via multiple targets including GIP, GLP-1, and glucagon receptors. The data suggest significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity and diabetes.

  18. Environmental and technical assessments of the potential utilization of sewage sludge ashes (SSAs) as secondary raw materials in construction.

    Science.gov (United States)

    Chen, Maozhe; Blanc, Denise; Gautier, Mathieu; Mehu, Jacques; Gourdon, Rémy

    2013-05-01

    Ashes produced by thermal treatments of sewage sludge exhibit common properties with cement. For example, major elements present in SSA are the same of major elements of cement. Hydraulic properties of SSA are quite the same of cement ones. They may therefore be used to substitute part of cement in concrete or other cementitious materials, provided that technical prescriptions are satisfied and that environmental risks are not significantly increased. The objective of the present study was to determine the appropriate substitution ratios to satisfy both technical and environmental criteria. In a first step, the elemental composition and particle size distribution of the ashes were measured. Then the ashes were used along with Portland cement and sand at different ratios of substitution to produce mortar and concrete which were cured for up to 90 days into parallelepipedic or cylindrical monoliths. The mechanical properties of the monoliths were measured using standard procedures for flexural and compressive strengths, and compared to blanks containing no ashes. The environmental criteria were assessed using leaching tests conducted according to standard protocols both on the ashes and the monoliths, and compared to the blanks. Results showed that the characteristics of the ashes ranged between those of cement and sand because of their larger particle size and higher content in SiO2 as compared to cement. The monoliths made with the highest substitution ratios exhibited a significant decrease in flexural and compressive strengths. However, when the ashes were used in partial substitution of cement at appropriate ratios, the concrete monoliths exhibited similar compressive strengths as the blank samples. The most appropriate ratios were found to be 10% substitution of cement and 2% substitution of sand. The leaching tests conducted on the ashes in their powdery form revealed that amongst the potential contaminants analyzed only Mo and Se were leached at

  19. Co-combustion of bituminous coal and biomass fuel blends: Thermochemical characterization, potential utilization and environmental advantage.

    Science.gov (United States)

    Zhou, Chuncai; Liu, Guijian; Wang, Xudong; Qi, Cuicui

    2016-10-01

    The thermochemical characteristics and gaseous trace pollutant behaviors during co-combustion medium-to-low ash bituminous coal with typical biomass residues (corn stalk and sawdust) were investigated. Lowering of ignition index, burnout temperature and activation energy in the major combustion stage are observed in the coal/biomass blends. The blending proportion of 20% and 30% are regarded as the optimum blends for corn stalk and sawdust, respectively, in according the limitations of heating value, activation energy, flame stability and base/acid ratio. The reductions of gaseous As, Cd, Cu, Pb, Zn and polycyclic aromatic hydrocarbon (PAHs) were 4.5%, 7.8%, 6.3%, 9.8%, 9.4% and 17.4%, respectively, when co-combustion coal with 20% corn stalk. The elevated capture of trace elements were found in coal/corn stalk blend, while the coal/sawdust blend has the better PAHs control potential. The reduction mechanisms of gaseous trace pollutants were attributed to the fuel property, ash composition and relative residence time during combustion. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels

    2015-01-01

    to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...... antagonists and describes the development of potent antagonists from partial agonists originally derived from the potent GABAAR agonist muscimol. In this process, several heterocyclic aromatic systems have been used in combination with structural models in order to map the orthosteric binding site...... and to reveal structural details to be used for obtaining potency and subtype selectivity. The challenges connected to functional characterization of orthosteric GABAAR partial agonists and antagonists, especially with regard to GABAAR stoichiometry and alternative binding sites are discussed. GABAAR...

  1. Concrete-polymer composite materials and their potential for construction, urban waste utilization, and nuclear waste storage

    International Nuclear Information System (INIS)

    Fowler, E.E.; Steinberg, Meyer.

    1974-01-01

    A wide range of concrete-polymer composites have been investigated by Brookhaven National Laboratory. Polymer impregnated concrete (PIC) is basically formed by drying cured conventional concrete, displacing the air from open cell void volume, diffusing low viscosity monomer (less than 10 cps) through the open cell structure, saturating the concrete with the monomer and in-situ polymerizing the monomer to polymer by most convenient means. Mainly free-radical vinyl type monomers are used. For increased thermal stability, crosslinking agents and thermosetting monomers such as styrene-trimethylol propane trimethacrylate (TMPTMA) and polyester-styrene are used. Much informations on the formation, structural properties and durability of PIC have been accumulated over past five years. U.S. Patent 3,567,496 has been issued on the production of PIC. Compressive strength can be increased from 352 kg/cm 2 of conventional concrete to 1,410 kg/cm 2 . Water absorption is reduced by 99% and the freeze-thaw resistance is remarkably improved. With high silica cement, strong basaltic aggregate, and high temperature steam curing, strength increase from 845 to over 2,630 kg/cm 2 can be obtained. A maximum of 238 kg/cm 2 tensile strength has been obtained with the steam-cured concrete. In the steam- cured concrete, polymer loading roughly around 8% by weight is obtained. Aggregates can include the urban solid waste discarded by man. Sewage and solid waste refuse-polymer concrete has been produced by using garbage as aggregate and sewage as the hydrating media for cement. The potentially important application of hydrauric cement concrete, in combination with the polymers in PIC and PC, is the storage of long-living radioactive wastes from nuclear industry. (Iwakiri, K.)

  2. Evaluation of the Green Microalga Monoraphidium sp. Dek19 Growth Utilizing Ethanol Plant Side Streams and Potential for Biofuel Production

    Science.gov (United States)

    Colson, David Michael

    This research was conducted to evaluate the potential for growth of Monoraphidium sp. Dek19 using side streams from an ethanol plant for culture medium. Additionally, the potential of using enzymes to break down the cell wall material to release fermentable sugars and oil was examined. The ethanol streams selected were methanator influent, methanator effluent, and thin stillage. This species of microalgae has been previously studied and found to have the ability to grow in and remediate the effluent water from the DeKalb Sanitary District (DSD). The Monoraphidium sp. Dek19 was grown in various concentrations of the ethanol plant side streams concurrently with algae cultures grown in the DSD effluent. The algae cultures were grown in 250ml flasks to determine the optimal concentrations of the ethanol streams. The concentrations with the growth rate and cell counts closest to or higher than the DSD effluents were selected for further examination. These concentrations were repeated to evaluate the most optimal growth conditions using the ethanol streams in comparison to the DSD effluent grown algae. The selected growth condition for the ethanol streams was determined to be using the methanator effluent as the base water component with the thin stillage added to a 2% concentration. The 2% concentration showed an average increase in cell count to be 8.49% higher than the control cell count. The methanator influent was discarded as a base water component, as the growth of the algae was 40.18% less than that of the control. Other concentrations considered resulted in a decrease in cell. count ranging from 9.20-48.97%. The three closest growth results of the concentration of thin stillage and methanator effluent (1%, 2%, and 4%) were scaled up to 2L flasks to confirm the results on a larger scale. The results showed a greater reduction in the cell count of the 1% and 4% concentrations, 23.52% and 16.31% reduction in cell count respectively. The 2% concentration showed a

  3. Workshop on the role of enhancement of utilization of primary and secondary hydro potential in the context of environmental protection. Part I

    International Nuclear Information System (INIS)

    1997-01-01

    The publication has been set up as proceedings of the workshop on the role of enhancement of utilization of primary and secondary hydro potential in the context of environmental protection. The proceedings consist of the following chapters: (1) BOT schemes as financial model of hydro power projects; (2) Application of pumped storage plants in the control of the Slovak power system and the possibility of pumped storage plant Ipel exploitation towards the year 2010; (3) Use of hydro energetic potential of streams from the aspects of nature conservation on the example of north Slovakia; (4) Ecological aspects of the hydro power industry and possible means to improve ecological conditions of water reservoirs; (5) Preparation and realization of HPP Zilina; (6) Freudenau HPP. ecological measures and groundwater management; (7) Present state of hydro power development in Austria

  4. Exploring the Potential Competitiveness of Utility-Scale Photovoltaics plus Batteries with Concentrating Solar Power, 2015–2030

    Energy Technology Data Exchange (ETDEWEB)

    Feldman, David [National Renewable Energy Lab. (NREL), Golden, CO (United States); Margolis, Robert [National Renewable Energy Lab. (NREL), Golden, CO (United States); Denholm, Paul [National Renewable Energy Lab. (NREL), Golden, CO (United States); Stekli, Joseph [Dept. of Energy (DOE), Washington DC (United States). Office of Solar Energy Technologies Program

    2016-08-01

    ancillary services and the ability to store off-peak grid energy. Alternatively, direct thermal energy storage allows a greater capture of solar energy, reducing the potential for curtailments in very high solar scenarios. So while this analysis evaluates a key performance metric (cost per unit of generation) under a range of cost projections, additional analysis of the value per unit of generation will be needed to comprehensively assess the relative competitiveness of solar energy systems deployed with energy storage.

  5. Cold suppresses agonist-induced activation of TRPV1.

    Science.gov (United States)

    Chung, M-K; Wang, S

    2011-09-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

  6. GLP-1 Receptor Agonists: Nonglycemic Clinical Effects in Weight Loss and Beyond

    Science.gov (United States)

    Ryan, Donna; Acosta, Andres

    2015-01-01

    Obective Glucagon-like peptide-1 (GLP-1) receptor agonists are indicated for treatment of type 2 diabetes since they mimic the actions of native GLP-1 on pancreatic islet cells, stimulating insulin release, while inhibiting glucagon release, in a glucose-dependent manner. The observation of weight loss has led to exploration of their potential as antiobesity agents, with liraglutide 3.0 mg day−1 approved for weight management in the US on December 23, 2014, and in the EU on March 23, 2015. This review examines the potential nonglycemic effects of GLP-1 receptor agonists. Methods A literature search was conducted to identify preclinical and clinical evidence on nonglycemic effects of GLP-1 receptor agonists. Results GLP-1 receptors are distributed widely in a number of tissues in humans, and their effects are not limited to the well-recognized effects on glycemia. Nonglycemic effects include weight loss, which is perhaps the most widely recognized nonglycemic effect. In addition, effects on the cardiovascular, neurologic, and renal systems and on taste perception may occur independently of weight loss. Conclusions GLP-1 receptor agonists may provide other nonglycemic clinical effects besides weight loss. Understanding these effects is important for prescribers in using GLP-1 receptor agonists for diabetic patients, but also if approved for chronic weight management. PMID:25959380

  7. FXR agonist activity of conformationally constrained analogs of GW 4064

    Energy Technology Data Exchange (ETDEWEB)

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)

    2010-09-27

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  8. Detecting associations between behavioral addictions and dopamine agonists in the Food & Drug Administration's Adverse Event database.

    Science.gov (United States)

    Gendreau, Katherine E; Potenza, Marc N

    2014-03-01

    Studies have reported higher prevalences of four behavioral addictions (binge eating, compulsive shopping, hypersexuality, and pathological gambling) in dopamine agonist-treated Parkinson's disease relative to non-dopamine agonist-treated Parkinson's. However, recent case-control and epidemiological studies suggest that prevalences of behavioral addictions in dopamine agonist-treated Parkinson's may be similar to background population rates. This study tests that hypothesis by examining the FDA Adverse Event Reporting System (FAERS) for evidence of these associations, taking into account the potential impact of publicity on reporting rates. FAERS reports in 2004 (pre-publicity for all but pathological gambling) and 2007 (post-publicity for all four behaviors) were analyzed. A threshold consisting of ≥3 cases, proportional reporting ratio ≥2, and χ (2) with Yates' correction ≥4 was used to detect signals (drug-associated adverse reactions) involving any of five dopamine agonists and any of four behavioral addictions. No reports containing compulsive shopping and no signal for binge eating and dopamine agonists were found in either year. A weak signal was found for hypersexuality in 2004, with a stronger signal in 2007. A robust signal was found for pathological gambling in 2004, with a more robust signal in 2007. These results suggest that publicity may increase reporting rates in the FAERS. Findings for binge eating, compulsive shopping, and hypersexuality suggest that prevalences of these behaviors among those treated with dopamine agonists may be similar to background population rates and thus may not reflect an adverse safety signal. Further investigation of the relationship between dopamine agonists and behavioral addictions is warranted.

  9. Effects of potential once-through improvements on the uranium utilization in the closed LWR cycle assuming self generated recycling of uranium and plutonium

    International Nuclear Information System (INIS)

    1979-06-01

    This paper is concerned with potential improvements to the resource utilization of current generation light water reactors operating on a closed U/Pu fuel cycle. Only those modifications to existing systems layout and fuel cycle practise are discussed that have been considered in Working Group 8 A for the once-through cycle. The objective is to give an impression how much the difference in resource utilization between the once-through and the closed U/Pu cycle were changed if both cycles were reoptimized independantly from each other with respect to uranium consumption. No commercial recycling of U/Pu has been taken place to date in 1300 MWe light water reactors. The feasibility of thermal recycling has been demonstrated however on an industrial scale in reactors of the 300 MWe class. (Obrigheim, Gundremmingen). From this experience and from extensive design calculations it has been concluded that for Pu bearing fuel assemblies of 1300 MWe plants it would be favorable to use the same structural layout and similar fuel management procedures as for uranium assemblies. This would result in plant life-time averaged uranium savings on the order of 35 - 40 % relative to the once-through cycle in case of the Self Generated Recycling Mode

  10. A technical analysis for cogeneration systems with potential applications in twelve California industrial plants. [energy saving heat-electricity utility systems

    Science.gov (United States)

    Moretti, V. C.; Davis, H. S.; Slonski, M. L.

    1978-01-01

    In a study sponsored by the State of California Energy Resources Conservation and Development Commission, 12 industrial plants in five utility districts were surveyed to assess the potential applications of the cogeneration of heat and electricity in California industry. Thermodynamic calculations were made for each plant in determining the energy required to meet the existing electrical and steam demands. The present systems were then compared to conceptual cogeneration systems specified for each plant. Overall energy savings were determined for the cogeneration applications. Steam and gas turbine topping cycle systems were considered as well as bottoming cycle systems. Types of industries studied were: pulp and paper, timber, cement, petroleum refining, enhanced oil recovery, foods processing, steel and glass

  11. Sports doping: Emerging designer and therapeutic B2-agonists

    NARCIS (Netherlands)

    Fragkaki, A.G.; Georgakopoulos, C.; Sterk, S.S.; Nielen, M.W.F.

    2013-01-01

    Beta2-adrenergic agonists, or ß2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of ß2-agonists is prohibited in sports by the World Anti-Doping

  12. Early investigational β3 adreno-receptor agonists for the management of the overactive bladder syndrome.

    Science.gov (United States)

    Thiagamoorthy, Ganesh; Giarenis, Ilias; Cardozo, Linda

    2015-01-01

    Antimuscarinic drugs form the mainstay of medical treatment for Overactive bladder Syndrome (OAB). With a proven efficacy but poor tolerability, other treatment modalities have been sought. Recent concerns regarding cumulative anticholinergic load and risk of dementia have provided further impetus to find novel OAB treatments. β3-adrenoceptor (β3-AR) agonists improve OAB symptoms by relaxing bladder tissue. As such, the search is underway to develop β3-AR agonist drugs for the treatment of OAB. The authors discuss studies on the only approved β3-AR agonist, mirabegron, followed by reports on β3-AR agonists in development, namely ritobegron and solabegron. The authors also discuss the early investigations of novel and putative β3-AR agonist drugs which are being assessed for management of OAB, including aryloxypropanolamine, TRK-380, AJ-9677, BRL37344 and CL 316,243. These investigations have also highlighted alternative unexpected modes of β3-AR action. There are a number of β3-ARs in the pipeline but it is uncertain which, if any, will come to market and aid in the management of OAB. A picture of a β3-AR dual action which was unknown previously is emerging. Overall, the authors believe that it is an exciting time for the pharmacological management of OAB with new drugs on the horizon which could potentially improve the patient's quality of life.

  13. At-risk for pathological gambling: imaging neural reward processing under chronic dopamine agonists.

    Science.gov (United States)

    Abler, Birgit; Hahlbrock, Roman; Unrath, Alexander; Grön, Georg; Kassubek, Jan

    2009-09-01

    Treatment with dopamine receptor agonists has been associated with impulse control disorders and pathological gambling (PG) secondary to medication in previously unaffected patients with Parkinson's disease or restless legs syndrome (RLS). In a within-subjects design, we investigated the underlying neurobiology in RLS patients using functional magnetic resonance imaging. We scanned 12 female RLS patients without a history of PG. All patients were scanned twice: once whilst taking their regular medication with low dose dopamine receptor agonists and once after a washout phase interval. They performed an established gambling game task involving expectation and receipt or omission of monetary rewards at different levels of probabilities. Upon expectation of rewards, reliable ventral striatal activation was detected only when patients were on, but not when patients were off medication. Upon receipt or omission of rewards, the observed ventral striatal signal under medication differed markedly from its predicted pattern which by contrast was apparent when patients were off medication. Orbitofrontal activation was not affected by medication. Chronic dopamine receptor agonist medication changed the neural signalling of reward expectation predisposing the dopaminergic reward system to mediate an increased appetitive drive. Even without manifest PG, chronic medication with dopamine receptor agonists led to markedly changed neural processing of negative consequences probably mediating dysfunctional learning of contingencies. Intact orbitofrontal functioning, potentially moderating impulse control, may explain why none of the patients actually developed PG. Our results support the notion of a general medication effect in patients under dopamine receptor agonists in terms of a sensitization towards impulse control disorders.

  14. Receptors and Channels Targeted by Synthetic Cannabinoid Receptor Agonists and Antagonists

    Science.gov (United States)

    Pertwee, R.G.

    2010-01-01

    It is widely accepted that non-endogenous compounds that target CB1 and/or CB2 receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Δ9-tetrahydrocannabinol or nabilone, both CB1/CB2 receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB2-selective agonists, peripherally restricted CB1/CB2 receptor agonists and CB1/CB2 antagonists and inverse agonists as medicines. Already, numerous cannabinoid receptor ligands have been developed and their interactions with CB1 and CB2 receptors well characterized. This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB1, non-CB2 G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner. It begins with a brief description of how each of these ligands interacts with CB1 and/or CB2 receptors. PMID:20166927

  15. Antinociceptive action of NOP and opioid receptor agonists in the mouse orofacial formalin test.

    Science.gov (United States)

    Rizzi, A; Ruzza, C; Bianco, S; Trapella, C; Calo', G

    2017-08-01

    Nociceptin/orphanin FQ (N/OFQ) modulates several biological functions, including pain transmission via selective activation of a specific receptor named NOP. The aim of this study was the investigation of the antinociceptive properties of NOP agonists and their interaction with opioids in the trigeminal territory. The orofacial formalin (OFF) test in mice was used to investigate the antinociceptive potential associated to the activation of NOP and opioid receptors. Mice subjected to OFF test displayed the typical biphasic nociceptive response and sensitivity to opioid and NSAID drugs. Mice knockout for the NOP gene displayed a robust pronociceptive phenotype. The NOP selective agonist Ro 65-6570 (0.1-1mgkg -1 ) and morphine (0.1-10mgkg -1 ) elicited dose dependent antinociceptive effects in the OFF with the alkaloid showing larger effects; the isobologram analysis of their actions demonstrated an additive type of interaction. The mixed NOP/opioid receptor agonist cebranopadol elicited potent (0.01-0.1mgkg -1 ) and robust antinociceptive effects. In the investigated dose range, all drugs did not modify the motor performance of the mice in the rotarod test. Collectively the results of this study demonstrated that selective NOP agonists and particularly mixed NOP/opioid agonists are worthy of development as innovative drugs to treat painful conditions of the trigeminal territory. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Drug-induced Hypothermia by 5HT1A Agonists Provide Neuroprotection in Experimental Stroke

    DEFF Research Database (Denmark)

    Johansen, Flemming Fryd; Hasseldam, Henrik; Nybro Smith, Matthias

    2014-01-01

    BACKGROUND: Drug-induced hypothermia reduces brain damage in animal stroke models and is an undiscovered potential in human stroke treatment. We studied hypothermia induced by the serotonergic agonists S14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7- methoxynaphtyl)]piperazine) and ipsapirone in a rat...

  17. Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91

    Directory of Open Access Journals (Sweden)

    Mette Trauelsen

    2017-12-01

    Conclusions: These novel, synthetic non-metabolite GPR91 agonists will be valuable both as pharmacological tools to delineate the GPR91-mediated functions of succinate and as leads for the development of GPR91-targeted drugs to potentially treat low grade metabolic inflammation and diabetic complications such as retinopathy and nephropathy.

  18. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action

    DEFF Research Database (Denmark)

    Lucas, Guillaume; Rymar, Vladimir V; Du, Jenny

    2007-01-01

    Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain...

  19. Isoprenylated flavonoids from Morus nigra and their PPAR γ agonistic activities.

    Science.gov (United States)

    Xu, Liang-Jin; Yu, Mei-Hua; Huang, Chun-Yue; Niu, Li-Xin; Wang, Yi-Fan; Wu, Chun-Zhen; Yang, Pei-Ming; Hu, Xiao

    2018-02-08

    A novel dihydroflavonol unprecedentedly with a prenyl group at C-2, nigragenon A (1), four new sanggenon-type flavonones, nigragenons B-E (2-5), along with six known isoprenylated flavonoids (6-11) were isolated from the twigs of Morus nigra. Their structures were elucidated through extensive analysis of spectroscopic data. Interestingly, compound 1 was the first reported biogenetic precursor of sanggenon-type flavanones and the biogenetic pathway from 1 to sanggenol F was proposed. The PPAR γ agonistic activity was investigated in HEK293 cells using dual luciferase reporter assay. Compounds 2, 4, 7, and 9 showed obvious agonistic activities on PPAR γ, and compound 2 was a potential PPAR γ partial agonist. Moreover, the preliminary structure-activity relationships for the tested compounds were discussed. Copyright © 2018. Published by Elsevier B.V.

  20. Cyclic AMP agonist inhibition increases at low levels of histamine release from human basophils

    Energy Technology Data Exchange (ETDEWEB)

    Tung, R.S.; Lichtenstein, L.M.

    1981-09-01

    The relationship between the intensity of the signal for antigen-induced immunoglobulin E-mediated histamine release from human basophils and the concentration of agonist needed to inhibit release has been determined. The agonists, prostaglandin E1, dimaprit, fenoterol, isobutylmethylxanthine and dibutyryl cyclic AMP, all act by increasing the cyclic AMP level. Each agonist was 10- to 1000-fold more potent (relative ID50) at low levels of histamine release (5-10% of total histamine) than at high levels (50-80%). Thus, the inhibitory potential of a drug is a function of the concentration of antigen used to initiate the response. Our results are now more in accord with the inhibitory profile of these drugs in human lung tissue. It is suggested that in vivo release is likely to be low and that this is the level at which to evaluate drugs in vitro.

  1. Utility of toluidine blue as a diagnostic adjunct in the detection of potentially malignant disorders of the oral cavity--a clinical and histological assessment.

    Science.gov (United States)

    Awan, Kh; Yang, Yh; Morgan, Pr; Warnakulasuriya, S

    2012-11-01

     The value of chairside adjunctive tests in the detection of oral potentially malignant disorders (OPMDs) remains uncertain.  To determine the effectiveness of toluidine blue in detecting leukoplakia and erythroplakia and its accuracy in identifying cases with oral epithelial dysplasia.  Ninety-two patients attending two oral medicine clinics in London, presenting with white and red patches of the oral mucosa, were investigated by the application of toluidine blue. Eighty-two patients were clinically diagnosed as OPMDs and 10 were frictional keratoses. A surgical biopsy was performed to assess epithelial dysplasia. Of 64 oral leukoplakias, 34 (53.1%) were positive for toluidine blue and among nine erythroplakias seven stained positive. Of 41 oral dysplasia cases, a little more than half of the lesions (n = 23) were stain positive, an estimated sensitivity of 56.1%. TBlue test had a higher sensitivity for detecting higher-grade dysplastic lesions (5/8 moderate dysplasia, sensitivity 62.5%; 5/7 severe dysplasia; sensitivity 71.4%) compared with lower grades of dysplasia, but the differences were not significant (P = 0.60). We report here the utility of TBlue for the detection of oral leukoplakia and erythroplakia. The test has the potential to detect OPMDs and yielded a sensitivity of 56.1% and specificity of 56.9% to detect oral epithelial dysplasia. © 2012 John Wiley & Sons A/S.

  2. ROR inverse agonist suppresses insulitis and prevents hyperglycemia in a mouse model of type 1 diabetes.

    Science.gov (United States)

    Solt, Laura A; Banerjee, Subhashis; Campbell, Sean; Kamenecka, Theodore M; Burris, Thomas P

    2015-03-01

    Hyperglycemia associated with type 1 diabetes is a consequence of immune-mediated destruction of insulin producing pancreatic β-cells. Although it is apparent that both CD8(+) T cells and TH1 cells are key contributors to type 1 diabetes, the function of TH17 cells in disease onset and progression remains unclear. The nuclear receptors retinoic acid receptor-related orphan receptors-α and γt (RORα and RORγt) play critical roles in the development of TH17 cells and ROR-specific synthetic ligands have proven efficacy in several mouse models of autoimmunity. To investigate the roles and therapeutic potential for targeting the RORs in type 1 diabetes, we administered SR1001, a selective RORα/γ inverse agonist, to nonobese diabetic mice. SR1001 significantly reduced diabetes incidence and insulitis in the treated mice. Furthermore, SR1001 reduced proinflammatory cytokine expression, particularly TH17-mediated cytokines, reduced autoantibody production, and increased the frequency of CD4(+)Foxp3(+) T regulatory cells. These data suggest that TH17 cells may have a pathological role in the development of type 1 diabetes, and use of ROR-specific synthetic ligands targeting this cell type may prove utility as a novel treatment for type 1 diabetes.

  3. Subtype selective kainic acid receptor agonists

    DEFF Research Database (Denmark)

    Bunch, Lennart; Krogsgaard-Larsen, Povl

    2009-01-01

    (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (m......GluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists...

  4. Adverse Effects of GLP-1 Receptor Agonists

    OpenAIRE

    Filippatos, Theodosios D.; Panagiotopoulou, Thalia V.; Elisaf, Moses S.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of ...

  5. Toll-Like Receptor 9 Agonists for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Davide Melisi

    2014-08-01

    Full Text Available The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

  6. Toll-Like Receptor 9 Agonists for Cancer Therapy.

    Science.gov (United States)

    Melisi, Davide; Frizziero, Melissa; Tamburrino, Anna; Zanotto, Marco; Carbone, Carmine; Piro, Geny; Tortora, Giampaolo

    2014-08-04

    The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs) have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC) and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs) have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

  7. Cannabidiol, a novel inverse agonist for GPR12.

    Science.gov (United States)

    Brown, Kevin J; Laun, Alyssa S; Song, Zhao-Hui

    2017-11-04

    GPR12 is a constitutively active, G s protein-coupled receptor that currently has no confirmed endogenous ligands. GPR12 may be involved in physiological processes such as maintenance of oocyte meiotic arrest and brain development, as well as pathological conditions such as metastatic cancer. In this study, the potential effects of various classes of cannabinoids on GPR12 were tested using a cAMP accumulation assay. Our data demonstrate that cannabidiol (CBD), a major non-psychoactive phytocannabinoid, acted as an inverse agonist to inhibit cAMP accumulation stimulated by the constitutively active GPR12. Thus, GPR12 is a novel molecular target for CBD. The structure-activity relationship studies of CBD indicate that both the free hydroxyl and the pentyl side chain are crucial for the effects of CBD on GPR12. Furthermore, studies using cholera toxin, which blocks G s protein and pertussis toxin, which blocks G i protein, revealed that G s , but not G i is involved in the inverse agonism of CBD on GPR12. CBD is a promising novel therapeutic agent for cancer, and GPR12 has been shown to alter viscoelasticity of metastatic cancer cells. Since we have demonstrated that CBD is an inverse agonist for GPR12, this provides novel mechanism of action for CBD, and an initial chemical scaffold upon which highly potent and efficacious agents acting on GPR12 may be developed with the ultimate goal of blocking cancer metastasis. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. NKT-cell glycolipid agonist as adjuvant in synthetic vaccine.

