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Sample records for agonist phenylephrine pe

  1. Phenylephrine

    MedlinePlus

    Rynatuss® (as a combination product containing Carbetapentane, Chlorpheniramine, Ephedrine, Phenylephrine) ... Tuss® (as a combination product containing Carbetapentane, Chlorpheniramine, Ephedrine, Phenylephrine)

  2. Effects of α1-adrenoceptor agonist phenylephrine on swelling-activated chloride currents in human atrial myocytes.

    PubMed

    Li, Yetao; Du, Xinling

    2015-02-01

    Swelling-activated chloride currents (ICl.swell) play an important role in cardiac electrophysiology and arrhythmogenesis. However, the regulation of these currents has not been clarified to date. In this research, we focused on the function of phenylephrine, an α1-adrenoceptor agonist, in the regulation of I(Cl.swell) in human atrial myocytes. We recorded I(Cl.swell) evoked by a hypotonic bath solution with the whole-cell patch-clamp technique. We found that I(Cl.swell) increased over time, and it was difficult to achieve absolute steady state. Phenylephrine potentiated I(Cl.swell) from -1.00 ± 0.51 pA/pF at -90 mV and 2.58 ± 1.17 pA/pF at +40 mV to -1.46 ± 0.70 and 3.84 ± 1.67 pA/pF, respectively (P < 0.05, n = 6), and the upward trend in ICl.swell was slowed after washout. This effect was concentration-dependent, and the α1-adrenoceptor antagonist prazosin shifted the dose-effect curve rightward. Addition of prazosin or the protein kinase C (PKC) inhibitor bisindolylmaleimide (BIM) attenuated the effect of phenylephrine. The PKC activator phorbol 12,13-dibutyrate (PDBu) activated I(Cl.swell) from -1.69 ± 1.67 pA/pF at -90 mV and 5.58 ± 6.36 pA/pF at +40 mV to -2.41 ± 1.95 pA/pF and 7.05 ± 6.99 pA/pF, respectively (P < 0.01 at -90 mV and P < 0.05 at +40 mV; n = 6). In conclusion, the α1-adrenoceptor agonist phenylephrine augmented I(Cl.swell), a result that differs from previous reports in other animal species. The effect was attenuated by BIM and mimicked by PDBu, which indicates that phenylephrine might modulate I(Cl,swell) in a PKC-dependent manner.

  3. alpha-Adrenoceptors in the ventricular myocardium: clonidine, naphazoline and methoxamine as partial alpha-agonists exerting a competitive dualism in action to phenylephrine.

    PubMed

    Schümann, H J; Endoh, M

    1976-04-01

    Tha alpha-sympathomimetic agonists, clonidine, naphazoline, methoxamine, oxymetazoline and phenylephrine were used to further characterize the alpha-adrenoceptors mediating the positive inotropic effect in the isolated papillary muscle of the rabbit heart. The maximal inotropic effects of these amines were compared with the effect of isoprenaline and it was examined whether or not these amines compete for alpha-adrenoceptors. On the papillary muscle stimulated at 0.5 Hz, phenylephrine showed a high affinity (pD2 value=6.13) and produced the most pronounced intrinsic activity of the alpha-sympathomimetic amines. Therefore, the intrinsic activity of phenylephrine, in the presence of prindolol (3 X 10(-8) M), was used for comparison with those of the other alpha-agonists. Clonidine caused a positive inotropic effect: the intrinsic activity amounted to 0.32 of that of phenylephrine; the affinity was the highest among the amines tested (pD2 value=6.46); its effect was inhibited by 10(-6) M phentolamine. The affinity and the intrinsic activity of naphazoline were slightly lower than those of clonidine. Methoxamine showed a relatively high intrinsic activity (0.56) but the lowest affinity (4.68). Oxymetazoline did not cause any positive inotropic effect. Clonidine, naphazoline and oxymetazoline antagonized the positive inotropic effect of phenylephrine, mediated via the alpha-adrenocaptors in the presence of 3 X 10(-8) M prindolol, in a competitive manner. This observation suggests that these alpha-sympathomimetic amines compete with phenylephrine for the same receptor site. Thus the present results provide additional evidence for alpha-adrenoceptors mediating the positive inotropic actions of sympathomimetic amines in the rabbit papillary muscle.

  4. Phenylephrine Decreases Vascular Tension in Goat Arteries in Specific Circumstances.

    PubMed

    Raj, Renu R; Subramani, Sathya

    2016-01-01

    Phenylephrine (PE) causes vasoconstriction through alpha adrenergic receptors. PE-induced vasodilatation has also been reported earlier in pre-constricted vessels. Here we demonstrate in spiral strips of goat arteries that addition of PE can decrease tone even from base-line levels (i.e. not pre-constricted) and show that this process requires nitric oxide (NO) and alpha adrenergic stimulation, but is cGMP-independent. Under control conditions, PE caused vasoconstriction, but under conditions where NO levels are higher, as with L-Arginine or sodium nitroprusside, PE decreased vessel tension. L-Arginine/PE combination was not able to decrease tension when alpha adrenoceptors were blocked with Phentolamine or endothelial nitric oxide synthase (eNOS) was blocked with Nω-Nitro-L-arginine (L-NNA). Propranolol, a beta blocker, was unable to prevent the reduction in tension by the L-Arginine/PE combination. Adrenaline and noradrenaline (and not isoproterenol) also reduced vessel tension in the presence of L-Arginine. Even when NO levels were not enhanced, relieving NO from having to stimulate the enzyme soluble guanylyl cyclase (sGC) (either by using sGC blockers, namely ODQ or methylene blue, or by enhancing cGMP levels (with sildenafil) which by negative feedback probably inhibits sGC) led to PE-induced reduction of vascular tension. PMA-phorbol myristate acetate-an agonist which stimulates Protein Kinase C was able to prevent the ability of PE to reduce vascular tension in a high NO environment. Our conclusion is that PE reduces vascular tension through alpha adrenoceptors if there is excess NO availability to activate a putative pathway. Though the reduction of vessel tone by PE is dependent on NO, it is independent of cGMP. Prior treatment with PMA or PE itself can prevent further PE-induced reduction of tension in a high NO environment. The results here suggest, counter-intuitively, that alpha blockers may be of help in the treatment of septic shock where nitric

  5. Phenylephrine Decreases Vascular Tension in Goat Arteries in Specific Circumstances.

    PubMed

    Raj, Renu R; Subramani, Sathya

    2016-01-01

    Phenylephrine (PE) causes vasoconstriction through alpha adrenergic receptors. PE-induced vasodilatation has also been reported earlier in pre-constricted vessels. Here we demonstrate in spiral strips of goat arteries that addition of PE can decrease tone even from base-line levels (i.e. not pre-constricted) and show that this process requires nitric oxide (NO) and alpha adrenergic stimulation, but is cGMP-independent. Under control conditions, PE caused vasoconstriction, but under conditions where NO levels are higher, as with L-Arginine or sodium nitroprusside, PE decreased vessel tension. L-Arginine/PE combination was not able to decrease tension when alpha adrenoceptors were blocked with Phentolamine or endothelial nitric oxide synthase (eNOS) was blocked with Nω-Nitro-L-arginine (L-NNA). Propranolol, a beta blocker, was unable to prevent the reduction in tension by the L-Arginine/PE combination. Adrenaline and noradrenaline (and not isoproterenol) also reduced vessel tension in the presence of L-Arginine. Even when NO levels were not enhanced, relieving NO from having to stimulate the enzyme soluble guanylyl cyclase (sGC) (either by using sGC blockers, namely ODQ or methylene blue, or by enhancing cGMP levels (with sildenafil) which by negative feedback probably inhibits sGC) led to PE-induced reduction of vascular tension. PMA-phorbol myristate acetate-an agonist which stimulates Protein Kinase C was able to prevent the ability of PE to reduce vascular tension in a high NO environment. Our conclusion is that PE reduces vascular tension through alpha adrenoceptors if there is excess NO availability to activate a putative pathway. Though the reduction of vessel tone by PE is dependent on NO, it is independent of cGMP. Prior treatment with PMA or PE itself can prevent further PE-induced reduction of tension in a high NO environment. The results here suggest, counter-intuitively, that alpha blockers may be of help in the treatment of septic shock where nitric

  6. Phenylephrine Decreases Vascular Tension in Goat Arteries in Specific Circumstances

    PubMed Central

    Raj, Renu R.

    2016-01-01

    Phenylephrine (PE) causes vasoconstriction through alpha adrenergic receptors. PE-induced vasodilatation has also been reported earlier in pre-constricted vessels. Here we demonstrate in spiral strips of goat arteries that addition of PE can decrease tone even from base-line levels (i.e. not pre-constricted) and show that this process requires nitric oxide (NO) and alpha adrenergic stimulation, but is cGMP-independent. Under control conditions, PE caused vasoconstriction, but under conditions where NO levels are higher, as with L-Arginine or sodium nitroprusside, PE decreased vessel tension. L-Arginine/PE combination was not able to decrease tension when alpha adrenoceptors were blocked with Phentolamine or endothelial nitric oxide synthase (eNOS) was blocked with Nω-Nitro-L-arginine (L-NNA). Propranolol, a beta blocker, was unable to prevent the reduction in tension by the L-Arginine/PE combination. Adrenaline and noradrenaline (and not isoproterenol) also reduced vessel tension in the presence of L-Arginine. Even when NO levels were not enhanced, relieving NO from having to stimulate the enzyme soluble guanylyl cyclase (sGC) (either by using sGC blockers, namely ODQ or methylene blue, or by enhancing cGMP levels (with sildenafil) which by negative feedback probably inhibits sGC) led to PE-induced reduction of vascular tension. PMA—phorbol myristate acetate—an agonist which stimulates Protein Kinase C was able to prevent the ability of PE to reduce vascular tension in a high NO environment. Our conclusion is that PE reduces vascular tension through alpha adrenoceptors if there is excess NO availability to activate a putative pathway. Though the reduction of vessel tone by PE is dependent on NO, it is independent of cGMP. Prior treatment with PMA or PE itself can prevent further PE-induced reduction of tension in a high NO environment. The results here suggest, counter-intuitively, that alpha blockers may be of help in the treatment of septic shock where

  7. Phenylephrine activates eNOS Ser 1177 phosphorylation and nitric oxide signaling in renal hypertensive rat aorta.

    PubMed

    Silva, Bruno R; Pernomian, Laena; Grando, Marcella D; Bendhack, Lusiane M

    2014-09-01

    The endothelial nitric oxide synthase (eNOS) plays an important role in the control of the vascular tone. This work aimed to evaluate the role of an α1-adrenoceptor agonist phenylephrine (PE) on eNOS activity and downstream signaling pathway activation in normotensive (2K) and renal hypertensive (2K-1C) intact-endothelium rat aortas. Concentration-effect curves were performed for PE in intact-endothelium aortas from 2K and 2K-1C rats, in the absence of or in the presence of NOS or soluble guanylyl cyclase (sGC) inhibitor. Intact endothelium aortas were stimulated with PE in organ chambers and eNOS Ser(1177)/Thr(495) phosphorylation expression was evaluated by western blot. Nitric Oxide (NO) production was evaluated in isolated endothelial cells from 2K and 2K-1C rat aortas by flow-cytometry using NO selective fluorescent probe, DAF-2DA. The sGC activity/expression was also evaluated. PE-induced contractile response is lower in 2K-1C than in 2K intact-endothelium rat aorta. This is due to higher eNOS Ser(1177) phosphorylation in 2K-1C, which induces the eNOS overactivation. It was abolished by NOS or sGC inhibition. Phenylephrine reduces NO production in 2K as compared to the basal level, but it is not modified in 2K-1C. In PE-stimulated endothelial cells, the NO production is higher in 2K-1C than in 2K. Phenylephrine induces higher cGMP production in 2K-1C than in 2K, despite the lower expression of sGC in 2K-1C. Our results suggest that alpha1-adrenoceptor activation contributes to the increased activity of the enzyme eNOS by Ser(1177) phosphorylation in 2K-1C intact-endothelium aorta, which consequently decreases PE-induced contractile response.

  8. Pseudoephedrine, Phenylephrine and Pregnancy

    MedlinePlus

    ... I use pseudoephedrine or phenylephrine if I am breastfeeding? At recommended doses, only a small amount of pseudoephedrine gets into breast milk. In general, pseudoephedrine does not cause any side effects in the breastfed baby, but a few cases ...

  9. Alpha/sub 1/ receptor coupling events initiated by methoxy-substituted tolazoline partial agonists

    SciTech Connect

    Wick, P.; Keung, A.; Deth, R.

    1986-03-01

    A series of mono- and dimethyoxy substituted tolazoline derivatives, known to be partial agonists at the alpha/sub 1/ receptor, were compared with the ..cap alpha../sub 1/ selective full agonist phenylephrine (PE) on isolated strips of rabbit aorta Agonist activity was evaluated in contraction, /sup 45/Ca influx, /sup 45/Ca efflux, and /sup 32/P-Phospholipid labelling studies. Maximum contractile responses for the 2-, 3-, and 3, 5- methoxy substituted tolazoline derivatives (10/sup -5/M) were 53.8, 67.6 and 99.7% of the PE (10/sup -5/M) response respectively. These same partial agonists caused a stimulation of /sup 45/Ca influx to the extent of 64, 86, and 95% of the PE response respectively. In /sup 45/Ca efflux studies, (a measure of the intracellular Ca/sup +2/ release) the tolazolines caused: 30%, 63%, and 78% of the PE stimulated level. /sup 32/P-Phosphatidic acid (PA) labelling was measured as an index of PI turnover after ..cap alpha../sub 1/ receptor stimulation. Compared to PE, the 2-, 3-, and 3,5- methoxy substituted tolazoline derivatives caused 22, 46, and 72% PA labelling. The above values are all in reasonable accord with the rank order or agonist activity shown in maximum contractile responses. The results of this investigation suggest that partial agonists stimulate ..cap alpha.. receptor coupling events at a level which is quantitatively comparable to their potencies in causing contraction of arterial smooth muscle.

  10. Stereoselective synthesis of (R)-phenylephrine using recombinant Escherichia coli cells expressing a novel short-chain dehydrogenase/reductase gene from Serratia marcescens BCRC 10948.

    PubMed

    Peng, Guan-Jhih; Kuan, Yi-Chia; Chou, Hsiao-Yi; Fu, Tze-Kai; Lin, Jia-Shin; Hsu, Wen-Hwei; Yang, Ming-Te

    2014-01-20

    (R)-Phenylephrine [(R)-PE] is an α1-adrenergic receptor agonist and is widely used as a nasal decongestant to treat the common cold without the side effects of other ephedrine adrenergic drugs. We identified a short-chain dehydrogenase/reductase (SM_SDR) from Serratia marcescens BCRC 10948 that was able to convert 1-(3-hydroxyphenyl)-2-(methylamino) ethanone (HPMAE) into (R)-PE. The SM_SDR used NADPH and NADH as cofactors with specific activities of 17.35±0.71 and 5.57±0.07mU/mg protein, respectively, at 30°C and pH 7.0, thereby indicating that this enzyme could be categorized as an NADPH-preferring short-chain dehydrogenase/reductase. Escherichia coli strain BL21 (DE3) expressing SM_SDR could convert HPMAE into (R)-PE with more than 99% enantiomeric excess. The productivity and conversion yield were 0.57mmolPE/lh and 51.06%, respectively, using 10mM HPMAE. Fructose was the most effective carbon source for the conversion of HPMAE to (R)-PE.

  11. Response of the parotid gland of red kangaroos, Macropus rufus, to phenylephrine stimulation.

    PubMed

    Beal, A M

    2003-01-01

    Intracarotid infusions of l-phenylephrine at 1.0 or 10 nmol kg(-1) min(-1) were accompanied by increases in salivary amylase activity, protein, potassium, magnesium and chloride relative to cholinergically-stimulated saliva. Intravenous infusions of phenylephrine at the same dose rates had a lesser effect on salivary composition particularly protein. Propranolol administered with phenylephrine via the carotid artery, at an antagonist/agonist ratio of 10:1, was much more effective in blocking the phenylephrine-induced changes in salivary composition than equimolar infusion of phentolamine with phenylephrine. It was concluded that alpha(1)-adrenoreceptors were not present in functionally significant numbers in the gland and that the effect of phenylephrine on the kangaroo parotid was mediated by beta-adrenoreceptors. As the phenylephrine dose rates in the kangaroos were comparable with those used to determine alpha-adrenergic responses of eutherian salivary glands and as phentolamine appeared to have minor beta-sympathomimetic activity, at least one subtype of beta-adrenoreceptors in macropods may not be identical to its eutherian counterpart.

  12. Effect of adrenergic antagonists during phenylephrine stimulation of the mandibular gland of red kangaroos, Macropus rufus.

    PubMed

    Beal, A M

    2002-07-01

    Intracarotid infusions of l-phenylephrine at 1.0 nmol.kg(-1).min(-1) or(.)10 nmol.kg(-1).min(-1) were accompanied by increases in salivary protein, urea, magnesium and bicarbonate, and by decreases in osmolality, hydrogen ion activity, sodium, potassium and chloride relative to cholinergically stimulated saliva. Intravenous infusions of phenylephrine at the same dose rates had much less effect on salivary composition with the differences between the routes of administration being greatest for the higher dose rate. Propranolol administered with phenylephrine via the carotid artery, at an antagonist:agonist ratio of 10:1, was much more effective in blocking the phenylephrine-induced changes in salivary composition than equimolar infusion of phentolamine with phenylephrine. Simultaneous intracarotid infusions of either a beta(1)-antagonist (CGP20712A) or a beta(2)-antagonist (ICI118551) with phenylephrine showed that ICI118551 was more potent than CGP20712A at preventing the changes in salivary composition associated with phenylephrine administration. It was concluded that alpha(1)-adrenoreceptors were not present in functionally significant numbers in the gland and that the effect of phenylephrine on the kangaroo mandibular was mediated by beta-adrenoreceptors predominantly of the beta(2)-subtype. As the phenylephrine dose rates in the kangaroos were comparable with those used to determine alpha-adrenergic responses of eutherian salivary glands and as both propranolol and phentolamine appeared to have minor beta-sympathomimetic activity, at least one subtype of beta-adrenoreceptors in macropods may not be identical to its eutherian counterpart.

  13. Maximizing myocardial perfusion with combined dipyridamole and phenylephrine

    SciTech Connect

    Lyons, K.P.; Lyons, J.; Eugene, J.; McColgan, S.; Gelezunas, V.; Swan, L.

    1984-01-01

    Intravenous dipyridamole (DP), a potent coronary vasodilator, has been used as a pharmacological exercise substitute for Thallium scintigraphy. Increased coronary artery flow occurs in animals. Humans with severe coronary disease have been imaged with Thallium using this technique. However, in both animals and man, the systemic blood pressure decreases especially at higher dosages. Myocardial perfusion (MP) is dependent on delivery pressure as well as the diameter of the coronary artery. The authors therefore maintained blood pressure by infusion of phenylephrine (PE) during maximal coronary artery dilatation from DP. Seven anesthetized, mongrel, open chest dogs weighing 20-25 kgs were infused with DP alone, 0.075 mg/kg/min for 10 minutes. Mp was measured in a highly localized small volume (0.5 cm/sup 3/) of myocardium using a silicon avalanche radiation detector to record the washout of a 2-5 mCi bolus of xenon in saline using the Kety-Schmidt formula. Polyethylene tubing (O.D. 0.03 inches) was directed into the proximal LAD using a brass canula introduced through the carotid artery. In 5 other dogs, 0.1 mg of PE was added to the DP. DP alone caused only a minor elevation of MP (15%) while the blood pressure decreased. In contrast with PE, the pressure was maintained and MP more than doubled. With continued infusion, both pressure and MP fell. In conclusion, elevation of MP by a coronary dilator DP can be enhanced when combined with a vasopressor (PE) and may be better for pharmacological stimulation of MP for Thallium imaging. Prolonged administration of DP may decrease rather than increase MP even during infusion of phenylephrine.

  14. Evidence for a requirement of agonist-induced diacylglycerol production during tonic contraction of rat aorta

    SciTech Connect

    Not Available

    1986-03-01

    A possible role for protein kinase C during the tonic phase of arterial contraction was examined in rat aorta by observing the effects of the phorbol ester, 12-0-tetradecanoylphorbol-13-acetate (TPA), on angiotensin II (AII)-induced responses. The ability of AII and phenylephrine (PE) to induce diacylglycerol (DAG) production was monitored as agonist-stimulated /sup 32/P-labelling of phosphatidic acid (PA). AII (5 x 10/sup -7/M) causes only a transient contractile response, while PE (10/sup -5/M) causes a sustained tonic contraction. /sup 32/P-labelling studies showed that AII caused an initial increase of PA synthesis equal to PE, however, AII failed to sustain this increase at 5 and 10 min while PE was able to do so, indicating the failure of AII to provide DAG to sustain protein kinase C activation. Activation of protein kinase C with TPA prior to and during AII exposure converted the normally transient contraction to a more sustained, tonic pattern. These results suggest that the inability of AII to maintain tension, unlike PE, is due to its inability to produce DAG continuously and activate protein kinase C.

  15. Metformin exaggerates phenylephrine-induced AMPK phosphorylation independent of CaMKKβ and attenuates contractile response in endothelium-denuded rat aorta.

    PubMed

    Pyla, Rajkumar; Osman, Islam; Pichavaram, Prahalathan; Hansen, Paul; Segar, Lakshman

    2014-11-15

    Metformin, a widely prescribed antidiabetic drug, has been shown to reduce the risk of cardiovascular disease, including hypertension. Its beneficial effect toward improved vasodilation results from its ability to activate AMPK and enhance nitric oxide formation in the endothelium. To date, metformin regulation of AMPK has not been fully studied in intact arterial smooth muscle, especially during contraction evoked by G protein-coupled receptor (GPCR) agonists. In the present study, ex vivo incubation of endothelium-denuded rat aortic rings with 3mM metformin for 2h resulted in significant accumulation of metformin (∼ 600 pmoles/mg tissue), as revealed by LC-MS/MS MRM analysis. However, metformin did not show significant increase in AMPK phosphorylation under these conditions. Exposure of aortic rings to a GPCR agonist (e.g., phenylephrine) resulted in enhanced AMPK phosphorylation by ∼ 2.5-fold. Importantly, in metformin-treated aortic rings, phenylephrine challenge showed an exaggerated increase in AMPK phosphorylation by ∼ 9.7-fold, which was associated with an increase in AMP/ATP ratio. Pretreatment with compound C (AMPK inhibitor) prevented AMPK phosphorylation induced by phenylephrine alone and also that induced by phenylephrine after metformin treatment. However, pretreatment with STO-609 (CaMKKβ inhibitor) diminished AMPK phosphorylation induced by phenylephrine alone but not that induced by phenylephrine after metformin treatment. Furthermore, attenuation of phenylephrine-induced contraction (observed after metformin treatment) was prevented by AMPK inhibition but not by CaMKKβ inhibition. Together, these findings suggest that, upon endothelial damage in the vessel wall, metformin uptake by the underlying vascular smooth muscle would accentuate AMPK phosphorylation by GPCR agonists independent of CaMKKβ to promote vasorelaxation.

  16. Phenylephrine protects autotransplanted rabbit submandibular gland from apoptosis

    SciTech Connect

    Xiang Bin; Zhang Yan; Li Yuming; Gao Yan; Gan Yehua; Wu Liling Yu Guangyan

    2008-12-05

    Submandibular gland (SMG) autotransplantation is an effective treatment for severe keratoconjunctivitis sicca. Our previous studies have shown that phenylephrine attenuates structural injury and promotes cell proliferation in autotransplanted rabbit SMG. However, the mechanism by which phenylephrine reduces the injury has not been fully evaluated. In this study, we investigate the ability of phenylephrine to inhibit apoptosis in autotransplanted rabbit SMG. We observed that apoptosis occurred in the early phase of SMG transplantation and that phenylephrine treatment protected transplanted SMG from apoptosis. Furthermore, we found that phenylephrine could significantly upregulate the expression of Bcl-2, downregulate the expression of Bax, and inhibit the activation of both caspase-3 and p38 mitogen-activated protein kinase in autotransplanted SMG. Therefore, the cytoprotective effects of phenylephrine on autotransplanted SMG may be a novel clinical strategy for autotransplanted SMG protection during the early postoperative stage of transplantation.

  17. Sulfation of phenylephrine by the human cytosolic sulfotransferases.

    PubMed

    Yamamoto, Akihiro; Kim, Jiwan; Liu, Ming-Yih; Kurogi, Katsuhisa; Sakakibara, Yoichi; Suiko, Masahito; Liu, Ming-Cheh

    2014-01-01

    Previous studies had demonstrated that sulfation constituted a major pathway for the metabolism of phenylephrine in vivo. The current study was designed to identify the major human SULT(s) responsible for the sulfation of phenylephrine. Of the twelve human SULTs analyzed, SULT1A3 displayed the strongest sulfating activity toward phenylephrine. The enzyme exhibited a pH optimum spanning 7 - 10.5. Kinetic analysis revealed that SULT1A3- mediated sulfation of phenylephrine occurred in the same order of magnitude compared with that previously reported for SULT1A3-mediated sulfation of dopamine. Moreover, sulfation of phenylephrine was shown to occur in HepG2 cells under metabolic setting. Collectively, these results provided useful information concerning the biochemical basis underlying the metabolism of phenylephrine in vivo as previously reported.

  18. Preparation and in vitro characterization of thermosensitive and mucoadhesive hydrogels for nasal delivery of phenylephrine hydrochloride.

    PubMed

    Xu, Xiaofeng; Shen, Yan; Wang, Wei; Sun, Chunmeng; Li, Chang; Xiong, Yerong; Tu, Jiasheng

    2014-11-01

    The aim of the present work was to develop a nasal delivery system of phenylephrine hydrochloride (PE) in spray form to make prolonged remedy of nasal congestion. The formulations contain the thermosensitive hydrogel, i.e., Poloxamer 407 (P407) and Poloxamer 188 (P188) mixtures, and mucoadhesives, i.e., ε-polylysine (ε-PL) and low molecular weight sodium hyaluronate (MW 11,000Da). The in vitro characterizations of formulations including rheology studies, texture profiles and in vitro mucoadhesion potential were investigated after gelation temperatures measurements. The results showed that the concentration of P407 or P188 had significant influence on gelation temperature and texture profiles. The addition of mucoadhesives, though lowered the gel strength of formulations, increased interaction with mucin. After screening, two formulations (i.e., 1.0% PE/0.5% ε-PL/17% P407/0.5% P188 or Formulation A; and 1.0% PE/0.5% HA/17% P407/0.8% P188 or Formulation B) presenting suitable gelation temperatures (∼32°C) were used for further studies on in vitro release behaviors and mucosa ciliotoxicity. Both formulations showed sustained release of PE for up to 8h and similar toxicity to saline, the negative control. Thus, the thermosensitive and mucoadhesive PE-containing hydrogels are promising to achieve prolonged decongestion in nasal cavity.

  19. Ultrasound-assisted (R)-phenylephrine whole-cell bioconversion by S. marcescens N10612.

    PubMed

    Zang, Chi-Zong; Kan, Shu-Chen; Yeh, Chiung-Wen; Lin, Chia-Chi; Shieh, Chwen-Jen; Liu, Yung-Chuan

    2015-09-01

    The strain Serratia marcescens N10612 is used to perform the bioconversion of 1-(3-hydroxyphenyl)-2-(methyamino)-ethanone (HPMAE) to (R)-phenylephrine ((R)-PE), which is an ephedrine drug substitute. The use of an ultrasound approach is found to improve the efficiency of the (R)-PE bioconversion. The optimization of the (R)-PE bioconversion is carried out by means of statistical experiment design. The optimal conditions obtained are 1.0mM HPMAE, 18.68 g/L glucose and ultrasound power of 120 W, where the predicted specific rate of the (R)-PE bioconversion is 31.46 ± 2.22 (ìmol/h/g-cells) and the experimental specific rate is 33.27 ± 1.46 (ìmol/h/g-cells), which is 3-fold higher than for the operation under ultrasound power of 200 W (11.11 ìmol/h/g-cells) and 4.3-fold higher than for the shaking operation (7.69 ìmol/h/g-cells). The kinetics study of the bioconversion also shows that under the ultrasound operation, the optimal rate (Vmax) of the (R)-PE bioconversion increases from 7.69 to 11.11 (μmol/h/g-cells) and the substrate inhibition constant (KSi) increases from 1.063 mM for the shaking operation to 1.490 mM for ultrasound operation.

  20. Early NADPH oxidase-2 activation is crucial in phenylephrine-induced hypertrophy of H9c2 cells.

    PubMed

    Hahn, Nynke E; Musters, René J P; Fritz, Jan M; Pagano, Patrick J; Vonk, Alexander B A; Paulus, Walter J; van Rossum, Albert C; Meischl, Christof; Niessen, Hans W M; Krijnen, Paul A J

    2014-09-01

    Reactive oxygen species (ROS) produced by different NADPH oxidases (NOX) play a role in cardiomyocyte hypertrophy induced by different stimuli, such as angiotensin II and pressure overload. However, the role of the specific NOX isoforms in phenylephrine (PE)-induced cardiomyocyte hypertrophy is unknown. Therefore we aimed to determine the involvement of the NOX isoforms NOX1, NOX2 and NOX4 in PE-induced cardiomyocyte hypertrophy. Hereto rat neonatal cardiomyoblasts (H9c2 cells) were incubated with 100 μM PE to induce hypertrophy after 24 and 48h as determined via cell and nuclear size measurements using digital imaging microscopy, electron microscopy and an automated cell counter. Digital-imaging microscopy further revealed that in contrast to NOX1 and NOX4, NOX2 expression increased significantly up to 4h after PE stimulation, coinciding and co-localizing with ROS production in the cytoplasm as well as the nucleus. Furthermore, inhibition of NOX-mediated ROS production with apocynin, diphenylene iodonium (DPI) or NOX2 docking sequence (Nox2ds)-tat peptide during these first 4h of PE stimulation significantly inhibited PE-induced hypertrophy of H9c2 cells, both after 24 and 48h of PE stimulation. These data show that early NOX2-mediated ROS production is crucial in PE-induced hypertrophy of H9c2 cells.

  1. Early NADPH oxidase-2 activation is crucial in phenylephrine-induced hypertrophy of H9c2 cells

    PubMed Central

    Hahn, Nynke E.; Musters, René J.P.; Fritz, Jan M.; Pagano, Patrick J.; Vonk, Alexander B.A.; Paulus, Walter J.; van Rossum, Albert C.; Meischl, Christof; Niessen, Hans W.M.; Krijnen, Paul A.J.

    2015-01-01

    Reactive oxygen species (ROS) produced by different NADPH oxidases (NOX) play a role in cardiomyocyte hypertrophy induced by different stimuli, such as angiotensin II and pressure overload. However, the role of the specific NOX isoforms in phenylephrine (PE)-induced cardiomyocyte hypertrophy is unknown. Therefore we aimed to determine the involvement of the NOX isoforms NOX1, NOX2 and NOX4 in PE-induced cardiomyocyte hypertrophy. Hereto rat neonatal cardiomyoblasts (H9c2 cells) were incubated with 100 μM PE to induce hypertrophy after 24 and 48 h as determined via cell and nuclear size measurements using digital imaging microscopy, electron microscopy and an automated cell counter. Digital-imaging microscopy further revealed that in contrast to NOX1 and NOX4, NOX2 expression increased significantly up to 4 h after PE stimulation, coinciding and co-localizing with ROS production in the cytoplasm as well as the nucleus. Furthermore, inhibition of NOX-mediated ROS production with apocynin, diphenylene iodonium (DPI) or NOX2 docking sequence (Nox2ds)-tat peptide during these first 4 h of PE stimulation significantly inhibited PE-induced hypertrophy of H9c2 cells, both after 24 and 48 h of PE stimulation. These data show that early NOX2-mediated ROS production is crucial in PE-induced hypertrophy of H9c2 cells. PMID:24794531

  2. Acute ischaemic colitis associated with oral phenylephrine decongestant use.

    PubMed

    Ward, Paul W; Shaneyfelt, Terrence M; Roan, Ronald M

    2014-01-01

    In this case, the authors have presented for the first time that ischaemic colitis may be associated with phenylephrine use. Since phenylephrine is the more common active ingredient in over-the-counter (OTC) cold medications, other presentations may follow this case. A MEDLINE search was performed for all case reports or case series of ischaemic colitis secondary to pseudoephedrine or phenylephrine use published between 1966 and 2013. The search resulted in four case reports and one case series describing patients with acute onset ischaemic colitis with exposure to pseudoephedrine immediately prior to onset. However, we found no case reports of ischaemic colitis associated with phenylephrine use. We present this case as an unexpected clinical outcome of phenylephrine, which has not been associated with ischaemic colitis in the literature. Also, this case serves as a reminder of the important clinical lesson to question all patients' use of OTC and prescribed medications.

  3. Effect of phenylephrine infusion on atrial electrophysiological properties.

    PubMed Central

    Leitch, J. W.; Basta, M.; Fletcher, P. J.

    1997-01-01

    OBJECTIVE: To determine the effect of changes in autonomic tone induced by phenylephrine infusion on atrial refractoriness and conduction. DESIGN: Left and right atrial electrophysiological properties were measured before and after a constant phenylephrine infusion designed to increase sinus cycle length by 25%. SUBJECTS: 20 patients, aged 53 (SD 6) years, undergoing electrophysiological study for investigation of idiopathic paroxysmal atrial fibrillation (seven patients) or for routine follow up after successful catheter ablation of supraventricular tachycardia (13 patients). MAIN OUTCOME MEASURES: Changes in left and right atrial effective refractory periods, atrial activation times, and frequency of induction of atrial fibrillation. RESULTS: Phenylephrine (mean dose 69 (SD 18) mg/min) increased mean blood pressure by 22 (12) mm Hg (range 7 to 44) and lengthened sinus cycle length by 223 (94) ms (20 to 430). Left atrial effective refractory period lengthened following phenylephrine infusion from 250 (25) to 264 (21) ms (P < 0.001) but there was no significant change in right atrial effective refractory period: 200 (20) v 206 (29), P = 0.11. There was a significant relation between the effect of phenylephrine on sinus cycle length and on right atrial refractoriness (r = 0.6, P = 0.005) with shortening of right atrial refractoriness in patients with the greatest prolongation in sinus cycle length. During phenylephrine infusion, the right atrial stimulus to left atrial activation time at the basic pacing cycle length of 600 ms was unchanged, at 130 (18) v 131 (17) ms, but activation delay with a premature extrastimulus increased: 212 (28) v 227 (38) ms, P = 0.002. Atrial fibrillation was induced by two of 58 refractory period measurements at baseline and by 12 of 61 measurements during phenylephrine infusion (P < 0.01). Phenylephrine increased the difference between left and right atrial refractory periods by 22.8 (19.4) ms in the five patients with induced atrial

  4. Patient considerations in cataract surgery – the role of combined therapy using phenylephrine and ketorolac

    PubMed Central

    Gonzalez-Salinas, Roberto; Guarnieri, Adriano; Guirao Navarro, María Concepción; Saenz-de-Viteri, Manuel

    2016-01-01

    Cataract, a degradation of the optical quality of the crystalline lens, progressive and age-related, is the leading cause of treatable blindness worldwide. Cataract surgery is the most common surgical procedure performed by ophthalmologists and is the only effective treatment for cataracts. Advances in the surgical techniques and better postoperative visual outcomes have progressively changed the primary concern of cataract surgery to become a procedure refined to yield the best possible refractive results. Sufficient mydriasis during cataract removal is critical to a successful surgical outcome. Poor pupil dilation can lead to serious sight-threatening complications that significantly increase the cost of surgery and decrease patients comfort. Mydriasis is obtained using anticholinergic and sympathomimetic drugs. Phenylephrine, an α1-adrenergic receptor agonist, can efficiently dilate the pupil when administered by intracameral injection. Additionally, nonsteroidal anti-inflammatory drugs (NSAIDs) like ketorolac, which inhibit the synthesis of prostaglandins, are used to decrease intraoperative miosis, control pain and inflammation associated with cataract surgery, and to prevent the development of cystoid macular edema following surgery. Recently, a new combination of phenylephrine and ketorolac (Omidria®) has been approved by United States Food and Drug Administration for use during cataract surgery to maintain intraoperative mydriasis, prevent miosis, and reduce postoperative pain and inflammation. Clinical trials have shown that this new combination is effective, combining the positive effects of both drugs with a good safety profile and patient tolerability. Moreover, recent reports suggest that this combination is also effective in patients with high risk of poor pupil dilation. In conclusion, cataract is a global problem that significantly affects patients’ quality of life. However, they can be managed with a safe and minimally invasive surgery

  5. Patient considerations in cataract surgery – the role of combined therapy using phenylephrine and ketorolac

    PubMed Central

    Gonzalez-Salinas, Roberto; Guarnieri, Adriano; Guirao Navarro, María Concepción; Saenz-de-Viteri, Manuel

    2016-01-01

    Cataract, a degradation of the optical quality of the crystalline lens, progressive and age-related, is the leading cause of treatable blindness worldwide. Cataract surgery is the most common surgical procedure performed by ophthalmologists and is the only effective treatment for cataracts. Advances in the surgical techniques and better postoperative visual outcomes have progressively changed the primary concern of cataract surgery to become a procedure refined to yield the best possible refractive results. Sufficient mydriasis during cataract removal is critical to a successful surgical outcome. Poor pupil dilation can lead to serious sight-threatening complications that significantly increase the cost of surgery and decrease patients comfort. Mydriasis is obtained using anticholinergic and sympathomimetic drugs. Phenylephrine, an α1-adrenergic receptor agonist, can efficiently dilate the pupil when administered by intracameral injection. Additionally, nonsteroidal anti-inflammatory drugs (NSAIDs) like ketorolac, which inhibit the synthesis of prostaglandins, are used to decrease intraoperative miosis, control pain and inflammation associated with cataract surgery, and to prevent the development of cystoid macular edema following surgery. Recently, a new combination of phenylephrine and ketorolac (Omidria®) has been approved by United States Food and Drug Administration for use during cataract surgery to maintain intraoperative mydriasis, prevent miosis, and reduce postoperative pain and inflammation. Clinical trials have shown that this new combination is effective, combining the positive effects of both drugs with a good safety profile and patient tolerability. Moreover, recent reports suggest that this combination is also effective in patients with high risk of poor pupil dilation. In conclusion, cataract is a global problem that significantly affects patients’ quality of life. However, they can be managed with a safe and minimally invasive surgery

  6. Low doses of esmolol and phenylephrine act as diuretics during intravenous anesthesia

    PubMed Central

    2012-01-01

    Introduction The renal clearance of infused crystalloid fluid is very low during anaesthesia and surgery, but experiments in conscious sheep indicate that the renal fluid clearance might approach a normal rate when the adrenergic balance is modified. Methods Sixty females (mean age, 32 years) undergoing laparoscopic gynecological surgery were randomized to control group and received only the conventional anesthetic drugs and 20 ml/kg of lactated Ringer's over 30 mins. The others were also given an infusion of 50 μg/kg/min of esmolol (beta1-receptor blocker) or 0.01 μg/kg/min of phenylephrine (alpha1-adrenergic agonist) over 3 hours. The distribution and elimination of infused fluid were studied by volume kinetic analysis based on urinary excretion and blood hemoglobin level. Results Both drugs significantly increased urinary excretion while heart rate and arterial pressure remained largely unaffected. The urine flows during non-surgery were 43, 147, and 176 ml in the control, esmolol, and phenylephrine groups, respectively (medians, P < 0.03). When surgery had started the corresponding values were 34, 65 and 61 ml (P < 0.04). At 3 hours, averages of 9%, 20%, and 25% of the infused volume had been excreted in the three groups (P < 0.01). The kinetic analyses indicated that both treatments slowed down the distribution of fluid from the plasma to the interstitial fluid space, thereby preventing hypovolemia. Conclusions Esmolol doubled and phenylephrine almost tripled urinary excretion during anesthesia-induced depression of renal fluid clearance. PMID:22289281

  7. Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an α-1 adrenoceptor agonist.

    PubMed

    Drummond, Peter D

    2011-01-20

    Iontophoresis of α(1)-adrenoceptor agonists in the human forearm evoke axon reflex vasodilatation, possibly due to an accumulation of inflammatory agents at the site of iontophoresis. To investigate this possibility, skin sites in the forearm of healthy participants were treated with an anti-inflammatory gel containing ibuprofen 5% before the iontophoresis of the α(1)-adrenoceptor agonist phenylephrine (350μA for 3min). Red cell flux was measured with laser Doppler flowmetry at the site of iontophoresis and 8mm away in the region of axon reflex vasodilatation. In additional experiments, skin sites were treated with the vasodilator sodium nitroprusside (to counteract vasoconstriction and disperse inflammatory mediators produced during the iontophoresis of phenylephrine); local anaesthetic agent (to determine whether the axon reflex to phenylephrine was neurally-mediated); or the α(2)-adrenoceptor agonist clonidine (to investigate the specificity of the adrenergic axon reflex). Phenylephrine evoked marked vasodilatation 8mm from the site of iontophoresis whereas clonidine and saline-control did not (mean flux increase±S.E. 485±132% for phenylephrine; 44±24% for clonidine; 39±19% for saline-control; p<0.05 for phenylephrine versus control). Axon reflex vasodilatation to phenylephrine was unaffected by variations in blood flow at the site of phenylephrine iontophoresis, but was reduced by ibuprofen pretreatment and abolished by local anaesthetic pretreatment. These findings suggest that prostaglandin synthesis at the site of iontophoresis contributes to but does not account entirely for axon reflex vasodilatation to phenylephrine. Alpha-1 adrenoceptor mediation of axon reflexes could play a role in aberrant sensory-sympathetic coupling in neuro-inflammatory diseases.

  8. Use of hollow microneedles for targeted delivery of phenylephrine to treat fecal incontinence.

    PubMed

    Jun, Hyesun; Han, Mee-Ree; Kang, Nae-Gyu; Park, Jung-Hwan; Park, Jung Ho

    2015-06-10

    A hollow microneedle (HM) was prepared to deliver a phenylephrine (PE) solution into the anal sphincter muscle as a method for treating fecal incontinence. The goal of this study was the local targeted delivery of PE into the sphincter muscle through the perianal skin with minimal pain using hollow microneedles, resulting in the increase of resting anal sphincter pressure. PE was administered on the left and the right sides of the anus of a rat through the perianal skin using 1.5mm long HM. An in vivo imaging system study was conducted after injection of Rhodamine B, and a histological study was performed after injection of gentian violet. The resting anal sphincter pressure in response to various drug doses was measured by using an air-charged catheter. Anal pressure change produced by HM administration was compared with change produced by intravenous injection (IV), subcutaneous (SC) injection and intramuscular (IM) injection. The change in mean blood pressure produced by HM administration as a function of PE dose was compared with change produced by PBS injection. A pharmacokinetic study of the new HM administration method was performed. A model drug solution was localized in the muscle layer under the perianal skin at the injection site and then diffused out over time. HM administration of PE induced significant contraction of internal anal sphincter pressure over 12h after injection, and the maximum anal pressure was obtained between 5 and 6h. Compared to IV, SC and IM treatments, HM treatment produced greater anal pressure. There was no increase in blood pressure after HM administration of PE within the range of predetermined concentration. Administration of 800μg/kg of PE using HM produced 0.81±0.38h of tmax. Our study suggests that HM administration enables local delivery of a therapeutic dose of PE to the anal sphincter muscle layer with less pain. This new treatment has great potential as a clinical application because of the ease of the procedure

  9. Computationally-designed phenylephrine prodrugs - a model for enhancing bioavailability

    NASA Astrophysics Data System (ADS)

    Karaman, Rafik; Karaman, Donia; Zeiadeh, Isra'

    2013-11-01

    DFT calculations at B3LYP 6-31G (d,p) for intramolecular proton transfer in a number of Kirby's enzyme models demonstrated that the driving force for the proton transfer efficiency is the distance between the two reactive centres (rGM) and the attack angle (α); and the rate of the reaction is linearly correlated with rGM2 and sin (180°- α). Based on these results three phenylephrine prodrugs were designed to provide phenylephrine with higher bioavailability than their parent drug. Using the experimental t1/2 (the time needed for the conversion of 50% of the reactants to products) and EM (effective molarity) values for these processes the t1/2 values for the conversion of the three prodrugs to the parent drug, phenylephrine were calculated. The calculated t1/2 values for ProD 1 and ProD 2 were very high (145 days and several years, respectively) whereas that of ProD 3 was found to be about 35 hours. Therefore, the intra-conversion rates of the phenylephrine prodrugs to phenylephrine can be programmed according to the nature of the prodrug linker.

  10. Safety and Efficacy of Phenylephrine Nasal Drops in Bronchiolitis

    PubMed Central

    Soleimani, Gholamreza; Akbarpour, Marzieh; Mohammadi, Mehdi

    2014-01-01

    Objective: Bronchiolitis is a common lower respiratory tract infection in the first year of life. In this disease upper respiratory tract infection is associated with nasal congestion, respiratory distress and hypoxia. We studied the effect of phenylephrine drops as a decongestant in treatment of light and moderately severe cases of acute bronchiolitis. Methods: This is a double blind randomized trial involving 100 children aged 4 weeks to 12 months. The patients were divided into two groups, the first group received 0.1 ml phenylephrine 0.5% and the second group 0.1 ml sodium chloride (NaCl) 0.9% as placebo in both nostrils. Respiratory rate, heart rate, O2 saturation, dyspnea, retractions and wheezing were assessed before and 30 minutes after medication. Findings: After medication, O2 saturation and respiratory muscles retractions in the phenylephrine group were significantly better than those of the placebo group (P=0.004 and P=0.002, respectively). In the phenylephrine group, O2 saturation, retractions and wheezing were also significantly better before than those after medication (P=0.003 and P<0.0001 respectively). In the placebo group no significant difference before and after intervention was observed. Conclusion: Phenylephrine as a topical decongestant is an inexpensive, easily available and suitable means in the treatment of mild to moderately severe bronchiolitis. PMID:25793067

  11. Protein kinase Cδ contributes to phenylephrine-mediated contraction in the aortae of high fat diet-induced obese mice.

    PubMed

    Liu, Limei; Liu, Jian; Gao, Yuansheng; Yu, Xiaoxing; Dou, Dou; Huang, Yu

    2014-04-18

    The down-regulation of α-adrenoceptor-mediated signaling casacade has been implicated in obesity but the underlying mechanism remains largely unknown. The present study investigated whether inositol 1,4,5-trisphosphate (IP3) receptor and protein kinase C (PKC) were involved in the reduction of α1-adrenoceptor agonist phenylephrine-evoked contraction in aortae of high fat diet-induced obese (DIO) mice. C57BL/6 mice were fed with a rodent diet containing 45 kcal% fat for 16 weeks to induce obesity. Isolated mouse aortae were suspended in myograph for isometric force measurement. Protein phosphorylations and expressions were determined by Western blotting. In C57BL/6 mouse aortae, phenylephrine-induced contraction was partially inhibited by either IP3 receptor antagonist heparin or PKC inhibitor GFX, and the combined treatment with heparin and GFX abolished the contraction. Phenylephrine-induced contraction was significantly less in the aortae of DIO mice than those of control mice; only GFX but not heparin attenuated the contraction, indicating a diminishing role of IP3 receptor in DIO mice. Western blotting showed the reduced expression and phosphorylation of IP3 receptor and the down-regulated expression of PKC, PKCβ, PKCδ, and PKCζ in DIO mouse aortae. Importantly, PKCδ was more likely to maintain phenylephrine-mediated contraction in DIO mouse aortae because that (1) PKCδ inhibitor rottlerin but not PKCα and PKCβ inhibitor Gö6976, PKCβ inhibitor hispidin, or PKCζ pseudosubstrate inhibitor attenuated the contraction; and (2) PKCδ phosphorylation was increased but phosphorylations of PKCα, PKCβ, and PKCζ were reduced in DIO mouse aortae. The present study thus provides additional insights into the cellular mechanisms responsible for vascular dysfunction in obesity.

  12. Agonist-specific behaviour of the intracellular Ca2+ response in rat hepatocytes.

    PubMed Central

    Chatton, J Y; Cao, Y; Stucki, J W

    1997-01-01

    A variety of agonists stimulate in hepatocytes a response that takes the shape of repetitive cytosolic free Ca2+ transients called Ca2+ oscillations. The shape of spikes and the pattern of oscillations in a given cell differ depending on the agonist of the phosphoinositide pathway that is applied. In this study, the response of individual rat hepatocytes to maximal stimulation by arginine vasopressin (AVP), phenylephrine and ADP was investigated by fluorescence microscopy and flash photolysis. Hepatocytes loaded with Ca2+-sensitive probes were stimulated with a first agonist to evoke a maximal response, and then a second agonist was added. When phenylephrine or ADP was used as the first agonist, AVP applied subsequently could elicit an additional response, which did not happen when AVP was first applied and phenylephrine or ADP was applied later. Cells microinjected with caged myo-inositol 1,4,5-trisphosphate (IP3) were challenged with the different agonists and, when a maximal response was obtained, photorelease of IP3 was triggered. Cells maximally stimulated with AVP did not respond to IP3 photorelease, whereas those stimulated with phenylephrine or ADP responded with a fast Ca2+ spike above the elevated steady-state level, which was followed by an undershoot. In contrast, with all three agonists, IP3 photorelease triggered at the top of an oscillatory Ca2+ transient was able to mobilize additional Ca2+. These experiments indicate that the differential response of cells to agonists is found not only during Ca2+ oscillations but also during maximal agonist stimulation and that potency and efficacy differences exist among agonists. PMID:9371717

  13. The modulation of vascular ATP-sensitive K+ channel function via the phosphatidylinositol 3-kinase-Akt pathway activated by phenylephrine.

    PubMed

    Haba, Masanori; Hatakeyama, Noboru; Kinoshita, Hiroyuki; Teramae, Hiroki; Azma, Toshiharu; Hatano, Yoshio; Matsuda, Naoyuki

    2010-08-01

    The present study examined the modulator role of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway activated by the alpha-1 adrenoceptor agonist phenylephrine in ATP-sensitive K(+) channel function in intact vascular smooth muscle. We evaluated the ATP-sensitive K(+) channel function and the activity of the PI3K-Akt pathway in the rat thoracic aorta without endothelium. The PI3K inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) (10(-5) M) augmented relaxation in response to the ATP-sensitive K(+) channel opener levcromakalim (10(-8) to 3 x 10(-6) M) in aortic rings contracted with phenylephrine (3 x 10(-7) M) but not with 9,11-dideoxy-11alpha,9alpha-epoxy-methanoprostaglandin F(2alpha) (U46619; 3 x 10(-8) M), although those agents induced similar contraction. ATP-sensitive K(+) channel currents induced by levcromakalim (10(-6) M) in the presence of phenylephrine (3 x 10(-7) M) were enhanced by the nonselective alpha-adrenoceptor antagonist phentolamine (10(-7) M) and LY294002 (10(-5) M). Levels of the regulatory subunits of PI3K p85-alpha and p55-gamma increased in the membrane fraction from aortas without endothelium treated with phenylephrine (3 x 10(-7) M) but not with U46619 (3 x 10(-8) M). Phenylephrine simultaneously augmented Akt phosphorylation at Ser473 and Thr308. Therefore, activation of the PI3K-Akt pathway seems to play a role in the impairment of ATP-sensitive K(+) channel function in vascular smooth muscle exposed to alpha-1 adrenergic stimuli.

  14. Charge-transfer complexes of phenylephrine with nitrobenzene derivatives

    NASA Astrophysics Data System (ADS)

    El-Mossalamy, E. H.

    2004-04-01

    The molecular charge-transfer complexes of phenylephrine with picric acid and m-dinitrobenzene have been studied and investigated by IR, 1H NMR electronic spectra in organic solvents and buffer solutions, respectively. Simple and selective methods are proposed for the determination of phenylephrine hydrochloride in bulk form and in tablets. The two methods are based on the formation of charge-transfer complexes between drug base as a n-donor (D) and picric acid, m-dinitrobenzene as π-acceptor (A). The products exhibit absorption maxima at 497 and 560 nm in acetonitrile for picric acid and m-dinitrobenzene, respectively. The coloured product exhibits an absorption maximum at 650 nm in dioxane. The sensitive kinetic methods for the determination phynylephrine hydrochloride are described. The method is based upon a kinetic investigation of the oxidation reaction of the drug with alkaline potassium permanganate at room temperature for a fixed time at 20 min.

  15. Magnesium and diltiazem relaxes phenylephrine-precontracted rat aortic rings

    PubMed Central

    Dogan, Mustafa; Peker, Recep O.; Donmez, Soner; Gokalp, Osman

    2012-01-01

    Perioperative vasospasm during cardiovascular surgery is a challenging problem. Several vasodilator agents are frequently utilized for its prevention in surgical practice. Magnesium and diltiazem both have known potential vasorelaxant effects. We planned to compare the efficacy of diltiazem and magnesium in relieving phenylephrine-precontracted rat aortic rings. Ten young adult female Wistar albino rats weighing 230–260 g were used in this study. The aortic rings in the organ bath equilibrated and reached their baseline tension. Precontraction was induced by 0.001 mmol/l phenylephrine and cumulative concentration–relaxation curves were obtained by consecutively increasing the addition of either diltiazem (10−6-0.1 mmol/l) or magnesium (0.1–10 mmol/l). The mean maximal relaxation responses observed by diltiazem and magnesium on separate aortic rings were 90 ± 3 and 53 ± 2%, respectively. The calculated EC50 of diltiazem was 0.01035 mmol/l, whereas the EC50 of magnesium was 4.064 mmol/l (P < 0.05). Both magnesium and diltiazem produced vasorelaxation on phenylephrine-precontracted rat aortic rings in this study, but the potency of diltiazem regarding the EC50 value was significantly higher than that of magnesium. Magnesium could be a candidate together with diltiazem to inhibit vasospasm on arterial grafts during coronary bypass surgery. PMID:22523136

  16. Effects of cyclooxygenase inhibition on vascular responses evoked in fingers of men and women by iontophoresis of α1- and α2-adrenoceptor agonists

    PubMed Central

    Srinivasa, Amar; Marshall, Janice M

    2011-01-01

    Abstract In 10 men and nine women aged 20–23 years, we aimed to establish whether endogenous prostanoids synthesised by cyclooxygenase (COX) affect responses evoked in the finger by α1- or α2-adrenoceptor agonists. Cutaneous red cell flux (cRCF) was recorded in dorsal finger during iontophoresis of phenylephrine (PE) or clonidine (0.5 mm, seven 0.1 mA pulses followed by one 0.2 mA pulse: 30 s each at 60 s intervals) before and after the COX inhibitor aspirin (600 mg p.o.). In men, PE evoked a biphasic mean increase/decrease in cRCF before but a monophasic mean decrease in cRCF of 30–40% after aspirin (P < 0.05). In women in the low oestrogen (E2) phase of the menstrual cycle, PE evoked a decrease in cRCF (30–40%; P < 0.05) that was unchanged by aspirin, whereas in the high E2 phase, PE evoked no change before but a graded decrease in cRCF (30–40%; P < 0.05) after aspirin. Clonidine evoked a decrease in cRCF (∼30%; P < 0.05) in men before, but not after, aspirin. Clonidine evoked both increases and decreases in cRCF before and after aspirin in women in the low and high E2 phases (P > 0.05). We propose that finger vasoconstriction evoked by extraluminal α1-adrenoceptor stimulation is blunted by vasodilator COX products in young men and overcome by their action in women in the high, but not low E2, phase of the menstrual cycle. By contrast, α2-adrenoceptor stimulation evokes finger vasoconstriction that is mediated by vasoconstrictor COX products in young men, but evokes no consistent response in women in the low or high E2 phases of the menstrual cycle. PMID:21807614

  17. Influence of circulating alpha adrenoceptor agonists on lung function in patients with exercise induced asthma and healthy subjects.

    PubMed Central

    Larsson, K; Martinsson, A; Hjemdahl, P

    1986-01-01

    The influence of circulating noradrenaline (in this context primarily a non-selective alpha agonist) and the alpha 1 selective agonist phenylephrine on bronchial tone, blood pressure, and heart rate was studied in eight patients with exercise induced asthma and eight age and sex matched controls. All subjects refrained from taking treatment for at least one week before the trial. The agonists were infused intravenously in stepwise increasing doses of 0.04, 0.085, 0.17, and 0.34 micrograms/kg a minute for noradrenaline and 0.5, 1.0, 2.0, and 4.0 micrograms/kg a minute for phenylephrine. At the highest dose the plasma concentration of noradrenaline was about 30 nmol/l, resembling the concentrations found during intense exercise, and that of phenylephrine was about 400 nmol/l. Both agonists caused dose dependent and similar increases in blood pressure in the two groups. Despite clearcut cardiovascular effects (systolic and diastolic blood pressure increased by about 40-50/25-30 mm Hg), neither agonist altered lung function, as assessed by measurements of specific airway compliance (sGaw), peak expiratory flow (PEF), or end expiratory flow rate, in either group. It is concluded that circulating alpha agonists, whether alpha 1 selective (phenylephrine) or non-selective (noradrenaline), fail to alter basal bronchial tone in patients with exercise induced asthma or in healthy subjects. PMID:3787535

  18. Differing effects when using phenylephrine and norepinephrine to augment cerebral blood flow after traumatic brain injury in the immature brain.

    PubMed

    Friess, Stuart H; Bruins, Benjamin; Kilbaugh, Todd J; Smith, Colin; Margulies, Susan S

    2015-02-15

    Low cerebral blood flow (CBF) states have been demonstrated in children early after traumatic brain injury (TBI), and have been correlated with poorer outcomes. Cerebral perfusion pressure (CPP) support following severe TBI is commonly implemented to correct cerebral hypoperfusion, but the efficacy of various vasopressors has not been determined. Sixteen 4-week-old female swine underwent nonimpact inertial brain injury in the sagittal plane. Intraparenchymal monitors were placed to measure intracranial pressure (ICP), CBF, brain tissue oxygen tension (PbtO2), and cerebral microdialysis 30 min to 6 h post-injury. One hour after injury, animals were randomized to receive either phenylephrine (PE) or norepinephrine (NE) infusions titrated to a CPP>70 mm Hg for 5 h. Animals were euthanized 6 h post-TBI, and brains were fixed and stained to assess regions of cell and axonal injury. After initiation of CPP augmentation with NE or PE infusions, there were no differences in ICP between the groups or over time. Animals receiving NE had higher PbtO2 than those receiving PE (29.6±10.2 vs. 19.6±6.4 torr at 6 h post-injury, p<0.05). CBF increased similarly in both the NE and PE groups. CPP support with PE resulted in a greater reduction in metabolic crisis than with NE (lactate/pyruvate ratio 16.7±2.4 vs. 42.7±10.2 at 6 h post-injury, p<0.05). Augmentation of CPP to 70 mm Hg with PE resulted in significantly smaller cell injury volumes at 6 h post-injury than CPP support with NE (0.4% vs. 1.4%, p<0.05). Despite similar increases in CBF, CPP support with NE resulted in greater brain tissue oxygenation and hypoxic-ischemic injury than CPP support with PE. Future clinical studies comparing the effectiveness of various vasopressors for CPP support are warranted.

  19. Middle cerebral O₂ delivery during the modified Oxford maneuver increases with sodium nitroprusside and decreases during phenylephrine.

    PubMed

    Stewart, Julian M; Medow, Marvin S; DelPozzi, Andrew; Messer, Zachary R; Terilli, Courtney; Schwartz, Christopher E

    2013-06-01

    The modified Oxford maneuver is the reference standard for assessing arterial baroreflex function. The maneuver comprises a systemic bolus injection of 100 μg sodium nitroprusside (SNP) followed by 150 μg phenylephrine (PE). On the one hand, this results in an increase in oxyhemoglobin and total hemoglobin followed by a decrease within the cerebral sample volume illuminated by near-infrared spectroscopy (NIRS). On the other hand, it produces a decrease in cerebral blood flow velocity (CBFv) within the middle cerebral artery (MCA) during SNP and an increase in CBFv during PE as measured by transcranial Doppler ultrasound. To resolve this apparent discrepancy, we hypothesized that SNP dilates, whereas PE constricts, the MCA. We combined transcranial Doppler ultrasound of the right MCA with NIRS illuminating the right frontal cortex in 12 supine healthy subjects 18-24 yr old. Assuming constant O₂ consumption and venous saturation, as estimated by partial venous occlusion plethysmography, we used conservation of mass (continuity) equations to estimate the changes in arterial inflow (ΔQa) and venous outflow (ΔQv) of the NIRS-illuminated area. Oxyhemoglobin and total hemoglobin, respectively, increased by 13.6 ± 1.6 and 15.2 ± 1.4 μmol/kg brain tissue with SNP despite hypotension and decreased by 6 ± 1 and 7 ± 1 μmol/kg with PE despite hypertension. SNP increased ΔQa by 0.36 ± .03 μmol·kg(-1)·s(-1) (21.6 μmol·kg(-1)·min(-1)), whereas CBFv decreased from 71 ± 2 to 62 ± 2 cm/s. PE decreased ΔQa by 0.27 ± .2 μmol·kg(-1)·s(-1) (16.2 μmol·kg(-1)·min(-1)), whereas CBFv increased to 75 ± 3 cm/s. These results are consistent with dilation of the MCA by SNP and constriction by PE. PMID:23564308

  20. Middle cerebral O2 delivery during the modified Oxford maneuver increases with sodium nitroprusside and decreases during phenylephrine

    PubMed Central

    Medow, Marvin S.; DelPozzi, Andrew; Messer, Zachary R.; Terilli, Courtney; Schwartz, Christopher E.