    Science.gov (United States)

    Liu, Zheng; Guo, Jun

    2017-11-27

    NKT cells are CD1d-restricted, glycolipid antigen-reactive, immunoregulatory T lymphocytes that can serve as a bridge between the innate and adaptive immunities. NKT cells have a wide range of therapeutic application in autoimmunity, transplant biology, infectious disease, cancer, and vaccinology. Rather than triggering "danger signal" and eliciting an innate immune response, αGalCer-based NKT-cell agonist act via a unique mechanism, recruiting NKT cells which play a T helper-like role even without peptide as Th epitope. Importantly, the non-polymorphism of CD1d render glycolipid a universal helper epitope, offering the potential to simplify the vaccine construct capable of eliciting consistent immune response in different individuals. This review details recent advances in the design of synthetic vaccines using NKT-cell agonist as adjuvant, highlighting the role of organic synthesis and conjugation technique to enhance the immunological actives and to simplify the vaccine constructs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Perceived quality of and access to care among poor urban women in Kenya and their utilization of delivery care: harnessing the potential of private clinics?

    Science.gov (United States)

    Fotso, Jean Christophe; Mukiira, Carol

    2012-09-01

    This paper uses data from a maternal health study carried out in 2006 in two slums of Nairobi, Kenya, to: describe perceptions of access to and quality of care among women living in informal settlements of Nairobi, Kenya; quantify the effects of women's perceived quality of, and access to, care on the utilization of delivery services; and draw policy implications regarding the delivery of maternal health services to the urban poor. Based on the results of the facility survey, all health facilities were classified as 'appropriate' or 'inappropriate'. The research was based on the premise that despite the poor quality of these maternal health facilities, their responsiveness to the socio-cultural and economic sensitivities of women would result in good perceptions and higher utilization by women. Our results show a pattern of women's good perceptions in terms of access to, and quality of, health care provided by the privately owned, sub-standard and often unlicensed clinics and maternity homes located within their communities. In the multivariate model, the association between women's perceptions of access to and quality of care, and delivery at these 'inappropriate' facilities remained strong, graded and in the expected direction. Women from the study area are seldom able to reach not-for-profit private providers of maternal health care services like missionary and non-governmental organization (NGO) clinics and hospitals. Against the backdrop of challenges faced by the public sector in health care provision, we recommend that the government should harness the potential of private clinics operating in urban, resource-deprived settings. First, the government should regulate private health facilities operating in urban slum settlements to ensure that the services they offer meet the acceptable minimum standards of obstetric care. Second, 'good' facilities should be given technical support and supplied with drugs and equipment.

  10. Calculation of 29Si NMR shifts of silicate complexes with carbohydrates, amino acids, and muhicarboxylic acids: potential role in biological silica utilization

    Science.gov (United States)

    Sahai, Nita

    2004-01-01

    The existence of ether or ester-like complexes of silicate with organic compounds has long been debated in the literature on biological utilization of silicon. Comparison of theoretically calculated 29Si NMR chemical shifts for such complexes with experimentally measured values in biological systems could provide a diagnostic tool for identifying which, if any of these molecules exist under physiological conditions. Results are presented here for ab initio molecular orbital calculations of 29Si NMR shifts and formation energies of silicate complexes with polyalcohols, sugar-acids, pyranose sugars, amino acids and multicarboxylic acids. The effects of functional group and molecular structure including ligand size, denticity, ring size, silicon polymerization and coordination number on calculated 29Si shifts were considered. The potential role of such compounds in biological silica utilization pathways is discussed. 29Si NMR shifts and energies were calculated at the HF/6-311+G(2d,p)//HF/6-31G* level. The main result is that only five-membered rings containing penta- and hexa-coordinated Si can explain experimentally observed resonances at ˜ -101 and -141 ppm. Further, the heptet observed in 1H- 29Si coupled spectra can only be explained by structures where Si bonds to oxygens atoms in H-C-O-Si linkages with six symmetrically equivalent H atoms. While compounds containing quadra-coordinated silicon may exist in intracellular silicon storage pools within diatoms, calculated reaction energies suggest that the organism has no thermodynamic advantage in taking up extracellular organ-silicate compounds, instead of silicic acid, from the ambient aqueous environment. Hyper-coordinated complexes are deemed unlikely for transport and storage, though they may exist as transient reactive intermediates or activated complexes during enzymatically- catalyzed silica polymerization, as known previously from sol-gel silica synthesis studies.

  11. Pareto utility

    NARCIS (Netherlands)

    Ikefuji, M.; Laeven, R.J.A.; Magnus, J.R.; Muris, C.H.M.

    2013-01-01

    In searching for an appropriate utility function in the expected utility framework, we formulate four properties that we want the utility function to satisfy. We conduct a search for such a function, and we identify Pareto utility as a function satisfying all four desired properties. Pareto utility

  12. PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

    Directory of Open Access Journals (Sweden)

    Monica Puligheddu

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα, nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p. or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2% for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.. Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key

  13. Utilizing the age-related widening of the gingival crevice as a potential non-invasive vaccination route: Prospects for elderly vaccination.

    Science.gov (United States)

    Cueno, Marni E; Tamura, Muneaki; Seki, Keisuke; Ohya, Manabu; Ochiai, Kuniyasu

    2016-03-01

    Gingival crevice (GC) increases with age allowing periodontopathic bacteria and its products to enter. We hypothesize that by mimicking this event we can utilize the GC as a potential vaccination route. Here, we used 20 wk-old (young) and 77 wk-old (old) Sprague-Dawley rats. Initially, we elucidated the difference between oral-administration and oral-supplementation in both young and old rats and, subsequently, we determined the optimal component concentration for xanthan gel-encapsulation. Next, through molecular docking, we simulated xanthan gel-encapsulation of a representative antigen (for this study we used influenza H5N1 hemagglutinin) in order to verify that target epitopes were not blocked. Lastly, we compared the antibody titer among gingival-vaccinated rats (old and young) and, likewise, we evaluated the antibody titer produced via the gingival route as compared to other vaccination routes (intradermal, oral, sublingual). Rat blood serum was collected for further downstream analyses. Throughout the study, we were able to establish the following conditions: higher target components enter old rats via oral-supplementation; 100 μg mL(-1) is the optimal component concentration for xanthan gel-encapsulation; and xanthan gel-encapsulation leaves antibody epitopes exposed. More importantly, we observed that gingival-vaccinated old rats have higher antibody titer as compared to young rats and, likewise, we found that antibody titer elicited via gingival vaccination is comparable to other mucosal vaccination routes. Thus, we propose that the GC has the potential to serve as a non-invasive vaccination route. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Evaluation of allergenic potential for rice seed protein components utilizing a rice proteome database and an allergen database in combination with IgE-binding of recombinant proteins.

    Science.gov (United States)

    Hirano, Kana; Hino, Shingo; Oshima, Kenzi; Nadano, Daita; Urisu, Atsuo; Takaiwa, Fumio; Matsuda, Tsukasa

    2016-01-01

    Among 131 rice endosperm proteins previously identified by MS-based proteomics, most of the proteins showed low or almost no sequence similarity to known allergens in databases, whereas nine proteins did it significantly. The sequence of two proteins showed high overall identity with Hsp70-like hazel tree pollen allergen (Cor a 10) and barley α-amylase (Hor v 16), respectively, whereas the others showed low identity (28-58%) with lemon germin-like protein (Cit l 1), corn zein (Zea m 50 K), wheat chitinase-like xylanase inhibitor (Tri a XI), and kinase-like pollen allergen of Russian thistle (Sal k 1). Immuno-dot blot analysis showed that recombinant proteins for these rice seed homologs were positive in the IgE-binding, but not necessarily similarity dependent, from some allergic patients. These results suggest that utilization of proteome and sequence databases in combination with IgE-binding analysis was effective to screen and evaluate allergenic potential of rice seed protein components.

  15. Disqualified qualifiers: evaluating the utility of the revised DSM-5 definition of potentially traumatic events among area youth following the Boston marathon bombing.

    Science.gov (United States)

    Chou, Tommy; Carpenter, Aubrey L; Kerns, Caroline E; Elkins, R Meredith; Green, Jennifer Greif; Comer, Jonathan S

    2017-04-01

    The DSM-5 includes a revised definition of the experiences that qualify as potentially traumatic events. This revised definition now offers a clearer and more exclusive definition of what qualifies as a traumatic exposure, but little is known about the revision's applicability to youth populations. The present study evaluated the predictive utility of the revised DSM definitional boundaries of traumatic exposure in a sample of youth exposed to the 2013 Boston Marathon bombing and related events METHODS: Caregivers (N = 460) completed surveys 2 to 6 months postbombing about youth experiences during the events and youth posttraumatic stress (PTS) symptoms RESULTS: Experiencing DSM-5 qualifying traumatic events (DSM-5 QTEs) significantly predicted child PTS symptoms (PTSS), whereas DSM-5 nonqualifying stressful experiences (DSM-5 non-QSEs) did not after accounting for DSM-5 QTEs. Importantly, child age moderated the relationship between DSM-5 QTEs and PTSS such that children 7 and older who experienced DSM-5 QTEs showed greater postbombing PTSS, whereas there was no such relationship in children ages 6 and below CONCLUSIONS: Data largely support the revised posttraumatic stress disorder (PTSD) definition of QTEs in older youth, and also highlight the need for further refinement of the QTE definition for children ages 6 and below. © 2016 Wiley Periodicals, Inc.

  16. Biliary anatomy in potential right hepatic lobe living donor liver transplantation (LDLT): The utility of CT cholangiography in the setting of inconclusive MRCP

    International Nuclear Information System (INIS)

    McSweeney, Sean E.; Kim, Tae Kyoung; Jang, Hyun-Jung; Khalili, Korosh

    2012-01-01

    Objective: To determine the utility of CT cholangiography (CT-Ch) in preoperative evaluation of the biliary anatomy of living-donor liver transplantation (LDLT) donors when magnetic resonance cholangiopancreatography (MRCP) is inconclusive. Materials and methods: Over a 2-year period, 22 potential living liver donors underwent contrast-enhanced CT-Ch for preoperative evaluating biliary anatomy due to inconclusive results on MRCP and subsequently donated their right hepatic lobe. Nineteen of them underwent intraoperative cholangiography and were included in this study. Two radiologists retrospectively reviewed both MRCP and CT-Ch with 1-month interval and documented the types of bile duct branching patterns and visualization score of intrahepatic bile ducts (4-point scale). Results: There were no complications associated with CT-Ch examinations. CT-Ch was concordant with the reference standard in 18/19 (95%) including 7/8 typical branching type and 11/11 anomalous branching types. MRCP was concordant with the reference standard in 14/19 (74%) including 4/8 typical branching types and 10/11 anomalous branching types. The discordant case by CT-Ch was the identification of a tiny accessory right intrahepatic duct joining the common bile duct which was not visualized on intraoperative cholangiography. CT-Ch showed higher visualization score (mean, 3.9) than MRCP (mean, 2.6) (P < .001). Conclusion: CT-Ch can be effectively used for the depiction of the branching pattern of the bile duct at the hepatic hilum when MRCP is inconclusive.

  17. Epidemiology of animal bites and other potential rabies exposures and anti-rabies vaccine utilization in a rural area in Southern Ethiopia

    Directory of Open Access Journals (Sweden)

    José M Ramos

    2015-02-01

    Full Text Available The presented report describes the epidemiology of potential rabies exposures and examines the utilization of anti-rabies vaccine in a rural area of Ethiopia during a period of 43 months. A total of 683 persons (51.1% females, 73% children with animal- related bites were included in the retrospective, registry-based study. The most common site of exposure was the leg (66.8%. In children under 8 years of age the face was more often involved than in adults (9.5% vs. 4.8%; p=0.03. The main type of exposure was a bite with bleeding (66.3% followed by contamination of mucous membranes with saliva (19.7%. The primary sources were dogs (93.4% followed by cats (2.6%. Children under 15 years were more likely to be exposed to dogs (94.9% than adults (88.7% (p=0.01. The most common way of coming in contact with animals was ‘walking by’ (83.9%. Children came in contact with animals while ‘playing with’ (10.7% more often than adults (1.1% (p<0.001. All the patients received an anti-rabies nervous-tissue vaccine, 99% of whom completed the vaccination course. Animal bites continue to be a problem in rural Ethiopia, mainly among children. Efforts to protect children against animal bites must be of paramount importance in preventing rabies in this population.

  18. Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

    International Nuclear Information System (INIS)

    Reubi, Jean Claude; Cescato, Renzo; Waser, Beatrice; Erchegyi, Judit; Rivier, Jean E.

    2010-01-01

    Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst 1 -sst 5 ) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst 2 and sst 3 internalization in vitro in HEK293 cells stably expressing the human sst 2 or sst 3 receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst 2 internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst 3 internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst 3 receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

  19. Agonist trigger: what is the best approach? Agonist trigger and low dose hCG

    DEFF Research Database (Denmark)

    Humaidan, Peter; Al Humaidan, Peter Samir Heskjær

    2012-01-01

    Low-dose hCG supplementation after GnRH agonist trigger may normalize reproductive outcome while minimizing the occurrence of OHSS in high risk IVF patients. (Fertil Steril (R) 2012;97:529-30. (C) 2012 by American Society for Reproductive Medicine.)......Low-dose hCG supplementation after GnRH agonist trigger may normalize reproductive outcome while minimizing the occurrence of OHSS in high risk IVF patients. (Fertil Steril (R) 2012;97:529-30. (C) 2012 by American Society for Reproductive Medicine.)...

  20. The GABAA receptor agonist THIP is neuroprotective in organotypic hippocampal slice cultures

    DEFF Research Database (Denmark)

    Kristensen, Bjarne Winther; Noraberg, Jens; Zimmer, Jens

    2003-01-01

    The potential neuroprotective effects of the GABA(A) receptor agonists THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and muscimol, and the selective GluR5 kainate receptor agonist ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid), which activates GABAergic interneu......The potential neuroprotective effects of the GABA(A) receptor agonists THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and muscimol, and the selective GluR5 kainate receptor agonist ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid), which activates GABAergic...... interneurons, were examined in hippocampal slice cultures exposed to N-methyl-D-aspartate (NMDA). The NMDA-induced excitotoxicity was quantified by densitometric measurements of propidium iodide (PI) uptake. THIP (100-1000 microM) was neuroprotective in slice cultures co-exposed to NMDA (10 microM) for 48 h......, while muscimol (100-1000 microM) and ATPA (1-3 microM) were without effect. The results demonstrate that direct GABA(A) agonism can mediate neuroprotection in the hippocampus in vitro as previously suggested in vivo....

  1. Starch films: production, properties and potential of utilization / Filmes de amido: produção, propriedades e potencial de utilização

    Directory of Open Access Journals (Sweden)

    Fábio Yamashita

    2010-04-01

    Full Text Available There is an increasing interest in the utilization of renewable resources for the production of food packaging. Among the biopolymers, starches from several sources have been considered as one of the most promising material for this purpose, and the reasons for this are that starches are biodegradable, are inexpensive and available in the worldwide. This work presents a bibliography review about biodegradable starch films characterization and potential of utilization. Discusses the starch films mechanical and barrier properties, the cristallinity and the effects of the use of plasticizers over these properties. The discussed informations indicate that exist great possibilities for these materials in food packaging, which depend on the production of more stable materials and the development of production technology in industrial scale.O interesse no emprego de matérias-primas provenientes de recursos renováveis para a produção de embalagens de alimentos vem crescendo. Dentre os biopolímeros mais promissores para este fim estão os amidos de diversas fontes botânicas, que são biodegradáveis, têm custo baixo e estão disponíveis em todo o mundo. Diante disto, este trabalho apresenta uma revisão bibliográfica sobre a caracterização e o potencial de utilização de filmes biodegradáveis a base de amido. Discute as propriedades mecânicas, de barreira e a cristalinidade dos filmes de amido e o efeito do uso de plastificantes sobre estas propriedades. As informações disponibilizadas mostram que existem grandes possibilidades de utilização destes materiais como embalagens de alimentos que, no entanto, dependem da produção de materiais mais estáveis às condições de armazenamento e do desenvolvimento de tecnologia de produção em escala industrial.

  2. [Safety and tolerability of GLP-1 receptor agonists].

    Science.gov (United States)

    Soldevila, Berta; Puig-Domingo, Manel

    2014-09-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  3. Simultaneous determination of 11 β-agonists in human urine using high-performance liquid chromatography/tandem mass spectrometry with isotope dilution.

    Science.gov (United States)

    Wang, Xiaoli; Guo, Tao; Wang, Shanshan; Yuan, Jinpeng; Zhao, Rusong

    2015-04-01

    The misuse of β-agonists constitutes a potential risk to public health and has been forbidden in many countries. In this study, we describe a method for specific, sensitive and rapid detection of β-agonists in human urine. Urine samples were extracted with ethyl acetate, without any additional purification step, and analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) with Clenbuterol-D9 and Salbuterol-D3 as internal standards. The intra- and interday precision values of the method were all application of UPLC-MS-MS method in β-agonists detection of human urine will be helpful in veterinary control of β-agonists and for studying the effect of β-agonists on human health. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Effect of Delta-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans

    NARCIS (Netherlands)

    Beaumont, H.; Jensen, J.; Carlsson, A.; Ruth, M.; Lehmann, A.; Boeckxstaens, G. E.

    2009-01-01

    Background and purpose: Transient lower oesophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-oesophageal reflux and are a potential pharmacological treatment target. We evaluated the effect of the CB(1)/CB(2) receptor agonist Delta(9)-tetrahydrocannabinol

  5. GLP-1 agonists for type 2 diabetes

    DEFF Research Database (Denmark)

    Jespersen, Maria J; Knop, Filip K; Christensen, Mikkel

    2013-01-01

    and safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches...... and obesity. The difference in chemical structure have strong implications for key pharmacokinetic parameters such as absorption and clearance, and eventually the safety and efficacy of the individual GLP-1-RA. The main safety concerns are pancreatitis and neoplasms, for which there are no identifiable...

  6. Dopamine agonist: pathological gambling and hypersexuality.

    Science.gov (United States)

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication.

  7. Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics

    Directory of Open Access Journals (Sweden)

    Liu L

    2013-04-01

    2 diabetes did in activating PPARα and PPARγ, but they also had more favorable conformation for binding to the two receptors. Moreover, the residues involved in forming the binding pockets of PPARα and PPARγ among the top ten compounds are explicitly presented, and this will be very useful for the in-depth conduction of mutagenesis experiments. It is anticipated that the ten compounds may become potential drug candidates, or at the very least, the findings reported here may stimulate new strategies or provide useful insights for designing new and more powerful dual-agonist drugs for treating type 2 diabetes. Keywords: diabetes, PPAR-alpha, PPAR-gamma, dual-agonist drug, core hopping, molecular docking, ADME, binding pocket

  8. Pharmacology of AMG 416 (Velcalcetide), a novel peptide agonist of the calcium-sensing receptor, for the treatment of secondary hyperparathyroidism in hemodialysis patients.

    Science.gov (United States)

    Walter, Sarah; Baruch, Amos; Dong, Jin; Tomlinson, James E; Alexander, Shawn T; Janes, Julie; Hunter, Tom; Yin, Qun; Maclean, Derek; Bell, Gregory; Mendel, Dirk B; Johnson, Randolph M; Karim, Felix

    2013-08-01

    A novel peptide, AMG 416 (formerly KAI-4169, and with a United States Adopted Name: velcalcetide), has been identified that acts as an agonist of the calcium-sensing receptor (CaSR). This article summarizes the in vitro and in vivo characterization of AMG 416 activity and the potential clinical utility of this novel compound. AMG 416 activates the human CaSR in vitro, acting by a mechanism distinct from that of cinacalcet, the only approved calcimimetic, since it can activate the CaSR both in the presence or the absence of physiologic levels of extracellular calcium. Administration of AMG 416 in vivo into either normal or renally compromised rats results in dose-dependent reductions in parathyroid hormone (PTH) levels and corresponding decreases in serum calcium, regardless of the baseline level of PTH. Treatment of 5/6 nephrectomized rats with AMG 416 resulted in dramatic improvements in their metabolic profile, including lower PTH and serum creatinine levels, reduced amounts of vascular calcification, attenuated parathyroid hyperplasia, and greater expression of the parathyroid gland regulators CaSR, vitamin D receptor, and FGF23 receptor compared with vehicle-treated animals. No drug accumulation was observed under this dosing regimen, and the terminal half-life of AMG 416 was estimated to be 2-4.5 hours. As a long-acting CaSR agonist, AMG 416 is an innovative new therapy for the treatment of hemodialysis patients with secondary hyperparathyroidism.

  9. Repeated 7-Day Treatment with the 5-HT2C Agonist Lorcaserin or the 5-HT2A Antagonist Pimavanserin Alone or in Combination Fails to Reduce Cocaine vs Food Choice in Male Rhesus Monkeys.

    Science.gov (United States)

    Banks, Matthew L; Negus, S Stevens

    2017-04-01

    Cocaine use disorder is a global public health problem for which there are no Food and Drug Administration-approved pharmacotherapies. Emerging preclinical evidence has implicated both serotonin (5-HT) 2C and 2A receptors as potential mechanisms for mediating serotonergic attenuation of cocaine abuse-related neurochemical and behavioral effects. Therefore, the present study aim was to determine whether repeated 7-day treatment with the 5-HT 2C agonist lorcaserin (0.1-1.0 mg/kg per day, intramuscular; 0.032-0.1 mg/kg/h, intravenous) or the 5-HT 2A inverse agonist/antagonist pimavanserin (0.32-10 mg/kg per day, intramuscular) attenuated cocaine reinforcement under a concurrent 'choice' schedule of cocaine and food availability in rhesus monkeys. During saline treatment, cocaine maintained a dose-dependent increase in cocaine vs food choice. Repeated pimavanserin (3.2 mg/kg per day) treatments significantly increased small unit cocaine dose choice. Larger lorcaserin (1.0 mg/kg per day and 0.1 mg/kg/h) and pimavanserin (10 mg/kg per day) doses primarily decreased rates of operant behavior. Coadministration of ineffective lorcaserin (0.1 mg/kg per day) and pimavanserin (0.32 mg/kg per day) doses also failed to significantly alter cocaine choice. These results suggest that neither 5-HT 2C receptor activation nor 5-HT 2A receptor blockade are sufficient to produce a therapeutic-like decrease in cocaine choice and a complementary increase in food choice. Overall, these results do not support the clinical utility of 5-HT 2C agonists and 5-HT 2A inverse agonists/antagonists alone or in combination as candidate anti-cocaine use disorder pharmacotherapies.

  10. Observer study for evaluating potential utility of a super-high-resolution LCD in the detection of clustered microcalcifications on digital mammograms.

    Science.gov (United States)

    Shiraishi, Junji; Abe, Hiroyuki; Ichikawa, Katsuhiro; Schmidt, Robert A; Doi, Kunio

    2010-04-01

    We evaluated the potential utility of a newly developed liquid-crystal display (LCD), which used an independent sub-pixel drive (ISD) technique for increasing the spatial resolution of a standard LCD three times in one direction, by use of receiver operating characteristic (ROC) analysis and a two-alternative-forced-choice (2AFC) method to determine improvement in radiologists' accuracy in the detection of clustered microcalcifications (MCLs) on digital mammograms. We used a standard LCD without and with the ISD technique, which can increase the spatial resolution of the LCD three times in one direction from three mega- to nine megapixels without changes in the size of the display. We used 60 single views of digital mammograms (30 with and 30 without clustered MCLs) for ROC studies and 60 regions of interest (ROIs) with clustered MCLs for 2AFC studies. In the ROC study, seven radiologists attempted to detect clustered MCLs without and with the ISD on the same LCD. In the 2AFC study, the same observer group compared the visibility of MCLs by use of the LCD without and with the ISD. Our institutional review board approved the use of this database and the participation of radiologists in this study. The accuracy in detecting clustered MCLs in the ROC study was improved by use of the LCD with the ISD, but the improvement was not statistically significant (p = 0.08). However, the superiority of the LCD with the ISD was demonstrated as significant (p LCD with ISD can improve the visibility of clustered MCLs when high-resolution digital mammograms are available.

  11. Modeling of Dust Levels Associated with Potential Utility-Scale Solar Development in the San Luis Valley-Taos Plateau Study Area

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Y. -S. [Argonne National Lab. (ANL), Argonne, IL (United States); Kotamarthi, R. [Argonne National Lab. (ANL), Argonne, IL (United States); Hartmann, H. M. [Argonne National Lab. (ANL), Argonne, IL (United States); Patton, T. [Argonne National Lab. (ANL), Argonne, IL (United States); Finster, M. [Argonne National Lab. (ANL), Argonne, IL (United States)

    2016-07-01

    The San Luis Valley (SLV)–Taos Plateau study area in south-central Colorado and north-central New Mexico is a large alpine valley surrounded by mountains with an area of approximately 6,263,000 acres (25,345 km2) (Figure ES.1-1). This area receives ample sunshine throughout the year, making it an ideal location for solar energy generation, and there are currently five photovoltaic facilities operating on private lands in the SLV, ranging in capacity from 1 to 30 megawatt (MW). In 2012 the Bureau of Land Management (BLM) launched its Solar Energy Program, which included the identification of four solar energy zones (SEZs) in the SLV totaling 16,308 acres (66 km2), as well as over 50,000 (202 km2) acres of other BLM-administered lands potentially available for application for solar development. The SEZ areas, named Antonito Southeast, De Tilla Gulch, Fourmile East, and Los Mogotes East, were defined by the BLM as areas well-suited for utility-scale (i.e., larger than 20 MW) production of solar energy where solar energy development would be prioritized (BLM 2012). Nonetheless, it was recognized that solar development in the SEZs would result in some unavoidable adverse impacts, and so the BLM initiated a solar regional mitigation strategy (SRMS) study for three of the SEZs (BLM and Argonne 2016). The SRMS is designed to identify residual impacts of solar development in the SEZs (that is, those that cannot be avoided or minimized onsite), identify those residual impacts that warrant compensatory mitigation when considering the regional status and trends of the resources, identify appropriate regional compensatory mitigation locations and actions to address those residual impacts, and recommend appropriate fees to implement those compensatory mitigation measures.

  12. Quantitative protein and fat metabolism in bull calves treated with beta-adrenergic agonist

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G

    1996-01-01

    Protein and energy utilization and quantitative retention of protein, fat and energy was investigated with 12 Red Danish bulls during two subsequent 6 weeks trials (Sections A and B) at a mean live weight of 195 and 335 kg respectively. Treatments were control (Group 1) and beta-agonist (L-644...... was strongly influenced by treatment, with the highest values for Group 2 in both sections. The protein retention increased with 25% in Group 2, with the highest increment of 113 g/d in Section B. The fat retention decreased in treated animals, most pronounced in Group 3, where the reduction was about 50......% with a mean decrease of 145 g/d in Section B. The total energy retention was not different between control animals and Group 2 in both sections, but there was a shift in energy retention from fat to protein. The higher levels of beta-agonist used in Group 3 generated the same increase in protein retention...

  13. Investigating Aging-Related Changes in the Coordination of Agonist and Antagonist Muscles Using Fuzzy Entropy and Mutual Information

    Directory of Open Access Journals (Sweden)

    Wenbo Sun

    2016-06-01

    Full Text Available Aging alters muscular coordination patterns. This study aimed to investigate aging-related changes in the coordination of agonist and antagonist muscles from two aspects, the activities of individual muscles and the inter-muscular coupling. Eighteen young subjects and 10 elderly subjects were recruited to modulate the agonist muscle activity to track a target during voluntary isometric elbow flexion and extension. Normalized muscle activation and fuzzy entropy (FuzzyEn were applied to depict the activities of biceps and triceps. Mutual information (MI was utilized to measure the inter-muscular coupling between biceps and triceps. The agonist activation decreased and the antagonist activation increased significantly during elbow flexion and extension with aging. FuzzyEn values of agonist electromyogram (EMG were similar between the two age groups. FuzzyEn values of antagonist EMG increased significantly with aging during elbow extension. MI decreased significantly with aging during elbow extension. These results indicated increased antagonist co-activation and decreased inter-muscular coupling with aging during elbow extension, which might result from the reduced reciprocal inhibition and the recruitment of additional cortical-spinal pathways connected to biceps. Based on FuzzyEn and MI, this study provided a comprehensive understanding of the mechanisms underlying the aging-related changes in the coordination of agonist and antagonist muscles.

  14. Heterologous Expression in Remodeled C. elegans: A Platform for Monoaminergic Agonist Identification and Anthelmintic Screening.

    Directory of Open Access Journals (Sweden)

    Wenjing Law

    2015-04-01

    Full Text Available Monoamines, such as 5-HT and tyramine (TA, paralyze both free-living and parasitic nematodes when applied exogenously and serotonergic agonists have been used to clear Haemonchus contortus infections in vivo. Since nematode cell lines are not available and animal screening options are limited, we have developed a screening platform to identify monoamine receptor agonists. Key receptors were expressed heterologously in chimeric, genetically-engineered Caenorhabditis elegans, at sites likely to yield robust phenotypes upon agonist stimulation. This approach potentially preserves the unique pharmacologies of the receptors, while including nematode-specific accessory proteins and the nematode cuticle. Importantly, the sensitivity of monoamine-dependent paralysis could be increased dramatically by hypotonic incubation or the use of bus mutants with increased cuticular permeabilities. We have demonstrated that the monoamine-dependent inhibition of key interneurons, cholinergic motor neurons or body wall muscle inhibited locomotion and caused paralysis. Specifically, 5-HT paralyzed C. elegans 5-HT receptor null animals expressing either nematode, insect or human orthologues of a key Gαo-coupled 5-HT1-like receptor in the cholinergic motor neurons. Importantly, 8-OH-DPAT and PAPP, 5-HT receptor agonists, differentially paralyzed the transgenic animals, with 8-OH-DPAT paralyzing mutant animals expressing the human receptor at concentrations well below those affecting its C. elegans or insect orthologues. Similarly, 5-HT and TA paralyzed C. elegans 5-HT or TA receptor null animals, respectively, expressing either C. elegans or H. contortus 5-HT or TA-gated Cl- channels in either C. elegans cholinergic motor neurons or body wall muscles. Together, these data suggest that this heterologous, ectopic expression screening approach will be useful for the identification of agonists for key monoamine receptors from parasites and could have broad application for

  15. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review.

    Science.gov (United States)

    Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M; Heiss, Elke H; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M; Atanasov, Atanas G

    2014-11-01

    Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Regulation of Glial Cell Functions by PPAR- Natural and Synthetic Agonists

    Directory of Open Access Journals (Sweden)

    Antonietta Bernardo

    2008-01-01

    Full Text Available In the recent years, the peroxisome proliferator-activated receptor- (PPAR-, a well known target for type II diabetes treatment, has received an increasing attention for its therapeutic potential in inflammatory and degenerative brain disorders. PPAR- agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy Δ12,14 prostaglandin J2, and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory drugs have shown anti-inflammatory and protective effects in several experimental models of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis and stroke, as well as in few clinical studies. The pleiotropic effects of PPAR- agonists are likely to be mediated by several mechanisms involving anti-inflammatory activities on peripheral immune cells (macrophages and lymphocytes, as well as direct effects on neural cells including cerebral vascular endothelial cells, neurons, and glia. In the present article, we will review the recent findings supporting a major role for PPAR- agonists in controlling neuroinflammation and neurodegeneration through their activities on glial cells, with a particular emphasis on microglial cells as major macrophage population of the brain parenchyma and main actors in brain inflammation.

  17. Extremely high-frequency electromagnetic radiation enhances neutrophil response to particulate agonists.

    Science.gov (United States)

    Vlasova, Irina I; Mikhalchik, Elena V; Gusev, Alexandr A; Balabushevich, Nadezhda G; Gusev, Sergey A; Kazarinov, Konstantin D

    2018-02-01

    The growing use of extremely high-frequency electromagnetic radiation (EHF EMR) in information and communication technology and in biomedical applications has raised concerns regarding the potential biological impact of millimeter waves (MMWs). Here, we elucidated the effects of MMW radiation on neutrophil activation induced by opsonized zymosan or E. coli in whole blood ex vivo. After agonist addition to blood, two samples were prepared. A control sample was incubated at ambient conditions without any treatment, and a test sample was exposed to EHF EMR (32.9-39.6 GHz, 100 W/m 2 ). We used methods that allowed us to assess the functional status of neutrophils immediately after exposure: oxidant production levels were measured by luminol-dependent chemiluminescence, and morphofunctional changes to neutrophils were observed in blood smears. Results revealed that the response of neutrophils to both agonists was intensified if blood was exposed to MMW radiation for 15 min. Neutrophils were intact in both the control and irradiated samples if no agonist was added to blood before incubation. Similarly, exposing suspensions of isolated neutrophils in plasma to MMW radiation enhanced cell response to both zymosan and E. coli. Heating blood samples was shown to be the primary mechanism underlying enhanced EHF EMR-induced oxidant production by neutrophils in response to particulate agonists. Bioelectromagnetics. 39:144-155, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  18. Water exposure assessment of aryl hydrocarbon receptor agonists in Three Gorges Reservoir, China using SPMD-based virtual organisms.

    Science.gov (United States)

    Wang, Jingxian; Bernhöft, Silke; Pfister, Gerd; Schramm, Karl-Werner

    2014-10-15

    SPMD-based virtual organisms (VOs) were deployed at five to eight sites in the Three Gorges Reservoir (TGR), China for five periods in 2008, 2009 and 2011. The water exposure of aryl hydrocarbon receptor (AhR) agonists was assessed by the VOs. The chosen bioassay response for the extracts of the VOs, the induction of 7-ethoxyresorufin-O-deethylase (EROD) was assayed using a rat hepatoma cell line (H4IIE). The results show that the extracts from the VOs could induce AhR activity significantly, whereas the chemically derived 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalent (TEQcal) accounted for effects in the mixture. The levels of AhR agonists in VOs from upstream TGR were in general higher than those from downstream reservoir, indicating urbanization effect on AhR agonist pollution. The temporal variation showed that levels of AhR agonists in 2009 and 2011 were higher than those in 2008, and the potential non-additive effects in the area close to the dam were also obviously higher in 2009 and 2011 than in 2008, indicating big changes in the composition of pollutants in the area after water level reached a maximum of 175 m. Although the aqueous concentration of AhR agonists of 0.8-4.8 pg TCDDL(-1) in TGR was not alarming, the tendency of accumulating high concentration of AhR agonists in VO lipid and existence of possible synergism or antagonism in the water may exhibit a potential hazard to local biota being exposed to AhR agonists. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. The non-biphenyl-tetrazole AT1 receptor blocker eprosartan is a unique and robust inverse agonist of the active state of AT1 receptor.

    Science.gov (United States)

    Takezako, Takanobu; Unal, Hamiyet; Karnik, Sadashiva S; Node, Koichi

    2018-03-23

    Diseases such as hypertension and renal-allograft rejection are accompanied by chronic agonist-independent signaling by the angiotensin II (Ang II) type 1 receptor (AT1R). The current treatment paradigm for these diseases embraces the preferred use of inverse agonist AT1R blockers (ARBs). However, variability in the inverse agonist activities of common biphenyl-tetrazole ARBs for the active state of AT1R often leads to treatment failure. Therefore, characterization of robust inverse agonist ARBs for the active state of AT1R is necessary. To identify the robust inverse agonist for active state of AT1R and its molecular mechanism, we performed site-directed mutagenesis, competition binding assay, inositol phosphate production assay and molecular modeling for both ground state wild-type AT1R (WT-AT1R) and active state N111G-AT1R. Although candesartan and telmisartan exhibited weaker inverse agonist activity for N111G-AT1 compared to WT-AT1, only eprosartan exhibited robust inverse agonist activity for both N111G-AT1 and WT-AT1. Specific ligand-receptor contacts for candesartan and telmisartan are altered in the active state N111G-AT1R compare to in the ground state WT-AT1R, suggesting a potential basis for their attenuated inverse agonist activity for the active state of AT1R. In contrast, interactions between eprosartan and N111G-AT1R were not significantly altered, and the inverse agonist activity of eprosartan was robust. These findings suggest that eprosartan may be a better therapeutic option than other ARBs, and that comparative studies investigating eprosartan and other ARBs for the treatment of diseases caused by chronic agonist-independent AT1R activation are warranted. This article is protected by copyright. All rights reserved.

  20. Oil drilling rig diesel power-plant fuel efficiency improvement potentials through rule-based generator scheduling and utilization of battery energy storage system

    International Nuclear Information System (INIS)

    Pavković, Danijel; Sedić, Almir; Guzović, Zvonimir

    2016-01-01

    Highlights: • Isolated oil drilling rig microgrid power flows are analyzed over 30 days. • Rule-based diesel generator scheduling is proposed to reduce fuel consumption. • A battery energy storage is parameterized and used for peak load leveling. • The effectiveness of proposed hybrid microgrid is verified by simulations. • Return-of-investment might be expected within 20% of battery system lifetime. - Abstract: This paper presents the development of a rule-based energy management control strategy suitable for isolated diesel power-plants equipped with a battery energy storage system for peak load shaving. The proposed control strategy includes the generator scheduling strategy and peak load leveling scheme based on current microgrid active and reactive power requirements. In order to investigate the potentials for fuel expenditure reduction, 30 days-worth of microgrid power flow data has been collected on an isolated land-based oil drilling rig powered by a diesel generator power-plant, characterized by highly-variable active and reactive load profiles due to intermittent engagements and disengagements of high-power electric machinery such as top-drive, draw-works and mud-pump motors. The analysis has indicated that by avoiding the low-power operation of individual generators and by providing the peak power requirements (peak shaving) from a dedicated energy storage system, the power-plant fuel efficiency may be notably improved. An averaged power flow simulation model has been built, comprising the proposed rule-based power flow control strategy and the averaged model of a suitably sized battery energy storage system equipped with grid-tied power converter and state-of-charge control system. The effectiveness of the proposed rule-based strategy has been evaluated by means of computer simulation analysis based on drilling rig microgrid active and reactive power data recorded during the 30 day period. The analysis has indicated that fuel consumption of

  1. The importance of β2-agonists in myocardial infarction

    DEFF Research Database (Denmark)

    Rørth, Rasmus; Fosbøl, Emil L; Mogensen, Ulrik M

    2016-01-01

    PURPOSE: β2-Agonists are widely used for relief of respiratory symptoms. Studies so far have reported conflicting results regarding use of β2-agonists and risk of myocardial infarction (MI). Yet, coronary angiographical data and longitudinal outcomes data are sparse and could help explain...

  2. Agonist induction, conformational selection, and mutant receptors.

    Science.gov (United States)

    Giraldo, Jesús

    2004-01-02

    Current models of receptor activation are based on either of two basic mechanisms: agonist induction or conformational selection. The importance of one pathway relative to the other is controversial. In this article, the impossibility of distinguishing between the two mechanisms under a thermodynamic approach is shown. The effect of receptor mutation on the constants governing ligand-receptor equilibria is discussed. The two-state model of agonism both in its original formulation (one cycle) and including multiple active states (multiple cycles) is used. Pharmacological equations for the double (two cycles) two-state model are derived. The simulations performed suggest that the double two-state model of agonism can be a useful model for assessing quantitatively the changes in pharmacological activity following receptor mutation.

  3. Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

    DEFF Research Database (Denmark)

    Maolanon, Alex R.; Risgaard, Rune; Wang, Shuang Yan

    2017-01-01

    A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist...... efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit......-selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission....

  4. Behavioral effects of the novel potent cannabinoid CB1 agonist AM 4054.

    Science.gov (United States)

    McLaughlin, Peter J; Thakur, Ganesh A; Vemuri, V Kiran; McClure, Evan D; Brown, Cara M; Winston, Keisha M; Wood, Jodianne T; Makriyannis, Alexandros; Salamone, John D

    2013-08-01

    Due to the ubiquity of the CB1 cannabinoid receptor throughout the nervous system, as well as the many potential therapeutic uses of CB1 agonist-based interventions, it is desirable to synthesize novel probes of the CB1 receptor. Here, the acute behavioral effects of systemic (i.p.) administration of the putative novel CB1 full agonist AM 4054 were tested in rats. In Experiment 1, a dose range (0.15625-1.25 mg/kg) of AM 4054 produced effects consistent with CB1 agonism in the cannabinoid tetrad of tasks in rats, including induction of analgesia, catalepsy, hypothermia, and locomotor suppression. These effects were reversed with the CB1-selective inverse agonist AM 251 in Experiment 2, indicating that AM 4054 produced CB1 receptor-mediated effects. Analysis of open-field activity indicated that the reduction in locomotion is more consistent with general motor slowing than anxiogenesis. AM 4054 (0.0625-0.5 mg/kg) also dose-dependently reduced fixed-ratio 5 (FR5) operant responding for food in Experiment 3, and microanalysis of the timing and rate of lever pressing indicated a pattern of suppression similar to other CB1 agonists. Minimum doses of AM 4054 (0.125-0.3125 mg/kg) required to produce significant effects in these behavioral assays were lower than those of many CB1 agonists. It is likely that AM 4054 is a potent pharmacological tool for assessment of cannabinoid receptor function. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Factors affecting the potential of direct load control for non-generating utilities. Final report. [Distribution and wholesale power supply interaction

    Energy Technology Data Exchange (ETDEWEB)

    None

    1979-04-01

    Several alternatives are available for achieving load management, including direct or voluntary control of customer loads, customer or utility energy storage systems for diurnal load shifting, and expanded interconnection and operation of electric power systems. All of these alternatives are available to the fully integrated (generating, transmitting and distributing) electric utility and the analysis of their effects encompasses the power supply and delivery system. However, the costs and benefits of the alternatives to the fully integrated electric utility are perhaps not so obvious. Therefore, by considering a non-generating utility, this analysis focuses upon the distribution system and wholesale power supply interaction as a step toward an analysis including the power supply and delivery system. This report develops an analysis procedure and discusses some of the relevant factors to be consdered in the application of direct load control for a non-generating utility system. The analysis concentrates on the distribution system only to determine the effect of rates and payback as a result of direct load control. Thus, the study is responsive to the specific needs of the non-generating utility. This analysis of direct load control encompasses the determination of those loads amenable to control, the selection of a suitable one-way communications system to rend control and the estimation of expected benefits and costs. The complementary functions to the application of direct load control such as automatic meter reading via the addition of a bi-directional communications system and voltage control are not included in the analysis but are detailed for future consideration.

  6. α1 -AR agonist induced piloerection protects against the development of traction alopecia.

    Science.gov (United States)

    Goren, Andy; Shapiro, Jerry; Sinclair, Rodney; Kovacevic, Maja; McCoy, John

    2016-05-01

    Traction alopecia is hair loss that occurs after persistent pulling (e.g., during cosmetic procedures) on the roots of hair over time. Unlike plucking, which is painful, persistent pulling may go unnoticed until a patient presents with either bald spots or diffuse telogen shedding. Each hair follicle in the scalp contains an arrector pili muscle that, when contracted, erects the hair. The smooth muscle in the arrector pili expresses α1 adrenergic receptors (α1 -AR). As such, we hypothesized that contraction of the arrector pili muscle via an α1 -AR agonist would increase the threshold of force required to pluck hair during cosmetic procedures. Female subjects, ages 18-40, were recruited to study the effect of topically applied phenylephrine, a selective α1 -AR agonist, on epilation force and hair shedding during cosmetic procedures. In our blinded study, 80% of subjects demonstrated reduced shedding on days using phenylephrine compared to days using a placebo solution. The average reduction in hair loss was approximately 42%. In addition, the force threshold required for epilation increased by approximately 172% following topical phenylephrine application. To our knowledge this is the first study demonstrating the utility of α1 -AR agonists in the treatment of traction alopecia and hair shedding during cosmetic procedures. © 2015 Wiley Periodicals, Inc.

  7. Treating ADHD in Prison: Focus on Alpha-2 Agonists (Clonidine and Guanfacine).

    Science.gov (United States)

    Mattes, Jeffrey A

    2016-06-01

    Attention deficit/hyperactivity disorder (ADHD) is prevalent in prison populations, but optimal treatment recommendations in prison are uncertain. Stimulants are problematic because of the potential for abuse. This article is a review of medication options for ADHD, focusing on the α2 agonists clonidine and guanfacine, which, in their extended-release (ER) forms, are U.S. Food and Drug Administration (FDA) approved for the treatment of ADHD, although they are probably less efficacious, overall, than stimulants. Advantages of α2 agonists in prison include: they are not controlled substances and have no known abuse potential; they may be particularly helpful for ADHD with associated aggression and other features of conduct disorder; they may reduce anxiety and symptoms of posttraumatic stress disorder; and they are somewhat sedating. The pharmacology of these agents and the presumed mechanism of action are discussed, including the fact that guanfacine more specifically affects α2A receptors, which are postsynaptic in the frontal cortex. Other differences between clonidine and guanfacine and between the generic immediate-release (IR) forms and the ER forms are also discussed. The IR forms, while themselves not FDA approved for ADHD, may, with dosage adjustment, be reasonable alternatives (with considerable cost savings). Overall, given the FDA-accepted evidence of efficacy, the lack of abuse potential, and the favorable side effect profile, α agonists may be the treatment of choice for prison inmates with ADHD. © 2016 American Academy of Psychiatry and the Law.

  8. Detecting associations between behavioral addictions and dopamine agonists in the Food & Drug Administration’s Adverse Event database

    Science.gov (United States)

    Gendreau, Katherine E.; Potenza, Marc N.

    2014-01-01

    Background/Aims: Studies have reported higher prevalences of four behavioral addictions (binge eating, compulsive shopping, hypersexuality, and pathological gambling) in dopamine agonist-treated Parkinson’s disease relative to non-dopamine agonist-treated Parkinson’s. However, recent case-control and epidemiological studies suggest that prevalences of behavioral addictions in dopamine agonist-treated Parkinson’s may be similar to background population rates. This study tests that hypothesis by examining the FDA Adverse Event Reporting System (FAERS) for evidence of these associations, taking into account the potential impact of publicity on reporting rates. Methods: FAERS reports in 2004 (pre-publicity for all but pathological gambling) and 2007 (post-publicity for all four behaviors) were analyzed. A threshold consisting of ≥3 cases, proportional reporting ratio ≥2, and χ2 with Yates’ correction ≥4 was used to detect signals (drug-associated adverse reactions) involving any of five dopamine agonists and any of four behavioral addictions. Results: No reports containing compulsive shopping and no signal for binge eating and dopamine agonists were found in either year. A weak signal was found for hypersexuality in 2004, with a stronger signal in 2007. A robust signal was found for pathological gambling in 2004, with a more robust signal in 2007. Discussion/Conclusions: These results suggest that publicity may increase reporting rates in the FAERS. Findings for binge eating, compulsive shopping, and hypersexuality suggest that prevalences of these behaviors among those treated with dopamine agonists may be similar to background population rates and thus may not reflect an adverse safety signal. Further investigation of the relationship between dopamine agonists and behavioral addictions is warranted. PMID:25215211

  9. In vivo pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107: preclinical considerations in Alzheimer's disease.

    Science.gov (United States)

    Bitner, R Scott; Bunnelle, William H; Decker, Michael W; Drescher, Karla U; Kohlhaas, Kathy L; Markosyan, Stella; Marsh, Kennan C; Nikkel, Arthur L; Browman, Kaitlin; Radek, Rich; Anderson, David J; Buccafusco, Jerry; Gopalakrishnan, Murali

    2010-09-01

    We previously reported that alpha7 nicotinic acetylcholine receptor (nAChR) agonism produces efficacy in preclinical cognition models correlating with activation of cognitive and neuroprotective signaling pathways associated with Alzheimer's disease (AD) pathology. In the present studies, the selective and potent alpha7 nAChR agonist 5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole (ABT-107) was evaluated in behavioral assays representing distinct cognitive domains. Studies were also conducted to address potential issues that may be associated with the clinical development of an alpha7 nAChR agonist. Specifically, ABT-107 improved cognition in monkey delayed matching to sample, rat social recognition, and mouse two-trial inhibitory avoidance, and continued to improve cognitive performance at injection times when exposure levels continued to decline. Rats concurrently infused with ABT-107 and donepezil at steady-state levels consistent with clinical exposure showed improved short-term recognition memory. Compared with nicotine, ABT-107 did not produce behavioral sensitization in rats or exhibit psychomotor stimulant activity in mice. Repeated (3 days) daily dosing of ABT-107 increased extracellular cortical acetylcholine in rats, whereas acute administration increased cortical extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation in mice, neurochemical and biochemical events germane to cognitive function. ABT-107 increased cortical phosphorylation of the inhibitory residue (Ser9) of glycogen synthase kinase-3, a primary tau kinase associated with AD pathology. In addition, continuous infusion of ABT-107 in tau/amyloid precursor protein transgenic AD mice reduced spinal tau hyperphosphorylation. These findings show that targeting alpha7 nAChRs may have potential utility for symptomatic alleviation and slowing of disease progression in the treatment AD, and expand the understanding of the potential

  10. Glass melting and its innovation potentials: the impact of the input and output geometries on the utilization of the melting space

    Czech Academy of Sciences Publication Activity Database

    Polák, M.; Němec, Lubomír

    2010-01-01

    Roč. 54, č. 3 (2010), s. 212-218 ISSN 0862-5468 R&D Projects: GA MPO 2A-1TP1/063 Institutional research plan: CEZ:AV0Z40320502 Keywords : space utilization, * sand dissolution * bubble removal * space geometry Subject RIV: JH - Ceramics, Fire-Resistant Materials and Glass Impact factor: 0.297, year: 2010

  11. Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice

    OpenAIRE

    Li, Xia; Risbrough, Victoria B.; Cates-Gatto, Chelsea; Kaczanowska, Katarzyna; Finn, M. G.; Roberts, Amanda J; Markou, Athina

    2013-01-01

    γ-Aminobutyric acid B (GABAB) receptor activation is a potential therapeutic approach for the treatment of drug addiction, pain, anxiety, and depression. However, full agonists of this receptor induce side-effects, such as sedation, muscle relaxation, tolerance, and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptor may have similar therapeutic effects as agonists with superior side-effect profiles. The present study behaviorally characterized N-([1R,2R,4S]-bicy...

  12. PPAR and Agonists against Cancer: Rational Design of Complementation Treatments

    Directory of Open Access Journals (Sweden)

    Dorina Veliceasa

    2008-01-01

    Full Text Available PPAR is a member of the ligand-activated nuclear receptor superfamily: its ligands act as insulin sensitizers and some are approved for the treatment of metabolic disorders in humans. PPAR has pleiotropic effects on survival and proliferation of multiple cell types, including cancer cells, and is now subject of intensive preclinical cancer research. Studies of the recent decade highlighted PPAR role as a potential modulator of angiogenesis in vitro and in vivo. These observations provide an additional facet to the PPAR image as potential anticancer drug. Currently PPAR is regarded as an important target for the therapies against angiogenesis-dependent pathological states including cancer and vascular complications of diabetes. Some of the studies, however, identify pro-angiogenic and tumor-promoting effects of PPAR and its ligands pointing out the need for further studies. Below, we summarize current knowledge of PPAR regulatory mechanisms and molecular targets, and discuss ways to maximize the beneficial activity of the PPAR agonists.

  13. Adenosine receptor agonists modulate visceral hyperalgesia in the rat.

    Science.gov (United States)

    Sohn, Chong-Il; Park, Hyo Jin; Gebhart, G F

    2008-06-01

    Adenosine is an endogenous modulator of nociception. Its role in visceral nociception, particularly in visceral hyperalgesia, has not been studied. The aim of this study was to determine the effects of adenosine receptor agonists in a model of visceral hyperalgesia. The visceromotor response (VMR) in rats to colorectal distension (CRD; 80 mmHg, 20 seconds) was quantified by electromyographic recordings from the abdominal musculature. Three hours after the intracolonic administration of zymosan (25 mg/mL, 1 mL), VMRs to CRD were measured before and after either subcutaneous or intrathecal administration of an adenosine receptor agonist. Subcutaneous injection of 5'-N-ethylcarboxyamidoadenosine (NECA; an A1 and A2 receptor agonist), R(-)-N6-(2-phenylisopropyl)-adenosine (R-PIA; a selective A1 receptor agonist), or CGS-21680 hydrochloride (a selective A2a receptor agonist) dose-dependently (10-100 mg/kg) attenuated the VMR to CRD, although hindlimb weakness occurred at the higher doses tested. Intrathecal administration of NECA or R-PIA dose-dependently (0.1-1.0 microg/kg) decreased the VMR, whereas CGS-21680 hydrochloride was ineffective over the same concentration range. Higher intrathecal doses of the A1/A2 receptor agonist NECA produced motor weakness. Adenosine receptor agonists are antihyperalgesic, but also produce motor weakness at high doses. However, activation of the spinal A1 receptor significantly attenuates the VMR to CRD without producing motor weakness.

  14. Discovery of acylurea isosteres of 2-acylaminothiadiazole in the azaxanthene series of glucocorticoid receptor agonists.

    Science.gov (United States)

    Gong, Hua; Yang, Michael; Xiao, Zili; Doweyko, Arthur M; Cunningham, Mark; Wang, Jinhong; Habte, Sium; Holloway, Deborah; Burke, Christine; Shuster, David; Gao, Ling; Carman, Julie; Somerville, John E; Nadler, Steven G; Salter-Cid, Luisa; Barrish, Joel C; Weinstein, David S

    2014-08-01

    Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity

    Science.gov (United States)

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don; Hurd, Alexander; Aicher, Thomas D.; Toogood, Peter L.; Glick, Gary D.; Paulos, Chrystal M.; Zou, Weiping; Carter, Laura L.

    2016-01-01

    ABSTRACT RORγt is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are RORγ+ cells. To evaluate the role of RORγ in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate RORγ to a greater extent than the endogenous agonist desmosterol. These RORγ agonists enhance effector function of Type 17 cells by increasing the production of cytokines/chemokines such as IL-17A and GM-CSF, augmenting expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. RORγ agonists also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors including PD-1 and TIGIT on tumor-reactive lymphocytes. The effects of RORγ agonists were not observed in RORγ−/− T cells, underscoring the selective on-target activity of the compounds. In vitro treatment of tumor-specific T cells with RORγ agonists, followed by adoptive transfer to tumor-bearing mice is highly effective at controlling tumor growth while improving T cell survival and maintaining enhanced IL-17A and reduced PD-1 in vivo. The in vitro effects of RORγ agonists translate into single agent, immune system-dependent, antitumor efficacy when compounds are administered orally in syngeneic tumor models. RORγ agonists integrate multiple antitumor mechanisms into a single therapeutic that both increases immune activation and decreases immune suppression resulting in robust inhibition of tumor growth. Thus, RORγ agonists represent a novel immunotherapy approach for cancer. PMID:28123897

  16. Dopamine agonist withdrawal syndrome: implications for patient care.

    Science.gov (United States)

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper.