    2013-01-01

    The modified Oxford maneuver is the reference standard for assessing arterial baroreflex function. The maneuver comprises a systemic bolus injection of 100 μg sodium nitroprusside (SNP) followed by 150 μg phenylephrine (PE). On the one hand, this results in an increase in oxyhemoglobin and total hemoglobin followed by a decrease within the cerebral sample volume illuminated by near-infrared spectroscopy (NIRS). On the other hand, it produces a decrease in cerebral blood flow velocity (CBFv) within the middle cerebral artery (MCA) during SNP and an increase in CBFv during PE as measured by transcranial Doppler ultrasound. To resolve this apparent discrepancy, we hypothesized that SNP dilates, whereas PE constricts, the MCA. We combined transcranial Doppler ultrasound of the right MCA with NIRS illuminating the right frontal cortex in 12 supine healthy subjects 18–24 yr old. Assuming constant O2 consumption and venous saturation, as estimated by partial venous occlusion plethysmography, we used conservation of mass (continuity) equations to estimate the changes in arterial inflow (ΔQa) and venous outflow (ΔQv) of the NIRS-illuminated area. Oxyhemoglobin and total hemoglobin, respectively, increased by 13.6 ± 1.6 and 15.2 ± 1.4 μmol/kg brain tissue with SNP despite hypotension and decreased by 6 ± 1 and 7 ± 1 μmol/kg with PE despite hypertension. SNP increased ΔQa by 0.36 ± .03 μmol·kg−1·s−1 (21.6 μmol·kg−1·min−1), whereas CBFv decreased from 71 ± 2 to 62 ± 2 cm/s. PE decreased ΔQa by 0.27 ± .2 μmol·kg−1·s−1 (16.2 μmol·kg−1·min−1), whereas CBFv increased to 75 ± 3 cm/s. These results are consistent with dilation of the MCA by SNP and constriction by PE. PMID:23564308

  1. The role of UHMW-PE in microporous PE separators

    SciTech Connect

    Wang, L.C.; Harvey, M.K.; Stein, H.L.; Scheunemann, U.

    1997-12-01

    Microporous PE separators have gained large popularity in the lead acid battery industry, particularly in SLI (Starting, Lighting and Ignition) Automotive Applications. The PE (Polyethylene) in battery separator is actually UHMW-PE (Ultra High Molecular Weight Polyethylene). UHMW-PE has a molecular weight more than ten times that of conventional HDPE (High Density Polyethylene). This paper gives an overview of the UHMW-PE`s contributions to the PE battery separator process, assembly, and performance, in comparison to other conventional separators, such as PVC (Polyvinyl Chloride), cellulose, and glass fiber.

  2. Dissecting out the Complex Ca2+-Mediated Phenylephrine-Induced Contractions of Mouse Aortic Segments

    PubMed Central

    Fransen, Paul; Van Hove, Cor E.; Leloup, Arthur J. A.; Martinet, Wim; De Meyer, Guido R. Y.; Lemmens, Katrien; Bult, Hidde; Schrijvers, Dorien M.

    2015-01-01

    L-type Ca2+ channel (VGCC) mediated Ca2+ influx in vascular smooth muscle cells (VSMC) contributes to the functional properties of large arteries in arterial stiffening and central blood pressure regulation. How this influx relates to steady-state contractions elicited by α1-adrenoreceptor stimulation and how it is modulated by small variations in resting membrane potential (Vm) of VSMC is not clear yet. Here, we show that α1-adrenoreceptor stimulation of aortic segments of C57Bl6 mice with phenylephrine (PE) causes phasic and tonic contractions. By studying the relationship between Ca2+ mobilisation and isometric tension, it was found that the phasic contraction was due to intracellular Ca2+ release and the tonic contraction determined by Ca2+ influx. The latter component involves both Ca2+ influx via VGCC and via non-selective cation channels (NSCC). Influx via VGCC occurs only within the window voltage range of the channel. Modulation of this window Ca2+ influx by small variations of the VSMC Vm causes substantial effects on the contractile performance of aortic segments. The relative contribution of VGCC and NSCC to the contraction by α1-adrenoceptor stimulation could be manipulated by increasing intracellular Ca2+ release from non-contractile sarcoplasmic reticulum Ca2+ stores. Results of this study point to a complex interactions between α1-adrenoceptor-mediated VSMC contractile performance and Ca2+ release form contractile or non-contractile Ca2+ stores with concomitant Ca2+ influx. Given the importance of VGCC and their blockers in arterial stiffening and hypertension, they further point toward an additional role of NSCC (and NSCC blockers) herein. PMID:25803863

  3. Dissecting out the complex Ca2+-mediated phenylephrine-induced contractions of mouse aortic segments.

    PubMed

    Fransen, Paul; Van Hove, Cor E; Leloup, Arthur J A; Martinet, Wim; De Meyer, Guido R Y; Lemmens, Katrien; Bult, Hidde; Schrijvers, Dorien M

    2015-01-01

    L-type Ca2+ channel (VGCC) mediated Ca2+ influx in vascular smooth muscle cells (VSMC) contributes to the functional properties of large arteries in arterial stiffening and central blood pressure regulation. How this influx relates to steady-state contractions elicited by α1-adrenoreceptor stimulation and how it is modulated by small variations in resting membrane potential (Vm) of VSMC is not clear yet. Here, we show that α1-adrenoreceptor stimulation of aortic segments of C57Bl6 mice with phenylephrine (PE) causes phasic and tonic contractions. By studying the relationship between Ca2+ mobilisation and isometric tension, it was found that the phasic contraction was due to intracellular Ca2+ release and the tonic contraction determined by Ca2+ influx. The latter component involves both Ca2+ influx via VGCC and via non-selective cation channels (NSCC). Influx via VGCC occurs only within the window voltage range of the channel. Modulation of this window Ca2+ influx by small variations of the VSMC Vm causes substantial effects on the contractile performance of aortic segments. The relative contribution of VGCC and NSCC to the contraction by α1-adrenoceptor stimulation could be manipulated by increasing intracellular Ca2+ release from non-contractile sarcoplasmic reticulum Ca2+ stores. Results of this study point to a complex interactions between α1-adrenoceptor-mediated VSMC contractile performance and Ca2+ release form contractile or non-contractile Ca2+ stores with concomitant Ca2+ influx. Given the importance of VGCC and their blockers in arterial stiffening and hypertension, they further point toward an additional role of NSCC (and NSCC blockers) herein.

  4. The Ultimate PE Challenge

    ERIC Educational Resources Information Center

    Cerny, Eleanor; Wojehowski, Ken

    2005-01-01

    This article features the Ultimate PE Challenge. The idea had been born when the fifth-grade teachers complained that teaching physical geography was boring, and the technology instructor simultaneously noticed a climbing wall in the gym. "Could physical education simulate the geographic characteristics and obstacles of North America?" This…

  5. Prevention of hypotension associated with the induction dose of propofol: A randomized controlled trial comparing equipotent doses of phenylephrine and ephedrine

    PubMed Central

    Farhan, Muhammad; Hoda, Muhammad Qamarul; Ullah, Hameed

    2015-01-01

    Background and Aims: Propofol, the most commonly used intravenous (IV) anesthetic agent is associated with hypotension on induction of anesthesia. Different methods have been used to prevent hypotension but with variable results. The objective of this study was to evaluate efficacy of equipotent doses of phenylpehrine and ephedrine in preventing the hypotensive response to the induction dose of propofol. Material and Methods: One hundred thirty five adult patients were randomised to one of the study groups: propofol-saline (PS), propofol-phenylephrine (PP) or propofol-ephedrine (PE) by adding study drugs to propofol. Anesthesia was induced with a mixture of propofol and the study drug. Patients were manually mask-ventilated for 5 min using 40% oxygen in nitrous oxide and isoflurane at 1%. A baseline mean arterial pressure (MAP) was recorded prior to induction of anesthesia. Systolic, diastolic and mean blood pressure and heart rate were recorded every minute for up to 5 min after induction. Hypotension was defined as a 20% decrease from the baseline MAP. Results: There were no significant demographic differences between the groups. Overall incidence of hypotension in this study was 38.5% (52/135). Rate of hypotension was significantly higher in group PS than group PP (60% vs. 24.4% P = 0.001) and group PE (60% vs. 31.1% P = 0.005). In contrast, a significant difference in rate of hypotension was not observed between groups PP and group PE. Conclusion: In equipotent doses, phenylephrine is as good as ephedrine in preventing the hypotensive response to an induction dose of propofol. PMID:26702213

  6. Estrogen, nitric oxide, and hypertension differentially modulate agonist-induced contractile responses in female transgenic (mRen2)27 hypertensive rats.

    PubMed

    Brosnihan, K Bridget; Li, Ping; Figueroa, Jorge P; Ganten, Detlev; Ferrario, Carlos M

    2008-05-01

    Clinical trials revealed that estrogen may result in cardiovascular risk in patients with coronary heart disease, despite earlier studies demonstrating that estrogen provided cardiovascular protection. It is possible that the preexisting condition of hypertension and the ability of estrogen to activate the renin-angiotensin system could confound its beneficial effects. Our hypothesis is that the attenuation of estrogen to agonist-induced vasoconstrictor responses through the activation of nitric oxide (NO) synthase (NOS) is impaired by hypertension. We investigated the effects of 17beta-estradiol (E(2)) replacement in normotensive Sprague-Dawley (SD) and (mRen2)27 hypertensive transgenic (TG) rats on contractile responses to three vasoconstrictors, angiotensin II (ANG II), serotonin (5-HT), and phenylephrine (PE), and on the modulatory role of vascular NO to these responses. The aorta was isolated from ovariectomized SD and TG rats treated chronically with 5 mg E(2) or placebo (P). The isometric tension of the aortic rings was measured in organ chambers, and endothelial NOS (eNOS) in the rat aorta was detected using Western blot analysis. E(2) treatment increased eNOS expression in the SD and TG aorta and reduced ANG II- and 5-HT- but not PE-induced contractions in SD and TG rats. The inhibition of NOS with N(omega)-nitro-L-arginine methyl ester enhanced ANG II-, 5-HT-, and PE-induced contractions in P-treated and ANG II and PE responses in E(2)-treated SD and TG rats. Only the responses to 5-HT were augmented in hypertensive rats. In conclusion, this study shows that the preexisting condition of hypertension augmented the vascular responsiveness of 5-HT, whereas the attenuation of estrogen by ANG II and 5-HT vascular responses was not impaired by hypertension. The adrenergic agonist was unresponsive to estrogen treatment. The contribution of NO as a factor contributing to the relative refractoriness of the vascular responses is dependent on the nature of the

  7. Cardiovascular effects of dobutamine and phenylephrine infusion in sevoflurane-anesthetized Thoroughbred horses.

    PubMed

    Ohta, Minoru; Kurimoto, Shinjiro; Ishikawa, Yuhiro; Tokushige, Hirotaka; Mae, Naomi; Nagata, Shun-ichi; Mamada, Masayuki

    2013-11-01

    To determine dose-dependent cardiovascular effects of dobutamine and phenylephrine during anesthesia in horses, increasing doses of dobutamine and phenylephrine were infused to 6 healthy Thoroughbred horses. Anesthesia was induced with xylazine, guaifenesin and thiopental and maintained with sevoflurane at 2.8% of end-tidal concentration in all horses. The horses were positioned in right lateral recumbency and infused 3 increasing doses of dobutamine (0.5, 1.0 and 2.0 µg/kg/min) for 15 min each dose. Following to 30 min of reversal period, 3 increasing doses of phenylephrine (0.25, 0.5 and 1.0 µg/kg/min) were infused. Cardiovascular parameters were measured before and at the end of each 15-min infusion period for each drug. Blood samples were collected every 5 min during phenylephrine infusion period. There were no significant changes in heart rate throughout the infusion period. Both dobutamine and phenylephrine reversed sevoflurane-induced hypotension. Dobutamine increased both mean arterial blood pressure (MAP) and cardiac output (CO) as the result of the increase in stroke volume, whereas phenylephrine increased MAP but decreased CO as the result of the increase in systemic vascular resistance. Plasma phenylephrine concentration increased dose-dependently, and these values at 15, 30 and 45 min were 6.2 ± 1.2, 17.0 ± 4.8 and 37.9 ± 7.3 ng/ml, respectively.

  8. Cardiovascular effects of dobutamine and phenylephrine infusion in sevoflurane-anesthetized Thoroughbred horses.

    PubMed

    Ohta, Minoru; Kurimoto, Shinjiro; Ishikawa, Yuhiro; Tokushige, Hirotaka; Mae, Naomi; Nagata, Shun-ichi; Mamada, Masayuki

    2013-11-01

    To determine dose-dependent cardiovascular effects of dobutamine and phenylephrine during anesthesia in horses, increasing doses of dobutamine and phenylephrine were infused to 6 healthy Thoroughbred horses. Anesthesia was induced with xylazine, guaifenesin and thiopental and maintained with sevoflurane at 2.8% of end-tidal concentration in all horses. The horses were positioned in right lateral recumbency and infused 3 increasing doses of dobutamine (0.5, 1.0 and 2.0 µg/kg/min) for 15 min each dose. Following to 30 min of reversal period, 3 increasing doses of phenylephrine (0.25, 0.5 and 1.0 µg/kg/min) were infused. Cardiovascular parameters were measured before and at the end of each 15-min infusion period for each drug. Blood samples were collected every 5 min during phenylephrine infusion period. There were no significant changes in heart rate throughout the infusion period. Both dobutamine and phenylephrine reversed sevoflurane-induced hypotension. Dobutamine increased both mean arterial blood pressure (MAP) and cardiac output (CO) as the result of the increase in stroke volume, whereas phenylephrine increased MAP but decreased CO as the result of the increase in systemic vascular resistance. Plasma phenylephrine concentration increased dose-dependently, and these values at 15, 30 and 45 min were 6.2 ± 1.2, 17.0 ± 4.8 and 37.9 ± 7.3 ng/ml, respectively. PMID:23832627

  9. Cardiovascular Effects of Dobutamine and Phenylephrine Infusion in Sevoflurane-anesthetized Thoroughbred Horses

    PubMed Central

    OHTA, Minoru; KURIMOTO, Shinjiro; ISHIKAWA, Yuhiro; TOKUSHIGE, Hirotaka; MAE, Naomi; NAGATA, Shun-ichi; MAMADA, Masayuki

    2013-01-01

    ABSTRACT To determine dose-dependent cardiovascular effects of dobutamine and phenylephrine during anesthesia in horses, increasing doses of dobutamine and phenylephrine were infused to 6 healthy Thoroughbred horses. Anesthesia was induced with xylazine, guaifenesin and thiopental and maintained with sevoflurane at 2.8% of end-tidal concentration in all horses. The horses were positioned in right lateral recumbency and infused 3 increasing doses of dobutamine (0.5, 1.0 and 2.0 µg/kg/min) for 15 min each dose. Following to 30 min of reversal period, 3 increasing doses of phenylephrine (0.25, 0.5 and 1.0 µg/kg/min) were infused. Cardiovascular parameters were measured before and at the end of each 15-min infusion period for each drug. Blood samples were collected every 5 min during phenylephrine infusion period. There were no significant changes in heart rate throughout the infusion period. Both dobutamine and phenylephrine reversed sevoflurane-induced hypotension. Dobutamine increased both mean arterial blood pressure (MAP) and cardiac output (CO) as the result of the increase in stroke volume, whereas phenylephrine increased MAP but decreased CO as the result of the increase in systemic vascular resistance. Plasma phenylephrine concentration increased dose-dependently, and these values at 15, 30 and 45 min were 6.2 ± 1.2, 17.0 ± 4.8 and 37.9 ± 7.3 ng/ml, respectively. PMID:23832627

  10. Studies on the positive inotropic effect of phenylephrine: a comparison with isoprenaline.

    PubMed

    Ledda, F; Marchetti, P; Mugelli, A

    1975-05-01

    1. The effects of phenylephrine and isoprenaline on the isometric contraction of guinea-pig ventricle were compared over the whole range of their respective dose-response curves. 2. In preparations driven at 2.5 Hz the increase in contractile force induced by either isoprenaline of phenylephrine was linearly correlated to an increase in maximum velocity of force development. The relaxation time was shortened by isoprenaline but not by phenylephrine. 3. The negative inotropic effect induced by delta [N-(3,4-dimethoxyphenethyl)-N-methyl-amino]-alpha-(3,4,5-trimethoxyphenyl)alpha-isopropylvaleronitrile hydrochloride (D(600)) was reversed by isoprenaline, but little influenced by phenylephrine. 4. The study of the interval-force relationship shows that the increase in contractile force induced by phenylephrine (3 X 10(-5) M) was relatively greater at low frequencies of stimulation, and that the maximum effect was reached at the frequency of 1 Hz. 5. The positive inotropic effect of phenylephrine (10-4 M) was significantly higher at a frequency of 1 Hz than at 2.5 Hz; the effect of isoprenaline (3 x 10-8 M) was not significantly different at the two driving frequencies. 6. In preparations driven at 1 Hz the inotropic effect of the lower concentrations of phenylephrine was due to an increase in the time to peak tension without any change of the maximum velocity of force development; however an increase of this parameter became evident only after higher concentrations of the amine (10-5 M or more), associated with a progressive shortening of the time to peak. 7. A correlation between mechanical and electrophysiological effects of phenylephrine is attempted; the suggestion is advanced that the prolongation of the action potential and of the active state duration may be an important factor in the inotropic effect of phenylephrine.

  11. Short-term effects of phenylephrine on systemic and regional hemodynamics in patients with septic shock: a crossover pilot study.

    PubMed

    Morelli, Andrea; Lange, Matthias; Ertmer, Christian; Dünser, Martin; Rehberg, Sebastian; Bachetoni, Alessandra; D'Alessandro, Marladomenica; Van Aken, Hugo; Guarracino, Fabio; Pietropaoli, Paolo; Traber, Daniel L; Westphal, Martin

    2008-04-01

    Clinical studies evaluating the use of phenylephrine in septic shock are lacking. The present study was designed as a prospective, crossover pilot study to compare the effects of norepinephrine (NE) and phenylephrine on systemic and regional hemodynamics in patients with catecholamine-dependent septic shock. In 15 septic shock patients, NE (0.82 +/- 0.689 microg x kg(-1) x min(-1)) was replaced with phenylephrine (4.39 +/- 5.23 microg x kg(-1) x min(-1)) titrated to maintain MAP between 65 and 75 mmHg. After 8 h of phenylephrine infusion treatment was switched back to NE. Data from right heart catheterization, acid-base balance, thermo-dye dilution catheter, gastric tonometry, and renal function were obtained before, during, and after replacing NE with phenylephrine. Variables of systemic hemodynamics, global oxygen transport, and acid-base balance remained unchanged after replacing NE with phenylephrine except for a significant decrease in heart rate (phenylephrine, 89 +/- 18 vs. NE, 93 +/- 18 bpm; P < 0.05). However, plasma disappearance rate (phenylephrine, 13.5 +/- 7.1 vs. NE, 16.4 +/- 8.7% x min(-1)) and clearance of indocyanine green (phenylephrine, 330 +/- 197 vs. NE, 380 +/- 227 mL x min(-1) x m(-2)), as well as creatinine clearance (phenylephrine, 81.3 +/- 78.4 vs. NE, 94.3 +/- 93.5 mL x min(-1)) were significantly decreased by phenylephrine infusion (each P < 0.05). In addition, phenylephrine increased arterial lactate concentrations as compared with NE infusion (1.7 +/- 1.0 vs. 1.4 +/- 1.1 mM; P < 0.05). After switching back to NE, all variables returned to values obtained before phenylephrine infusion except creatinine clearance and gastric tonometry values. Our results suggest that for the same MAP, phenylephrine causes a more pronounced hepatosplanchnic vasoconstriction as compared with NE.

  12. Inhibition by trifluoperazine of glycogenolytic effects of phenylephrine, vasopressin, and angiotensin II.

    PubMed

    Koide, Y; Kimura, S; Tada, R; Kugai, N; Yamashita, K

    1982-06-01

    The effects of trifluoperazine on the activation of glycogenolysis by various hormones were studied in perfused rat liver. Trifluoperazine significantly inhibited glycogenolytic effect of phenylephrine and angiotensin II by lowering maximal response, and that of vasopressin by shifting the dose-response curve to the right, while alpha-antagonist phentolamine was inhibitory only to phenylephrine. Phosphorylase activation of phenylephrine was inhibited by trifluoperazine in parallel with glycogenolytic response. The increase in 45Ca2+ efflux induced by phenylephrine, angiotensin II, and vasopressin was also inhibited by the agent. These inhibitory effects of trifluoperazine were not related to the change in tissue cyclic AMP or cyclic GMP levels. On the other hand, neither the glycogenolytic effect of glucagon, cyclic AMP, and N6,O2-dibutyryl cyclic AMP nor phosphorylase activation by glucagon was affected by trifluoperazine. Thus, trifluoperazine specifically inhibits the activation of glycogenolysis by Ca2+-dependent hormones.

  13. Phenylephrine as an alternative to cocaine for nasal vasoconstriction before nasal surgery: A randomised trial

    PubMed Central

    AlHaddad, Sawsan T; Khanna, Ashish K; Mascha, Edward J; Abdelmalak, Basem B

    2013-01-01

    Background: Cocaine is often used topically to provide the profound vasoconstriction required for nasal surgery; however, it has been associated with intraoperative cardiac adverse effects. We compared cocaine with phenylephrine as an alternative to ascertain their relative efficacy as vasoconstrictors in nasal septoplasty. Methods: Adult patients, presenting for elective nasal septoplasty, of American Society of Anaesthesiologists physical status I-III, were randomised to either 0.5% phenylephrine or 4% cocaine. The primary outcome was quality of vasoconstriction on a 5-point scale (1=unacceptable, 5=excellent), rated by the surgeon at the end of the procedure. Results: Twenty-nine patients received phenylephrine and 26 received cocaine. The median rating for quality of the vasoconstriction was 4.0 (good) in both the phenylephrine and cocaine groups (P=0.84). Median blood loss was 50 ml in the phenylephrine group and 62.5 ml in the cocaine group (P=0.49). In secondary analyses, phenylephrine was shown to be non-inferior to cocaine on both quality of vasoconstriction (non-inferiority delta of 1 point, P=0.009) and estimated blood loss (non-inferiority delta of 25 ml, P=0.028). The frequency of ventricular ectopy, ST segment changes or blood pressure changes after nasal packing was not significantly different between the two groups. Conclusion: Phenylephrine in a concentration of 0.5% is not different from 4% cocaine on the quality of vasoconstriction in septoplasty. Given the abuse potential of cocaine and the added administrative burden associated with its handling, phenylephrine might serve as an alternative. PMID:23825816

  14. Development and validation of RP-HPLC method for simultaneous estimation of nimesulide, phenylephrine hydrochloride, chlorpheniramine maleate and caffeine anhydrous in pharmaceutical dosage form.

    PubMed

    Kumar, Ashok; Sharma, Rishbha; Nair, Anroop; Saini, Gautam

    2012-01-01

    In this study, a simple, specific and accurate reverse phase high performance liquid chromatographic method was developed for the simultaneous determination of nimesulide (NS), phenylephrine hydrochloride (PE), chlorpheniramine maleate (CPM) and caffeine anhydrous (CF) in pharmaceutical dosage forms. A reversed phase Hypersil phenyl column (4.6 mm x 25 cm) with mobile phase having pH 5.5 consisting of methanol and buffer (55:45, v/v) was used. The flow rate was 1.0 mL per minute and the effluents were monitored at 214 nm. The retention times of all the drugs were found to be 7.47 min (NS), 3.944 min (PE), 4.55 min (CF) and 17.15 min (CPM), respectively. The linearity for all the drugs was obtained in the range of 300-800 microg/mL (NS), 15-32 microg/mL (PE), 16-32 microg/mL (CPM) and 30-180 microg/mL (CF), respectively. The results of analysis have been well validated according to guidelines of International Conference of Harmonisation of technical requirements for registration of pharmaceuticals for human use. The method was found to be simple, precise, economical, less time consuming and reproducible. Hence, the suggested procedure could be used for the determination of all the four drugs in commercial preparations.

  15. Development and validation of RP-HPLC method for simultaneous estimation of nimesulide, phenylephrine hydrochloride, chlorpheniramine maleate and caffeine anhydrous in pharmaceutical dosage form.

    PubMed

    Kumar, Ashok; Sharma, Rishbha; Nair, Anroop; Saini, Gautam

    2012-01-01

    In this study, a simple, specific and accurate reverse phase high performance liquid chromatographic method was developed for the simultaneous determination of nimesulide (NS), phenylephrine hydrochloride (PE), chlorpheniramine maleate (CPM) and caffeine anhydrous (CF) in pharmaceutical dosage forms. A reversed phase Hypersil phenyl column (4.6 mm x 25 cm) with mobile phase having pH 5.5 consisting of methanol and buffer (55:45, v/v) was used. The flow rate was 1.0 mL per minute and the effluents were monitored at 214 nm. The retention times of all the drugs were found to be 7.47 min (NS), 3.944 min (PE), 4.55 min (CF) and 17.15 min (CPM), respectively. The linearity for all the drugs was obtained in the range of 300-800 microg/mL (NS), 15-32 microg/mL (PE), 16-32 microg/mL (CPM) and 30-180 microg/mL (CF), respectively. The results of analysis have been well validated according to guidelines of International Conference of Harmonisation of technical requirements for registration of pharmaceuticals for human use. The method was found to be simple, precise, economical, less time consuming and reproducible. Hence, the suggested procedure could be used for the determination of all the four drugs in commercial preparations. PMID:23285660

  16. Myosin light chain phosphorylation in sup 32 P-labeled rabbit aorta stimulated by phorbol 12,13-dibutyrate and phenylephrine

    SciTech Connect

    Singer, H.A.; Oren, J.W.; Benscoter, H.A. )

    1989-12-15

    The mechanism(s) of force development in vascular smooth muscle following pharmacological activation of protein kinase C by phorbol esters are not known. In this study, we examined the myosin light chain phosphorylation response following stimulation by phorbol 12,13-dibutyrate (PDB) or phenylephrine in rabbit aorta which had been incubated with 32PO4 in order to label ATP pools. Through tryptic phosphopeptide mapping of myosin light chain from intact tissue and comparison to controls using purified components, we inferred that Ca2+-dependent force stimulated by PDB was associated with small increases in serine-19 phosphorylation, consistent with a contractile mechanism involving indirect activation of myosin light chain kinase. Additional residues, consistent with the in vitro substrate specificity of protein kinase C, were also observed to be phosphorylated in response to PDB and represented proportionately a larger fraction of the total phosphorylated myosin light chain in Ca2+-depleted tissues. Stimulation by an alpha 1-adrenergic agonist (phenylephrine) resulted in phosphorylation of residues which were consistent with an activation mechanism involving myosin light chain kinase only. These results indicate that in rabbit aorta the contractile effects of PDB may be partially mediated by Ca2+-dependent activation of myosin light chain kinase. However, the data do not rule out a component of the PDB-stimulated contractile response which is independent of myosin light chain phosphorylation on the serine-19 residue. In addition, activation by a more physiological stimulus, phenylephrine, does not result in protein kinase C-mediated myosin light chain phosphorylation.

  17. EGCG Blocked Phenylephrin-Induced Hypertrophy in H9C2 Cardiomyocytes, by Activating AMPK-Dependent Pathway.

    PubMed

    Cai, Yi; Zhao, Li; Qin, Yuan; Wu, Xiao-Qian

    2015-05-01

    AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism. Previous studies have shown that activation of AMPK results in suppression of cardiac myocyte hypertrophy via inhibition of the p70S6 kinase (p70S6K) and eukaryotic elongation factor-2 (eEF2) signaling pathways. Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, possesses multiple protective effects on the cardiovascular system including cardiac hypertrophy. However, the molecular mechanisms has not been well investigated. In this study, we found that EGCG could significantly reduce natriuretic peptides type A (Nppa), brain natriuretic polypeptide (BNP) mRNA expression and decrease cell surface area in H9C2 cardiomyocytes stimulated with phenylephrine (PE). Moreover, we showed that AMPK is activated in H9C2 cardiomyocytes by EGCG, and AMPK-dependent pathway participates in the inhibitory effects of EGCG on cardiac hypertrophy. Taken together, our findings provide the first evidence that the effect of EGCG against cardiac hypertrophy may be attributed to its activation on AMPK-dependent signaling pathway, suggesting the therapeutic potential of EGCG on the prevention of cardiac remodeling in patients with pressure overload hypertrophy. PMID:25954124

  18. Visualizing the endocytosis of phenylephrine in living cells by quantum dot-based tracking.

    PubMed

    Ma, Jing; Wu, Lina; Hou, Zhun; Song, Yao; Wang, Lei; Jiang, Wei

    2014-08-01

    To study the intracellular receptor-drug transportation, a fluorescent probe consisting of phenylephrine-polyethylene glycol-quantum dots conjugate was employed to track endocytosis process of phenylephrine in living cells. This type of movement was studied by continuously filming fluorescent images in the same cell. We also calculated the movement parameters, and divided the endocytosis process into 6 stages. Furthermore, the movement parameters of this probe in different organelles were determined by co-localization of the probe fluorescent images and different cellular organelles. After comparing the parameters in cellular organelles with these in 6 stages, the whole endocytosis pathway was demonstrated. These results verified that this probe successfully tracked the whole intracellular dynamic endocytosis process of phenylephrine. Our method realized the visual tracking the whole receptor-mediated endocytosis, which is a new approach on investigating the molecular mechanisms and kinetic properties of intracellular receptor-drug transportation.

  19. Phenylephrine enhances glutamate release in the medial prefrontal cortex through interaction with N-type Ca2+ channels and release machinery.

    PubMed

    Luo, Fei; Li, Si-Hai; Tang, Hua; Deng, Wei-Ke; Zhang, Yu; Liu, Ying

    2015-01-01

    α1 -adrenoceptors (α1 -ARs) stimulation has been found to enhance excitatory processes in many brain regions. A recent study in our laboratory showed that α1 -ARs stimulation enhances glutamatergic transmission via both pre- and post-synaptic mechanisms in layer V/VI pyramidal cells of the rat medial prefrontal cortex (mPFC). However, a number of pre-synaptic mechanisms may contribute to α1 -ARs-induced enhancement of glutamate release. In this study, we blocked the possible post-synaptic action mediated by α1 -ARs to investigate how α1 -ARs activation regulates pre-synaptic glutamate release in layer V/VI pyramidal neurons of mPFC. We found that the α1 -ARs agonist phenylephrine (Phe) induced a significant enhancement of glutamatergic transmission. The Phe-induced potentiation was mediated by enhancing pre-synaptic glutamate release probability and increasing the number of release vesicles via a protein kinase C-dependent pathway. The mechanisms of Phe-induced potentiation included interaction with both glutamate release machinery and N-type Ca(2+) channels, probably via a pre-synaptic Gq /phospholipase C/protein kinase C pathway. Our results may provide a cellular and molecular mechanism that helps explain α1 -ARs-mediated influence on PFC cognitive functions. Alpha1 -adrenoceptor (α1 -ARs) stimulation has been reported to enhance glutamatergic transmission in layer V/VI pyramidal neurons of the rat medial prefrontal cortex (mPFC). We found that α1 -ARs agonist phenylephrine (Phe) increases pre-synaptic glutamate release probability and the number of released vesicles via interaction with both glutamate release machinery and N-type Ca(2+) channels. Our results may provide a cellular and molecular mechanism that helps explain α1 -ARs-mediated influence on PFC cognitive functions. Gq, Gq protein; PLC, phospholipase C; PKC, protein kinase C; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-d-aspartate; Glu, glutamate; Phe

  20. Determination of phenylephrine hydrochloride, chlorpheniramine maleate, and methscopolamine nitrate in tablets or capsules by liquid chromatography with two UV absorbance detectors in series.

    PubMed

    Cieri, Uco R

    2006-01-01

    A procedure is presented for the simultaneous determination of phenylephrine HCI (PE), chlorpheniramine maleate (CM), and methscopolamine nitrate in commercial tablets or capsules by liquid chromatography (LC) with 2 UV absorbance detectors in series. Reference and sample solutions are prepared in methanol. LC separations are performed on a 7.5 cm Novapak silica column. The mobile phase is prepared by mixing 930 mL methanol with 70 mL of a 0.5% aqueous solution of 1-pentanesulfonic acid, sodium salt. The injection volume is 20 microL; the flow rate is approximately 1 mL/min. Retention times are approximately 1.5 min for PE, 3 min for CM, and 6 min for methscopolamine nitrate. One detector determines the first 2 compounds at 265 nm, but the third compound does not produce a detectable peak. The other detector set at 210 nm generates peaks for all 3 compounds, but only methscopolamine is within the recorder range; the other 2 compounds are exceedingly off scale. If it is not feasible or desirable to arrange 2 UV absorbance detectors in series, separate determinations can be made, one for the first 2 compounds and the other for the third component of the mixture. Two commercial samples of tablets and 2 commercial samples of capsules were analyzed by the proposed method. Recovery studies were also conducted with amounts of the 3 compounds ranging from 80 to 120% of the quantities present in the sample solutions.

  1. Phenylephrine potentiates the anticonvulsant effect and neutralizes the sedative effect of diazepam in rats upon combined intragastric administration.

    PubMed

    Serdyuk, S E; Gmiro, V E

    2014-12-01

    High doses of phenylephrine and diazepam (1 and 10 mg/kg, respectively) suppressed the development of generalized tonic-clonic pentylenetetrazole-induced convulsions in 86-100% rats, but did not prevent local clonic pentylenetetrazole-induced convulsions. Diazepam in the specified dose produced strong sedation, while phenylephrine had no sedative effect in the open-field test. Combined intragastric administration of phenylephrine in a medium and individually ineffective dose (0.3 mg/kg) and diazepam in a high dose (10 mg/kg) potentiated the anticonvulsant effect of diazepam: it prevented not only tonic-clonic, but also clonic pentylenetetrazole-induced convulsions in 100% rats and 2.6-fold increased anticonvulsant activity of diazepam. The specified combination of diazepam and phenylephrine had no sedative effect. The mechanism of potentiation of the anticonvulsive effect and elimination of the sedative side effect is based on stimulation of gastric mucosa afferents by phenylephrine.

  2. Prophylactic phenylephrine for caesarean section under spinal anaesthesia: systematic review and meta-analysis.

    PubMed

    Heesen, M; Kölhr, S; Rossaint, R; Straube, S

    2014-02-01

    We conducted a systematic review to determine the harm and benefit associated with prophylactic phenylephrine for caesarean section under spinal anaesthesia. We included 21 randomised controlled trials with 1504 women. The relative risk (95% CI) of hypotension with phenylephrine infusion – as defined by authors – before delivery was 0.36 (0.18–0.73) vs placebo, p = 0.004; 0.58 (0.39–0.88) vs an ephedrine infusion, p = 0.009; and 0.73 (0.55–0.96) when added to an ephedrine infusion, p = 0.02. After delivery, the relative risks of hypotension and nausea and vomiting with phenylephrine compared with placebo were 0.37 (0.19–0.71), p = 0.003, and 0.39 (0.17–0.91), p = 0.03, respectively. There was no evidence that hypertension, bradycardia or neonatal endpoints were affected. Phenylephrine reduced the risk for hypotension and nausea and vomiting after spinal doses of bupivacaine generally exceeding 8 mg, but there was no evidence that it reduced other maternal or neonatal morbidities.

  3. Phenylephrine-induced elevations in arterial blood pressure are attenuated in heat-stressed humans

    NASA Technical Reports Server (NTRS)

    Cui, Jian; Wilson, Thad E.; Crandall, Craig G.

    2002-01-01

    To test the hypothesis that phenylephrine-induced elevations in blood pressure are attenuated in heat-stressed humans, blood pressure was elevated via steady-state infusion of three doses of phenylephrine HCl in 10 healthy subjects in both normothermic and heat stress conditions. Whole body heating significantly increased sublingual temperature by 0.5 degrees C, muscle sympathetic nerve activity (MSNA), heart rate, and cardiac output and decreased total peripheral vascular resistance (TPR; all P < 0.005) but did not change mean arterial blood pressure (MAP; P > 0.05). At the highest dose of phenylephrine, the increase in MAP and TPR from predrug baselines was significantly attenuated during the heat stress [DeltaMAP 8.4 +/- 1.2 mmHg; DeltaTPR 0.96 +/- 0.85 peripheral resistance units (PRU)] compared with normothermia (DeltaMAP 15.4 +/- 1.4 mmHg, DeltaTPR 7.13 +/- 1.18 PRU; all P < 0.001). The sensitivity of baroreflex control of MSNA and heart rate, expressed as the slope of the relationship between MSNA and diastolic blood pressure, as well as the slope of the relationship between heart rate and systolic blood pressure, respectively, was similar between thermal conditions (each P > 0.05). These data suggest that phenylephrine-induced elevations in MAP are attenuated in heat-stressed humans without affecting baroreflex control of MSNA or heart rate.

  4. Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine

    NASA Technical Reports Server (NTRS)

    Rudas, L.; Crossman, A. A.; Morillo, C. A.; Halliwill, J. R.; Tahvanainen, K. U.; Kuusela, T. A.; Eckberg, D. L.

    1999-01-01

    We evaluated a method of baroreflex testing involving sequential intravenous bolus injections of nitroprusside followed by phenylephrine and phenylephrine followed by nitroprusside in 18 healthy men and women, and we drew inferences regarding human sympathetic and vagal baroreflex mechanisms. We recorded the electrocardiogram, photoplethysmographic finger arterial pressure, and peroneal nerve muscle sympathetic activity. We then contrasted least squares linear regression slopes derived from the depressor (nitroprusside) and pressor (phenylephrine) phases with 1) slopes derived from spontaneous fluctuations of systolic arterial pressures and R-R intervals, and 2) baroreflex gain derived from cross-spectral analyses of systolic pressures and R-R intervals. We calculated sympathetic baroreflex gain from integrated muscle sympathetic nerve activity and diastolic pressures. We found that vagal baroreflex slopes are less when arterial pressures are falling than when they are rising and that this hysteresis exists over pressure ranges both below and above baseline levels. Although pharmacological and spontaneous vagal baroreflex responses correlate closely, pharmacological baroreflex slopes tend to be lower than those derived from spontaneous fluctuations. Sympathetic baroreflex slopes are similar when arterial pressure is falling and rising; however, small pressure elevations above baseline silence sympathetic motoneurons. Vagal, but not sympathetic baroreflex gains vary inversely with subjects' ages and their baseline arterial pressures. There is no correlation between sympathetic and vagal baroreflex gains. We recommend repeated sequential nitroprusside followed by phenylephrine doses as a simple, efficientmeans to provoke and characterize human vagal and sympathetic baroreflex responses.

  5. Effect of acute and chronic ethanol on the agonist responses of vascular smooth muscle

    SciTech Connect

    Strickland, J.; Wooles, W.R.

    1986-03-05

    The authors studied the effects of ETOH on the response of isolated rat thoracic aorta rings to phenylephrine (PE) and angiotensin II (AII). They also examined the effect of chronic ETOH on vascular reactivity to PE and ETOH in vitro for up to 18 weeks during the development of ETOH-induced hypertension. The dose-responses (DR) of both PE and AII were shifted to the right by ETOH in a dose dependent manner. All was more sensitive to this shift which was significantly different from the controls at 50 mM ETOH compared to 150 mM ETOH for PE. The combination of 1 nM saralasin and 150 mM ETOH depressed the AII DR more than saralasin alone but was comparable to that of ETOH. The combination of 150 mM ETOH and 0.3 nM prazosin depressed the PE DR less than prazosin alone but more than ETOH alone. The effect of .01 nM verapamil on the PE DR was similar to that of saralasin on the AII DR. The results of the chronic study showed that the PE DR of the aortic rings from ETOH rats was comparable to that of control rats until the 18th week when it was shifted to the right. The PE DR was shifted rightward by 150 mM ETOH to the same extent in both control and ETOH rats which suggests that ETOH has ..cap alpha..-receptor blocking properties. Vascular reactivity to PE and to ETOH remained the same throughout the ETOH drinking period indicating a lack of development of hypersensitivity to PE or tolerance to ETOH which may contribute to the hypertensive effect of ETOH.

  6. Pharmacological actions of the slow release hydrogen sulfide donor GYY4137 on phenylephrine-induced tone in isolated bovine ciliary artery.

    PubMed

    Chitnis, Madhura Kulkarni; Njie-Mbye, Ya Fatou; Opere, Catherine A; Wood, Mark E; Whiteman, Matthew; Ohia, Sunny E

    2013-11-01

    Hydrogen sulfide (H2S), a colorless gas characterized by its pungent odor of rotten eggs has been reported to elicit relaxation effects on basal and pre-contracted non-ocular smooth muscles of several mammalian species. In the present study, we investigated the pharmacological actions of a H2S donor, GYY4137 on isolated bovine posterior ciliary artery after contraction with the adrenergic receptor agonist, phenylephrine. Furthermore, we studied the underlying mechanism of inhibitory action of GYY4137 on the posterior ciliary arteries. Isolated bovine posterior ciliary arteries were mounted in oxygenated organ baths and changes in isometric tension were measured with a Grass FT03 transducer connected to a recorder using a Grass Polyview Software. The relaxant actions of GYY4137 on phenylephrine pre-contracted arteries were observed in the absence and presence of an inhibitor of cyclo-oxygenase, flurbiprofen. Furthermore, the inhibitory effects of GYY4137 were studied in the absence or presence of inhibitors/activators of biosynthetic enzymes for H2S and nitric oxide production, as well as specific ion channel blockers. In the concentration range, 100 nM to 100 μM, GYY4137 elicited a concentration-dependant relaxation of phenylephrine-induced tone in isolated posterior ciliary arteries, with IC50 value of 13.4 ± 1.9 μM (n = 6). The cyclo-oxygenase inhibitor, flurbiprofen, significantly (p < 0.01) enhanced the relaxation induced by GYY4137 yielding IC50 value of 0.13 ± 0.08 μM (n = 6). Both the inhibitors of cystathionine β-synthase (aminooxyacetic acid, AOAA, 30 μM) and cystathionine γ-lyase (propargylglycine, PAG, 1 mM) caused significant (p < 0.05) rightward shifts in the concentration-response curve to GYY4137. Furthermore, the KATP channel antagonist, glibenclamide (100 μM) significantly (p < 0.01) attenuated the relaxant action induced by GYY4137 on bovine ciliary artery. Conversely, the activator of cystathionine β-synthase, SAM (100 μM) and an

  7. Potent contractile actions of prostanoid EP3-receptor agonists on human isolated pulmonary artery.

    PubMed

    Qian, Y M; Jones, R L; Chan, K M; Stock, A I; Ho, J K

    1994-10-01

    1. In 13 of 15 experiments, prostaglandin E2 (PGE2) and sulprostone (a prostanoid EP1/EP3-receptor agonist) contracted isolated rings of human pulmonary artery at low concentrations (> or = 5 and > or = 0.5 nM respectively). Tissue was obtained from patients undergoing surgery mainly for carcinoma of the lung. Characterization of the receptors involved was complicated by loss of sensitivity to the contractile PGE action over the experimental period. In contrast, contractile responses to KCl, phenylephrine and the specific thromboxane (TP-) receptor agonist, U-46619, did not decrease with time. 2. The relative contractile potencies for seven PGE analogues, measured during the first few hours after setting up the preparations, were as follows: sulprostone > misoprostol = gemeprost > or = PGE2 > or = GR 63799X > 17-phenyl-omega-trinor PGE2 > or = 11-deoxy PGE1. This ranking indicates that an EP3-receptor is involved. 3. The contractile action of sulprostone was not blocked by the TP-receptor antagonists, EP 169 and GR 32191, and the EP1-receptor antagonist, AH 6809. 4. In two experiments, PGE2 (50 nM) reduced basal tone and sulprostone was a weak contractile agent. Phenylephrine-induced tone was also inhibited by PGE2 (EC50 = 5-20 nM), 11-deoxy PGE1 and butaprost (a selective EP2-receptor agonist); the latter prostanoids were about 2 and 4 times less potent than PGE2 respectively. Interactions with phenylephrine were different in experiments where PGE2 alone was contractile: PGE2 induced contraction superimposed on the phenylephrine response and 11-deoxy PGE1 induced either further contraction or had no effect. Butaprost produced relaxation at high concentrations;this may not be an EP2 action since preparations were highly sensitive to relaxant actions of prostacyclin (IP-) receptor agonists (cicaprost and TEI-9063).5 The study has shown that in the majority of experiments on the human isolated pulmonary artery,the contractile EP3 system outweighed the relaxant EP2

  8. The New P.E.

    ERIC Educational Resources Information Center

    Vandertie, Joan; Corner, Amy B.; Corner, Kevin J.

    2012-01-01

    Marana Middle School in Tucson, Ariz., scrapped its traditional P.E. program that emphasized team sports and shifted to a program that focuses on lifetime fitness, student choice in activities, and nutrition and health education. The program also includes student leadership development and informal community service. As a result, Marana students…

  9. The clinical utility of new combination phenylephrine/ketorolac injection in cataract surgery.

    PubMed

    Lawuyi, Lola Elizabeth; Gurbaxani, Avinash

    2015-01-01

    The maintenance of mydriasis throughout cataract extraction surgery and the control of ocular inflammation are crucial for successful surgical outcomes. The development of miosis during cataract surgery compromises the visualization of the surgical field and working space for surgeons. This may lead to complications that include posterior capsular tear and associated vitreous loss, longer surgical time, and postoperative inflammation. Postoperative inflammation is often uncomfortable and frustrating for patients. It causes pain, redness, and photophobia. This compromises the best-uncorrected vision following surgery and often leads to multiple clinic visits. This article examines the literature published on the current treatments used to manage mydriasis, pain, and inflammation in cataract extraction surgery. Combination phenylephrine/ketorolac injection offers an exciting new class of medication for use in cataract surgery. With the recent approval of Omidria™ (combination of phenylephrine 1% and ketorolac 0.3%) by the US Food and Drug Administration (FDA) for intraocular use, we review the clinical utility of this new combination injection in cataract surgery. PubMed, MEDLINE, and conference proceedings were searched for the relevant literature using a combination of the following search terms: cataract extraction surgery, pupil dilation (mydriasis), miosis, phenylephrine, ketorolac, Omidria™, intracameral mydriatic. Relevant articles were reviewed and their references checked for further relevant literature. All abstracts were reviewed and full texts retrieved where available.

  10. The clinical utility of new combination phenylephrine/ketorolac injection in cataract surgery.

    PubMed

    Lawuyi, Lola Elizabeth; Gurbaxani, Avinash

    2015-01-01

    The maintenance of mydriasis throughout cataract extraction surgery and the control of ocular inflammation are crucial for successful surgical outcomes. The development of miosis during cataract surgery compromises the visualization of the surgical field and working space for surgeons. This may lead to complications that include posterior capsular tear and associated vitreous loss, longer surgical time, and postoperative inflammation. Postoperative inflammation is often uncomfortable and frustrating for patients. It causes pain, redness, and photophobia. This compromises the best-uncorrected vision following surgery and often leads to multiple clinic visits. This article examines the literature published on the current treatments used to manage mydriasis, pain, and inflammation in cataract extraction surgery. Combination phenylephrine/ketorolac injection offers an exciting new class of medication for use in cataract surgery. With the recent approval of Omidria™ (combination of phenylephrine 1% and ketorolac 0.3%) by the US Food and Drug Administration (FDA) for intraocular use, we review the clinical utility of this new combination injection in cataract surgery. PubMed, MEDLINE, and conference proceedings were searched for the relevant literature using a combination of the following search terms: cataract extraction surgery, pupil dilation (mydriasis), miosis, phenylephrine, ketorolac, Omidria™, intracameral mydriatic. Relevant articles were reviewed and their references checked for further relevant literature. All abstracts were reviewed and full texts retrieved where available. PMID:26203214

  11. Polydatin prevents hypertrophy in phenylephrine induced neonatal mouse cardiomyocytes and pressure-overload mouse models.

    PubMed

    Dong, Ming; Ding, Wenwen; Liao, Yansong; Liu, Ye; Yan, Dewen; Zhang, Yi; Wang, Rongming; Zheng, Na; Liu, Shuaiye; Liu, Jie

    2015-01-01

    Recent evidence suggests that polydatin (PD), a resveratrol glucoside, may have beneficial actions on the cardiac hypertrophy. Therefore, the current study focused on the underlying mechanism of the PD anti-hypertrophic effect in cultured cardiomyocytes and in progression from cardiac hypertrophy to heart failure in vivo. Experiments were performed on cultured neonatal rat, ventricular myocytes as well as adult mice subjected to transverse aortic constriction (TAC). Treatment of cardiomyocytes with phenylephrine for three days produced a marked hypertrophic effect as evidenced by significantly increased cell surface area and atrial natriuretic peptide (ANP) protein expression. These effects were attenuated by PD in a concentration-dependent manner with a complete inhibition of hypertrophy at the concentration of 50 µM. Phenylephrine increased ROCK activity, as well as intracellular reactive oxygen species production and lipid peroxidation. The oxidizing agent DTDP similarly increased Rho kinase (ROCK) activity and induced hypertrophic remodeling. PD treatment inhibited phenylephrine-induced oxidative stress and consequently suppressed ROCK activation in cardiomyocytes. Hypertrophic remodeling and heart failure were demonstrated in mice subjected to 13 weeks of TAC. Upregulation of ROCK signaling pathway was also evident in TAC mice. PD treatment significantly attenuated the increased ROCK activity, associated with a markedly reduced hypertrophic response and improved cardiac function. Our results demonstrated a robust anti-hypertrophic remodeling effect of polydatin, which is mediated by inhibition of reactive oxygen species dependent ROCK activation.

  12. Genetic variation in the α1A-adrenergic receptor and phenylephrine-mediated venoconstriction.

    PubMed

    Adefurin, A; Ghimire, L V; Kohli, U; Muszkat, M; Sofowora, G G; Li, C; Paranjape, S Y; Stein, C M; Kurnik, D

    2015-08-01

    There is large interindividual variability and ethnic differences in phenylephrine-mediated vasoconstriction. We tested the hypothesis that genetic variation in ADRA1A, the α1A adrenergic receptor gene, contributes to the variability and ethnic differences. We measured local dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 42 African-Americans and genotyped for 32 ADRA1A single nucleotide polymorphisms. The ED50 ranged from 11 to 5442 ng min(-1), and the Emax ranged from 13.5-100%. The rs574647 variant was associated with a trend towards lower logED50 in each race and in the combined cohort (P=0.008). In addition, rs1079078 was associated with a trend to higher logED50 in each race and in the combined cohort (P=0.011). Neither variant accounted for the ethnic differences in response. None of the ADRA1A haplotypes was associated with the outcomes. In conclusion, ADRA1A variants do not contribute substantially to the marked interindividual variability or ethnic differences in phenylephrine-mediated venoconstriction.

  13. Safety of peripheral administration of phenylephrine in a neurologic intensive care unit: A pilot study.

    PubMed

    Delgado, Tim; Wolfe, Brianne; Davis, Gary; Ansari, Safdar

    2016-08-01

    Integral to the management of the neurocritically injured patient are the prevention and treatment of hypotension, maintenance of cerebral perfusion pressure, and occasionally blood pressure augmentation. When adequate volume resuscitation fails to meet perfusion needs, vasopressors are often used to restore end-organ perfusion. This has historically necessitated central venous access given well-documented incidence of extravasation injuries associated with peripheral administration of vasopressors. In this pilot study, we report our 6-month experience with peripheral administration of low-concentration phenylephrine (40 μg/mL) in our neurocritical care unit. We were able to administer peripheral phenylephrine, up to a dose of 2 μg/(kg min), for an average of 14.29hours (1-54.3) in 20 patients with only 1 possible minor complication and no major complications. This was achieved by adding additional safety measures in our computerized physician order entry system and additional nurse-driven safety protocols. Thus, with careful monitoring and safety precautions, peripheral administration of phenylephrine at an optimized concentration appears to have an acceptable safety profile for use in the neurocritical care unit up to a mean infusion time of 14hours. PMID:27288620

  14. The clinical utility of new combination phenylephrine/ketorolac injection in cataract surgery

    PubMed Central

    Lawuyi, Lola Elizabeth; Gurbaxani, Avinash

    2015-01-01

    The maintenance of mydriasis throughout cataract extraction surgery and the control of ocular inflammation are crucial for successful surgical outcomes. The development of miosis during cataract surgery compromises the visualization of the surgical field and working space for surgeons. This may lead to complications that include posterior capsular tear and associated vitreous loss, longer surgical time, and postoperative inflammation. Postoperative inflammation is often uncomfortable and frustrating for patients. It causes pain, redness, and photophobia. This compromises the best-uncorrected vision following surgery and often leads to multiple clinic visits. This article examines the literature published on the current treatments used to manage mydriasis, pain, and inflammation in cataract extraction surgery. Combination phenylephrine/ketorolac injection offers an exciting new class of medication for use in cataract surgery. With the recent approval of Omidria™ (combination of phenylephrine 1% and ketorolac 0.3%) by the US Food and Drug Administration (FDA) for intraocular use, we review the clinical utility of this new combination injection in cataract surgery. PubMed, MEDLINE, and conference proceedings were searched for the relevant literature using a combination of the following search terms: cataract extraction surgery, pupil dilation (mydriasis), miosis, phenylephrine, ketorolac, Omidria™, intracameral mydriatic. Relevant articles were reviewed and their references checked for further relevant literature. All abstracts were reviewed and full texts retrieved where available. PMID:26203214

  15. The antimetastatic drug NAMI-A potentiates the phenylephrine-induced contraction of aortic smooth muscle cells and induces a transient increase in systolic blood pressure.

    PubMed

    Vadori, M; Florio, C; Groppo, B; Cocchietto, M; Pacor, S; Zorzet, S; Candussio, L; Sava, G

    2015-07-01

    The ruthenium-based drug imidazolium trans-imidazoledimethylsulphoxidetetrachlorido ruthenate (NAMI-A) is a novel antitumour drug under clinical evaluation. In this study, NAMI-A is tested on aortic rings in vitro and on the systolic blood pressure in vivo with the aim of evaluating its effects on smooth muscle cells and, more in general, on the vascular system. Pre-incubation of aortic rings with 10 µM NAMI-A for 10 min potentiates the contraction induced by phenylephrine (PE). The reduction of the B max value of [(3)H]-prazosin bound to NAMI-A-treated aortic rings and the ability of NAMI-A to displace [(3)H]-prazosin and [(3)H]-IP3 binding by 25 and 42%, respectively, suggest the involvement of α1-adrenoceptor in mediating the effects on smooth muscle cells. NAMI-A also decreases the number of maximal sites of [(3)H]-prazosin bound to kidney membrane preparation from 34 to 24 fmol/mg proteins. A single i.p. dose (105 mg/kg) or a repeated treatment for 6 consecutive days (17 mg/kg/day) in Wistar rats increases the systolic blood pressure, respectively, 1 h and 3 days after treatment, and the responsiveness of rat aortic rings to PE. Atomic absorption spectroscopy confirms the presence of ruthenium in the aortic rings excised from the treated rats. These findings suggest monitoring the cardiovascular parameters when the drug is used in humans for treating cancer patients, particularly if the drug is associated with chemicals that are potentially active at the cardiovascular level.

  16. Determinants of PE Teachers Career Intentions

    ERIC Educational Resources Information Center

    Mäkelä, Kasper; Hirvensalo, Mirja; Whipp, Peter R.

    2015-01-01

    One of the cause's célèbre in the field of education has been teacher attrition; Physical education (PE) is no different. Some PE teachers are leaving the profession because they encounter stress and dissatisfaction in their profession. The purpose of this study is to determine the aspects that keep PE teachers happy and remaining in the…

  17. Reliability of a new 4th generation FloTrac algorithm to track cardiac output changes in patients receiving phenylephrine.

    PubMed

    Ji, Fuhai; Li, Jian; Fleming, Neal; Rose, David; Liu, Hong

    2015-08-01

    Phenylephrine is often used to treat intra-operative hypotension. Previous studies have shown that the FloTrac cardiac monitor may overestimate cardiac output (CO) changes following phenylephrine administration. A new algorithm (4th generation) has been developed to improve performance in this setting. We performed a prospective observational study to assess the effects of phenylephrine administration on CO values measured by the 3rd and 4th generation FloTrac algorithms. 54 patients were enrolled in this study. We used the Nexfin, a pulse contour method shown to be insensitive to vasopressor administration, as the reference method. Radial arterial pressures were recorded continuously in patients undergoing surgery. Phenylephrine administration times were documented. Arterial pressure recordings were subsequently analyzed offline using three different pulse contour analysis algorithms: FloTrac 3rd generation (G3), FloTrac 4th generation (G4), and Nexfin (nf). One minute of hemodynamic measurements was analyzed immediately before phenylephrine administration and then repeated when the mean arterial pressure peaked. A total of 157 (4.6 ± 3.2 per patient, range 1-15) paired sets of hemodynamic recordings were analyzed. Phenylephrine induced a significant increase in stroke volume (SV) and CO with the FloTrac G3, but not with FloTrac G4 or Nexfin algorithms. Agreement between FloTrac G3 and Nexfin was: 0.23 ± 1.19 l/min and concordance was 51.1%. In contrast, agreement between FloTrac G4 and Nexfin was: 0.19 ± 0.86 l/min and concordance was 87.2%. In conclusion, the pulse contour method of measuring CO, as implemented in FloTrac 4th generation algorithm, has significantly improved its ability to track the changes in CO induced by phenylephrine.

  18. Flaxseed oil increases aortic reactivity to phenylephrine through reactive oxygen species and the cyclooxygenase-2 pathway in rats

    PubMed Central

    2014-01-01

    Background Flaxseed oil has the highest concentration of omega-3 α-linolenic acid, which has been associated with cardiovascular benefit. However, the mechanism underlying the vascular effects induced through flaxseed oil is not well known. Thus, in the present study, we investigated the effects of flaxseed oil on vascular function in isolated rat aortic rings. Methods Wistar rats were treated daily with flaxseed oil or a control (mineral oil) intramuscular (i.m.) for fifteen days. Isolated aortic segments were used to evaluate cyclooxygenase-2 (COX-2) protein expression, superoxide anion levels and vascular reactivity experiments. Results Flaxseed oil treatment increased the vasoconstrictor response of aortic rings to phenylephrine. Endothelium removal increased the response to phenylephrine in aortic segments isolated from both groups, but the effect was smaller in the treated group. L-NAME incubation similarly increased the phenylephrine response in segments from both groups. The TXA2 synthase inhibitor furegrelate, the selective COX-2 inhibitor NS 398, the TP receptor antagonist SQ 29.548, the reactive oxygen species (ROS) scavenger apocynin, the superoxide anion scavengers tiron and the phospholipase A2 inhibitor dexamethasone partially reversed the flaxseed oil-induced increase in reactivity to phenylephrine. Conclusions These findings suggest that flaxseed oil treatment increased vascular reactivity to phenylephrine through an increase in ROS production and COX-2-derived TXA2 production. The results obtained in the present study provide new insight into the effects of flaxseed oil treatment (i.m.) on vascular function. PMID:24993607

  19. Phenylephrine infusion for spinal-induced hypotension in elective cesarean delivery: Does preload make a difference?

    PubMed Central

    Bottiger, Brandi A; Bezinover, Dmitri S; Mets, Berend; Dalal, Priti G; Prozesky, Jansie; Ural, Serdar; Vaida, Sonia

    2016-01-01

    Background and Aims: Patients undergoing elective cesarean delivery (CD) have a high-risk of spinal-induced hypotension (SIH). We hypothesized that a colloid preload would further reduce SIH when compared with a crystalloid preload. Material and Methods: Eighty-two healthy parturients undergoing elective CD were included in the study. Patients were randomly assigned to two groups (41 patients in each group) to receive either Lactated Ringer's solution (1500 ml) or hydroxyethyl starch (6% in normal saline, 500 ml) 30 min prior to placement of spinal anesthesia. All patients were treated with a phenylephrine infusion (100 mcg/min), titrated during the study. Results: There was no statistical difference between groups with regards to the incidence of hypotension (10.8% in the colloid group vs. 27.0% in the crystalloid group, P = 0.12). There was also no difference between groups with respect to bradycardia, APGAR scores, and nausea and vomiting. Significantly less phenylephrine (1077.5 ± 514 mcg) was used in the colloid group than the crystalloid group (1477 ± 591 mcg, P = 0.003). Conclusion: The preload with 6% of hydroxyethyl starch before CD might be beneficial for the prevention of SIH. PMID:27625478

  20. [Phenylephrine dosing error in Intensive Care Unit. Case of the trimester].

    PubMed

    2013-01-01

    A real clinical case reported to SENSAR is presented. A patient admitted to the surgical intensive care unit following a lung resection, suffered arterial hypotension. The nurse was asked to give the patient 1 mL of phenylephrine. A few seconds afterwards, the patient experienced a hypertensive crisis, which resolved spontaneously without damage. Thereafter, the nurse was interviewed and a dosing error was identified: she had mistakenly given the patient 1 mg of phenylephrine (1 mL) instead of 100 mcg (1 mL of the standard dilution, 1mg in 10 mL). The incident analysis revealed latent factors (event triggers) due to the lack of protocols and standard operating procedures, communication errors among team members (physician-nurse), suboptimal training, and underdeveloped safety culture. In order to preempt similar incidents in the future, the following actions were implemented in the surgical intensive care unit: a protocol for bolus and short lived infusions (<30 min) was developed and to close the communication gap through the adoption of communication techniques. The protocol was designed by physicians and nurses to standardize the administration of drugs with high potential for errors. To close the communication gap, repeated checks about saying and understanding was proposed ("closed loop"). Labeling syringes with the drug dilution was also recommended.

  1. Phenylephrine stimulated breakdown of phosphoinositides in brown adipocytes is attenuated by adenosine

    SciTech Connect

    Schimmel, R.J.