  17. Synthetic ROR? agonists regulate multiple pathways to enhance antitumor immunity

    OpenAIRE

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don

    2016-01-01

    ABSTRACT ROR?t is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are ROR?+ cells. To evaluate the role of ROR? in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate ROR? to a greater extent than the endogenous agonist desmosterol. These ROR? agonists enhance effector function of Type 17...

  18. A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain

    Directory of Open Access Journals (Sweden)

    Arden Perkins

    2014-10-01

    Full Text Available The aryl hydrocarbon receptor (AHR is a ligand-activated transcription factor that regulates the expression of a diverse group of genes. Exogenous AHR ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, which is a potent agonist, and the synthetic AHR antagonist N-2-(1H-indol-3ylethyl-9-isopropyl-2- (5-methylpyridin-3-yl-9H-purin-6-amine (GNF351. As no experimentally determined structure of the ligand binding domain exists, homology models have been utilized for virtual ligand screening (VLS to search for novel ligands. Here, we have developed an “agonist-optimized” homology model of the human AHR ligand binding domain, and this model aided in the discovery of two human AHR agonists by VLS. In addition, we performed molecular dynamics simulations of an agonist TCDD-bound and antagonist GNF351-bound version of this model in order to gain insights into the mechanics of the AHR ligand-binding pocket. These simulations identified residues 307–329 as a flexible segment of the AHR ligand pocket that adopts discrete conformations upon agonist or antagonist binding. This flexible segment of the AHR may act as a structural switch that determines the agonist or antagonist activity of a given AHR ligand.

  19. Synthesis of constrained benzocinnolinone analogues of CEP-26401 (irdabisant) as potent, selective histamine H3 receptor inverse agonists.

    Science.gov (United States)

    Josef, Kurt A; Aimone, Lisa D; Lyons, Jacquelyn; Raddatz, Rita; Hudkins, Robert L

    2012-06-15

    A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Dipeptidyl peptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) agonists

    DEFF Research Database (Denmark)

    Madsbad, Sten

    2012-01-01

    Incretin-based therapies, which include the GLP-1 receptor agonists and DPP-4 inhibitors, use the antidiabetic properties of potentiating the GLP-1 receptor signalling via the regulation of insulin and glucagon secretion, inhibition of gastric emptying and suppression of appetite. Most physicians...

  1. Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats

    DEFF Research Database (Denmark)

    Castoldi, Giovanna; di Gioia, Cira Rt; Bombardi, Camila

    2014-01-01

    Aim of the study was to evaluate the effect of compound 21 (C21), selective AT2 receptor agonist, in diabetic nephropathy and the potential additive effect of C21, when associated to losartan treatment, on the development of albuminuria and renal fibrosis in Zucker diabetic fatty (ZDF) rats. The ...

  2. Agonistic anti-CD40 antibody profoundly suppresses the immune response to infection with lymphocytic choriomeningitis virus

    DEFF Research Database (Denmark)

    Bartholdy, Christina; Kauffmann, Susanne Ørding; Christensen, Jan Pravsgaard

    2007-01-01

    -CD40 treatment of MHC class II-deficient mice infected with a moderate dose of LCMV resulted in severe suppression of the antiviral CD8 T cell response and uncontrolled virus spread, rather than improved CD8 T cell immune surveillance. In Ab-treated wild-type mice, the antiviral CD8 T cell response......Previous work has shown that agonistic Abs to CD40 (anti-CD40) can boost weak CD8 T cell responses as well as substitute for CD4 T cell function during chronic gammaherpes virus infection. Agonistic anti-CD40 treatment has, therefore, been suggested as a potential therapeutic strategy...... in immunocompromised patients. In this study, we investigated whether agonistic anti-CD40 could substitute for CD4 T cell help in generating a sustained CD8 T cell response and prevent viral recrudescence following infection with lymphocytic choriomeningitis virus (LCMV). Contrary to expectations, we found that anti...

  3. Beyond glucose lowering: glucagon-like peptide-1 receptor agonists, body weight and the cardiovascular system.

    Science.gov (United States)

    Vergès, B; Bonnard, C; Renard, E

    2011-12-01

    Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family: in the presence of elevated blood glucose, it stimulates insulin secretion and inhibits glucagon production. In addition, GLP-1 slows gastric emptying. GLP-1 secretion has also been reported to potentially affect patients with type 2 diabetes (T2DM) compared with non-diabetics and, as enzymatic inactivation by dipeptidyl peptidase-4 (DPP-4) shortens the GLP-1 half-life to a few minutes, GLP-1 receptor agonists such as exenatide twice daily (BID) and liraglutide have been developed, and have become part of the management of patients with T2DM. This review focuses on the potential beneficial effects of these compounds beyond those associated with improvements in blood glucose control and weight loss, including changes in the cardiovascular and central nervous systems. This was a state-of-the-art review of the literature to evaluate the relationships between GLP-1, GLP-1 receptor agonists, weight and the cardiovascular system. GLP-1 receptor agonists improve glucose control and do not significantly increase the risk of hypoglycaemia. Also, this new class of antidiabetic drugs was shown to favour weight loss. Mechanisms may involve central action, direct action by reduction of food intake and probably indirect action through slowing of gastric emptying. The relative importance of each activity remains unclear. Weight loss may improve cardiovascular outcomes in patients with T2DM, although GLP-1 receptor agonists may have other direct and indirect effects on the cardiovascular system. Reductions in myocardial infarct size and improvements in cardiac function have been seen in animal models. Beneficial changes in cardiac function were also demonstrated in patients with myocardial infarcts or heart failure. Indirect effects could involve a reduction in blood pressure and potential effects on oxidation. However, the mechanisms involved in the pleiotropic effects of GLP-1 receptor agonists have yet to

  4. Identification of Natural Compound Carnosol as a Novel TRPA1 Receptor Agonist

    Directory of Open Access Journals (Sweden)

    Chenxi Zhai

    2014-11-01

    Full Text Available The transient receptor potential ankyrin 1 (TRPA1 cation channel is one of the well-known targets for pain therapy. Herbal medicine is a rich source for new drugs and potentially useful therapeutic agents. To discover novel natural TRPA1 agonists, compounds isolated from Chinese herbs were screened using a cell-based calcium mobilization assay. Out of the 158 natural compounds derived from traditional Chinese herbal medicines, carnosol was identified as a novel agonist of TRPA1 with an EC50 value of 12.46 µM. And the agonistic effect of carnosol on TRPA1 could be blocked by A-967079, a selective TRPA1 antagonist. Furthermore, the specificity of carnosol was verified as it showed no significant effects on two other typical targets of TRP family member: TRPM8 and TRPV3. Carnosol exhibited anti-inflammatory and anti-nociceptive properties; the activation of TRPA1 might be responsible for the modulation of inflammatory nociceptive transmission. Collectively, our findings indicate that carnosol is a new anti-nociceptive agent targeting TRPA1 that can be used to explore further biological role in pain therapy.

  5. Anticancer Role of PPARγ Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes

    Directory of Open Access Journals (Sweden)

    P. J. Simpson-Haidaris

    2010-01-01

    Full Text Available The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR-γ agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPARγ agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPARγ agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPARγ and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow.

  6. Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2014-01-01

    , slowing of gastric emptying and suppression of appetite. In circulation, GLP-1 has a half-life of approximately 2min due to rapid degradation by the enzyme dipeptidyl peptidase 4 (DPP-4). Because of this short half-life GLP-1 receptor (GLP-1R) agonists, resistant to degradation by DPP-4 have been...... effects. This review gives an overview of the clinical data on GLP-1R agonists that have been compared in head-to-head studies and focuses on relevant differences between the compounds. Highlighting these similarities and differences could be beneficial for physicians in choosing the best treatment......Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, secreted in response to ingestion of nutrients, and has important effects on several of the pathophysiological features of type 2 diabetes (T2D). The effects include potentiation of insulin secretion, suppression of glucagon secretion...

  7. Nicotine receptor partial agonists for smoking cessation.

    Science.gov (United States)

    Cahill, Kate; Stead, Lindsay F; Lancaster, Tim

    2012-04-18

    Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including cytisine, dianicline and varenicline for smoking cessation. We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, PsycINFO and Web of Science using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialised register was in December 2011. We also searched online clinical trials registers. We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow-up.The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model. Two recent cytisine trials (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow-up, with a pooled RR of

  8. Albiglutide: a unique GLP-1 receptor agonist.

    Science.gov (United States)

    Rendell, Marc S

    2016-12-01

    Albiglutide is a long acting GLP-1 receptor agonist (GLP-1 RA) administered by weekly injection. Area covered: The pharmacokinetic and pharmacodynamic properties of albiglutide and its clinical effects are discussed. The review encompassed a search of PubMed and a thorough analysis of the European Union and US Food and Drug Administration approval documents. Expert opinion: Albiglutide has a chemical structure quite distinct from that of other marketed GLP-1 RAs. The agent has less gastrointestinal side effects than other comparable GLP-1 RAs and is safe in patients with renal failure. As a sole treatment for diabetes and used with other hypoglycemic agents, it achieves a lowering of HbA1c of up to 1%, less than several competitor GLP-1 RAs. The benefit on weight reduction is minimal compared to other GLP-1 RAs. There exists concern about an imbalance of pancreatitis cases in the approval program as well as injection site reactions which led to discontinuance of therapy in up to 2% of participants. A large long term study now underway will determine if albiglutide, with its lower level of GI intolerance, has a place in the treatment of patients with increased risk of cardiovascular events.

  9. Nicotine receptor partial agonists for smoking cessation

    Directory of Open Access Journals (Sweden)

    Kate Cahill

    Full Text Available BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist and reducing smoking satisfaction (acting as an antagonist. OBJECTIVES: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including cytisine, dianicline and varenicline for smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist' in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, PsycINFO and Web of Science using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialized register was in December 2011. We also searched online clinical trials registers. SELECTION CRITERIA: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow-up. The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs, using the Mantel-Haenszel fixed-effect model. MAIN RESULTS: Two recent cytisine trials (937 people

  10. GPR119 Agonist AS1269574 Activates TRPA1 Cation Channels to Stimulate GLP-1 Secretion.

    Science.gov (United States)

    Chepurny, Oleg G; Holz, George G; Roe, Michael W; Leech, Colin A

    2016-06-01

    GPR119 is a G protein-coupled receptor expressed on intestinal L cells that synthesize and secrete the blood glucose-lowering hormone glucagon-like peptide-1 (GLP-1). GPR119 agonists stimulate the release of GLP-1 from L cells, and for this reason there is interest in their potential use as a new treatment for type 2 diabetes mellitus. AS1269574 is one such GPR119 agonist, and it is the prototype of a series of 2,4,6 trisubstituted pyrimidines that exert positive glucoregulatory actions in mice. Here we report the unexpected finding that AS1269574 stimulates GLP-1 release from the STC-1 intestinal cell line by directly promoting Ca(2+) influx through transient receptor potential ankyrin 1 (TRPA1) cation channels. These GPR119-independent actions of AS1269574 are inhibited by TRPA1 channel blockers (AP-18, A967079, HC030031) and are not secondary to intracellular Ca(2+) release or cAMP production. Patch clamp studies reveal that AS1269574 activates an outwardly rectifying membrane current with properties expected of TRPA1 channels. However, the TRPA1 channel-mediated action of AS1269574 to increase intracellular free calcium concentration is not replicated by GPR119 agonists (AR231453, oleoylethanolamide) unrelated in structure to AS1269574. Using human embryonic kidney-293 cells expressing recombinant rat TRPA1 channels but not GPR119, direct TRPA1 channel activating properties of AS1269574 are validated. Because we find that AS1269574 also acts in a conventional GPR119-mediated manner to stimulate proglucagon gene promoter activity in the GLUTag intestinal L cell line, new findings reported here reveal the surprising capacity of AS1269574 to act as a dual agonist at two molecular targets (GPR119/TRPA1) important to the control of L-cell function and type 2 diabetes mellitus drug discovery research.

  11. Estimating Utility

    DEFF Research Database (Denmark)

    Arndt, Channing; Simler, Kenneth R.

    2010-01-01

    A fundamental premise of absolute poverty lines is that they represent the same level of utility through time and space. Disturbingly, a series of recent studies in middle- and low-income economies show that even carefully derived poverty lines rarely satisfy this premise. This article proposes...... an information-theoretic approach to estimating cost-of-basic-needs (CBN) poverty lines that are utility consistent. Applications to date illustrate that utility-consistent poverty measurements derived from the proposed approach and those derived from current CBN best practices often differ substantially......, with the current approach tending to systematically overestimate (underestimate) poverty in urban (rural) zones....

  12. Directed evolution of a three-finger neurotoxin by using cDNA display yields antagonists as well as agonists of interleukin-6 receptor signaling

    Directory of Open Access Journals (Sweden)

    Naimuddin Mohammed

    2011-01-01

    Full Text Available Abstract Background Directed evolution of biomolecules such as DNA, RNA and proteins containing high diversity has emerged as an effective method to obtain molecules for various purposes. In the recent past, proteins from non-immunoglobulins have attracted attention as they mimic antibodies with respect to binding potential and provide further potential advantages. In this regard, we have attempted to explore a three-finger neurotoxin protein (3F. 3F proteins are small (~7 kDa, structurally well defined, thermally stable and resistant to proteolysis that presents them as promising candidates for directed evolution. Results We have engineered a snake α-neurotoxin that belongs to the 3F family by randomizing the residues in the loops involved in binding with acetylcholine receptors and employing cDNA display to obtain modulators of interleukin-6 receptor (IL-6R. Selected candidates were highly specific for IL-6R with dissociation constants and IC50s in the nanomolar range. Antagonists as well as agonists were identified in an IL-6 dependent cell proliferation assay. Size minimization yielded peptides of about one-third the molecular mass of the original proteins, without significant loss of activities and, additionally, lead to the identification of the loops responsible for function. Conclusions This study shows 3F protein is amenable to introduce amino acid changes in the loops that enable preparation of a high diversity library that can be utilized to obtain ligands against macromolecules. We believe this is the first report of protein engineering to convert a neurotoxin to receptor ligands other than the parent receptor, the identification of an agonist from non-immunoglobulin proteins, the construction of peptide mimic of IL-6, and the successful size reduction of a single-chain protein.

  13. Metabolic engineering of a glycerol-oxidative pathway in Lactobacillus panis PM1 for utilization of bioethanol thin stillage: potential to produce platform chemicals from glycerol.

    Science.gov (United States)

    Kang, Tae Sun; Korber, Darren R; Tanaka, Takuji

    2014-12-01

    Lactobacillus panis PM1 has the ability to produce 1,3-propanediol (1,3-PDO) from thin stillage (TS), which is the major waste material after bioethanol production, and is therefore of significance. However, the fact that L. panis PM1 cannot use glycerol as a sole carbon source presents a considerable problem in terms of utilization of this strain in a wide range of industrial applications. Accordingly, L. panis PM1 was genetically engineered to directly utilize TS as a fermentable substrate for the production of valuable platform chemicals without the need for exogenous nutrient supplementation (e.g., sugars and nitrogen sources). An artificial glycerol-oxidative pathway, comprised of glycerol facilitator, glycerol kinase, glycerol 3-phosphate dehydrogenase, triosephosphate isomerase, and NADPH-dependent aldehyde reductase genes of Escherichia coli, was introduced into L. panis PM1 in order to directly utilize glycerol for the production of energy for growth and value-added chemicals. A pH 6.5 culture converted glycerol to mainly lactic acid (85.43 mM), whereas a significant amount of 1,3-propanediol (59.96 mM) was formed at pH 7.5. Regardless of the pH, ethanol (82.16 to 83.22 mM) was produced from TS fermentations, confirming that the artificial pathway metabolized glycerol for energy production and converted it into lactic acid or 1,3-PDO and ethanol in a pH-dependent manner. This study demonstrates the cost-effective conversion of TS to value-added chemicals by the engineered PM1 strain cultured under industrial conditions. Thus, application of this strain or these research findings can contribute to reduced costs of bioethanol production. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  14. Analysis of the metabolic utilization of carbon sources and potential functional diversity of the bacterial community in lab-scale horizontal subsurface-flow constructed wetlands.

    Science.gov (United States)

    Deng, Huanhuan; Ge, Liyun; Xu, Tan; Zhang, Minghua; Wang, Xuedong; Zhang, Yalei; Peng, Hong

    2011-01-01

    Microorganisms are an integral part of the biogeochemical processes in wetlands. To improve the performance of constructed wetlands, it is very important to know the metabolic properties and functional diversity of the microbial communities. The purpose of this study is to analyze the metabolic properties and functional diversity of the microbial community in a horizontal subsurface-flow constructed wetland (CW) in a laboratory study through the sole-carbon-source utilization profiles using Biolog-ECO microplates. The technique has advantages over traditional cell culture techniques, such as molecular-level techniques-RNA amplification, which are time-consuming, expensive, and only applicable to the small number of species that may be cultured. This CW was designed to treat rural eutrophic water in China, using the plant L. This study showed that the metabolic activities of upper front substrate microorganisms (UF) were greater than those of the lower back substrate microorganisms (LB) in the CW. Integrated areas under average well color development (AWCD) curves of substrate microorganisms in the UF were 131.9, 4.8, and 99.3% higher than in the lower front part (LF), the upper back part (UB), and the LB part of the CW, respectively. Principal components analysis showed significant differences in both community structure and metabolic utilization of carbon sources between substrate microorganisms from different sampling sites. Carbon source utilization of polymers, carbohydrates, carboxylic acids, and amino acids was higher in UF than in LF, but that of amines and phenolic compounds was very similar in UF and LF. The richness, evenness, and diversity of upper substrate microbial communities were significantly higher than those of lower substrate. The LF substrate microbial communities had lower evenness than the other sampling plots, and the lowest richness of substrate microbial community was found in the LB part of the CW. Copyright © by the American Society of

  15. Development of a radioreceptor assay for β2 adrenergic agonists

    International Nuclear Information System (INIS)

    Helbo, V.; Vandenbroeck, M.; Maghuin-Rogister, G.

    1994-01-01

    Several β 2 adrenergic agonists are illegally used as growth promoters in meat production. We have developed and evaluated a radioreceptor assay for the multianalyte detection of these compounds. The method is based on a competition for binding with receptors (plasma membranes prepared from bovine teat muscles) between a radioactive tracer ( 3 H-dihydroalprenolol) and β 2 agonist residues present in the samples. The method has been validated for three β 2 agonists (clenbuterol, mabuterol and cimaterol) in bovine urine samples. The detection limit (mean of ''blank'' values + 3 SEM) in urine was 2.4 ppb clenbuterol. Using this procedure, samples containing at least 5 ppb of clenbuterol, mabuterol or cimaterol could be identified as positive for the presence of β 2 agonists. (orig.) [de

  16. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    Directory of Open Access Journals (Sweden)

    Akinori Hirashima

    2003-04-01

    Full Text Available The compounds 1-(2,6-diethylphenylimidazolidine-2-thione and 2-(2,6-diethylphenylimidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor.

  17. Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

    Science.gov (United States)

    Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. © 2010 American Academy of Forensic Sciences.

  18. MELATONIN DAN MELATONIN RECEPTOR AGONIST SEBAGAI PENANGANAN INSOMNIA PRIMER KRONIS

    Directory of Open Access Journals (Sweden)

    Ni Luh Putu Ayu Maha Iswari

    2013-04-01

    Full Text Available Melatonin is a hormone that has an important role in the mechanism of sleep. Hypnotic effects of melatonin and melatonin receptor agonist are mediated via MT1 and MT2 receptors, especially in circadian rhythm pacemaker, suprachiasmatic nucleus, which is worked on the hypothalamic sleep switch. This mechanism is quite different with the GABAergic drugs such as benzodiazepine. Agonist melatonin triggers the initiation of sleep and normalize circadian rhythms so that makes it easier to maintain sleep. The main disadvantage of melatonin in helping sleep maintenance on primary insomnia is that the half life is very short. The solution to this problem is the use of prolonged-release melatonin and melatonin receptor agonist agents such as ramelteon. Melatoninergic agonist does not cause withdrawal effects, dependence, as well as cognitive and psychomotor disorders as often happens on the use of benzodiazepine.  

  19. An evaluation of selected in silico models for the assessment of skin sensitization potential – performance and practical utility considerations (QSAR conference)

    Science.gov (United States)

    Skin sensitization remains an important endpoint for consumers, manufacturers and regulators. Although the development of alternative approaches to assess skin sensitization potential has been extremely active over many years, the implication of regulations such as REACH and the ...

  20. A preliminary PET evaluation of the new dopamine D2 receptor agonist [11C]MNPA in cynomolgus monkey

    International Nuclear Information System (INIS)

    Finnema, Sjoerd J.; Seneca, Nicholas; Farde, Lars; Shchukin, Evgeny; Sovago, Judit; Gulyas, Balazs; Wikstroem, Hakan V.; Innis, Robert B.; Neumeyer, John L.; Halldin, Christer

    2005-01-01

    This study describes the preliminary positron emission tomography (PET) evaluation of a dopamine D 2 -like receptor agonist (R)-2- 11 CH 3 O-N-n-propylnorapomorphine ([ 11 C]MNPA), as a potential new radioligand for in vivo imaging of the high-affinity state of the dopamine D 2 receptor (D 2 R). MNPA is a selective D 2 -like receptor agonist with a high affinity (K i =0.17 nM). [ 11 C]MNPA was successfully synthesized by direct O-methylation of (R)-2-hydroxy-NPA using [ 11 C]methyl iodide and was evaluated in cynomolgus monkeys. This study included baseline PET experiments and a pretreatment study using unlabeled raclopride (1 mg/kg). High uptake of radioactivity was seen in regions known to contain high D 2 R, with a maximum striatum-to-cerebellum ratio of 2.23±0.21 at 78 min and a maximum thalamus-to-cerebellum ratio of 1.37±0.06 at 72 min. The pretreatment study demonstrated high specific binding to D 2 R by reducing the striatum-to-cerebellum ratio to 1.26 at 78 min. This preliminary study indicates that the dopamine agonist [ 11 C]MNPA has potential as an agonist radioligand for the D 2 -like receptor and has potential for examination of the high-affinity state of the D 2 R in human subjects and patients with neuropsychiatric disorders

  1. Sleep attacks in patients taking dopamine agonists: review.

    Science.gov (United States)

    Homann, Carl Nikolaus; Wenzel, Karoline; Suppan, Klaudia; Ivanic, Gerd; Kriechbaum, Norbert; Crevenna, Richard; Ott, Erwin

    2002-06-22

    To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinson's disease, the type of drugs implicated, and strategies for prevention and treatment. Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic-like attacks were discussed in patients with Parkinson's disease. 124 patients with sleep events were found in 20 publications. Overall, 6.6% of patients taking dopamine agonists who attended movement disorder centres had sleep events. Men were over-represented. Sleep events occurred at both high and low doses of the drugs, with different durations of treatment (0-20 years), and with or without preceding signs of tiredness. Sleep attacks are a class effect, having been found in patients taking the following dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists (apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32, ropinirole in 38). Reports suggest two distinct types of events: those of sudden onset without warning and those of slow onset with prodrome drowsiness. Insufficient data are available to provide effective guidelines for prevention and treatment of sleep events in patients taking dopamine agonists for Parkinson's disease. Prospective population based studies are needed to provide this information.

  2. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond

    Directory of Open Access Journals (Sweden)

    Lalita Prasad-Reddy

    2015-07-01

    Full Text Available The prevalence of type 2 diabetes is increasing at an astounding rate. Many of the agents used to treat type 2 diabetes have undesirable adverse effects of hypoglycemia and weight gain. Glucagon-like peptide-1 (GLP-1 receptor agonists represent a unique approach to the treatment of diabetes, with benefits extending outside glucose control, including positive effects on weight, blood pressure, cholesterol levels, and beta-cell function. They mimic the effects of the incretin hormone GLP-1, which is released from the intestine in response to food intake. Their effects include increasing insulin secretion, decreasing glucagon release, increasing satiety, and slowing gastric emptying. There are currently four approved GLP-1 receptor agonists in the United States: exenatide, liraglutide, albiglutide, and dulaglutide. A fifth agent, lixisenatide, is available in Europe. There are important pharmacodynamic, pharmacokinetic, and clinical differences of each agent. The most common adverse effects seen with GLP-1 therapy include nausea, vomiting, and injection-site reactions. Other warnings and precautions include pancreatitis and thyroid cell carcinomas. GLP-1 receptor agonists are an innovative and effective option to improve blood glucose control, with other potential benefits of preserving beta-cell function, weight loss, and increasing insulin sensitivity. Once-weekly formulations may also improve patient adherence. Overall, these are effective agents for patients with type 2 diabetes, who are either uncontrolled on metformin or intolerant to metformin.

  3. Osteoprotegerin and β2-Agonists Mitigate Muscular Dystrophy in Slow- and Fast-Twitch Skeletal Muscles.

    Science.gov (United States)

    Dufresne, Sébastien S; Boulanger-Piette, Antoine; Frenette, Jérôme

    2017-03-01

    Our recent work showed that daily injections of osteoprotegerin (OPG)-immunoglobulin fragment complex (OPG-Fc) completely restore the function of fast-twitch extensor digitorum longus muscles in dystrophic mdx mice, a murine model of Duchenne muscular dystrophy. However, despite marked improvements, OPG-Fc was not as effective in preventing the loss of function of slow-twitch soleus and diaphragm muscles. Because β 2 -agonists enhance the function of slow- and fast-twitch dystrophic muscles and because their use is limited by their adverse effects on bone and cardiac tissues, we hypothesized that OPG-Fc, a bone and skeletal muscle protector, acts synergistically with β 2 -agonists and potentiates their positive effects on skeletal muscles. We observed that the content of β 2 -adrenergic receptors, which are mainly expressed in skeletal muscle, is significantly reduced in dystrophic muscles but is rescued by the injection of OPG-Fc. Most important, OPG-Fc combined with a low dose of formoterol, a member of a new generation of β 2 -agonists, histologically and functionally rescued slow-twitch dystrophic muscles. This combination of therapeutic agents, which have already been tested and approved for human use, may open up new therapeutic avenues for Duchenne muscular dystrophy and possibly other neuromuscular diseases. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  4. Beta-Adrenergic Receptors and Mechanisms in Asthma: The New Long-Acting Beta-Agonists

    Directory of Open Access Journals (Sweden)

    Robert G Townley

    1996-01-01

    Full Text Available The objective is to review β-adrenergic receptors and mechanisms in the immediate and late bronchial reaction in asthma and the new long-acting β-agonist. This will be discussed in light of the controversy of the potential adverse effect of regular use of long-acting β-agonists. We studied the effect of formoterol on the late asthmatic response (LAR and airway inflammation in guinea-pigs. Formoterol suppressed the LAR, antigen-induced airway inflammation and hyperresponsiveness, although isoproterenol failed to inhibit these parameters. β-Adrenergic hyporesponsiveness, and cholinergic and a- adrenergic hyperresponsiveness have been implicated in the pathogenesis of asthma. A decrease in β-adrenoreceptor function can result either from exogenously administered β-agonist or from exposure to allergens resulting in a late bronchial reaction. There is increasing evidence that eosinophils, macrophages, and lymphocytes which are of primary importance in the late bronchial reaction are also modulated by β2- adrenoreceptors. In functional studies of guinea-pig or human isolated trachea and lung parenchyma, PAF and certain cytokines significantly reduced the potency of isoproterenol to reverse methacholine- or histamine-induced contraction. The effect of glucocorticoids on pulmonary β-adrenergic receptors and responses suggests an important role for glucocorticoids to increase β-adrenergic receptors and responsiveness.

  5. Nanoparticles containing a liver X receptor agonist inhibit inflammation and atherosclerosis.

    Science.gov (United States)

    Zhang, Xue-Qing; Even-Or, Orli; Xu, Xiaoyang; van Rosmalen, Mariska; Lim, Lucas; Gadde, Suresh; Farokhzad, Omid C; Fisher, Edward A

    2015-01-28

    Liver X receptor (LXR) signaling pathways regulate lipid metabolism and inflammation, which has generated widespread interest in developing synthetic LXR agonists as potential therapeutics for the management of atherosclerosis. In this study, it is demonstrated that nanoparticles (NPs) containing the synthetic LXR agonist GW3965 (NP-LXR) exert anti-inflammatory effects and inhibit the development of atherosclerosis without causing hepatic steatosis. These NPs are engineered through self-assembly of a biodegradable diblock poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) copolymer. NP-LXR is significantly more effective than free GW3965 at inducing LXR-target gene expression and suppressing inflammatory factors in macrophages in vitro and in vivo. Additionally, the NPs elicit negligible lipogenic gene stimulation in the liver. Using the Ldlr (-/-) mouse model of atherosclerosis, abundant colocalization of fluorescently labeled NPs within plaque macrophages following systemic administration is seen. Notably, six intravenous injections of NP-LXR over 2 weeks markedly reduce the CD68-positive cell (macrophage) content of plaques (by 50%) without increasing total cholesterol or triglycerides in the liver and plasma. Together, these findings identify GW3965-encapsulated PLGA-b-PEG NPs as a promising nanotherapeutic approach to combat atherosclerosis, providing the benefits of LXR agonists without their adverse effects on hepatic and plasma lipid metabolism. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Structure-Based Screening of Uncharted Chemical Space for Atypical Adenosine Receptor Agonists.

    Science.gov (United States)

    Rodríguez, David; Chakraborty, Saibal; Warnick, Eugene; Crane, Steven; Gao, Zhan-Guo; O'Connor, Robert; Jacobson, Kenneth A; Carlsson, Jens

    2016-10-21

    Small molecule screening libraries cover only a small fraction of the astronomical number of possible drug-like compounds, limiting the success of ligand discovery efforts. Computational screening of virtual libraries representing unexplored chemical space could potentially bridge this gap. Drug development for adenosine receptors (ARs) as targets for inflammation and cardiovascular diseases has been hampered by the paucity of agonist scaffolds. To identify novel AR agonists, a virtual library of synthetically tractable nucleosides with alternative bases was generated and structure-based virtual screening guided selection of compounds for synthesis. Pharmacological assays were carried out at three AR subtypes for 13 ribosides. Nine compounds displayed significant activity at the ARs, and several of these represented atypical agonist scaffolds. The discovered ligands also provided insights into receptor activation and revealed unknown interactions of endogenous and clinical compounds with the ARs. The results demonstrate that virtual compound databases provide access to bioactive matter from regions of chemical space that are sparsely populated in commercial libraries, an approach transferrable to numerous drug targets.

  7. A step ahead of PPARγ full agonists to PPARγ partial agonists: therapeutic perspectives in the management of diabetic insulin resistance.

    Science.gov (United States)

    Chigurupati, Sridevi; Dhanaraj, Sokkalingam A; Balakumar, Pitchai

    2015-05-15

    Described since long as a member of the nuclear receptor superfamily, peroxisome proliferator-activated receptors (PPARs) regulate the gene expression of proteins involved in glucose and lipid metabolism. PPARs indeed regulate several physiologic processes, including lipid homeostasis, adipogenesis, inflammation, and wound healing. PPARs bind natural or synthetic PPAR ligands can function as cellular sensors to regulate the gene transcription. Dyslipidemia, and type 2 diabetes mellitus (T2DM) with insulin resistance are treated using agonists of PPARα and PPARγ, respectively. The PPARγ is a key regulator of insulin sensitization and glucose metabolism, and therefore is considered as an imperative pharmacological target to combat diabetic metabolic disease and insulin resistance. Of note, currently available PPARγ full agonists like rosiglitazone display serious adverse effects such as fluid retention/oedema, weight gain, and increased incidence of cardiovascular events. On the other hand, PPARγ partial agonists are being suggested to devoid or having less incidence of these undesirable events, and are under developmental stages. Current research is on the way for the development of novel PPARγ partial agonists with enhanced therapeutic efficacy and reduced adverse effects. This review sheds lights on the current status of development of PPARγ partial agonists, for the management of T2DM, having comparatively less or no adverse effects to that of PPARγ full agonists. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Chronic exposure to dopamine agonists affects the integrity of striatal D2 receptors in Parkinson's patients

    Directory of Open Access Journals (Sweden)

    Marios Politis

    2017-01-01

    Full Text Available We aimed to investigate the integrity and clinical relevance of striatal dopamine receptor type-2 (D2R availability in Parkinson's disease (PD patients. We studied 68 PD patients, spanning from early to advanced disease stages, and 12 healthy controls. All participants received one [11C]raclopride PET scan in an OFF medication condition for quantification of striatal D2R availability in vivo. Parametric images of [11C]raclopride non-displaceable binding potential were generated from the dynamic [11C]raclopride scans using implementation of the simplified reference tissue model with cerebellum as the reference tissue. PET data were interrogated for correlations with clinical data related to disease burden and dopaminergic treatment. PD patients showed a mean 16.7% decrease in caudate D2R and a mean 3.5% increase in putaminal D2R availability compared to healthy controls. Lower caudate [11C]raclopride BPND correlated with longer PD duration. PD patients on dopamine agonist treatment had 9.2% reduced D2R availability in the caudate and 12.8% in the putamen compared to PD patients who never received treatment with dopamine agonists. Higher amounts of lifetime dopamine agonist therapy correlated with reduced D2Rs availability in both caudate and putamen. No associations between striatal D2R availability and levodopa treatment and dyskinesias were found. In advancing PD the caudate and putamen D2R availability are differentially affected. Chronic exposure to treatment with dopamine agonists, but no levodopa, suppresses striatal D2R availability, which may have relevance to output signaling to frontal lobes and the occurrence of executive deficits, but not dyskinesias.

  9. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.

    Science.gov (United States)

    Oh, Da Young; Walenta, Evelyn; Akiyama, Taro E; Lagakos, William S; Lackey, Denise; Pessentheiner, Ariane R; Sasik, Roman; Hah, Nasun; Chi, Tyler J; Cox, Jason M; Powels, Mary Ann; Di Salvo, Jerry; Sinz, Christopher; Watkins, Steven M; Armando, Aaron M; Chung, Heekyung; Evans, Ronald M; Quehenberger, Oswald; McNelis, Joanne; Bogner-Strauss, Juliane G; Olefsky, Jerrold M

    2014-08-01

    It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.

  10. Prediction of selective estrogen receptor beta agonist using open data and machine learning approach.

    Science.gov (United States)

    Niu, Ai-Qin; Xie, Liang-Jun; Wang, Hui; Zhu, Bing; Wang, Sheng-Qi

    2016-01-01

    Estrogen receptors (ERs) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. ERs have been validated as important drug targets for the treatment of various diseases, including breast cancer, ovarian cancer, osteoporosis, and cardiovascular disease. ERs have two subtypes, ER-α and ER-β. Emerging data suggest that the development of subtype-selective ligands that specifically target ER-β could be a more optimal approach to elicit beneficial estrogen-like activities and reduce side effects. Herein, we focused on ER-β and developed its in silico quantitative structure-activity relationship models using machine learning (ML) methods. The chemical structures and ER-β bioactivity data were extracted from public chemogenomics databases. Four types of popular fingerprint generation methods including MACCS fingerprint, PubChem fingerprint, 2D atom pairs, and Chemistry Development Kit extended fingerprint were used as descriptors. Four ML methods including Naïve Bayesian classifier, k-nearest neighbor, random forest, and support vector machine were used to train the models. The range of classification accuracies was 77.10% to 88.34%, and the range of area under the ROC (receiver operating characteristic) curve values was 0.8151 to 0.9475, evaluated by the 5-fold cross-validation. Comparison analysis suggests that both the random forest and the support vector machine are superior for the classification of selective ER-β agonists. Chemistry Development Kit extended fingerprints and MACCS fingerprint performed better in structural representation between active and inactive agonists. These results demonstrate that combining the fingerprint and ML approaches leads to robust ER-β agonist prediction models, which are potentially applicable to the identification of selective ER-β agonists.

  11. Characterization of 12 GnRH peptide agonists – a kinetic perspective

    Science.gov (United States)

    Nederpelt, Indira; Georgi, Victoria; Schiele, Felix; Nowak‐Reppel, Katrin; Fernández‐Montalván, Amaury E.; IJzerman, Adriaan P.

    2015-01-01

    Background and Purpose Drug‐target residence time is an important, yet often overlooked, parameter in drug discovery. Multiple studies have proposed an increased residence time to be beneficial for improved drug efficacy and/or longer duration of action. Currently, there are many drugs on the market targeting the gonadotropin‐releasing hormone (GnRH) receptor for the treatment of hormone‐dependent diseases. Surprisingly, the kinetic receptor‐binding parameters of these analogues have not yet been reported. Therefore, this project focused on determining the receptor‐binding kinetics of 12 GnRH peptide agonists, including many marketed drugs. Experimental Approach A novel radioligand‐binding competition association assay was developed and optimized for the human GnRH receptor with the use of a radiolabelled peptide agonist, [125I]‐triptorelin. In addition to radioligand‐binding studies, a homogeneous time‐resolved FRET Tag‐lite™ method was developed as an alternative assay for the same purpose. Key Results Two novel competition association assays were successfully developed and applied to determine the kinetic receptor‐binding characteristics of 12 high‐affinity GnRH peptide agonists. Results obtained from both methods were highly correlated. Interestingly, the binding kinetics of the peptide agonists were more divergent than their affinities with residence times ranging from 5.6 min (goserelin) to 125 min (deslorelin). Conclusions and Implications Our research provides new insights by incorporating kinetic, next to equilibrium, binding parameters in current research and development that can potentially improve future drug discovery targeting the GnRH receptor. PMID:26398856

  12. Histamine therapeutic efficacy in metastatic melanoma: Role of histamine H4 receptor agonists and opportunity for combination with radiation.

    Science.gov (United States)

    Massari, Noelia A; Nicoud, Melisa B; Sambuco, Lorena; Cricco, Graciela P; Martinel Lamas, Diego J; Herrero Ducloux, María V; Blanco, Horacio; Rivera, Elena S; Medina, Vanina A

    2017-04-18

    The aims of the work were to improve our knowledge of the role of H4R in melanoma proliferation and assess in vivo the therapeutic efficacy of histamine, clozapine and JNJ28610244, an H4R agonist, in a preclinical metastatic model of melanoma. Additionally, we aimed to investigate the combinatorial effect of histamine and gamma radiation on the radiobiological response of melanoma cells.Results indicate that 1205Lu metastatic melanoma cells express H4R and that histamine inhibits proliferation, in part through the stimulation of the H4R, and induces cell senescence and melanogenesis. Daily treatment with H4R agonists (1 mg/kg, sc) exhibited a significant in vivo antitumor effect and importantly, compounds reduced metastatic potential, particularly in the group treated with JNJ28610244, the H4R agonist with higher specificity. H4R is expressed in benign and malignant lesions of melanocytic lineage, highlighting the potential clinical use of histamine and H4R agonists. In addition, histamine increased radiosensitivity of melanoma cells in vitro and in vivo. We conclude that stimulation of H4R by specific ligands may represent a novel therapeutic strategy in those tumors that express this receptor. Furthermore, through increasing radiation-induced response, histamine could improve cancer radiotherapy for the treatment of melanoma.

  13. G-protein mediates voltage regulation of agonist binding to muscarinic receptors: effects on receptor-Na/sup +/ channel interaction

    Energy Technology Data Exchange (ETDEWEB)

    Cohen-Armon, M.; Garty, H.; Sokolovsky, M.

    1988-01-12

    The authors previous experiments in membranes prepared from rat heart and brain led them to suggest that the binding of agonist to the muscarinic receptors and to the Na/sup +/ channels is a coupled event mediated by guanine nucleotide binding protein(s) (G-protein(s)). These in vitro findings prompted us to employ synaptoneurosomes from brain stem tissue to examine (i) the binding properties of (/sup 3/H) acetylcholine at resting potential and under depolarization conditions in the absence and presence of pertussis toxin; (ii) the binding of (/sup 3/H)batrachotoxin to Na/sup +/ channel(s) in the presence of the muscarinic agonists; and (iii) muscarinically induced /sup 22/Na/sup +/ uptake in the presence and absence of tetrodotoxin, which blocks Na/sup +/ channels. The findings indicate that agonist binding to muscarinic receptors is voltage dependent, that this process is mediated by G-protein(s), and that muscarinic agonists induce opening of Na/sup +/channels. The latter process persists even after pertussis toxin treatment, indicating that it is not likely to be mediated by pertussis toxin sensitive G-protein(s). The system with its three interacting components-receptor, G-protein, and Na/sup +/ channel-is such that at resting potential the muscarinic receptor induces opening of Na/sup +/ channels; this property may provide a possible physiological mechanism for the depolarization stimulus necessary for autoexcitation or repetitive firing in heart or brain tissues.

  14. Pimavanserin, a 5-HT2A inverse agonist, reverses psychosis-like behaviors in a rodent model of Parkinson's disease.

    Science.gov (United States)

    McFarland, Krista; Price, Diana L; Bonhaus, Douglas W

    2011-10-01

    Parkinson's disease psychosis (PDP) is a condition for which a safe, tolerated, and effective therapy is lacking. Treatment with typical or atypical antipsychotics may be contraindicated in patients with PDP because of the potential for aggravating motor symptoms. This study used a novel animal model with features of both Parkinson's disease (PD) and psychosis to examine a potential mechanism for reversing PDP. Animals with bilateral 6-hydroxydopamine lesions of the substantia nigra displayed motoric impairments characteristic of humans with PD. In addition, they displayed augmented head twitches, augmented amphetamine-induced locomotor activity, and disrupted prepulse inhibition compared with sham controls, behavioral indices frequently used to assess antipsychotic activity in animal models. Pimavanserin, a selective 5-HT2A antagonist/inverse agonist, reversed the psychotic-like behavioral deficits, suggesting that nigrostriatal (6-hydroxydopamine) lesions induced alterations in 5-HT2A-mediated signaling. The selective 5-HT2A inverse agonist M100907, but not the selective 5-HT2C inverse agonist SB 252084 paralleled the effects of pimavanserin. Of note, the reversal of psychotic-like behaviors produced by 5-HT2A inverse agonists occurred without disrupting motor behaviors in lesioned subjects, suggesting that 5HT2A antagonism/inverse agonism may be beneficial in the treatment of PDP.

  15. G-protein mediates voltage regulation of agonist binding to muscarinic receptors: effects on receptor-Na+ channel interaction

    International Nuclear Information System (INIS)

    Cohen-Armon, M.; Garty, H.; Sokolovsky, M.

    1988-01-01

    The authors previous experiments in membranes prepared from rat heart and brain led them to suggest that the binding of agonist to the muscarinic receptors and to the Na + channels is a coupled event mediated by guanine nucleotide binding protein(s) [G-protein(s)]. These in vitro findings prompted us to employ synaptoneurosomes from brain stem tissue to examine (i) the binding properties of [ 3 H] acetylcholine at resting potential and under depolarization conditions in the absence and presence of pertussis toxin; (ii) the binding of [ 3 H]batrachotoxin to Na + channel(s) in the presence of the muscarinic agonists; and (iii) muscarinically induced 22 Na + uptake in the presence and absence of tetrodotoxin, which blocks Na + channels. The findings indicate that agonist binding to muscarinic receptors is voltage dependent, that this process is mediated by G-protein(s), and that muscarinic agonists induce opening of Na + channels. The latter process persists even after pertussis toxin treatment, indicating that it is not likely to be mediated by pertussis toxin sensitive G-protein(s). The system with its three interacting components-receptor, G-protein, and Na + channel-is such that at resting potential the muscarinic receptor induces opening of Na + channels; this property may provide a possible physiological mechanism for the depolarization stimulus necessary for autoexcitation or repetitive firing in heart or brain tissues

  16. Potential of solid waste utilization as source of refuse derived fuel (RDF) energy (case study at temporary solid waste disposal site in West Jakarta)

    Science.gov (United States)

    Indrawati, D.; Lindu, M.; Denita, P.

    2018-01-01

    This study aims to measure the volume of solid waste generated as well asits density, composition, and characteristics, to analyze the potential of waste in TPS to become RDF materials and to analyze the best composition mixture of RDF materials. The results show that the average of solid waste generation in TPS reaches 40.80 m3/day, with the largest percentage of its share is the organic waste component of 77.9%, while the smallest amount of its share is metal and rubber of 0.1%. The average water content and ash content of solid waste at the TPS is 27.7% and 6.4% respectively, while the average calorific potential value is 728.71 kcal/kg. The results of solid waste characteristics comparison at three TPS indicate thatTPS Tanjung Duren has the greatest waste potential to be processed into RDF materials with a calorific value of 893.73 kcal/kg, water content level of 24.6%, andlow ash content of 6.11%. This research has also shown that the best composition for RDF composite materials is rubber, wood, and textile mixtureexposed to outdoor drying conditions because it produced low water content and low ash content of 10.8% and 9.6%, thus optimizedthe calorific value of 4,372.896 kcal/kg.

  17. Interaction between corticosteroid and beta-agonist drugs. Biochemical and cardiovascular effects in normal subjects.

    Science.gov (United States)

    Taylor, D R; Wilkins, G T; Herbison, G P; Flannery, E M

    1992-08-01

    The aim of this study was to investigate whether the administration of prednisone potentiates any of the acute biochemical and cardiovascular effects of high-dose inhaled beta-agonist drugs. These agents are known to cause dose-related changes in plasma potassium and glucose, as well as ECG changes in heart rate, corrected QT interval (QTc), T wave, and U wave. On theoretical grounds, the concomitant use of systemic corticosteroids might enhance these actions. Twenty-four healthy subjects were randomized to receive one of three treatments: salbutamol 5 mg or fenoterol 5 mg or normal saline solution. Each drug was administered twice, 30 min apart by nebulizer, and the procedure was repeated after each subject had received prednisone 30 mg daily for one week. Plasma potassium and glucose levels were measured, and ECGs were obtained after each treatment, together with 12-h Holter monitoring for arrhythmias. Changes in plasma potassium and glucose following nebulized beta-agonist were significantly greater after treatment with prednisone. Baseline potassium level fell from 3.75 mmol/L (95 percent CI 3.61, 3.89) to 3.50 mmol/L (95 percent CI 3.36, 3.64), and thereafter all values were significantly lower at each time point (p = 0.003). The lowest mean plasma potassium was obtained 90 min after fenoterol administration with prednisone pretreatment: 2.78 mmol/L (95 percent CI 2.44, 3.13). Increases in heart rate and QTc interval following both beta-agonist drugs were significant, but T-wave amplitude reductions did not reach significance. Prednisone treatment did not significantly alter the cardiovascular responses. Supraventricular and ventricular ectopic activity was related to beta-agonist use, but no potentiating effect was noted following steroid treatment. We conclude that the acute biochemical effects of beta-agonist administration are augmented by prior treatment with prednisone, but this is not the case for ECG effects. However, the degree of hypokalemia noted as

  18. Identification of PPARgamma partial agonists of natural origin (II: in silico prediction in natural extracts with known antidiabetic activity.

    Directory of Open Access Journals (Sweden)

    Laura Guasch

    Full Text Available BACKGROUND: Natural extracts have played an important role in the prevention and treatment of diseases and are important sources for drug discovery. However, to be effectively used in these processes, natural extracts must be characterized through the identification of their active compounds and their modes of action. METHODOLOGY/PRINCIPAL FINDINGS: From an initial set of 29,779 natural products that are annotated with their natural source and using a previously developed virtual screening procedure (carefully validated experimentally, we have predicted as potential peroxisome proliferators-activated receptor gamma (PPARγ partial agonists 12 molecules from 11 extracts known to have antidiabetic activity. Six of these molecules are similar to molecules with described antidiabetic activity but whose mechanism of action is unknown. Therefore, it is plausible that these 12 molecules could be the bioactive molecules responsible, at least in part, for the antidiabetic activity of the extracts containing them. In addition, we have also identified as potential PPARγ partial agonists 10 molecules from 16 plants with undescribed antidiabetic activity but that are related (i.e., they are from the same genus to plants with known antidiabetic properties. None of the 22 molecules that we predict as PPARγ partial agonists show chemical similarity with a group of 211 known PPARγ partial agonists obtained from the literature. CONCLUSIONS/SIGNIFICANCE: Our results provide a new hypothesis about the active molecules of natural extracts with antidiabetic properties and their mode of action. We also suggest plants with undescribed antidiabetic activity that may contain PPARγ partial agonists. These plants represent a new source of potential antidiabetic extracts. Consequently, our work opens the door to the discovery of new antidiabetic extracts and molecules that can be of use, for instance, in the design of new antidiabetic drugs or functional foods focused

  19. Utilization of potentials - regular reduction of costs. An intelligent regulation and control of cooling furniture; Potenziale nutzen - Kosten geregelt senken. Intelligente Regelung und Steuerung von Kuehlmoebeln

    Energy Technology Data Exchange (ETDEWEB)

    Di Lieto, Gianluca [Wurm GmbH und Co. KG Elektronische Systeme, Remscheid (Germany). Bereich Vertrieb und Marketing

    2011-02-15

    The trade installs new, energy-efficient refrigerant plants and equips its salesrooms with energy-saving cooling furniture. In order to work in such a way that all potentials are exhausted an intelligent regulation and control is necessary. At the same time these systems help to fulfil legal requirements to a large extent automatically as for example with the security of food by means of a correct storage temperature (HACCP). But in the sense of a positive environmental balance, not all options are used by the users so far. They renounce savings with the energy in the two digit percent area due to an individual adjustment of the plant operation.

  20. Ecdysone Agonist: New Insecticides with Novel Mode of Action

    Directory of Open Access Journals (Sweden)

    Y. Andi Trisyono

    2002-12-01

    Full Text Available Development of insect resistance to insecticide has been the major driving force for the development of new insecticides. Awareness and demand from public for more environmentally friendly insecticides have contributed in shifting the trend from using broad spectrum to selective insecticides. As a result, scientists have looked for new target sites beyond the nervous system. Insect growth regulators (IGRs are more selective insecticides than conventional insecticides, and ecdysone agonists are the newest IGRs being commercialized, e.g. tebufenozide, methoxyfenozide, and halofenozide. Ecdysone agonists bind to the ecdysteroid receptors, and they act similarly to the molting hormone 20-hydroxyecdysone. The binding provides larvae or nymphs with a signal to enter a premature and lethal molting cycle. In addition, the ecdysone agonists cause a reduction in the number of eggs laid by female insects. The ecdysone agonists are being developed as selective biorational insecticides. Tebufenozide and methoxyfenozide are used to control lepidopteran insect pests, whereas halofenozide is being used to control coleopteran insect pests. Their selectivity is due to differences in the binding affinity between these compounds to the receptors in insects from different orders. The selectivity of these compounds makes them candidates to be used in combinations with other control strategies to develop integrated pest management programs in agricultural ecosystems. Key words: new insecticides, selectivity, ecdysone agonists

  1. Modification of opiate agonist binding by pertussis toxin

    Energy Technology Data Exchange (ETDEWEB)

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  2. Agonistic behavior enhances adult neurogenesis in male Acheta domesticus crickets.

    Science.gov (United States)

    Ghosal, Kaushik; Gupta, Mohit; Killian, Kathleen A

    2009-07-01

    We examined the effect of agonistic behavior on cell proliferation and neurogenesis in the central nervous system (CNS) of adult male Acheta domesticus crickets. We combined 5-bromo,2'deoxyuridine (BrdU)-labeling of dividing cells with immunocytochemical detection of the neuronal marker horseradish peroxidase to examine the proliferation of progenitor cells and the survival of newborn neurons. In crickets, the mushroom bodies of the brain contain clusters of proliferative cells that divide and generate new neurons in adulthood. Pairs of male crickets were allowed to fight and establish social rank and were then injected with BrdU. Proliferation of mushroom body neurogenic cluster cells was unaffected by agonistic interactions; 24 h after a fight, the number of BrdU positive cells in fought and un-fought males did not significantly differ. However, agonistic interactions did influence cell survival. Two weeks after an agonistic interaction, fought males had more newborn neurons than males that did not fight. There was also a rank-specific effect because dominant males had significantly more new neurons than subordinates. We also report for the first time that neurogenesis in adult crickets can occur in other regions of the brain and in other CNS ganglia, including the terminal abdominal ganglion (TAG). Agonistic interactions enhanced the proliferation of these distributed precursor cells but did not increase the survival of the newborn neurons generated by these cells.

  3. Unique interaction pattern for a functionally biased ghrelin receptor agonist

    DEFF Research Database (Denmark)

    Sivertsen, Bjørn Behrens; Lang, Manja; Frimurer, Thomas M.

    2011-01-01

    Based on the conformationally constrained D-Trp-Phe-D-Trp (wFw) core of the prototype inverse agonist [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]substance P, a series of novel, small, peptide-mimetic agonists for the ghrelin receptor were generated. By using various simple, ring-constrained spacers...... connecting the D-Trp-Phe-D-Trp motif with the important C-terminal carboxyamide group, 40 nm agonism potency was obtained and also in one case (wFw-Isn-NH(2), where Isn is isonipecotic acid) ~80% efficacy. However, in contrast to all previously reported ghrelin receptor agonists, the piperidine-constrained w......Fw-Isn-NH(2) was found to be a functionally biased agonist. Thus, wFw-Isn-NH(2) mediated potent and efficacious signaling through the Ga(q) and ERK1/2 signaling pathways, but in contrast to all previous ghrelin receptor agonists it did not signal through the serum response element, conceivably the Ga(12...

  4. Modification of opiate agonist binding by pertussis toxin

    International Nuclear Information System (INIS)

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-01-01

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in 3 (H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding

  5. The risky business of dopamine agonists in Parkinson disease and impulse control disorders.

    Science.gov (United States)

    Claassen, Daniel O; van den Wildenberg, Wery P M; Ridderinkhof, K Richard; Jessup, Charles K; Harrison, Madaline B; Wooten, G Frederick; Wylie, Scott A

    2011-08-01

    Risk-taking behavior is characterized by pursuit of reward in spite of potential negative consequences. Dopamine neurotransmission along the mesocorticolimbic pathway is a potential modulator of risk behavior. In patients with Parkinson's disease (PD), impulse control disorder (ICD) can result from dopaminergic medication use, particularly dopamine agonists (DAA). Behaviors associated with ICD include hypersexuality as well as compulsive gambling, shopping, and eating, and these behaviors are potentially linked to alterations to risk processing. Using the Balloon Analogue Risk Task, we assessed the role of agonist therapy on risk-taking behavior in PD patients with (n = 22) and without (n = 19) active ICD symptoms. Patients performed the task both "on" and "off" DAA. DAA increased risk-taking in PD patients with active ICD symptoms, but it did not affect risk behavior of PD controls. DAA dose was also important in explaining risk behavior. Both groups similarly reduced their risk-taking in high compared to low risk conditions and following the occurrence of a negative consequence, suggesting that ICD patients do not necessarily differ in their abilities to process and adjust to some aspects of negative consequences. Our findings suggest dopaminergic augmentation of risk-taking behavior as a potential contributing mechanism for the emergence of ICD in PD patients. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

  6. ECUT: Energy Conversion and Utilization Technologies program biocatalysis research activity. Potential membrane applications to biocatalyzed processes: Assessment of concentration polarization and membrane fouling

    Science.gov (United States)

    Ingham, J. D.