    1986-03-01

    Selective activation of alpha adrenergic receptors on brown adipocytes brings about increased mitochondrial respiration. This response is associated with a rapid breakdown of phosphoinositides in the plasma membrane. The authors have shown that respiration increased by alpha receptor activation can be inhibited by adenosine but the mechanisms underlying this effect are unknown. The present study probes the possibility that adenosine inhibition of alpha receptor stimulated respiration is secondary to an inhibition of stimulated breakdown of inositol phospholipids. Phospholipids were labeled with (/sup 32/P) by incubation with (/sup 32/P)-Pi for up to four hours. Phenylephrine and other ligands were then added and the radioactivity present in individual lipids determined following their resolution by thin layer chromatography. Addition of 2-chloroadenosine or phenylisopropyl adenosine, but not 2',5'-dideoxyadenosine, inhibited phenylephrine promoted breakdown of phosphoinositides. The dose response relation for this effect was similar to that for attenuation of stimulated respiration. This finding demonstrates adenosine inhibition of a phospholipase in brown fat cells and suggests the possibility that breakdown of inositol phospholipids is a critical control site for stimulation and attenuation of respiration.

  2. Phenylephrine infusion for spinal-induced hypotension in elective cesarean delivery: Does preload make a difference?

    PubMed Central

    Bottiger, Brandi A; Bezinover, Dmitri S; Mets, Berend; Dalal, Priti G; Prozesky, Jansie; Ural, Serdar; Vaida, Sonia

    2016-01-01

    Background and Aims: Patients undergoing elective cesarean delivery (CD) have a high-risk of spinal-induced hypotension (SIH). We hypothesized that a colloid preload would further reduce SIH when compared with a crystalloid preload. Material and Methods: Eighty-two healthy parturients undergoing elective CD were included in the study. Patients were randomly assigned to two groups (41 patients in each group) to receive either Lactated Ringer's solution (1500 ml) or hydroxyethyl starch (6% in normal saline, 500 ml) 30 min prior to placement of spinal anesthesia. All patients were treated with a phenylephrine infusion (100 mcg/min), titrated during the study. Results: There was no statistical difference between groups with regards to the incidence of hypotension (10.8% in the colloid group vs. 27.0% in the crystalloid group, P = 0.12). There was also no difference between groups with respect to bradycardia, APGAR scores, and nausea and vomiting. Significantly less phenylephrine (1077.5 ± 514 mcg) was used in the colloid group than the crystalloid group (1477 ± 591 mcg, P = 0.003). Conclusion: The preload with 6% of hydroxyethyl starch before CD might be beneficial for the prevention of SIH.

  3. The modification of the flexibility of radiation crosslinked PE by blending PE with EVA and CPE

    NASA Astrophysics Data System (ADS)

    Hui, Zhang; Jiufu, Xu

    1993-07-01

    Polyethylene (PE) is used as an insulation material for wires and cables because of its excellent electrical properties. Most of the properties of PE are improved greatly after irradiation, but, it was harden and split easily in low temperature. According to ethylene-vinyl acetate polymer (EVA) and chlor-poly-ethylene (CPE) possesing good flexibility. Blending of EVA/PE, CPE/PE systems were performed individually. As the results of experiment, suitable radiation dose and percentage of EVA/PE, CPE/PE systems have been determined to overcome the split of heat-shrinking tube after shrinkage.

  4. Effect of different phenylephrine bolus doses for treatment of hypotension during spinal anaesthesia in patients undergoing elective caesarean section.

    PubMed

    Mohta, M; Harisinghani, P; Sethi, A K; Agarwal, D

    2015-01-01

    The efficacy of phenylephrine might be improved by giving doses higher than that traditionally used (100 µg). This study compared the effects of three initial bolus doses of intravenous phenylephrine; 100 µg (group P100), 125 µg (group P125) and 150 µg (group P150), for the treatment of post-spinal hypotension in patients undergoing elective caesarean delivery. If hypotension was not corrected by this dose, additional boluses of 25 µg were given every minute. Further hypotensive episodes were treated with half the initial bolus dose, followed by 25 µg boluses, as required. Umbilical arterial and venous blood samples were obtained for blood gas analysis and Apgar scores recorded. One hundred and twenty subjects (40 per group) who developed post-spinal hypotension (75%) were included in this randomised, double blind trial. Although systolic blood pressure was higher at certain time-points after 150 µg phenylephrine, there were no statistically significant differences in the effectiveness of the first bolus of phenylephrine to treat hypotension (85%, 95% and 95% in groups P100, P125 and P150, respectively, P=0.215); the additional dose of phenylephrine after the first bolus (P=0.810); the number of additional boluses (P=0.318) or of hypotensive episodes (P=0.118). There were no significant differences in the number of patients developing reactive hypertension or bradycardia, in maternal side-effects or in neonatal outcomes. Although the study may have been underpowered, initial phenylephrine bolus doses of 100 µg, 125 µg and 150 µg did not significantly differ in efficacy to treat post-spinal hypotension in these patients.

  5. [Separation and determination of optical isomers of phenylephrine by chiral ligand exchange capillary elcctrophoresis coupling with the promoting effect of ionic liquid].

    PubMed

    Yang, Simei; Zhang, Jiayao; Li, Fei; Hu, Xufang; Cao, Qiue

    2016-01-01

    A method for the separation and determination of optical isomers of phenylephrine was developed based on the promoting effect of non-chiral ionic liquid on chiral ligand-exchange capillary electrophoresis after the electrophoretic parameters were optimized systematically. R-phenylephrine and S-phenylephrine can be separated and determined effectively in 20 mmol/L Tris-H3PO4 buffer solution (pH 5.4) composed of 4.0 mmol/L Cu(II), 8.0 mmol/L L-proline (L-Pro) and 15 mmol/L 1-butyl-3-methylimidazolium chloride ([BMIM] Cl) with the applied voltage of 20 kV, capillary temperature of 25 °C , detection wavelength of 254 nm, and injection of 5 s at 3,447 Pa. The resolution of R- and S-phenylephrines was 1. 42. The linear ranges for the determination of R-phenylephrine and S-phenylephrine were 12. 5 - 150 mg/L and 15. 0-150 mg/L, respectively. The method has been satisfactorily used for the determination of R-phenylephrine and S-phenylephrine in the spiked blood and urine samples. The spiked recoveries in the urine sample were in the range of 93. 7% -108. 2% with the RSDs lower than 3. 18% (n= 3) , and the spiked recoveries in the blood sample were in the range of 91. 4% and 113. 1% with the RSDs lower than 4. 82% (n =3).

  6. [Separation and determination of optical isomers of phenylephrine by chiral ligand exchange capillary elcctrophoresis coupling with the promoting effect of ionic liquid].

    PubMed

    Yang, Simei; Zhang, Jiayao; Li, Fei; Hu, Xufang; Cao, Qiue

    2016-01-01

    A method for the separation and determination of optical isomers of phenylephrine was developed based on the promoting effect of non-chiral ionic liquid on chiral ligand-exchange capillary electrophoresis after the electrophoretic parameters were optimized systematically. R-phenylephrine and S-phenylephrine can be separated and determined effectively in 20 mmol/L Tris-H3PO4 buffer solution (pH 5.4) composed of 4.0 mmol/L Cu(II), 8.0 mmol/L L-proline (L-Pro) and 15 mmol/L 1-butyl-3-methylimidazolium chloride ([BMIM] Cl) with the applied voltage of 20 kV, capillary temperature of 25 °C , detection wavelength of 254 nm, and injection of 5 s at 3,447 Pa. The resolution of R- and S-phenylephrines was 1. 42. The linear ranges for the determination of R-phenylephrine and S-phenylephrine were 12. 5 - 150 mg/L and 15. 0-150 mg/L, respectively. The method has been satisfactorily used for the determination of R-phenylephrine and S-phenylephrine in the spiked blood and urine samples. The spiked recoveries in the urine sample were in the range of 93. 7% -108. 2% with the RSDs lower than 3. 18% (n= 3) , and the spiked recoveries in the blood sample were in the range of 91. 4% and 113. 1% with the RSDs lower than 4. 82% (n =3). PMID:27319173

  7. Elementary Students' Construct of PE Teacher Credibility

    ERIC Educational Resources Information Center

    Ramos, Nilo O.; McCullick, Bryan A.

    2015-01-01

    The purpose of this study was to investigate elementary students' perceptions of PE teacher credibility. Eight high- and low-skilled students from grades 3 and 5 were selected from a school employing a PE teacher holding a National Board Certification. Data were collected in the school setting utilizing observations, field notes, an open-ended…

  8. No, Really: P.E. Online

    ERIC Educational Resources Information Center

    Stover, Del

    2005-01-01

    Because some students need to drop some extracurricular activities in order to enroll in a PE class, public schools have developed PE courses that can be fitted into students' tight schedules. These programs are popular because of convenience. Not only can workouts be scheduled as desired, but students can sweat it out almost anywhere: the local…

  9. Comparison of the involvement protein kinase C in agonist-induced contractions in mouse aorta and corpus cavernosum

    PubMed Central

    Jin, Liming; Teixeira, Cleber E; Webb, R. Clinton; Leite, Romulo

    2008-01-01

    Protein kinase C (PKC) is involved in the regulation of vascular smooth muscle contraction. However, the role of PKC in erectile function is poorly understood. This study investigated whether PKC mediates agonist-induced contractions in mouse penile tissue (corpora cavernosa). We also compared the effects of PKC activators and inhibitors on contractile responses in mouse corpus cavernosum with those in mouse aorta. Aortic rings and corpus cavernosal strips from C57BL/6J mice was isolated, mounted in the organ bath for isometric tension recording. Our data showed that a PKCα/β selective inhibitor, Gö6976 (10 µM), inhibited phenylephrine and 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F2α (U46619, a thromboxane mimetic)-induced contractions in mouse aorta, reducing the maximum contraction from 123 ± 2% of KCl-induced maximum contraction to 7 ± 2% and 13 ± 1%, respectively. A non-selective PKC inhibitor, chelerythrine (30 µM), also significantly reduced phenylephrine-and U46619-induced maximum contractions in mouse aorta. However, Gö6976 and chelerythrine had no significant effects on phenylephrine-and U46619-induced contractions in corpus cavernosum. Furthermore, a PKC activator, phorbol-12,13-dibutyrate (0.1 µM), significantly increased contractions in aorta (208 ± 14% of KCl-induced maximum contraction) but failed to cause contractions in corpus cavernosum at 1 and 10 µM. Western blot analysis data suggested that protein expression of PKC was similar in aorta and corpus cavernosum. Taken together, our data indicate that PKC does not have a significant role in agonist-induced contractions in mouse corpus cavernosum, whereas it mediates the contractile response to agonists in the aorta. PMID:18614166

  10. A compact PE memory for vision chips

    NASA Astrophysics Data System (ADS)

    Cong, Shi; Zhe, Chen; Jie, Yang; Nanjian, Wu; Zhihua, Wang

    2014-09-01

    This paper presents a novel compact memory in the processing element (PE) for single-instruction multiple-data (SIMD) vision chips. The PE memory is constructed with 8 × 8 register cells, where one latch in the slave stage is shared by eight latches in the master stage. The memory supports simultaneous read and write on the same address in one clock cycle. Its compact area of 14.33 μm2/bit promises a higher integration level of the processor. A prototype chip with a 64 × 64 PE array is fabricated in a UMC 0.18 μm CMOS technology. Five types of the PE memory cell structure are designed and compared. The testing results demonstrate that the proposed PE memory architecture well satisfies the requirement of the vision chip in high-speed real-time vision applications, such as 1000 fps edge extraction.

  11. Simultaneous determination of dextromethorphan, diphenhydramine and phenylephrine in expectorant and decongestant syrups by capillary electrophoresis.

    PubMed

    Gomez, María R; Olsina, Roberto A; Martínez, Luis D; Silva, María F

    2002-10-15

    The separation of basic nitrogenous compounds commonly used as active ingredients in cold medicine formulations by micellar electrokinetic capillary chromatography and capillary zone electrophoresis with direct absorptiometric detection was investigated. The type and composition of the background electrolyte (BGE) were investigated with respect to separation selectivity and BGE stability. BGE of 10 mM sodium dihydrogenphosphate-sodium tetraborate buffer containing 10 mM SDS and 10% acetonitrile, pH 9.0 was found to be optimal. Dextromethorphan hydrobhromide, diphenhydramine hydrochloride and phenylephrine hydrochloride were baseline-separated in less than 11 min, giving separation efficiencies of up to 494,000 theoretical plates, reproducibility of corrected peaks areas below 3% relative standard deviation and concentration detection limits from 2.5 to 5.5 microg ml(-1). Detection was performed at 196 and 214 nm.

  12. Simultaneous determination of paracetamol, phenylephrine hydrochloride and chlorpheniramine maleate in pharmaceutical preparations using multivariate calibration 1

    NASA Astrophysics Data System (ADS)

    Samadi-Maybodi, Abdolraouf; Hassani Nejad-Darzi, Seyed Karim

    2010-04-01

    Resolution of binary mixtures of paracetamol, phenylephrine hydrochloride and chlorpheniramine maleate with minimum sample pre-treatment and without analyte separation has been successfully achieved by methods of partial least squares algorithm with one dependent variable, principal component regression and hybrid linear analysis. Data of analysis were obtained from UV-vis spectra of the above compounds. The method of central composite design was used in the ranges of 1-15 mg L -1 for both calibration and validation sets. The models refinement procedure and their validation were performed by cross-validation. Figures of merit such as selectivity, sensitivity, analytical sensitivity and limit of detection were determined for all three compounds. The procedure was successfully applied to simultaneous determination of the above compounds in pharmaceutical tablets.

  13. Simultaneous determination of paracetamol, phenylephrine hydrochloride and chlorpheniramine maleate in pharmaceutical preparations using multivariate calibration 1.

    PubMed

    Samadi-Maybodi, Abdolraouf; Hassani Nejad-Darzi, Seyed Karim

    2010-04-01

    Resolution of binary mixtures of paracetamol, phenylephrine hydrochloride and chlorpheniramine maleate with minimum sample pre-treatment and without analyte separation has been successfully achieved by methods of partial least squares algorithm with one dependent variable, principal component regression and hybrid linear analysis. Data of analysis were obtained from UV-vis spectra of the above compounds. The method of central composite design was used in the ranges of 1-15 mg L(-1) for both calibration and validation sets. The models refinement procedure and their validation were performed by cross-validation. Figures of merit such as selectivity, sensitivity, analytical sensitivity and limit of detection were determined for all three compounds. The procedure was successfully applied to simultaneous determination of the above compounds in pharmaceutical tablets.

  14. JROTC as a Substitute for PE: Really?

    PubMed Central

    Lounsbery, Monica A. F.; Holt, Kathryn A.; Monnat, Shannon A.; McKenzie, Thomas L.; Funk, Brian

    2014-01-01

    Purpose Even though physical education (PE) is an evidence-based strategy for providing and promoting physical activity, alternative programs such as Junior Reserve Officer Training Corps (JROTC) are commonly substituted for PE in many states. The purpose of this study was to compare student physical activity and lesson contexts during high school PE and JROTC sessions. Method SOFIT (System for Observing Fitness Instruction Time) was used to assess PE and JROTC sessions (N=38 each) in 4 high schools that provided both programs. Data were analyzed using t-tests, negative binomial regression, and logistic regression. Results Students engaged in significantly more moderate to vigorous physical activity during PE than JROTC sessions and they were significantly less sedentary. Significant differences between the two program types were also found among lesson contexts. Conclusions PE and JROTC provide substantially different content and contexts and students in them engage in substantially different amounts of moderate to vigorous physical activity. Students in JROTC, and perhaps other alternative programs, are less likely to accrue health-supporting physical activity and engage in fewer opportunities to be physically fit and motorically skilled. Policies and practices for providing substitutions for PE should be carefully examined. PMID:25141093

  15. Comparison of Prophylactic Infusion of Phenylephrine with Ephedrine for Prevention of Hypotension in Elective Cesarean Section under Spinal Anesthesi: A Randomized Clinical Trial

    PubMed Central

    Moslemi, Farnaz; Rasooli, Sousan

    2015-01-01

    Background Spinal anesthesia is an accepted technique in elective cesarean sections. However, hypotension, resulted from sympathectomy is a common problem, especially in pregnant women. Prevention of this complication by sympathomimetic agents is of potential clinical significance. The aim of this study is to compare the effect of prophylactic infusion of Phenylephrine versus Ephedrine in the prevention of hypotension during spinal anesthesia in elective cesarean section. Methods Eighty-three patients were enrolled in this study and randomly divided into three groups. Group Ph received phenylephrine infusion, group E received ephedrine infusion while group P were delivered placebo. Vital signs (blood pressure, heart rate, and arterial oxygen saturation) were recorded throughout the surgery. Maternal and neonatal perioperative complications were also controlled and recorded. Results There was an insignificant difference in demographic data between the groups. Systolic and diastolic blood pressures were higher in the phenylephrine group than control, but not higher than the ephedrine group. Maternal dysrhythmias were more common in ephedrine and phenylephrine groups than the control group. Vomiting was more common in ephedrine group (P<0.05). In addition, the fifth-minute Apgar score of neonates was higher in phenylephrine and ephedrine groups than the control group (P<0.05). Neonates of phenylephrine group had less acidosis than the other groups. Conclusion Prophylactic infusion of phenylephrine can effectively decrease spinal anesthesia related hypotension without any significant complication for mother or her fetus. Trial Registration Number: IRCT2012120911700N1 PMID:25649721

  16. COPD and PE: A clinical dilemma

    PubMed Central

    Moua, Teng; Wood, Kenneth

    2008-01-01

    Dyspnea in patients with known chronic obstructive pulmonary disease (COPD) can be a clinical challenge due to the nonspecific nature of atypical presentations. Typical features of fever, productive cough, and wheezing on presentation support COPD exacerbation, while absence of such findings may warrant further evaluation for underlying etiologies, including pulmonary embolism (PE). It is suspected that one in four patients with atypical COPD exacerbation may have PE as an underlying or concomitant cause of acute dyspnea. This review discusses the clinical presentation of COPD and PE, and presents an overview of the rationale for pursuing work-up for thromboembolic disease in the setting of known obstructive lung diseases. PMID:18686736

  17. Effect of Phenylephrine Pretreatment on the Expressions of Aquaporin 5 and c-Jun N-Terminal Kinase in Irradiated Submandibular Gland.

    PubMed

    Han, Lichi; Wang, Lei; Zhang, Fuyin; Liu, Ke Jian; Xiang, Bin

    2015-06-01

    Radiotherapy for malignant tumors of the head and neck commonly leads to radiation-induced sialadenitis as a result of radiation-induced salivary gland dysfunction. We demonstrated previously that phenylephrine could protect the irradiated submandibular gland against apoptosis, although the mechanism is unclear. In this study, we investigated the influence of phenylephrine pretreatment on the expressions of aquaporin 5 (AQP5) and c-Jun N-terminal kinase (JNK) that were presumed to have a role in radiation-induced salivary gland dysfunction. Rats pretreated with phenylephrine (5 mg/kg) were locally irradiated (20 Gy) in the head and neck region. The submandibular glands were removed on day 7 after irradiation. The expression of AQP5 and activation of JNK were measured by immunohistochemistry and Western blot. The localization of AQP5 at the apical and lateral plasma membrane of acinar cells was significantly reduced by irradiation, but markedly enhanced with phenylephrine pretreatment. The protein expression of AQP5 was decreased by 84.91% in irradiated glands, whereas it was fully recovered to the control level in phenylephrine-pretreated glands. Moreover, many acinar, ductal and granular convoluted tubular cells in the irradiated glands exhibited intense immunoreactivity for p-JNK, while in the phenylephrine-pretreated irradiated glands, only a few acinar cells exhibited very faint immunoreactivity for p-JNK. The protein expression level of p-JNK was increased by 41.65% in the irradiated alone glands, but was significantly decreased in the phenylephrine-pretreated irradiated glands. These results suggest that the protective mechanism of phenylephrine might be related to the improved expression of AQP5 and decreased activation of JNK. Pretreatment with phenylephrine in patients undergoing radiotherapy may provide a helpful strategy for suppression of radiation-induced sialadenitis.

  18. The cytotoxic and pro-apoptotic effects of phenylephrine on corneal stromal cells via a mitochondrion-dependent pathway both in vitro and in vivo.

    PubMed

    Zhao, Jun; Qiu, Yue; Tian, Cheng-Lei; Fan, Ting-Jun

    2016-08-01

    Phenylephrine (PHE), a selective α1-adrenergic receptor agonist, is often used as a decongestant for mydriasis prior to cataract surgery, and its abuse might be cytotoxic to the cornea and result in blurred vision. However, the cytotoxicity of PHE to the cornea and its cellular and molecular mechanisms remain unknown. To provide references for secure medication and prospective therapeutic interventions of PHE, we investigated the cytotoxicity of PHE to corneal stroma and its possible mechanisms using an in vitro model of human corneal stromal (HCS) cells and an in vivo model of cat keratocytes. We found that PHE, above the concentration of 0.0781125% (1/128 of its clinical therapeutic dosage), had a dose- and time-dependent cytotoxicity to HCS cells by inducing morphological abnormality and viability decline, as well as S phase arrest. Moreover, PHE induced apoptosis of HCS cells by inducing plasma membrane permeability elevation, phosphatidylserine externalization, DNA fragmentation and apoptotic body formation. Furthermore, PHE could induce activations of caspase-3 and -9, disruption of mitochondrial transmembrane potential, downregulation of anti-apoptotic Bcl-xL, upregulation of pro-apoptotic Bax, along with upregulation of cytoplasmic cytochrome c and apoptosis-inducing factor. The cytotoxic and pro-apoptotic effects of PHE were also proven by the induced apoptotic-like ultrastructural alterations of keratocytes in vivo. Taken together, our results suggest that PHE has a significant cytotoxicity to corneal stroma cells both in vitro and in vivo by inducing cell apoptosis, and the pro-apoptotic effect of PHE is achieved via a Bcl-2 family proteins-mediated mitochondrion-dependent pathway. PMID:27344612

  19. Quantitative analysis of mitragynine, codeine, caffeine, chlorpheniramine and phenylephrine in a kratom (Mitragyna speciosa Korth.) cocktail using high-performance liquid chromatography.

    PubMed

    Chittrakarn, Somsmorn; Penjamras, Pimpimol; Keawpradub, Niwat

    2012-04-10

    A simple HPLC technique for determining mitragynine, codeine, caffeine, chlorpheniramine and phenylephrine in 'kratom cocktail' was developed. The analytical method for mitragynine, codeine and caffeine used an Eclipse XDB-C8 column. A Lichrospher CN column was using for analysing chlorpheniramine and phenylephrine. The correlation coefficient of each standard was between 0.9957 and 0.9993. The precision of the methods were between 0.700 and 7.108% RSD. The concentration of mitragynine, codeine, caffeine, chlorpheniramine and phenylephrine in 'kratom cocktail' was 90.021, 234.174, 73.986, 7.053 and 1.486 mg/L, respectively. PMID:22018854

  20. Tributyltin chloride increases phenylephrine-induced contraction and vascular stiffness in mesenteric resistance arteries from female rats.

    PubMed

    Ribeiro Júnior, Rogério Faustino; Marques, Vinicius Bermond; Nunes, Dieli Oliveira; Ronconi, Karoline de Sousa; de Araújo, Julia F P; Rodrigues, Paula Lopes; Padilha, Alessandra Simão; Vassallo, Dalton Valentim; Graceli, Jones B; Stefanon, Ivanita

    2016-03-15

    Tributyltin chloride (TBT) is an organotin compound that reduces estrogen levels in female rats. We aimed to investigate the effects of TBT exposure on vascular tonus and vascular remodelling in the resistance arteries of female rats. Rats were treated daily with TBT (500 ng/kg) for 15 days. TBT did not change arterial blood pressure but did modify some morpho-physiological parameters of third-order mesenteric resistance arteries in the following ways: (1) decreased lumen and external diameters; (2) increased wall/lm ratio and wall thickness; (3) decreased distensibility and increased stiffness; (4) increased collagen deposition; and (5) increased pulse wave velocity. TBT exposure increased the phenylephrine-induced contractile response in mesenteric resistance arteries. However, vasodilatation responses induced by acetylcholine and sodium nitroprusside were not modified by TBT. It is suggested that TBT exposure reduces vascular nitric oxide (NO) production, because:(1) L-NAME incubation did not cause a leftward shift in the concentration-response curve for phenylephrine; (2) both eNOS protein expression; (3) in situ NO production were reduced. Incubation with L-NAME; and (4) SOD shifted the phenylephrine response curve to the left in TBT rats. Tiron, catalase, ML-171 and VAS2870 decreased vascular reactivity to phenylephrine only in TBT rats. Moreover, increased superoxide anion production was observed in the mesenteric resistance arteries of TBT rats accompanied by an increase in gp91phox, catalase, AT1 receptor and total ERK1/2 protein expression. In conclusion, these findings show that TBT induced alterations are most likely due to a reduction of NO production combined with increased O2(-) production derived from NADPH oxidase and ERK1/2 activation. These findings offer further evidence that TBT is an environmental risk factor for cardiovascular disease.

  1. Comparison Between Phenylephrine and Dopamine in Maintaining Cerebral Oxygen Saturation in Thoracic Surgery: A Randomized Controlled Trial.

    PubMed

    Choi, Ji Won; Joo Ahn, Hyun; JooAhn, Hyun; Yang, Mikyung; Kim, Jie Ae; Lee, Sangmin M; Ahn, Jin Hee

    2015-12-01

    Fluid is usually restricted during thoracic surgery, and vasoactive agents are often administered to maintain blood pressure. One-lung ventilation (OLV) decreases arterial oxygenation; thus oxygen delivery to the brain can be decreased. In this study, we compared phenylephrine and dopamine with respect to maintaining cerebral oxygenation during OLV in major thoracic surgery.Sixty-three patients undergoing lobectomies were randomly assigned to the dopamine (D) or phenylephrine (P) group. The patients' mean arterial pressure was maintained within 20% of baseline by a continuous infusion of dopamine or phenylephrine. Maintenance fluid was kept at 5 mL/kg/h. The depth of anesthesia was maintained with desflurane 1MAC and remifentanil infusion under bispectral index guidance. Regional cerebral oxygen saturation (rScO2) and hemodynamic variables were recorded using near-infrared spectroscopy and esophageal cardiac Doppler.The rScO2 was higher in the D group than the P group during OLV (OLV 60 min: 71 ± 6% vs 63 ± 12%; P = 0.03). The number of patients whose rScO2 dropped more than 20% from baseline was 0 and 6 in the D and P groups, respectively (P = 0.02). The D group showed higher cardiac output, but lower mean arterial pressure than the P group (4.7 ± 1.0 vs 3.9 ± 1.2 L/min; 76.7 ± 8.1 vs 84.5 ± 7.5 mm Hg; P = 0.02, P = 0.02). Among the variables, age, hemoglobin concentration, and cardiac output were associated with rScO2 by correlation analysis.Dopamine was superior to phenylephrine in maintaining cerebral oxygenation during OLV in thoracic surgery.

  2. Derivative emission spectrofluorimetry for the simultaneous determination of guaifenesin and phenylephrine hydrochloride in pharmaceutical tablets.

    PubMed

    Maher, Hadir M; Alshehri, Mona M; Al-taweel, Shorog M

    2015-05-01

    Rapid, simple and sensitive derivative emission spectrofluorimetric methods have been developed for the simultaneous analysis of binary mixtures of guaifenesin (GUA) and phenylephrine hydrochloride (PHE). The methods are based upon measurement of the native fluorescence intensity of the two drugs at λex = 275 nm in methanolic solutions, followed by differentiation using first (D1) and second (D2) derivative techniques. The derivative fluorescence intensity-concentration plots were rectilinear over a range of 0.1-2 µg/mL for both GUA and PHE. The limits of detection were 0.027 (D1, GUA), 0.025 (D2, GUA), 0.031 (D1, PHE) and 0.033 (D2, PHE) µg/mL and limits of quantitation were 0.089 (D1, GUA), 0.083 (D2, GUA), 0.095 (D1, PHE) and 0.097 (D2, PHE) µg/mL. The proposed derivative emission spectrofluorimetric methods (D1 and D2) were successfully applied for the determination of the two compounds in binary mixtures and tablets with high precision and accuracy. The proposed methods were fully validated as per ICH guidelines.

  3. Derivative emission spectrofluorimetry for the simultaneous determination of guaifenesin and phenylephrine hydrochloride in pharmaceutical tablets.

    PubMed

    Maher, Hadir M; Alshehri, Mona M; Al-taweel, Shorog M

    2015-05-01

    Rapid, simple and sensitive derivative emission spectrofluorimetric methods have been developed for the simultaneous analysis of binary mixtures of guaifenesin (GUA) and phenylephrine hydrochloride (PHE). The methods are based upon measurement of the native fluorescence intensity of the two drugs at λex = 275 nm in methanolic solutions, followed by differentiation using first (D1) and second (D2) derivative techniques. The derivative fluorescence intensity-concentration plots were rectilinear over a range of 0.1-2 µg/mL for both GUA and PHE. The limits of detection were 0.027 (D1, GUA), 0.025 (D2, GUA), 0.031 (D1, PHE) and 0.033 (D2, PHE) µg/mL and limits of quantitation were 0.089 (D1, GUA), 0.083 (D2, GUA), 0.095 (D1, PHE) and 0.097 (D2, PHE) µg/mL. The proposed derivative emission spectrofluorimetric methods (D1 and D2) were successfully applied for the determination of the two compounds in binary mixtures and tablets with high precision and accuracy. The proposed methods were fully validated as per ICH guidelines. PMID:25044215

  4. Simultaneous determination of naphazoline, diphenhydramine and phenylephrine in nasal solutions by capillary electrophoresis.

    PubMed

    Marchesini, A F; Williner, M R; Mantovani, V E; Robles, J C; Goicoechea, H C

    2003-02-01

    A capillary zone electrophoresis (CZE) method has been developed to separate and quantitate naphazoline (NAPH), dyphenhydramine (DIP) and phenylephrine (PHE) in nasal solutions. Samples were diluted 1:25 in ultrapure water and injected at the anodic end. A central composite design has been used to optimise the experimental conditions for a complete and fast separation of the active ingredients studied. Critical parameters such as voltage, pH and buffer concentration have been studied to evaluate how they affect responses such as resolution and migration times. Separation was performed on a silica capillary with 75 microm I.D. and 70 cm total length at an applied voltage of 17.7 kV with a phosphate run buffer of pH 3.72 and 0.063 mol l(-1). Calibration curves were prepared for NAPH, DIP and PHE. For each analyte, the correlation coefficients were >0.999 (n=15). The RSD% of six replicate injections for each analyte were reasonably good. The method was applied to the quantitation of the three components in a commercial dosage form. The proposed method has the advantage of needing a very simple sample pretreatment and being faster than a typical HPLC chromatographic method.

  5. Simultaneous determination of phenylephrine hydrochloride, guaifenesin, and chlorpheniramine maleate in cough syrup by gradient liquid chromatography.

    PubMed

    Amer, Sawsan M; Abbas, Samah S; Shehata, Mostafa A; Ali, Nahed M

    2008-01-01

    A simple and reliable high-performance liquid chromatographic method was developed for the simultaneous determination of mixture of phenylephrine hydrochloride (PHENYL), guaifenesin (GUAIF), and chlorpheniramine maleate (CHLO) either in pure form or in the presence of methylparaben and propylparaben in a commercial cough syrup dosage form. Separation was achieved on a C8 column using 0.005 M heptane sulfonic acid sodium salt (pH 3.4 +/- 0.1) and acetonitrile as a mobile phase by gradient elution at different flow rates, and detection was done spectrophotometrically at 210 nm. A linear relationship in the range of 30-180, 120-1800, and 10-60 microg/mL was obtained for PHENYL, GUAIF, and CHLO, respectively. The results were statistically analyzed and compared with those obtained by applying the British Pharmacopoeia (2002) method and showed that the proposed method is precise, accurate, and can be easily applied for the determination of the drugs under investigation in pure form and in cough syrup formulations.

  6. Simultaneous determination of phenylephrine hydrochloride, guaifenesin, and chlorpheniramine maleate in cough syrup by gradient liquid chromatography.

    PubMed

    Amer, Sawsan M; Abbas, Samah S; Shehata, Mostafa A; Ali, Nahed M

    2008-01-01

    A simple and reliable high-performance liquid chromatographic method was developed for the simultaneous determination of mixture of phenylephrine hydrochloride (PHENYL), guaifenesin (GUAIF), and chlorpheniramine maleate (CHLO) either in pure form or in the presence of methylparaben and propylparaben in a commercial cough syrup dosage form. Separation was achieved on a C8 column using 0.005 M heptane sulfonic acid sodium salt (pH 3.4 +/- 0.1) and acetonitrile as a mobile phase by gradient elution at different flow rates, and detection was done spectrophotometrically at 210 nm. A linear relationship in the range of 30-180, 120-1800, and 10-60 microg/mL was obtained for PHENYL, GUAIF, and CHLO, respectively. The results were statistically analyzed and compared with those obtained by applying the British Pharmacopoeia (2002) method and showed that the proposed method is precise, accurate, and can be easily applied for the determination of the drugs under investigation in pure form and in cough syrup formulations. PMID:18476338

  7. Mesenteric artery responsiveness to acetylcholine and phenylephrine in cirrhotic rats challenged with endotoxin: the role of TLR4.

    PubMed

    Ostadhadi, Sattar; Rezayat, Seyed-Mahdi; Ejtemaei-Mehr, Shahram; Tavangar, Seyed-Mohammad; Nikoui, Vahid; Jazaeri, Farahnaz; Eftekhari, Golnar; Abdollahi, Alireza; Dehpour, Ahmad-Reza

    2015-06-01

    Cirrhosis is associated with vascular dysfunction and endotoxemia. These experiments were designed to investigate the hypothesis that the administration of a low-dose of lipopolysaccharide (LPS) worsens vascular dysfunction in rats subjected to bile-duct ligation (BDL), and to determine whether LPS initiates changes in vascular Toll-like receptor 4 (TLR4) expression. Four weeks after BDL, the animals were given an intraperitoneal injection of either saline or LPS (1.0 mg/kg body mass). Three hours later, the superior mesenteric artery was isolated, perfused, and then subjected to the vasoconstriction and vasodilatation effects of phenylephrine and acetylcholine, respectively. Our results show that phenylephrine-induced vasoconstriction decreased in the cirrhotic vascular bed (BDL rats) compared with the vascular bed of the sham-operated animals, and that the LPS injections in the cirrhotic (BDL) rats worsened this response. LPS injection administered to the sham-operated animals had no such effect. On the other hand, both the BDL procedure and the LPS injection increased acetylcholine-induced vasorelaxation, but LPS administration to the BDL rats had no effect on this response. The mRNA levels of TLR4 did not change, but immunohistochemical studies showed that TLR4 localization switched from the endothelium to vascular smooth muscle cells following chronic BDL. In conclusion, acute endotoxemia in cirrhotic rats is associated with hyporesponsiveness to phenylephrine and tolerance to the effects of acetylcholine. Altered localization of TLR4 may be responsible for these effects.

  8. Differential effects of vasopressin and phenylephrine on protein kinase C-mediated protein phosphorylations in isolated hepatocytes

    SciTech Connect

    Cooper, R.H.; Johanson, R.A.; Wiliamson, J.R.

    1986-05-01

    Receptor-mediated breakdown of inositol lipids produces two intracellular signals, diacylglycerol, which activates protein kinase C, and inositol trisphosphate, which causes release of intracellular vesicular Ca/sup 2 +/. This study examined the effects of Ca/sup 2 +/-ionophores, vasopressin, phenylephrine, and phorbol ester (PMA) on hepatocyte protein phosphorylations. (/sup 32/P) Phosphoproteins from hepatocytes prelabeled with /sup 32/P were resolved by 2-dimensional SDS-PAGE and corresponding autoradiographs were quantitated by densitometric analysis. The phosphorylation of five proteins, a plasma membrane bound 16 kDa protein with pI 6.4, a cytosolic 16 kDa protein with pI 5.8, and proteins with Mr's of 36 kDa, 52 kDa, and 68 kDa, could be attributed to phosphorylation by protein kinase C since the phosphorylation was stimulated by PMA. When the vasopressin concentration was varied, low vasopressin stimulated the phosphorylation of only the membrane bound 16 kDa protein of the above set of proteins, while higher vasopressin concentrations were required to stimulate the phosphorylation of all five proteins. Phenylephrine, even at supramaximal concentrations, stimulated the phosphorylation of only the membrane bound 16 kDa protein. These results suggest that phenylephrine is a less potent activator of protein kinase C than vasopressin by virtue of limited or localized diacylglycerol production.

  9. Phenylephrine alteration of cerebral blood flow during orthostasis: effect on n-back performance in chronic fatigue syndrome.

    PubMed

    Medow, Marvin S; Sood, Shilpa; Messer, Zachary; Dzogbeta, Seli; Terilli, Courtney; Stewart, Julian M

    2014-11-15

    Chronic fatigue syndrome (CFS) with orthostatic intolerance is characterized by neurocognitive deficits and impaired working memory, concentration, and information processing. In CFS, upright tilting [head-up tilt (HUT)] caused decreased cerebral blood flow velocity (CBFv) related to hyperventilation/hypocapnia and impaired cerebral autoregulation; increasing orthostatic stress resulted in decreased neurocognition. We loaded the baroreflex with phenylephrine to prevent hyperventilation and performed n-back neurocognition testing in 11 control subjects and 15 CFS patients. HUT caused a significant increase in heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decrease in end-tidal CO2 (ETCO2; 42.8 ± 1.2 vs. 33.9 ± 1.1 Torr, P < 0.05) in CFS vs. control. HUT caused CBFv to decrease 8.7% in control subjects but fell 22.5% in CFS. In CFS, phenylephrine prevented the HUT-induced hyperventilation/hypocapnia and the significant drop in CBFv with HUT (-8.1% vs. -22.5% untreated). There was no difference in control subject n-back normalized response time (nRT) comparing supine to HUT (106.1 ± 6.9 vs. 97.6 ± 7.1 ms at n = 4), and no difference comparing control to CFS while supine (97.1 ± 7.1 vs 96.5 ± 3.9 ms at n = 4). However, HUT of CFS subjects caused a significant increase in nRT (148.0 ± 9.3 vs. 96.4 ± 6.0 ms at n = 4) compared with supine. Phenylephrine significantly reduced the HUT-induced increase in nRT in CFS to levels similar to supine (114.6 ± 7.1 vs. 114.6 ± 9.3 ms at n = 4). Compared with control subjects, CFS subjects are more sensitive both to orthostatic challenge and to baroreflex/chemoreflex-mediated interventions. Increasing blood pressure with phenylephrine can alter CBFv. In CFS subjects, mitigation of the HUT-induced CBFv decrease with phenylephrine has a beneficial effect on n-back outcome.

  10. A natural history of "agonist".

    PubMed

    Russo, Ruth

    2002-01-01

    This paper constructs a brief history of the biochemical term agonist by exploring the multiple meanings of the root agôn in ancient Greek literature and describing how agonist first appeared in the scientific literature of the 20th century in the context of neurophysiologists' debates about the existence and properties of cellular receptors. While the narrow scientific definition of agonist may appear colorless and dead when compared with the web of allusions spun by the ancient Greek agôn, the scientific power and creativity of agonist actually resides precisely in its exact, restricted meaning for biomedical researchers.

  11. Computerised clinical decision support for suspected PE.

    PubMed

    Jiménez, David; Resano, Santiago; Otero, Remedios; Jurkojc, Carolina; Portillo, Ana Karina; Ruiz-Artacho, Pedro; Corres, Jesús; Vicente, Agustina; den Exter, Paul L; Huisman, Menno V; Moores, Lisa; Yusen, Roger D

    2015-09-01

    This study aimed to determine the effect of an evidence-based clinical decision support (CDS) algorithm on the use and yield of CT pulmonary angiography (CTPA) and on outcomes of patients evaluated in the emergency department (ED) for suspected PE. The study included 1363 consecutive patients evaluated for suspected PE in an ED during 12 months before and 12 months after initiation of CDS use. Introduction of CDS was associated with decreased CTPA use (55% vs 49%; absolute difference (AD), 6.3%; 95% CI 1.0% to 11.6%; p=0.02). The use of CDS was associated with fewer symptomatic venous thromboembolic events during follow-up in patients with an initial negative diagnostic evaluation for PE (0.7% vs 3.2%; AD 2.5%; 95% CI 0.9% to 4.6%; p<0.01).

  12. Agonist-induced redistribution of calponin in contractile vascular smooth muscle cells.

    PubMed

    Parker, C A; Takahashi, K; Tao, T; Morgan, K G

    1994-11-01

    Calponin is a thin filament-associated protein that has been implicated in playing an auxiliary regulatory role in smooth muscle contraction. We have used immunofluorescence and digital imaging microscopy to determine the cellular distribution of calponin in single cells freshly isolated from the ferret portal vein. In resting cells calponin is distributed throughout the cytosol, associated with filamentous structures, and is excluded from the nuclear area of the cell. The ratio of surface cortex-associated calponin to cytosol-associated calponin (R) was found to be 0.639 +/- 0.021. Upon depolarization of the cell with physiological saline solution containing 96 mM K+, the distribution of calponin did not change from that of a resting cell (R = 0.678 +/- 0.025, P = 0.369). Upon stimulation with an agonist (10 microM phenylephrine) that is known to activate protein kinase C (PKC) in these cells, the cellular distribution of calponin changed from primarily cytosolic to primarily surface cortex associated (R = 1.24 +/- 0.085, P < 0.001). This agonist-induced redistribution of calponin was partially inhibited by the PKC inhibitor calphostin, overlapped in time with PKC translocation, and preceded contraction of these cells. These results suggest that the physiological function of calponin may be to mediate agonist-activated contraction via a PKC-dependent pathway. PMID:7526695

  13. School PE through Internet Discussion Forums

    ERIC Educational Resources Information Center

    Lauritsalo, Kirsti; Sääkslahti, Arja; Rasku-Puttonen, Helena

    2015-01-01

    Background: Physical education is a subject that generates strong feelings and emotions, as can be seen in written accounts of PE experiences. It is also important to listen to students' voices in the research context. Nowadays, students can be listened to in a new way--through the Internet. Various discussion forums on the Internet make it…

  14. What Is the PE Password? Incorporating Vocabulary in Your Elementary PE Program

    ERIC Educational Resources Information Center

    Robelee, Margaret E.

    2016-01-01

    This article describes a novel program for third through fifth grade called "What is the PE Password?" that teaches vocabulary words and concepts without sacrificing activity time in order to support Common Core learning.

  15. Validated spectrophotometric and chromatographic methods for simultaneous determination of ketorolac tromethamine and phenylephrine hydrochloride.

    PubMed

    Belal, T S; El-Kafrawy, D S; Mahrous, M S; Abdel-Khalek, M M; Abo-Gharam, A H

    2016-07-01

    This work describes five simple and reliable spectrophotometric and chromatographic methods for analysis of the binary mixture of ketorolac tromethamine (KTR) and phenylephrine hydrochloride (PHE). Method I is based on the use of conventional Amax and derivative spectrophotometry with the zero-crossing technique where KTR was determined using its Amax and (1)D amplitudes at 323 and 341nm respectively, while PHE was determined by measuring the (1)D amplitudes at 248.5nm. Method II involves the application of the ratio spectra derivative spectrophotometry. For KTR, 12μg/mL PHE was used as a divisor and the (1)DD amplitudes at 265nm were plotted against KTR concentrations; while - by using 4μg/mL KTR as divisor - the (1)DD amplitudes at 243.5nm were found proportional to PHE concentrations. Method III depends on ratio-difference measurement where the peak to trough amplitudes between 260 and 284nm were measured and correlated to KTR concentration. Similarly, the peak to trough amplitudes between 235 and 260nm in the PHE ratio spectra were recorded. For method IV, the two compounds were separated using Merck HPTLC sheets of silica gel 60 F254 and a mobile phase composed of chloroform/methanol/ammonia (70:30:2, by volume) followed by densitometric measurement of KTR and PHE spots at 320 and 278nm respectively. Method V depends on HPLC-DAD. Effective chromatographic separation was achieved using Zorbax eclipse plus C8 column (4.6×250mm, 5μm) with a mobile phase consisting of 0.05M o-phosphoric acid and acetonitrile (50:50, by volume) at a flow rate 1mL/min and detection at 313 and 274nm for KTR and PHE respectively. Analytical performance of the developed methods was statistically validated according to the ICH guidelines with respect to linearity, ranges, precision, accuracy, detection and quantification limits. The validated spectrophotometric and chromatographic methods were successfully applied to the simultaneous analysis of KTR and PHE in synthetic mixtures

  16. Comparison of Mechanical Properties Between PE80 and PE100 Pipe Materials

    NASA Astrophysics Data System (ADS)

    Zhang, Yi; Jar, P.-Y. Ben

    2016-10-01

    Mechanical properties, including yield stress, relaxation behavior, moduli (elastic modulus at the strain of 0.5% and strain hardening modulus at strains above 70%), viscous stress, and quasi-static stress, are compared between polyethylene (PE) pipes that are made of PE80 and PE100 resins. The mechanical properties are measured using D-split tensile test on modified notched pipe ring specimens. The comparison includes the influence of strain rate (by the change of crosshead speed) on the yield strength and influence of pre-strain on the relaxation behavior and the modulus values. A two-stage approach is used to characterize the influence of pre-strain on the moduli, to ensure that viscous recovery from the first-stage of the test, to introduce the pre-strain, does not affect the modulus measurement from the second-stage test. The results show that elastic modulus, yield stress, strain hardening modulus, viscous stress, and quasi-static stress for PE100 are higher than those for PE80, but PE80 shows higher resistance to stress relaxation. The results also show that with the increase in the pre-strain level, the elastic modulus drops but the strain hardening modulus remains relatively constant.

  17. Comparison of Mechanical Properties Between PE80 and PE100 Pipe Materials

    NASA Astrophysics Data System (ADS)

    Zhang, Yi; Jar, P.-Y. Ben

    2016-08-01

    Mechanical properties, including yield stress, relaxation behavior, moduli (elastic modulus at the strain of 0.5% and strain hardening modulus at strains above 70%), viscous stress, and quasi-static stress, are compared between polyethylene (PE) pipes that are made of PE80 and PE100 resins. The mechanical properties are measured using D-split tensile test on modified notched pipe ring specimens. The comparison includes the influence of strain rate (by the change of crosshead speed) on the yield strength and influence of pre-strain on the relaxation behavior and the modulus values. A two-stage approach is used to characterize the influence of pre-strain on the moduli, to ensure that viscous recovery from the first-stage of the test, to introduce the pre-strain, does not affect the modulus measurement from the second-stage test. The results show that elastic modulus, yield stress, strain hardening modulus, viscous stress, and quasi-static stress for PE100 are higher than those for PE80, but PE80 shows higher resistance to stress relaxation. The results also show that with the increase in the pre-strain level, the elastic modulus drops but the strain hardening modulus remains relatively constant.

  18. Vascular Dysfunction in a Transgenic Model of Alzheimer's Disease: Effects of CB1R and CB2R Cannabinoid Agonists

    PubMed Central

    Navarro-Dorado, Jorge; Villalba, Nuria; Prieto, Dolores; Brera, Begoña; Martín-Moreno, Ana M.; Tejerina, Teresa; de Ceballos, María L.

    2016-01-01

    There is evidence of altered vascular function, including cerebrovascular, in Alzheimer's disease (AD) and transgenic models of the disease. Indeed vasoconstrictor responses are increased, while vasodilation is reduced in both conditions. β-Amyloid (Aβ) appears to be responsible, at least in part, of alterations in vascular function. Cannabinoids, neuroprotective and anti-inflammatory agents, induce vasodilation both in vivo and in vitro. We have demonstrated a beneficial effect of cannabinoids in models of AD by preventing glial activation. In this work we have studied the effects of these compounds on vessel density in amyloid precursor protein (APP) transgenic mice, line 2576, and on altered vascular responses in aortae isolated ring. First we showed increased collagen IV positive vessels in AD brain compared to control subjects, with a similar increase in TgAPP mice, which was normalized by prolonged oral treatment with the CB1/CB2 mixed agonist WIN 55,212-2 (WIN) and the CB2 selective agonist JWH-133 (JWH). In Tg APP mice the vasoconstriction induced by phenylephrine and the thromboxane agonist U46619 was significantly increased, and no change in the vasodilation to acetylcholine (ACh) was observed. Tg APP displayed decreased vasodilation to both cannabinoid agonists, which were able to prevent decreased ACh relaxation in the presence of Aβ. In summary, we have confirmed and extended the existence of altered vascular responses in Tg APP mice. Moreover, our results suggest that treatment with cannabinoids may ameliorate the vascular responses in AD-type pathology.

  19. Vascular Dysfunction in a Transgenic Model of Alzheimer's Disease: Effects of CB1R and CB2R Cannabinoid Agonists

    PubMed Central

    Navarro-Dorado, Jorge; Villalba, Nuria; Prieto, Dolores; Brera, Begoña; Martín-Moreno, Ana M.; Tejerina, Teresa; de Ceballos, María L.

    2016-01-01

    There is evidence of altered vascular function, including cerebrovascular, in Alzheimer's disease (AD) and transgenic models of the disease. Indeed vasoconstrictor responses are increased, while vasodilation is reduced in both conditions. β-Amyloid (Aβ) appears to be responsible, at least in part, of alterations in vascular function. Cannabinoids, neuroprotective and anti-inflammatory agents, induce vasodilation both in vivo and in vitro. We have demonstrated a beneficial effect of cannabinoids in models of AD by preventing glial activation. In this work we have studied the effects of these compounds on vessel density in amyloid precursor protein (APP) transgenic mice, line 2576, and on altered vascular responses in aortae isolated ring. First we showed increased collagen IV positive vessels in AD brain compared to control subjects, with a similar increase in TgAPP mice, which was normalized by prolonged oral treatment with the CB1/CB2 mixed agonist WIN 55,212-2 (WIN) and the CB2 selective agonist JWH-133 (JWH). In Tg APP mice the vasoconstriction induced by phenylephrine and the thromboxane agonist U46619 was significantly increased, and no change in the vasodilation to acetylcholine (ACh) was observed. Tg APP displayed decreased vasodilation to both cannabinoid agonists, which were able to prevent decreased ACh relaxation in the presence of Aβ. In summary, we have confirmed and extended the existence of altered vascular responses in Tg APP mice. Moreover, our results suggest that treatment with cannabinoids may ameliorate the vascular responses in AD-type pathology. PMID:27695396

  20. The effect of urapidil, an alpha-1 adrenoceptor antagonist and a 5-HT1A agonist, on the vascular tone of the porcine coronary and pulmonary arteries, the rat aorta and the human pulmonary artery.

    PubMed

    Bopp, Claire; Auger, Cyril; Diemunsch, Pierre; Schini-Kerth, Valérie

    2016-05-15

    Urapidil (Eupressyl(®)) an antihypertensive drug acting as an α1 antagonist and a 5-HT1A agonist, may be of special interest in the treatment of hypertension associated with preeclamptic toxaemia and hypoxia-induced pulmonary arterial vasoconstriction. However, the effect of urapidil on vascular tone has been poorly investigated. Vascular reactivity was evaluated using pulmonary and coronary arteries from 36 pigs, aortae from 22 rats and 9 human pulmonary artery samples suspended in organ chambers. Concentration-relaxation curves either to urapidil, 5-HT, or the 5-HT1A receptor agonist 8-OH-DPAT were constructed after pre-contraction of rings. Pig pulmonary and coronary artery rings were contracted with U46619, a thromboxane mimetic, rat aortic rings with either endothelin-1 or phenylephrine, and human pulmonary artery rings with U46619 or phenylephrine. Urapidil markedly inhibited phenylephrine-induced contractions in rat aortic rings with and without endothelium with a more pronounced effect observed in rings without endothelium. Both 5-HT and 8-OH-DPAT failed to induce relaxation in rat aortic rings with an intact endothelium. 5-HT, but not urapidil and 8-OH-DPAT, induced a concentration-dependent relaxation in the porcine coronary and pulmonary artery rings with an intact endothelium (P<0.05). 5-HT and phenylephrine but not urapidil caused concentration-dependent contractions in human pulmonary artery rings. The present findings, while confirming that urapidil is a potent inhibitor of α1-adrenoceptor-induced contraction, do not support the role of 5-HT1A receptor activation in the control of the vascular tone of the different types of arteries tested in response to urapidil. In addition, they indicate that urapidil seems to preferentially target arteries with endothelial dysfunction.

  1. BIM LAU-PE: Seedlings in Microgravity

    NASA Astrophysics Data System (ADS)

    Gass, S.; Pennese, R.; Chapuis, D.; Dainesi, P.; Nebuloni, S.; Garcia, M.; Oriol, A.

    2015-09-01

    The effect of gravity on plant roots is an intensive subject of research. Sounding rockets represent a costeffective platform to study this effect under microgravity conditions. As part of the upcoming MASER 13 sounding rocket campaign, two experiments on Arabidopsis thaliana seedlings have been devised: GRAMAT and SPARC. These experiments are aimed at studying (1) the genes that are specifically switched on or off during microgravity, and (2) the position of auxin-transporting proteins during microgravity. To perform these experiments, RUAG Space Switzerland site of Nyon, in collaboration with the Swedish Space Corporation (SSC) and the University of Freiburg, has developed the BIM LAU-PE (Biolology In Microgravity Late Access Unit Plant Experiment). In the following an overview of the BIM LAU-PE design is presented, highlighting specific module design features and verifications performed. A particular emphasis is placed on the parabolic flight experiments, including results of the micro-g injection system validation.

  2. Synthesis and activity of (R)-(-)-m-trimethylacetoxy-alpha-[(methylamino)methyl]benzyl alcohol hydrochloride: a prodrug form of (R)-(-)-phenylephrine.

    PubMed

    Yuan, S S; Bador, N

    1976-06-01

    Optically pure (R)-(-)-m-trimethylacetoxy-alpha-[(methylamino)methyl]benzyl alcohol hydrochloride was synthesized by the following sequence: (R)-(-)-phenylephrine was condensed with acetone in the presence of calcium carbide to give an oxazolidine derivative and then treated with thallous ethoxide in ether followed by trimethylacetyl chloride to yield the phenolic ester. Finally, the oxazolidine ring was cleaved by one equivalent of hydrogen chloride in ethanol. Condensation of phenylephrine with benzaldehyde, with or without solvents, gave either 1,1,2-trimethyl-4,6-dihydroxy-1,2,3,4-tetrahydroisoquinoline or a mixture of side-chain oxazolidine and the tetrahydroisoquinoline. Condensation of epinephrine with opianic acid in pyridine also gave a tetrahydroisoquinoline only. When applied on rabbit eyes, the prodrug (R)-(-)-m-trimethylacetoxy-alpha[(methylamino)methyl]benzyl alcohol hydrochloride exhibited an unexpected, three times higher mydriatic activity than the corresponding racemic prodrug and was 15 times more active than the parent, (R)-(-)-phenylephrine.

  3. NG-nitro-L-arginine and phenylephrine have similar effects on the vascular waterfall in the canine hindlimb.

    PubMed

    Shrier, I; Magder, S

    1995-02-01

    Hindlimb pressure-flow relationships are well characterized by modeling a vascular waterfall at the arteriolar level. Under these conditions, Q = (Pper - Pcrit)/Rart, where Q is blood flow, Pper is perfusion pressure, Pcrit is waterfall pressure, and Rart is the resistance upstream from the waterfall. To determine the effects of endothelium-derived relaxing factor (EDRF) on Pcrit, Rart, and venous resistance (Rv), we varied Pper in the canine hindlimb between 100 and 200 mmHg before and after NG-nitro-L-arginine infusion (L-NNA, an inhibitor of EDRF synthesis). Before L-NNA, Pcrit increased with increasing Pper. After L-NNA, Pcrit was higher at each Pper, and the increase in Pcrit with increases in Pper was greater than under control conditions. In contrast to Pcrit, Rart decreased with increasing Pper before L-NNA. After L-NNA, Rart was higher at each Pper and no longer decreased with increasing Pper. Rv was not affected by Pper under control conditions but decreased with increasing Pper after L-NNA. The pressure in the small venules at each Pper decreased after L-NNA. In a second group of animals, we infused phenylephrine to control for increased tone produced by L-NNA. Results were similar to those seen with L-NNA. In conclusion, blocking EDRF synthesis increases both Pcrit and Rart, but the same response was also obtained with phenylephrine.

  4. Search for D{sup 0}{yields}pe{sup +} and D{sup 0}{yields}pe{sup -}

    SciTech Connect

    Rubin, P.; Lowrey, N.; Mehrabyan, S.; Selen, M.; Wiss, J.; Mitchell, R. E.; Shepherd, M. R.; Besson, D.; Pedlar, T. K.; Cronin-Hennessy, D.; Gao, K. Y.; Hietala, J.; Kubota, Y.; Klein, T.; Poling, R.; Scott, A. W.; Zweber, P.; Dobbs, S.; Metreveli, Z.; Seth, K. K.

    2009-05-01

    We search for simultaneous baryon and lepton number violating decays of the D{sup 0} meson. Specifically, we use 281 pb{sup -1} of data taken on the {psi}(3770) resonance with the CLEO-c detector at the CESR collider to look for decays D{sup 0}{yields}pe{sup +}, D{sup 0}{yields}pe{sup +}, D{sup 0}{yields}pe{sup -}, and D{sup 0}{yields}pe{sup -}. We find no significant signals and set the following branching fraction upper limits: D{sup 0}{yields}pe{sup +}(D{sup 0}{yields}pe{sup +})<1.1x10{sup -5} and D{sup 0}{yields}pe{sup -}(D{sup 0}{yields}pe{sup -})<1.0x10{sup -5}, both at the 90% confidence level.

  5. p90 ribosomal S6 kinases play a significant role in early gene regulation in the cardiomyocyte response to G(q)-protein-coupled receptor stimuli, endothelin-1 and α(1)-adrenergic receptor agonists.

    PubMed

    Amirak, Emre; Fuller, Stephen J; Sugden, Peter H; Clerk, Angela

    2013-03-01

    ERK1/2 (extracellular-signal-regulated kinase 1/2) and their substrates RSKs (p90 ribosomal S6 kinases) phosphorylate different transcription factors, contributing differentially to transcriptomic profiles. In cardiomyocytes ERK1/2 are required for >70% of the transcriptomic response to endothelin-1. In the present study we investigated the role of RSKs in the transcriptomic responses to the G(q)-protein-coupled receptor agonists endothelin-1, phenylephrine (a generic α(1)-adrenergic receptor agonist) and A61603 (α(1A)-adrenergic receptor selective). Phospho-ERK1/2 and phospho-RSKs appeared in cardiomyocyte nuclei within 2-3 min of stimulation (endothelin-1>A61603≈phenylephrine). All agonists increased nuclear RSK2, but only endothelin-1 increased the nuclear RSK1 content. PD184352 (inhibits ERK1/2 activation) and BI-D1870 (inhibits RSKs) were used to dissect the contribution of RSKs to the endothelin-1-responsive transcriptome. Of the 213 RNAs up-regulated after 1 h, 51% required RSKs for their up-regulation, whereas 29% required ERK1/2 but not RSKs. The transcriptomic response to phenylephrine overlapped with, but was not identical with, endothelin-1. As with endothelin-1, PD184352 inhibited the up-regulation of most phenylephrine-responsive transcripts, but the greater variation in the effects of BI-D1870 suggests that differential RSK signalling influences global gene expression. A61603 induced similar changes in RNA expression in cardiomyocytes as phenylephrine, indicating that the signal was mediated largely through α(1A)-adrenergic receptors. A61603 also increased expression of immediate early genes in perfused adult rat hearts and, as in cardiomyocytes, up-regulation of the majority of genes was inhibited by PD184352. PD184352 or BI-D1870 prevented the increased surface area induced by endothelin-1 in cardiomyocytes. Thus RSKs play a significant role in regulating cardiomyocyte gene expression and hypertrophy in response to G

  6. The characterisation of two different degradable polyethylene (PE) sacks

    SciTech Connect

    Davis, G. . E-mail: gudavis@cytanet.com.cy

    2006-12-15

    The compostability of two different polyethylene (PE) products on the UK market under open-windrow composting conditions is explored within this paper. Chemical analysis of the PE bags has established their constituents in order to examine how the PE bags have an increased degradability depending on additives. Weight loss of the two different PE products within open-windrow composting conditions was recorded in order to establish the percentage weight loss as an indication of the degradability of the two products and their relative suitability for open-windrow composting. Scanning electron microscopy (SEM) of the PE products over the composting duration established the degradation processes for the PE products within the compost. These analyses concluded that one of the PE product mixes was more degradable than the other. However, neither product completed degraded within the timeframe of 12-14 weeks generally accepted for open-windrow composting in the UK.

  7. Functional Dissection of the PE Domain Responsible for Translocation of PE_PGRS33 across the Mycobacterial Cell Wall

    PubMed Central

    Cascioferro, Alessandro; Donà, Valentina; Delogu, Giovanni; Palù, Giorgio; Bitter, Wilbert; Manganelli, Riccardo

    2011-01-01

    PE are peculiar exported mycobacterial proteins over-represented in pathogenic mycobacterial species. They are characterized by an N-terminal domain of about 110 amino acids (PE domain) which has been demonstrated to be responsible for their export and localization. In this paper, we characterize the PE domain of PE_PGRS33 (PERv1818c), one of the best characterized PE proteins. We constructed several mutated proteins in which portions of the PE domain were deleted or subjected to defined mutations. These proteins were expressed in different mycobacterial species and their localization was characterized. We confirmed that the PE domain is essential for PE_PGRS33 surface localization, and demonstrated that a PE domain lacking its first 30 amino acids loses its function. However, single amino acid substitutions in two regions extremely well conserved within the N-terminal domain of all PE proteins had some effect on the stability of PE_PGRS33, but not on its localization. Using Mycobacterium marinum we could show that the type VII secretion system ESX-5 is essential for PE_PGRS33 export. Moreover, in M. marinum, but not in Mycobacterium bovis BCG and in Mycobacterium tuberculosis, the PE domain of PE_PGRS33 is processed and secreted into the culture medium when expressed in the absence of the PGRS domain. Finally, using chimeric proteins in which different portions of the PERv1818c domain were fused to the N-terminus of the green fluorescent protein, we could hypothesize that the first 30 amino acids of the PE domain contain a sequence that allows protein translocation. PMID:22110736

  8. Denatonium and 6-n-Propyl-2-thiouracil, Agonists of Bitter Taste Receptor, Inhibit Contraction of Various Types of Smooth Muscles in the Rat and Mouse.