    1983-01-01

    Separation and purification of the products of biocatalyzed fermentation processes, such as ethanol or butanol, consumes most of the process energy required. Since membrane systems require substantially less energy for separation than most alternatives (e.g., distillation) they have been suggested for separation or concentration of fermentation products. This report is a review of the effects of concentration polarization and membrane fouling for the principal membrane processes: microfiltration, ultrafiltration, reverse osmosis, and electrodialysis including a discussion of potential problems relevant to separation of fermentation products. It was concluded that advanced membrane systems may result in significantly decreased energy consumption. However, because of the need to separate large amounts of water from much smaller amounts of product that may be more volatile than wate, it is not clear that membrane separations will necessarily be more efficient than alternative processes.

  7. Utilizing a Two-stage Design to Investigate the Safety and Potential Efficacy of Monthly Naltrexone Plus Once-daily Bupropion as a Treatment for Methamphetamine Use Disorder.

    Science.gov (United States)

    Mooney, Larissa J; Hillhouse, Maureen P; Thomas, Christie; Ang, Alfonso; Sharma, Gaurav; Terry, Garth; Chang, Linda; Walker, Robrina; Trivedi, Madhukar; Croteau, David; Sparenborg, Steven; Ling, Walter

    2016-01-01

    This 2-stage open-label pilot study evaluated the safety and potential efficacy of naltrexone + bupropion as a pharmacotherapy for methamphetamine (MA) use disorder. The study was conducted in 2 stages of recruitment across 3 sites; 20 participants were enrolled in stage 1 and 29 participants were enrolled in stage 2. Eight weeks of open-label pharmacotherapy with a combination of extended-release injectable naltrexone (XR-NTX; Vivitrol) plus extended-release oral bupropion (BRP; Wellbutrin XL) were provided with a smartphone-assisted medication adherence platform. Participants met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for severe MA use disorder, self-reported ≥20 days of MA use in the 30 days prior to consent, and submitted 3 MA-positive urine drug screens (UDS) out of 4 collected during screening. Participants attended clinic twice weekly for observed BRP dosing, UDS testing, assessments, and medical management; XR-NTX was administered at weeks 1 and 5. A BRP taper and follow-up visit occurred in week 9. Analyses evaluated effects of XR-NTX + BRP to determine the number of "responders" according to a statistically predefined response criterion (6 of 8 MA-negative UDS during the last 4 weeks of medication). The 2-stage design required that stage 1 yield ≥3 responders to continue to stage 2; 11 of the 49 participants met responder criteria across both stages (5 in stage 1, 6 in stage 2). Under the statistical analysis plan, study "success" required ≥9 responders. With 11 responders, the study demonstrated sufficient potential of naltrexone plus bupropion as a combination pharmacotherapy for MA use disorder to warrant further study.

  8. Utilizing metal tolerance potential of soil fungus for efficient synthesis of gold nanoparticles with superior catalytic activity for degradation of rhodamine B.

    Science.gov (United States)

    Bhargava, Arpit; Jain, Navin; Khan, Mohd Azeem; Pareek, Vikram; Dilip, R Venkataramana; Panwar, Jitendra

    2016-12-01

    In recent years, the surging demand of nanomaterials has boosted unprecedented expansion of research for the development of high yielding and sustainable synthesis methods which can deliver nanomaterials with desired characteristics. Unlike the well-established physico-chemical methods which have various limitations, biological methods inspired by mimicking natural biomineralization processes have great potential for nanoparticle synthesis. An eco-friendly and sustainable biological method that deliver particles with well-defined shape, size and compositions can be developed by selecting a proficient organism followed by fine tuning of various process parameter. The present study revealed high metal tolerance ability of a soil fungus Cladosporium oxysporum AJP03 and its potential for extracellular synthesis of gold nanoparticles. The morphology, composition and crystallinity of nanoparticles were confirmed using standard techniques. The synthesized particles were quasi-spherical in shape with fcc packing and an average particle size of 72.32 ± 21.80 nm. A series of experiments were conducted to study the effect of different process parameters on particle size and yield. Biomass: water ratio of 1:5 and 1 mM precursor salt concentration at physiological pH (7.0) favoured the synthesis of well-defined gold nanoparticles with maximum yield. The as-synthesized nanoparticles showed excellent catalytic efficiency towards sodium borohydride mediated reduction of rhodamine B (2.5 × 10(-5) M) within 7 min of reaction time under experimental conditions. Presence of proteins as capping material on the nanoparticle surface was found to be responsible for this remarkable catalytic efficiency. The present approach can be extrapolated to develop controlled and up-scalable process for mycosynthesis of nanoparticles for diverse applications. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Identification of small-molecule agonists of human relaxin family receptor 1 (RXFP1) by using a homogenous cell-based cAMP assay.

    Science.gov (United States)

    Chen, Catherine Z; Southall, Noel; Xiao, Jingbo; Marugan, Juan J; Ferrer, Marc; Hu, Xin; Jones, Raisa E; Feng, Shu; Agoulnik, Irina U; Zheng, Wei; Agoulnik, Alexander I

    2013-07-01

    The relaxin hormone is involved in a variety of biological functions, including female reproduction and parturition, as well as regulation of cardiovascular, renal, pulmonary, and hepatic functions. It regulates extracellular matrix remodeling, cell invasiveness, proliferation, differentiation, and overall tissue homeostasis. The G protein-coupled receptor (GPCR) relaxin family receptor 1 (RXFP1) is a cognate relaxin receptor that mainly signals through cyclic AMP second messenger. Although agonists of the receptor could have a wide range of pharmacologic utility, until now there have been no reported small-molecule agonists for relaxin receptors. Here, we report the development of a quantitative high-throughput platform for an RXFP1 agonist screen based on homogenous cell-based HTRF cyclic AMP (cAMP) assay technology. Two small molecules of similar structure were independently identified from a screen of more than 365 677 compounds. Neither compound showed activity in a counterscreen with HEK293T cells transfected with an unrelated GPCR vasopressin 1b receptor. These small-molecule agonists also demonstrated selectivity against the RXFP2 receptor, providing a basis for future medicinal chemistry optimization of selective relaxin receptor agonists.

  10. Tactical Approaches to Interconverting GPCR Agonists and Antagonists.

    Science.gov (United States)

    Dosa, Peter I; Amin, Elizabeth Ambrose

    2016-02-11

    There are many reported examples of small structural modifications to GPCR-targeted ligands leading to major changes in their functional activity, converting agonists into antagonists or vice versa. These shifts in functional activity are often accompanied by negligible changes in binding affinity. The current perspective focuses on outlining and analyzing various approaches that have been used to interconvert GPCR agonists, partial agonists, and antagonists in order to achieve the intended functional activity at a GPCR of therapeutic interest. An improved understanding of specific structural modifications that are likely to alter the functional activity of a GPCR ligand may be of use to researchers designing GPCR-targeted drugs and/or probe compounds, specifically in cases where a particular ligand exhibits good potency but not the preferred functional activity at the GPCR of choice.

  11. Pharmacophore-driven identification of PPARγ agonists from natural sources

    DEFF Research Database (Denmark)

    Petersen, R. K.; Christensen, Kathrine Bisgaard; Assimopoulou, A. N.

    2011-01-01

    mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPARγ. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPARγ agonists; while......In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk...... medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPARγ agonist through bioassay-guided chromatographic fractionations of Chios...

  12. Principles of agonist recognition in Cys-loop receptors

    Directory of Open Access Journals (Sweden)

    Timothy eLynagh

    2014-04-01

    Full Text Available Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine and GABA. After the term chemoreceptor emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands.

  13. GnRH antagonist versus long agonist protocols in IVF

    DEFF Research Database (Denmark)

    Lambalk, C B; Banga, F R; Huirne, J A

    2017-01-01

    was not the only variable between the compared study arms. OBJECTIVE AND RATIONALE: The aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules. SEARCH......BACKGROUND: Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist...... METHODS: The Cochrane Menstrual Disorders and Subfertility Review Group specialized register of controlled trials and Pubmed and Embase databases were searched from inception until June 2016. Eligible trials were those that compared GnRH antagonist protocols and standard long GnRH agonist protocols...

  14. TPO receptor agonist for chronic idiopathic thrombocytopenic purpura.

    Science.gov (United States)

    Zeng, Yan; Duan, Xin; Xu, Jiajun; Ni, Xun

    2011-07-06

    Chronic idiopathic thrombocytopenic purpura (ITP) is an acquired autoimmune disorder that is characterized predominantly by a low platelet count. Thrombopoietin (TPO) receptor agonists increase production of platelets by stimulating the TPO receptor in people with chronic ITP. To determine the efficacy and safety of TPO receptor agonists in chronic ITP patients. We searched MEDLINE (from 1950 to March 2011), EMBASE (from 1974 to March 2011), and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3) to identify all randomized trials in chronic ITP. We also contacted authors of included studies and TPO receptor agonists manufacturers. Randomized controlled trials (RCTs) comparing TPO receptor agonists alone, or in combination with other drugs, to placebo, no treatment, other drugs, splenectomy or another TPO receptor agonist in patients with chronic ITP. Two review authors independently screened papers, extracted data and assessed the risk of bias in the included studies. Six trials with 808 patients were included. Five studies compared TPO receptor agonists with placebo (romiplostim: 100, eltrombopag: 299, placebo: 175); one study compared TPO receptor agonists with standard of care (SOC) (romiplostim: 157; SOC: 77). SOC included a variety of therapies, such as glucocorticoid, anti-D immune globulin, intravenous immune globulin, rituximab, azathioprine, and so on. Overall survival, one of our primary outcomes, was not studied by these RCTs and we could not estimate number needed to treat (NNT). Another primary outcome, improving significant bleeding events, did not reveal any significant differences between the TPO receptor agonists group and the control group (placebo or SOC) (versus placebo risk ratio (RR) 0.48, 95% confidence interval (CI) 0.20 to 1.15; versus SOC RR 0.49, 95% CI 0.15 to 1.63).For secondary outcomes, TPO receptor agonists statistically significantly improved overall platelet response (versus placebo RR

  15. Neuronal nicotinic receptor agonists ameliorate spontaneous motor asymmetries and motor discoordination in a unilateral mouse model of Parkinson's disease.

    Science.gov (United States)

    Kucinski, Aaron; Wersinger, Scott; Stachowiak, Ewa K; Corso, Thomas D; Parry, Matthew J; Zhang, Jenny; Jordan, Kristen; Letchworth, Sharon; Bencherif, Merouane; Stachowiak, Michal K

    2013-10-01

    The degeneration of the nigrostriatal dopamine (DA) system underlies the motor deficits in Parkinson's disease (PD). In recent years, epidemiological reports that smokers have lower incidences of PD have brought attention to the nicotinic acetylcholine system as a potential target for novel therapeutics. Nicotine, an agonist of neuronal nicotinic receptors (NNRs), modulates functions relevant to PD via stimulation of dopaminergic transmission in the nigrostriatal pathway, particularly via activation of α6β2* and α4β2* NNRs. Recently, reduced support of DA neurons by neurotrophic growth factors has been described in PD. Fibroblast growth factor (FGF) is critical for the development and protection of adult DA neurons. In FGF-2 knockout mice and the related th-fgfr1(tk-) mouse model there is heightened sensitivity to DA neuronal oxidative neurotoxin 6-hydroxydopamine (6-OHDA). In the present study, FGF-deficient transgenic mice th-fgfr1(tk-) were used to analyze the effects of novel full (TC-8831) and partial (TC-8581) agonists of β2-containing nicotinic receptors on impaired motor behavior following unilateral 6-OHDA lesions. The lesions generated spontaneous (drug-naïve) turning asymmetries that correlated exponentially with the depletion of DA biomarkers in the lesioned striata. These mice also exhibited a reduced capacity to remain on the accelerating rotarod. Oral administration of TC-8831, an NNR agonist with high specificity for β2 subunits and a full agonist at producing DA release from striatal synaptosomes, attenuated unidirectional turning and improved motor coordination. In contrast, partial β2 NNR agonist TC-8581 had no effect on behaviors in this model. This study demonstrates the potential of NNR targeting-compounds to facilitate motor function in PD. © 2013. Published by Elsevier Inc. All rights reserved.

  16. Effect of NaCl concentration on productivity and mineral composition of Salicornia europaea as a potential crop for utilization NaCl in LSS

    Science.gov (United States)

    Ushakova, S. A.; Kovaleva, N. P.; Gribovskaya, I. V.; Dolgushev, V. A.; Tikhomirova, N. A.

    The accumulation of solid and liquid wastes in manmade ecosystems presents a problem that has not been efficiently solved yet. Urine, containing NaCl, are part of these products. This is an obstacle to the creation of biological systems with a largely closed material cycling, because the amount of solid and liquid wastes in them must be reduced to a minimum. A possible solution to the problem is to select plant species capable of utilizing sufficiently high concentrations of NaCl, edible for humans, and featuring high productivity. Until recently, the life support systems have included the higher plants that were either sensitive to salinization (wheat, many of the legumes, carrot, potato, maize) or relatively salt-resistant (barley, sugar beet, spinach). Salicomia europaea, whose above-ground part is fully edible for humans, is one of the most promising candidates to be included in life support systems. It is reported in the literature that this plant is capable of accumulating up to 50% NaCl (dry basis). Besides, excessive accumulation of sodium ions should bring forth a decrease in the uptake of potassium ions and other biogenic elements. The aim of this work is to study the feasibility of using S. europaea plants in growth chambers to involve NaCl into material cycling. Plants were grown in vegetation chambers at the irradiance of 100 or 150 W/m 2 PAR (photosynthetically active radiation) and the air temperature 24 °C, by two methods. The first method was to grow the plants on substrate - peat. The peat was supplemented with either 3% NaCl (Variant 1) or 6% NaCl (Variant 2) of the oven-dry mass of the peat. The second method was to grow the plants in water culture, using the solution with a full complement of nutrients, which contained 0.0005% of NaCl, 1% or 2%. The study showed that the addition of NaCl to the substrate or to the solution resulted in the formation of more succulent plants, which considerably increased their biomass. The amount of NaCl uptake

  17. An Experimental Determination of the Quasi-Rest Potential of Copper Indium Disulfide Utilizing the Novel Open-Circuit Voltage Transient

    Science.gov (United States)

    Newell, Michael Jason

    Environmental sustainability requires resource management that takes future generations into account. The present generation has witnessed changes across the planet, unprecedented in human history and disrupting communities and cities around the world, due to shifting global climate. This is primarily the result of fossil fuels, which powered modern civilization but dramatically increased levels of CO2 and other greenhouse gases, and may be the least sustainable aspect of human civilization. Chapter 1 justifies the research from an environmental perspective and provides initial research parameters. Thin film photovoltaic (PV) modules are reported the most sustainable among energy production technologies currently available. Electrodeposited PV layers offer significant improvement to sustainability metrics over current thin film production methods, at reduced cost, but have rarely been demonstrated on an industrial scale. Quasi-rest potential (QRP) ultimately led to large-scale, electrodeposited thin film CdTe modules. An in-situ material characterization technique that allows adjustment of the deposition voltage (Vdep) to match the exact experimental conditions, QRP enabled precise control of deposit stoichiometry and crystallinity. Chapter 2 discusses theory and literature regarding QRP, and introduces the open-circuit voltage transient (Voc T), developed by the present research for analyzing QRP as a function of both Vdep and time. VocT data from a CdTe ethylene glycol bath matches details and speculations from the literature. Although predicted to have wide applicability, experimental QRP data have never been published for compounds unrelated to CdTe. Chapter 3 discusses VocTs performed in pursuit of electrodeposited CuInS2, demonstrating functionality as a QRP scan in a variety of ethylene glycol solutions. Stoichiometries of deposited films were improved by using the V ocT to determine appropriate plating voltages. VocTs enabled QRP, in-situ rest potential (EM

  18. Essential oils of culinary herbs and spices display agonist and antagonist activities at human aryl hydrocarbon receptor AhR.

    Science.gov (United States)

    Bartoňková, Iveta; Dvořák, Zdeněk

    2018-01-01

    Essential oils (EOs) of culinary herbs and spices are used to flavor, color and preserve foods and drinks. Dietary intake of EOs is significant, deserving an attention of toxicologists. We examined the effects of 31 EOs of culinary herbs and spices on the transcriptional activity of human aryl hydrocarbon receptor (AhR), which is a pivotal xenobiotic sensor, having also multiple roles in human physiology. Tested EOs were sorted out into AhR-inactive ones (14 EOs) and AhR-active ones, including full agonists (cumin, jasmine, vanilla, bay leaf), partial agonists (cloves, dill, thyme, nutmeg, oregano) and antagonists (tarragon, caraway, turmeric, lovage, fennel, spearmint, star anise, anise). Major constituents (>10%) of AhR-active EOs were studied in more detail. We identified AhR partial agonists (carvacrol, ligustilide, eugenol, eugenyl acetate, thymol, ar-turmerone) and antagonists (trans-anethole, butylidine phtalide, R/S-carvones, p-cymene), which account for AhR-mediated activities of EOs of fennel, anise, star anise, caraway, spearmint, tarragon, cloves, dill, turmeric, lovage, thyme and oregano. We also show that AhR-mediated effects of some individual constituents of EOs differ from those manifested in mixtures. In conclusion, EOs of culinary herbs and spices are agonists and antagonists of human AhR, implying a potential for food-drug interactions and interference with endocrine pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. HIV-1 subtype CRF01_AE and B differ in utilization of low levels of CCR5, Maraviroc susceptibility and potential N-glycosylation sites.

    Science.gov (United States)

    Joshi, Anjali; Cox, Emily K; Sedano, Melina J; Punke, Erin B; Lee, Raphael Tc; Maurer-Stroh, Sebastian; Kaur, Palvinder; Ng, Oon Tek; Garg, Himanshu

    2017-12-01

    HIV subtypes not only predominate in different geographical regions but also differ in key phenotypic characteristics. To determine if genotypic and/or phenotypic differences in the Envelope (Env) glycoprotein can explain subtype related differences, we cloned 37 full length Envs from Subtype B and AE HIV infected individuals from Singapore. Our data demonstrates that CRF01_AE Envs have lower Potential N Glycosylation Sites and higher risk of ×4 development. Phenotypically, CRF01_AE were less infectious than subtype B Envs in cells expressing low levels of CCR5. Moreover, the Maraviroc IC 50 was higher for subtype B Envs and correlated with infectivity in low CCR5 expressing cells as well as PNGS. Specifically, the glycosylation site N301 in the V3 loop was seen less frequently in AE subtype and CXCR4 topic viruses. CRF01_AE differs from B subtype in terms of CCR5 usage and Maraviroc susceptibility which may have implications for HIV pathogenesis and virus evolution. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. THE DEVELOPMENT OF BIOTECHNOLOGY’S LEARNING INSTRUMENTS ORIENTED HIGHER-ORDER THINKING AND THE UTILIZATION OF NATURAL RESOURCES TUNDA'S ISLAND POTENTIAL

    Directory of Open Access Journals (Sweden)

    Siti Gia Syauqiyah Fitri

    2017-05-01

    Full Text Available Science and technology learning should not just provide a collection of facts, laws and theories but rather is a process conducted by the students to acquire knowledge through interaction with the surrounding environment. The students are trained in scientific thinking critically, creatively and independently through active and meaningful learning process, for example by using the environment as a learning resource. This study aims to develop learning equipments oriented higher-order thinking skills (critical and creative to explore the potential of biological resources of Tunda island, as a learning resource in the subject of Biotechnology. This study used research and development (R & D method, which consists of the stages of analysis, design, validation and revision. Learning equipments that produced are RPS (lesson plans for 1 semester, the student worksheets (LKM, and evaluation (test instruments. The results of the validation team of experts showed that the learning equipments are good categorized, with the values 77.14 for RPS, 85 for LKM, and 94 for instrument test. Criticisms and suggestions from the experts were used as the basis of revision, so that the learning equipments are eligible for learning.

  1. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    Science.gov (United States)

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  2. Molybdenum and copper in four varieties of common bean (Phaseolus vulgaris): new data of potential utility in designing healthy diet for diabetic patients.

    Science.gov (United States)

    Ojeda, Armando Gómez; Wrobel, Kazimierz; Escobosa, Alma Rosa Corrales; Elguera, Julio César Torres; Garay-Sevilla, Ma Eugenia; Wrobel, Katarzyna

    2015-02-01

    Experimental evidence indicates that diabetic patients and individuals with impaired copper homeostasis could be at risk of molybdenum toxicity. A self-administered food frequency questionnaire revealed that in central Mexico, diabetic patients with severe complications tend to consume beans more often than individuals with less advanced disease. Four varieties of Phaseolus vulgaris were comparatively evaluated as the dietary sources of two elements; the results showed molybdenum concentration decreasing in the order peruvian > pinto > mayflower > black, whereas for copper, the order was peruvian > pinto ∼ black > mayflower. The two elements were determined in pre-soaking water, cooked legumes, and broth obtained in cooking procedure; an in vitro gut model was also applied to assess potentially bioavailable fraction of both elements in cooked beans. The results indicated that the black variety would be the healthiest bean choice for diabetic patients and individuals susceptible to Mo toxicity. Relatively low total molybdenum was found in this variety (2.9 ± 1.4 versus 4.3-10.9 μg g(-1) in other types), element availability was also low (15 % in supernatant from enzymolysis, 24.9 % in combined broth + supernatant fractions), and the molar ratio of Cu/Mo was the highest among four types (41, versus Cu/Mo <10 in peruvian, pinto, or mayflower). Considering peruvian and pinto beans, broth elimination would help to lower molybdenum intake with marginal effect on Cu/Mo molar ratio. This recommendation would be especially important for peruvian variety, which provided 1090, 803, and 197 μg day(-1) of molybdenum in raw grains, broth + supernatant, and supernatant, respectively (based on 100-g portion), exceeding the recommended daily allowance of 45 μg day(-1).

  3. Results of the American College of Surgeons Oncology Group Z0050 trial: the utility of positron emission tomography in staging potentially operable non-small cell lung cancer.

    Science.gov (United States)

    Reed, Carolyn E; Harpole, David H; Posther, Katherine E; Woolson, Sandra L; Downey, Robert J; Meyers, Bryan F; Heelan, Robert T; MacApinlac, Homer A; Jung, Sin-Ho; Silvestri, Gerard A; Siegel, Barry A; Rusch, Valerie W

    2003-12-01

    The American College of Surgeons Oncology Group undertook a trial to ascertain whether positron emission tomography with 18F-fluorodeoxyglucose could detect lesions that would preclude pulmonary resection in a group of patients with documented or suspected non-small cell lung cancer found to be surgical candidates by routine staging procedures. A total of 303 eligible patients registered from 22 institutions underwent positron emission tomography after routine staging (computed tomography of chest and upper abdomen, bone scintigraphy, and brain imaging) had deemed their tumors resectable. Positive findings required confirmatory procedures. Positron emission tomography was significantly better than computed tomography for the detection of N1 and N2/N3 disease (42% vs 13%, P =.0177, and 58% vs 32%, P =.0041, respectively). The negative predictive value of positron emission tomography for mediastinal node disease was 87%. Unsuspected metastatic disease or second primary malignancy was identified in 18 of 287 patients (6.3%). Distant metastatic disease indicated in 19 of 287 patients (6.6%) was subsequently shown to be benign. By correctly identifying advanced disease (stages IIIA, IIIB, and IV) or benign lesions, positron emission tomography potentially avoided unnecessary thoracotomy in 1 of 5 patients. In patients with suspected or proven non-small cell lung cancer considered resectable by standard staging procedures, positron emission tomography can prevent nontherapeutic thoracotomy in a significant number of cases. Use of positron emission tomography for mediastinal staging should not be relied on as a sole staging modality, and positive findings should be confirmed by mediastinoscopy. Metastatic disease, especially a single site, identified by positron emission tomography requires further confirmatory evaluation.

  4. The Potential Utility of Curcumin in the Treatment of HER-2-Overexpressed Breast Cancer: An In Vitro and In Vivo Comparison Study with Herceptin

    Directory of Open Access Journals (Sweden)

    Hung-Wen Lai

    2012-01-01

    Full Text Available HER-2 is an important oncoprotein overexpressed in about 15–25% of breast cancers. We hypothesized that the ability of curcumin to downregulate HER-2 oncoprotein and inhibit the signal transduction pathway of PI3K/Akt, MAPK, and NF-κB activation may be important in the treatment of HER-2-overexpressed breast cancer. To examine the effect of curcumin on breast cancer cells, MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr (a herceptin resistant strain from SK-BR-3 cells were used for in vitro analysis. The in vivo effect of curcumin on HER-2-overexpressed breast cancer was investigated with the HER-2-overexpressed BT-474 xenograft model. Cell growth, cell cycle change, the antimobility effect, signal transduction, and xenograft volume analysis between groups treated with herceptin and/or curcumin were tested. Curcumin decreased the cell growth of various breast cancer cell lines (MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr. In Western blot analysis, the phosphorylation of Akt, MAPK, and expression of NF-κB were reduced in BT-474 cells, but not in SK-BR-3-hr cells, after treatment with herceptin. When treated with curcumin, the HER-2 oncoprotein, phosphorylation of Akt, MAPK and expression of NF-κB were decreased in both BT-474 and SK-BR-3-hr cells. In the BT-474 xenograft model, though not as much as herceptin, curcumin did effectively decrease the tumor size. The combination of curcumin with herceptin was not better than herceptin alone; however, the combination of taxol and curcumin had an antitumor effect comparable with taxol and herceptin. The results suggested that curcumin has potential as a treatment for HER-2-overexpressed breast cancer.

  5. Preparation, characterization and molecular modeling of PEGylated human growth hormone with agonist activity.

    Science.gov (United States)

    Khameneh, Bahman; Jaafari, Mahmoud Reza; Hassanzadeh-Khayyat, Mohammad; Varasteh, AbdolReza; Chamani, JamshidKhan; Iranshahi, Mehrdad; Mohammadpanah, Hamid; Abnous, Khalil; Saberi, Mohammad Reza

    2015-09-01

    In this study, site-specific PEGylated human growth hormone (hGH) was prepared by microbial transglutaminase, modeled and characterized. To this end, the effects of different reaction parameters including reaction media, PEG:protein ratios, reaction time and pH value were investigated. PEG-hGH was purified by size exclusion chromatography method and analyzed by SDS-PAGE, BCA, peptide mapping, ESI and MALDI-TOF-TOF mass spectroscopy methods. Biophysical and biological properties of PEG-hGH were evaluated. Molecular simulation was utilized to provide molecular insight into the protein-receptor interaction. The optimum conditions that were obtained for PEGylation were phosphate buffer with pH of 7.4, 48 h of stirring and PEG:protein ratio of 40:1. By this method, mono-PEG-hGH with high reaction yield was obtained and PEGylation site was at Gln-40 residue. The circular dichroism and fluorescence spectrum indicated that PEGylation did not change the secondary structure while tertiary structure was altered. Upon enzymatic PEGylation, agonistic activity of hGH was preserved; however, Somavert(®), which is prepared by chemical PEGylation, is an antagonist form of protein. These data were confirmed by the total energy of affinity obtained by computational protein-receptor interaction. In conclusion, PEGylation of hGH was led to prepare a novel form of hormone with an agonist activity which merits further investigations. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero.

    Science.gov (United States)

    Jia, Shihai; Zhou, Jing; Fanelli, Christopher; Wee, Yinshen; Bonds, John; Schneider, Pascal; Mues, Gabriele; D'Souza, Rena N

    2017-10-15

    Clefts of the palate and/or lip are among the most common human craniofacial malformations and involve multiple genetic and environmental factors. Defects can only be corrected surgically and require complex life-long treatments. Our studies utilized the well-characterized Pax9 -/- mouse model with a consistent cleft palate phenotype to test small-molecule Wnt agonist therapies. We show that the absence of Pax9 alters the expression of Wnt pathway genes including Dkk1 and Dkk2 , proven antagonists of Wnt signaling. The functional interactions between Pax9 and Dkk1 are shown by the genetic rescue of secondary palate clefts in Pax9 -/- Dkk1 f/+ ;Wnt1Cre embryos. The controlled intravenous delivery of small-molecule Wnt agonists (Dkk inhibitors) into pregnant Pax9 +/- mice restored Wnt signaling and led to the growth and fusion of palatal shelves, as marked by an increase in cell proliferation and osteogenesis in utero , while other organ defects were not corrected. This work underscores the importance of Pax9-dependent Wnt signaling in palatogenesis and suggests that this functional upstream molecular relationship can be exploited for the development of therapies for human cleft palates that arise from single-gene disorders. © 2017. Published by The Company of Biologists Ltd.

  7. AVE 0991, a non-peptide Mas-receptor agonist, facilitates penile erection.

    Science.gov (United States)

    da Costa Gonçalves, Andrey C; Fraga-Silva, Rodrigo A; Leite, Romulo; Santos, Robson A S

    2013-03-01

    The renin-angiotensin system plays a crucial role in erectile function. It has been shown that elevated levels of angiotensin II contribute to the development of erectile dysfunction both in humans and in aminals. On the contrary, the heptapeptide angiotensin-(1-7) appears to mediate penile erection by activation of the Mas receptor. Recently, we have shown that the erectile function of Mas gene-deleted mice was substantially reduced, which was associated with a marked increase in fibrous tissue in the corpus cavernosum. We have hypothesized that the synthetic non-peptide Mas agonist, AVE 0991, would potentiate penile erectile function. We showed that intracavernosal injection of AVE 0991 potentiated the erectile response of anaesthetized Wistar rats, measured as the ratio between corpus cavernosum pressure and mean arterial pressure, upon electrical stimulation of the major pelvic ganglion. The facilitatory effect of AVE 0991 on erectile function was dose dependent and completely blunted by the nitric oxide synthesis inhibitor, l-NAME. Importantly, concomitant intracavernosal infusion of the specific Mas receptor blocker, A-779, abolished the effect of AVE 0991. We demonstrated that AVE 0991 potentiates the penile erectile response through Mas in an NO-dependent manner. Importantly, these results suggest that Mas agonists, such as AVE 0991, might have significant therapeutic benefits for the treatment of erectile dysfunction.

  8. A novel aminotetralin-type serotonin (5-HT) 2C receptor-specific agonist and 5-HT2A competitive antagonist/5-HT2B inverse agonist with preclinical efficacy for psychoses.

    Science.gov (United States)

    Canal, Clinton E; Morgan, Drake; Felsing, Daniel; Kondabolu, Krishnakanth; Rowland, Neil E; Robertson, Kimberly L; Sakhuja, Rajeev; Booth, Raymond G

    2014-05-01

    Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (-)-trans-(2S,4R)-4-(3'[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (-)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (-)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy-4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (-)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (-)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (-)-MBP, the enantiomer (+)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (-)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.

  9. Isomeric C12-alkamides isolated from purple coneflower (Echinacea purpurea (L.) Moench) exhibit characteristics of a PPARγ partial agonist

    DEFF Research Database (Denmark)

    El-Houri, Rime Bahij; Kotowska, Dorota; Wolber, Gerhard

    . Two novel isomeric dodeca-2E,4E,8Z,10E/Z-tetraenoic acid 2-methylbutylamides together with two known C12-alkamides and -linolenic acid were isolated from active fractions. The compounds were found to activate PPARγ but only the isomeric alkamides were able to increase basal and insulin-dependent GU...... in adipocytes in a dose dependent manner. Docking studies were performed to determine possible binding modes of the novel isomeric C12-alkamides and the potential contacts within the PPARγ ligand binding domain. The weak activation of PPARγ by the novel isomeric C12-alkamides as well as the results of docking...... mode of the novel isomeric C12-alkamides suggests that these compounds exhibit characteristics of a PPARγ partial agonist indicating that they may represent a chemical scaffold for the development of novel compounds with insulin sensitizing potential. Partial PPARγ agonists are believed not to promote...

  10. Emerging Role of Melatonin and Melatonin Receptor Agonists in Sleep and Delirium in Intensive Care Unit Patients.

    Science.gov (United States)

    Mo, Yoonsun; Scheer, Corey E; Abdallah, George T

    2016-08-01

    Delirium, an acute state of mental confusion, can lead to many adverse sequelae in intensive care unit (ICU) patients. Although the etiology of ICU delirium is often multifactorial, and at times not fully understood, sleep deprivation is considered to be a major contributing factor to its development. It has been postulated that administration of exogenous melatonin and melatonin receptor agonists such as ramelteon may prevent delirium by promoting nocturnal sleep in ICU patients. The purpose of this review is to summarize the pharmacology of melatonin and melatonin receptor agonists and investigate their potential roles in sleep promotion and delirium prevention in ICU patients. Although few studies evaluating the impact of melatonergic agents on sleep and delirium in the ICU have been completed, some data suggest their potential positive effects on sleep and delirium. However, large-scale randomized controlled trials are warranted to determine the optimal role of melatonergic agents in the prevention of ICU delirium. © The Author(s) 2015.

  11. The potential of utilizing wood ash and peat ash on organic soils in Sweden; Arealer foer skogsgoedsling med traeaska och torvaska paa organogena jordar i Sverige

    Energy Technology Data Exchange (ETDEWEB)

    Haanell, Bjoern [Swedish Univ. of Agricultural Sciences, Umeaa (Sweden). Dept. of Silviculture

    2004-01-01

    Nutrients removed from the forest when branches and treetops are harvested as fuel can be returned to the site by recycling the remaining wood ash after combustion. This compensation measure is presently not carried out to any appreciable extent, partly because there is no economic incentive for the landowner. In sites where this measure has been applied, only on mineral soils (e.g. moraine) until now, greater margins for sustainable maintenance of the long-term site productivity can be expected. The ash contains all elements required for tree growth except for nitrogen (N). Therefore the ash amendment does not result in increased stand growth on these soils because the most important element for a growth response (N) is missing. In contrast, on organic soils N is often abundant whereas the amounts of other mineral nutrients are small. Thus, the elements lacking in the soils of peatland forests are available in the ash. This is especially true for phosphorus (P) and potassium (K). This means that peatland forests provide an opportunity for ash amendment in order to increase forest production. Old fertilization trials using wood ash show that the growth increase can be very large. The aim of this study was to (i) calculate the area of peat covered land that with respect to stand growth responses could be regarded as most suitable for bio-ash (wood ash and peat ash) fertilization, and (ii) assess the amount of bio-ash needed for fertilizing this area. Peat ash, although not as much studied, also has potential to be used to provide nutrients for increasing peatland forest growth. Most of the area calculations were based on data from the National Forest Inventory (NFI) 1997-2001. Sites were selected with guidance from existing knowledge about ash fertilization effects on tree growth and with the aid of registrations made in NFI regarding peat depth, site productivity, drainage, condition of drains, dominating field vegetation, and degree of stand development

  12. Use of ß-adrenergic agonists in hybrid catfish

    Science.gov (United States)

    Ractopamine hydrochloride (RH) is a potent ß-adrenergic agonist that has been used in some species of fish to improve growth performance and dress out characteristics. While this metabolic modifier has been shown to have positive effects on growth of fish, little research has focused on the mechani...

  13. Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonists

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Due-Hansen, Maria E; Urban, Christian

    2012-01-01

    FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metabolic...

  14. Glucagon-like peptide 1 receptor agonist (GLP-1 RA)

    DEFF Research Database (Denmark)

    von Scholten, Bernt Johan; Hansen, Tine Willum; Goetze, Jens Peter

    2015-01-01

    AIMS: In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim...

  15. Beta2-adrenoceptors: mechanisms of action of beta2-agonists.

    Science.gov (United States)

    Johnson, M

    2001-03-01

    The human beta2-adrenoceptor is a member of the 7 transmembrane family of receptors. It is encoded by a gene on chromosome 5 and is widely distributed in the respiratory tract. Following beta2-adrenoceptor activation, intracellular signalling is mainly produced by inducing cyclic AMP. This produces airway relaxation through phosphorylation of muscle regulatory proteins and modification of cellular Ca2+concentrations. Beta2-agonists have been characterised into those which directly activate the receptor (salbutamol/terbutaline), those which are taken up into a membrane depot (formoterol) and those which interact with a receptor-specific, auxiliary binding site (salmeterol). These differences in mechanism of action are reflected in the kinetics of airway smooth muscle relaxation and bronchodilation in asthmatic patients. Beta-adrenoceptor desensitisation is associated with beta2-agonist activation and differs depending on the cell type. It is reflected in the different profiles of clinical tolerance to chronic beta2-agonist therapy. A number of polymorphisms of the beta2-receptor have been described which appear to alter the behaviour of the receptor, including the degree of downregulation and response to beta2-agonists.

  16. Innovations in agonist maintenance treatment of opioid-dependent patients

    NARCIS (Netherlands)

    Haasen, Christian; van den Brink, Wim

    2006-01-01

    PURPOSE OF REVIEW: To provide an overview of published studies on agonist maintenance treatment options for opioid-dependent patients. RECENT FINDINGS: The recent publication of controlled trials confirms earlier clinical evidence of the efficacy of diamorphine (heroin) in the treatment of opioid

  17. The elusive endogenous adipogenic PPARγ agonists: Lining up the suspects

    DEFF Research Database (Denmark)

    Hallenborg, Philip; Petersen, Rasmus K.; Kouskoumvekaki, Irene

    2016-01-01

    and their derivatives are known to bind to and activate PPARγ, the identity of the ligand(s) responsible for initiating adipocyte differentiation is still a matter of debate. Here we review recent data on pathways involved in ligand production as well as possible endogenous, adipogenic PPARγ agonists....

  18. Dipeptidylpeptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) receptor agonists: yes.

    Science.gov (United States)

    Scheen, André J

    2012-03-01

    The pharmacological treatment of type 2 diabetes (T2DM) is becoming increasingly complex, especially since the availability of incretin-based therapies. Compared with other glucose-lowering strategies, these novel drugs offer some advantages such as an absence of weight gain and a negligible risk of hypoglycaemia and, possibly, better cardiovascular and β-cell protection. The physician has now multiple choices to manage his/her patient after secondary failure of metformin, and the question whether it is preferable to add an oral dipeptidylpeptidase-4 (DPP-4) inhibitor (gliptin) or an injectable glucagon-like peptide-1 (GLP-1) receptor agonist will emerge. Obviously, DPP-4 inhibitors offer several advantages compared with GLP-1 receptor agonists, especially regarding easiness of use, tolerance profile and cost. However, because they can only increase endogenous GLP-1 concentrations to physiological (rather than pharmacological) levels, they are less potent to improve glucose control, promote weight reduction ("weight neutrality") and reduce blood pressure compared to GLP-1 receptor agonists. Of note, none of the two classes have proven long-term safety and positive impact on diabetic complications yet. The role of DPP-4 inhibitors and GLP-1 receptor agonists in the therapeutic armamentarium of T2DM is rapidly evolving, but their respective potential strengths and weaknesses should be better defined in long-term head-to-head comparative controlled trials. Instead of trying to answer the question whether DPP-4 inhibitors are favourable to GLP-1 receptor agonists (or vice versa), it is probably more clinically relevant to look at which T2DM patient will benefit more from one or the other therapy considering all his/her individual clinical characteristics ("personalized medicine"). Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  19. Buprenorphine-Mediated Transition from Opioid Agonist to Antagonist Treatment: State of the Art and New Perspectives

    Science.gov (United States)

    Mannelli, Paolo; Peindl, Kathleen S.; Lee, Tong; Bhatia, Kamal S.; Wu, Li-Tzy

    2012-01-01

    Constant refinement of opioid dependence (OD) therapies is a condition to promote treatment access and delivery. Among other applications, the partial opioid agonist buprenorphine has been studied to improve evidence-based interventions for the transfer of patients from opioid agonist to antagonist medications. This paper summarizes PubMed-searched clinical investigations and conference papers on the transition from methadone maintenance to buprenorphine and from buprenorphine to naltrexone, discussing challenges and advances. The majority of the 26 studies we examined were uncontrolled investigations. Many small clinical trials have demonstrated the feasibility of in- or outpatient transfer to buprenorphine from low to moderate methadone doses (up to 60–70 mg). Results on the conversion from higher methadone doses, on the other hand, indicate significant withdrawal discomfort, and need for ancillary medications and inpatient treatment. Tapering high methadone doses before the transfer to buprenorphine is not without discomfort and the risk of relapse. The transition buprenorphine-naltrexone has been explored in several pilot studies, and a number of treatment methods to reduce withdrawal intensity warrant further investigation, including the co-administration of buprenorphine and naltrexone. Outpatient transfer protocols using buprenorphine, and direct comparisons with other modalities of transitioning from opioid agonist to antagonist medications are limited. Given its potential salience, the information gathered should be used in larger clinical trials on short and long-term outcomes of opioid agonist-antagonist transition treatments. Future studies should also test new pharmacological mechanisms to help reduce physical dependence, and identify individualized approaches, including the use of pharmacogenetics and long-acting opioid agonist and antagonist formulations. PMID:22280332

  20. Selective adenosine A2A receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects

    Directory of Open Access Journals (Sweden)

    Esposito Emanuela

    2011-04-01

    Full Text Available Abstract Background Permanent functional deficits following spinal cord injury (SCI arise both from mechanical injury and from secondary tissue reactions involving inflammation. Enhanced release of adenosine and glutamate soon after SCI represents a component in the sequelae that may be responsible for resulting functional deficits. The role of adenosine A2A receptor in central ischemia/trauma is still to be elucidated. In our previous studies we have demonstrated that the adenosine A2A receptor-selective agonist CGS21680, systemically administered after SCI, protects from tissue damage, locomotor dysfunction and different inflammatory readouts. In this work we studied the effect of the adenosine A2A receptor antagonist SCH58261, systemically administered after SCI, on the same parameters. We investigated the hypothesis that the main action mechanism of agonists and antagonists is at peripheral or central sites. Methods Spinal trauma was induced by extradural compression of SC exposed via a four-level T5-T8 laminectomy in mouse. Three drug-dosing protocols were utilized: a short-term systemic administration by intraperitoneal injection, a chronic administration via osmotic minipump, and direct injection into the spinal cord. Results SCH58261, systemically administered (0.01 mg/kg intraperitoneal. 1, 6 and 10 hours after SCI, reduced demyelination and levels of TNF-α, Fas-L, PAR, Bax expression and activation of JNK mitogen-activated protein kinase (MAPK 24 hours after SCI. Chronic SCH58261 administration, by mini-osmotic pump delivery for 10 days, improved the neurological deficit up to 10 days after SCI. Adenosine A2A receptors are physiologically expressed in the spinal cord by astrocytes, microglia and oligodendrocytes. Soon after SCI (24 hours, these receptors showed enhanced expression in neurons. Both the A2A agonist and antagonist, administered intraperitoneally, reduced expression of the A2A receptor, ruling out the possibility that the

  1. Bilateral deficit in explosive force production is not caused by changes in agonist neural drive.

    Directory of Open Access Journals (Sweden)

    Matthew W Buckthorpe

    Full Text Available Bilateral deficit (BLD describes the phenomenon of a reduction in performance during synchronous bilateral (BL movements when compared to the sum of identical unilateral (UL movements. Despite a large body of research investigating BLD of maximal voluntary force (MVF there exist a paucity of research examining the BLD for explosive strength. Therefore, this study investigated the BLD in voluntary and electrically-evoked explosive isometric contractions of the knee extensors and assessed agonist and antagonist neuromuscular activation and measurement artefacts as potential mechanisms. Thirteen healthy untrained males performed a series of maximum and explosive voluntary contractions bilaterally (BL and unilaterally (UL. UL and BL evoked twitch and octet contractions were also elicited. Two separate load cells were used to measure MVF and explosive force at 50, 100 and 150 ms after force onset. Surface EMG amplitude was measured from three superficial agonists and an antagonist. Rate of force development (RFD and EMG were reported over consecutive 50 ms periods (0-50, 50-100 and 100-150 ms. Performance during UL contractions was compared to combined BL performance to measure BLD. Single limb performance during the BL contractions was assessed and potential measurement artefacts, including synchronisation of force onset from the two limbs, controlled for. MVF showed no BLD (P = 0.551, but there was a BLD for explosive force at 100 ms (11.2%, P = 0.007. There was a BLD in RFD 50-100 ms (14.9%, P = 0.004, but not for the other periods. Interestingly, there was a BLD in evoked force measures (6.3-9.0%, P<0.001. There was no difference in agonist or antagonist EMG for any condition (P≥0.233. Measurement artefacts contributed minimally to the observed BLD. The BLD in volitional explosive force found here could not be explained by measurement issues, or agonist and antagonist neuromuscular activation. The BLD in voluntary and evoked explosive force

  2. Utility planning for decommissioning

    International Nuclear Information System (INIS)

    Williams, D.H.

    1982-01-01

    Though the biggest impact on a utility of nuclear power plant decommissioning may occur many years from now, procrastination of efforts to be prepared for that time is unwarranted. Foresight put into action through planning can significantly affect that impact. Financial planning can assure the recovery of decommissioning costs in a manner equitable to customers. Decision-making planning can minimize adverse affects of current decisions on later decommissioning impacts and prepare a utility to be equipped to make later decommissioning decisions. Technological knowledge base planning can support all other planning aspects for decommissioning and prepare a utility for decommissioning decisions. Informed project planning can ward off potentially significant pitfalls during decommissioning and optimize the effectiveness of the actual decommissioning efforts

  3. Agonists and inverse agonists for the herpesvirus 8-encoded constitutively active seven-transmembrane oncogene product, ORF-74

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Kledal, T N; Bräuner-Osborne, Hans

    1999-01-01

    , whereas IP-10 and stromal cell-derived factor-1alpha surprisingly acted as inverse agonists. These peptides had similar pharmacological properties with regard to enhancing or inhibiting, respectively, the stimulatory effect of ORF-74 on NIH-3T3 cell proliferation. Construction of a high affinity zinc...

  4. Agonist signalling properties of radiotracers used for imaging of dopamine D2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, Jan-Peter; Michel, Martin C.; Janssen, Henk M.; Janssen, Anton G.; Elsinga, Philip H.; Booij, Jan

    2014-01-01

    Dopamine D2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists are more

  5. Agonist signalling properties of radiotracers used for imaging of dopamine D-2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, Jan-Peter; Michel, Martin C.; Janssen, Henk M.; Janssen, Anton G.; Elsinga, Philip H.; Booij, Jan

    2014-01-01

    Background: Dopamine D-2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists

  6. characterization qualitative and potentialities of utilization of ...

    African Journals Online (AJOL)

    Y. M’Sadak et A. Ben M’Barek

    1 sept. 2016 ... Parmi les ressources énergétiques renouvelables, l'énergie de biomasse est la seule issue des ressources organiques [6]. Cette solution innovante de gestion efficace des matières organiques [7, 8, 9, 10, 11, 12] constitue une source renouvelable d'énergie propre. (appelée encore énergie verte) [13, 9, ...

  7. MELATONIN: POTENTIAL UTILITY FOR IMPROVING PUBLIC HEALTH

    Directory of Open Access Journals (Sweden)

    Russel J REITER; Fatih GULTEKIN; Luis J FLORES; Ma Pilar TERRON; Dun-Xian TAN

    2006-04-01

    Full Text Available This review summarizes the beneficial actions of melatonin in various experimental conditions/diseases and identifies where the use of melatonin may be helpful in improving public health. The nightly use of melatonin supplements by humans often improves their sleep and helps correct the circadian dyssynchronization associated with “jet lag”. Additionally, melatonin has been found effective in curtailing the growth of a variety of experimental cancers. Mechanistically, this is achieved by melatonin’s ability to limit fatty acid uptake, especially linoleic acid, by tumor cells. Fatty acids are growth factors for many tumors. Additionally, melatonin inhibits the elevated telomerase activity of tumor cells thus making them more fragile and vulnerable to chemotherapies. Melatonin also may inhibit angiogenesis in tumors by suppressing endothelin-1 production and the indole interferes with the stimulatory action of steroids on hormone-responsive tumors. As an ubiquitously-acting antioxidant, melatonin reduces cardiac damage during ischemia/reperfusion (I/R injury (heart attack and during I/R to the brain (stroke. Melatonin also limits the toxicity of amyloid  peptide and of neurofibrillary tangles, two of the cardinal signs of Alzheimer’s disease. Collectively, these data suggest supplementation with melatonin, whose endogenous levels decrease with age, may improve the quality of life in the aged and, as a consequence, be beneficial for public health generally. [TAF Prev Med Bull 2006; 5(2.000: 131-158

  8. characterization qualitative and potentialities of utilization of ...

    African Journals Online (AJOL)

    Y. M’Sadak et A. Ben M’Barek

    1 sept. 2016 ... the plant especially: respect of pH, percen contents of minerals. The present work aim biomethaniser; one is obtained from the dig different periods). It appears from the following ... production combinée d'énergie (sous forme de biogaz) et d'un digestat (apte à être utilisé en tant qu'ingrédient des substrats ...

  9. Agonists and partial agonists of rhodopsin: retinal polyene methylation affects receptor activation.

    Science.gov (United States)

    Vogel, Reiner; Lüdeke, Steffen; Siebert, Friedrich; Sakmar, Thomas P; Hirshfeld, Amiram; Sheves, Mordechai

    2006-02-14

    Using Fourier transform infrared (FTIR) difference spectroscopy, we have studied the impact of sites and extent of methylation of the retinal polyene with respect to position and thermodynamic parameters of the conformational equilibrium between the Meta I and Meta II photoproducts of rhodopsin. Deletion of methyl groups to form 9-demethyl and 13-demethyl analogues, as well as addition of a methyl group at C10 or C12, shifted the Meta I/Meta II equilibrium toward Meta I, such that the retinal analogues behaved like partial agonists. This equilibrium shift resulted from an apparent reduction of the entropy gain of the transition of up to 65%, which was only partially offset by a concomitant reduction of the enthalpy increase. The analogues produced Meta II photoproducts with relatively small alterations, while their Meta I states were significantly altered, which accounted for the aberrant transitions to Meta II. Addition of a methyl group at C14 influenced the thermodynamic parameters but had little impact on the position of the Meta I/Meta II equilibrium. Neutralization of the residue 134 in the E134Q opsin mutant increased the Meta II content of the 13-demethyl analogue, but not of the 9-demethyl analogue, indicating a severe impairment of the allosteric coupling between the conserved cytoplasmic ERY motif involved in proton uptake and the Schiff base/Glu 113 microdomain in the 9-demethyl analogue. The 9-methyl group appears therefore essential for the correct positioning of retinal to link protonation of the cytoplasmic motif with protonation of Glu 113 during receptor activation.

  10. Economic and environmental advantages for the utilization of the industrial potential of cogeneration in Mexico; Ventajas economicas y ambientales para el aprovechamiento del potencial industrial de cogeneracion en Mexico

    Energy Technology Data Exchange (ETDEWEB)

    Leon de los Santos, G [Division de Estudios Posgrado, Facultad de ingenieria, Universidad Nacional Autonoma de Mexico, Mexico, D.F. (Mexico)

    2003-01-15

    Mexico has an industrial cogeneration potential very important, not evaluated or projected within its historical growth. The objective of the present work consist of studying the industrial cogeneration potential that exists in Mexico, as well as the economic and environmental savings that it would be achieved if one took advantage of this potential. As a result of the present work we can conclude that the cogeneration in Mexico offers a theoretical potential middle of 28,000 MWe to the 2007. It is estimated an economic saving potential in the construction of generation infrastructure electrical, for the high stage of its utilization of almost 7000 million dollars and a stage of emissions reduction of 2007- 21.4%, instead of 2007- 0.35%, for the industrial sector of the country. Provided that change the vision of the government of seeing to the cogeneration as a measure of energy saving and substitute it by that of political of complement to the development of the national electrical sector. [Spanish] Mexico tiene un importante potencial de cogeneracion industrial que no ha sido evaluado ni proyectado dentro de su crecimiento historico, por ello, el objetito de este trabajo consiste en estudiar y conocer los ahorros economicos y ambientales que se podrian lograr si se aprovechara dicho potencial. Como resultado, se muestra que la cogeneracion en Mexico ofrece un potencial teorico medio de 28,000 MW e al ano 2007. Se estima tambien un ahorro economico en la construccion de infraestructura de generacion electrica para el escenario alto de su aprovechamiento de casi 7000 mdd, y un escenario de reduccion de emisiones para el sector industrial del pais de un 0.35% a un 21.47% para el ano 2007. Estos pronosticos se pueden lograr, siempre y cunado el gobierno cambie la vision de manejar este tema como una medida de ahorro de energia, y la sustituya por la politica de complemento al desarrollo del sector electrico nacional.

  11. Liver X receptors agonists impede hepatitis C virus infection in an Idol-dependent manner.

    Science.gov (United States)

    Zeng, Jing; Wu, Yang; Liao, Qingjiao; Li, Lixia; Chen, Xinwen; Chen, Xulin

    2012-09-01

    Hepatitis C virus (HCV) is a major human pathogen that causes many serious diseases, including acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma. Treatments for this virus are inadequate, and improved antiviral therapies are necessary. Although the precise mechanisms regulating HCV entry into hepatic cells are still unknown, the low-density lipoprotein receptor (LDLR) has been shown to be essential for entry of infectious HCV particles. Liver X receptors (LXR) were recently reported to control LDLR expression through the regulation of the expression of the Idol (inducible degrader of the LDLR) protein, which could trigger the ubiquitination and degradation of LDLR. In this study, we analyzed the antiviral effect of Idol in vitro. The results demonstrated that Huh7.5.1 cells that exogenously expressed Idol were resistant to HCV infection. Next, the treatment of HCV-infected Huh7.5.1 cells with either synthetic LXR agonists (GW3965 or T0901317) or the natural LXR ligand 24(S),25-epoxycholesterol inhibited HCV infection in a dose-dependent manner. Furthermore, a combination of LXR agonists and HCV RNA replication inhibitors exerted additive effects against HCV, as revealed by isobologram analysis. In conclusion, our data indicate that molecules such as LXR agonists, which could stimulate the expression of Idol, represent a new class of potential anti-HCV compounds, and these compounds could be developed for therapeutic use against HCV infection, either as a monotherapy, or in combination with other anti-HCV drugs. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. Progenitor cells are mobilized by acute psychological stress but not beta-adrenergic receptor agonist infusion.