    PubMed

    Sakai, Hiroyasu; Sato, Ken; Kai, Yuki; Chiba, Yoshihiko; Narita, Minoru

    2016-01-01

    Recently the global expression of taste 2 receptors (TAS2Rs) on smooth muscle cells in human airways was demonstrated. Here, the effects of agonists of taste receptor, type 2, denatonium and 6-n-propyl-2-thiouracil, on smooth-muscle contraction were examined in the rat and mouse. Contractions induced by carbachol (CCh), high K(+), and sodium fluoride, but not calyculin-A, were inhibited significantly in the presence of a TAS2R agonist in the bronchial smooth muscle of mice. The contraction induced by CCh was inhibited by TAS2R agonists in ileal smooth muscle. Phenylephrine-induced contraction was also inhibited by TAS2R agonists in aortic smooth muscle. Gastrointestinal motility and blood pressure were attenuated by administration of TAS2R agonists in vivo. These findings suggest that TAS2R may be receptor for endogenous biologically active substances as well as for bitter tastes on the tongue. TAS2R signaling could be employed in the development of anti-asthmatic, anti-spasmodic, and anti-hypertensive drugs.

  9. Denatonium and 6-n-Propyl-2-thiouracil, Agonists of Bitter Taste Receptor, Inhibit Contraction of Various Types of Smooth Muscles in the Rat and Mouse.

    PubMed

    Sakai, Hiroyasu; Sato, Ken; Kai, Yuki; Chiba, Yoshihiko; Narita, Minoru

    2016-01-01

    Recently the global expression of taste 2 receptors (TAS2Rs) on smooth muscle cells in human airways was demonstrated. Here, the effects of agonists of taste receptor, type 2, denatonium and 6-n-propyl-2-thiouracil, on smooth-muscle contraction were examined in the rat and mouse. Contractions induced by carbachol (CCh), high K, and sodium fluoride, but not calyculin-A, were inhibited significantly in the presence of a TAS2R agonist in the bronchial smooth muscle of mice. The contraction induced by CCh was inhibited by TAS2R agonists in ileal smooth muscle. Phenylephrine-induced contraction was also inhibited by TAS2R agonists in aortic smooth muscle. Gastrointestinal motility and blood pressure were attenuated by administration of TAS2R agonists in vivo. These findings suggest that TAS2R may be receptor for endogenous biologically active substances as well as for bitter tastes on the tongue. TAS2R signaling could be employed in the development of anti-asthmatic, anti-spasmodic, and anti-hypertensive drugs. PMID:27110632

  10. Denatonium and 6-n-Propyl-2-thiouracil, Agonists of Bitter Taste Receptor, Inhibit Contraction of Various Types of Smooth Muscles in the Rat and Mouse.

    PubMed

    Sakai, Hiroyasu; Sato, Ken; Kai, Yuki; Chiba, Yoshihiko; Narita, Minoru

    2016-01-01

    Recently the global expression of taste 2 receptors (TAS2Rs) on smooth muscle cells in human airways was demonstrated. Here, the effects of agonists of taste receptor, type 2, denatonium and 6-n-propyl-2-thiouracil, on smooth-muscle contraction were examined in the rat and mouse. Contractions induced by carbachol (CCh), high K(+), and sodium fluoride, but not calyculin-A, were inhibited significantly in the presence of a TAS2R agonist in the bronchial smooth muscle of mice. The contraction induced by CCh was inhibited by TAS2R agonists in ileal smooth muscle. Phenylephrine-induced contraction was also inhibited by TAS2R agonists in aortic smooth muscle. Gastrointestinal motility and blood pressure were attenuated by administration of TAS2R agonists in vivo. These findings suggest that TAS2R may be receptor for endogenous biologically active substances as well as for bitter tastes on the tongue. TAS2R signaling could be employed in the development of anti-asthmatic, anti-spasmodic, and anti-hypertensive drugs. PMID:26567724

  11. Alterations in phenylephrine-induced contractions and the vascular expression of Na+,K+-ATPase in ouabain-induced hypertension

    PubMed Central

    Rossoni, Luciana V; Salaices, Mercedes; Marín, Jesús; Vassallo, Dalton V; Alonso, María J

    2002-01-01

    Hypertension development, phenylephrine-induced contraction and Na+,K+-ATPase functional activity and protein expression in aorta (AO), tail (TA) and superior mesenteric (SMA) arteries from ouabain- (25 μg day−1, s.c., 5 weeks) and vehicle-treated rats were evaluated.Ouabain treatment increased systolic blood pressure (127±1 vs 160±2 mmHg, n=24, 35; P<0.001) while the maximum response to phenylephrine was reduced (P<0.01) in AO (102.8±3.9 vs 67.1±10.1% of KCl response, n=12, 9) and SMA (82.5±7.5 vs 52.2±5.8%, n=12, 9).Endothelium removal potentiated the phenylephrine response to a greater extent in segments from ouabain-treated rats. Thus, differences of area under the concentration-response curves (dAUC) in endothelium-denuded and intact segments for control and ouabain-treated rats were, respectively: AO, 56.6±9.6 vs 198.3±18.3 (n=9, 7); SMA, 85.5±15.4 vs 165.4±24.8 (n=6, 6); TA, 13.0±6.1 vs 39.5±10.4% of the corresponding control AUC (n=6, 6); P<0.05.The relaxation to KCl (1 – 10 mM) was similar in segments from both groups. Compared to controls, the inhibition of 0.1 mM ouabain on KCl relaxation was greater in AO (dAUC: 64.8±4.6 vs 84.0±5.1%, n=11, 14; P<0.05), similar in SMA (dAUC: 39.1±3.9 vs 43.3±7.8%, n=6, 7; P>0.05) and smaller in TA (dAUC: 62.1±5.5 vs 41.4±8.2%, n=12, 13; P<0.05) in ouabain-treated rats.Protein expression of both α1 and α2 isoforms of Na+,K+-ATPase was augmented in AO, unmodified in SMA and reduced in TA from ouabain-treated rats.These results suggest that chronic administration of ouabain induces hypertension and regional vascular alterations, the latter possibly as a consequence of the hypertension. PMID:11834625

  12. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs.

  13. From PE Experiences to PE Teaching Practices? Insights from Scottish Primary Teachers' Experiences of PE, Teacher Education, School Entry and Professional Development

    ERIC Educational Resources Information Center

    Elliot, Dely L.; Atencio, Matthew; Campbell, Theresa; Jess, Mike

    2013-01-01

    Morgan and Hansen suggest that further research is needed to explore how non-specialist primary teachers approach and teach physical education (PE) based on their personal school PE backgrounds, teacher education experiences and ongoing professional development. This paper adopts Lawson's socialisation model, a theoretical framework…

  14. Chemometrics resolution and quantification power evaluation: Application on pharmaceutical quaternary mixture of Paracetamol, Guaifenesin, Phenylephrine and p-aminophenol

    NASA Astrophysics Data System (ADS)

    Yehia, Ali M.; Mohamed, Heba M.

    2016-01-01

    Three advanced chemmometric-assisted spectrophotometric methods namely; Concentration Residuals Augmented Classical Least Squares (CRACLS), Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Principal Component Analysis-Artificial Neural Networks (PCA-ANN) were developed, validated and benchmarked to PLS calibration; to resolve the severely overlapped spectra and simultaneously determine; Paracetamol (PAR), Guaifenesin (GUA) and Phenylephrine (PHE) in their ternary mixture and in presence of p-aminophenol (AP) the main degradation product and synthesis impurity of Paracetamol. The analytical performance of the proposed methods was described by percentage recoveries, root mean square error of calibration and standard error of prediction. The four multivariate calibration methods could be directly used without any preliminary separation step and successfully applied for pharmaceutical formulation analysis, showing no excipients' interference.

  15. Chemometrics resolution and quantification power evaluation: Application on pharmaceutical quaternary mixture of Paracetamol, Guaifenesin, Phenylephrine and p-aminophenol.

    PubMed

    Yehia, Ali M; Mohamed, Heba M

    2016-01-01

    Three advanced chemmometric-assisted spectrophotometric methods namely; Concentration Residuals Augmented Classical Least Squares (CRACLS), Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Principal Component Analysis-Artificial Neural Networks (PCA-ANN) were developed, validated and benchmarked to PLS calibration; to resolve the severely overlapped spectra and simultaneously determine; Paracetamol (PAR), Guaifenesin (GUA) and Phenylephrine (PHE) in their ternary mixture and in presence of p-aminophenol (AP) the main degradation product and synthesis impurity of Paracetamol. The analytical performance of the proposed methods was described by percentage recoveries, root mean square error of calibration and standard error of prediction. The four multivariate calibration methods could be directly used without any preliminary separation step and successfully applied for pharmaceutical formulation analysis, showing no excipients' interference.

  16. Chemometrics resolution and quantification power evaluation: Application on pharmaceutical quaternary mixture of Paracetamol, Guaifenesin, Phenylephrine and p-aminophenol.

    PubMed

    Yehia, Ali M; Mohamed, Heba M

    2016-01-01

    Three advanced chemmometric-assisted spectrophotometric methods namely; Concentration Residuals Augmented Classical Least Squares (CRACLS), Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Principal Component Analysis-Artificial Neural Networks (PCA-ANN) were developed, validated and benchmarked to PLS calibration; to resolve the severely overlapped spectra and simultaneously determine; Paracetamol (PAR), Guaifenesin (GUA) and Phenylephrine (PHE) in their ternary mixture and in presence of p-aminophenol (AP) the main degradation product and synthesis impurity of Paracetamol. The analytical performance of the proposed methods was described by percentage recoveries, root mean square error of calibration and standard error of prediction. The four multivariate calibration methods could be directly used without any preliminary separation step and successfully applied for pharmaceutical formulation analysis, showing no excipients' interference. PMID:26254602

  17. Simultaneous spectrophotometric-multivariate calibration determination of several components of ophthalmic solutions: phenylephrine, chloramphenicol, antipyrine, methylparaben and thimerosal.

    PubMed

    Collado, M S; Mantovani, V E; Goicoechea, H C; Olivieri, A C

    2000-08-16

    The use of multivariate spectrophotometric calibration for the simultaneous determination of several active components and excipients in ophthalmic solutions is presented. The resolution of five-component mixtures of phenylephrine, chloramphenicol, antipyrine, methylparaben and thimerosal has been accomplished by using partial least-squares (PLS-1) and a variant of the so-called hybrid linear analysis (HLA). Notwithstanding the presence of a large number of components and their high degree of spectral overlap, they have been determined simultaneously with high accuracy and precision, with no interference, rapidly and without resorting to extraction procedures using non aqueous solvents. A simple and fast method for wavelength selection in the calibration step is presented, based on the minimisation of the predicted error sum of squares (PRESS) calculated as a function of a moving spectral window.

  18. Simultaneous high-performance liquid chromatographic determination of paracetamol, phenylephrine HCl, and chlorpheniramine maleate in pharmaceutical dosage forms.

    PubMed

    Senyuva, Hamide; Ozden, Tuncel

    2002-02-01

    A rapid, precise, and specific high-performance liquid chromatographic method is described for the simultaneous determination of paracetamol, phenylephrine HCI, and chlorpheniramine maleate in combined pharmaceutical dosage forms. The method involves the use of a microBondapak CN RP analytical column (125 A, 10 microm, 3.9 x 150 mm) at 22 degrees C as the stationary phase with the mixture of acetonitrile and phosphate buffer (pH 6.22, 78:22) as the mobile phase. Derivatization of the drugs is not required. The method is applied to commercial pediatric cough-cold syrups, tablets, and capsules marketed in Turkey. The relative standard deviation for 10 replicate measurements of each drug in the medicaments is always less than 2%.

  19. Generalized transduction Of shigella flexneri by converting phage PE5.

    PubMed

    Financsek, I; Kétyi, I

    1976-01-01

    Phage PE5, responsible for the conversion of type V antigen in Shigella flexneri, has the ability to produce generalized transduction. The correlation between phage multiplicity and the number of transductants, the specific inhibitory activity of anti-PE5 serum, and the lack of transduction in PE5 resistant recipients, indicate the role of phage PE5 in generalized transduction. Transduction of the R100-1 factor resulted in a non-transmissible tetracycline resistance segragation. The characteristics of the tetracycline resistance determinant suggest the possibility of integration.

  20. PE11, a PE/PPE family protein of Mycobacterium tuberculosis is involved in cell wall remodeling and virulence

    PubMed Central

    Singh, Parul; Rao, Rameshwaram Nagender; Reddy, Jala Ram Chandra; Prasad, RBN; Kotturu, Sandeep Kumar; Ghosh, Sudip; Mukhopadhyay, Sangita

    2016-01-01

    The role of the unique proline-glutamic acid (PE)/proline-proline-glutamic acid (PPE) family of proteins in the pathophysiology and virulence of Mycobacterium tuberculosis is not clearly understood. One of the PE family proteins, PE11 (LipX or Rv1169c), specific to pathogenic mycobacteria is found to be over-expressed during infection of macrophages and in active TB patients. In this study, we report that M. smegmatis expressing PE11 (Msmeg-PE11) exhibited altered colony morphology and cell wall lipid composition leading to a marked increase in resistance against various environmental stressors and antibiotics. The cell envelope of Msmeg-PE11 also had greater amount of glycolipids and polar lipids. Msmeg-PE11 was found to have better survival rate in infected macrophages. Mice infected with Msmeg-PE11 had higher bacterial load, showed exacerbated organ pathology and mortality. The liver and lung of Msmeg-PE11-infected mice also had higher levels of IL-10, IL-4 and TNF-α cytokines, indicating a potential role of this protein in mycobacterial virulence. PMID:26902658

  1. PE11, a PE/PPE family protein of Mycobacterium tuberculosis is involved in cell wall remodeling and virulence.

    PubMed

    Singh, Parul; Rao, Rameshwaram Nagender; Reddy, Jala Ram Chandra; Prasad, R B N; Kotturu, Sandeep Kumar; Ghosh, Sudip; Mukhopadhyay, Sangita

    2016-02-23

    The role of the unique proline-glutamic acid (PE)/proline-proline-glutamic acid (PPE) family of proteins in the pathophysiology and virulence of Mycobacterium tuberculosis is not clearly understood. One of the PE family proteins, PE11 (LipX or Rv1169c), specific to pathogenic mycobacteria is found to be over-expressed during infection of macrophages and in active TB patients. In this study, we report that M. smegmatis expressing PE11 (Msmeg-PE11) exhibited altered colony morphology and cell wall lipid composition leading to a marked increase in resistance against various environmental stressors and antibiotics. The cell envelope of Msmeg-PE11 also had greater amount of glycolipids and polar lipids. Msmeg-PE11 was found to have better survival rate in infected macrophages. Mice infected with Msmeg-PE11 had higher bacterial load, showed exacerbated organ pathology and mortality. The liver and lung of Msmeg-PE11-infected mice also had higher levels of IL-10, IL-4 and TNF-α cytokines, indicating a potential role of this protein in mycobacterial virulence.

  2. PE11, a PE/PPE family protein of Mycobacterium tuberculosis is involved in cell wall remodeling and virulence.

    PubMed

    Singh, Parul; Rao, Rameshwaram Nagender; Reddy, Jala Ram Chandra; Prasad, R B N; Kotturu, Sandeep Kumar; Ghosh, Sudip; Mukhopadhyay, Sangita

    2016-01-01

    The role of the unique proline-glutamic acid (PE)/proline-proline-glutamic acid (PPE) family of proteins in the pathophysiology and virulence of Mycobacterium tuberculosis is not clearly understood. One of the PE family proteins, PE11 (LipX or Rv1169c), specific to pathogenic mycobacteria is found to be over-expressed during infection of macrophages and in active TB patients. In this study, we report that M. smegmatis expressing PE11 (Msmeg-PE11) exhibited altered colony morphology and cell wall lipid composition leading to a marked increase in resistance against various environmental stressors and antibiotics. The cell envelope of Msmeg-PE11 also had greater amount of glycolipids and polar lipids. Msmeg-PE11 was found to have better survival rate in infected macrophages. Mice infected with Msmeg-PE11 had higher bacterial load, showed exacerbated organ pathology and mortality. The liver and lung of Msmeg-PE11-infected mice also had higher levels of IL-10, IL-4 and TNF-α cytokines, indicating a potential role of this protein in mycobacterial virulence. PMID:26902658

  3. Candida glabrata binds to glycosylated and lectinic receptors on the coronary endothelial luminal membrane and inhibits flow sense and cardiac responses to agonists.

    PubMed

    Torres-Tirado, David; Knabb, Maureen; Castaño, Irene; Patrón-Soberano, Araceli; De Las Peñas, Alejandro; Rubio, Rafael

    2016-01-01

    Candida glabrata (CG) is an opportunistic fungal pathogen that initiates infection by binding to host cells via specific lectin-like adhesin proteins. We have previously shown the importance of lectin-oligosaccharide binding in cardiac responses to flow and agonists. Because of the lectinic-oligosaccharide nature of CG binding, we tested the ability of CG to alter the agonist- and flow-induced changes in cardiac function in isolated perfused guinea pig hearts. Both transmission and scanning electron microscopy showed strong attachment of CG to the coronary endothelium, even after extensive washing. CG shifted the coronary flow vs. auricular-ventricular (AV) delay relationship upward, indicating that greater flow was required to achieve the same AV delay. This effect was completely reversed with mannose, partially reversed with galactose and N-acetylgalactosamine, but hyaluronan had no effect. Western blot analysis was used to determine binding of CG to isolated coronary endothelial luminal membrane (CELM) receptors, and the results indicate that flow-sensitive CELM receptors, ANG II type I, α-adrenergic 1A receptor, endothelin-2, and VCAM-1 bind to CG. In addition, CG inhibited agonist-induced effects of bradykinin, angiotensin, and phenylephrine on AV delay, coronary perfusion pressure, and left ventricular pressure. Mannose reversed the inhibitory effects of CG on the agonist responses. These results suggest that CG directly binds to flow-sensitive CELM receptors via lectinic-oligosaccharide interactions with mannose and disrupts the lectin-oligosaccharide binding necessary for flow-induced cardiac responses.

  4. Improvement of barrier properties of rotomolded PE containers with nanoclay

    SciTech Connect

    Jamshidi, Shadi; Sundararaj, Uttandaraman

    2015-05-22

    Polyethylene (PE) is widely used to make bulk containers in rotational molding process. The challenge in this study is to improve permeation resistance of PE to hydrocarbon solvents and gases. Adding organomodified clay improves the thermal, barrier and mechanical properties of PE. In fact, clay layers create a tortuous path against the permeant, yielding better barrier properties. Due to the non-polar hydrophobic nature of PE and polar hydrophilic structure of clay minerals, the compatibilizer plays a crucial role to enhance the dispersion level of clay in the matrix. In this study High Density Polyethylene (HDPE) and Linear Low Density Polyethylene (LLDPE) layered silicate nanocomposite were melt-compounded with two concentrations of organomodified clay (2 and 4 wt. %). The interaction between nanoclay, compatibilizer and rotomolding grade of PE were examined by using X-ray diffraction, transmission electron microscopy (TEM) and rheology test. Rheology was used to determine the performance of our material at low shear processing condition.

  5. Improvement of barrier properties of rotomolded PE containers with nanoclay

    NASA Astrophysics Data System (ADS)

    Jamshidi, Shadi; Sundararaj, Uttandaraman

    2015-05-01

    Polyethylene (PE) is widely used to make bulk containers in rotational molding process. The challenge in this study is to improve permeation resistance of PE to hydrocarbon solvents and gases. Adding organomodified clay improves the thermal, barrier and mechanical properties of PE. In fact, clay layers create a tortuous path against the permeant, yielding better barrier properties. Due to the non-polar hydrophobic nature of PE and polar hydrophilic structure of clay minerals, the compatibilizer plays a crucial role to enhance the dispersion level of clay in the matrix. In this study High Density Polyethylene (HDPE) and Linear Low Density Polyethylene (LLDPE) layered silicate nanocomposite were melt-compounded with two concentrations of organomodified clay (2 and 4 wt. %). The interaction between nanoclay, compatibilizer and rotomolding grade of PE were examined by using X-ray diffraction, transmission electron microscopy (TEM) and rheology test. Rheology was used to determine the performance of our material at low shear processing condition.

  6. Novel diazabicycloalkane delta opioid agonists.

    PubMed

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80.

  7. [ROLE OF THROMBOXANE AND LEUKOTRIENES IN MECHANISMS OF CONTRACTILE REACTIONS OF PORTAL VEIN, INDUCED BY ACETYLCHLINE AND PHENYLEPHRINE].

    PubMed

    Vinogradova, O O; Yanchuk, P I; Pasichnichenko, O M

    2015-01-01

    Effects of picotamide and zileuton on tonic contractile activity of the rat portal vein preparations, induced by acetylcholine (2.10(-5) mol/1) and phenylephrine (5.10(-7) mol/1) were investigated. Conversion of arachidonic acid products (prostaglandins, leukotrienes) synthesized by endothelial cells, plays an important role in the local regulation of vascular tone. The compounds formed in a cascade of enzymatic transformations can modulate the effect of other vasoactive factors. Picotamide (6,5.10(-5) mol/1) - thromboxane receptor and thromboxane -synthase blocker - depress acetylcholine-induction tonic contraction of isolated segments of portal vein with intact endothelium by 29% and norepinephrine-induction reduction of 45% relative to the control values. The obtained results indicate a participation of thromboxane and/or endoperoxide H2 in this reaction. Partial inhibition of the contractions by 5-lipoxygenase blocker zileuton(4,2.10(-5) mol/1) at 23% relative to control values suggests, that products of lipoxigenase pathways of arachidonic acid conversion are involved in mechanisms of specified reactions. These data indicate complex mechanisms of regulation of vascular tone of the portal vein, which play an important role eicosanoids. Further study of these mechanisms is necessary for the formation of basic knowledge, as well as to elucidate the mechanisms of occurrence and development of pathological conditions of vessels and the development of methods of their correction.

  8. Polyunsaturated fatty acid biosynthesis is involved in phenylephrine-mediated calcium release in vascular smooth muscle cells.

    PubMed

    Irvine, Nicola A; Lillycrop, Karen A; Fielding, Barbara; Torrens, Christopher; Hanson, Mark A; Burdge, Graham C

    2015-10-01

    Stimulation of vascular smooth muscle (VSM) α1-adrenoceptors induces myosin phosphorylation and vasoconstriction via mobilisation of intracellular calcium and production of specific eicosanoids. Polyunsaturated fatty acid (PUFA) biosynthesis in VSM cells is involved, although the precise mechanism is not known. To address this, we characterised PUFA biosynthesis in VSM cells and determined its role in intracellular calcium release and eicosanoid production. Murine VSM cells converted 18:2n-6 to longer chain PUFA including 22:5n-6. Δ6 (D6d) and Δ5 (D5d) desaturase, and elongase (Elovl) 5 were expressed. Elovl2 was not detected in human, mouse or rat VSM cells, or in rat or mouse aortae, but tit was not associated with hypermethylation of its promoter. D6d or D5d inhibition reduced 18:3n-6 and 20:4n-6 synthesis, respectively, and induced concentration-related decrease in phenylephrine-mediated calcium release, and in PGE2 and PGF2α secretion. Together these findings suggest that PUFA biosynthesis in VSM cells is involved in calcium release associated with vasoconstriction.

  9. Polyunsaturated fatty acid biosynthesis is involved in phenylephrine-mediated calcium release in vascular smooth muscle cells.

    PubMed

    Irvine, Nicola A; Lillycrop, Karen A; Fielding, Barbara; Torrens, Christopher; Hanson, Mark A; Burdge, Graham C

    2015-10-01

    Stimulation of vascular smooth muscle (VSM) α1-adrenoceptors induces myosin phosphorylation and vasoconstriction via mobilisation of intracellular calcium and production of specific eicosanoids. Polyunsaturated fatty acid (PUFA) biosynthesis in VSM cells is involved, although the precise mechanism is not known. To address this, we characterised PUFA biosynthesis in VSM cells and determined its role in intracellular calcium release and eicosanoid production. Murine VSM cells converted 18:2n-6 to longer chain PUFA including 22:5n-6. Δ6 (D6d) and Δ5 (D5d) desaturase, and elongase (Elovl) 5 were expressed. Elovl2 was not detected in human, mouse or rat VSM cells, or in rat or mouse aortae, but tit was not associated with hypermethylation of its promoter. D6d or D5d inhibition reduced 18:3n-6 and 20:4n-6 synthesis, respectively, and induced concentration-related decrease in phenylephrine-mediated calcium release, and in PGE2 and PGF2α secretion. Together these findings suggest that PUFA biosynthesis in VSM cells is involved in calcium release associated with vasoconstriction. PMID:26324193

  10. [Stimulation of gastric mucosa afferents by phenylephrine potentiates anticonvulsive and eliminates sedative action of sodium valproate in the pentylenetetrazol kindling model in rats].

    PubMed

    Serdiuk, S E; Gmiro, V E; Veselkina, O S

    2014-01-01

    Sodium valproate after chronic intragastric administration in the high dose of 100-200 mg/kg eliminates generalized clonic-tonic pentylenetetrazol seizures in 100 % of rats, but only in 33-57 % of rats it prevents local clonic kindling seizures. Strong sedation is induced by the specified doses of sodium valproate. The combined oral chronic administration of phenylephrine in threshold, noneffective alone dose of 0.2 mg/kg and sodium valproate in high doses of 100 mg/kg and 200 mg/kg potentiates anticonvulsive action of sodium valproate, because prevents both clonic-tonic kindling. seizures in 100 % of rats and clonic kindling seizures in 86-100 % of rats, and also it increases in 1.7-1.9 times anticonvulsive activity of valproate. The specified combinations of sodium valproate with phenylephrine do not produce the sedative side effect. The basis of the mechanism of potentiation of anticonvulsive action and elimination of sedative action of sodium valproate in high doses is the stimulation of gastric mucosa afferents by phenylephrine.

  11. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  12. Temporospatial dissociation of Pe subcomponents for perceived and unperceived errors

    PubMed Central

    Endrass, Tanja; Klawohn, Julia; Preuss, Julia; Kathmann, Norbert

    2012-01-01

    Previous research on performance monitoring revealed that errors are followed by an initial fronto-central negative deflection (error-related negativity, ERN or Ne) and a subsequent centro-parietal positivity (error positivity, Pe). It has been shown that error awareness mainly influences the Pe, whereas the ERN seems unaffected by conscious awareness of an error. The aim of the present study was to investigate the relation of ERN and Pe to error awareness in a visual size discrimination task in which errors are not elicited by impulsive responding but by perceptual difficulty. Further, we applied a temporospatial principal component analysis (PCA) to examine whether the temporospatial subcomponents of the Pe would differentially relate to error awareness. Event-related potential (ERP) results were in accordance with earlier studies: a significant error awareness effect was found for the Pe, but not for the ERN. Interestingly, a modulation with error perception on correct trials was found: correct responses considered as incorrect had larger correct-related negativity (CRN) and lager Pe amplitudes than correct responses considered as correct. The PCA yielded two relevant spatial factors accounting for the Pe (latency 300 ms). A temporospatial factor characterized by a centro-parietal positivity varied significantly with error awareness. Of the two temporospatial factors corresponding to ERN and CRN, one factor with central topography varied with response correctness and subjective error perception on correct responses. The PCA results indicate that the error awareness effect is specifically related to the centro-parietal subcomponent of the Pe. Since this component has also been shown to be related to the importance of an error, the present variation with error awareness indicates that this component is sensitive to the salience of an error and that salience secondarily may trigger error awareness. PMID:22737113

  13. Fast HPLC method using ion-pair and hydrophilic interaction liquid chromatography for determination of phenylephrine in pharmaceutical formulations.

    PubMed

    Dousa, Michal; Gibala, Petr

    2010-01-01

    A rapid procedure based on a direct extraction and HPLC determination with fluorescence detection of phenylephrine in pharmaceutical sachets that include a large excess of paracetamol (65 + 1, w/w), ascorbic acid (5 + 1, w/w), and other excipients (aspartame and sucrose) was developed and validated. The final optimized chromatographic method for ion-pair chromatography used an XTerra RP18 column, 3 microm particle size, 50 x 3.0 mm id. The mobile phase consisted of a mixture of acetonitrile and buffer (10 mM sodium octane-1-sulfonate, adjusted with H3PO4 to pH 2.2; 200 + 800, v/v), with a constant flow rate of 0.3 mL/min. The separation was carried out at 30 degrees C, and the injection volume was 3 microL. Fluorescence detection was performed at excitation and emission wavelengths of 275 and 310 nm, respectively. The mobile phase parameters, such as the organic solvent fraction (acetonitrile) in mobile phase as an organic modifier, the concentration of sodium octane-1-sulfonate as a counter-ion, temperature, and pH of mobile phase, were studied. As an alternative to ion-pair chromatography, hydrophilic interaction liquid chromatography (HILIC) was investigated using a Luna HILIC column, 3 microm, 100 x 4.6 mm id. The mobile phase consisted of acetonitrile and buffer (5 mM potassium dihydrogen phosphate, adjusted with H3PO4 to pH 2.5; 750 + 250, v/v) at a flow rate of 0.8 mL/min. The separation was carried out at 25 degrees C, and the injection volume was 5 microL. The proposed method has an advantage of a very simple sample pretreatment, and is much faster than the currently utilized HPLC methods using gradient elution and UV detection. Commercial samples of sachets were successfully analyzed by the proposed HPLC method.

  14. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  15. [Adrenergic beta-agonist intoxication].

    PubMed

    Carrola, Paulo; Devesa, Nuno; Silva, José Manuel; Ramos, Fernando; Alexandrino, Mário B; Moura, José J

    2003-01-01

    The authors describe two clinical cases (father and daughter), observed in the Hospital Urgency with distal tremors, anxiety, palpitations, nausea, headaches and dizziness, two hours after ingestión of cow liver. They also had leucocytosis (with neutrophylia), hypokalemia and hyperglycaemia. After treatment with potassium i.v. and propranolol, the symptoms disappeared. The symptoms recurred at home because the patients didn't take the prescribed medication and persisted for five days, with spontaneous disappearance. The serum of both patients revealed the presence of clenbuterol (65 hg/ml - father and 58 hg/ml - daughter). The animal's liver had a concentration of 1,42 mg/kg. Clenbuterol is a ß-adrenergic agonist with low specificity, with some veterinary indications. However, this substance has been illegally used as a growth's promotor. We intend to alert doctors for this problem, particularly those that work in the Urgency.

  16. β2-agonist therapy in lung disease.

    PubMed

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  17. Surface modification of PE film by DBD plasma in air

    NASA Astrophysics Data System (ADS)

    Ren, C.-S.; Wang, K.; Nie, Q.-Y.; Wang, D.-Z.; Guo, S.-H.

    2008-12-01

    In this paper, surface modification of polyethylene (PE) films is studied by dielectric barrier discharge plasma treatment in air. The treated samples were examined by water contact angle measurement, calculation of surface free energy, Fourier transform infrared attenuated total reflection spectroscopy (FTIR-ATR), X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). The water contact angle changes from the original value of 93.2° to the minimum value of 53.3° and surface free energy increases from 27.3 to 51.89 J/m 2 after treatment time of 50 s. Both ATR and XPS show some oxidized species are introduced into the sample surface by the plasma treatment and that the change tendencies of the water contact angle and surface free energy with the treatment time are the same as that of the oxygen concentration on the treated sample surface. Cu films were deposited on the treated and untreated PE surfaces. The peel adhesive strength between the Cu film and the treated sample is 1.5 MPa, whereas the value is only 0.8 MPa between the Cu film and the untreated PE. SEM pictures show that the Cu film deposited on the plasma treated PE surface is smooth and the crystal grain is smaller, contrarily the Cu film on the untreated PE surface is rough and the crystal grain is larger.

  18. Different affinity states of alpha-1 adrenergic receptors defined by agonists and antagonists in bovine aorta plasma membranes

    SciTech Connect

    Jagadeesh, G.; Deth, R.C.

    1987-11-01

    Evidence for a nonlinear relationship between alpha-1 adrenergic receptor occupancy and tissue responses, together with the finding of different affinity states for agonist binding, has raised the possibility of functional heterogeneity of alpha-1 adrenergic receptors. We have conducted studies to examine: 1) binding characteristics of (/sup 3/H)prazosin, 2) competition of antagonists at these sites and 3) different affinity states of the receptor for agonists and modulation of these states by 5'-guanylylimidodiphosphate (Gpp(NH)p). A plasma membrane-enriched vesicular fraction (F2; 15%/33% sucrose interphase) was prepared from the muscular medial layer of bovine thoracic aorta. (/sup 3/H)Prazosin binding was characterized by a monophasic saturation isotherm (KD = 0.116 nM, Bmax = 112 fmol/mg of protein). Antagonist displacement studies yielded a relative potency order of prazosin greater than or equal to WB4104 much greater than phentolamine greater than corynanthine greater than yohimbine greater than or equal to idazoxan greater than rauwolscine. Competition curves for unlabeled prazosin, WB4101 (2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4 benzodioxane) and phentolamine were shallow and were best modeled to two binding sites with picomolar and nanomolar KD values. Gpp(NH)p was without effect on antagonist affinity. Agonist (epinephrine, norepinephrine and phenylephrine) competition with (/sup 3/H)prazosin binding was biphasic with pseudo-Hill slopes less than 1.0. Binding was best described by a two-site model in which the average contribution of high affinity sites was 23% of total binding. KD values for the high affinity site ranged from 2.9 to 18 nM, and 3.9 to 5.0 microM for the low affinity site.

  19. The evolution of beta2-agonists.

    PubMed

    Sears, M R

    2001-08-01

    Beta-agonists have been widely used in the treatment of asthma for many years Although concerns have been expressed over their safety based largely upon epidemics of increased mortality in asthmatics associated with high doses of isoprenaline in the 1960s and fenoterol in the 1970s and 1980s, the specific beta2-agonists are vital drugs in asthma management. The short-acting beta2-agonists have an important prophylactic role in the prevention of exercise-induced bronchoconstriction, and are essential in the emergency treatment of severe asthma. However, little if any benefit seems to be derived from regular use of short-acting beta2-agonists and regular or frequent use can increase the severity of the condition. The development of beta2-agonists with long-acting properties, such as salmeterol and formoterol, has provided advantages over short-acting beta-agonists, such as prolonged bronchodilation, reduced day- and night-time symptoms and improved quality of sleep, and has reduced the requirement for short-acting beta2-agonists as relief medication. Both drugs are well tolerated and, when added to inhaled corticosteroids, produce greater mprovement in lung function than increased steroid dose alone. Because of its rapid onset of action, formoterol also has the potential to be used for as-needed bronchodilator therapy in asthma.

  20. Amyloid arthropathy revealed by RS3PE syndrome.

    PubMed

    Magy, N; Michel, F; Auge, B; Toussirot, E; Wendling, D

    2000-01-01

    Amyloid arthropathy is a form of primary AL amyloidosis with a monoclonal component in the blood and/or urine, and RS3PE syndrome is acute edematous polysynovitis in subjects older than 60 years. A 74-year-old man was diagnosed with both disorders. He was admitted for benign acute polyarthritis of the hands and feet and reported carpal tunnel symptoms predominating on the right. A synovial biopsy at the right wrist disclosed deposits that stained with Congo red even after potassium permanganate treatment (positive Wright's test). Articular AL amyloidosis was diagnosed. The symptoms resolved under glucocorticoid therapy alone, casting some doubt on their relationship with the amyloidosis. Roentgenograms showed geodes, a feature not present in RS3PE. Whether RS3PE may be among the possible presentations of articular amyloidosis is discussed.

  1. Au-nanoparticles grafted on plasma treated PE

    NASA Astrophysics Data System (ADS)

    Švorčík, V.; Chaloupka, A.; Řezanka, P.; Slepička, P.; Kolská, Z.; Kasálková, N.; Hubáček, T.; Siegel, J.

    2010-03-01

    Polyethylene (PE) surface was treated with Ar plasma. Activated surface was grafted from methanol solution of 1,2-ethanedithiol. Then the sample was immersed into freshly prepared colloid solution of Au-nanoparticles. Finally Au layer was sputtered on the samples. Properties of the modified PE were studied using various methods: AFM, EPR, RBS and nanoindentation. It was shown that the plasma treatment results in degradation of polymer chain (AFM) and creation of free radicals by EPR. After grafting with dithiol, the concentration of free radicals declines. The presence of Au and S in the surface layer after the coating with Au-nanoparticles was proved by RBS. Plasma treatment changes PE surface morphology and increases surface roughness, too. Another significant change in surface morphology and roughness was observed after deposition of Au-nanoparticles. Nanoindentation measurements show that the grafting with Au-nanoparticles increases adhesion of subsequently sputtered Au layer.

  2. Aspirin metabolites are GPR35 agonists.

    PubMed

    Deng, Huayun; Fang, Ye

    2012-07-01

    Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472

  3. Monoterpenoid agonists of TRPV3

    PubMed Central

    Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H

    2007-01-01

    Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement. PMID:17420775

  4. [Safety of beta-agonists in asthma].

    PubMed

    Oscanoa, Teodoro J

    2014-01-01

    Beta 2 agonist bronchodilators (β2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The β2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting β2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting β2 agonists (LABAs) The long-acting bronchodilators β2A (Long acting β2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

  5. "Race" Talk! Tensions and Contradictions in Sport and PE

    ERIC Educational Resources Information Center

    Hylton, Kevin

    2015-01-01

    Background: The universal sport discourses of meritocracy and equality are so engrained that few challenge them. The most cursory interest in sport, Physical Education (PE), and society will reveal that the lived reality is quite different. Racial disparities in the leadership and administration of sport are commonplace worldwide; yet, from…

  6. Temperature, pressure critical in PE line pipe use

    SciTech Connect

    Oney, C.L.

    1988-01-01

    Polyethylene (PE) line pipe is used for low-pressure gas (gathering, supply gas, etc.) and water lines and, in some cases for flow lines. API Spec 15LE specifies minimum requirements for qualification of product and quality control by manufacturers of polyethylene pipe. Spec 15LE also provides guidelines for design of polyethylene. Thermoplastic pipe (PE and PVC) is manufactured by melting resin pellets or powder and extruding the melt through dies. Thermoplastic pipe pressure classes are designated by ''standard dimension ratios'' (SDR). The SDR is the average OD divided by the wall thickness (w.t.). Thus 2 3/8-in. OD pipe (nominal 2 in.) with 0.216-in. w.t. is SDR 11. Nominal 3-in. pipe (3 1/2-in. OD) must have a minimum 0.318-in. w.t. to be SDR 11. Table 5.1 in Spec 15LE lists the most commonly used SDRs. Quality control during manufacture required by Spec 15LE for PE pipe includes short-term hydrostatic tests and dimensional checks. Frequency of tests depend on whether the pipe is coiled or cut into lengths. PE pipe sizes of 3 in. and smaller sizes usually are coiled. In addition, annual tests for verification of long-term pressure rating are required by Spec 15LE.

  7. "Cool PE" and Confronting the Negative Stereotypes of Physical Education

    ERIC Educational Resources Information Center

    Gaudreault, Karen Lux

    2014-01-01

    To change the public's negative perceptions, it may be necessary to change the nature of physical education programming. One way of doing so is by adopting "Cool PE," which refers to physical education that "moves" students, empowers students with choice, and is meaningful to students outside of the gym.

  8. Serving PE Teachers' Professional Learning Experiences in Social Circus

    ERIC Educational Resources Information Center

    Li, Chung

    2010-01-01

    Background: Social circus has long been the folklore in the Chinese culture. Recently, initiatives have been undergoing to introduce it in the school physical education curriculum in Hong Kong. Aims: This article reports a study on 38 PE teachers' professional learning experiences while attending two 2-day workshops respectively concerning…

  9. Building a Model PE Curriculum: Education Reform in Action

    ERIC Educational Resources Information Center

    Moore, John

    2012-01-01

    The blueprint to build a model physical education (PE) curriculum begins by establishing a sound curricular foundation based on a lesson plan template that incorporates clear and concise program goals, the alignment of lessons to state or national content standards, and the collection, analysis and use of objective assessment data that informs…

  10. Dopamine receptor partial agonists and addiction.

    PubMed

    Moreira, Fabricio A; Dalley, Jeffrey W

    2015-04-01

    Many drugs abused by humans acutely facilitate, either directly or indirectly, dopamine neurotransmission in the mesolimbic pathway. As a consequence dopamine receptor agonists and antagonists have been widely investigated as putative pharmacological therapies for addiction. This general strategy, however, has had only limited success due in part to poor treatment adherence and efficacy and the significant adverse effects of dopaminergic medications. In this perspective, we discuss the potential therapeutic use of dopamine receptor partial agonists in addiction, developed initially as antipsychotic agents. Recent research indicates that the dopamine D2 receptor partial agonists, such as aripiprazole, also shows useful ancillary efficacy in several animal models of psychostimulant and opioid addiction. Notably, these findings suggest that unlike full dopamine receptor agonists and antagonists these compounds have low abuse liability and are generally well tolerated. Indeed, partial dopamine agonists attenuate the rewarding properties of opioids without interfering with their analgesic effects. Herein we discuss the utility and potential of dopamine receptor partial agonists as treatments for both stimulant and non-stimulant drug addiction.

  11. PPAR Agonists and Cardiovascular Disease in Diabetes.

    PubMed

    Calkin, Anna C; Thomas, Merlin C

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARalpha agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARgamma agonists, and more recently dual PPARalpha/gamma coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARgamma receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

  12. PPAR Agonists and Cardiovascular Disease in Diabetes

    PubMed Central

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease. PMID:18288280

  13. Beta-agonist- and prostaglandin E1-induced translocation of the beta-adrenergic receptor kinase: evidence that the kinase may act on multiple adenylate cyclase-coupled receptors.

    PubMed Central

    Strasser, R H; Benovic, J L; Caron, M G; Lefkowitz, R J

    1986-01-01

    beta-Adrenergic receptor kinase (beta-AR kinase) is a cytosolic enzyme that phosphorylates the beta-adrenergic receptor only when it is occupied by an agonist [Benovic, J. Strasser, R. H., Caron, M. G. & Lefkowitz, R. J. (1986) Proc. Natl. Acad. Sci. USA 83, 2797-2801.] It may be crucially involved in the processes that lead to homologous or agonist-specific desensitization of the receptor. Stimulation of DDT1MF-2 hamster smooth muscle cells or S49 mouse lymphoma cells with a beta-agonist leads to translocation of 80-90% of the beta-AR kinase activity from the cytosol to the plasma membrane. The translocation process is quite rapid, is concurrent with receptor phosphorylation, and precedes receptor desensitization and sequestration. It is also transient, since much of the activity returns to the cytosol as the receptors become sequestered. Stimulation of beta-AR kinase translocation is a receptor-mediated event, since the beta-antagonist propranolol blocks the effect of agonist. In the kin- mutant of the S49 cells (lacks cAMP-dependent protein kinase), prostaglandin E1, which provokes homologous desensitization of its own receptor, is at least as effective as isoproterenol in promoting beta-AR kinase translocation to the plasma membrane. However, in the DDT1MF-2 cells, which contain alpha 1-adrenergic receptors coupled to phosphatidylinositol turnover, the alpha 1-agonist phenylephrine is ineffective. These results suggest that the first step in homologous desensitization of the beta-adrenergic receptor may be an agonist-promoted translocation of beta-AR kinase from cytosol to plasma membrane and that beta-AR kinase may represent a more general adenylate cyclase-coupled receptor kinase that participates in regulating the function of many such receptors. Images PMID:3018728

  14. The effect of cold storage on the inhibitory action of isoprenaline, phenylephrine and nicotine on the mechanical and membranal activities of guinea-pig taenia caecum

    PubMed Central

    Fukuda, Hiroyuki; Shibata, Shoji

    1972-01-01

    1. The effects of prolonged cold storage on the mechanical and membranal responses to stimulation of α- and β-adrenoceptors by phenylephrine and isoprenaline, respectively, were studied on the guinea-pig taenia caecum. 2. Cold storage invariably caused a decrease in the resting membrane potential, and this effect was enhanced as the duration of treatment was prolonged. 3. After cold storage (18 days) the tissue potassium ion content (89·7 ± 1·7 mmol/kg wet wt.) was decreased to 30·5 ± 1·9 mmol/kg wet wt. whereas that for sodium (69·2 ± 1·4 mmol/kg wet wt.) increased to 134·0 ± 2·3 mmol/kg wet wt. 4. In the fresh preparations, phenylephrine (1 and 2 μM) caused a cessation of spontaneous action potentials, accompanied by hyperpolarization of the membrane and relaxation of the muscle. These effects were markedly diminished after 18 days of cold storage. Isoprenaline (1 and 2 μM) also blocked the action potentials and caused a concomitant muscle relaxation, but in most cases the hyperpolarization was not observed. After 14 days of cold storage these mechanical and membranal changes associated with isoprenaline treatment were not demonstrable in most preparations. 5. Nicotine (5 μM and 50 μM) produced a biphasic effect, cessation of the action potential, hyperpolarization and subsequent relaxation followed by a long lasting depolarization, an accelerated discharge of action potentials and an increase in muscle tension. After a few days of cold storage the hyperpolarization effect disappeared but the intensity of the long-lasting depolarization as well as the contractile effects were increased. After cold storage for more than 7 days, nicotine did not affect mechanical or electrical activity. 6. Dibutyryl 3′5′ cyclic AMP (1 μM to 500 μM) failed to affect the mechanical and electrical activities of taenia caecum. 7. Phenylephrine and isoprenaline had no effect on the high potassiumdepolarized taenia. 8. These observations suggest that the electro

  15. What Can Veterinary Educators Learn from PE Teachers?

    PubMed

    Hofmeister, Erik H; McCullick, Bryan A

    2016-01-01

    Veterinary education requires the training of students in cognitive, affective, and psychomotor domains. However, the veterinary education literature tends to focus more on the cognitive domain, with less emphasis on the affective and psychomotor domains. Physical education (PE) teachers have been teaching psychomotor skills to students for decades using a variety of teaching models. Teaching models provide a framework encompassing theory, student and teacher interactions, instructional themes, research support, and valid assessments. This paper reviews some of the models used by PE teachers, including the Direct Instruction Model, the Cooperative Learning Model, the Personalized System for Instruction, and the Peer Teaching Model. We posit that these models might be particularly helpful for novice teachers in veterinary education settings, providing a structure for the teaching and assessment of psychomotor skills. PMID:27075278

  16. What Can Veterinary Educators Learn from PE Teachers?

    PubMed

    Hofmeister, Erik H; McCullick, Bryan A

    2016-01-01

    Veterinary education requires the training of students in cognitive, affective, and psychomotor domains. However, the veterinary education literature tends to focus more on the cognitive domain, with less emphasis on the affective and psychomotor domains. Physical education (PE) teachers have been teaching psychomotor skills to students for decades using a variety of teaching models. Teaching models provide a framework encompassing theory, student and teacher interactions, instructional themes, research support, and valid assessments. This paper reviews some of the models used by PE teachers, including the Direct Instruction Model, the Cooperative Learning Model, the Personalized System for Instruction, and the Peer Teaching Model. We posit that these models might be particularly helpful for novice teachers in veterinary education settings, providing a structure for the teaching and assessment of psychomotor skills.

  17. Making the Case for Developing New PE-for-Health Pedagogies

    ERIC Educational Resources Information Center

    Armour, Kathleen; Harris, Jo

    2013-01-01

    This article argues for a new direction in research on health education within physical education (PE). Governments are increasingly looking to schools as a convenient form of public health investment. PE is implicated in health because of its core focus on physical activity, but there is little evidence to suggest that PE improves health…

  18. Attitudes toward and Motivation for PE. Who Collects the Benefits of the Subject?

    ERIC Educational Resources Information Center

    Säfvenbom, Reidar; Haugen, Tommy; Bulie, Marte

    2015-01-01

    Background and purpose: Due to attitudinal and motivational aims in the national curriculum, and to lack of research on adolescents' experiences with physical education (PE) in Norway, the purposes of this study were to (1) attain data on attitudes toward PE and self-determined motivation for PE among a representative sample of adolescents (N =…

  19. Targeting the Body and the Mind: Evaluation of a P.E. Curriculum Intervention for Adolescents

    ERIC Educational Resources Information Center

    Loukaitou-Sideris, Anastasia

    2015-01-01

    P.E. classes are often the only opportunity for inner-city youth to engage in physical activity, but budget cuts and pressure to perform well on standardized tests has made P.E. an afterthought for many school administrators. This study evaluated the effectiveness of a new P.E. curriculum in five Los Angeles inner-city schools. Interviews were…

  20. Failure analysis of retrieved PE-UHMW acetabular liners.

    PubMed

    Laska, Anna; Archodoulaki, Vasiliki-Maria; Duscher, Bernadette

    2016-08-01

    Ultra-high molecular weight polyethylene (PE-UHMW) acetabular liners have a limited lifespan in a patient's body. There are many factors affecting the performance of the implant and furthermore the properties of the polymeric material are changing after implantation. In this work material changes according to structure and morphology and their implication on mechanical properties are in focus. The physical and mechanical properties of ten crosslinked (xL) PE-UHMW and nine conventional (conv) gamma-sterilized PE-UHMW hip components, used as sliding surface in total hip joint replacement, with different in-vivo times are compared. The evaluation of the retrieved acetabular liners is performed in view of crosslinking and conventional gamma-sterilization but also in terms of the influence of gender concerning alteration in properties. The oxidative degradation in the PE-UHMW is investigated by means of Fourier Transformed Infrared Spectroscopy (FTIR). The characterization of the morphology is carried out via differential scanning calorimetry (DSC). A depth profile of the micro-hardness and elastic modulus is taken over the cross-section of the components in order to find the influence of chemical constitution and morphology on the micro-mechanical properties. It could be shown that crosslinking and oxidative degradation influence the degree of crystallinity of the polymer. Oxidation occurs for both types of the material due to in-vivo time. Higher degree of crystallinity can be correlated to higher hardness and indentation modulus. No unequivocal superiority of crosslinked over conventional liners can be observed. The influence of sex concerning alteration of the evaluated properties matters but need to be further investigated. PMID:26849029

  1. The new geographic information system in ETVA VI.PE.

    NASA Astrophysics Data System (ADS)

    Xagoraris, Zafiris; Soulis, George

    2016-08-01

    ETVA VI.PE. S.A. is a member of the Piraeus Bank Group of Companies and its activities include designing, developing, exploiting and managing Industrial Areas throughout Greece. Inside ETVA VI.PE.'s thirty-one Industrial Parks there are currently 2,500 manufacturing companies established, with 40,000 employees and € 2.5 billion of invested funds. In each one of the industrial areas ETVA VI.PE guarantees the companies industrial lots of land (sites) with propitious building codes and complete infrastructure networks of water supply, sewerage, paved roads, power supply, communications, cleansing services, etc. The development of Geographical Information System for ETVA VI.PE.'s Industrial Parks started at the beginning of 1992 and consists of three subsystems: Cadastre, that manages the information for the land acquisition of Industrial Areas; Street Layout - Sites, that manages the sites sold to manufacturing companies; Networks, that manages the infrastructure networks (roads, water supply, sewerage etc). The mapping of each Industrial Park is made incorporating state-of-the-art photogrammetric, cartographic and surveying methods and techniques. Passing through the phases of initial design (hybrid GIS) and system upgrade (integrated Gis solution with spatial database), the system is currently operating on a new upgrade (integrated gIS solution with spatial database) that includes redesigning and merging the system's database schemas, along with the creation of central security policies, and the development of a new web GIS application for advanced data entry, highly customisable and standard reports, and dynamic interactive maps. The new GIS bring the company to advanced levels of productivity and introduce the new era for decision making and business management.

  2. SCoPE: an efficient method of Cosmological Parameter Estimation

    SciTech Connect

    Das, Santanu; Souradeep, Tarun E-mail: tarun@iucaa.ernet.in

    2014-07-01

    Markov Chain Monte Carlo (MCMC) sampler is widely used for cosmological parameter estimation from CMB and other data. However, due to the intrinsic serial nature of the MCMC sampler, convergence is often very slow. Here we present a fast and independently written Monte Carlo method for cosmological parameter estimation named as Slick Cosmological Parameter Estimator (SCoPE), that employs delayed rejection to increase the acceptance rate of a chain, and pre-fetching that helps an individual chain to run on parallel CPUs. An inter-chain covariance update is also incorporated to prevent clustering of the chains allowing faster and better mixing of the chains. We use an adaptive method for covariance calculation to calculate and update the covariance automatically as the chains progress. Our analysis shows that the acceptance probability of each step in SCoPE is more than 95% and the convergence of the chains are faster. Using SCoPE, we carry out some cosmological parameter estimations with different cosmological models using WMAP-9 and Planck results. One of the current research interests in cosmology is quantifying the nature of dark energy. We analyze the cosmological parameters from two illustrative commonly used parameterisations of dark energy models. We also asses primordial helium fraction in the universe can be constrained by the present CMB data from WMAP-9 and Planck. The results from our MCMC analysis on the one hand helps us to understand the workability of the SCoPE better, on the other hand it provides a completely independent estimation of cosmological parameters from WMAP-9 and Planck data.

  3. Failure analysis of retrieved PE-UHMW acetabular liners.

    PubMed

    Laska, Anna; Archodoulaki, Vasiliki-Maria; Duscher, Bernadette

    2016-08-01

    Ultra-high molecular weight polyethylene (PE-UHMW) acetabular liners have a limited lifespan in a patient's body. There are many factors affecting the performance of the implant and furthermore the properties of the polymeric material are changing after implantation. In this work material changes according to structure and morphology and their implication on mechanical properties are in focus. The physical and mechanical properties of ten crosslinked (xL) PE-UHMW and nine conventional (conv) gamma-sterilized PE-UHMW hip components, used as sliding surface in total hip joint replacement, with different in-vivo times are compared. The evaluation of the retrieved acetabular liners is performed in view of crosslinking and conventional gamma-sterilization but also in terms of the influence of gender concerning alteration in properties. The oxidative degradation in the PE-UHMW is investigated by means of Fourier Transformed Infrared Spectroscopy (FTIR). The characterization of the morphology is carried out via differential scanning calorimetry (DSC). A depth profile of the micro-hardness and elastic modulus is taken over the cross-section of the components in order to find the influence of chemical constitution and morphology on the micro-mechanical properties. It could be shown that crosslinking and oxidative degradation influence the degree of crystallinity of the polymer. Oxidation occurs for both types of the material due to in-vivo time. Higher degree of crystallinity can be correlated to higher hardness and indentation modulus. No unequivocal superiority of crosslinked over conventional liners can be observed. The influence of sex concerning alteration of the evaluated properties matters but need to be further investigated.

  4. Polyelectrolyte (PE) induced interactions between Charged and zwitterionic Colloids

    NASA Astrophysics Data System (ADS)

    Pryamitsyn, Victor; Ganesan, Venkat

    2014-03-01

    A numerical self-consistent field (SCF) theory approach was developed for studying mixture of polyelectrolytes with charged and uncharged nanoparticles. Such an approach was used to analyze within the mean-field limit the polyelectrolyte-mediated effective interactions between the particles. The system considered allows for the local PE and particle charges to be defined by the local concentration of ionizable on groups on the particles and polyelectrolytes, ambient conditions like pH and the local electrostatic potential. Calculation of the free energy of a system of one, two and three particles in the polyelectrolyte solution allowdd us to calculate the particle insertion free energy, two and three body particle-particle interactions as a function of the properties of solution, polymer-particle interactions and the particle size. For the situation involving acidic PE and a base type positively charged particles, the PE mediated particle-particle interaction is purely repulsive for the larger particle-particle distances at low polymer concentrations. At short-particle particle distances and/or higher polyelectrolyte concentrations the particle-particle interaction becomes a depletion-type attraction. For Zwitterionic positively chaged paticles particles we have found a a range

  5. beta2-Agonists at the Olympic Games.

    PubMed

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  6. Comparison study of PE epitaxy on carbon nanotubes and graphene oxide and PE/graphene oxide as amphiphilic molecular structure for solvent separation

    NASA Astrophysics Data System (ADS)

    He, Linghao; Zheng, Xiaoli; Xu, Qun; Chen, Zhimin; Fu, Jianwei

    2012-03-01

    Carbon nanotubes (CNTs) and graphene nanosheets, as one-dimensional and two-dimensional carbon-based nanomaterials respectively, have different abilities to induce the polymer crystallization. In this study, hybrid materials, polyethylene (PE) decorating on CNTs and graphene oxide (GO), were prepared by a facile and efficient method using supercritical carbon dioxide (SC CO2) as anti-solvent. And the morphology and crystallization behavior of PE on CNTs and GO were investigated by transmission electron microscopy, Fourier transform infrared spectroscopy, Raman spectra, wide angle X-ray diffraction, and differential scanning calorimetry. Although both CNTs and GO could act as nucleating agents to induce PE epitaxial growth, CNTs were decorated by PE lamellar crystals forming nanohybrid "shish-kebab" (NHSK) structure, whereas GO sheets were only decorated with petal-like PE crystals. The varying morphologies of the nanohybrids depend on the PE epitaxy and the interactions between polymer chains and substrates. High surface curvature and the perfect ordered crystal structure of CNTs make PE crystals periodically grow on CNTs. While PE crystals grow and form multiple orientation-lamellae on GO due to the lattice matching and complex interactions between PE chains and GO. In addition, our experimental results show an interesting and evident stratification phenomenon for the PE/GO hybrid material, implying that GO decorated by PE have a screening function for the solvents. We anticipate that this work can widen the area of functionalization of carbon-based nanomaterials with a controlled means by an environmentally benign method, which are important for the functional design in nanodevice applications.

  7. Identification of Selective ERRγ Inverse Agonists.

    PubMed

    Kim, Jina; Im, Chun Young; Yoo, Eun Kyung; Ma, Min Jung; Kim, Sang-Bum; Hong, Eunmi; Chin, Jungwook; Hwang, Hayoung; Lee, Sungwoo; Kim, Nam Doo; Jeon, Jae-Han; Lee, In-Kyu; Jeon, Yong Hyun; Choi, Hueng-Sik; Kim, Seong Heon; Cho, Sung Jin

    2016-01-12

    GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

  8. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

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

    SciTech Connect

    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

    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.

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

    PubMed

    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, Frank; Parks, Derek J; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Bruce Wisely, G

    2009-08-15

    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.

  11. Optimum Topical Delivery of Adrenergic Agonists to Oral Mucosa Vasculature

    PubMed Central

    Soref, Cheryl M.

    2015-01-01

    Purpose Identify an orotopical vehicle to deliver an α-adrenergic vasoconstrictor to submucosal vasculature that is readily palatable to cancer/bone marrow transplant patients that suppresses chemo-radiotherapy-associated oral mucositis. Methods A [3H] norepinephrine ligand binding assay was developed to quantify receptor binding in hamster oral mucosa. Vehicle components (alcohols, polyols, cellulose, PVP) were tested versus [3H] norepinephrine binding. Vehicle refinement was also done to mask phenylephrine bitter taste and achieve human subject acceptance. The optimized vehicle was tested with α-adrenergic active agents to suppress radiation-induced oral mucositis in mice. Results The ligand binding assay quantified dose- and time-dependent, saturable binding of [3H] norepinephrine. An ethanol:glycerol:propylene glycol:water (6:6:8:80) vehicle provided the best delivery and binding. Further vehicle modification (flavoring and sucralose) yielded a vehicle with excellent taste scores in humans. Addition of phenylephrine, norepinephrine or epinephrine to the optimized vehicle and painting into mouse mouths 20 min before 19 Gy irradiation conferred significant suppression of the weight loss (P < 0.001) observed in mice who received oral vehicle. Conclusion We identified a highly efficient vehicle for the topical delivery of phenylephrine to the oral mucosa of both hamster and human subjects. This will enable its testing to suppress oral mucositis in an upcoming human clinical trial. PMID:25079392

  12. "We Should Assess the Students in More Authentic Situations": Swedish PE Teacher Educators' Views of the Meaning of Movement Skills for Future PE Teachers

    ERIC Educational Resources Information Center

    Backman, Erik; Pearson, Phil

    2016-01-01

    The question of what knowledge a student of Physical Education (PE) needs to develop during PE teacher education (PETE) was recently discussed. One form of knowledge is the movement practices that students must meet during their education. Given the limited time, a delicate matter is whether to prioritize movement knowledge and consider it as…

  13. Evolution of Smooth Tubercle Bacilli PE and PE_PGRS Genes: Evidence for a Prominent Role of Recombination and Imprint of Positive Selection

    PubMed Central

    Fabre, Michel; Gutierrez, Maria Cristina; Mardassi, Helmi

    2013-01-01

    Background PE and PE_PGRS are two mycobateria-restricted multigene families encoding membrane associated and secreted proteins that have expanded mainly in the pathogenic species, notably the Mycobacterium tuberculosis complex (MTBC). Several lines of evidence attribute to PE and PE_PGRS genes critical roles in mycobacterial pathogenicity. To get more insight into the nature of these genes, we sought to address their evolutionary trajectories in the group of smooth tubercle bacilli (STB), the putative ancestor of the clonal MTBC. Methodology/Principal Findings By focussing on six polymorphic STB PE/PE_PGRS genes, we demonstrate significant incongruence among single gene genealogies and detect strong signals of recombination using various approaches. Coalescent-based estimation of population recombination and mutation rates (ρ and θ, respectively) indicates that the two mechanisms are of roughly equal importance in generating diversity (ρ/θ = 1.457), a finding in a marked contrast to house keeping genes (HKG) whose evolution is chiefly brought about by mutation (ρ/θ = 0.012). In comparison to HKG, we found 15 times higher mean rate of nonsynonymous substitutions, with strong evidence of positive selection acting on PE_PGRS62 (dN/dS = 1.42), a gene that has previously been shown to be essential for mycobacterial survival in macrophages and granulomas. Imprint of positive selection operating on specific amino acid residues or along branches of PE_PGRS62 phylogenetic tree was further demonstrated using maximum likelihood- and covarion-based approaches, respectively. Strikingly, PE_PGR62 proved highly conserved in present-day MTBC strains. Conclusions/Significance Overall the data indicate that, in STB, PE/PE_PGRS genes have undergone a strong diversification process that is speeded up by recombination, with evidence of positive selection. The finding that positive selection involved an essential PE_PGRS gene whose sequence appears to be driven to

  14. Gamma radiation induced degradation in PE-PP block copolymer

    SciTech Connect

    Ravi, H. R.; Sreepad, H. R.; Ahmed, Khaleel; Govindaiah, T. N.

    2012-06-05

    In the present investigation, effect of gamma irradiation on the PP-PE block copolymer has been studied. The polymer has been subjected to gamma irradiation from 100 to 500 Mrad dosages. Characterization of the polymer using XRD and FTIR was done both before irradiation and after irradiation in each step. Effect of irradiation on the electrical properties of the material has also been studied. FTIR study shows that the sample loses C - C stretching mode of vibration but gains C=C stretching mode of vibration after irradiation. Present investigation clearly indicates that though the electrical conductivity increases in the material, it undergoes degradation and shows brittleness due to irradiation.

  15. Combustion of PMMA, PE, and PS in a ramjet

    SciTech Connect

    van der Geld, C.W.M. ); Korting, P.A.O.G. ); Wijchers, T. )

    1990-03-01

    This paper reports the combustion behavior of polymethylmetharcrylate (PMMA), polyethylene (PE), and polystyrene (PS) with air investigated in a connected pipe test facility; spectroscopy showed the presence of OH, C{sub 2}, and CH and temperatures between 1300 and 3000 K during combustion. Particular attention was focused on regression rate and combustion efficiency and the role of temperature and soot production. The present investigation gives an understanding of the most important phenomena that control (or emanate from) the combustion of a cylindrical solid fuel with a rearward facing step, and this has application for solid fuel ramjets, the safe burning of toxic waste, and hot gas generators. The results are summarized.

  16. Local void and slip model used in BODYFIT-2PE

    SciTech Connect

    Chen, B.C.J.; Chien, T.H.; Kim, J.H.; Lellouche, G.S.

    1983-01-01

    A local void and slip model has been proposed for a two-phase flow without the need of fitting any empirical parameters. This model is based on the assumption that all bubbles have reached their terminal rise velocities in the two-phase region. This simple model seems to provide reasonable calculational results when compared with the experimental data and other void and slip models. It provides a means to account for the void and slip of a two-phase flow on a local basis. This is particularly suitable for a fine mesh thermal-hydraulic computer program such as BODYFIT-2PE.

  17. Gamma radiation induced degradation in PE-PP block copolymer

    NASA Astrophysics Data System (ADS)

    Ravi, H. R.; Sreepad, H. R.; Ahmed, Khaleel; Govindaiah, T. N.

    2012-06-01

    In the present investigation, effect of gamma irradiation on the PP-PE block copolymer has been studied. The polymer has been subjected to gamma irradiation from 100 to 500 Mrad dosages. Characterization of the polymer using XRD and FTIR was done both before irradiation and after irradiation in each step. Effect of irradiation on the electrical properties of the material has also been studied. FTIR study shows that the sample loses C - C stretching mode of vibration but gains C=C stretching mode of vibration after irradiation. Present investigation clearly indicates that though the electrical conductivity increases in the material, it undergoes degradation and shows brittleness due to irradiation.

  18. Cosmic ray anisotropies to 5 PeV

    SciTech Connect

    Erlykin, A. D.; Wolfendale, A. W. E-mail: a.w.wolfendale@durham.ac.uk

    2013-04-01

    Several large cosmic ray (CR) detectors have recently provided data on the arrival directions of CR, which taken together with previous data recorded over many decades allow the amplitude and phase of the first harmonic to be derived with reasonable precision and up to higher energies. We find a high degree of consistency amongst the various measurements. The new data indicate that at an energy above ∼ 0.1 PeV a change of the CR anisotropy sets in. The amplitude of the first harmonic, which rises to 3 TeV, then diminishes and begins to rise again. The direction of the phase also changes to the opposite one. A measure of understanding follows from the use of two-dimensional maps of cosmic ray excesses over the mean background. When the energy of cosmic rays approaches the PeV region, the excess of cosmic rays moves from the Galactic Anti-Centre to the opposite direction of the Galactic Centre. The possible role of such potential cosmic ray sources as the supernovae Monogem Ring and Vela, which could help to explain some of the observed results, is discussed.

  19. New software forecasts service life and integrity of PE piping

    SciTech Connect

    Kuhlman, C.J.; Kanninen, M.F.; Mamoun, M.M.

    1995-04-01

    New software from the Gas Research Institute (GRI) is especially useful to local distribution companies (LDCs) who have older plastic gas pipe installations and are in warmer climates. The new software, LIFESPAN, enables these companies to predict pipe lifetimes and plan for long range replacement programs. LIFESPAN also is useful for assessing the operational benefits by changing scenarios, such as: what will the pipe lifetime be if pressure is increased (or reduced) by 25%? In addition to its ability to forecast the longterm performance of polyethylene (PE) gas pipe materials by using data from short-term, laboratory-based slow crack growth (SCG) tests, LIFESPAN also can evaluate existing piping systems. Also, it can be used to design new systems, select PE gas piping materials in a cost effective manner for specific operating conditions, and improve inspection and maintenance operations. With information from LIFESPAN, pipe replacements, repairs, or rehabilitation can be done in a scheduled manner for effective use of manpower and equipment resources.

  20. Recent advances in the discovery of alpha1-adrenoceptor agonists.

    PubMed

    Bishop, Michael J

    2007-01-01

    The alpha(1) adrenoceptors are three of nine well-characterized receptors that are activated by epinephrine and norepinephrine. Agonists acting at the alpha(1) adrenoceptors produce numerous physiological effects, and are used therapeutically for several indications. Many known alpha(1) adrenoceptor agonists are alpha(1A) selective, but the discovery of highly selective alpha(1B) and alpha(1D) adrenoceptor agonists has proven to be an extremely difficult goal to achieve. This review will focus on recent advances in the discovery, development and clinical utility of subtype-specific alpha(1) agonists as well as contributions to our understanding of agonist-receptor interactions.

  1. Increased agonist affinity at the mu-opioid receptor induced by prolonged agonist exposure

    PubMed Central

    Birdsong, William T.; Arttamangkul, Seksiri; Clark, Mary J.; Cheng, Kejun; Rice, Kenner C.; Traynor, John R.; Williams, John T.

    2013-01-01

    Prolonged exposure to high-efficacy agonists results in desensitization of the mu opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling, however the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased following prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa 594, was unaffected by similar agonist pre-treatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knockout animals increased following treatment of the cells with the desensitization protocol. Thus, opioid receptors were “imprinted” with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long lasting but reversible conformational change in the receptor. PMID:23447620

  2. Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro.

    PubMed

    Dietz, Birgit M; Mahady, Gail B; Pauli, Guido F; Farnsworth, Norman R

    2005-08-18

    Insomnia is the most frequently encountered sleep complaint worldwide. While many prescription drugs are used to treat insomnia, extracts of valerian (Valeriana officinalis L., Valerianaceae) are also used for the treatment of insomnia and restlessness. To determine novel mechanisms of action, radioligand binding studies were performed with valerian extracts (100% methanol, 50% methanol, dichloromethane [DCM], and petroleum ether [PE]) at the melatonin, glutamate, and GABA(A) receptors, and 8 serotonin receptor subtypes. Both DCM and PE extracts had strong binding affinity to the 5-HT(5a) receptor, but only weak binding affinity to the 5-HT(2b) and the serotonin transporter. Subsequent binding studies focused on the 5-HT(5a) receptor due to the distribution of this receptor in the suprachiasmatic nucleus of the brain, which is implicated in the sleep-wake cycle. The PE extract inhibited [(3)H]lysergic acid diethylamide (LSD) binding to the human 5-HT(5a) receptor (86% at 50 microg/ml) and the DCM extract inhibited LSD binding by 51%. Generation of an IC(50) curve for the PE extract produced a biphasic curve, thus GTP shift experiments were also performed. In the absence of GTP, the competition curve was biphasic (two affinity sites) with an IC(50) of 15.7 ng/ml for the high-affinity state and 27.7 microg/ml for the low-affinity state. The addition of GTP (100 microM) resulted in a right-hand shift of the binding curve with an IC(50) of 11.4 microg/ml. Valerenic acid, the active constituent of both extracts, had an IC(50) of 17.2 microM. These results indicate that valerian and valerenic acid are new partial agonists of the 5-HT(5a) receptor. PMID:15921820

  3. Angiotensin receptor agonistic autoantibody-mediated TNF-α induction contributes to increased soluble endoglin production in preeclampsia

    PubMed Central

    Zhou, Cissy Chenyi; Irani, Roxanna A.; Zhang, Yujin; Blackwell, Sean; Mi, Tiejuan; Wen, Jiaming; Shelat, Harnath; Geng, Yong-Jian; Ramin, Susan M.; Kellems, Rodney E.; Xia, Yang

    2010-01-01

    Background Preeclampsia (PE) is a prevalent life-threatening hypertensive disorder of pregnancy. The circulating antiangiogenic factor, soluble endoglin (sEng), is elevated in the blood circulation of women with PE and contributes to disease pathology. However, the underlying mechanisms responsible for its induction in PE are unknown. Methods and Results Here we discovered that a circulating autoantibody, the angiotensin receptor agonistic autoantibody (AT1-AA), stimulates sang production via AT1 angiogenesis receptor activation in pregnant mice but not non-pregnant mice. Subsequently we demonstrate that the placenta is a major source contributing to sang induction in vivo and AT1-AA injected pregnant mice display the impaired placental angiogenesis. Using drug screening, we identified TNF-α as a circulating factor increased in the serum of autoantibody-injected pregnant mice contributing to AT1-AA-mediated sang induction in human umbilical vascular endothelial cells (HUVECs). Subsequently, among all the drugs screened we found that hemin, an inducer of heme oxygenase-1 (HO-1), functions as a break to control AT1-AA mediated sang induction by suppressing TNF-α signaling in Havocs. Finally, we demonstrated that AT1-AA-mediated decreased angiogenesis seen in human placenta villous explants was attenuated by TNF-α neutralizing antibodies, soluble TNF-α receptors and hemi, an inducer of home oxygenase, by abolishing both sang and sFlt-1 induction. Conclusions Our findings demonstrate that AT1-AA-mediated TNF-α induction, by overcoming its negative regulator, HO-1, is a key underlying mechanism responsible for impaired placenta angiogenesis by inducing both sEng and sFlt-1 secretion from human villous explants and provide important new targets for diagnosis and therapeutic intervention in the management of PE. PMID:20065159

  4. Agonistic and reproductive interactions in Betta splendens.

    PubMed

    Bronstein, P M

    1984-12-01

    Reproductive and agonistic behaviors in Siamese fighting fish were investigated in eight experiments, and some consequences and determinants of these sequences were isolated. First, fights and the formation of dominance-subordinancy relations were studied. Second, it was determined that large body size as well as males' prior residency in a tank produced an agonistic advantage; the magnitude of this advantage was positively related to the duration of residency. Third, the prior-residency effect in Bettas was determined by males' familiarity with visual and/or tactile cues in their home tanks. Fourth, dominant males had greater access to living space and were more likely to display at a mirror, build nests, and approach females than were subordinates. Finally, it was discovered that chemical cues associated with presumedly inert plastic tank dividers influence Bettas' social behavior.

  5. Effect of the administration of Solanum nigrum fruit on blood glucose, lipid profiles, and sensitivity of the vascular mesenteric bed to phenylephrine in streptozotocin-induced diabetic rats

    PubMed Central

    Sohrabipour, Shahla; Kharazmi, Fatemah; Soltani, Nepton; Kamalinejad, Mohammad

    2013-01-01

    Background Solanum nigrum fruit is traditionally used in Asia to manage, control, and treat diabetes but there is no scientific evidence of the efficacy of Solanum nigrum fruit in treatment of diabetes. We designed this study to investigate the effect of the administration of oral doses of aqueous extract from Solanum nigrum fruit on plasma glucose, lipid profiles, and the sensitivity of the vascular mesenteric bed to Phenylephrine in diabetic and non-diabetic rats. Material/Methods Animals were divided into 5 groups (n=10): 2 groups served as non-diabetic controls (NDC), and the other groups had diabetes induced with a single injection of streptozotocin (STZ). Solanum nigrum-treated chronic diabetic (CD-SNE) and Solanum nigrum-treated controls (ND-SNE) received 1g/l of Solanum nigrum added to drinking water for 8 weeks. The mesenteric vascular beds were prepared using the McGregor method. Results Administration of Solanum nigrum caused Ca/Mg ratio, plasma glucose, high-density lipoprotein (HDL), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), total cholesterol, and triglyceride concentrations to return to normal levels, and was shown to decrease alteration in vascular reactivity to vasoconstrictor agents. Conclusions Our results support the hypothesis that Solanum nigrum could play a role in the management of diabetes and the prevention of vascular complications in STZ-induced diabetic rats. PMID:23660828

  6. Kinetic properties of C-11 phenylephrine in isolated rat heart: Effects of di-deuterium substitution, age, MAO inhibition, and reserpine

    SciTech Connect

    Raffel, D.M.; Rosario, R.B. del; Tluczek, L.

    1995-05-01

    Elimination of the {alpha}-carbon CH{sub 3} group from C-11 hydroxyephedrine (HED) yields a new radiotracer for cardiac sympathetic neurons: C-11 phenylephrine (PHEN). This small structural change has profound effects on the tracer kinetics - HED is not metabolized by neuronal monoamine oxidase (MAO), while PHEN is an excellent MAO substrate. To assess the influence of MAO metabolism and vesicular storage on PHEN kinetics a series of constant infusion studies were performed. Isolated working rat hearts were perfused under control conditions for 25 min, then switched to a second perfusate circuit containing PHEN at tracer concentrations. PHEN was infused for 10 min then the heart switched back to normal perfusate to effect washout of PHEN. The amount of PHEN in the heart was externally measured using coinsidence detection. The data between 1 and 4 min were used to estimate an uptake constant, K{sub up} (ml/min/g wet). Washout data were fit to multiple exponentials. Several studies were done: (1) To slow MAO metabolism, the dideuterium substituted analog C-11 D{sub 2-}PHEN was made and studied as described above. (2) For both tracers, the effect of age on washout kinetics was studied as rat heart MAO levels steadily increase throughout the animal`s life. (3) The effect of MAO inhibition was studied using 100 {mu}M pargyline throughout the experiment. (4) Reserpine pretreated rats were used to assess the influence of vesicular storage on tracer kinetics.

  7. Clinical assessment of the warming sensation accompanying flavor 316282 in a cold and cough syrup containing paracetamol, phenylephrine hydrochloride, and guaifenesin

    PubMed Central

    Monnet, Joëlle

    2014-01-01

    Objective: The primary objective was to assess the warming sensation caused by flavor 316282 in a cold and cough product in the target population. Methods: A single-cohort, single-treatment arm, open-label study. Subjects received one 30-mL dose of syrup containing flavor 316282, paracetamol, phenylephrine hydrochloride, and guaifenesin and recorded onset and disappearance of any warming sensation in the mouth/throat. Subjects’ assessment of strength and appeal of the sensation, taste, texture, and acceptability of the product as a cold and cough remedy was investigated using questionnaires. Results: A total of 51 subjects were included; 47 (92.1%) experienced a warming sensation. The median duration of the warming sensation was 100 s (95% confidence interval = 82 s, 112 s). The majority of subjects rated the syrup as excellent, good, or fair for treatment of cough and cold symptoms (96.1%), taste (80.4%), and texture (98.0%). There were no safety concerns, and the syrup was well tolerated. Most subjects liked the warming sensation. Conclusions: Flavor 316282 in a cold and cough syrup is associated with a warming sensation. The syrup is well tolerated, safe, and palatable. PMID:26770699

  8. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  9. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits.

  10. TG/FTIR analysis on co-pyrolysis behavior of PE, PVC and PS.

    PubMed

    Wu, Jingli; Chen, Tianju; Luo, Xitao; Han, Dezhi; Wang, Zhiqi; Wu, Jinhu

    2014-03-01

    The pyrolysis and co-pyrolysis behaviors of polyethylene (PE), polystyrene (PS) and polyvinyl chloride (PVC) under N2 atmosphere were analyzed by Thermal gravimetric/Fourier transform infrared (TG/FTIR). The volatile products were analyzed to investigate the interaction of the plastic blends during the thermal decomposition process. The TGA results showed that the thermal stability increased followed by PVC, PS and PE. The pyrolysis process of PE was enhanced when mixed with PS. However, PS was postponed when mixed with PVC. As for PE and PVC, mutual block was happened when mixed together. The FTIR results showed that the free radical of the decomposition could combine into a stable compound. When PE mixed with PVC or PS, large amount of unsaturated hydrocarbon groups existed in products while the content of alkynes was decreased. The methyl (-CH3) and methylene (-CH2-) bonds were disappeared while PVC mixed with PE.

  11. Reduction in renal blood flow following administration of norepinephrine and phenylephrine in septic rats treated with Kir6.1 ATP-sensitive and KCa1.1 calcium-activated K+ channel blockers.

    PubMed

    da Rosa Maggi Sant'Helena, Bruna; Guarido, Karla L; de Souza, Priscila; Crestani, Sandra; da Silva-Santos, J Eduardo

    2015-10-15

    We evaluated the effects of K+ channel blockers in the vascular reactivity of in vitro perfused kidneys, as well as on the influence of vasoactive agents in the renal blood flow of rats subjected to the cecal ligation and puncture (CLP) model of sepsis. Both norepinephrine and phenylephrine had the ability to increase the vascular perfusion pressure reduced in kidneys of rats subjected to CLP at 18 h and 36 h before the experiments. The non-selective K+ channel blocker tetraethylammonium, but not the Kir6.1 blocker glibenclamide, normalized the effects of phenylephrine in kidneys from the CLP 18 h group. Systemic administration of tetraethylammonium, glibenclamide, or the KCa1.1 blocker iberiotoxin, did not change the renal blood flow in control or septic rats. Norepinephrine or phenylephrine also had no influence on the renal blood flow of septic animals, but its injection in rats from the CLP 18 h group previously treated with either glibenclamide or iberiotoxin resulted in an exacerbated reduction in the renal blood flow. These results suggest an abnormal functionality of K+ channels in the renal vascular bed in sepsis, and that the blockage of different subtypes of K+ channels may be deleterious for blood perfusion in kidneys, mainly when associated with vasoactive drugs.

  12. Reduction in renal blood flow following administration of norepinephrine and phenylephrine in septic rats treated with Kir6.1 ATP-sensitive and KCa1.1 calcium-activated K+ channel blockers.

    PubMed

    da Rosa Maggi Sant'Helena, Bruna; Guarido, Karla L; de Souza, Priscila; Crestani, Sandra; da Silva-Santos, J Eduardo

    2015-10-15

    We evaluated the effects of K+ channel blockers in the vascular reactivity of in vitro perfused kidneys, as well as on the influence of vasoactive agents in the renal blood flow of rats subjected to the cecal ligation and puncture (CLP) model of sepsis. Both norepinephrine and phenylephrine had the ability to increase the vascular perfusion pressure reduced in kidneys of rats subjected to CLP at 18 h and 36 h before the experiments. The non-selective K+ channel blocker tetraethylammonium, but not the Kir6.1 blocker glibenclamide, normalized the effects of phenylephrine in kidneys from the CLP 18 h group. Systemic administration of tetraethylammonium, glibenclamide, or the KCa1.1 blocker iberiotoxin, did not change the renal blood flow in control or septic rats. Norepinephrine or phenylephrine also had no influence on the renal blood flow of septic animals, but its injection in rats from the CLP 18 h group previously treated with either glibenclamide or iberiotoxin resulted in an exacerbated reduction in the renal blood flow. These results suggest an abnormal functionality of K+ channels in the renal vascular bed in sepsis, and that the blockage of different subtypes of K+ channels may be deleterious for blood perfusion in kidneys, mainly when associated with vasoactive drugs. PMID:26277325

  13. Classification of principal connections on W{sup r}PE

    SciTech Connect

    Vondra, Jan

    2008-11-18

    We assume a vector bundle E{yields}M and the principal bundle PE of frames of E. Let K be a general linear connection on E and let {lambda} be a linear connection on M. We classify all connections on W{sup r}PE = P{sup r}Mx{sub M}J{sup r}PE naturally given by K and {lambda}.

  14. PE-induced apoptosis in SMMC-7721 cells: Involvement of Erk and Stat signalling pathways

    PubMed Central

    XUE, LI; LI, MING; CHEN, TENG; SUN, HAIFENG; ZHU, JIE; LI, XIA; WU, FENG; WANG, BIAO; LI, JUPING; CHEN, YANJIONG

    2014-01-01

    Emerging evidence indicates that the redistribution of phosphatidylethanolamine (PE) across the bilayer of the plasma membrane is an important molecular marker for apoptosis. However, the effect of PE on apoptosis and the underlying mechanism of PE remain unclear. In the current study, MTT and flow cytometric assays were used to examine the effects of PE on apoptosis in SMMC-7721 cells. The level of mitochondrial membrane potential (ΔΨm) and the expression of Bax, Bcl-2, caspase-3, phospho-Erk and phospho-Stat1/2 in SMMC-7721 cells that were exposed to PE were also investigated. The results showed that PE inhibited proliferation, caused G0/G1 phase cell cycle arrest and induced apoptosis in SMMC-7721 cells in a dose-dependent manner. Rhodamine 123 staining showed that the treatment of SMMC-7721 cells with different concentrations of PE for 24 h significantly decreased the level of ΔΨm and exerted dose-dependent effects. Using immunofluorescence and western blotting, we found that the expression of Bax was upregulated, whereas that of Bcl-2 was downregulated in PE-induced apoptotic cells. In addition, these events were accompanied by an increase in caspase-3 expression in a dose-dependent manner following PE treatment. PE-induced apoptosis was accompanied by a decrease in Erk phosphorylation and by the activation of Stat1/2 phosphorylation in SMMC-7721 cells. In conclusion, the results suggested that PE-induced apoptosis is involved in upregulating the Bax/Bcl-2 protein ratio and decreasing the ΔΨm. Moreover, the results showed that the Erk and Stat1/2 signalling pathways may be involved in the process of PE-induced apoptosis. PMID:24821075

  15. Modulation of the Activity of Mycobacterium tuberculosis LipY by Its PE Domain

    PubMed Central

    Garrett, Christopher K.; Broadwell, Lindsey J.; Hayne, Cassandra K.; Neher, Saskia B.

    2015-01-01

    Mycobacterium tuberculosis harbors over 160 genes encoding PE/PPE proteins, several of which have roles in the pathogen’s virulence. A number of PE/PPE proteins are secreted via Type VII secretion systems known as the ESX secretion systems. One PE protein, LipY, has a triglyceride lipase domain in addition to its PE domain. LipY can regulate intracellular triglyceride levels and is also exported to the cell wall by one of the ESX family members, ESX-5. Upon export, LipY’s PE domain is removed by proteolytic cleavage. Studies using cells and crude extracts suggest that LipY’s PE domain not only directs its secretion by ESX-5, but also functions to inhibit its enzymatic activity. Here, we attempt to further elucidate the role of LipY’s PE domain in the regulation of its enzymatic activity. First, we established an improved purification method for several LipY variants using detergent micelles. We then used enzymatic assays to confirm that the PE domain down-regulates LipY activity. The PE domain must be attached to LipY in order to effectively inhibit it. Finally, we determined that full length LipY and the mature lipase lacking the PE domain (LipYΔPE) have similar melting temperatures. Based on our improved purification strategy and activity-based approach, we concluded that LipY’s PE domain down-regulates its enzymatic activity but does not impact the thermal stability of the enzyme. PMID:26270534

  16. PE_PGRS33 Contributes to Mycobacterium tuberculosis Entry in Macrophages through Interaction with TLR2.

    PubMed

    Palucci, Ivana; Camassa, Serena; Cascioferro, Alessandro; Sali, Michela; Anoosheh, Saber; Zumbo, Antonella; Minerva, Mariachiara; Iantomasi, Raffaella; De Maio, Flavio; Di Sante, Gabriele; Ria, Francesco; Sanguinetti, Maurizio; Palù, Giorgio; Brennan, Michael J; Manganelli, Riccardo; Delogu, Giovanni

    2016-01-01

    PE_PGRS represent a large family of proteins typical of pathogenic mycobacteria whose members are characterized by an N-terminal PE domain followed by a large Gly-Ala repeat-rich C-terminal domain. Despite the abundance of PE_PGRS-coding genes in the Mycobacterium tuberculosis (Mtb) genome their role and function in the biology and pathogenesis still remains elusive. In this study, we generated and characterized an Mtb H37Rv mutant (MtbΔ33) in which the structural gene of PE_PGRS33, a prototypical member of the protein family, was inactivated. We showed that this mutant entered macrophages with an efficiency up to ten times lower than parental or complemented strains, while its efficiency in infecting pneumocytes remained unaffected. Interestingly, the lack of PE_PGRS33 did not affect the intracellular growth of this mutant in macrophages. Using a series of functional deletion mutants of the PE_PGRS33 gene to complement the MtbΔ33 strain, we demonstrated that the PGRS domain is required to mediate cell entry into macrophages, with the key domain encompassing position 140-260 amino acids of PE_PGRS33. PE_PGRS33-mediated entry into macrophages was abolished in TLR2-deficient mice, as well as following treatment with wortmannin or an antibody against the complement receptor 3 (CR3), indicating that PE_PGRS33-mediated entry of Mtb in macrophages occurs through interaction with TLR2.

  17. PE_PGRS33 Contributes to Mycobacterium tuberculosis Entry in Macrophages through Interaction with TLR2

    PubMed Central

    Palucci, Ivana; Camassa, Serena; Cascioferro, Alessandro; Sali, Michela; Anoosheh, Saber; Zumbo, Antonella; Minerva, Mariachiara; Iantomasi, Raffaella; De Maio, Flavio; Di Sante, Gabriele; Ria, Francesco; Sanguinetti, Maurizio; Palù, Giorgio; Brennan, Michael J.; Manganelli, Riccardo; Delogu, Giovanni

    2016-01-01

    PE_PGRS represent a large family of proteins typical of pathogenic mycobacteria whose members are characterized by an N-terminal PE domain followed by a large Gly-Ala repeat-rich C-terminal domain. Despite the abundance of PE_PGRS-coding genes in the Mycobacterium tuberculosis (Mtb) genome their role and function in the biology and pathogenesis still remains elusive. In this study, we generated and characterized an Mtb H37Rv mutant (MtbΔ33) in which the structural gene of PE_PGRS33, a prototypical member of the protein family, was inactivated. We showed that this mutant entered macrophages with an efficiency up to ten times lower than parental or complemented strains, while its efficiency in infecting pneumocytes remained unaffected. Interestingly, the lack of PE_PGRS33 did not affect the intracellular growth of this mutant in macrophages. Using a series of functional deletion mutants of the PE_PGRS33 gene to complement the MtbΔ33 strain, we demonstrated that the PGRS domain is required to mediate cell entry into macrophages, with the key domain encompassing position 140–260 amino acids of PE_PGRS33. PE_PGRS33-mediated entry into macrophages was abolished in TLR2-deficient mice, as well as following treatment with wortmannin or an antibody against the complement receptor 3 (CR3), indicating that PE_PGRS33-mediated entry of Mtb in macrophages occurs through interaction with TLR2. PMID:26978522

  18. PeV-scale supersymmetry from new inflation

    SciTech Connect

    Nakayama, Kazunori; Takahashi, Fuminobu E-mail: fumi@tuhep.phys.tohoku.ac.jp

    2012-05-01

    We show that heavy supersymmetric particles around O(100) TeV to O(1) PeV naturally appear in new inflation in which the Higgs boson responsible for the breaking of U(1){sub B−L} plays the role of inflaton. Most important, the supersymmetric breaking scale is bounded above by the inflationary dynamics, in order to suppress the Coleman-Weinberg potential which would otherwise spoil the slow-roll inflation. Our scenario has rich phenomenological and cosmological implications: the Higgs boson mass at around 125 GeV can be easily explained, non-thermal leptogenesis works automatically, the gravitino production from inflaton decay is suppressed, the dark matter is either the lightest neutralino or the QCD axion, and the upper bound on the inflation scale for the modulus stabilization can be marginally satisfied.

  19. Structural Bioinformatics Inspection of neXtProt PE5 Proteins in the Human Proteome.

    PubMed

    Dong, Qiwen; Menon, Rajasree; Omenn, Gilbert S; Zhang, Yang

    2015-09-01

    One goal of the Human Proteome Project is to identify at least one protein product for each of the ∼20,000 human protein-coding genes. As of October 2014, however, there are 3564 genes (18%) that have no or insufficient evidence of protein existence (PE), as curated by neXtProt; these comprise 2647 PE2-4 missing proteins and 616 PE5 dubious protein entries. We conducted a systematic examination of the 616 PE5 protein entries using cutting-edge protein structure and function modeling methods. Compared to a random sample of high-confidence PE1 proteins, the putative PE5 proteins were found to be over-represented in the membrane and cell surface proteins and peptides fold families. Detailed functional analyses show that most PE5 proteins, if expressed, would belong to transporters and receptors localized in the plasma membrane compartment. The results suggest that experimental difficulty in identifying membrane-bound proteins and peptides could have precluded their detection in mass spectrometry and that special enrichment techniques with improved sensitivity for membrane proteins could be important for the characterization of the PE5 "dark matter" of the human proteome. Finally, we identify 66 high scoring PE5 protein entries and find that six of them were reported in recent mass spectrometry databases; an illustrative annotation of these six is provided. This work illustrates a new approach to examine the potential folding and function of the dubious proteins comprising PE5, which we will next apply to the far larger group of missing proteins comprising PE2-4.

  20. PE_PGRS30 of Mycobacterium tuberculosis mediates suppression of proinflammatory immune response in macrophages through its PGRS and PE domains.

    PubMed

    Chatrath, Shweta; Gupta, Vineet Kumar; Dixit, Aparna; Garg, Lalit C

    2016-09-01

    The success of Mycobacterium tuberculosis as a pathogen relies on its ability to survive inside macrophages and evade host immune mechanisms. M. tuberculosis employs multiple strategies to confer resistance against immune system including inhibition of phago-lysosomal fusion, modulation of cytokine responses and granuloma formation. PE_PGRS proteins, uniquely present in pathogenic mycobacteria, are cell surface molecules that are suggested to interact with host cells. PE_PGRS proteins have also been implicated in its pathogenesis. In the present study, immuno-regulatory property of Rv1651c-encoded PE_PGRS30 protein was explored. Infection of PMA-differentiated human THP-1 macrophages with Mycobacterium smegmatis harbouring pVV(1651c) resulted in reduced production of IL-12, TNF-α and IL-6, as compared to infection with M. smegmatis harbouring the control plasmid pVV16. No differential effect was observed on bacterial persistence inside macrophages or on macrophage mortality upon infection with the two recombinant strains. Infection of THP-1 macrophages with recombinant M. smegmatis expressing deletion variants of PE_PGRS30 indicated that anti-inflammatory function of the protein is possessed by its PGRS and PE domains while the C-terminal domain, when expressed alone, displayed antagonistic effect in terms of TNF-α secretion. These results suggest that PE_PGRS30 interferes with macrophage immune functions important for activation of adaptive T-cell responses. PMID:27129781

  1. PE_PGRS30 of Mycobacterium tuberculosis mediates suppression of proinflammatory immune response in macrophages through its PGRS and PE domains.

    PubMed

    Chatrath, Shweta; Gupta, Vineet Kumar; Dixit, Aparna; Garg, Lalit C

    2016-09-01

    The success of Mycobacterium tuberculosis as a pathogen relies on its ability to survive inside macrophages and evade host immune mechanisms. M. tuberculosis employs multiple strategies to confer resistance against immune system including inhibition of phago-lysosomal fusion, modulation of cytokine responses and granuloma formation. PE_PGRS proteins, uniquely present in pathogenic mycobacteria, are cell surface molecules that are suggested to interact with host cells. PE_PGRS proteins have also been implicated in its pathogenesis. In the present study, immuno-regulatory property of Rv1651c-encoded PE_PGRS30 protein was explored. Infection of PMA-differentiated human THP-1 macrophages with Mycobacterium smegmatis harbouring pVV(1651c) resulted in reduced production of IL-12, TNF-α and IL-6, as compared to infection with M. smegmatis harbouring the control plasmid pVV16. No differential effect was observed on bacterial persistence inside macrophages or on macrophage mortality upon infection with the two recombinant strains. Infection of THP-1 macrophages with recombinant M. smegmatis expressing deletion variants of PE_PGRS30 indicated that anti-inflammatory function of the protein is possessed by its PGRS and PE domains while the C-terminal domain, when expressed alone, displayed antagonistic effect in terms of TNF-α secretion. These results suggest that PE_PGRS30 interferes with macrophage immune functions important for activation of adaptive T-cell responses.

  2. Agonist-Directed Desensitization of the β2-Adrenergic Receptor

    PubMed Central

    Goral, Vasiliy; Jin, Yan; Sun, Haiyan; Ferrie, Ann M.; Wu, Qi; Fang, Ye

    2011-01-01

    The β2-adrenergic receptor (β2AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β2AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β2AR desensitization at the whole cell level. PMID:21541288

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

    PubMed

    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.

  4. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists

    PubMed Central

    2015-01-01

    We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID:26640818

  5. Use of Mobile Testing System PeLe for Developing Language Skills

    ERIC Educational Resources Information Center

    Titova, Svetlana

    2015-01-01

    One of the objectives of this paper is to investigate the pedagogical impact of both the mobile testing system PeLe (Norway, HiST) and the enquiry-based learning approach on language skills development in the context of mobile-assisted learning. The research aims to work out a methodological framework of PeLe implementation into the language…

  6. The Swedish Sports Movement and the PE Teacher 1940-2003: From Supporter to Challenger

    ERIC Educational Resources Information Center

    Olofsson, Eva

    2007-01-01

    The Swedish Sports Confederation (RF) used to be the foremost advocate and defender of physical education (PE) as a subject and the work of PE teachers. This paper deals with the way in which this support manifested itself during 1940-2003 and is based on a discourse analysis of texts from RF. The analysis shows that RF has assigned three…

  7. Whole-School Management Issues Concerning the PE Department: "A Natural Division of Labour?"

    ERIC Educational Resources Information Center

    Williams, Gareth Mark; Williams, Dean

    2013-01-01

    Utilising the labour ideas of Adam Smith and Emile Durkheim as a theoretical basis, the main objective of this study was to investigate the perception that Heads of Physical Education (HoPE) face unique management and leadership challenges. Results showed that HoPE believe that they are overburdened with tasks primarily involving the delegation of…

  8. Impact of ICT and PE on Disaffected Pupils: Interim Report March 2004

    ERIC Educational Resources Information Center

    Mostert, Andre; Needham, Richard

    2004-01-01

    Over a three month period in spring 2004, The British Association of Advisers and Lecturers in Physical Education (BAALPE) and New Media (a PLATO Learning Company) researched and evaluated models for harnessing ICT in physical education (PE). The project developed a unique ICT infrastructure for two PE departments to evaluate the impact of ICT on…

  9. Are the PE-PGRS proteins of Mycobacterium tuberculosis variable surface antigens?

    PubMed

    Banu, Sayera; Honoré, Nadine; Saint-Joanis, Brigitte; Philpott, Dana; Prévost, Marie-Christine; Cole, Stewart T

    2002-04-01

    Mycobacterium tuberculosis H37Rv contains 67 PE-PGRS genes, with multiple tandem repetitive sequences, encoding closely related proteins that are exceptionally rich in glycine and alanine. As no functional information was available, 10 of these genes were selected and shown to be expressed in vitro by reverse transcription-polymerase chain reaction (RT-PCR). Antibodies against five PE-PGRS proteins, raised in mice by DNA vaccination, detected single proteins when the same plasmid constructs used for immunization were expressed in epithelial cells or in reticulocyte extracts, confirming that the PE-PGRS proteins are antigenic. As expected from the conserved repetitive structure, the antibodies cross-reacted with more than one PE-PGRS protein, suggesting that different proteins share common epitopes. PE-PGRS proteins were detected by West-ern blotting in five different mycobacterial species (M. tuberculosis, M. bovis BCG, M. smegmatis, M. marinum and M. gordonae) and 11 clinical isolates of M. tuberculosis. Whole-genome comparisons of M. tuberculosis predicted allelic diversity in the PE-PGRS family, and this was confirmed by immunoblot studies as size variants were detected in clinical strains. Subcellular fractionation studies and immunoelectron microscopy localized many PE-PGRS proteins in the cell wall and cell membrane of M. tuberculosis. The data suggest that some PE-PGRS proteins are variable surface antigens.

  10. Physical Activity during Physical Education Lessons: A Qualitative Investigation of Australian PE Teacher Perceptions

    ERIC Educational Resources Information Center

    Bennie, Andrew; Langan, Edel

    2015-01-01

    School physical education (PE) experiences play a critical role in adolescents' physical activity (PA) levels. Teachers are crucial to students' initial experiences in PA; however, limited research has explored teachers' perspectives about PA during PE using in-depth qualitative research techniques. We conducted interviews with 25 current…

  11. How Active are Rural Children and Adolescents During PE Class? An Examination of Light Physical Activity

    PubMed Central

    Matthews-Ewald, Molly R.; Kelley, George A.; Moore, Lucas C.; Gurka, Matthew J.

    2015-01-01

    BACKGROUND Few studies have examined non-exercise activity thermogenesis (NEAT) or light physical activity among a group of rural youth, particularly during physical education (PE) class. The purpose of this study was to determine whether the percent of PE class time spent in NEAT is related to school level (elementary versus high school) in a group of rural youth. METHODS Accelerometer data from 357 students (192 elementary, 165 high school) were included in the analysis. Mixed model linear regression was performed to examine the effect of school level on the percent of PE class time spent in NEAT. Covariates included gender, PE teacher, and the duration of the PE class. RESULTS School level was a significant predictor of the percent of PE class time spent in NEAT. Specifically, elementary school students spent more of their PE class time in NEAT than high school students (p< .001). No other significant predictors were identified. CONCLUSIONS The results of this study suggest an association between lower levels of light (NEAT) physical activity among high school versus elementary school students during PE class. PMID:24902465

  12. 23 CFR 661.33 - What percentage of IRRBP funding is available for PE and construction?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 23 Highways 1 2010-04-01 2010-04-01 false What percentage of IRRBP funding is available for PE and construction? 661.33 Section 661.33 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD BRIDGE PROGRAM § 661.33 What percentage of IRRBP funding is available for PE...

  13. The complete genome sequence of PE3-1, a novel E. coli O153 phage.

    PubMed

    Liu, Honghui; Liu, Xinchun; Yi, Xin; Liu, Ruyin; Huang, Jing

    2016-11-01

    A novel virulent phage PE3-1 against E. coli O153 was isolated from an aeration tank in a wastewater treatment plant. Transmission electron microscopy images showed that phage PE3-1 had an icosahedral head and a short tail, which revealed that it was a member of the family Podoviridae of the order Caudovirales. The complete PE3-1 genome consisted of 39,093 bp and was a linear double-stranded DNA with an average GC content of 49.93 %. Phage PE3-1 showed homology to the T7-like phages in 48 open reading frames (ORFs), but it differed from previously reported E .coli phages in morphology and bioinformatics analysis. This indicated that phage PE3-1 is a new member of the genus T7 virus. PMID:27541819

  14. Small Molecule Bax Agonists for Cancer Therapy

    PubMed Central

    Xin, Meiguo; Li, Rui; Xie, Maohua; Park, Dongkyoo; Owonikoko, Taofeek K.; Sica, Gabriel L.; Corsino, Patrick E.; Zhou, Jia; Ding, Chunyong; White, Mark A.; Magis, Andrew T.; Ramalingam, Suresh S.; Curran, Walter J.; Khuri, Fadlo R.; Deng, Xingming

    2014-01-01

    Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently identified serine 184 (S184) of Bax as a critical functional switch controlling its proapoptotic activity. Here, we employed the structural pocket around S184 as a docking site to screen the NCI library of small molecules using the UCSF-DOCK program suite. Three compounds, small molecule Bax agonists SMBA1, SMBA2 and SMBA3, induce conformational changes in Bax by blocking S184 phosphorylation, facilitating Bax insertion into mitochondrial membranes and forming Bax oligomers. The latter leads to cytochrome c release and apoptosis in human lung cancer cells, which occurs in a Bax- but not Bak-dependent fashion. SMBA1 potently suppresses lung tumor growth via apoptosis by selectively activating Bax in vivo without significant normal tissue toxicity. Development of Bax agonists as a new class of anti-cancer drugs offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies. PMID:25230299

  15. [Cloning and functional analysis of Phyllostachys edulis MYB transcription factor PeMYB2].

    PubMed

    Xiao, Dong-Chang; Zhang, Zhi-Jun; Xu, Ying-Wu; Yang, Li; Zhang, Feng-Xue; Wang, Chao-Li

    2013-10-01

    MYB-type transcription factor is one of the largest families in plants, which plays important roles in accepting stress signals from environment and regulating the expression of stress-tolerant genes. In this paper, using homologous cloning and RACE technology, a MYB-type transcription factor, designated PeMYB2, was cloned from Phyllostachys edulis. The results of bioinformatics showed that PeMYB2 is a typical R2R3-MYB. It contained two tandem repeats in its N-terminus, and a membrane protein DUF3651 in its C-terminus. In addition, phylogenetic analysis indicated that PeMYB2 shared the highest homology with 85.98% to OsMYB18 protein from Oryza sativa spp. Japonica. In addition, a yeast one-hybrid assay showed that PeMYB2 could activate the expression of downstream genes. After PeMYB2 was transformed into Arabidopsis thaliana, seven PeMYB2 transgenic Arabidopsis lines were obtained. Phenotypic analysis of the transgenic and wild-type Arabidopsis showed that over-expression of PeMYB2 caused delayed flower or dwarfism in transgenic Arabidopsis. Under the abiotic stress conditions, such as salt and cold stresses, the over-expression of PeMYB2 in Arabidopsis had higher survival rate than the wild-type Arabidopsis. Expression analysis of saline stress response marker genes in the transgenic and wild-type plants under the salt stress condition showed that PeMYB2 regulated the expression of NXH1, SOS1, RD29A, and COR15A. As the result, PeMYB2 might play an important role in various responses to abiotic stresses in P. edulis.

  16. Relationship between alpha/sub 1/-adrenergic receptor occupancy and regulation of intracellular Ca/sup + +/ in BC3H-1 muscle cells

    SciTech Connect

    Brown, R.D.; Berger, K.D.; Button, D.; Taylor, P.

    1986-05-01

    The relationship between ..cap alpha../sub 1/-adrenergic receptor occupancy by agonists or antagonists and functional response was examined. Receptor occupancy was measured using the antagonist (/sup 3/H)prazosin, and correlated with agonist-elicited unidirectional /sup 45/Ca/sup + +/ efflux. The agonists epinephrine (E), norepinephrine (NE), and phenylephrine (PE) activated /sup 45/Ca/sup + +/ efflux with the order of potency expected for ..cap alpha../sub 1/ receptors (E greater than or equal to NE > PE). A parabolic relationship suggesting the presence of a modest receptor reserve was observed between the number of activatable receptors after equilibration with specified (/sup 3/H)prazosin concentrations and residual /sup 45/Ca/sup + +/ efflux responses elicited by E or NE. A linear relationship was previously observed for PE. Agonist occupancy was independently measured by competition with the initial rate of (/sup 3/H)prazosin association. Both E and NE inhibited (/sup 3/H)prazosin binding over higher concentration ranges than those required to elicit /sup 45/Ca/sup + +/ efflux. Equilibration of cultures with agonist prior to measurement of (/sup 3/H)prazosin binding resulted in small decreases in apparent agonist affinities. These results indicate that BC3H-1 cells possess a small ..cap alpha../sub 1/-receptor reserve for agonist-elicited /sup 45/Ca/sup + +/ efflux which is reflected in the catecholamine agonists, and that exposure to agonist converts receptors to a state of reduced agonist affinity.

  17. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…

  18. GLP-1 agonist treatment: implications for diabetic retinopathy screening.

    PubMed

    Varadhan, Lakshminarayanan; Humphreys, Tracy; Hariman, Christian; Walker, Adrian B; Varughese, George I

    2011-12-01

    Rapid improvement in glycaemic control induced by GLP-1 agonist therapy could be yet another illustration of transient or permanent progression of diabetic retinopathy, similar to documented examples such as pregnancy and continuous subcutaneous insulin infusion. Specific guidelines would be needed to monitor this paradoxical phenomenon during treatment with GLP-1 agonists. PMID:21906831

  19. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  20. Phylogeny to function: PE/PPE protein evolution and impact on Mycobacterium tuberculosis pathogenicity.

    PubMed

    Fishbein, S; van Wyk, N; Warren, R M; Sampson, S L

    2015-06-01

    The pe/ppe genes represent one of the most intriguing aspects of the Mycobacterium tuberculosis genome. These genes are especially abundant in pathogenic mycobacteria, with more than 160 members in M. tuberculosis. Despite being discovered over 15 years ago, their function remains unclear, although various lines of evidence implicate selected family members in mycobacterial virulence. In this review, we use PE/PPE phylogeny as a framework within which we examine the diversity and putative functions of these proteins. We report on the evolution and diversity of the respective gene families, as well as the implications thereof for function and host immune recognition. We summarize recent findings on pe/ppe gene regulation, also placing this in the context of PE/PPE phylogeny. We collate data from several large proteomics datasets, providing an overview of PE/PPE localization, and discuss the implications this may have for host responses. Assessment of the current knowledge of PE/PPE diversity suggests that these proteins are not variable antigens as has been so widely speculated; however, they do clearly play important roles in virulence. Viewing the growing body of pe/ppe literature through the lens of phylogeny reveals trends in features and function that may be associated with the evolution of mycobacterial pathogenicity.

  1. Impact of Protein Domains on PE_PGRS30 Polar Localization in Mycobacteria

    PubMed Central

    Minerva, Mariachiara; Anoosheh, Saber; Palucci, Ivana; Iantomasi, Raffaella; Palmieri, Valentina; Camassa, Serena; Sali, Michela; Sanguinetti, Maurizio; Bitter, Wilbert; Manganelli, Riccardo; De Spirito, Marco; Delogu, Giovanni

    2014-01-01

    PE_PGRS proteins are unique to the Mycobacterium tuberculosis complex and a number of other pathogenic mycobacteria. PE_PGRS30, which is required for the full virulence of M. tuberculosis (Mtb), has three main domains, i.e. an N-terminal PE domain, repetitive PGRS domain and the unique C-terminal domain. To investigate the role of these domains, we expressed a GFP-tagged PE_PGRS30 protein and a series of its functional deletion mutants in different mycobacterial species (Mtb, Mycobacterium bovis BCG and Mycobacterium smegmatis) and analysed protein localization by confocal microscopy. We show that PE_PGRS30 localizes at the mycobacterial cell poles in Mtb and M. bovis BCG but not in M. smegmatis and that the PGRS domain of the protein strongly contributes to protein cellular localization in Mtb. Immunofluorescence studies further showed that the unique C-terminal domain of PE_PGRS30 is not available on the surface, except when the PGRS domain is missing. Immunoblot demonstrated that the PGRS domain is required to maintain the protein strongly associated with the non-soluble cellular fraction. These results suggest that the repetitive GGA-GGN repeats of the PGRS domain contain specific sequences that contribute to protein cellular localization and that polar localization might be a key step in the PE_PGRS30-dependent virulence mechanism. PMID:25390359

  2. Cytocompatibility of Ar + plasma treated and Au nanoparticle-grafted PE

    NASA Astrophysics Data System (ADS)

    Švorčík, V.; Kasálková, N.; Slepička, P.; Záruba, K.; Král, V.; Bačáková, L.; Pařízek, M.; Lisá, V.; Ruml, T.; Gbelcová, H.; Rimpelová, S.; Macková, A.

    2009-06-01

    Polyethylene (PE) was irradiated with inert Ar plasma, and the chemically active PE surface was grafted with Au nanoparticles. The composition and the structure of the modified PE surface were studied using X-ray photoelectron spectroscopy (XPS) and Rutherford backscattering spectroscopy (RBS). Changes in the surface wettability were determined from the contact angle measured in a reflection goniometer. The changes in the surface roughness and morphology were followed by atomic force microscopy (AFM). The modified PE samples were seeded with rat vascular smooth muscle cells (VSMC) or mouse NIH 3T3 fibroblasts, and their adhesion and proliferation were studied. We found that plasma discharge and Au grafting lead to dramatic changes in the surface morphology and roughness of PE. The Au nanoparticles were found not only on the sample surface, but also in the sample interior up to the depth of about 100 nm. In addition, plasma modification of the PE surface, followed with grafting Au-nanoparticles, significantly increased the attractiveness of the PE surface for the adhesion and growth of VSMC, and particularly for mouse embryonic 3T3 fibroblasts.

  3. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  4. Dark matter from PeV physics and the neutrino sector

    NASA Astrophysics Data System (ADS)

    Shakya, Bibhushan; Roland, Samuel B.; Wells, James D.

    2016-06-01

    It is well known that the neutrino sector can provide a dark matter candidate in the form of a light sterile neutrino. This note discusses a framework that naturally leads to light (keV-GeV) sterile neutrino dark matter produced via the freeze-in mechanism: a modified, low energy seesaw with the right-handed neutrinos charged under a new symmetry broken by a PeV scale vacuum expectation value. This framework can accommodate the recently observed 3.5 keV X-ray line, while a straightforward extension, using the new symmetry and the PeV energy scale, can explain the PeV energy neutrino events at IceCube. Together, these can therefore be taken as hints of the existence of a PeV scale neutrino sector.

  5. Production and crosslinking of multi-layer tubes (PE & metal) by E-beam

    NASA Astrophysics Data System (ADS)

    Zyball, Alfred

    2000-03-01

    Irradiation crosslinking of PE-tubes has been used for heating floors for about 25 years. Such tubes are also used today for drinking water supply. A further development has been the coating of such tubes with Ethylene-Vinyl-Alcohol-Copolymers (EVAL), in order to prevent oxygen diffusion into the water through the PE tube. For about 15 years composite tubes made of PE and aluminum have been available. These tubes are crosslinked with electron beams. The energy of the accelerated electrons must be adjusted for the particular tube configuration, so that the inner PE-layer will be crosslinked. This paper will concern itself with the manufacture and the crosslinking of composite tubes.

  6. An analytic approach to 2D electronic PE spectra of molecular systems

    NASA Astrophysics Data System (ADS)

    Szöcs, V.

    2011-05-01

    The three-pulse photon echo (3 P- PE) spectra of finite molecular systems and simplified line broadening models is presented. The Fourier picture of a heterodyne detected three-pulse rephasing PE signal in the δ-pulse limit of the external field is derived in analytic form. The method includes contributions of one and two-excitonic states and allows direct calculation of Fourier PE spectrogram from corresponding Hamiltonian. As an illustration, the proposed treatment is applied to simple systems, e.g. 2-site two-level system (TLS) and n-site TLS model of photosynthetic unit. The importance of relation between Fourier picture of 3 P- PE dynamics (corresponding to nonzero population time, T) and coherent inter-state coupling is emphasized.

  7. Conversion of post-industrial PET-PE scraps into compatibilized plastic blends for new applications

    NASA Astrophysics Data System (ADS)

    Bartoli, Flavia; Bruni, Cosimo; Coltelli, Maria-Beatrice; Castelvetro, Valter; Ciardelli, Francesco

    2012-07-01

    Poly(ethylene terephthalate) (PET) / poly(ethylene) (PE) granules coming from a post-industrial packaging stream were directed to new applications. The collected material was first characterized through selective extractions followed by infrared analysis. After the characterization work the presence of poly(ethylene-co-vinyl acetate) (EVA) copolymer was evidenced. Moreover the degree of yellowing was shown to increase by increasing the PE content in the granules batch. The blending of PET/PE with a stabilizer allowed to control its thermal stability, moreover the addition of compatibilizers resulted in the possibility of modulating both rheological and mechanical properties. Hence the use of stabilizers and compatibilizers allowed to upgrade postindustrial PET/PE based materials for the use in different industrial applications

  8. Detecting and discriminating PE and PP polymers for plastics recycling using NIR imaging spectroscopy

    NASA Astrophysics Data System (ADS)

    De Biasio, Martin; Arnold, Thomas; McGunnigle, Gerald; Leitner, Raimund; Balthasar, Dirk; Rehrmann, Volker

    2010-05-01

    There are commercially available industrial systems for identifying and separating polymers, for instance PE from PP. However, there is a demand for analyzers that can separate within polymer classes: e.g. PE-LD from PE-HD or different polypropylenes characterised by different melting points. First, the feasibility of a reliable spectral identification was tested by extracting different PE and PP samples from an industrial recycling process, and acquiring diffuse reflectance NIR spectra using an FTIR spectrometer. The resulting spectra were then subjected to a chemometrics analysis. We successfully identified characteristic spectral features; these are determined by the chemical bonds of the material, and can be correlated to the melting points of the materials. These features were then adapted for use on a NIR hyper-spectral (HS) system, making it possible to distinguish not only different polymers, but also different types of one polymer in real-time.

  9. Ultra-high molecular weight polyethylene (UHMW-PE) and its application in microporous separators for lead/acid batteries

    NASA Astrophysics Data System (ADS)

    Wang, L. C.; Harvey, M. K.; Ng, J. C.; Scheunemann, U.

    The polyethylene (PE) used in separators for automotive lead/acid batteries is actually UHMW-PE (ultra high molecular weight polyethylene). Microporous PE separators were commercialized in the early 1970s. Since then, they have gained in popularity in the lead/acid battery industry, particularly in SLI (starting, lighting and ignition) automotive applications. This paper provides an introductory overview of the UHMW-PE polymer and its contributions to the PE battery separator manufacturing process, battery assembly and battery performance, in comparison with other conventional separators such as polyvinyl chloride (PVC) and glass fibre.

  10. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation. PMID:22269613

  11. [PPAR receptors and insulin sensitivity: new agonists in development].

    PubMed

    Pégorier, J-P

    2005-04-01

    Thiazolidinediones (or glitazones) are synthetic PPARgamma (Peroxisome Proliferator-Activated Receptors gamma) ligands with well recognized effects on glucose and lipid metabolism. The clinical use of these PPARgamma agonists in type 2 diabetic patients leads to an improved glycemic control and an inhanced insulin sensitivity, and at least in animal models, to a protective effect on pancreatic beta-cell function. However, they can produce adverse effects, generally mild or moderate, but some of them (mainly peripheral edema and weight gain) may conduct to treatment cessation. Several pharmacological classes are currently in pre-clinical or clinical development, with the objective to retain the beneficial metabolic properties of PPARgamma agonists, either alone or in association with the PPARalpha agonists (fibrates) benefit on lipid profile, but devoid of the side-effects on weight gain and fluid retention. These new pharmacological classes: partial PPARgamma agonists, PPARgamma antagonists, dual PPARalpha/PPARgamma agonists, pan PPARalpha/beta(delta)/gamma agonists, RXR receptor agonists (rexinoids), are presented in this review. Main results from in vitro cell experiments and animal model studies are discussed, as well as the few published short-term studies in type 2 diabetic patients. PMID:15959400

  12. Irreversible binding of a carbostyril-based agonist and antagonist to the β-adrenoceptor in DDT1 MF-2 cells and rat aorta

    PubMed Central

    Deyrup, Malgorzata D; Greco, Phillip G; Otero, Deborah H; Dennis, Donn M; Gelband, Craig H; Baker, Stephen P

    1998-01-01

    The chemoreactive ligands 5(2-(((1′-(4′-isothiocyanatophenylamino)thiocarbonyl)-amino)-2-methyl-propyl)amino-2-hydroxypropoxy)-3,4-dihydrocarbostyril (DCITC) and 8-hydroxy-5(2-(((1′-(4′-isothiocya-natophenylamino)thiocarbonyl)amino)-2-methylprop-2-yl)amino-1-hydroxyethyl)-carbostyril (HCITC)were synthesized and shown to be potent irreversible antagonist and agonist ligands, respectively, for the β-adrenoceptor in DDT1 MF-2 (DDT) cells and the rat isolated aorta.In DDT cell membranes DCITC and HCITC inhibited (−)[125I]-iodocyanopindolol (CYP) binding to the β-adrenoceptor with IC50 values of 1.1 and 18 nM, respectively. (−)-Isoprenaline inhibited [125I]-CYP binding with an IC50 of 355 nM. Pretreatment of membranes with either chemoreactive ligand produced a time- and concentration-dependent decrease in the β-adrenoceptor content, indicating irreversible receptor binding. DCITC at concentrations up to 10 μM did not stimulate cyclic AMP accumulation in DDT cells nor did it amplify forskolin-stimulated cyclic AMP accumulation.In the rat isolated aorta, DCITC (0.1 μM) did not affect either the phenylephrine-mediated tissue contraction or the acetylcholine-mediated relaxation. DCITC attenuated the maximal (−)-isoprenaline-mediated relaxation of a phenylephrine contracted aorta in a concentration-dependent manner and shifted the dose-response curves for (−)-isoprenaline to the right. The DCITC-induced decrease in maximal response was not reversed by extensive tissue washing. By use of the operational model of agonism, the calculated dissociation constant for (−)-isoprenaline ws 286 nM and the estimated receptor reserve for this agonist was 23% at the maximal response.HCITC and (−)-isoprenaline stimulated cyclic AMP accumulation in DDT cells with pD2 values (negative logarithm to base 10 of EC50) of 7.95 and 7.97, respectively, and both mediated the same maximal stimulation. In the rat isolated aorta, HCITC produced a concentration

  13. Comparison of BIASI and Columbia CHF correlations using BODYFIT-2PE

    SciTech Connect

    Chen, B.C.J.; Chien, T.H.; Sha, W.T.; Kim, J.H.

    1984-01-01

    This paper compares the BIASI critical heat flux (CHF) correlation with the Columbia CHF correlation by using both the homogeneous equilibrium two-phase model with algebraic slip and the drift flux model in BODYFIT-2PE. All calculations were compared with the GE 3 x 3 CHF experiment. This comparison serves as a qualification process for the CHF correlations in the framework of BODYFIT-2PE.

  14. Risk Factors for DVT/PE in Patients with Stroke and Intracranial Hemorrhage

    PubMed Central

    Stecker, Mark; Michel, Kathleen; Antaky, Karin; Cherian, Sarah; Koyfmann, Feliks

    2014-01-01

    Objective: Deep venous thrombosis (DVT) and pulmonary embolus (PE) are serious problems for patients admitted to the hospital with stroke, subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH) and transient ischemic attack (TIA). The purpose of this paper is to further understand the factors that place certain patients at increased risk of DVT/PE. Methods: At a 600 bed hospital, a retrospective analysis of data from 2613 patients admitted with a diagnosis of stroke, SAH, ICH or TIA in the time range 1/2008 through 3/2012 was carried out. The data was taken from the hospital’s Get with the Guidelines database and included 28 variables. These included initial NIH stroke scale, length of stay, heart failure, ambulatory by day 2 after admission, altered mental status,and renal failure among others. Multiple analyses were carried out to determine whether there were univariable or multivariable effects of any of the factors on the risk for DVT/PE. Results: The risk of DVT/PE was highest in patients with SAH and ICH and smallest with TIA. Multivariable analyses were performed and revealed only altered level of consciousness or heart failure as significant risks for DVT/PE. With the limited available data, administration of subcutaneous heparin or other chemoprophylaxis did not reduce the risk of DVT/PE. Conclusion: Although many of the variables used to describe the stroke patient are correlated, in multivariable analyses only heart failure and altered level of consciousness were important risk factors for DVT/PE. The risk of DVT/PE was 7 fold greater in patients in patients with both of these risk factors. PMID:24847389

  15. Pre-eclampsia (PE) and Chorionicity in Women with Twin Gestations

    PubMed Central

    Singh, Anupama; Singh, Arati; Surapaneni, Tarakeswari; Nirmalan, Praveen Kumar

    2014-01-01

    Background: Pre-Eclampsia (PE) affects 6-31% of pregnant women with multiple gestations. There are conflicting reports on the association of PE with Chorionicity and zygosity; however, there is a lack of information on this potential association in a population of pregnant Asian Indian women. Aim: To determine as to whether chorionicity and zygosity were associated with PE in a population of Asian Indian women with twin gestations. Settings and Design: A retrospective observational study was done at a single tertiary care centre in Southern India. Material and Methods: The study included pregnant women with twin gestations, who was delivered at the study institute in 2012. Hypertension in pregnancy was categorized, based on the criteria of the International Society for the Study of Hypertension in Pregnancy. Chorionicity was determined by using ultrasonography and zygosity was determined, based on clinical criteria. Point estimates and the 95% Confidence Intervals (CI) around point estimates of PE and associations of chorionicity and zygosity with PE were determined by using bivariate analysis, logistic regression models and area under Receiver Operator Characteristic (ROC) curves. Results: This study included 208 women with twin gestations. The incidence of PE in dichorionic twin gestations was 13.17% (n=22, 95% CI: 8.66, 18.96), it was 4.87% (n=2, 95% CI: 0.83, 15.19) in monochorionic twin gestations, it was 16.36% (n=9, 95% CI: 8.29, 27.91) in dizygous twin gestations and it was 4.88% (n=2, 95% CI: 0.83, 15.19) in monozygous twin gestations. Neither chorionicity (adjusted OR: 2.59, 95% CI: 0.55, 12.19) nor zygosity (adjusted OR 2.72, 95% CI: 0.49, 15.13) were associated with PE In a multivariate logistic regression model. Conclusion: Although it was not statistically significant, the clinical incidence of PE was higher in dichorionic and dizygous twin gestations. PMID:24596736

  16. [Clinical probability of PE: should we use a clinical prediction rule?].

    PubMed

    Le Gal, G; Righini, M; Perrier, A

    2008-12-01

    The determination of the clinical pretest probability using clinical prediction models is an important step in the assessment of patients with suspected pulmonary embolism (PE). It helps establish which test or sequence of tests can effectively corroborate or safely rule out PE. For example, it has been demonstrated that it is safe to withhold anticoagulant therapy in patients with negative d-dimer results and low pretest probability at initial presentation. Clinical probability will also increase the diagnostic yield of ventilation perfusion lung scan. Compared with clinical gestalt, clinical prediction rules provide a standardized and more reproducible estimate of a patient's probability of having a PE. Clinical prediction models combine aspects of the history and physical examination to categorize a patient's probability of having a disease. The models classify patients as having a low, moderate, or high likelihood of having PE. Clinical prediction models have been validated and are well established for the diagnosis of PE in symptomatic patients. They allow all physicians, whatever their expertise, to reliably determine the clinical pretest probability of PE, and thus safely manage their patients using diagnostic and therapeutic algorithms. PMID:19084205

  17. PE-Swab Direct STR Amplification of Forensic Touch DNA Samples.

    PubMed

    Liu, Jason Y

    2015-05-01

    The PE-Swab direct STR amplification workflow was developed to process low-level "touch DNA" samples. In this workflow, a forensic sample is first collected on a 4-mm PE-Swab (a novel sample collection device); two 2-mm punches containing collected samples are then generated from the PE-Swab and directly amplified for STR typing. Compared to the conventional STR workflow, which involves DNA extraction, purification, and elution volume reduction, the PE-Swab direct STR amplification workflow does not require sample preparation and takes <60 sec before a touch sample is ready for STR amplification. Because there is no DNA loss due to sample preparation, the PE-Swab workflow is more sensitive than the conventional STR workflow. The average peak height per sample obtained by the PE-swab workflow is 3 times higher than that from the conventional workflow with both low-level single source and two-contributor mixture samples tested in this study.

  18. Optimization of esterification of oleic acid and trimethylolpropane (TMP) and pentaerythritol (PE)

    SciTech Connect

    Mahmud, Hamizah Ammarah; Salimon, Jumat

    2014-09-03

    Vegetable oil (VO) is the most potential alternative to replace mineral oil for lubricant due to better lubricating properties and great physicochemical properties. Chemical modification has to be done to overcome low temperature performance and low oxidation instability due to the presence of β-hydrogen atoms of glycerol molecule. The optimization of esterification of oleic acid and polyhydric alcohol with sulfuric acid catalyst was carried out to find the optimum conditions with the highest yield. Reeaction variables such as; molar ratio, temperature, duration and catalyst concentration. Two types of polyhydric alcohol have been used; TMP and PE. The optimum results showed oleic acid successfully converted 91.2% ester TMP and 92.7% ester PE at duration: 5 hours (Ester TMP), 6 hours (Ester PE); temperature: 150°C (ester TMP), 180°C (Ester PE); catalyst concentration: 1.5% (w/w); and mol ratio: 3.9:1 (ester TMP), 4.9:1 (ester PE). From the data obtained, mole ratio showed most influenced factors to the increasing yields of ester conversions.. The TMP/PE ester was confirmed using gas chromatography (GC-FID), Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance (NMR)

  19. Optimization of esterification of oleic acid and trimethylolpropane (TMP) and pentaerythritol (PE)

    NASA Astrophysics Data System (ADS)

    Mahmud, Hamizah Ammarah; Salimon, Jumat

    2014-09-01

    Vegetable oil (VO) is the most potential alternative to replace mineral oil for lubricant due to better lubricating properties and great physicochemical properties. Chemical modification has to be done to overcome low temperature performance and low oxidation instability due to the presence of β-hydrogen atoms of glycerol molecule. The optimization of esterification of oleic acid and polyhydric alcohol with sulfuric acid catalyst was carried out to find the optimum conditions with the highest yield. Reeaction variables such as; molar ratio, temperature, duration and catalyst concentration. Two types of polyhydric alcohol have been used; TMP and PE. The optimum results showed oleic acid successfully converted 91.2% ester TMP and 92.7% ester PE at duration: 5 hours (Ester TMP), 6 hours (Ester PE); temperature: 150°C (ester TMP), 180°C (Ester PE); catalyst concentration: 1.5% (w/w); and mol ratio: 3.9:1 (ester TMP), 4.9:1 (ester PE). From the data obtained, mole ratio showed most influenced factors to the increasing yields of ester conversions.. The TMP/PE ester was confirmed using gas chromatography (GC-FID), Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance (NMR).

  20. Fabry-Pérot interferometer utilized for displacement measurement in a large measuring range.

    PubMed

    Wang, Yung-Cheng; Shyu, Lih-Horng; Chang, Chung-Ping

    2010-09-01

    The optical configuration of a Fabry-Pérot interferometer is uncomplicated. This has already been applied in different measurement systems. For the displacement measurement with the Fabry-Pérot interferometer, the result is significantly influenced by the tilt angles of the measurement mirror in the interferometer. Hence, only for the rather small measuring range, the Fabry-Pérot interferometer is available. The goal of this investigation is to enhance the measuring range of Fabry-Pérot interferometer by compensating the tilt angles. To verify the measuring characteristic of the self-developed Fabry-Pérot interferometer, some comparison measurements with a reference standard have been performed. The maximum deviation of comparison experiments is less than 0.3 μm in the traveling range of 30 mm. The experimental results show that the Fabry-Pérot interferometer is highly stable, insensitive to environment effects, and can meet the measuring requirement of the submicrometer order.

  1. Brief review on PE method application to propagation channel modeling in sea environment

    NASA Astrophysics Data System (ADS)

    Sirkova, Irina

    2012-03-01

    This work provides an introduction to one of the most widely used advanced methods for wave propagation modeling, the Parabolic Equation (PE) method, with emphasis on its application to tropospheric radio propagation in coastal and maritime regions. The assumptions of the derivation, the advantages and drawbacks of the PE, the numerical methods for solving it, and the boundary and initial conditions for its application to the tropospheric propagation problem are briefly discussed. More details are given for the split-step Fourier-transform (SSF) solution of the PE. The environmental input to the PE, the methods for tropospheric refractivity profiling, their accuracy, limitations, and the average refractivity modeling are also summarized. The reported results illustrate the application of finite element (FE) based and SSF-based solutions of the PE for one of the most difficult to treat propagation mechanisms, yet of great significance for the performance of radars and communications links working in coastal and maritime zones — the tropospheric ducting mechanism. Recent achievements, some unresolved issues and ongoing developments related to further improvements of the PE method application to the propagation channel modeling in sea environment are highlighted.

  2. Swelling, ion uptake and biodegradation studies of PE film modified through radiation induced graft copolymerization

    NASA Astrophysics Data System (ADS)

    Kaur, Inderjeet; Gupta, Nitika; Kumari, Vandna

    2011-09-01

    An attempt to develop biodegradable polyethylene film grafting of mixture of hydrophilic monomers methacrylic acid (MAAc) and acrylamide (AAm) onto PE film has been carried out by preirradiation method using benzoyl peroxide as the radical initiator. Since ether linkages are susceptible to easy cleavage during degradation process, PE film was irradiated before the grafting reactions by γ-rays to introduce peroxidic linkages (PE-OO-PE) that offer sites for grafting. The effect of irradiation dose, monomer concentration, initiator concentration, temperature, time and amount of water on the grafting percent was determined. Maximum percentage of grafting of binary mixture (MAAc+AAm), (1792%) was obtained at a total concentration of binary monomer mixture=204.6×10 -2 mol/L ([MAAc]=176.5×10 -2 mol/L, [AAm]=28.1×10 -2 mol/L), [BPO]=8.3×10 -2 mol/L at 100 °C in 70 min. The grafted PE film was characterized by the Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric Analysis (TGA) and Scanning Electron Microscopic (SEM) methods. Some selective properties of grafted films such as swelling studies, ion uptake and biodegradation studies have been investigated. The grafted films show good swelling in water, ion uptake studies shows promising results for desalination of brackish water and the soil burial test shows that PE film grafted with binary monomer mixture degrades up to 47% within 50 days.

  3. Antifertility effects of luteinizing hormone-releasing hormone (LHRH) agonists.

    PubMed

    Labrie, F; Bélanger, A; Kelly, P A; Séguin, C; Cusan, L; Lefebvre, F A; Reeves, J J; Lemay, A; Faure, N; Gourdeau, Y; Raynaud, J P

    1981-01-01

    This paper reviews the mechanisms responsible for the antifertility effects of luteinizing hormone-releasing hormone (LHRH) agonists. Large doses of the LHRH agonist LHRH-EA lead to a marked reduction of testicular and secondary sex organ weight, LH receptor levels, and plasma testosterone concentration. A marked inhibition of basal testicular and testosterone concentrations is obtained after daily administration of the LHRH agonists at doses greater than 10 ng. Treatment with low doses of the LHRH agonist can lead to an increased steroidogenic response to LH. Treatment with low doses of LHRH agonists could stimulate Leydig cell function while high doses are history. A study of the effects of longterm treatment with an LHRH agonsist on spermatogenesis revelaed that testis, prostate, and seminal vesicle weight decreased and plasma LH and FSH levels increased over 12 weeks. Comparison of the effects of increasing doses of LHRH agonist on testicular and ovarian gonadotropin receptors and steroidogenesis in male rats indicates that single or repeated administration of LHRH agonists can lead to loss of testicular LH receptors in the absence of the pituitary gland. The loss of ovarian gonadotropin receptors in female rats is also investigated. Antifertility effects of LHRH ethylamide are accompanied by a marked loss of LH/hCG and FSH receptors in ovarian tissue. The injection of 1,3, or 10 ng LHRH-EA in intact rats has no significant effect on ovarian LH receptor levels. A study of the direct action of LHRH agonists at the ovarian level demonstrates a close relationship between the binding activity of a large series of LHRH agonists and antagonists in the anterior pituitary gland and the ovary. Inhibition of testicular steroidogenesis in man by treatment with a potent LHRH agonist is also demonstrated. Intranasal administration of LHRH ethylamide has luteolytic effects in normal women. Daily administration of LHRH-EA inhibited ovulation in all but 2 of 89 treatment

  4. Monte-Carlo Analysis of the Composition Dependence of the Flory-Huggins Interaction Parameter in PE-dPE Blends

    NASA Astrophysics Data System (ADS)

    Russell, Travis; Edwards, Brian; Khomami, Bamin

    2012-02-01

    Experimental SANS research displays a significant concentration dependence of the Flory-Huggins (χ) interaction parameter in isotopic polymer blends. At the extremes of the deuterated polymer concentration (φD< 0.2, φD > 0.8), χ is shown to exhibit a greater than fourfold increase over its value at φD = 0.5. However, despite numerous attempts to theoretically describe the nature of this phenomenon, consensus is still lacking regarding the mechanisms at work in this system. This study uses free-space, spatially discretized Monte Carlo simulations to investigate the χ composition dependence of PE-dPE blends. Initial simulations are run on simple Lennard-Jones fluids to display the capability of the simulation method to track local concentration and energy across the discretized space as well as to investigate the concentration dependence of the radial distribution function, g(r), and structure factor, S(k). After which, MC simulations are performed on the PE-dPE system with varying φD. Both local and average system energies are tracked in addition to g(r) and S(k). The Flory-Huggins interaction parameter is then calculated using the Random Phase Approximation.

  5. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    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.

  6. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    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.

  7. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    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. PMID:25437461

  8. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    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. PMID:25326839

  9. PPAR dual agonists: are they opening Pandora's Box?

    PubMed

    Balakumar, Pitchai; Rose, Madhankumar; Ganti, Subrahmanya S; Krishan, Pawan; Singh, Manjeet

    2007-08-01

    Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARalpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in

  10. Identification of M-CSF agonists and antagonists

    SciTech Connect

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  11. Global Gridded Emission Inventories of Pentabrominated Diphenyl Ether (PeBDE)

    NASA Astrophysics Data System (ADS)

    Li, Yi-Fan; Tian, Chongguo; Yang, Meng; Jia, Hongliang; Ma, Jianmin; Li, Dacheng

    2010-05-01

    Polybrominated diphenyl ethers (PBDEs) are flame retardants widely used in many everyday products such as cars, furniture, textiles, and other electronic equipment. The commercial PBDEs have three major technical mixtures: penta-(PeBDE), octa-(OBDE) and decabromodiphenyl ethers (DeBDE). PeBDE is a mixture of several BDE congeners, such as BDE-47, -99, and -100, and has been included as a new member of persistent organic pollutants (POPs) under the 2009 Stockholm Convention. In order to produce gridded emission inventories of PeBDE on a global scale, information of production, consumption, emission, and physiochemical properties of PeBDE have been searched for published papers, government reports, and internet publications. A methodology to estimate the emissions of PeBDE has been developed and global gridded emission inventories of 2 major congener in PeBDE mixture, BDE-47 and -99, on a 1 degree by 1degree latitude/longitude resolution for 2005 have been compiled. Using these emission inventories as input data, the Canadian Model for Environmental Transport of Organochlorine Pesticides (CanMETOP) model was used to simulate the transport of these chemicals and their concentrations in air were calculated for the year of 2005. The modeled air concentration of BDE-47 and -99 were compared with the monitoring air concentrations of these two congeners in the same year obtained from renowned international/national monitoring programs, such as Global Atmospheric Passive Sampling (GAPS), the Integrated Atmospheric Deposition Network (IADN), and the Chinese POPs Soil and Air Monitoring Program (SAMP), and significant correlations between the modeled results and the monitoring data were found, indicating the high quality of the produced emission inventories of BDE-47 and -99. Keywords: Pentabrominated Diphenyl Ether (PeBDE), Emission Inventories, Global, Model

  12. Conserved Immune Recognition Hierarchy of Mycobacterial PE/PPE Proteins during Infection in Natural Hosts

    PubMed Central

    Vordermeier, H. Martin; Hewinson, R. Glyn; Wilkinson, Robert J.; Wilkinson, Katalin A.; Gideon, Hannah P.; Young, Douglas B.; Sampson, Samantha L.

    2012-01-01

    The Mycobacterium tuberculosis genome contains two large gene families encoding proteins of unknown function, characterized by conserved N-terminal proline and glutamate (PE and PPE) motifs. The presence of a large number of PE/PPE proteins with repetitive domains and evidence of strain variation has given rise to the suggestion that these proteins may play a role in immune evasion via antigenic variation, while emerging data suggests that some family members may play important roles in mycobacterial pathogenesis. In this study, we examined cellular immune responses to a panel of 36 PE/PPE proteins during human and bovine infection. We observed a distinct hierarchy of immune recognition, reflected both in the repertoire of PE/PPE peptide recognition in individual cows and humans and in the magnitude of IFN-γ responses elicited by stimulation of sensitized host cells. The pattern of immunodominance was strikingly similar between cattle that had been experimentally infected with Mycobacterium bovis and humans naturally infected with clinical isolates of M. tuberculosis. The same pattern was maintained as disease progressed throughout a four-month course of infection in cattle, and between humans with latent as well as active tuberculosis. Detailed analysis of PE/PPE responses at the peptide level suggests that antigenic cross-reactivity amongst related family members is a major determinant in the observed differences in immune hierarchy. Taken together, these results demonstrate that a subset of PE/PPE proteins are major targets of the cellular immune response to tuberculosis, and are recognized at multiple stages of infection and in different disease states. Thus this work identifies a number of novel antigens that could find application in vaccine development, and provides new insights into PE/PPE biology. PMID:22870206

  13. Pharmacogenetics of beta2 adrenergic receptor agonists in asthma management.

    PubMed

    Ortega, V E

    2014-07-01

    Beta2 (β2) adrenergic receptor agonists (beta agonists) are a commonly prescribed treatment for asthma despite the small increase in risk for life-threatening adverse responses associated with long-acting beta agonist (LABA). The concern for life-threatening adverse effects associated with LABA and the inter-individual variability of therapeutic responsiveness to LABA-containing combination therapies provide the rationale for pharmacogenetic studies of beta agonists. These studies primarily evaluated genes within the β2-adrenergic receptor and related pathways; however, recent genome-wide studies have identified novel loci for beta agonist response. Recent studies have identified a role for rare genetic variants in determining beta agonist response and, potentially, the risk for rare, adverse responses to LABA. Before genomics research can be applied to the development of genetic profiles for personalized medicine, it will be necessary to continue adapting to the analysis of an increasing volume of genetic data in larger cohorts with a combination of analytical methods and in vitro studies.

  14. Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli.

    PubMed

    Chatterjee, Manash S; Purvis, Jeremy E; Brass, Lawrence F; Diamond, Scott L

    2010-07-01

    Prediction of cellular response to multiple stimuli is central to evaluating patient-specific clinical status and to basic understanding of cell biology. Cross-talk between signaling pathways cannot be predicted by studying them in isolation and the combinatorial complexity of multiple agonists acting together prohibits an exhaustive exploration of the complete experimental space. Here we describe pairwise agonist scanning (PAS), a strategy that trains a neural network model based on measurements of cellular responses to individual and all pairwise combinations of input signals. We apply PAS to predict calcium signaling responses of human platelets in EDTA-treated plasma to six different agonists (ADP, convulxin, U46619, SFLLRN, AYPGKF and PGE(2)) at three concentrations (0.1, 1 and 10 x EC(50)). The model predicted responses to sequentially added agonists, to ternary combinations of agonists and to 45 different combinations of four to six agonists (R = 0.88). Furthermore, we use PAS to distinguish between the phenotypic responses of platelets from ten donors. Training neural networks with pairs of stimuli across the dose-response regime represents an efficient approach for predicting complex signal integration in a patient-specific disease milieu. PMID:20562863

  15. Strong Antibody Responses to Mycobacterium tuberculosis PE-PGRS62 Protein Are Associated with Latent and Active Tuberculosis▿

    PubMed Central

    Koh, Kah Wee; Soh, Shu E; Seah, Geok Teng

    2009-01-01

    Mycobacterium tuberculosis has a unique family of PE-PGRS proteins with conserved N-terminal domains (PE) containing site-specific proline-glutamine residues and polymorphic GC-rich repetitive sequences (PGRS). Tuberculosis (TB) patients produce antibodies against some such proteins, but it is not clear whether these responses correlate with disease. Clinical groups with different mycobacterium exposure were studied for their seroreactivity to PE-PGRS17 and PE-PGRS62 proteins and their respective PE domains. There were minimal antibody responses against both PE domains and full-length PE-PGRS17, even in patients with active TB. However, patients with active and latent TB showed significantly higher PE-PGRS62-specific immunoglobulin G antibody responses than treated TB patients and mycobacterium-reactive TB contacts without latent infection. Latently infected persons had high anti-PE-PGRS62 responses but low responses to the 38-kDa antigen commonly used for TB serology, while treated TB cases showed the opposite response. Thus, patterns of seroreactivity to PE-PGRS62 correlate with clinical status and are associated with latent TB infection. PMID:19487480

  16. Comparative Analysis of Mycobacterium tuberculosis pe and ppe Genes Reveals High Sequence Variation and an Apparent Absence of Selective Constraints

    PubMed Central

    McEvoy, Christopher R. E.; Cloete, Ruben; Müller, Borna; Schürch, Anita C.; van Helden, Paul D.; Gagneux, Sebastien; Warren, Robin M.; Gey van Pittius, Nicolaas C.

    2012-01-01

    Mycobacterium tuberculosis complex (MTBC) genomes contain 2 large gene families termed pe and ppe. The function of pe/ppe proteins remains enigmatic but studies suggest that they are secreted or cell surface associated and are involved in bacterial virulence. Previous studies have also shown that some pe/ppe genes are polymorphic, a finding that suggests involvement in antigenic variation. Using comparative sequence analysis of 18 publicly available MTBC whole genome sequences, we have performed alignments of 33 pe (excluding pe_pgrs) and 66 ppe genes in order to detect the frequency and nature of genetic variation. This work has been supplemented by whole gene sequencing of 14 pe/ppe (including 5 pe_pgrs) genes in a cohort of 40 diverse and well defined clinical isolates covering all the main lineages of the M. tuberculosis phylogenetic tree. We show that nsSNP's in pe (excluding pgrs) and ppe genes are 3.0 and 3.3 times higher than in non-pe/ppe genes respectively and that numerous other mutation types are also present at a high frequency. It has previously been shown that non-pe/ppe M. tuberculosis genes display a remarkably low level of purifying selection. Here, we also show that compared to these genes those of the pe/ppe families show a further reduction of selection pressure that suggests neutral evolution. This is inconsistent with the positive selection pressure of “classical” antigenic variation. Finally, by analyzing such a large number of genes we were able to detect large differences in mutation type and frequency between both individual genes and gene sub-families. The high variation rates and absence of selective constraints provides valuable insights into potential pe/ppe function. Since pe/ppe proteins are highly antigenic and have been studied as potential vaccine components these results should also prove informative for aspects of M. tuberculosis vaccine design. PMID:22496726

  17. Perception of specific trigeminal chemosensory agonists

    PubMed Central

    Frasnelli, J; Albrecht, J; Bryant, B; Lundström, JN

    2011-01-01

    The intranasal trigeminal system is a third chemical sense in addition to olfaction and gustation. As opposed to smell and taste, we still lack knowledge on the relationship between receptor binding and perception for the trigeminal system. We therefore investigated the sensitivity of the intranasal trigeminal system towards agonists of the trigeminal receptors TRPM8 and TRPA1 by assessing subjects’ ability to identify which nostril has been stimulated in a monorhinal stimulation design. We summed the number of correct identifications resulting in a lateralization score. Stimuli were menthol (activating TRPM8 receptors), eucalyptol (TRPM8), mustard oil (TRPA1) and two mixtures thereof (menthol/eucalyptol and menthol/mustard oil). In addition, we examined the relationship between intensity and lateralization scores and investigated whether intensity evaluation and lateralization scores of the mixtures show additive effects. All stimuli were correctly lateralized significantly above chance. Across subjects the lateralization scores for single compounds activating the same receptor showed a stronger correlation than stimuli activating different receptors. Although single compounds were isointense, the mixture of menthol and eucalyptol (activating only TRPM8) was perceived as weaker and was lateralized less accurately than the mixture of menthol and mustard oil (activating both TRPM8 and TRPA1) suggesting suppression effects in the former mixture. In conclusion, sensitivity of different subpopulations of trigeminal sensory neurons seems to be related, but only to a certain degree. The large coherence in sensitivity between various intranasal trigeminal stimuli suggests that measuring sensitivity to one single trigeminal chemical stimulus may be sufficient to generally assess the trigeminal system’s chemosensitivity. Further, for stimuli activating the same receptor a mixture suppression effect appears to occur similar to that observed in the other chemosensory

  18. Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

    PubMed Central

    Schmidt, Philipp; Ritscher, Lars; Dong, Elizabeth N.; Hermsdorf, Thomas; Cöster, Maxi; Wittkopf, Doreen; Meiler, Jens

    2013-01-01

    The ADP receptor P2Y12 belongs to the superfamily of G protein–coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y12 and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y12. The potency at P2Y12 was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y12, with Y105, E188, R256, Y259, and K280 playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3′-OH of the 2′-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y12 and half of the constitutive active P2Y12 mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y12 but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. PMID:23093496

  19. Suppression of autophagy and antigen presentation by Mycobacterium tuberculosis PE_PGRS47.

    PubMed

    Saini, Neeraj K; Baena, Andres; Ng, Tony W; Venkataswamy, Manjunatha M; Kennedy, Steven C; Kunnath-Velayudhan, Shajo; Carreño, Leandro J; Xu, Jiayong; Chan, John; Larsen, Michelle H; Jacobs, William R; Porcelli, Steven A

    2016-08-15

    Suppression of major histocompatibility complex (MHC) class II antigen presentation is believed to be among the major mechanisms used by Mycobacterium tuberculosis to escape protective host immune responses. Through a genome-wide screen for the genetic loci of M. tuberculosis that inhibit MHC class II-restricted antigen presentation by mycobacteria-infected dendritic cells, we identified the PE_PGRS47 protein as one of the responsible factors. Targeted disruption of the PE_PGRS47 (Rv2741) gene led to attenuated growth of M. tuberculosis in vitro and in vivo, and a PE_PGRS47 mutant showed enhanced MHC class II-restricted antigen presentation during in vivo infection of mice. Analysis of the effects of deletion or over-expression of PE_PGRS47 implicated this protein in the inhibition of autophagy in infected host phagocytes. Our findings identify PE_PGRS47 as a functionally relevant, non-redundant bacterial factor in the modulation of innate and adaptive immunity by M. tuberculosis, suggesting strategies for improving antigen presentation and the generation of protective immunity during vaccination or infection.

  20. Home Assessment of Person-Environment Interaction (HoPE): content validation process.

    PubMed

    Rousseau, Jacqueline; Potvin, Louise; Dutil, Élisabeth; Falta, Patricia

    2013-10-01

    The purpose of this paper is to present the content validation, including a pilot test, of the Home Assessment of the Person-Environment Interaction (HoPE). The HoPE fills a gap for evaluating issues related to home adaptation. Using qualitative methods, a two-phase study was conducted: an expert consultation and a pilot test. The expert consultation was conducted via focus groups with occupational therapists (n = 20), and individual interviews with adults who had undergone home adaptation (n = 5). The pilot test was undertaken using a multiple case study design of four adults awaiting home adaptation. Data were audio-recorded, transcribed, and analyzed using NUD.IST software. In phase 1, experts agreed with the content of HoPE and suggested minor changes. In phase 2, HoPE enabled occupational therapists to identify handicap-creating situations. After both phases, the final version of HoPE is more comprehensive than other current tools and addresses the complex experiences of clients with whom occupational therapists work which suggests a new approach for practice regarding home adaptation. PMID:24102587

  1. Suppression of autophagy and antigen presentation by Mycobacterium tuberculosis PE_PGRS47.

    PubMed

    Saini, Neeraj K; Baena, Andres; Ng, Tony W; Venkataswamy, Manjunatha M; Kennedy, Steven C; Kunnath-Velayudhan, Shajo; Carreño, Leandro J; Xu, Jiayong; Chan, John; Larsen, Michelle H; Jacobs, William R; Porcelli, Steven A

    2016-01-01

    Suppression of major histocompatibility complex (MHC) class II antigen presentation is believed to be among the major mechanisms used by Mycobacterium tuberculosis to escape protective host immune responses. Through a genome-wide screen for the genetic loci of M. tuberculosis that inhibit MHC class II-restricted antigen presentation by mycobacteria-infected dendritic cells, we identified the PE_PGRS47 protein as one of the responsible factors. Targeted disruption of the PE_PGRS47 (Rv2741) gene led to attenuated growth of M. tuberculosis in vitro and in vivo, and a PE_PGRS47 mutant showed enhanced MHC class II-restricted antigen presentation during in vivo infection of mice. Analysis of the effects of deletion or over-expression of PE_PGRS47 implicated this protein in the inhibition of autophagy in infected host phagocytes. Our findings identify PE_PGRS47 as a functionally relevant, non-redundant bacterial factor in the modulation of innate and adaptive immunity by M. tuberculosis, suggesting strategies for improving antigen presentation and the generation of protective immunity during vaccination or infection. PMID:27562263

  2. Adsorption of urease on PE-MCM-41 and its catalytic effect on hydrolysis of urea.

    PubMed

    Hossain, Kazi-Zakir; Monreal, Carlos M; Sayari, Abdelhamid

    2008-03-15

    Pore-expanded MCM-41 (PE-MCM-41) silica exhibits a unique combination of high specific surface area (ca. 1000 m(2)/g), pore size (up to 25 nm) and pore volume (up to 3.5 cm(3)/g). As such, this material is highly suitable for the adsorption of large biomolecules. The current study focused primarily on the application of PE-MCM-41 material as suitable host for urease (nickel-based large metalloenzyme) in controlled hydrolysis of urea. Urease adsorbed on PE-MCM-41, regular MCM-41 and silica gel (SGA) were used as catalysts for urea hydrolysis reaction. Adsorption studies of urease on these materials from aqueous solution at pH 7.2 revealed that the adsorption capacity of PE-MCM-41 (102 mg/g) is significantly higher than that of MCM-41 (56 mg/g) and SGA (21 mg/g). The equilibrium adsorption data were well fitted using the Langmuir-Freundlich model. Furthermore, the kinetic study revealed that the uptake of urease follow the pseudo-first order kinetics. The in vitro urea hydrolysis reaction on pristine urease and different urease-loaded catalysts showed that the rate of hydrolysis reaction is significantly slower on U/PE-MCM-41 compared to that of bulk urease and urease on MCM-41 and SGA. This technique could be an alternative means to the use of urease inhibitors to control the ammonia release from urea fertilizer. PMID:17961995

  3. Adsorption of urease on PE-MCM-41 and its catalytic effect on hydrolysis of urea.

    PubMed

    Hossain, Kazi-Zakir; Monreal, Carlos M; Sayari, Abdelhamid

    2008-03-15

    Pore-expanded MCM-41 (PE-MCM-41) silica exhibits a unique combination of high specific surface area (ca. 1000 m(2)/g), pore size (up to 25 nm) and pore volume (up to 3.5 cm(3)/g). As such, this material is highly suitable for the adsorption of large biomolecules. The current study focused primarily on the application of PE-MCM-41 material as suitable host for urease (nickel-based large metalloenzyme) in controlled hydrolysis of urea. Urease adsorbed on PE-MCM-41, regular MCM-41 and silica gel (SGA) were used as catalysts for urea hydrolysis reaction. Adsorption studies of urease on these materials from aqueous solution at pH 7.2 revealed that the adsorption capacity of PE-MCM-41 (102 mg/g) is significantly higher than that of MCM-41 (56 mg/g) and SGA (21 mg/g). The equilibrium adsorption data were well fitted using the Langmuir-Freundlich model. Furthermore, the kinetic study revealed that the uptake of urease follow the pseudo-first order kinetics. The in vitro urea hydrolysis reaction on pristine urease and different urease-loaded catalysts showed that the rate of hydrolysis reaction is significantly slower on U/PE-MCM-41 compared to that of bulk urease and urease on MCM-41 and SGA. This technique could be an alternative means to the use of urease inhibitors to control the ammonia release from urea fertilizer.

  4. PE and PS Lipids Synergistically Enhance Membrane Poration by a Peptide with Anticancer Properties.

    PubMed

    Leite, Natália Bueno; Aufderhorst-Roberts, Anders; Palma, Mario Sergio; Connell, Simon D; Ruggiero Neto, João; Beales, Paul A

    2015-09-01

    Polybia-MP1 (MP1) is a bioactive host-defense peptide with known anticancer properties. Its activity is attributed to excess serine (phosphatidylserine (PS)) on the outer leaflet of cancer cells. Recently, higher quantities of phosphatidylethanolamine (PE) were also found at these cells' surface. We investigate the interaction of MP1 with model membranes in the presence and absence of POPS (PS) and DOPE (PE) to understand the role of lipid composition in MP1's anticancer characteristics. Indeed we find that PS lipids significantly enhance the bound concentration of peptide on the membrane by a factor of 7-8. However, through a combination of membrane permeability assays and imaging techniques we find that PE significantly increases the susceptibility of the membrane to disruption by these peptides and causes an order-of-magnitude increase in membrane permeability by facilitating the formation of larger transmembrane pores. Significantly, atomic-force microscopy imaging reveals differences in the pore formation mechanism with and without the presence of PE. Therefore, PS and PE lipids synergistically combine to enhance membrane poration by MP1, implying that the combined enrichment of both these lipids in the outer leaflet of cancer cells is highly significant for MP1's anticancer action. These mechanistic insights could aid development of novel chemotherapeutics that target pathological changes in the lipid composition of cancerous cells.

  5. PE and PS Lipids Synergistically Enhance Membrane Poration by a Peptide with Anticancer Properties

    PubMed Central

    Leite, Natália Bueno; Aufderhorst-Roberts, Anders; Palma, Mario Sergio; Connell, Simon D.; Neto, João Ruggiero; Beales, Paul A.

    2015-01-01

    Polybia-MP1 (MP1) is a bioactive host-defense peptide with known anticancer properties. Its activity is attributed to excess serine (phosphatidylserine (PS)) on the outer leaflet of cancer cells. Recently, higher quantities of phosphatidylethanolamine (PE) were also found at these cells’ surface. We investigate the interaction of MP1 with model membranes in the presence and absence of POPS (PS) and DOPE (PE) to understand the role of lipid composition in MP1’s anticancer characteristics. Indeed we find that PS lipids significantly enhance the bound concentration of peptide on the membrane by a factor of 7–8. However, through a combination of membrane permeability assays and imaging techniques we find that PE significantly increases the susceptibility of the membrane to disruption by these peptides and causes an order-of-magnitude increase in membrane permeability by facilitating the formation of larger transmembrane pores. Significantly, atomic-force microscopy imaging reveals differences in the pore formation mechanism with and without the presence of PE. Therefore, PS and PE lipids synergistically combine to enhance membrane poration by MP1, implying that the combined enrichment of both these lipids in the outer leaflet of cancer cells is highly significant for MP1’s anticancer action. These mechanistic insights could aid development of novel chemotherapeutics that target pathological changes in the lipid composition of cancerous cells. PMID:26331251

  6. RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists

    PubMed Central

    2012-01-01

    Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates. PMID:24900488

  7. Dihydrocodeine/Agonists for Alcohol Dependents

    PubMed Central

    Ulmer, Albrecht; Müller, Markus; Frietsch, Bernhard

    2012-01-01

    Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients. Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC) to 102 heavily alcohol addicted patients, later, also Buprenorphine, Clomethiazole (>6 weeks), Baclofen, and in one case Amphetamine, each on individual indication. This paper focuses on the data with DHC, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-steps scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details. Conclusion: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around 1/4 of the patients already. Many further

  8. Multivariate optimization and validation of a capillary electrophoresis method for the simultaneous determination of dextromethorphan hydrobromur, phenylephrine hydrochloride, paracetamol and chlorpheniramine maleate in a pharmaceutical preparation using response surface methodology.

    PubMed

    Palabiyik, I Murat; Onur, Feyyaz

    2010-01-01

    A fast, accurate, precise and sensitive capillary electrophoresis method for the simultaneous determination of dextromethorphan hydrobromide, phenylephrine hydrochloride, paracetamol and chlorpheniramine maleate has been developed. Response surface methodology with a central composite design was used for optimization of the concentration of the buffer, pH of the buffer and applied voltage. Therefore, working with Na(2)HPO(4) buffer (pH 8.00, 0.01 M) at 20 kV as an applied voltage in the capillary electrophoresis method were found to be suitable; under these optimal conditions, these four active ingredients were separated in about 7 min. This developed method was validated and successfully applied to a pharmaceutical preparation, sugar-coated tablet, and the results were compared with a high-performance liquid chromatographic method developed by us.

  9. A nuclear-directed human pancreatic ribonuclease (PE5) targets the metabolic phenotype of cancer cells.

    PubMed

    Vert, Anna; Castro, Jessica; Ribó, Marc; Benito, Antoni; Vilanova, Maria

    2016-04-01

    Ribonucleases represent a new class of antitumor RNA-damaging drugs. However, many wild-type members of the vertebrate secreted ribonuclease family are not cytotoxic because they are not able to evade the cytosolic ribonuclease inhibitor. We previously engineered the human pancreatic ribonuclease to direct it to the cell nucleus where the inhibitor is not present. The best characterized variant is PE5 that kills cancer cells through apoptosis mediated by the p21(WAF1/CIP1) induction and the inactivation of JNK. Here, we have used microarray-derived transcriptional profiling to identify PE5 regulated genes on the NCI/ADR-RES ovarian cancer cell line. RT-qPCR analyses have confirmed the expression microarray findings. The results show that PE5 cause pleiotropic effects. Among them, it is remarkable the down-regulation of multiple genes that code for enzymes involved in deregulated metabolic pathways in cancer cells.

  10. A nuclear-directed human pancreatic ribonuclease (PE5) targets the metabolic phenotype of cancer cells

    PubMed Central

    Vert, Anna; Castro, Jessica; Ribó, Marc; Benito, Antoni; Vilanova, Maria

    2016-01-01

    Ribonucleases represent a new class of antitumor RNA-damaging drugs. However, many wild-type members of the vertebrate secreted ribonuclease family are not cytotoxic because they are not able to evade the cytosolic ribonuclease inhibitor. We previously engineered the human pancreatic ribonuclease to direct it to the cell nucleus where the inhibitor is not present. The best characterized variant is PE5 that kills cancer cells through apoptosis mediated by the p21WAF1/CIP1 induction and the inactivation of JNK. Here, we have used microarray-derived transcriptional profiling to identify PE5 regulated genes on the NCI/ADR-RES ovarian cancer cell line. RT-qPCR analyses have confirmed the expression microarray findings. The results show that PE5 cause pleiotropic effects. Among them, it is remarkable the down-regulation of multiple genes that code for enzymes involved in deregulated metabolic pathways in cancer cells. PMID:26918450

  11. Aggregation behaviour of PE-PEP copolymers and the winterization of diesel fuel

    NASA Astrophysics Data System (ADS)

    Monkenbusch, M.; Schneiders, D.; Richter, D.; Willner, L.; Leube, W.; Fetters, L. J.; Huang, J. S.; Lin, M.

    2000-03-01

    Results from multicontrast SANS investigations of aggregates that form on cooling a solution of polyethylene(PE)-polyethylenepropylene(PEP) block copolymer in decane are reported. The PE-cores form extended crystalline platelets covered by a “brush” of PEP-“hairs” on both sides. Added wax (paraffin) is taken up by these aggregates. Decane may be considered as a model for diesel fuel and the waxes as contaminants in diesel fuel that crystallize at low temperatures and clog the filters of engines. It is explained why compounds of the PE-PEP family efficiently reduce the minimum temperature down to which these fuels may be used by directing the wax precipitation/nucleation into aggregates that are small enough to pass the filters.

  12. Dual roles of Atg8−PE deconjugation by Atg4 in autophagy

    PubMed Central

    Yu, Zhong-Qiu; Ni, Tao; Hong, Bing; Wang, Hai-Yan; Jiang, Fen-Jun; Zou, Shenshen; Chen, Yong; Zheng, Xi-Long; Klionsky, Daniel J.; Liang, Yongheng; Xie, Zhiping

    2012-01-01

    Modification of target molecules by ubiquitin or ubiquitin-like (Ubl) proteins is generally reversible. Little is known, however, about the physiological function of the reverse reaction, deconjugation. Atg8 is a unique Ubl protein whose conjugation target is the lipid phosphatidylethanolamine (PE). Atg8 functions in the formation of double-membrane autophagosomes, a central step in the well-conserved intracellular degradation pathway of macroautophagy (hereafter autophagy). Here we show that the deconjugation of Atg8−PE by the cysteine protease Atg4 plays dual roles in the formation of autophagosomes. During the early stage of autophagosome formation, deconjugation releases Atg8 from non-autophagosomal membranes to maintain a proper supply of Atg8. At a later stage, the release of Atg8 from intermediate autophagosomal membranes facilitates the maturation of these structures into fusion-capable autophagosomes. These results provide new insights into the functions of Atg8−PE and its deconjugation. PMID:22652539

  13. Surface modification by γ-ray-induced grafting of PDMAEMA/PEGMEMA onto PE films

    NASA Astrophysics Data System (ADS)

    Titaux, G. A.; Contreras-García, A.; Bucio, E.

    2009-07-01

    Radiation grafting of poly[2-(dimethylamino) ethyl methacrylate] (PDMAEMA) and poly(ethylene glycol) methyl ether methacrylate (PEGMEMA) onto polyethylene (PE) films was synthesized using gamma radiation from a 60Co source. PE was modified by the PDMAEMA and PEGMEMA by pre-irradiation and one-step method. Grafting as a function of the pre-irradiation dose between 50 and 200 kGy, dose rate of 9 kGy h -1, and monomer concentration 50% of PDMAEMA/PEGMEMA (1/1) in toluene. The characterization of the graft copolymer obtained was carried out by FTIR-ATR, TGA, and DSC. Stimuli-responsive behavior and critical pH point were studied by swelling in water, pH and thermo-responsive films of PE-g-(DMAEMA/PEGMEMA) presented a lower critical solution temperature (LCST) of 55 °C and critical pH point around 8.5.

  14. Fate of ultrahigh molecular weight polyethylene (UHMW-PE) wear debris in patients with hip implants.

    PubMed

    Witkiewicz, H; Vidovszky, T; Turner, R T; Rock, M G; Morrey, B F; Bolander, M E

    1993-01-01

    The process of ultrahigh molecular weight polyethylene (UHMW-PE) breakdown, started at the articular surface of the cup, continues in small fragments after generation. An assiduous interaction between the UHMW-PE particles and the host cells leads to oxidative changes of the UHMW-PE and to size reduction of the particles simultaneous with transporting them toward, and finally by, lymphatic or blood vessels. The particles are mobilized by means of enzymatic, extracellular matrix-degrading activity of cells that have phagocytosed them or adhered to them. Together, these characteristics indicate an attempt by the natural cellular immunity system to eliminate the implant wear debris. Macrophages are the main effector cells acting as scavengers; however, excessive amount of the wear debris evokes phagocytic activity of cells other than macrophages as well. PMID:11539273

  15. Fabrication and properties of HDPE/CF/CaCO3/PE-g-MAH quaternary composites

    NASA Astrophysics Data System (ADS)

    Wang, X.-L.; Ming, H.; Yin, H.

    2015-07-01

    In this research, carbon fiber (CF) was taken as reinforcing filler, nano calcium carbonate (CaCO3) was taken as toughener, maleic anhydride grafted polyethylene (PE-g-MAH) was taken as compatibilizer for high density polyethylene (HDPE) modification. Through orthogonal test, the influence of different amount of ingredient CF, CaCO3 and PE-g-MAH on the mechanical properties of the HDPE composites was researched. The optimal composition of the quaternary composites with the good toughness and high strength was obtained.

  16. Honokiol: A non-adipogenic PPARγ agonist from nature☆

    PubMed Central

    Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H.

    2013-01-01

    Background Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators. Methods We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists. Results The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. Conclusion We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo. General significance This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. PMID:23811337

  17. Modification of opiate agonist binding by pertussis toxin

    SciTech Connect

    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.

  18. Sound production during agonistic behavior of male Drosophila melanogaster

    PubMed Central

    Jonsson, Thorin; Kravitz, Edward A

    2011-01-01

    Male Drosophila fruit flies acquire and defend territories in order to attract females for reproduction. Both, male-directed agonistic behavior and female-directed courtship consist of series of recurrent stereotypical components. Various studies demonstrated the importance of species-specific sound patterns generated by wing vibration as being critical for male courtship success. In this study we analyzed the patterns and importance of sound signals generated during agonistic interactions of male Drosophila melanogaster. In contrast to acoustic courtship signals that consist of sine and pulse patterns and are generated by one extended wing, agonistic signals lack sine-like components and are generally produced by simultaneous movements of both wings. Though intra-pulse oscillation frequencies (carrier frequency) are identical, inter-pulse intervals are twice as long and more variable in aggression signals than in courtship songs, where their precise temporal pattern serves species recognition. Acoustic signals accompany male agonistic interactions over their entire course but occur particularly often after tapping behavior which is a major way to identify the gender of the interaction partner. Since similar wing movements may either be silent or generate sound and wing movements with sound have a greater impact on the subsequent behavior of a receiver, sound producing wing movements seem to be generated intentionally to serve as a specific signal during fruit fly agonistic encounters. PMID:20953152

  19. Radiation therapy generates platelet-activating factor agonists

    PubMed Central

    Sahu, Ravi P.; Harrison, Kathleen A.; Weyerbacher, Jonathan; Murphy, Robert C.; Konger, Raymond L.; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R.; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F.; Travers, Jeffrey B.

    2016-01-01

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  20. Radiation therapy generates platelet-activating factor agonists.

    PubMed

    Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan; Murphy, Robert C; Konger, Raymond L; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F; Travers, Jeffrey B

    2016-04-12

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  1. Tolerance with beta 2-adrenoceptor agonists: time for reappraisal.

    PubMed Central

    Grove, A; Lipworth, B J

    1995-01-01

    1. In spite of the widespread use of beta 2-adrenoceptor agonists in the treatment of asthma controversy continues regarding their possible role in increasing asthma mortality and morbidity. There is however no evidence available to suggest that tolerance to the bronchodilator or anti-bronchoconstrictor effects of these drugs is responsible for the deleterious effects reported with the regular use of bronchodilators. 2. There is no conclusive evidence to suggest that tolerance develops to the bronchodilator effects of short-acting beta 2-adrenoceptor agonists. Tolerance does however appear to develop to the anti-bronchoconstrictor effects of these drugs. 3. With regard to the long-acting beta 2-adrenoceptor agonists, there is evidence to suggest that tolerance develops both to their anti-bronchoconstrictor, and bronchodilator effects. Tolerance was however demonstrated in the presence of improved symptom control, therefore the clinical relevance of this phenomenon is uncertain. 4. Systemic corticosteroids can modulate lymphocyte beta 2-adrenoceptor function both preventing, and reversing tolerance. The situation regarding the effects of systemic or inhaled corticosteroids on modulating bronchodilator responses in asthmatics is less clear. There is some evidence to suggest that inhaled corticosteroids are unable to prevent bronchodilator or systemic tolerance to long-acting beta 2-adrenoceptor agonists. 5. On the basis of the current evidence, the British Thoracic Society guidelines for the management of asthma appear appropriate with regard to their recommendations for the use of long-acting beta 2-adrenoceptor agonists. PMID:7742147

  2. Current issues with beta2-adrenoceptor agonists: historical background.

    PubMed

    Tattersfield, Anne E

    2006-01-01

    The discovery that dessicated adrenal glands had beneficial effects in asthma arose in 1900 following a vogue for studying organotherapy at the end of the 19th century. The adrenal hormone adrenaline was found to have sympathomimetic properties and was isolated and synthesized in 1901. The first nonselective beta-agonist, isoproterenol, was isolated in 1940, followed by the development of selective beta2-agonists in the 1960s and the introduction of the long-acting beta2-agonists in the 1990s. The introduction of beta2-selectivity reduced adverse effects, as did developments in inhaler technology that allowed subjects to inhale much smaller doses of drug selectively to the airways. The beta2-agonists are some of the more important drugs to have been developed in the 20th century. Excessive doses can cause problems, and attempts to maximize the benefit from beta2-agonists and to reduce adverse effects has led to considerable epidemiological, clinical, and mechanistic research over the last 50 yr.

  3. Confounding of the Comparative Safety of Prenatal Opioid Agonist Therapy

    PubMed Central

    Brogly, Susan B; Hahn, Kristen A; Diaz, Sonia Hernandez; Werler, Martha

    2016-01-01

    Prenatal opioid agonist therapy with methadone or buprenorphine prevents maternal illicit opioid use and withdrawal and improves pregnancy outcomes compared to heroin use alone. Historically, methadone has been the first-line opioid agonist therapy for pregnant opioid dependent women; in recent years buprenorphine has become first-line treatment for some opioid dependent pregnant women. While there is some evidence of better outcomes in neonates exposed to buprenorphine vs. methadone, the effect of confounding from differences in women who use buprenorphine and methadone has not been carefully examined in most studies. This review explores mechanisms by which confounding can arise in measuring associations between prenatal buprenorphine vs. methadone exposure on neonatal outcomes using a graphical approach, directed acyclic graphs. The goal of this paper is to facilitate better understanding of the factors influencing neonatal abstinence syndrome and accurate assessment of the comparative safety of opioid agonist therapies on the neonate. PMID:27547489

  4. Adenosine receptor agonists for promotion of dermal wound healing

    PubMed Central

    Valls, María D.; Cronstein, Bruce N.; Montesinos, M. Carmen

    2009-01-01

    Wound healing is a dynamic and complex process that involves a well coordinated, highly regulated series of events including inflammation, tissue formation, revascularization and tissue remodeling. However, this orderly sequence is impaired in certain pathophysiological conditions such as diabetes mellitus, venous insufficiency, chronic glucocorticoid use, aging and malnutrition. Together with proper wound care, promotion of the healing process is the primary objective in the management of chronic poorly healing wounds. Recent studies have demonstrated that A2A adenosine receptor agonists promote wound healing in normal and diabetic animals and one such agonist, Sonedenoson, is currently being evaluated as a prospective new therapy of diabetic foot ulcers. We will review the mechanisms by which adenosine receptor activation affects the function of the cells and tissues that participate in wound healing, emphasizing the potential beneficial impact of adenosine receptor agonists in diabetic impaired healing. PMID:19041853

  5. Design, evaluation, and comparison of ghrelin receptor agonists and inverse agonists as suitable radiotracers for PET imaging.

    PubMed

    Chollet, Constance; Bergmann, Ralf; Pietzsch, Jens; Beck-Sickinger, Annette G

    2012-04-18

    Ghrelin agonist and inverse agonist radiotracers, suitable for positron emission tomography (PET), were developed to study the behavior of ghrelin receptor ligands in vivo and for further design of druggable peptides. The target peptides were synthesized on solid support and conjugated to the bifunctional chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), which is known to form a stable complex with Ga(3+). Complexation with (68)Ga could be achieved under mild conditions and led to radiotracers with high radiochemical purity and specific activity. The biological activity of the radiotracers was evaluated in vitro by an inositol phosphate turnover assay. Pharmacokinetic profile and metabolic stability of the (68)Ga-NODAGA-radiotracers were investigated by small animal PET in rodent. Ghrelin derived agonists presented very high kidney accumulation, negligible tissue distribution, fast blood clearance, and poor stability in blood. Contrarily, the inverse agonist radiotracer exhibited very high stability in blood, large diffusion in tissues, reasonable kidney and liver metabolism, and slow blood clearance. This pharmacokinetic profile makes the ghrelin inverse agonist motif KwFwLL-CONH(2) suitable for further development of radiotracers and a promising lead to design peptide-based therapeutics against obesity. PMID:22372770

  6. Agonist treatment in opioid use: advances and controversy.

    PubMed

    Viswanath, Biju; Chand, Prabhat; Benegal, Vivek; Murthy, Pratima

    2012-06-01

    Opioid dependence is a chronic relapsing condition which requires comprehensive care; pharmacological agents form the mainstay of its long term treatment. The two most popular approaches are the harm reduction method using agonists and the complete abstinence method using antagonists. Currently, particularly from the harm minimization perspective and the low feasibility of an abstinence based approach, there is an increasing trend toward agonist treatment. The use of buprenorphine has gained popularity in view of its safety profile and the availability of the buprenorphine-naloxone combination has made it popular as a take-home treatment. This review outlines the pharmacological advances and controversies in this area. PMID:22813654

  7. Insect Nicotinic Receptor Agonists as Flea Adulticides in Small Animals

    PubMed Central

    Vo, Dai Tan; Hsu, Walter H.; Martin, Richard J.

    2013-01-01

    Fleas are significant ectoparasites of small animals. They can be a severe irritant to animals and serve as a vector for a number of infectious diseases. In this article, we discuss the pharmacological characteristics of four insect nicotinic acetylcholine receptor (nAChR) agonists used as fleacides in dogs and cats, which include three neonicotinoids (imidacloprid, nitenpyram, and dinotefuran) and spinosad. Insect nAChR agonists are one of the most important new classes of insecticides, which are used to control sucking insects both on plants and on companion animals. These new compounds provide a new approach for practitioners to safely and effectively eliminate fleas. PMID:20646191

  8. Beta2-agonist extraction procedures for chromatographic analysis.

    PubMed

    dos Ramos, F J

    2000-06-01

    Normally, different procedures were necessary to prepare sample matrices for chromatographic determination of beta2-agonists. The present review includes sampling, pre-treatment and extraction/purification for urine, plasma, liver, meat, feeds, hair and milk powder, as previous steps for chromatographic analysis of beta2-agonists. Six methodologies were especially revised for extraction/purification namely, liquid-liquid extraction, solid-phase extraction (SPE), matrix solid-phase dispersion, immunoaffinity chromatography, dialysis and supercritical fluid extraction. SPE was discussed in detail and five mechanisms were described: adsorption, apolar, polar, ion-exchange and mixed phase. A brief conclusion in this field was also outlined.

  9. Addressing Educational Reform: Exploring PE Metrics as a System to Measure Student Achievement in Physical Education

    ERIC Educational Resources Information Center

    Hushman, Glenn; Hushman, Carolyn; Carbonneau, Kira

    2015-01-01

    The current educational reform movement in the United States is focused on measuring the effectiveness of teachers. One component of teacher effectiveness is student achievement. The effectiveness of using PE Metrics as a measure of student achievement in a physical activity setting with a low socioeconomic, culturally diverse population was…

  10. "Really on the Ball": Exploring the Implications of Teachers' PE-CPD Experience

    ERIC Educational Resources Information Center

    Elliot, Dely L.; Campbell, Theresa

    2015-01-01

    Continuing professional development (CPD) is currently high on the Scottish Education agenda. Recent curriculum reform in Scotland, with the introduction of Curriculum for Excellence, places physical education (PE) at the forefront for its role in directly supporting learners' mental, emotional, social and physical well-being. This emphasis…

  11. The Disciplinary and Pleasurable Spaces of Boys' PE--The Art of Distributions

    ERIC Educational Resources Information Center

    Gerdin, Göran

    2016-01-01

    In taking heed of the so-called "spatial turn" in social theory this paper explores how the spatial intersects with boys' performances of gender and (dis)pleasures in school physical education (PE). In particular, the paper aims to contribute to our understanding of how the organisation and implementation of physical and social spaces in…

  12. Development of PE Metrics Elementary Assessments for National Physical Education Standard 1

    ERIC Educational Resources Information Center

    Dyson, Ben; Placek, Judith H.; Graber, Kim C.; Fisette, Jennifer L.; Rink, Judy; Zhu, Weimo; Avery, Marybell; Franck, Marian; Fox, Connie; Raynes, De; Park, Youngsik

    2011-01-01

    This article describes how assessments in PE Metrics were developed following six steps: (a) determining test blueprint, (b) writing assessment tasks and scoring rubrics, (c) establishing content validity, (d) piloting assessments, (e) conducting item analysis, and (f) modifying the assessments based on analysis and expert opinion. A task force,…

  13. PeV Neutrinos Observed by IceCube from Cores of Active Galactic Nuclei

    NASA Technical Reports Server (NTRS)

    Stecker, Floyd W.

    2013-01-01

    I show that the high energy neutrino flux predicted to arise from active galactic nuclei cores can explain the PeV neutrinos detected by IceCube without conflicting with the constraints from the observed extragalactic cosmic-ray and gamma-ray backgrounds.

  14. PE on YouTube--Investigating Participation in Physical Education Practice

    ERIC Educational Resources Information Center

    Quennerstedt, Mikael

    2013-01-01

    Background: In this article, students' diverse ways of participating in physical education (PE) practice shown in clips on YouTube were investigated. YouTube is the largest user-generated video-sharing website on the Internet, where different video content is presented. The clips on YouTube, as used in this paper, can be seen as a user-generated…

  15. Representing Valued Bodies in PE: A Visual Inquiry with British Asian Girls

    ERIC Educational Resources Information Center

    Hill, Joanne; Azzarito, Laura

    2012-01-01

    Background: Status or value in sport and physical education (PE) contexts is often associated with performances of highly proficient sporting bodies, which produce hierarchies of privileged and marginalised gendered and racialised positions. This may be communicated through text and images shared within school, physical cultures and media that…

  16. PE: It's Just Me: Physically Active and Healthy Teacher Bodies

    ERIC Educational Resources Information Center

    Wrench, Alison; Garrett, Robyne

    2015-01-01

    This paper focuses on the significance of embodied understandings to the emerging subjectivities and pedagogical practices of pre-service teachers undertaking a Physical Education (PE) specialisation through a B.Ed. (primary/middle). Data from a research project conducted at an Australian university with seven pre-service teachers will be…

  17. Not Your Father's PE: Obesity, Exercise, and the Role of Schools

    ERIC Educational Resources Information Center

    Cawley, John; Meyerhoefer, Chad; Newhouse, David

    2006-01-01

    American children are gaining weight at an alarming rate. Since the 1960s, according to the Centers for Disease Control and Prevention (CDC), the percentage of American six- to eleven-year-olds who fall into the CDC's highest weight classification for children has almost quadrupled. Requiring more physical education (PE) seems like a logical…

  18. 23 CFR 661.33 - What percentage of IRRBP funding is available for PE and construction?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... construction? 661.33 Section 661.33 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD BRIDGE PROGRAM § 661.33 What percentage of IRRBP funding is available for PE and construction? Up to 15 percent of the funding made available in any...

  19. 23 CFR 661.33 - What percentage of IRRBP funding is available for PE and construction?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... construction? 661.33 Section 661.33 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD BRIDGE PROGRAM § 661.33 What percentage of IRRBP funding is available for PE and construction? Up to 15 percent of the funding made available in any...

  20. A role for Atg8–PE deconjugation in autophagosome biogenesis

    PubMed Central

    Nair, Usha; Yen, Wei-Lien; Mari, Muriel; Cao, Yang; Xie, Zhiping; Baba, Misuzu; Reggiori, Fulvio; Klionsky, Daniel J.

    2012-01-01

    Formation of the autophagosome is likely the most complex step of macroautophagy, and indeed it is the morphological and functional hallmark of this process; accordingly, it is critical to understand the corresponding molecular mechanism. Atg8 is the only known autophagy-related (Atg) protein required for autophagosome formation that remains associated with the completed sequestering vesicle. Approximately one-fourth of all of the characterized Atg proteins that participate in autophagosome biogenesis affect Atg8, regulating its conjugation to phosphatidylethanolamine (PE), localization to the phagophore assembly site and/or subsequent deconjugation. An unanswered question in the field regards the physiological role of the deconjugation of Atg8–PE. Using an Atg8 mutant that bypasses the initial Atg4-dependent processing, we demonstrate that Atg8 deconjugation is an important step required to facilitate multiple events during macroautophagy. The inability to deconjugate Atg8–PE results in the mislocalization of this protein to the vacuolar membrane. We also show that the deconjugation of Atg8–PE is required for efficient autophagosome biogenesis, the assembly of Atg9-containing tubulovesicular clusters into phagophores/autophagosomes, and for the disassembly of PAS-associated Atg components. PMID:22622160

  1. The phosphatidylethanolamine derivative diDCP-LA-PE mimics intracellular insulin signaling.

    PubMed

    Nishizaki, Tomoyuki; Gotoh, Akinobu; Shimizu, Tadashi; Tanaka, Akito

    2016-06-02

    Insulin facilitates glucose uptake into cells by translocating the glucose transporter GLUT4 towards the cell surface through a pathway along an insulin receptor (IR)/IR substrate 1 (IRS-1)/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis. The newly synthesized phosphatidylethanolamine derivative 1,2-O-bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]-sn-glycero-3-phosphatidylethanolamine (diDCP-LA-PE) has the potential to inhibit protein tyrosine phosphatase 1B (PTP1B) and to directly activate PKCζ, an atypical isozyme, and PKCε, a novel isozyme. PTP1B inhibition enhanced insulin signaling cascades downstream IR/IRS-1 by preventing tyrosine dephosphorylation. PKCζ and PKCε directly activated Akt2 by phosphorylating at Thr309 and Ser474, respectively. diDCP-LA-PE increased cell surface localization of GLUT4 and stimulated glucose uptake into differentiated 3T3-L1 adipocytes, still with knocking-down IR or in the absence of insulin. Moreover, diDCP-LA-PE effectively reduced serum glucose levels in type 1 diabetes (DM) model mice. diDCP-LA-PE, thus, may enable type 1 DM therapy without insulin injection.

  2. The phosphatidylethanolamine derivative diDCP-LA-PE mimics intracellular insulin signaling

    PubMed Central

    Nishizaki, Tomoyuki; Gotoh, Akinobu; Shimizu, Tadashi; Tanaka, Akito

    2016-01-01

    Insulin facilitates glucose uptake into cells by translocating the glucose transporter GLUT4 towards the cell surface through a pathway along an insulin receptor (IR)/IR substrate 1 (IRS-1)/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis. The newly synthesized phosphatidylethanolamine derivative 1,2-O-bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]-sn-glycero-3-phosphatidylethanolamine (diDCP-LA-PE) has the potential to inhibit protein tyrosine phosphatase 1B (PTP1B) and to directly activate PKCζ, an atypical isozyme, and PKCε, a novel isozyme. PTP1B inhibition enhanced insulin signaling cascades downstream IR/IRS-1 by preventing tyrosine dephosphorylation. PKCζ and PKCε directly activated Akt2 by phosphorylating at Thr309 and Ser474, respectively. diDCP-LA-PE increased cell surface localization of GLUT4 and stimulated glucose uptake into differentiated 3T3-L1 adipocytes, still with knocking-down IR or in the absence of insulin. Moreover, diDCP-LA-PE effectively reduced serum glucose levels in type 1 diabetes (DM) model mice. diDCP-LA-PE, thus, may enable type 1 DM therapy without insulin injection. PMID:27251941

  3. But I like PE: Factors Associated with Enjoyment of Physical Education Class in Middle School Girls

    ERIC Educational Resources Information Center

    Barr-Anderson, Daheia J.; Neumark-Sztainer, Dianne; Schmitz, Kathryn H.; Ward, Dianne S.; Conway, Terry L.; Pratt, Charlotte; Baggett, Chris D.; Lytle, Leslie; Pate, Russell R.

    2008-01-01

    The current study examined associations between physical education (PE) class enjoyment and sociodemographic, personal, and perceived school environment factors among early adolescent girls. Participants included 1,511 sixth-grade girls who completed baseline assessments for the Trial of Activity in Adolescent Girls, with 50% indicating they…

  4. 23 CFR 661.41 - After a bridge project has been completed (either PE or construction) what happens with the...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 23 Highways 1 2010-04-01 2010-04-01 false After a bridge project has been completed (either PE or... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD BRIDGE PROGRAM § 661.41 After a bridge project has been completed (either PE or construction) what happens...

  5. 23 CFR 661.41 - After a bridge project has been completed (either PE or construction) what happens with the...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 23 Highways 1 2011-04-01 2011-04-01 false After a bridge project has been completed (either PE or... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD BRIDGE PROGRAM § 661.41 After a bridge project has been completed (either PE or construction) what happens...

  6. Detection of a multi-PeV neutrino-induced muon event from the Northern sky with IceCube

    NASA Astrophysics Data System (ADS)

    Schoenen, Sebastian; Raedel, Leif

    2015-07-01

    We observed a muon event with an energy of multiple PeV originating from a neutrino interaction in the vicinity of the IceCube detector. IceCube is a cubic-kilometer neutrino detector installed in the ice at the geographic South Pole mostly sensitive to neutrinos in the TeV-PeV energy range.

  7. "Governmentality" in the Origins of European Female PE and Sport: The Spanish Case Study (1883-1936)

    ERIC Educational Resources Information Center

    Garcia, Raul Sanchez; Herraiz, Antonio Rivero

    2013-01-01

    The purpose of the paper is twofold: (1) to contribute to the analysis of the origins of modern European female PE and sports from a power perspective, inspired by Foucault's work; and (2) to present a detailed analysis of female PE and sport in Spain (1883-1936) as a specific European case study. It is argued that these physical activities…

  8. "A Clear and Obvious "Ability" to "Perform Physical Activity"": Revisiting Physical Education Teachers' Perceptions of Talent in PE and Sport

    ERIC Educational Resources Information Center

    Croston, Amanda

    2013-01-01

    Background: This paper examines physical education (PE) teachers' perceptions of talent in PE and sport within the context of English policy, where the process of identifying talent has been formalised and supported through specific resources (YST 2009). English policy has merged educational and sporting targets, which has resulted in a shift in…

  9. Swedish Primary-School Teachers' Attitudes to Inclusion--The Case of PE and Pupils with Physical Disabilities

    ERIC Educational Resources Information Center

    Jerlinder, Kajsa; Danermark, Berth; Gill, Peter

    2010-01-01

    Teachers play a decisive role in making inclusive education a reality. The particular case of inclusion in physical education (PE) poses a specific challenge to teaching practice. How PE teachers view inclusion may provide special insights into teachers' general attitudes toward inclusion and inclusive practices in the general school curriculum.…

  10. Game Changers: New Concepts of PE and Sports Programs Are Making It More Fun for Everyone to Play

    ERIC Educational Resources Information Center

    McCollum, Sean

    2012-01-01

    In this article, the author reports an up-and-coming generation of teachers and coaches who are dedicated to inclusive PE practices. They are passionate about helping all kids discover the physical, social, and emotional benefits--as well as pleasures--of physical activity. The benefits of inclusive PE practices are too great to forfeit, says Lynn…

  11. (Re)Telling Lived Experiences in Different Tales: A Potential Pathway in Working towards an Inclusive PE

    ERIC Educational Resources Information Center

    Berg Svendby, Ellen

    2016-01-01

    Existing research reveals that there are large discrepancies between the rhetoric of inclusive practice and what actually takes place in physical education (PE) lessons. PE appears to be a conservative subject, where little has changed over the years, despite increased diversity in schools and new modes of movement in society at large. In this…

  12. 23 CFR 661.41 - After a bridge project has been completed (either PE or construction) what happens with the...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... PROGRAM § 661.41 After a bridge project has been completed (either PE or construction) what happens with... 23 Highways 1 2014-04-01 2014-04-01 false After a bridge project has been completed (either PE or construction) what happens with the excess or surplus funding? 661.41 Section 661.41 Highways FEDERAL...

  13. 23 CFR 661.41 - After a bridge project has been completed (either PE or construction) what happens with the...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... PROGRAM § 661.41 After a bridge project has been completed (either PE or construction) what happens with... 23 Highways 1 2012-04-01 2012-04-01 false After a bridge project has been completed (either PE or construction) what happens with the excess or surplus funding? 661.41 Section 661.41 Highways FEDERAL...

  14. 23 CFR 661.41 - After a bridge project has been completed (either PE or construction) what happens with the...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... PROGRAM § 661.41 After a bridge project has been completed (either PE or construction) what happens with... 23 Highways 1 2013-04-01 2013-04-01 false After a bridge project has been completed (either PE or construction) what happens with the excess or surplus funding? 661.41 Section 661.41 Highways FEDERAL...

  15. P-E Fit as Moderator of the Accountability--Employee Reactions Relationships: Convergent Results across Two Samples

    ERIC Educational Resources Information Center

    Lanivich, Stephen E.; Brees, Jeremy R.; Hochwarter, Wayne A.; Ferris, Gerald R.

    2010-01-01

    The current two-sample investigation, which incorporated Conservation of Resources (COR) and Person-Environment (P-E) fit theories, investigated the interaction effects of felt accountability x P-E fit on the work outcomes of job satisfaction, organizational commitment, depressed mood, and work intensity. Consistent with the conceptual…

  16. Overexpression of PeHA1 enhances hydrogen peroxide signaling in salt-stressed Arabidopsis.

    PubMed

    Wang, Meijuan; Wang, Yang; Sun, Jian; Ding, Mingquan; Deng, Shurong; Hou, Peichen; Ma, Xujun; Zhang, Yuhong; Wang, Feifei; Sa, Gang; Tan, Yeqing; Lang, Tao; Li, Jinke; Shen, Xin; Chen, Shaoliang

    2013-10-01

    The plant plasma membrane (PM) H(+)-ATPase plays a crucial role in controlling K(+)/Na(+) homeostasis under salt stress. Our previous microarray analysis indicated that Populus euphratica retained a higher abundance of PM H(+)-ATPase transcript versus a salt-sensitive poplar. To clarify the roles of the PM H(+)-ATPase in salt sensing and adaptation, we isolated the PM H(+)-ATPase gene PeHA1 from P. euphratica and introduced it into Arabidopsis thaliana. Compared to wild-type, PeHA1-transgenic Arabidopsis had a greater germination rate, root length, and biomass under NaCl stress (50-150 mM). Ectopic expression of PeHA1 remarkably enhanced the capacity to control the homeostasis of ions and reactive oxygen species in salinized Arabidopsis. Flux data from salinized roots showed that transgenic plants exhibited a more pronounced Na(+)/H(+) antiport and less reduction of K(+) influx versus wild-type. Enhanced PM ATP hydrolytic activity, proton pumping, and Na(+)/H(+) antiport in PeHA1-transgenic plants, were consistent to those observed in vivo, i.e., H(+) extrusion, external acidification, and Na(+) efflux. Activities of the antioxidant enzymes ascorbate peroxidase and catalase were typically higher in transgenic seedlings irrespective of salt concentration. In transgenic Arabidopsis roots, H2O2 production was higher under control conditions and increased more rapidly than wild-type when plants were subjected to NaCl treatment. Interestingly, transgenic plants were unable to control K(+)/Na(+) homeostasis when salt-induced H2O2 production was inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase. These observations suggest that PeHA1 accelerates salt tolerance partially through rapid H2O2 production upon salt treatment, which triggers adjustments in K(+)/Na(+) homeostasis and antioxidant defense in Arabidopsis. PMID:23872741

  17. αs-Casein-PE6400 mixtures: surface properties, miscibility and self-assembly.

    PubMed

    Kessler, Anne; Menéndez-Aguirre, Orquidéa; Hinrichs, Jörg; Stubenrauch, Cosima; Weiss, Jochen

    2014-06-01

    Surface properties, miscibility and self-assembly of mixtures of a food-grade αs-casein and the triblock copolymer PE6400 (PEO13-PPO30-PEO13) were examined. The properties at the surface were determined by surface pressure measurements for a 1:1 molar mixture. Comparison of the measured with the calculated isotherms show attractive interactions at surface pressures above 9mN/m. The miscibility gaps of solutions containing 0.004-0.2mmol/l αs-casein and 0.02-0.1mol/l polymer were examined. It was found that a one-phase region exists at distinct mixing ratios and temperatures. Comparison of the cloud points of mixtures of αs-casein and PE6400 with pure αs-casein showed that the presence of the triblock copolymer enhanced the solubility of the protein. The ζ-potential of the αs-casein solution decreased by addition of PE6400 to zero. Our results thus suggest that αs-casein and PE6400 are miscible. The results of the cloud point and ζ-potential measurements were explained by formation of a mixed aggregate where the PPO chains are anchored inside the hydrophobic part of the αs-casein while the PEO chains cover the charged hydrophilic part of the αs-casein thereby leading to an increase of the cloud point and a decrease in ζ-potential. This is in agreement with the attractive interactions between αs-casein and PE6400 as observed via surface pressure measurements at the surface.

  18. αs-Casein-PE6400 mixtures: surface properties, miscibility and self-assembly.

    PubMed

    Kessler, Anne; Menéndez-Aguirre, Orquidéa; Hinrichs, Jörg; Stubenrauch, Cosima; Weiss, Jochen

    2014-06-01

    Surface properties, miscibility and self-assembly of mixtures of a food-grade αs-casein and the triblock copolymer PE6400 (PEO13-PPO30-PEO13) were examined. The properties at the surface were determined by surface pressure measurements for a 1:1 molar mixture. Comparison of the measured with the calculated isotherms show attractive interactions at surface pressures above 9mN/m. The miscibility gaps of solutions containing 0.004-0.2mmol/l αs-casein and 0.02-0.1mol/l polymer were examined. It was found that a one-phase region exists at distinct mixing ratios and temperatures. Comparison of the cloud points of mixtures of αs-casein and PE6400 with pure αs-casein showed that the presence of the triblock copolymer enhanced the solubility of the protein. The ζ-potential of the αs-casein solution decreased by addition of PE6400 to zero. Our results thus suggest that αs-casein and PE6400 are miscible. The results of the cloud point and ζ-potential measurements were explained by formation of a mixed aggregate where the PPO chains are anchored inside the hydrophobic part of the αs-casein while the PEO chains cover the charged hydrophilic part of the αs-casein thereby leading to an increase of the cloud point and a decrease in ζ-potential. This is in agreement with the attractive interactions between αs-casein and PE6400 as observed via surface pressure measurements at the surface. PMID:24727118

  19. Genomic Comparison of PE and PPE Genes in the Mycobacterium avium Complex▿ †

    PubMed Central

    Mackenzie, Nick; Alexander, David C.; Turenne, Christine Y.; Behr, Marcel A.; De Buck, Jeroen M.

    2009-01-01

    The Mycobacterium avium complex (MAC) comprises genomically similar but phenotypically divergent bacteria that inhabit diverse environments and that cause disease in different hosts. In this study, a whole-genome approach was used to examine the polymorphic PE (Pro-Glu) and PPE (Pro-Pro-Glu) gene families, implicated in immunostimulation and virulence. The four major groups of MAC organisms were examined, including the newly sequenced type strains of M. intracellulare and M. avium subsp. avium, plus M. avium subsp. paratuberculosis and M. avium subsp. hominissuis, for the purpose of finding genetic differences that could be exploited to design diagnostic tests specific to these groups and that could help explain their divergence in pathogenesis and host specificity. Unique and missing PPE genes were found in all MAC members except M. avium subsp. avium. Only M. intracellulare had a unique PE gene. Apart from this, most PE and PPE sequences were conserved, with average nucleotide sequence identities of 99.1 and 98.1%, respectively, among the M. avium subspecies, but only 82.9 and 79.7% identities with the PE and PPE sequences of M. intracellulare, respectively. A detailed analysis of the amino acid sequences was performed between M. avium subsp. paratuberculosis and M. avium subsp. hominissuis. Most differences were detected in the PPE proteins, with amino acid substitutions and frame shifts leading to unique amino acid sequences. In conclusion, several unique PPE proteins were identified in MAC organisms next to numerous polymorphisms in both the PE and PPE gene families. These substantial differences could help explain the divergence in phenotypes within the MAC and could lead to diagnostic tests with better discriminatory abilities. PMID:19144814

  20. Sequence Diversity in the pe_pgrs Genes of Mycobacterium tuberculosis Is Independent of Human T Cell Recognition

    PubMed Central

    Copin, Richard; Coscollá, Mireia; Seiffert, Salome N.; Bothamley, Graham; Sutherland, Jayne; Mbayo, Georgetta; Gagneux, Sebastien; Ernst, Joel D.

    2014-01-01

    ABSTRACT The Mycobacterium tuberculosis genome includes the large family of pe_pgrs genes, whose functions are unknown. Because of precedents in other pathogens in which gene families showing high sequence variation are involved in antigenic variation, a similar role has been proposed for the pe_pgrs genes. However, the impact of immune selection on pe_pgrs genes has not been examined. Here, we sequenced 27 pe_pgrs genes in 94 clinical strains from five phylogenetic lineages of the M. tuberculosis complex (MTBC). We found that pe_pgrs genes were overall more diverse than the remainder of the MTBC genome, but individual members of the family varied widely in their nucleotide diversity and insertion/deletion (indel) content: some were more, and others were much less, diverse than the genome average. Individual pe_pgrs genes also differed in the ratio of nonsynonymous to synonymous mutations, suggesting that different selection pressures act on individual pe_pgrs genes. Using bioinformatic methods, we tested whether sequence diversity in pe_pgrs genes might be selected by human T cell recognition, the major mechanism of adaptive immunity to MTBC. We found that the large majority of predicted human T cell epitopes were confined to the conserved PE domain and experimentally confirmed the antigenicity of this domain in tuberculosis patients. In contrast, despite being genetically diverse, the PGRS domains harbored few predicted T cell epitopes. These results indicate that human T cell recognition is not a significant force driving sequence diversity in pe_pgrs genes, which is consistent with the previously reported conservation of human T cell epitopes in the MTBC. PMID:24425732

  1. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents. PMID:27194194

  2. Systemic cancer immunotherapy with Toll-like receptor 7 agonists

    PubMed Central

    Hotz, Christian; Bourquin, Carole

    2012-01-01

    Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy. PMID:22720251

  3. Synthesis and immunostimulatory activity of substituted TLR7 agonists.

    PubMed

    Akinbobuyi, Babatope; Wang, Lei; Upchurch, Katherine C; Byrd, Matthew R; Chang, Charles A; Quintana, Jeremy M; Petersen, Rachel E; Seifert, Zacharie J; Boquin, José R; Oh, SangKon; Kane, Robert R

    2016-09-01

    Fifteen new substituted adenines were synthesized as potential TLR7 agonists. These compounds, along with 9 previously reported compounds, were analyzed for TLR7 activity and for the selective stimulation of B cell proliferation. Several functionalized derivatives exhibit significant activity, suggesting their potential for use as vaccine adjuvants. PMID:27476423

  4. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents.

  5. Synthesis and immunostimulatory activity of substituted TLR7 agonists.

    PubMed

    Akinbobuyi, Babatope; Wang, Lei; Upchurch, Katherine C; Byrd, Matthew R; Chang, Charles A; Quintana, Jeremy M; Petersen, Rachel E; Seifert, Zacharie J; Boquin, José R; Oh, SangKon; Kane, Robert R

    2016-09-01

    Fifteen new substituted adenines were synthesized as potential TLR7 agonists. These compounds, along with 9 previously reported compounds, were analyzed for TLR7 activity and for the selective stimulation of B cell proliferation. Several functionalized derivatives exhibit significant activity, suggesting their potential for use as vaccine adjuvants.

  6. Activation of endplate nicotinic acetylcholine receptors by agonists.

    PubMed

    Auerbach, Anthony

    2015-10-15

    The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and energy changes associated with agonist activation is important for engineering drugs, receptors and synapses. The nicotinic acetylcholine receptor (AChR) is a ∼300kD ion channel that binds the neurotransmitter acetylcholine (ACh) and other cholinergic agonists to elicit electrical responses in the central and peripheral nervous systems. This mini-review is in two sections. First, general concepts of skeletal muscle AChR operation are discussed in terms of energy landscapes for conformational change. Second, adult vs. fetal AChRs are compared with regard to interaction energies between ACh and agonist-site side chains, measured by single-channel electrophysiology and molecular dynamics simulations. The five aromatic residues that form the core of each agonist binding site can be divided into two working groups, a triad (led by αY190) that behaves similarly at all sites and a coupled pair (led by γW55) that has a large influence on affinity only in fetal AChRs. Each endplate AChR has 5 homologous subunits, two of α(1) and one each of β, δ, and either γ (fetal) or ϵ (adult). These nicotinic AChRs have only 2 functional agonist binding sites located in the extracellular domain, at αδ and either αγ or αϵ subunit interfaces. The receptor undergoes a reversible, global isomerization between structures called C and O. The C shape does not conduct ions and has a relatively low affinity for ACh, whereas O conducts cations and has a higher affinity. When both agonist sites are empty (filled only with water) the probability of taking on the O conformation (PO) is low, <10(-6). When ACh molecules occupy the agonist sites the C→O opening rate constant and C↔O gating equilibrium constant increase dramatically. Following a pulse of ACh at the nerve-muscle synapse, the endplate current rises rapidly

  7. Preliminary experiments to estimate the PE.MA.M (PElagic MArine Mesocosm) offshore behaviour

    NASA Astrophysics Data System (ADS)

    Albani, Marta; Piermattei, Viviana; Stefanì, Chiara; Marcelli, Marco

    2016-04-01

    The phytoplankton community is controlled not only by local environmental conditions but also by physical processes occurring on different temporal and spatial scales. Hydrodynamic local conditions play an important role in marine ecosystems. Several studies have shown that hydrodynamic conditions can influence the phytoplankton settling velocity, vertical and horizontal distribution and formation of cyanobacterial blooms. Mesocosms are useful structures to simulate marine environment at mesoscale resolution; allowing to closely approximate biotic or abiotic parameters of interest directly in nature. In this work an innovative structure named PE.MA.M (PElagic MArine Mesocosm) is presented and tested. Laboratory experiments have been conducted in order to observe seasonal variations of biomass behaviour in two different hydrodynamic conditions: outside as well as whithin the PE.MA.M. We have evaluated whether it is possible to isolate a natural system from external water mass hydrodynamic exchanges and to assume that phytoplankton cells' transition is limited at the net and sea interface. Preliminary experiments test the isolating capacity of the net, to determine the currents' attenuation rate and to estimate the possible PE.MA.M. offshore behaviour. In the first investigation, we monitored the diffusion of phytoplankton cells. The PE.MA.M. exterior and interior were simulated using a plexiglass tank divided into two half-tanks (Aout-Bin) by a septum consisting of a net like a PE.MA.M. The tank was filled up with 10 L of water and only the half-tank Aout was filled up with 10 ml of phytoplankton culture (Clorella sp.). We monitored the chlorophyll concentrations for 24 hours. The two tanks had similar concentrations after 4 hours (2.70322 mg/m³ Aout and 2.37245 mg/m3 Bin) and this constant relationship was maintened until the end of the test. In the second investigation we used clod cards to measure water motions.We conducted two experiments within tank, the first

  8. EFFECTS OF TRITIUM EXPOSURE ON UHMW-PE, PTFE, AND VESPEL

    SciTech Connect

    Clark, E; Kirk Shanahan, K

    2006-05-31

    Samples of three polymers, Ultra-High Molecular Weight Polyethylene (UHMW-PE), polytetrafluoroethylene (PTFE, also known as Teflon{reg_sign}), and Vespel{reg_sign} polyimide were exposed to 1 atmosphere of tritium gas at ambient temperature for varying times up to 2.3 years in closed containers. Sample mass and size measurements (to calculate density), spectra-colorimetry, dynamic mechanical analysis (DMA), and Fourier-transform infrared spectroscopy (FT-IR) were employed to characterize the effects of tritium exposure on these samples. Changes of the tritium exposure gas itself were characterized at the end of exposure by measuring total pressure and by mass spectroscopic analysis of the gas composition. None of the polymers exhibited significant changes of density. The color of initially white UHMW-PE and PTFE dramatically darkened to the eye and the color also significantly changed as measured by colorimetry. The bulk of UHMW-PE darkened just like the external surfaces, however the fracture surface of PTFE appeared white compared to the PTFE external surfaces. The white interior could have been formed while the sample was breaking or could reflect the extra tritium dose at the surface directly from the gas. The dynamic mechanical response of UHMW-PE was typical of radiation effects on polymers- an initial stiffening (increased storage modulus) and reduction of viscous behavior after three months exposure, followed by lowering of the storage modulus after one year exposure and longer. The storage modulus of PTFE increased through about nine months tritium exposure, then the samples became too weak to handle or test using DMA. Characterization of Vespel{reg_sign} using DMA was problematic--sample-to-sample variations were significant and no systematic change with tritium exposure could be discerned. Isotopic exchange and incorporation of tritium into UHMW-PE (exchanging for protium) and into PTFE (exchanging for fluorine) was observed by FT-IR using an attenuated

  9. Sex differences in opioid antinociception: kappa and 'mixed action' agonists.

    PubMed

    Craft, R M; Bernal, S A

    2001-08-01

    A number of investigators have shown that male animals are more sensitive than females to the antinociceptive effects of mu-opioid agonists. The present study was conducted to examine sex differences in opioid antinociception in the rat using agonists known to differ in selectivity for and efficacy at kappa- versus mu-receptors. Dose- and time-effect curves were obtained for s.c. U69593, U50488, ethylketazocine, (-)-bremazocine, (-)-pentazocine, butorphanol and nalbuphine on the 50 or 54 degrees C hotplate and warm water tail withdrawal assays; spontaneous locomotor activity was measured 32-52 min post-injection in the same rats. On the hotplate assay, only butorphanol (54 degrees C) and nalbuphine (50 degrees C) were significantly more potent in males than females. On the tail withdrawal assay, all agonists were significantly more potent or efficacious in males than females at one or both temperatures. In contrast, no agonist was consistently more potent in one sex or the other in decreasing locomotor activity. Estrous stage in female rats only slightly influenced opioid effects, accounting for an average of 2.6% of the variance in females' antinociceptive and locomotor responses to drug (50 degrees C experiment). These results suggest that (1) sex differences in antinociceptive effects of opioids are not mu-receptor-dependent, as they may occur with opioids known to have significant kappa-receptor-mediated activity; (2) the mechanisms underlying sex differences in kappa-opioid antinociception may be primarily spinal rather than supraspinal; (3) sex differences in antinociceptive effects of opioid agonists are not secondary to sex differences in their sedative effects. PMID:11418226

  10. Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists.

    PubMed

    Gilmore, John L; Sheppeck, James E; Wang, Jim; Dhar, T G Murali; Cavallaro, Cullen; Doweyko, Arthur M; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Nadler, Steven G; Dodd, John H; Somerville, John E; Barrish, Joel C

    2013-10-01

    SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID:23916594

  11. Expression of the phycoerythrin gene of Gracilaria lemaneiformis (Rhodophyta) in E. coli and evaluation of the bioactivity of recombinant PE

    NASA Astrophysics Data System (ADS)

    Wen, Ruobing; Sui, Zhenghong; Zhang, Xuecheng; Zhang, Shuang; Qin, Song

    2007-10-01

    Phycoerythrin (PE) is one of the most important proteins involved in light capturing during photosynthesis in red algae. Its potential biological activities had gained wide concerns. In the present study, tumor cytotoxic and hydroxyl radical assay were preformed to detect the bioactivity of recombinant PE. Recombinant plasmids pGEX-PE and pBGL were transformed into E. coli BL21 to make two recombinant strains BEX (pGEX-PE) and BGL (pBGL). PE expressing in BEX (pGEX-PE) was validated by SDS-PAGE and Western blotting analysis. SDS-PAGE analysis indicated that the PE-GST fusion protein was mostly inclusion bodies. Specific expression of PE was confirmed by Western blotting analysis. The recombinant E. coli BEX (pGEX-PE) cells were collected and sonicated. The supernatants were reserved for the tumor cytotoxic experiments. The result of tumor cytotoxic assay indicated that the supernatants containing PE had the activity of inhibiting the growth of Hela cells and with the increase of protein concentration, the inhibiting rate increased from 37.31% to 63.26%, which showed significant difference from the control. Hydroxyl radical scavenging effect was tested with supernatants of BEX (pGEX-PE) and BGL (pBGL) cell lysates treated with sonication and heating. For the sonication samples, the scavenging rates of the supernatants of BEX (pGEX-PE) and BGL (pBGL) cell lysates were significantly higher than the negative control BL21(pGEX-4T) ( P<0.02), and the scavenging rates increased slowly following the increase of the protein content. For the heating samples, except for the 0.2 mg mL-1 BGL (pBGL) products, the scavenging effects of the supernatants of BEX (pGEX-PE) and BGL (pBGL) cell lysates were stronger than that of negative control BL21(pGEX-4T). However, the effect intensity was not positively correlated with the increase of the protein concentration. Though a partially decreased hydroxyl radical scavenging activity was led by heating, the biological activity was still

  12. Mechanical, Rheological and Thermal Properties of Polyethylene (PE)/Clay Nanocomposite for Rotomolded Containers

    NASA Astrophysics Data System (ADS)

    Jamshidi, Shadi

    Polyethylene (PE) is widely used to make bulk containers via rotational molding process. Adding 2 wt % and 4 wt % organo-modified clay improved the thermal, barrier and mechanical properties of PE. Clay layers create a tortuous path against the permeant, yielding better barrier properties. Due to the non-polar hydrophobic nature of PE and polar hydrophilic structure of clay minerals, a compatibilizer (PE-g-Maleic Anhydride) was required to enhance the dispersion level of clay in the matrix. In this study High Density Polyethylene (HDPE) and Linear Low Density Polyethylene (LLDPE) layered silicate nanocomposites were melt-compounded with two concentrations of organo-modified clay (2 and 4 weight %). The interaction between nanoclay, compatibilizer and rotomolding grade of PE were examined using X-ray diffraction (XRD), transmission electron microscopy (TEM), mechanical and rheological tests. The XRD results revealed an enhanced basal spacing of layered silicates within both LLDPE nanocomposites at low nanoclay loadings, in agreement with the TEM observations; TEM images showed a uniformly dispersed layered silicates. Through thermal and rheological characterization techniques, the results illustrated that the thermal resistance, elastic and viscous modulus of nanocomposites improved significantly with incorporation of layered silicates. Analyzing all the data showed enhanced properties of LLDPE nanocomposites, which can be attributed to a strong interfacial interaction between the compatibilizer with LLDPE backbone and LLDPE matrices compared with HDPE matrices. The influence of in-house organo-modification of layered silicates on the properties of nanocomposites was compared to that of nanocomposites prepared with commercially available nanoclay (Cloisite 20A). LLDPE nanocomposites prepared by the in-house organo-modified clay showed better mechanical properties, elastic and viscous modulus due to good dispersion of layered silicates as determined by the XRD

  13. Evaluation of the Dmt-Tic pharmacophore: conversion of a potent delta-opioid receptor antagonist into a potent delta agonist and ligands with mixed properties.

    PubMed

    Balboni, Gianfranco; Guerrini, Remo; Salvadori, Severo; Bianchi, Clementina; Rizzi, Daniela; Bryant, Sharon D; Lazarus, Lawrence H

    2002-01-31

    Analogues of the 2',6'-dimethyl-L-tyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) pharmacophore were prepared to test the hypothesis that a "spacer" and a third aromatic center in opioid peptides are required to convert a delta-antagonist into ligands with delta-agonist or with mixed delta-antagonist/mu-agonist properties. Potent delta-agonists and bifunctional compounds with high delta- and mu-opioid receptor affinities were obtained by varying the spacer length [none, NH-CH(2), NH-CH(2)-CH(2), Gly-NH-CH(2)] and C-terminal aromatic nucleus [1H-benzimidazole-2-yl, phenyl (Ph) and benzyl groups]. C-terminal modification primarily affected mu-opioid receptor affinities, which increased maximally 1700-fold relative to the prototype delta-antagonist H-Dmt-Tic-NH(2) and differentially modified bioactivity. In the absence of a spacer (1), the analogue exhibited dual delta-agonism (pEC(50), 7.28) and delta-antagonism (pA(2), 7.90). H-Dmt-Tic-NH-CH(2)-1H-benzimidazole-2-yl (Bid) (2) became a highly potent delta-agonist (pEC(50), 9.90), slightly greater than deltorphin C (pEC(50), 9.56), with mu-agonism (pE(50), 7.57), while H-Dmt-Tic-Gly-NH-CH(2)-Bid (4) retained potent delta-antagonism (pA(2), 9.0) but with an order of magnitude less mu-agonism. Similarly, H-Dmt-Tic-Gly-NH-Ph (5) had nearly equivalent high delta-agonism (pEC(50), 8.52) and mu-agonism (pEC(50), 8.59), while H-Dmt-Tic-Gly-NH-CH(2)-Ph (6) whose spacer was longer by a single methylene group exhibited potent delta-antagonism (pA(2), 9.25) and very high mu-agonism (pEC(50), 8.57). These data confirm that the distance between the Dmt-Tic pharmacophore and a third aromatic nucleus is an important criterion in converting Dmt-Tic from a highly potent delta-antagonist into a potent delta-agonist or into ligands with mixed delta- and mu-opioid properties.

  14. Synthesis and SAR of potent LXR agonists containing an indole pharmacophore

    SciTech Connect

    Washburn, David G.; Hoang, Tram H.; Campobasso, Nino; Smallwood, Angela; Parks, Derek J.; Webb, Christine L.; Frank, Kelly A.; Nord, Melanie; Duraiswami, Chaya; Evans, Christopher; Jaye, Michael; Thompson, Scott K.

    2009-03-27

    A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXR{alpha} will be disclosed.

  15. Agonists and partial agonists of rhodopsin: retinal polyene methylation affects receptor activation.

    PubMed

    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.

  16. Functional dissection of protein domains involved in the immunomodulatory properties of PE_PGRS33 of Mycobacterium tuberculosis.

    PubMed

    Zumbo, Antonella; Palucci, Ivana; Cascioferro, Alessandro; Sali, Michela; Ventura, Marcello; D'Alfonso, Pamela; Iantomasi, Raffaella; Di Sante, Gabriele; Ria, Francesco; Sanguinetti, Maurizio; Fadda, Giovanni; Manganelli, Riccardo; Delogu, Giovanni

    2013-12-01

    PE_PGRSs are a large family of proteins identified in Mycobacterium tuberculosis complex and in few other pathogenic mycobacteria. The PE domain of PE_PGRS33 mediates localization of the protein on the mycobacterial cell surface, where the PGRS domain is available to interact with host components. In this study, PE_PGRS33 and its functional deletion mutants were expressed in M. smegmatis, and in vitro and in vivo assays were used to dissect the protein domains involved in the immunomodulatory properties of the protein. We demonstrate that PE_PGRS33-mediated secretion of TNF-α by macrophages occurs by extracellular interaction with TLR2. Our results also show that while the PGRS domain of the protein is required for triggering TNF-α secretion, mutation in the PE domain affects the pro-inflammatory properties of the protein. These results indicate that PE_PGRS33 is a protein with immunomodulatory activity and that protein stability and localization on the mycobacterial surface can affect these properties.

  17. The PGRS Domain from PE_PGRS33 of Mycobacterium tuberculosis is Target of Humoral Immune Response in Mice and Humans.

    PubMed

    Cohen, Ingrid; Parada, Cristina; Acosta-Gío, Enrique; Espitia, Clara

    2014-01-01

    The PE_PGRS33 protein is a member of the PE family, which encompasses the PE and the PE_PGRS subfamilies. Among PE_PGRS's, this protein is one of the most studied antigens and its immunomodulatory properties are influence by both PE and PGRS domains. However, the contribution of these domains to the host immune recognition of the PE_PGRS33 protein and their potential role in latent tuberculosis infection in humans is still unknown. In this study, the immunogenic properties of the complete PE_PGRS33 protein and each domain separately were evaluated in BALB/c mice and latent tuberculosis infected (LTBI) humans. In mice, PE_PGRS33 and its domains induced similar antibody production and secretion of IFN-γ. PE_PGRS33 and the PE domain stimulated higher CD4(+) and CD8(+) T-cell proliferation compared to the PGRS domain. This demonstrated that the principal difference in the immune recognition of the domains is the higher activation of T-cell subpopulations involved in the control of tuberculosis. In humans, the secretion of IFN-γ in response to PE_PGRS33 was detected in both LTBI and in non-infected vaccinated individuals. The same was observed for antibody response, which targets epitopes located in the PGRS domain but not in the PE domain. These observations suggest that T and B cell responses to PE_PGRS33 are induced by BCG vaccination and can be maintained for many years in non-infected individuals. This also indicates that the IFN-γ response detected might not be associated with latent tuberculosis infection. These results contribute to the elucidation of the role of the PE_PGRS33 protein and its PE and PGRS domains in the immune response against Mycobacterium tuberculosis.

  18. The PGRS Domain from PE_PGRS33 of Mycobacterium tuberculosis is Target of Humoral Immune Response in Mice and Humans

    PubMed Central

    Cohen, Ingrid; Parada, Cristina; Acosta-Gío, Enrique; Espitia, Clara

    2014-01-01

    The PE_PGRS33 protein is a member of the PE family, which encompasses the PE and the PE_PGRS subfamilies. Among PE_PGRS’s, this protein is one of the most studied antigens and its immunomodulatory properties are influence by both PE and PGRS domains. However, the contribution of these domains to the host immune recognition of the PE_PGRS33 protein and their potential role in latent tuberculosis infection in humans is still unknown. In this study, the immunogenic properties of the complete PE_PGRS33 protein and each domain separately were evaluated in BALB/c mice and latent tuberculosis infected (LTBI) humans. In mice, PE_PGRS33 and its domains induced similar antibody production and secretion of IFN-γ. PE_PGRS33 and the PE domain stimulated higher CD4+ and CD8+ T-cell proliferation compared to the PGRS domain. This demonstrated that the principal difference in the immune recognition of the domains is the higher activation of T-cell subpopulations involved in the control of tuberculosis. In humans, the secretion of IFN-γ in response to PE_PGRS33 was detected in both LTBI and in non-infected vaccinated individuals. The same was observed for antibody response, which targets epitopes located in the PGRS domain but not in the PE domain. These observations suggest that T and B cell responses to PE_PGRS33 are induced by BCG vaccination and can be maintained for many years in non-infected individuals. This also indicates that the IFN-γ response detected might not be associated with latent tuberculosis infection. These results contribute to the elucidation of the role of the PE_PGRS33 protein and its PE and PGRS domains in the immune response against Mycobacterium tuberculosis. PMID:24904584

  19. The PE_PGRS Proteins of Mycobacterium tuberculosis Are Ca(2+) Binding Mediators of Host-Pathogen Interaction.

    PubMed

    Yeruva, Veena C; Kulkarni, Apoorva; Khandelwal, Radhika; Sharma, Yogendra; Raghunand, Tirumalai R

    2016-08-23

    The phenomenal success of Mycobacterium tuberculosis (M.tb) as a pathogen is primarily based on its ability to modulate host immune responses. The genome of M.tb encodes multiple immunomodulatory proteins, including several members of the multigenic PE_PPE family of which the PE_PGRS proteins are a subset. Curiously, 56 of the 61 PE_PGRS proteins contain multiple copies of the glycine-rich sequence motif GGXGXD/NXUX, a nonapeptide sequence predicted to bind Ca(2+), but the functional significance of these motifs remains a mystery. Here we provide evidence via isothermal titration calorimetry, (45)Ca blotting, fluorescence, and circular dichroism spectroscopy that Ca(2+) binds to the PE_PGRS proteins, PE_PGRS33 (Rv1818c) (10 motifs) and PE_PGRS61 (Rv3653) (one motif). Ca(2+) was observed not to bind to PE_PGRS8 (Rv0742), which lacks nonapeptide motifs. Using recombinant Mycobacterium smegmatis strains expressing Rv1818c and Rv3653 and the THP-1 macrophage model of infection, we show that the two proteins mediate Ca(2+)-dependent upregulation of the anti-inflammatory cytokine IL-10, events critical to the pathogenesis of M.tb. Both Rv1818c and Rv3653 interact with TLR2 in a Ca(2+)-dependent manner, providing a novel mechanistic basis for their immunomodulatory effects. Mutations in the nonapeptide motif of Rv3653 led to compromised Ca(2+) binding, validating the functional criticality of this motif. This study demonstrates for the first time not only their Ca(2+) binding properties but also an essential role for Ca(2+) in the functioning of the M.tb PE_PGRS proteins, opening up the possibility of developing novel anti-tuberculosis therapeutics that inhibit Ca(2+)-PE_PGRS binding. PMID:27483162

  20. The Multifunctional PE_PGRS11 Protein from Mycobacterium tuberculosis Plays a Role in Regulating Resistance to Oxidative Stress*

    PubMed Central

    Chaturvedi, Rashmi; Bansal, Kushagra; Narayana, Yeddula; Kapoor, Nisha; Sukumar, Namineni; Togarsimalemath, Shambhuprasad Kotresh; Chandra, Nagasuma; Mishra, Saurabh; Ajitkumar, Parthasarathi; Joshi, Beenu; Katoch, Vishwa Mohan; Patil, Shripad A.; Balaji, Kithiganahalli N.

    2010-01-01

    Mycobacterium tuberculosis utilizes unique strategies to survive amid the hostile environment of infected host cells. Infection-specific expression of a unique mycobacterial cell surface antigen that could modulate key signaling cascades can act as a key survival strategy in curtailing host effector responses like oxidative stress. We demonstrate here that hypothetical PE_PGRS11 ORF encodes a functional phosphoglycerate mutase. The transcriptional analysis revealed that PE_PGRS11 is a hypoxia-responsive gene, and enforced expression of PE_PGRS11 by recombinant adenovirus or Mycobacterium smegmatis imparted resistance to alveolar epithelial cells against oxidative stress. PE_PGRS11-induced resistance to oxidative stress necessitated the modulation of genetic signatures like induced expression of Bcl2 or COX-2. This modulation of specific antiapoptotic molecular signatures involved recognition of PE_PGRS11 by TLR2 and subsequent activation of the PI3K-ERK1/2-NF-κB signaling axis. Furthermore, PE_PGRS11 markedly diminished H2O2-induced p38 MAPK activation. Interestingly, PE_PGRS11 protein was exposed at the mycobacterial cell surface and was involved in survival of mycobacteria under oxidative stress. Furthermore, PE_PGRS11 displayed differential B cell responses during tuberculosis infection. Taken together, our investigation identified PE_PGRS11 as an in vivo expressed immunodominant antigen that plays a crucial role in modulating cellular life span restrictions imposed during oxidative stress by triggering TLR2-dependent expression of COX-2 and Bcl2. These observations clearly provide a mechanistic basis for the rescue of pathogenic Mycobacterium-infected lung epithelial cells from oxidative stress. PMID:20558725

  1. The Mycobacterium tuberculosis PE Proteins Rv0285 and Rv1386 Modulate Innate Immunity and Mediate Bacillary Survival in Macrophages

    PubMed Central

    Tiwari, Bhavana Mishra; Kannan, Nisha; Vemu, Lakshmi; Raghunand, Tirumalai R.

    2012-01-01

    The unique PE/PPE multigene family of proteins occupies almost 10% of the coding sequence of Mycobacterium tuberculosis (M.tb), the causative agent of human tuberculosis. Although some members of this family have been shown to be involved in pathways essential to M.tb pathogenesis, their precise physiological functions remain largely undefined. Here, we investigate the roles of the conserved members of the ‘PE only’ subfamily Rv0285 (PE5) and Rv1386 (PE15) in mediating host-pathogen interactions. Recombinant Mycobacterium smegmatis strains expressing PE5 and PE15 showed enhanced survival vs controls in J774.1 and THP-1 macrophages - this increase in viable counts was correlated with a reduction in transcript levels of inducible nitric oxide synthase. An up-regulation of anti- and down-regulation of pro-inflammatory cytokine levels was also observed in infected macrophages implying an immuno-modulatory function for these proteins. Induction of IL-10 production upon infection of THP-1 macrophages was associated with increased phosphorylation of the MAP Kinases p38 and ERK1/2, which was abolished in the presence of the pharmacological inhibitors SB203580 and PD98059. The PE5-PPE4 and PE15-PPE20 gene pairs were observed to be co-operonic in M.tb, hinting at an additional level of complexity in the functioning of these proteins. We conclude that M.tb exploits the PE proteins to evade the host immune response by altering the Th1 and Th2 type balance thereby favouring in vivo bacillary survival. PMID:23284742

  2. The PE_PGRS Proteins of Mycobacterium tuberculosis Are Ca(2+) Binding Mediators of Host-Pathogen Interaction.

    PubMed

    Yeruva, Veena C; Kulkarni, Apoorva; Khandelwal, Radhika; Sharma, Yogendra; Raghunand, Tirumalai R

    2016-08-23

    The phenomenal success of Mycobacterium tuberculosis (M.tb) as a pathogen is primarily based on its ability to modulate host immune responses. The genome of M.tb encodes multiple immunomodulatory proteins, including several members of the multigenic PE_PPE family of which the PE_PGRS proteins are a subset. Curiously, 56 of the 61 PE_PGRS proteins contain multiple copies of the glycine-rich sequence motif GGXGXD/NXUX, a nonapeptide sequence predicted to bind Ca(2+), but the functional significance of these motifs remains a mystery. Here we provide evidence via isothermal titration calorimetry, (45)Ca blotting, fluorescence, and circular dichroism spectroscopy that Ca(2+) binds to the PE_PGRS proteins, PE_PGRS33 (Rv1818c) (10 motifs) and PE_PGRS61 (Rv3653) (one motif). Ca(2+) was observed not to bind to PE_PGRS8 (Rv0742), which lacks nonapeptide motifs. Using recombinant Mycobacterium smegmatis strains expressing Rv1818c and Rv3653 and the THP-1 macrophage model of infection, we show that the two proteins mediate Ca(2+)-dependent upregulation of the anti-inflammatory cytokine IL-10, events critical to the pathogenesis of M.tb. Both Rv1818c and Rv3653 interact with TLR2 in a Ca(2+)-dependent manner, providing a novel mechanistic basis for their immunomodulatory effects. Mutations in the nonapeptide motif of Rv3653 led to compromised Ca(2+) binding, validating the functional criticality of this motif. This study demonstrates for the first time not only their Ca(2+) binding properties but also an essential role for Ca(2+) in the functioning of the M.tb PE_PGRS proteins, opening up the possibility of developing novel anti-tuberculosis therapeutics that inhibit Ca(2+)-PE_PGRS binding.

  3. Sitting and watching the others being active: the experienced difficulties in PE when having a disability.

    PubMed

    Bredahl, Anne-Mette

    2013-01-01

    The experience of participation in physical activity was explored in a qualitative study with twenty Norwegian adults with physical and visual disabilities. The interviews showed that more than 75% of negative experiences reported in this study originated from physical education (PE), suggesting that this was a particularly challenging arena. The negative experiences were centered in these common themes: experiences of not being included, experiences of failing, and experiences of not being listened to. The interviews were analyzed applying an existential-phenomenological approach. The participants with relatively minor degrees of disability and with the least visible disabilities were the ones who most often reported negative experiences regarding PE. This suggests the experiences were not generated solely by the actual physical or sensory limitations, but equally by how well the participants' challenges were understood by their teachers and to what degree adaptations were implemented. PMID:23283025

  4. OBSERVATIONAL SEARCH FOR PeV-EeV TAU NEUTRINO FROM GRB081203A

    SciTech Connect

    Aita, Y.; Aoki, T.; Asaoka, Y.; Chonan, T.; Jobashi, M.; Masuda, M.; Morimoto, Y.; Noda, K.; Sasaki, M.; Asoh, J.; Ishikawa, N.; Ogawa, S.; Learned, J. G.; Matsuno, S.; Olsen, S.; Binder, P.-M.; Hamilton, J.; Sugiyama, N.; Watanabe, Y. E-mail: sasakim@icrr.u-tokyo.ac.jp

    2011-07-20

    We report the first observational search for tau neutrinos ({nu}{sub {tau}}) from gamma-ray bursts (GRBs) using one of the Ashra light collectors. The Earth-skimming {nu}{sub {tau}} technique of imaging Cherenkov {tau} showers was applied as a detection method. We set stringent upper limits on the {nu}{sub {tau}} fluence in PeV-EeV region for 3780 s (between 2.83 and 1.78 hr before) and another 3780 s (between 21.2 and 22.2 hr after) surrounding GRB081203A triggered by the Swift satellite. This first search for PeV-EeV {nu}{sub {tau}} complements other experiments in energy range and methodology, and suggests the prologue of 'multi-particle astronomy' with a precise determination of time and location.

  5. Metabolic engineering of Saccharomyces cerevisiae ethanol strains PE-2 and CAT-1 for efficient lignocellulosic fermentation.

    PubMed

    Romaní, Aloia; Pereira, Filipa; Johansson, Björn; Domingues, Lucília

    2015-03-01

    In this work, Saccharomyces cerevisiae strains PE-2 and CAT-1, commonly used in the Brazilian fuel ethanol industry, were engineered for xylose fermentation, where the first fermented xylose faster than the latter, but also produced considerable amounts of xylitol. An engineered PE-2 strain (MEC1121) efficiently consumed xylose in presence of inhibitors both in synthetic and corn-cob hydrolysates. Interestingly, the S. cerevisiae MEC1121 consumed xylose and glucose simultaneously, while a CEN.PK based strain consumed glucose and xylose sequentially. Deletion of the aldose reductase GRE3 lowered xylitol production to undetectable levels and increased xylose consumption rate which led to higher final ethanol concentrations. Fermentation of corn-cob hydrolysate using this strain, MEC1133, resulted in an ethanol yield of 0.47 g/g of total sugars which is 92% of the theoretical yield.

  6. Testing the Dark Matter Scenario for PeV Neutrinos Observed in IceCube.

    PubMed

    Murase, Kohta; Laha, Ranjan; Ando, Shin'ichiro; Ahlers, Markus

    2015-08-14

    Late time decay of very heavy dark matter is considered as one of the possible explanations for diffuse PeV neutrinos observed in IceCube. We consider implications of multimessenger constraints, and show that proposed models are marginally consistent with the diffuse γ-ray background data. Critical tests are possible by a detailed analysis and identification of the sub-TeV isotropic diffuse γ-ray data observed by Fermi and future observations of sub-PeV γ rays by observatories like HAWC or Tibet AS+MD. In addition, with several-year observations by next-generation telescopes such as IceCube-Gen2, muon neutrino searches for nearby dark matter halos such as the Virgo cluster should allow us to rule out or support the dark matter models, independently of γ-ray and anisotropy tests. PMID:26317706

  7. Probable nonexistence of a 3Pe metastable excited state of the positronium negative ion

    NASA Astrophysics Data System (ADS)

    Mills, Allen P., Jr.

    1981-12-01

    The H- ion is known to have a metastable 2p2 3Pe triplet excited state. To see if an analog of this state is present in the positronium negative ion Ps- the Coulomb binding energy Eb of the lowest-energy even-parity L=1 configuration of two identical-charge -e fermions of mass m1 plus one spinless particle of mass m2 and charge +e is calculated. We find a value of Eb below the n=2 level of the neutral atom for 0<=m2M<=0.17 and 0.90Pe state exists for Ps-, where m2M=13.

  8. [Aquatic insects and water quality in Peñas Blancas watershed and reservoir].

    PubMed

    Mora, Meyer Guevara

    2011-06-01

    The aquatic insects have been used to evaluate water quality of aquatic environments. The population of aquatic insects and the water quality of the area were characterized according to the natural and human alterations present in the study site. During the monthly-survey, pH, DO, temperature, water level, DBO, PO4 and NO3 were measured. Biological indexes (abundance, species richness and the BMWP-CR) were used to evaluate the water quality. No relation between environmental and aquatic insects was detected. Temporal and spatial differences attributed to the flow events (temporal) and the presence of Peñas Blancas reservoir (spatial). In the future, the investigations in Peñas Blancas watershed need to be focused on determining the real influence of the flows, sediment release and the possible water quality degradation because of agriculture activities.

  9. PeV neutrinos from intergalactic interactions of cosmic rays emitted by active galactic nuclei.

    PubMed

    Kalashev, Oleg E; Kusenko, Alexander; Essey, Warren

    2013-07-26

    The observed very high energy spectra of distant blazars are well described by secondary gamma rays produced in line-of-sight interactions of cosmic rays with background photons. In the absence of the cosmic-ray contribution, one would not expect to observe very hard spectra from distant sources, but the cosmic ray interactions generate very high energy gamma rays relatively close to the observer, and they are not attenuated significantly. The same interactions of cosmic rays are expected to produce a flux of neutrinos with energies peaked around 1 PeV. We show that the diffuse isotropic neutrino background from many distant sources can be consistent with the neutrino events recently detected by the IceCube experiment. We also find that the flux from any individual nearby source is insufficient to account for these events. The narrow spectrum around 1 PeV implies that some active galactic nuclei can accelerate protons to EeV energies.

  10. Testing the Dark Matter Scenario for PeV Neutrinos Observed in IceCube.

    PubMed

    Murase, Kohta; Laha, Ranjan; Ando, Shin'ichiro; Ahlers, Markus

    2015-08-14

    Late time decay of very heavy dark matter is considered as one of the possible explanations for diffuse PeV neutrinos observed in IceCube. We consider implications of multimessenger constraints, and show that proposed models are marginally consistent with the diffuse γ-ray background data. Critical tests are possible by a detailed analysis and identification of the sub-TeV isotropic diffuse γ-ray data observed by Fermi and future observations of sub-PeV γ rays by observatories like HAWC or Tibet AS+MD. In addition, with several-year observations by next-generation telescopes such as IceCube-Gen2, muon neutrino searches for nearby dark matter halos such as the Virgo cluster should allow us to rule out or support the dark matter models, independently of γ-ray and anisotropy tests.

  11. Atmospheric-Pressure Non-thermal Plasma-JET effects on PS and PE surfaces

    NASA Astrophysics Data System (ADS)

    Arrieta, J.; Asenjo, J.; Vargas, I.; Solis, Y.

    2015-03-01

    The Atmospheric-Pressure Non-Thermal Plasma (APNTP) has become a topic of a great interest for a wide spectrum of applications in different industry branches, including the surface of treatment processes. In this work we evaluate the effect of an argon APNTP exposure to determine changes suffered by a polystyrene (PS) and polyethylene (PE) polymer surface through RAMAN spectroscopy and SEM. It was determined that the hydrophilic change in energetic terms, i.e. surface activation in the PS and PE polymers is addition of oxygen by surface activation when the samples with jet plasma are exposed with the inert argon gas. It was possible to characterize the hydrophilic shift based on the change in intensity of the spectra.

  12. Hard Coat Layers by PE-CVD Process for the Top Surface of Touch Panel

    NASA Astrophysics Data System (ADS)

    Okunishi, T.; Sato, N.; Yazawa, K.

    2013-06-01

    In order to protect surface from damages, the high pencil hardness and the high abrasion resistance are required for the hard coat layers on polyethylene telephthalate (PET) films for the application of touch panel surface. We have already found that the UV-curing-hard-coat-polymer (UHP) coated PET films show the poor abrasion resistance, while they have the high pencil hardness. It reveals that the abrasion resistance of hard coat layers of the UHP is not simply dependent on the pencil hardness. In this work, we have studied to improve the abrasion resistance of SiOC films as hard coat layers, which were formed by PE-CVD process on UHP coated PET. The abrasion resistance was evaluated by Taber abrasion test. PE-CVD hard coat layers which formed on UHP coater PET films have showed the better abrasion resistance and have the possibility of substitution to the thin glass sheets for touch panel application.

  13. Intraocular Ossification in the GSP/pe Chicken With Imperfect Albinism.

    PubMed

    Shibuya, K; Kinoshita, K; Mizutani, M; Oshima, A; Yamashita, R; Matsuda, Y

    2015-07-01

    The eyes of 2 male and 2 female GSP/pe chickens, the imperfect albino strain, were investigated at 52 weeks of age. Aged chickens of the GSP/pe colony became blind with bilateral ocular enlargement and opaque lenses. Affected eyes (bilateral in 2 males and unilateral in 2 females) were hard and difficult to section; histologic specimens were processed after decalcification. A large portion of the posterior chamber was occupied by cancellous bone containing fibrous and cartilaginous foci. Osseous tissues developed adjacent to the choroid, and no retinal pigment epithelium (RPE) was detected between osseous tissues and the choroid. Small segments of degenerate neuronal retina were scattered in the osseous tissue. The irises and ciliary bodies were deformed by osseous tissue, and the lenses had severe cataracts. These observations suggest that the intraocular osseous tissue may be derived from RPE in the hereditary incomplete-albino strain of chickens.

  14. Radiation effects of UHMW-PE fibre on gel fraction and mechanical properties

    NASA Astrophysics Data System (ADS)

    Zhao, Yanning; Wang, Mouhua; Tang, Zhongfeng; Wu, Guozhong

    2011-02-01

    The effect of gamma ray irradiation on ultra-high molecular weight polyethylene (UHMW-PE) fibre was investigated for the change of gel fraction, mechanical properties, and morphology of crystallites. In the case of irradiation in air, the oxidation was limited to the fibre surface where the gel fraction decreased by chain scission, and the depth of the oxidation area from the surface was estimated to be 2 μm. Tensile tests showed similar stress-strain curves for irradiation in vacuum or in air, but the elongation at break decreased more obviously for irradiation in air. The oxidation products, such as carboxylic acids, were detected by FTIR measurement. However, the DSC and XRD analyses indicated little change of crystallinity on irradiation in vacuum or in air. The oxidation was limited to a thin surface area on irradiation in air due to a low migration rate of the radicals trapped in the crystallite in the UHMW-PE fibre.

  15. Synthesis of Few-Layer Graphene Using DC PE-CVD

    NASA Astrophysics Data System (ADS)

    Kim, Jeong Hyuk; Castro, Edward Joseph D.; Hwang, Yong Gyoo; Lee, Choong Hun

    2011-12-01

    Few layer graphene (FLG) had been successfully grown on polycrystalline Ni films or foils on a large scale using DC Plasma Enhanced Chemical Vapor Deposition (DC PE-CVD) as a result of the Raman spectra drawn out of the sample. The size of graphene films is dependent on the area of the Ni film as well as the DC PE-CVD chamber size. Synthesis time has an effect on the quality of graphene produced. However, further analysis and experiments must be pursued to further identify the optimum settings and conditions of producing better quality graphene. Applied plasma voltage on the other hand, had an influence on the minimization of defects in the graphene grown. It has also presented a method of producing a free standing PMMA/graphene membrane on a FeCl3(aq) solution which could then be transferred to a desired substrate.

  16. Intraocular Ossification in the GSP/pe Chicken With Imperfect Albinism.

    PubMed

    Shibuya, K; Kinoshita, K; Mizutani, M; Oshima, A; Yamashita, R; Matsuda, Y

    2015-07-01

    The eyes of 2 male and 2 female GSP/pe chickens, the imperfect albino strain, were investigated at 52 weeks of age. Aged chickens of the GSP/pe colony became blind with bilateral ocular enlargement and opaque lenses. Affected eyes (bilateral in 2 males and unilateral in 2 females) were hard and difficult to section; histologic specimens were processed after decalcification. A large portion of the posterior chamber was occupied by cancellous bone containing fibrous and cartilaginous foci. Osseous tissues developed adjacent to the choroid, and no retinal pigment epithelium (RPE) was detected between osseous tissues and the choroid. Small segments of degenerate neuronal retina were scattered in the osseous tissue. The irises and ciliary bodies were deformed by osseous tissue, and the lenses had severe cataracts. These observations suggest that the intraocular osseous tissue may be derived from RPE in the hereditary incomplete-albino strain of chickens. PMID:25421422

  17. CHF prediction of GE 3 x 3 rod bundle based on BODYFIT-2PE. [BWR

    SciTech Connect

    Chien, T.H.; Chen, B.C.J.; Sha, W.T.; Kim, J.H.

    1983-01-01

    A General Electric 3 x 3 rod bundle critical heat flux (CHF) experiment was analyzed by using BODYFIT-2PE. (Boundary-fitted coordinates-2 phase partially elliptic). BODYFIT-2PE is a three-dimensional, steady-state/transient, single-phase rod-bundle thermal-hydraulic computer program based on the technique of boudnary-fitted coordinate system. In this coordinate system, all the physical boundaries are made to be coincident with the coordinate lines so that the boundary conditions, such as constant heat fluxes and zero velocities, can be accurately represented without interpolation. However, the transformed coordinate system is not unique for a given geometric configuration. The more orthogonal the coordinates are, the faster the rates of calculational convergence. The generation of the transformed coordinates is based on the solution of a set of second-order partial differential equations, subject to a set of geometric boundary conditions. A simple Laplacian is used in the present study.

  18. Biological network analysis with CentiScaPe: centralities and experimental dataset integration.

    PubMed

    Scardoni, Giovanni; Tosadori, Gabriele; Faizan, Mohammed; Spoto, Fausto; Fabbri, Franco; Laudanna, Carlo

    2014-01-01

    The growing dimension and complexity of the available experimental data generating biological networks have increased the need for tools that help in categorizing nodes by their topological relevance. Here we present CentiScaPe, a Cytoscape app specifically designed to calculate centrality indexes used for the identification of the most important nodes in a network. CentiScaPe is a comprehensive suite of algorithms dedicated to network nodes centrality analysis, computing several centralities for undirected, directed and weighted networks. The results of the topological analysis can be integrated with data set from lab experiments, like expression or phosphorylation levels for each protein represented in the network. Our app opens new perspectives in the analysis of biological networks, since the integration of topological analysis with lab experimental data enhance the predictive power of the bioinformatics analysis.

  19. Heavy right-handed neutrino dark matter and PeV neutrinos at IceCube

    NASA Astrophysics Data System (ADS)

    Bhupal Dev, P. S.; Kazanas, D.; Mohapatra, R. N.; Teplitz, V. L.; Zhang, Yongchao

    2016-08-01

    We discuss a simple non-supersymmetric model based on the electroweak gauge group SU(2)L × SU(2)' × U(1)B–L where the lightest of the right-handed neutrinos, which are part of the leptonic doublet of SU(2)', play the role of a long-lived unstable dark matter with mass in the multi-PeV range. We use a resonant s-channel annihilation to obtain the correct thermal relic density and relax the unitarity bound on dark matter mass. In this model, there exists a 3-body dark matter decay mode producing tau leptons and neutrinos, which could be the source for the PeV cascade events observed in the IceCube experiment. The model can be tested with more precise flavor information of the highest-energy neutrino events in future data.

  20. Metabolic engineering of Saccharomyces cerevisiae ethanol strains PE-2 and CAT-1 for efficient lignocellulosic fermentation.

    PubMed

    Romaní, Aloia; Pereira, Filipa; Johansson, Björn; Domingues, Lucília

    2015-03-01

    In this work, Saccharomyces cerevisiae strains PE-2 and CAT-1, commonly used in the Brazilian fuel ethanol industry, were engineered for xylose fermentation, where the first fermented xylose faster than the latter, but also produced considerable amounts of xylitol. An engineered PE-2 strain (MEC1121) efficiently consumed xylose in presence of inhibitors both in synthetic and corn-cob hydrolysates. Interestingly, the S. cerevisiae MEC1121 consumed xylose and glucose simultaneously, while a CEN.PK based strain consumed glucose and xylose sequentially. Deletion of the aldose reductase GRE3 lowered xylitol production to undetectable levels and increased xylose consumption rate which led to higher final ethanol concentrations. Fermentation of corn-cob hydrolysate using this strain, MEC1133, resulted in an ethanol yield of 0.47 g/g of total sugars which is 92% of the theoretical yield. PMID:25536512

  1. Illegal use of beta-adrenergic agonists: European Community.

    PubMed

    Kuiper, H A; Noordam, M Y; van Dooren-Flipsen, M M; Schilt, R; Roos, A H

    1998-01-01

    The use of veterinary medicinal products within the European Community is governed by a series of directives and regulations that describe the requirements for safety, quality, and efficacy of these products. Veterinary therapeutic use of beta-agonists has only been approved in the case of clenbuterol for bronchodilatation in horses and calves and for tocolysis in cows. No beta-agonists have been permitted in the European Community for growth-promoting purposes in farm animals. Surveillance for the presence of residues of veterinary agents in food-producing animals and meat is regulated by the Directive 86/469/EEC containing specific guidelines for sampling procedures on farms and in slaughterhouses. The level and frequency of sampling is dependent on the category of compounds and animal species. When positive samples have been identified (above certain action levels), sampling intensity is increased. Results of monitoring programs in EU member states during 1992 and 1993 for the occurrence of residues of beta-agonists in food-producing animals vary substantially with respect to the percentages of positive samples, ranging from 0 to 7%. The variability is partly explained by differences in sampling strategies, detection methods, and action levels applied. Identification of the proper matrices for sampling and detection of beta-agonists is important. In the case of clenbuterol, hair and choroid retinal tissue are appropriate tissues because clenbuterol accumulates in these matrices. A clear decrease in the use of clenbuterol in cattle has been observed in The Netherlands, Germany, Northern Ireland, and Spanish Basque Country over the last 3 yr. This is partly due to intensified surveillance activities at farms and slaughterhouses by governmental agencies and production sector organizations. There are data on human intoxication following consumption of liver or meat from cattle treated with beta-agonists. At the concentrations of clenbuterol measured in contaminated

  2. Cell type and gene-specific activity of the retinoid inverse agonist AGN 193109: divergent effects from agonist at retinoic acid receptor gamma in human keratinocytes.

    PubMed

    Thacher, S M; Nagpal, S; Klein, E S; Arefieg, T; Krasinski, G; DiSepio, D; Agarwal, C; Johnson, A; Eckert, R L; Chandraratna, R A

    1999-04-01

    Retinoids are important regulators of epithelial differentiation. AGN 193109 is a high-affinity antagonist and inverse agonist for the nuclear retinoic acid receptors (RARs). Paradoxically, both AGN 193109 and retinoid agonists inhibit the expression of the differentiation marker MRP-8 in normal human keratinocytes (NHKs). TTNPB, an RAR agonist, and AGN 193109 mutually antagonize MRP-8 inhibition at both mRNA and protein levels. We find that this antagonism, which is greatest at an AGN 193109:TTNPB ratio of about 10:1, is absent when either compound is in significant excess. The potent RARalpha-specific agonist, AGN 193836, has no effect on MRP-8 regulation. These data indicate that inverse agonists and agonists suppress MRP-8 in NHKs through RARgamma using distinct and mutually inhibitory mechanisms. The activity of AGN 193109 on MRP-8 is cell type specific. In differentiating ECE16-1 cervical cells, TTNPB inhibits while AGN 193109 induces MRP-8 mRNA levels. The effect of AGN 193109 on genes inhibited by retinoid agonists in NHKs is also selective; expression of the differentiation markers transglutaminase 1 and keratin 6 is not down-regulated by AGN 193109 whereas stromelysin-1 expression is suppressed. These results show a complex gene and cell context-specific interplay between agonist and inverse agonist for the regulation of gene expression.

  3. Water cycle research associated with the CaPE hydrometeorology project (CHymP

    NASA Technical Reports Server (NTRS)

    Duchon, Claude E.

    1993-01-01

    One outgrowth of the Convection and Precipitation/Electrification (CaPE) experiment that took place in central Florida during July and August 1991 was the creation of the CaPE Hydrometeorology Project (CHymP). The principal goal of this project is to investigate the daily water cycle of the CaPE experimental area by analyzing the numerous land and atmosphere in situ and remotely sensed data sets that were generated during the 40-days of observations. The water cycle comprises the atmospheric branch. In turn, the atmospheric branch comprises precipitation leaving the base of the atmospheric volume under study, evaporation and transpiration entering the base, the net horizontal fluxes of water vapor and cloud water through the volume and the conversion of water vapor to cloud water and vice-versa. The sum of these components results in a time rate of change in the water and liquid water (or ice) content of the atmospheric volume. The components of the land branch are precipitation input to and evaporation and transpiration output from the surface, net horizontal fluxes of surface and subsurface water, the sum of which results in a time rate of change in surface and subsurface water mass. The objective of CHymP is to estimate these components in order to determine the daily water budget for a selected area within the CaPE domain. This work began in earnest in the summer of 1992 and continues. Even estimating all the budget components for one day is a complex and time consuming task. The discussions below provides a short summary of the rainfall quality assessment procedures followed by a plan for estimating the horizontal moisture flux.

  4. Wind Transport of Radionuclide- Bearing Dust, Peña Blanca, Chihuahua, Mexico

    NASA Astrophysics Data System (ADS)

    Velarde, R.; Goodell, P. C.; Gill, T. E.; Arimoto, R.

    2007-05-01

    This investigation evaluates radionuclide fractionation during wind erosion of high-grade uranium ore storage piles at Peña Blanca (50km north of Chihuahua City), Chihuahua, Mexico. The aridity of the local environment promotes dust resuspension by high winds. Although active operations ceased in 1983, the Peña Blanca mining district is one of Mexico`s most important uranium ore reserves. The study site contains piles of high grade ore, left loose on the surface, and separated by the specific deposits from which they were derived (Margaritas, Nopal I, and Puerto I). Similar locations do not exist in the United States, since uranium mining sites in the USA have been reclaimed. The Peña Blanca site serves as an analog for the Yucca Mountain project. Dust deposition is collected at Peña Blanca with BSNE sediment catchers (Fryrear, 1986) and marble dust traps (Reheis, 1999). These devices capture windblown sediment; subsequently, the sample data will help quantify potentially radioactive short term field sediment loss from the repository surface and determine sediment flux. Aerosols and surface materials will be analyzed and radioactivity levels established utilizing techniques such as gamma spectroscopy. As a result, we will be able to estimate how much radionuclide contaminated dust is being transported or attached geochemically to fine grain soils or minerals (e.g., clays or iron oxides). The high-grade uranium-bearing material is at secular equilibrium, thus the entire decay series is present. Of resulting interest is not only the aeolian transport of uranium, but also of the other daughter products. These studies will improve our understanding of geochemical cycling of radionuclides with respect to sources, transport, and deposition. The results may also have important implications for the geosciences and homeland security, and potential applications to public health. Funding for this project is provided in part via a NSF grant to Arimoto.

  5. Method for PE Pipes Fusion Jointing Based on TRIZ Contradictions Theory

    NASA Astrophysics Data System (ADS)

    Sun, Jianguang; Tan, Runhua; Gao, Jinyong; Wei, Zihui

    The core of the TRIZ theories is the contradiction detection and solution. TRIZ provided various methods for the contradiction solution, but all that is not systematized. Combined with the technique system conception, this paper summarizes an integration solution method for contradiction solution based on the TRIZ contradiction theory. According to the method, a flowchart of integration solution method for contradiction is given. As a casestudy, method of fusion jointing PE pipe is analysised.

  6. EFFECTS OF TRITIUM ON UHMW-PE, PTFE, AND VESPEL POLYIMIDE

    SciTech Connect

    Clark, E; Kirk Shanahan, K

    2006-11-01

    Samples of ultrahigh molecular weight polyethylene (UHMW-PE), polytetrafluoroethylene (PTFE), and the polyimide Vespel{reg_sign} were exposed to tritium gas in closed containers initially at 101 kPa (1 atmosphere) pressure and ambient temperature for various times up to 2.3 years. Tritium exposure effects on the samples were characterized by dynamic mechanical analysis (DMA) and radiolysis products were characterized by measuring the total final pressure and composition in the exposure containers at the end of exposure period.

  7. Single-wavelength two-photon excitation–stimulated emission depletion (SW2PE-STED) superresolution imaging

    PubMed Central

    Bianchini, Paolo; Harke, Benjamin; Galiani, Silvia; Vicidomini, Giuseppe; Diaspro, Alberto

    2012-01-01

    We developed a new class of two-photon excitation–stimulated emission depletion (2PE-STED) optical microscope. In this work, we show the opportunity to perform superresolved fluorescence imaging, exciting and stimulating the emission of a fluorophore by means of a single wavelength. We show that a widely used red-emitting fluorophore, ATTO647N, can be two-photon excited at a wavelength allowing both 2PE and STED using the very same laser source. This fact opens the possibility to perform 2PE microscopy at four to five times STED-improved resolution, while exploiting the intrinsic advantages of nonlinear excitation. PMID:22493221

  8. Prediction of Certain Well-Characterized Domains of Known Functions within the PE and PPE Proteins of Mycobacteria.

    PubMed

    Sultana, Rafiya; Tanneeru, Karunakar; Kumar, Ashwin B R; Guruprasad, Lalitha

    2016-01-01

    The PE and PPE protein family are unique to mycobacteria. Though the complete genome sequences for over 500 M. tuberculosis strains and mycobacterial species are available, few PE and PPE proteins have been structurally and functionally characterized. We have therefore used bioinformatics tools to characterize the structure and function of these proteins. We selected representative members of the PE and PPE protein family by phylogeny analysis and using structure-based sequence annotation identified ten well-characterized protein domains of known function. Some of these domains were observed to be common to all mycobacterial species and some were species specific.

  9. Prediction of Certain Well-Characterized Domains of Known Functions within the PE and PPE Proteins of Mycobacteria

    PubMed Central

    Sultana, Rafiya; Tanneeru, Karunakar; Kumar, Ashwin B. R.; Guruprasad, Lalitha

    2016-01-01

    The PE and PPE protein family are unique to mycobacteria. Though the complete genome sequences for over 500 M. tuberculosis strains and mycobacterial species are available, few PE and PPE proteins have been structurally and functionally characterized. We have therefore used bioinformatics tools to characterize the structure and function of these proteins. We selected representative members of the PE and PPE protein family by phylogeny analysis and using structure-based sequence annotation identified ten well-characterized protein domains of known function. Some of these domains were observed to be common to all mycobacterial species and some were species specific. PMID:26891364

  10. Five-year summary of COMLEX-USA level 2-PE examinee performance and survey data.

    PubMed

    Langenau, Erik E; Dyer, Caitlin; Roberts, William L; Wilson, Crystal; Gimpel, John

    2010-03-01

    The authors present data on examination format and examinee demographics, performance, and survey results for the Comprehensive Osteopathic Medical Licensing Examination-USA Level 2-Performance Evaluation (COMLEX-USA Level 2-PE) from the first five testing cycles (2004-2005 to 2008-2009). First-time examinees in the 2004-2005 testing cycle had a pass rate of 96.1%, compared with a pass rate of 94.7% for first-time examinees in the 2008-2009 testing cycle. Pass rates were fairly consistent across all testing cycles. Based on postexamination survey results from all testing cycles, the majority of examinees reported that the cases in COMLEX-USA Level 2-PE represented appropriate challenges for fourth-year osteopathic medical students. The majority of examinees also reported that comprehensive standardized patient-based examinations and exercises were administered through their colleges of osteopathic medicine. In addition, survey results indicated overall satisfaction among examinees with the administration of COMLEX-USA Level 2-PE.

  11. Testing the Equivalence Principle and Lorentz Invariance with PeV Neutrinos from Blazar Flares.

    PubMed

    Wang, Zi-Yi; Liu, Ruo-Yu; Wang, Xiang-Yu

    2016-04-15

    It was recently proposed that a giant flare of the blazar PKS B1424-418 at redshift z=1.522 is in association with a PeV-energy neutrino event detected by IceCube. Based on this association we here suggest that the flight time difference between the PeV neutrino and gamma-ray photons from blazar flares can be used to constrain the violations of equivalence principle and the Lorentz invariance for neutrinos. From the calculated Shapiro delay due to clusters or superclusters in the nearby universe, we find that violation of the equivalence principle for neutrinos and photons is constrained to an accuracy of at least 10^{-5}, which is 2 orders of magnitude tighter than the constraint placed by MeV neutrinos from supernova 1987A. Lorentz invariance violation (LIV) arises in various quantum-gravity theories, which predicts an energy-dependent velocity of propagation in vacuum for particles. We find that the association of the PeV neutrino with the gamma-ray outburst set limits on the energy scale of possible LIV to >0.01E_{pl} for linear LIV models and >6×10^{-8}E_{pl} for quadratic order LIV models, where E_{pl} is the Planck energy scale. These are the most stringent constraints on neutrino LIV for subluminal neutrinos. PMID:27127950

  12. IceCube PeV neutrinos and leptophilic dark matter

    NASA Astrophysics Data System (ADS)

    Chianese, Marco

    2016-05-01

    We analyze the scenario where the IceCube high energy neutrino events are explained in terms of an extraterrestrial flux due to two different components: a contribution coming from know astrophysical sources for energies up to few hundreds TeV and a top-down contribution originated by the decay of heavy dark matter particles with a mass of few PeV. Contrary to previous approaches, we consider a leptophilic three-body decay that dominates at PeV energies due to the absence of quarks in the final state. We find that the theoretical predictions of such a scenario are in a slightly better agreement with the IceCube data if the astrophysical component has a cut-off at about 100 TeV. This interpretation of IceCube data can be easily tested in the near future since the decaying dark matter scenario predicts a sharp cut-off at PeV energy scale and the observation of an anisotropy towards Galactic Center of our Galaxy in contrast with the isotropic astrophysical flux.

  13. PeV neutrinos from the propagation of ultra-high energy cosmic rays

    SciTech Connect

    Roulet, Esteban; Mollerach, Silvia; Sigl, Guenter; Vliet, Arjen van E-mail: guenter.sigl@desy.de E-mail: mollerach@cab.cnea.gov.ar

    2013-01-01

    We discuss the possibility that the PeV neutrinos recently observed by IceCube are produced by the interactions of extragalactic cosmic rays during their propagation through the radiation backgrounds. We show that the fluxes resulting from the decays of neutrons produced in the interactions of cosmic ray protons with the CMB background are suppressed (E{sub ν}{sup 2}dΦ{sub ν}/dE < 10{sup −10} GeV/cm{sup 2} s sr), with those resulting from the decays of pions produced in the interactions with the UV/optical/IR backgrounds being the dominant ones at PeV energies. The anti-neutrino fluxes produced by the decay of neutrons resulting from the photodisintegration of heavy nuclei with CMB photons are also shown to be quite suppressed (E{sub ν}{sup 2}dΦ{sub ν}/dE < 10{sup −11} GeV/cm{sup 2} s sr), while those produced by photo-pion processes with UV/optical/IR backgrounds may be larger, although they are not expected to be above those achievable in the pure proton case. Scenarios with mixed composition and low cutoff rigidities can lead to PeV neutrino fluxes enhanced with respect to those in the pure Fe scenarios. We also discuss the possible impact of the Glashow resonance for the detection of these scenarios, showing that it plays a moderate role.

  14. Understanding the two-photon absorption spectrum of PE2 platinum acetylide complex.

    PubMed

    Vivas, Marcelo G; De Boni, Leonardo; Cooper, Thomas M; Mendonca, Cleber R

    2014-07-31

    Herein, we report on the two-absorption cross-section spectrum of trans-Pt(PBu3)2 (C≡C-C6H4-C≡C-C6H5)2 (PE2) platinum acetylide complex employing the femtosecond wavelength-tunable Z-scan technique. The PE2 complex can be visualized as two branches containing two phenylacetylene units, each one linked by a platinum center, completely transparent in the visible region. Because of this structure, large delocalization of π-electrons allied to the strong intramolecular interaction between the branches is expected. The 2PA absorption spectrum was measured using the femtosecond wavelength-tunable Z-scan technique with low repetition rate (1 kHz), in order to obtain the 2PA spectrum without excited-state contributions. Our results reveal that PE2 in dichloromethane solution presents two 2PA allowed bands located at 570 and 710 nm, with cross section of about 320 and 45 GM, respectively. The first one is related to the strong intramolecular interaction between the molecule's branches due to the presence of platinum atom, while the second one is associated with the breaking of symmetry of the chromophore in solution due, most probably to a large twisting angle of the ligand's phenyl rings relative to the Pt core.

  15. Testing the Equivalence Principle and Lorentz Invariance with PeV Neutrinos from Blazar Flares.

    PubMed

    Wang, Zi-Yi; Liu, Ruo-Yu; Wang, Xiang-Yu

    2016-04-15

    It was recently proposed that a giant flare of the blazar PKS B1424-418 at redshift z=1.522 is in association with a PeV-energy neutrino event detected by IceCube. Based on this association we here suggest that the flight time difference between the PeV neutrino and gamma-ray photons from blazar flares can be used to constrain the violations of equivalence principle and the Lorentz invariance for neutrinos. From the calculated Shapiro delay due to clusters or superclusters in the nearby universe, we find that violation of the equivalence principle for neutrinos and photons is constrained to an accuracy of at least 10^{-5}, which is 2 orders of magnitude tighter than the constraint placed by MeV neutrinos from supernova 1987A. Lorentz invariance violation (LIV) arises in various quantum-gravity theories, which predicts an energy-dependent velocity of propagation in vacuum for particles. We find that the association of the PeV neutrino with the gamma-ray outburst set limits on the energy scale of possible LIV to >0.01E_{pl} for linear LIV models and >6×10^{-8}E_{pl} for quadratic order LIV models, where E_{pl} is the Planck energy scale. These are the most stringent constraints on neutrino LIV for subluminal neutrinos.

  16. Testing the Equivalence Principle and Lorentz Invariance with PeV Neutrinos from Blazar Flares

    NASA Astrophysics Data System (ADS)

    Wang, Zi-Yi; Liu, Ruo-Yu; Wang, Xiang-Yu

    2016-04-01

    It was recently proposed that a giant flare of the blazar PKS B1424-418 at redshift z =1.522 is in association with a PeV-energy neutrino event detected by IceCube. Based on this association we here suggest that the flight time difference between the PeV neutrino and gamma-ray photons from blazar flares can be used to constrain the violations of equivalence principle and the Lorentz invariance for neutrinos. From the calculated Shapiro delay due to clusters or superclusters in the nearby universe, we find that violation of the equivalence principle for neutrinos and photons is constrained to an accuracy of at least 1 0-5, which is 2 orders of magnitude tighter than the constraint placed by MeV neutrinos from supernova 1987A. Lorentz invariance violation (LIV) arises in various quantum-gravity theories, which predicts an energy-dependent velocity of propagation in vacuum for particles. We find that the association of the PeV neutrino with the gamma-ray outburst set limits on the energy scale of possible LIV to >0.01 Ep l for linear LIV models and >6 ×10-8Ep l for quadratic order LIV models, where Ep l is the Planck energy scale. These are the most stringent constraints on neutrino LIV for subluminal neutrinos.

  17. Estimate from Gulmarg of PeV photon flux from Cygnus X-3 and its relevance

    NASA Astrophysics Data System (ADS)

    Bhat, C. L.; Sapru, M. L.; Razdan, H.

    1986-07-01

    Atmospheric pulses recorded at Gulmarg, India between January 1976 and December 1977 using wide-angle photomultipliers indicate a phase-dependent component exhibiting the Cygnus X-3 modulation period of 4.8 hr, and an amplitude, determined by the number of excess events in the phase peak relative to the total phase-independent events, of 1.8 + or - 0.4 percent (corresponding to a detected average flux of 1.6 + or - 0.4 gamma/sq cm per s above 0.5 PeV). The possibility of a long-term reduction in the luminosity of the PeV source by a factor of about 1.5/yr is also suggested by Haverah Park phase histograms of Cygnus X-3 obtained between January 1979 and December 1984, and by Plateau Rosa data from the December 1981 to March 1985 period. After accounting for losses in the PeV photon beam due to gamma-gamma interactions with the 2.7 K microwave background, the ultrahigh energy photon fluxes in the 10 to the 11th to 10 to the 12th eV region are found to be much lower than those of Cygnus X-3.

  18. Possible Domain Formation In PE/PC Bilayers Containing High Cholesterol

    NASA Astrophysics Data System (ADS)

    Hein, Matthew; Hussain, Fazle; Huang, Juyang

    2015-03-01

    Cholesterol is a significant component of animal cell membranes, and its presence has the effects of not only adding rigidity to the lipid bilayer, but also leading to the formation of lipid domains. Two other lipids of interest are phosphatidylethanolamine (PE), which constitutes about 45 percent of the phospholipids found in human nervous tissues, and phosphatidylcholine (PC), which is found in every cell of the human body. The maximum solubility of cholesterol is the highest mole fraction of cholesterol that the lipid bilayer can retain, at which point cholesterol begins to precipitate out to form cholesterol monohydrate crystals. We have measured the maximum solubility of cholesterol in mixtures of 16:0-18:1PE and 16:0-18:1PC using a new light scattering technique, which utilizes the anisotropic nature of light scattering by cholesterol crystals. This new method is highly accurate and reproducible. Our results show that the maximum solubility of cholesterol increases linearly as a function of the molar ratio POPC/(POPE+POPC), which suggests possible domain formation in mixtures of PE and PC containing maximum amount of cholesterol.

  19. Mycobacterial PE/PPE Proteins at the Host-Pathogen Interface

    PubMed Central

    Sampson, Samantha L.

    2011-01-01

    The mycobacterial PE/PPE proteins have attracted much interest since their formal identification just over a decade ago. It has been widely speculated that these proteins may play a role in evasion of host immune responses, possibly via antigenic variation. Although a cohesive understanding of their function(s) has yet to be established, emerging data increasingly supports a role for the PE/PPE proteins at multiple levels of the infectious process. This paper will delineate salient features of the families revealed by comparative genomics, bioinformatic analyses and genome-wide screening approaches and will summarise existing knowledge of subcellular localization, secretion pathways, and protein structure. These characteristics will be considered in light of findings on innate and adaptive host responses to PE/PPE proteins, and we will review the increasing body of data on B and T cell recognition of these proteins. Finally, we will consider how current knowledge and future explorations may contribute to a more comprehensive understanding of these intriguing proteins and their involvement in host pathogen interactions. Ultimately this information could underpin future intervention strategies, for example, in the area of new and improved diagnostic tools and vaccine candidates. PMID:21318182

  20. ESR study of free radicals in UHMW-PE fiber irradiated by gamma rays

    NASA Astrophysics Data System (ADS)

    Zhao, Yanning; Wang, Mouhua; Tang, Zhongfeng; Wu, Guozhong

    2010-04-01

    ESR spectra of the trapped radicals in an ultra-high molecular weight polyethylene (UHMW-PE) fiber irradiated by gamma rays showed well-resolved hyperfine splitting at room temperature since the c-axis of the crystallites is aligned with the fiber direction and the radicals are trapped in crystallites. The alkyl radical (-CH 2- •CH-CH 2-) was the major product after irradiation in vacuum and in air at room temperature. Some of the alkyl radicals converted to allyl radicals (-CH 2- •CH-CH=CH-) and polyenyl radicals (-CH 2- •CH-(CH=CH) n-CH 2-) during storage in vacuum. Upon storage in air atmosphere, the alkyl radicals decayed by reaction with oxygen. Of particular interest is the very slow decay rate of the alkyl radical trapped in UHMW-PE fiber, the half-life is 26 days in vacuum, and 13 days in air at room temperature, which is about 1/30 and 1/100 of that reported for high density polyethylene (HDPE), respectively. The extremely long lifetime of the alkyl radical is supposed to be caused by the large size of crystallites in UHMW-PE fiber. The rate of radical decay was accelerated by annealing at elevated temperature.

  1. Nano-cage-mediated refolding of insulin by PEG-PE micelle.

    PubMed

    Fang, Xiaocui; Yang, Tao; Wang, Luoyang; Yu, Jibing; Wei, Xiuli; Zhou, Yinjian; Wang, Chen; Liang, Wei

    2016-01-01

    Insulin aggregation has pronounced pharmaceutical implications and biological importance. Deposition of insulin aggregates is associated with type II diabetes and instability of pharmaceutical formulations. We present in this study the renaturation effect of PEG-PE micelle on dithiothreitol (DTT)-denatured insulin revealed by techniques including turbidity assay, circular dichroism (CD), thioflavinT (ThT) binding assay, bis-ANS binding assay, agarose gel electrophoresis and MALDI-TOF MS. The obtained results show that PEG-PE micelle having a hydrophilic nano-cage-like structure in which with a negative charge layer, can capture DTT-induced insulin A and B chains, and block their hydrophobic interaction, thereby preventing aggregation. The reduced insulin A and B chain in the nano-cage are capable of recognizing each other and form the native insulin with yields of ∼30% as measured by hypoglycemic activity analysis in mice. The observed insulin refolding assisted by PEG-PE micelle may be applicable to other proteins.

  2. Interfacial characterization of Pluronic PE9400 at biocompatible (air-water and limonene-water) interfaces.

    PubMed

    Pérez-Mosqueda, Luis M; Maldonado-Valderrama, Julia; Ramírez, Pablo; Cabrerizo-Vílchez, Miguel A; Muñoz, José

    2013-11-01

    In this work, we provide an accurate characterization of non-ionic triblock copolymer Pluronic PE9400 at the air-water and limonene-water interfaces, comprising a systematic analysis of surface tension isotherms, dynamic curves, dilatational rheology and desorption profiles. The surface pressure isotherms display two different slopes of the Π-c plot suggesting the existence of two adsorption regimes for PE9400 at both interfaces. Application of a theoretical model, which assumes the coexistence of different adsorbed states characterized by their molar areas, allows quantification of the conformational changes occurring at the adsorbed layer, indentifying differences between the conformations adopted at the air-water and the limonene-water interface. The presence of two maxima in the dilatational modulus vs. interfacial pressure importantly corroborates this conformational change from a 2D flat conformation to 3D brush one. Moreover, the dilatational response provides mechanical diferences between the interfacial layers formed at the two interfaces analyzed. Dynamic surface pressure data were transformed into a dimensionless form and fitted to another model which considers the influence of the reorganization process on the adsorption dynamics. Finally, the desorption profiles reveal that Pluronic PE9400 is irreversibly adsorbed at both interfaces regardless of the interfacial conformation and nature of the interface. The systematic characterization presented in this work provides important new findings on the interfacial properties of pluronics which can be applied in the rational development of new products, such as biocompatible limonene-based emulsions and/or microemulsions.

  3. Theory of 2 omega(sub pe) radiation induced by the bow shock

    NASA Technical Reports Server (NTRS)

    Yoon, Peter H.; Wu, C. S.; Vinas, A. F.-; Reiner, M. J.; Fainberg, J.; Stone, R. G.

    1994-01-01

    A new radiation emission mechanism is proposed to explain electomagnetic radiation observed at twice the electron plasma frequency, 2 omega(sub pe), in the upstream region of the Earth's bow shock. This radiation had its origin at the electron foreshock boundary where energetic electron beams and intense narrow-band Langmiur waves are observed. The proposed emission mechanism results from the interaction of the electron beam and Langmuir waves that are backscattered off thermal ions. This interaction is described by a nonlinear dispersion equation which incorporates an effect owing to electron trajectory modulation by the backscattered Langmuir waves. Subsequent analysis of the dispersion equation reveals two important consequences. First, a long-wavelength electrostatic quasi-mode with frequency at 2 omega(sub pe) is excited, and second, the quasi-mode and the electomagnetic mode are nonlinearly coupled. The implication is that, when the excited 2 omega(sub pe) quasi-mode propagates in an inhomgeneous medium with slightly decreasing density, the quasi-mode can be converted directly into an electromagnetic mode. Hense the electomagnetic radiation at twice the plasma frequency is generated. Numerical solutions of the dispersion equation with the choice of parameters that describe physical characteristics of the electron foreshock are presented, which illustrates the viability of the new mechanism.

  4. Sjogren's syndrome presenting as remitting seronegative symmetric synovitis with pitting edema (RS3PE).

    PubMed

    Choi, Young Mi; Sheen, Dong Hyuk; Lee, Yun Jong; Lee, Eun Bong; Song, Yeong Wook

    2003-08-01

    Remitting seronegative symmetric synovitis with pitting edema (RS3PE) syndrome is characterized by symmetrical and acute synovitis, pitting edema, the absence of rheumatoid factor, increased acute phase reactants, lack of bony erosions on radiography, and benign and short clinical course. Half of all patients with Sjogren's syndrome experience arthritis during the disease course. We here describe the first case of Sjogren's syndrome presenting as RS3PE. She had swelling in knees, ankles, and wrists. After then the swelling spread to her lower legs, feet, face, and both hands. She was admitted to another hospital and was suspected of lupus or rheumatoid arthritis. Three months later, she had dry mouth and had lower lip biopsy. She was admitted to this hospital due to development of swelling in face and lower legs for 3 days. On physical examination, she had pitting edema in both hands and feet dorsum. Laboratory test showed elevated erythrocyte sedimentation rate, positivity of rheumatoid factor, anti-nuclear antibody, and anti-Ro antibody. There was no erosion in the hands radiography. Schirmer's test and lip biopsy was compatible with Sjogren's syndrome. She was diagnosed RS3PE and Sjogren's syndrome. She was begun with prednisolone and her symptoms improved gradually.

  5. Relationship between alpha 1-adrenergic receptor occupancy and response in BC3H-1 muscle cells

    SciTech Connect

    Brown, R.D.; Berger, K.D.; Taylor, P.

    1987-07-01

    The relationship between alpha 1-adrenergic receptor occupancy by agonists or antagonists and the regulation of intracellular Ca/sup 2 +/ was examined. Receptor occupancy was measured using the antagonist (/sup 3/H)prazosin and correlated with agonist-elicited /sup 45/Ca/sup 2 +/ fluxes. The agonists epinephrine (E), norepinephrine (NE), and phenylephrine (PE) coordinately activated Ca/sup 2 +/ efflux, reflecting a substantial mobilization of intracellular Ca/sup 2 +/, as well as a smaller /sup 45/Ca/sup 2 +/ influx. The agonist concentration dependences for influx and efflux were similar, with the order of potency expected for alpha 1 receptors (E greater than or equal to NE greater than PE). To determine the relationship between receptor occupancy and response, the slowly dissociating antagonist prazosin was used to inactivate specified fractions of the receptor population. A linear relationship was observed between the remaining activatable receptors and residual /sup 45/Ca/sup 2 +/ efflux elicited by E or NE, except at saturating agonist concentrations where some curvature was observed. Moreover, the concentration dependence for agonist-elicited /sup 45/Ca/sup 2 +/ efflux was shifted toward slightly higher concentrations of E or NE following prazosin inactivation. These results suggest the presence of a modest receptor reserve which is revealed by E or NE, but not by PE. Agonist occupation was measured over the same interval as receptor activation by competition with the initial rate of (/sup 3/H)prazosin association. All three agonists exhibited the major fraction of receptor occupation over the same concentration ranges required for the functional response. Exposure of receptors to specified agonist concentrations for 30 min had little effect on the number of receptors or their ligand affinities, whereas a 2.5-hr exposure to agonist decreased apparent agonist affinity as well as the number of receptors recognized by (/sup 3/H)prazosin.

  6. Agonist-antagonist combinations in opioid dependence: a translational approach

    PubMed Central

    Mannelli, P.

    2011-01-01

    Summary The potential therapeutic benefits of co-administering opiate agonist and antagonist agents remain largely to be investigated. This paper focuses on the mechanisms of very low doses of naltrexone that help modulate the effects of methadone withdrawal and review pharmacological properties of the buprenorphine/naltrexone combination that support its clinical investigation. The bench-to-bedside development of the very low dose naltrexone treatment can serve as a translational paradigm to investigate and treat drug addiction. Further research on putative mechanisms elicited by the use of opioid agonist-antagonist combinations may lead to effective pharmacological alternatives to the gold standard methadone treatment, also useful for the management of the abuse of non opioid drugs and alcohol. PMID:22448305

  7. Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity

    PubMed Central

    2013-01-01

    Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [35S]GTPγS assay are predictive of the in vivo profile. PMID:23438330

  8. Orvinols with mixed kappa/mu opioid receptor agonist activity.

    PubMed

    Greedy, Benjamin M; Bradbury, Faye; Thomas, Mark P; Grivas, Konstantinos; Cami-Kobeci, Gerta; Archambeau, Ashley; Bosse, Kelly; Clark, Mary J; Aceto, Mario; Lewis, John W; Traynor, John R; Husbands, Stephen M

    2013-04-25

    Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [(35)S]GTPγS assay are predictive of the in vivo profile.

  9. Grooming, rank, and agonistic support in tufted capuchin monkeys.

    PubMed

    Schino, Gabriele; Di Giuseppe, Francesca; Visalberghi, Elisabetta

    2009-02-01

    Studies investigating the relation between allogrooming and social rank in capuchin monkeys (genus Cebus) have yielded inconsistent results. In this study, we investigated the relation between grooming, agonistic support, aggression and social rank in a captive group of tufted capuchin monkeys (C. apella). Differently from most previous studies, we based our analyses on a relatively large database and studied a group with known genealogical relationships. Tufted capuchin females did not exchange grooming for rank-related benefits such as agonistic support or reduced aggression. Coherently with this picture, they did not groom up the hierarchy and did not compete for accessing high-ranking grooming partners. It is suggested that a small group size, coupled with a strong kin bias, may make the exchange of grooming for rank-related benefits impossible or unprofitable, thus eliminating the advantages of grooming up the hierarchy. We provide several possible explanations for the heterogeneity of results across capuchin studies that have addressed similar questions.

  10. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor.

    PubMed

    Bock, Andreas; Bermudez, Marcel; Krebs, Fabian; Matera, Carlo; Chirinda, Brian; Sydow, Dominique; Dallanoce, Clelia; Holzgrabe, Ulrike; De Amici, Marco; Lohse, Martin J; Wolber, Gerhard; Mohr, Klaus

    2016-07-29

    G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site.

  11. Dopamine Agonists and the Suppression of Impulsive Motor Actions in Parkinson’s Disease

    PubMed Central

    Wylie, S.A.; Claassen, D.O.; Huizenga, H.M.; Schewel, K.D.; Ridderinkhof, K.R.; Bashore, T.R.; van den Wildenberg, W.P.M.

    2012-01-01

    The suppression of spontaneous motor impulses is an essential facet of cognitive control that is linked to frontal-basal ganglia circuitry. Basal ganglia dysfunction caused by Parkinson’s disease (PD) disrupts the proficiency of action suppression, but how pharmacotherapy for PD impacts impulsive motor control is poorly understood. Dopamine agonists improve motor symptoms of PD, but can also provoke impulsive-compulsive behaviors (ICB). We investigated whether dopamine agonist medication has a beneficial or detrimental effect on impulsive action control in thirty-eight PD patients, half of whom had current ICB. Participants performed the Simon conflict task, which measures susceptibility to acting on spontaneous action impulses as well as the proficiency of suppressing these impulses. Compared to an off agonist state, patients on their agonist were no more susceptible to reacting impulsively, but were less proficient at suppressing the interference from the activation of impulsive actions. Importantly, agonist effects depended on baseline performance in the off agonist state; more proficient suppressors off agonist experienced a reduction in suppression on agonist, whereas less proficient suppressors off agonist showed improved suppression on agonist. Patients with active ICB were actually less susceptible to making fast, impulsive response errors than patients without ICB, suggesting that behavioral problems in this subset of patients may be less related to impulsivity in motor control. Our findings provide further evidence that dopamine agonist medication impacts specific cognitive control processes and that the direction of its effects depends on individual differences in performance off medication. PMID:22571461

  12. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor.

    PubMed

    Bock, Andreas; Bermudez, Marcel; Krebs, Fabian; Matera, Carlo; Chirinda, Brian; Sydow, Dominique; Dallanoce, Clelia; Holzgrabe, Ulrike; De Amici, Marco; Lohse, Martin J; Wolber, Gerhard; Mohr, Klaus

    2016-07-29

    G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site. PMID:27298318

  13. Mixed Kappa/Mu Opioid Receptor Agonists: The 6β-Naltrexamines

    PubMed Central

    Cami-Kobeci, Gerta; Neal, Adrian P.; Bradbury, Faye A.; Purington, Lauren C.; Aceto, Mario D.; Harris, Louis S.; Lewis, John W.; Traynor, John R.; Husbands, Stephen M.

    2011-01-01

    Ligands from the naltrexamine series have consistently demonstrated agonist activity at kappa opioid receptors (KOR), with varying activity at the mu opioid receptor (MOR). Various 6β-cinnamoylamino derivatives were made with the aim of generating ligands with a KOR agonist/MOR partial agonist profile, as ligands with this activity may be of interest as treatment agents for cocaine abuse. The ligands all displayed the desired high affinity, non-selective binding in vitro and in the functional assays were high efficacy KOR agonists with some partial agonist activity at MOR. Two of the new ligands (12a, 12b) have been evaluated in vivo, with 12a acting as a KOR agonist, and therefore somewhat similar to the previously evaluated analogues 3–6, while 12b displayed predominant MOR agonist activity. PMID:19253970

  14. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    PubMed Central

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Eto, Morifusa

    2003-01-01

    The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine 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. Abbreviation: AEA arylethanolamine AII 2-(arylimino)imidazolidine AIO 2-(arylimino)oxazolidine AIT 2-(arylimino)thiazolidine APAT 2-(α-phenylethylamino)-2-thiazoline BPAT 2-(β-phenylethylamino)-2-thiazoline CAO 2-(3-chlorobenzylamino)-2-oxazoline DCAO 2-(3,5-dichlorobenzylamino)-2-oxazoline DET5 2-(2,6-diethylphenylimino)-5-methylthiazolidine DET6 2-(2,6-diethylphenylimino)thiazine EGTA ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid GFA genetic function approximation G/PLS genetic partial least squares IND 2-aminomethyl-2-indanol LAH lithium aluminum hydride MCSG maximum common subgroup MCT6 2-(2-methyl-4-chlorophenylimino)thiazine OA octopamine PLS partial least squares QSAR quantitative structure-activity relationship SBAT 2-(substituted benzylamino)-2-thiazoline SD the sum of squared deviations of the dependent variable values from their mean SPIT 3-(substituted phenyl)imidazolidine-2-thione THI 2-amino-1-(2-thiazoyl)ethanol TMS tetramethyl silane PMID:15841226

  15. Newspapers and newspaper ink contain agonists for the ah receptor.

    PubMed

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

    2008-04-01

    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 [(3)H]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

  16. Synthesis of fluorinated agonist of sphingosine-1-phosphate receptor 1.

    PubMed

    Aliouane, Lucie; Chao, Sovy; Brizuela, Leyre; Pfund, Emmanuel; Cuvillier, Olivier; Jean, Ludovic; Renard, Pierre-Yves; Lequeux, Thierry

    2014-09-01

    The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation, proliferation, survival and angiogenesis. A fluorinated analogue of S1P receptor agonist has been synthesized by utilizing a ring opening reaction of oxacycles by a lithiated difluoromethylphosphonate anion as the key reaction. In vitro activity of this S1P analogue is also reported.

  17. A human platelet calcium calculator trained by pairwise agonist scanning.

    PubMed

    Lee, Mei Yan; Diamond, Scott L

    2015-02-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide.

  18. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    PubMed

    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 were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline.

  19. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    PubMed

    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 were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline. PMID:20030735

  20. Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe?

    PubMed Central

    Lertxundi, Unax; Domingo-Echaburu, Saioa; Peral, Javier; García, Montserrat

    2011-01-01

    Published literature shows that dopamine agonists can reverse antipsychotic-induced hyperprolactinemia without worsening psychotic symptoms in the majority of schizophrenic patients. However, psychiatrists have been reluctant to use drugs with dopaminergic properties for fear of exacerbating psychiatric symptoms. There are reported cases of psychosis worsening published for both cabergoline and bromocriptine. Cabergoline has proven to be more effective and safe when used to treat hyperprolactinemia, but whether cabergoline is also safer than bromocriptine in antipsychotic induced hyperprolactinemia remains unproven.

  1. A human platelet calcium calculator trained by pairwise agonist scanning.

    PubMed

    Lee, Mei Yan; Diamond, Scott L

    2015-02-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  2. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    SciTech Connect

    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.

    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.

  3. A Human Platelet Calcium Calculator Trained by Pairwise Agonist Scanning

    PubMed Central

    Lee, Mei Yan; Diamond, Scott L.

    2015-01-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  4. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    PubMed Central

    Keane, Fergus; Navin, Patrick; Brett, Francesca; Dennedy, Michael C

    2016-01-01

    Summary Pituitary apoplexy represents an uncommon endocrine emergency with potentially life-threatening consequences. Drug-induced pituitary apoplexy is a rare but important consideration when evaluating patients with this presentation. We describe an unusual case of a patient with a known pituitary macroadenoma presenting with acute-onset third nerve palsy and headache secondary to tumour enlargement and apoplexy. This followed gonadotropin-releasing hormone (GNRH) agonist therapy used to treat metastatic prostate carcinoma. Following acute management, the patient underwent transphenoidal debulking of his pituitary gland with resolution of his third nerve palsy. Subsequent retrospective data interpretation revealed that this had been a secretory gonadotropinoma and GNRH agonist therapy resulted in raised gonadotropins and testosterone. Hence, further management of his prostate carcinoma required GNRH antagonist therapy and external beam radiotherapy. This case demonstrates an uncommon complication of GNRH agonist therapy in the setting of a pituitary macroadenoma. It also highlights the importance of careful, serial data interpretation in patients with pituitary adenomas. Finally, this case presents a unique insight into the challenges of managing a hormonal-dependent prostate cancer in a patient with a secretory pituitary tumour. Learning points While non-functioning gonadotropinomas represent the most common form of pituitary macroadenoma, functioning gonadotropinomas are exceedingly rare. Acute tumour enlargement, with potential pituitary apoplexy, is a rare but important adverse effect arising from GNRH agonist therapy in the presence of both functioning and non-functioning pituitary gonadotropinomas. GNRH antagonist therapy represents an alternative treatment option for patients with hormonal therapy-requiring prostate cancer, who also have diagnosed with a pituitary gonadotropinoma. PMID:27284452

  5. Energy flow in the cryptophyte PE545 antenna is directed by bilin pigment conformation.

    PubMed

    Curutchet, Carles; Novoderezhkin, Vladimir I; Kongsted, Jacob; Muñoz-Losa, Aurora; van Grondelle, Rienk; Scholes, Gregory D; Mennucci, Benedetta

    2013-04-25

    Structure-based calculations are combined with quantitative modeling of spectra and energy transfer dynamics to detemine the energy transfer scheme of the PE545 principal light-harvesting antenna of the cryptomonad Rhodomonas CS24. We use a recently developed quantum-mechanics/molecular mechanics (QM/MM) method that allows us to account for pigment-protein interactions at atomic detail in site energies, transition dipole moments, and electronic couplings. In addition, conformational flexibility of the pigment-protein complex is accounted for through molecular dynamics (MD) simulations. We find that conformational disorder largely smoothes the large energetic differences predicted from the crystal structure between the pseudosymmetric pairs PEB50/61C-PEB50/61D and PEB82C-PEB82D. Moreover, we find that, in contrast to chlorophyll-based photosynthetic complexes, pigment composition and conformation play a major role in defining the energy ladder in the PE545 complex, rather than specific pigment-protein interactions. This is explained by the remarkable conformational flexibility of the eight bilin pigments in PE545, characterized by a quasi-linear arrangement of four pyrrole units. The MD-QM/MM site energies allow us to reproduce the main features of the spectra, and minor adjustments of the energies of the three red-most pigments DBV19A, DBV19B, and PEB82D allow us to model the spectra of PE545 with a similar quality compared to our original model (model E from Novoderezhkin et al. Biophys. J.2010, 99, 344), which was extracted from the spectral and kinetic fit. Moreover, the fit of the transient absorption kinetics is even better in the new structure-based model. The largest difference between our previous and present results is that the MD-QM/MM calculations predict a much smaller gap between the PEB50/61C and PEB50/61D sites, in better accord with chemical intuition. We conclude that the current adjusted MD-QM/MM energies are more reliable in order to explore the

  6. Increased flow precedes remote arteriolar dilations for some microapplied agonists.

    PubMed

    Frame, M D

    2000-04-01

    This study asks which occurs first in time for remote responses: a dilation or a remote change in flow. Arteriolar diameter (approximately 20 microm) and fluorescently labeled red blood cell (RBC) velocity were measured in the cremaster muscle of anesthetized (pentobarbital sodium, 70 mg/kg) hamsters (n = 51). Arterioles were locally stimulated for 60 s with micropipette-applied 10 microg/ml LM-609 (alpha(v)beta(3)-integrin agonist), 10(-3) M adenosine, or 10(-3) M 3-morpholinosydnonimine (SIN-1, nitric oxide donor) as remote response agonists or with 10(-3) M papaverine, which dilates only locally. Observations were made at a remote site 1,200 microm upstream. With LM-609 or adenosine, the RBC velocity increased first (within 5 s), and the remote dilation followed 5-7 s later. N-nitro-L-arginine (100 microM) blocked the LM-609 (100%) and adenosine (60%) remote dilations. SIN-1 induced a concurrent remote dilation and decrease in RBC velocity (approximately 10 s), suggesting the primary signal was to dilate. Papaverine had no remote effects. This study suggests that, although remote responses to some agonists are induced by primary signals to dilate, additionally, network changes in flow can stimulate extensive remote changes in diameter.

  7. Suppression of atherosclerosis by synthetic REV-ERB agonist

    SciTech Connect

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    2015-05-08

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.

  8. Emerging strategies for exploiting cannabinoid receptor agonists as medicines.

    PubMed

    Pertwee, Roger G

    2009-02-01

    Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  9. Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.

    PubMed

    Toyota, Kenji; Kato, Yasuhiko; Miyakawa, Hitoshi; Yatsu, Ryohei; Mizutani, Takeshi; Ogino, Yukiko; Miyagawa, Shinichi; Watanabe, Hajime; Nishide, Hiroyo; Uchiyama, Ikuo; Tatarazako, Norihisa; Iguchi, Taisen

    2014-05-01

    Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical-specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH-responsive genes. PMID:24038158

  10. Structure of the agonist-bound neurotensin receptor.

    PubMed

    White, Jim F; Noinaj, Nicholas; Shibata, Yoko; Love, James; Kloss, Brian; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Shiloach, Joseph; Tate, Christopher G; Grisshammer, Reinhard

    2012-10-25

    Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8 Å resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity.

  11. Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.

    PubMed

    Toyota, Kenji; Kato, Yasuhiko; Miyakawa, Hitoshi; Yatsu, Ryohei; Mizutani, Takeshi; Ogino, Yukiko; Miyagawa, Shinichi; Watanabe, Hajime; Nishide, Hiroyo; Uchiyama, Ikuo; Tatarazako, Norihisa; Iguchi, Taisen

    2014-05-01

    Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical-specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH-responsive genes.

  12. Surface Expression of MPT64 as a Fusion with the PE Domain of PE_PGRS33 Enhances Mycobacterium bovis BCG Protective Activity against Mycobacterium tuberculosis in Mice▿

    PubMed Central

    Sali, Michela; Di Sante, Gabriele; Cascioferro, Alessandro; Zumbo, Antonella; Nicolò, Chiara; Donà, Valentina; Rocca, Stefano; Procoli, Annabella; Morandi, Matteo; Ria, Francesco; Palù, Giorgio; Fadda, Giovanni; Manganelli, Riccardo; Delogu, Giovanni

    2010-01-01

    To improve the current vaccine against tuberculosis, a recombinant strain of Mycobacterium bovis bacillus Calmette-Guérin (rBCG) expressing a Mycobacterium tuberculosis vaccine candidate antigen (MPT64) in strong association with the mycobacterial cell wall was developed. To deliver the candidate antigen on the surface, we fused the mpt64 gene to the sequence encoding the PE domain of the PE_PGRS33 protein of M. tuberculosis (to create strain HPE-ΔMPT64-BCG), which we have previously shown to transport proteins to the bacterial surface. In a series of protection experiments in the mouse model of tuberculosis, we showed that (i) immunization of mice with HPE-ΔMPT64-BCG provides levels of protection significantly higher than those afforded by the parental BCG strain, as assessed by bacterial colonization in lungs and spleens and by lung involvement (at both 28 and 70 days postchallenge), (ii) rBCG strains expressing MPT64 provide better protection than the parental BCG strain only when this antigen is surface expressed, and (iii) the HPE-ΔMPT64-BCG-induced MPT64-specific T cell repertoire when characterized by β chain variable region-β chain joining region (BV-BJ) spectratyping indicates that protection is correlated with the ability to recruit gamma interferon (IFN-γ)-secreting T cells carrying the BV8.3-BJ1.5 (172 bp) shared rearrangement. These results demonstrate that HPE-ΔMPT64-BCG is one of the most effective new vaccines tested so far in the mouse model of tuberculosis and underscore the impact of antigen cellular localization on the induction of the specific immune response induced by rBCG. PMID:20921146

  13. ESTIMATING PERSON-CENTERED TREATMENT (PeT) EFFECTS USING INSTRUMENTAL VARIABLES: AN APPLICATION TO EVALUATING PROSTATE CANCER TREATMENTS

    PubMed Central

    BASU, ANIRBAN

    2014-01-01

    SUMMARY This paper builds on the methods of local instrumental variables developed by Heckman and Vytlacil (1999, 2001, 2005) to estimate person-centered treatment (PeT) effects that are conditioned on the person’s observed characteristics and averaged over the potential conditional distribution of unobserved characteristics that lead them to their observed treatment choices. PeT effects are more individualized than conditional treatment effects from a randomized setting with the same observed characteristics. PeT effects can be easily aggregated to construct any of the mean treatment effect parameters and, more importantly, are well suited to comprehend individual-level treatment effect heterogeneity. The paper presents the theory behind PeT effects, and applies it to study the variation in individual-level comparative effects of prostate cancer treatments on overall survival and costs. PMID:25620844

  14. The furin protease cleavage recognition sequence of Sindbis virus PE2 can mediate virion attachment to cell surface heparan sulfate.

    PubMed

    Klimstra, W B; Heidner, H W; Johnston, R E

    1999-08-01

    Cell culture-adapted Sindbis virus strains attach to heparan sulfate (HS) receptors during infection of cultured cells (W. B. Klimstra, K. D. Ryman, and R. E. Johnston, J. Virol. 72:7357-7366, 1998). At least three E2 glycoprotein mutations (E2 Arg 1, E2 Lys 70, and E2 Arg 114) can independently confer HS attachment in the background of the consensus sequence Sindbis virus (TR339). In the studies reported here, we have investigated the mechanism by which the E2 Arg 1 mutation confers HS-dependent binding. Substitution of Arg for Ser at E2 1 resulted in a significant reduction in the efficiency of PE2 cleavage, yielding virus particles containing a mixture of PE2 and mature E2. Presence of PE2 was associated with an increase in HS-dependent attachment to cells and efficient attachment to heparin-agarose beads, presumably because the furin recognition site for PE2 cleavage also represents a candidate HS binding sequence. A comparison of mutants with partially or completely inhibited PE2 cleavage demonstrated that efficiency of cell binding was correlated with the amount of PE2 in virus particles. Viruses rendered cleavage defective due to deletions of portions or all of the furin cleavage sequence attached very poorly to cells, indicating that an intact furin cleavage sequence was specifically required for PE2-mediated attachment to cells. In contrast, a virus containing a partial deletion was capable of efficient binding to heparin-agarose beads, suggesting different requirements for heparin bead and cell surface HS binding. Furthermore, virus produced in C6/36 mosquito cells, which cleave PE2 more efficiently than BHK cells, exhibited a reduction in cell attachment efficiency correlated with reduced content of PE2 in particles. Taken together, these results strongly argue that the XBXBBX (B, basic; X, hydrophobic) furin protease recognition sequence of PE2 can mediate the binding of PE2-containing Sindbis viruses to HS. This sequence is very similar to an XBBXBX

  15. PE-Cy5.5 conjugates bind to the cells expressing mouse DEC205/CD205

    PubMed Central

    Park, Chae Gyu; Rodriguez, Anthony; Steinman, Ralph M.

    2012-01-01

    DEC205/CD205, an endocytic receptor of C-type multilectin, is expressed highly in dendritic cells (DCs). DEC205 was shown to efficiently deliver vaccine antigens in surrogate ligands to the antigen processing and presentation machinery of DCs, which resulted in the development of DC-targeted vaccines employing anti-DC monoclonal antibodies (mAbs). During our studies to characterize a variety of anti-DC mAbs including anti-DEC205 by flow cytometric analysis, we discovered that a secondary anti-immunoglobulin antibody conjugated with PE-Cy5.5 bound strongly to the cells expressing mouse DEC205 (mDEC205) without incubation of a primary anti-mDEC205 mAb. In the present study we demonstrate that various antibodies and streptavidin conjugated with PE-Cy5.5 bind to the mDEC205-expressing cells including CHO, KIT6, and HEK293 cells. The interaction between the PE-Cy5.5 conjugates and the cells expressing mDEC205 appears distinctive, since none of PE-Cy5.5 conjugates bind to the cells that express human DEC205 on surface. Besides, only PE-Cy5.5 conjugates bind strongly to mDEC205-expressing cells; PerCP-Cy5.5, APC-Cy5.5, and Cy5.5 conjugates bind weakly; PE, PE-Cy5, Cy5, FITC, or Alexa488 conjugates do not bind. Therefore the use of PE-Cy5.5 conjugates, widely utilized in multicolor flow cytometry, requires precaution against nonspecific binding to mDEC205-positive cells. PMID:22841832

  16. Autophagy Competes for a Common Phosphatidylethanolamine Pool with Major Cellular PE-Consuming Pathways in Saccharomyces cerevisiae

    PubMed Central

    Wilson-Zbinden, Caroline; dos Santos, Aline Xavier da Silveira; Stoffel-Studer, Ingrid; van der Vaart, Aniek; Hofmann, Kay; Reggiori, Fulvio; Riezman, Howard; Kraft, Claudine; Peter, Matthias

    2015-01-01

    Autophagy is a highly regulated pathway that selectively degrades cellular constituents such as protein aggregates and excessive or damaged organelles. This transport route is characterized by engulfment of the targeted cargo by autophagosomes. The formation of these double-membrane vesicles requires the covalent conjugation of the ubiquitin-like protein Atg8 to phosphatidylethanolamine (PE). However, the origin of PE and the regulation of lipid flux required for autophagy remain poorly understood. Using a genetic screen, we found that the temperature-sensitive growth and intracellular membrane organization defects of mcd4-174 and mcd4-P301L mutants are suppressed by deletion of essential autophagy genes such as ATG1 or ATG7. MCD4 encodes an ethanolamine phosphate transferase that uses PE as a precursor for an essential step in the synthesis of the glycosylphosphatidylinositol (GPI) anchor used to link a subset of plasma membrane proteins to lipid bilayers. Similar to the deletion of CHO2, a gene encoding the enzyme converting PE to phosphatidylcholine (PC), deletion of ATG7 was able to restore lipidation and plasma membrane localization of the GPI-anchored protein Gas1 and normal organization of intracellular membranes. Conversely, overexpression of Cho2 was lethal in mcd4-174 cells grown at restrictive temperature. Quantitative lipid analysis revealed that PE levels are substantially reduced in the mcd4-174 mutant but can be restored by deletion of ATG7 or CHO2. Taken together, these data suggest that autophagy competes for a common PE pool with major cellular PE-consuming pathways such as the GPI anchor and PC synthesis, highlighting the possible interplay between these pathways and the existence of signals that may coordinate PE flux. PMID:25519895

  17. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR.

    PubMed

    Huang, Wendong; Zhang, Jun; Wei, Ping; Schrader, William T; Moore, David D

    2004-10-01

    The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine (m) and human (h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP)2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans. PMID:15272053

  18. Additive antinociceptive effects of mixtures of the κ-opioid receptor agonist spiradoline and the cannabinoid receptor agonist CP55940 in rats.

    PubMed

    Maguire, David R; France, Charles P

    2016-02-01

    Pain is a significant clinical problem, and there is a need for pharmacotherapies that are more effective with fewer adverse effects than currently available medications. Cannabinoid receptor agonists enhance the antinociceptive effects of μ-opioid receptor agonists; it is unclear whether they impact the effects of agonists acting at other opioid receptors. κ-Opioid receptor agonists have antinociceptive effects, but their clinical use is precluded by adverse effects; however, their therapeutic potential might be realized if antinociceptive effects could be selectively enhanced. In this study, the antinociceptive effects of the cannabinoid receptor agonist CP55940 and the κ-opioid receptor agonist spiradoline, alone and in combination, were studied in rats (n=7) using a warm water tail-withdrawal procedure. When administered alone, CP55940 (0.032-1.0 mg/kg) and spiradoline (1.0-32.0 mg/kg) increased tail-withdrawal latency, and mixtures of CP55940 and spiradoline (ratios of 1 : 3, 1 : 1, and 3 : 1) produced additive effects. It remains to be determined whether this additive interaction between a κ-opioid receptor agonist and a cannabinoid receptor agonist is selective for antinociception and whether it can be generalized to other drugs. PMID:26292184

  19. Inhibitory effect of Paeonia lactiflora Pallas extract (PE) on poly (I:C)-induced immune response of epidermal keratinocytes.

    PubMed

    Choi, Mi-Ra; Choi, Dae-Kyoung; Sohn, Kyung-Cheol; Lim, Seul Ki; Kim, Dong-Il; Lee, Young Ho; Im, Myung; Lee, Young; Seo, Young-Joon; Kim, Chang Deok; Lee, Jeung-Hoon

    2015-01-01

    Epidermal keratinocytes provide protective role against external stimuli by barrier formation. In addition, kertinocytes exerts their role as the defense cells via activation of innate immunity. Disturbance of keratinocyte functions is related with skin disorders. Psoriasis is a common skin disease related with inflammatory reaction in epidermal cells. We attempted to find therapeutics for psoriasis, and found that Paeonia lactiflora Pallas extract (PE) has an inhibitory potential on poly (I:C)-induced inflammation of keratinocytes. PE significantly inhibited poly (I:C)-induced expression of crucial psoriatic cytokines, such as IL-6, IL-8, CCL20 and TNF-α, via down-regulation of NF-κB signaling pathway in human keratinocytes. In addition, PE significantly inhibited poly (I:C)-induced inflammasome activation, in terms of IL-1β and caspase-1 secretion. Finally, PE markedly inhibited poly (I:C)-increased NLRP3, an important component of inflammasome. These results indicate that PE has an inhibitory effect on poly (I:C)-induced inflammatory reaction of keratinocytes, suggesting that PE can be developed for the treatment of psoriasis.

  20. Low Pressure DC Glow Discharge Air Plasma Surface Treatment of Polyethylene (PE) Film for Improvement of Adhesive Properties

    NASA Astrophysics Data System (ADS)

    Krishnasamy Navaneetha, Pandiyaraj; Vengatasamy, Selvarajan; Rajendrasing, R. Deshmukh; Paramasivam, Yoganand; Suresh, Balasubramanian; Sundaram, Maruthamuthu

    2013-01-01

    The present work deals with the change in surface properties of polyethylene (PE) film using DC low pressure glow discharge air plasma and makes it useful for technical applications. The change in hydrophilicity of the modified PE film surface was investigated by measuring contact angle and surface energy as a function of exposure time. Changes in the morphological and chemical composition of PE films were analyzed by atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). The improvement in adhesion was studied by measuring T-peel and lap-shear strength. The results show that the wettability and surface energy of the PE film has been improved due to the introduction of oxygen-containing polar groups and an increase in surface roughness. The XPS result clearly shows the increase in concentration of oxygen content and the formation of polar groups on the polymer surface. The AFM observation on PE film shows that the roughness of the surface increased due to plasma treatment. The above morphological and chemical changes enhanced the adhesive properties of the PE film surfaces, which was confirmed by T-peel and lap-shear tests.

  1. Inhibitory effect of Paeonia lactiflora Pallas extract (PE) on poly (I:C)-induced immune response of epidermal keratinocytes

    PubMed Central

    Choi, Mi-Ra; Choi, Dae-Kyoung; Sohn, Kyung-Cheol; Lim, Seul Ki; Kim, Dong-Il; Lee, Young Ho; Im, Myung; Lee, Young; Seo, Young-Joon; Kim, Chang Deok; Lee, Jeung-Hoon

    2015-01-01

    Epidermal keratinocytes provide protective role against external stimuli by barrier formation. In addition, kertinocytes exerts their role as the defense cells via activation of innate immunity. Disturbance of keratinocyte functions is related with skin disorders. Psoriasis is a common skin disease related with inflammatory reaction in epidermal cells. We attempted to find therapeutics for psoriasis, and found that Paeonia lactiflora Pallas extract (PE) has an inhibitory potential on poly (I:C)-induced inflammation of keratinocytes. PE significantly inhibited poly (I:C)-induced expression of crucial psoriatic cytokines, such as IL-6, IL-8, CCL20 and TNF-α, via down-regulation of NF-κB signaling pathway in human keratinocytes. In addition, PE significantly inhibited poly (I:C)-induced inflammasome activation, in terms of IL-1β and caspase-1 secretion. Finally, PE markedly inhibited poly (I:C)-increased NLRP3, an important component of inflammasome. These results indicate that PE has an inhibitory effect on poly (I:C)-induced inflammatory reaction of keratinocytes, suggesting that PE can be developed for the treatment of psoriasis. PMID:26191223

  2. Inhibitory effect of Paeonia lactiflora Pallas extract (PE) on poly (I:C)-induced immune response of epidermal keratinocytes.

    PubMed

    Choi, Mi-Ra; Choi, Dae-Kyoung; Sohn, Kyung-Cheol; Lim, Seul Ki; Kim, Dong-Il; Lee, Young Ho; Im, Myung; Lee, Young; Seo, Young-Joon; Kim, Chang Deok; Lee, Jeung-Hoon

    2015-01-01

    Epidermal keratinocytes provide protective role against external stimuli by barrier formation. In addition, kertinocytes exerts their role as the defense cells via activation of innate immunity. Disturbance of keratinocyte functions is related with skin disorders. Psoriasis is a common skin disease related with inflammatory reaction in epidermal cells. We attempted to find therapeutics for psoriasis, and found that Paeonia lactiflora Pallas extract (PE) has an inhibitory potential on poly (I:C)-induced inflammation of keratinocytes. PE significantly inhibited poly (I:C)-induced expression of crucial psoriatic cytokines, such as IL-6, IL-8, CCL20 and TNF-α, via down-regulation of NF-κB signaling pathway in human keratinocytes. In addition, PE significantly inhibited poly (I:C)-induced inflammasome activation, in terms of IL-1β and caspase-1 secretion. Finally, PE markedly inhibited poly (I:C)-increased NLRP3, an important component of inflammasome. These results indicate that PE has an inhibitory effect on poly (I:C)-induced inflammatory reaction of keratinocytes, suggesting that PE can be developed for the treatment of psoriasis. PMID:26191223

  3. Different serotonin receptor agonists have distinct effects on sound-evoked responses in inferior colliculus.

    PubMed

    Hurley, Laura M

    2006-11-01

    The neuromodulator serotonin has a complex set of effects on the auditory responses of neurons within the inferior colliculus (IC), a midbrain auditory nucleus that integrates a wide range of inputs from auditory and nonauditory sources. To determine whether activation of different types of serotonin receptors is a source of the variability in serotonergic effects, four selective agonists of serotonin receptors in the serotonin (5-HT) 1 and 5-HT2 families were iontophoretically applied to IC neurons, which were monitored for changes in their responses to auditory stimuli. Different agonists had different effects on neural responses. The 5-HT1A agonist had mixed facilitatory and depressive effects, whereas 5-HT1B and 5-HT2C agonists were both largely facilitatory. Different agonists changed threshold and frequency tuning in ways that reflected their effects on spike count. When pairs of agonists were applied sequentially to the same neurons, selective agonists sometimes affected neurons in ways that were similar to serotonin, but not to other selective agonists tested. Different agonists also differentially affected groups of neurons classified by the shapes of their frequency-