    Science.gov (United States)

    Riddell, Natalie E; Burns, Victoria E; Wallace, Graham R; Edwards, Kate M; Drayson, Mark; Redwine, Laura S; Hong, Suzi; Bui, Jack C; Fischer, Johannes C; Mills, Paul J; Bosch, Jos A

    2015-10-01

    Stimuli that activate the sympathetic nervous system, such as acute psychological stress, rapidly invoke a robust mobilization of lymphocytes into the circulation. Experimental animal studies suggest that bone marrow-derived progenitor cells (PCs) also mobilize in response to sympathetic stimulation. Here we tested the effects of acute psychological stress and brief pharmacological β-adrenergic (βAR) stimulation on peripheral PC numbers in humans. In two studies, we investigated PC mobilization in response to an acute speech task (n=26) and βAR-agonist (isoproterenol) infusion (n=20). A subset of 8 participants also underwent the infusion protocol with concomitant administration of the βAR-antagonist propranolol. Flow cytometry was used to enumerate lymphocyte subsets, total progenitor cells, total haematopoietic stem cells (HSC), early HSC (multi-lineage potential), late HSC (lineage committed), and endothelial PCs (EPCs). Both psychological stress and βAR-agonist infusion caused the expected mobilization of total monocytes and lymphocytes and CD8(+) T lymphocytes. Psychological stress also induced a modest, but significant, increase in total PCs, HSCs, and EPC numbers in peripheral blood. However, infusion of a βAR-agonist did not result in a significant change in circulating PCs. PCs are rapidly mobilized by psychological stress via mechanisms independent of βAR-stimulation, although the findings do not exclude βAR-stimulation as a possible cofactor. Considering the clinical and physiological relevance, further research into the mechanisms involved in stress-induced PC mobilization seems warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models.

    Science.gov (United States)

    Guo, Dan-yang; Li, De-wen; Ning, Meng-meng; Dang, Xiang-yu; Zhang, Li-na; Zeng, Li-min; Hu, You-hong; Leng, Ying

    2015-10-30

    G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells and activated by long-chain fatty acids. GPR40 has drawn considerable interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in glucagon-like peptide-1 (GLP-1)-producing enteroendocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti-diabetic efficacy. In the present study, we discovered a novel GPR40 agonist, yhhu4488, which is structurally different from other reported GPR40 agonists. Yhhu4488 showed potent agonist activity with EC50 of 49.96 nM, 70.83 nM and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells (FRIC) via triggering endogenous calcium store mobilization and extracellular calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. Chronic administration of yhhu4488 effectively decreased fasting blood glucose level, improved β-cell function and lipid homeostasis in type 2 diabetic ob/ob mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 secretion, improves metabolic control and β-cell function, suggesting its promising potential for the treatment of type 2 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Build Resilience at Your Utility

    Science.gov (United States)

    CREAT allows users to evaluate potential impacts of climate change on their utility and to evaluate adaptation options to address them using both traditional risk assessment and scenario-based decision making.

  15. Cardiovascular Actions and Clinical Outcomes With Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors.

    Science.gov (United States)

    Nauck, Michael A; Meier, Juris J; Cavender, Matthew A; Abd El Aziz, Mirna; Drucker, Daniel J

    2017-08-29

    Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of type 2 diabetes mellitus by glucose-dependent control of insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight by reduction of food intake and lower circulating lipoproteins, inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and DPP-4 inhibitors exhibit cardioprotective actions in animal models of myocardial ischemia and ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists liraglutide (LEADER trial [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], -13%) and semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide], -24%). In contrast, cardiovascular outcome trials examining the safety of the shorter-acting GLP-1R agonist lixisenatide (ELIXA trial [Evaluation of Lixisenatide in Acute Coronary Syndrom]) and the DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53]), alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome]), and sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the

  16. Pharmacology and selectivity of various natural and synthetic Bombesin related peptide agonists for human and rat bombesin receptors differs

    Science.gov (United States)

    Uehara, Hirotsugu; González, Nieves; Sancho, Veronica; Mantey, Samuel A.; Nuche-Berenguer, Bernardo; Pradhan, Tapas; Coy, David H.; Jensen, Robert T.

    2011-01-01

    The mammalian bombesin (Bn)-receptor family[gastrin-releasing peptide-receptor(GRPR-receptor), neuromedin B-receptor(NMB-receptor)], their natural ligands,GRP/NMB, as well as the related orphan-receptor,BRS-3, are widely-distributed, and frequently overexpressed by tumors. There is increased interest in agonists for this receptor family to explore their roles in physiological/pathophysiological processes, and for receptor-imaging/cytotoxicity in tumors. However, there is minimal data on human pharmacology of Bn-receptor agonists and most results are based on nonhuman receptor studies, particular rodent-receptors, which with other receptors frequently differ from human-receptors. To address this issue we compared hNMB/GRP-receptor affinities and potencies/efficacies of cell-activation(assessing phospholipase C activity) for 24 putative Bn-agonists(12-natural,12-synthetic) in four different cells with these receptors, containing native-receptors or receptors expressed at physiological densities, and compared the results to native rat-GRP-receptor-containing cells-(AR42J–cells) or rat-NMB-receptor cells(C6-glioblastoma cells). There were close correlations(r=0.92–99,psynthetic Bn-analogues containing β−alanine11 had high affinity for hBRS-3, but t also had high affinities/potencies for all GRP-/hNMB-receptor cells. There was no correlation between affinities for human-GRP-receptors and rat-GRP-receptors(r=0.131,p=0.54), but hNMB-receptor results correlated with rat-NMB-receptor(r=0.71, p<0.0001). These results elucidate the human- and rat-GRP-receptor pharmacophore for agonists differ markedly,whereas they do not for NMB-receptors, therefore potential GRP-receptor agonists for human studies(such as Bn-receptor-imaging/cytotoxicity) must be assessed on human-Bn-receptors. The current study provides affinities/potencies on a large number of potential agonists that might be useful for human studies. PMID:21729729

  17. β2 agonists in athletes. An ergogenic aid? = β2 agonistas en deportistas. ¿Una ayuda ergogénica?

    Directory of Open Access Journals (Sweden)

    Ospina Uribe, Carlos Fernando

    2013-01-01

    Full Text Available Asthma is a chronic disorder of the airways with bronchial hyperresponsiveness and bronchoconstriction. Exercise can trigger asthma symptoms; this condition is known as exerciseinduced bronchospasm (EIB. Asthma is common in Olympic athletes who therefore use β2 agonists to prevent and treat its episodes. These drugs are preferably supplied by inhalation. In sports, the use of β2 agonists is restricted by anti-doping regulation, arguing that these drugs have the potential to improve physical performance, which can result in a competitive advantage. β2 agonists are prohibited by the WADA (World Anti-Doping Agency, except salbutamol (maximum dose: 1.600 μg over 24 hours and salmeterol. Oral administration of salbutamol can induce ergogenic effects in athletes. It has been documented that when given orally β2 agonists can improve performance in endurance disciplines, increase muscle strength and improve anaerobic power. However, according to scientific evidence, inhaled β2 agonists do not have a relevant performance-enhancing effect in nonasthmatic athletes.

  18. Peroxisome proliferator-activated receptor-γ agonist 15d-prostaglandin J2 mediates neuronal autophagy after cerebral ischemia-reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Feng Xu

    Full Text Available Peroxisome proliferator-activated receptor-γ (PPAR-γ has recently emerged as potential therapeutic agents for cerebral ischemia-reperfusion (I/R injury because of anti-neuronal apoptotic actions. However, whether PPAR-γ activation mediates neuronal autophagy in such conditions remains unclear. Therefore, in this study, we investigated the role of PPAR-γ agonist 15-PGJ(2 on neuronal autophagy induced by I/R. The expression of autophagic-related protein in ischemic cortex such as LC3-II, Beclin 1, cathepsin-B and LAMP1 increased significantly after cerebral I/R injury. Furthermore, increased punctate LC3 labeling and cathepsin-B staining occurred in neurons. Treatment with PPAR-γ agonist 15d-PGJ(2 decreased not only autophagic-related protein expression in ischemic cortex, but also immunoreactivity of LC3 and cathepsin-B in neurons. Autophagic inhibitor 3-methyladenine (3-MA decreased LC3-II levels, reduced the infarct volume, and mimicked some protective effect of 15d-PGJ(2 against cerebral I/R injury. These results indicate that PPAR-γ agonist 15d-PGJ(2 exerts neuroprotection by inhibiting neuronal autophagy after cerebral I/R injury. Although the molecular mechanisms underlying PPAR-γ agonist in mediating neuronal autophagy remain to be determined, neuronal autophagy may be a new target for PPAR-γ agonist treatment in cerebral I/R injury.

  19. Computer-aided discovery of aromatic L-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139

    DEFF Research Database (Denmark)

    Ísberg, Vignir; Andersen, Kirsten Bayer; Bisig, Christoph

    2014-01-01

    GPR139 is an orphan G protein-coupled receptor expressed mainly in the central nervous system. We developed a pharmacophore model based on known GPR139 surrogate agonists which led us to propose aromatic-containing dipeptides as potential ligands. Upon testing, the dipeptides demonstrated agonism...... in the Gq pathway. Next, testing all 20 proteinogenic L-α-amino acids; L-tryptophan and L-phenylalanine were found to have EC50 values of 220 µM and 320 µM, respectively, making them the first putative endogenous agonists for GPR139....

  20. Α-amino-β-fluorocyclopropanecarboxylic acids as a new tool for drug development: synthesis of glutamic acid analogs and agonist activity towards metabotropic glutamate receptor 4.

    Science.gov (United States)

    Lemonnier, Gérald; Lion, Cédric; Quirion, Jean-Charles; Pin, Jean-Philippe; Goudet, Cyril; Jubault, Philippe

    2012-08-01

    Herein we describe the diastereoselective synthesis of glutamic acid analogs and the evaluation of their agonist activity towards metabotropic glutamate receptor subtype 4 (mGluR4). These analogs are based on a monofluorinated cyclopropane core substituted with an α-aminoacid function. The potential of this new building block as a tool for the development of a novel class of drugs is demonstrated with racemic analog 11a that displayed the best agonist activity with an EC50 of 340 nM. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice

    NARCIS (Netherlands)

    Parlevliet, Edwin T.; Schröder-van der Elst, Janny P.; Corssmit, Eleonora P. M.; Picha, Kristen; O'Neil, Karyn; Stojanovic-Susulic, Vedrana; Ort, Tatiana; Havekes, Louis M.; Romijn, Johannes A.; Pijl, Hanno

    2009-01-01

    CNTO736 is a glucagon-like peptide (GLP) 1 receptor agonist that incorporates a GLP-1 peptide analog linked to the Mimetibody platform. We evaluate the potential of acute and chronic CNTO736 treatment on insulin sensitivity and very low-density lipoprotein (VLDL) metabolism. For acute studies,

  2. Intradermally administered TLR4 agonist GLA-SE enhances the capacity of human skin DCs to activate T cells and promotes emigration of Langerhans cells

    NARCIS (Netherlands)

    Schneider, Laura P.; Schoonderwoerd, Antoinet J.; Moutaftsi, Magdalini; Howard, Randall F.; Reed, Steven G.; de Jong, Esther C.; Teunissen, Marcel B. M.

    2012-01-01

    The natural TLR4 agonist lipopolysaccharide (LPS) has notable adjuvant activity. However, it is not useful as a vaccine adjuvant due to its toxicity. Glucopyranosyl lipid A (GLA) is a synthetic derivative of the lipid A tail of LPS with limited cytotoxicity, but strong potential to induce immune

  3. The metabotropic glutamate receptor agonist 1S,3R-ACPD stimulates and modulates NMDA receptor mediated excitotoxicity in organotypic hippocampal slice cultures

    DEFF Research Database (Denmark)

    Blaabjerg, M; Kristensen, Bjarne Winther; Bonde, C

    2001-01-01

    The potential toxic effects of the metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) and its interactions with the N-methyl-D-aspartate (NMDA) receptor were studied in hippocampal brain slice cultures, using densitometric measurements of the cellular...

  4. Prediction of selective estrogen receptor beta agonist using open data and machine learning approach

    Directory of Open Access Journals (Sweden)

    Niu AQ

    2016-07-01

    for the classification of selective ER-β agonists. Chemistry Development Kit extended fingerprints and MACCS fingerprint performed better in structural representation between active and inactive agonists. Conclusion: These results demonstrate that combining the fingerprint and ML approaches leads to robust ER-β agonist prediction models, which are potentially applicable to the identification of selective ER-β agonists. Keywords: estrogen receptor subtype β, selective estrogen receptor modulators, quantitative structure-activity relationship models, machine learning approach

  5. Application of agonist-receptor modeling to the sweetness synergy between high fructose corn syrup and sucralose, and between high-potency sweeteners.

    Science.gov (United States)

    Wolf, P A; Bridges, J R; Wicklund, R

    2010-03-01

    The agonist-receptor-transducer model of D. Ennis is applied to beverage formulations sweetened with high fructose corn syrup, sucralose, and other high-potency sweeteners, confirming the utility of the model, and supports the growing volume of evidence for multiple binding sites on the sweetness receptor. The model is further simplified to require less parameters for other sweetener blend systems whenever potency information is available for the single sweeteners.

  6. Virtual screening studies of Chinese medicine Coptidis Rhizoma as alpha7 nicotinic acetylcholine receptor agonists for treatment of Alzheimer's disease

    Science.gov (United States)

    Xiang, Li; Xu, Youdong; Zhang, Yan; Meng, Xianli; Wang, Ping

    2015-04-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease. Extensive in vitro and in vivo experiments have proved that the decreased activity of the cholinergic neuron is responsible for the memory and cognition deterioration. The alpha7 nicotinic acetylcholine receptor (α7-nAChR) is proposed to a drug target of AD, and compounds which acting as α7-nAChR agonists are considered as candidates in AD treatment. Chinese medicine CoptidisRhizoma and its compounds are reported in various anti-AD effects. In this study, virtual screening, docking approaches and hydrogen bond analyses were applied to screen potential α7-nAChR agonists from CoptidisRhizome. The 3D structure of the protein was obtained from PDB database. 87 reported compounds were included in this research and their structures were accessed by NCBI Pubchem. Docking analysis of the compounds was performed using AutoDock 4.2 and AutoDock Vina. The images of the binding modes hydrogen bonds and the hydrophobic interaction were rendered with PyMOL1.5.0.4. and LigPlot+ respectively. Finally, N-tran-feruloyltyramine, isolariciresinol, flavanone, secoisolariciresinol, (+)-lariciresinol and dihydrochalcone, exhibited the lowest docking energy of protein-ligand complex. The results indicate these 6 compounds are potential α7 nAChR agonists, and expected to be effective in AD treatment.

  7. On the Pharmacology of Farnesoid X Receptor Agonists: Give me an “A”, Like in “Acid”

    Directory of Open Access Journals (Sweden)

    Eva Hambruch

    2016-06-01

    Full Text Available The Farnesoid X Receptor (FXR has recently moved into the spotlight through the release of clinical data using Obeticholic Acid, an FXR agonist, that demonstrated effectiveness of this bile acid-like drug in patients with Primary Biliary Cirrhosis and Non-alcoholic Steatohepatitis (NASH. FXR holds the promise to become an attractive drug target for various conditions, from Non-alcoholic Fatty Liver Disease (NAFLD, NASH, liver cirrhosis, portal hypertension and a variety of cholestatic disorders to intestinal diseases including inflammatory bowel disease and bile acid diarrhea. Despite the wide therapeutic potential, surprisingly little is known about the pharmacology, pharmacokinetics and tissue distribution properties of drugs targeting FXR. Are tissue specific FXR agonists preferable for different indications, or might one type of ligand fit all purposes? This review aims to summarize the sparse data which are available on this clinically and pharmacologically relevant topic and provides a mechanistic model for understanding tissue-specific effects in vivo.

  8. Structure-activity relationship study of tachykinin peptides for the development of novel neurokinin-3 receptor selective agonists.

    Science.gov (United States)

    Misu, Ryosuke; Noguchi, Taro; Ohno, Hiroaki; Oishi, Shinya; Fujii, Nobutaka

    2013-04-15

    Neurokinin B (NKB) is a potential regulator of pulsatile gonadotropin-releasing hormone (GnRH) secretion via activation of the neurokinin-3 receptor (NK3R). NKB with the consensus sequence of the tachykinin peptide family also binds to other tachykinin receptors [neurokinin-1 receptor (NK1R) and neurokinin-2 receptor (NK2R)] with low selectivity. In order to identify the structural requirements for the development of novel potent and selective NK3R agonists, a structure-activity relationship (SAR) study of [MePhe(7)]-NKB and other naturally occurring tachykinin peptides was performed. The substitutions to naturally occurring tachykinins with Asp and MePhe improved the receptor binding and agonistic activity for NK3R. The corresponding substitutions to NKB provided an NK3R selective analog. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. The TLR9 agonist MGN1703 triggers a potent type I interferon response in the sigmoid colon

    DEFF Research Database (Denmark)

    Krarup, A R; Abdel-Mohsen, M; Schleimann, M H

    2017-01-01

    Toll-like receptor 9 (TLR9) agonists are being developed for treatment of colorectal and other cancers, yet the impact of these drugs on human intestines remains unknown. This, together with the fact that there are additional potential indications for TLR9 agonist therapy (e.g., autoimmune...... (60 mg s.c.) twice weekly for 4 weeks in a single-arm, phase 1b/2a study. Within sigmoid mucosa, global transcriptomic analyses revealed 248 modulated genes (false discovery rate...=0.001) and ISG15 (P=0.014) protein expression. No changes were observed in neutrophil infiltration (myeloperoxidase; P=0.97). No systematic effect on fecal microbiota structure was observed (analysis of similarity Global R=-0.105; P=0.929). TLR9 expression at baseline was inversely proportional...

  10. Preclinical Safety Assessment of the 5-HT(2A) Receptor Agonist PET Radioligand [ (11)C]Cimbi-36

    DEFF Research Database (Denmark)

    Ettrup, Anders; Holm, Søren; Hansen, Martin

    2013-01-01

    PURPOSE: [(11)C]Cimbi-36 was recently developed as an agonist radioligand for brain imaging of serotonin 2A receptors (5-HT(2A)) with positron emission tomography (PET). This may be used to quantify the high-affinity state of 5-HT(2A) receptors and may have the potential to quantify changes...... in cerebral 5-HT levels in vivo. We here investigated safety aspects related to clinical use of [(11)C]Cimbi-36, including radiation dosimetry and in vivo pharmacology. PROCEDURES: [(11)C]Cimbi-36 was injected in rats or pigs, and radiation dosimetry was examined by ex vivo dissection or with PET scanning......, respectively. Based on animal data, the Organ Level INternal Dose Assessment software was used to estimate extrapolated human dosimetry for [(11)C]Cimbi-36. The 5-HT(2A) receptor agonist actions of [(11)C]Cimbi-36 in vivo pharmacological effects in mice elicited by increasing doses of Cimbi-36 were assessed...

  11. The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns (Review)

    Science.gov (United States)

    Zhou, Hongyan; Zhang, Wensong; Bi, Miaomiao; Wu, Jie

    2016-01-01

    Corneal alkali burns (CAB) are characterized by injury-induced inflammation, fibrosis and neovascularization (NV), and may lead to blindness. This review evaluates the current knowledge of the molecular mechanisms responsible for CAB. The processes of cytokine production, chemotaxis, inflammatory responses, immune response, cell signal transduction, matrix metalloproteinase production and vascular factors in CAB are discussed. Previous evidence indicates that peroxisome proliferator-activated receptor γ (PPAR-γ) agonists suppress immune responses, inflammation, corneal fibrosis and NV. This review also discusses the role of PPAR-γ as an anti-inflammatory, anti-fibrotic and anti-angiogenic agent in the treatment of CAB, as well as the potential role of PPAR-γ in the pathological process of CAB. There have been numerous studies evaluating the clinical profiles of CAB, and the aim of this systematic review was to summarize the evidence regarding the treatment of CAB with PPAR-γ agonists. PMID:27499172

  12. The adenosine A2A receptor agonist CGS 21680 exhibits antipsychotic-like activity in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Andersen, M B; Fuxe, K; Werge, T

    2002-01-01

    The adenosine A2A receptor agonist CGS 21680 has shown effects similar to dopamine antagonists in behavioural assays in rats predictive for antipsychotic activity, without induction of extrapyramidal side-effects (EPS). In the present study, we examined whether this functional dopamine antagonism......-induced behaviours (unrest, stereotypies, arousal) were unaffected. EPS were not observed at any dose. At 0.05 mg/kg CGS 21680 produced vomiting. The two lower doses did not produce observable side-effects. Though the differential effect on amphetamine- and apomorphine-induced behaviours is intriguing, CGS 21680...... showed a functional anti-dopaminergic effect in Cebus apella monkeys without production of EPS. This further substantiates that adenosine A2A receptor agonists may have potential as antipsychotics with atypical profiles....

  13. Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor

    Energy Technology Data Exchange (ETDEWEB)

    Biggadike, Keith; Bledsoe, Randy K.; Coe, Diane M.; Cooper, Tony W.J.; House, David; Iannone, Marie A.; Macdonald, Simon J.F.; Madauss, Kevin P.; McLay, Iain M.; Shipley, Tracy J.; Taylor, Simon J.; Tran, Thuy B.; Uings, Iain J.; Weller, Victoria; Williams, Shawn P.; (GSKNC); (GSK)

    2010-09-17

    Crystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain-agonist complex of the D-prolinamide derivative 11. The utility of the channel was further exemplified through the design of a potent phenylindazole in which structural motifs, seen to interact with the traditional GR ligand pocket, were abandoned and replaced by interactions within the new channel. Occupation of the channel was confirmed with a second GR crystal structure of this truncated D-alaninamide derivative 13. Compound 11 displays properties compatible with development as an intranasal solution formulation, whereas oral bioavailability has been demonstrated with a related truncated exemplar 14. Data with the pyrrolidinone amide 12 demonstrate the potential for further elaboration within the 'meta' channel to deliver compounds with selectivity for the desired transrepressive activity of glucocorticoids. The discovery of these interactions with this important receptor offers significant opportunities for the design of novel GR modulators.

  14. CF101, An Agonist to the A3 Adenosine Receptor, Enhances the Chemotherapeutic Effect of 5-Fluorouracil in a Colon Carcinoma Murine Model

    Directory of Open Access Journals (Sweden)

    Sara Bar-Yehuda

    2005-01-01

    Full Text Available NF-κB and the upstream kinase PKB/Akt are highly expressed in chemoresistance tumor cells and may hamper the apoptotic pathway. CF101, a specific agonist to the A3 adenosine receptor, inhibits the development of colon carcinoma growth in cell cultures and xenograft murine models. Because CF101 has been shown to downregulate PKB/Akt and NF-κB protein expression level, we presumed that its combination with chemotherapy will enhance the antitumor effect of the cytotoxic drug. In this study, we utilized 3-[4,5Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT and colony formation assays and a colon carcinoma xenograft model. It has been shown that a combined treatment of CF101 and 5-fluorouracil (5-FU enhanced the cytotoxic effect of the latter on HCT-116 human colon carcinoma growth. Downregulation of PKB/Akt, NF-κB, and cyclin D1, and upregulation of caspase-3 protein expression level were observed in cells and tumor lesions on treatment with a combination of CF101 and 5-FU. Moreover, in mice treated with the combined therapy, myelotoxicity was prevented as was evidenced by normal white blood cell and neutrophil counts. These results show that CF101 potentiates the cytotoxic effect of 5-FU, thus preventing drug resistance. The myeloprotective effect of CF101 suggests its development as an add-on treatment to 5-FU.

  15. High hopes for cannabinoid agonists in the treatment of rheumatic diseases.

    Science.gov (United States)

    Staunton, Caroline A; Mobasheri, Ali; Barrett-Jolley, Richard

    2014-12-04

    There are two well-characterised isoforms of cannabinoid receptor; CB1 and CB2 and of these CB2 is under active investigation as a potential target for treatment of the chronic pain associated with widespread and intractable joint diseases osteoarthritis and rheumatoid arthritis. The recent report by Fukuda et al (BMC Musculoskelet Disord15:275, 2014) in BMC Musculoskeletal Disorders investigates the efficacy of a selective CB2 agonist, JW133, in both in vitro and in vivo models of rheumatoid arthritis and provides encouraging data. The report shows that JW133 inhibits expression of the CCL2 cytokine, osteoclastogenesis and reduces histological indicators of joint degeneration. Each of these could potentially contribute to beneficial analgesic effects in a therapeutic context.

  16. Beta-adrenergic agonists as additive in beef cattle

    Directory of Open Access Journals (Sweden)

    Marcelo Vedovatto

    2014-10-01

    Full Text Available The agonists receptor beta-adrenergic (β-AA are present in virtually all types of mammalian cells and are stimulated by catecholamines (epinephrine and norepinephrine produced by the organism itself. The β-AA agonists are synthetic substances with similar structure to these amines. When provided in the diet they alter the body composition of animals, affecting the distribution of nutrients toward to protein deposition, and decreasing lipogenesis. Although the mechanisms of action are not fully understood, these may cause morphological and physiological changes such as increased blood flow decrease in plasma insulin, decreased lipogenesis, and muscle hypertrophy mainly in type II fibers. We also observed changes in motility and secretions grastointestinal tract, beyond the direct influence on the rumen bacteria, altering the digestibility of the diet. The β-AA agonists released in some countries for use in beef cattle are ractopamine hydrochloride and zilpaterol hydrochloride. According to literature data, the inclusion of these additives in the diet of feedlot cattle has been associated with an increase infeed efficiency with the increase in daily weight gain and with equal or lower feed intake. Carcass characteristics improvement was verified in carcass weight, and increased loin eye area, but with the possibility to decrease the subcutaneous fat thickness and marbling. Reviews in sensory panel of meat from animals consuming β-AA agonists showed decreased tenderness and juiciness. Thus β-AA improve performance and carcass characteristics, but more studies are needed to confirm whether they have negative influence on the organoleptic characteristics of the meat.

  17. Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

    Science.gov (United States)

    2010-05-01

    agents histamine and cowhage activate separate populations of Ko and Naughtonto antinociceptive effects of spinally administered mor- phine or/and NOP...similar to other opioid receptor agonists at the cellular level (Meunier et al., 1995; Rizzi et al., 2007). However, the effects of NOP receptor...the hypotheses that in the non-human primate (1) the functions and behavioral effects of the NOP receptor are independent of classical opioid receptors

  18. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    Energy Technology Data Exchange (ETDEWEB)

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K. (GSKPA)

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  19. GnRH agonist for triggering of final oocyte maturation

    DEFF Research Database (Denmark)

    Al Humaidan, Peter Samir Heskjær; Kol, S; Papanikolaou, E G

    2011-01-01

    GnRH agonist (GnRHa) triggering has been shown to significantly reduce the occurrence of ovarian hyperstimulation syndrome (OHSS) compared with hCG triggering; however, initially a poor reproductive outcome was reported after GnRHa triggering, due to an apparently uncorrectable luteal phase...... deficiency. Therefore, the challenge has been to rescue the luteal phase. Studies now report a luteal phase rescue, with a reproductive outcome comparable to that seen after hCG triggering....

  20. State Estimation For An Agonistic-Antagonistic Muscle System

    OpenAIRE

    Nguyen, Thang; Warner, Holly; La, Hung; Mohammadi, Hanieh; Simon, Dan; Richter, Hanz

    2017-01-01

    Research on assistive technology, rehabilitation, and prosthesis requires the understanding of human machine interaction, in which human muscular properties play a pivotal role. This paper studies a nonlinear agonistic-antagonistic muscle system based on the Hill muscle model. To investigate the characteristics of the muscle model, the problem of estimating the state variables and activation signals of the dual muscle system is considered. In this work, parameter uncertainty and unknown input...

  1. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    Science.gov (United States)

    Haenisch, Britta; Walstab, Jutta; Herberhold, Stephan; Bootz, Friedrich; Tschaikin, Marion; Ramseger, René; Bönisch, Heinz

    2010-12-01

    Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α(2A) > α(1A) ≥ α(2B) > α(1D) ≥ α(2C) > α(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α(1A) - but a lower affinity at α(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals w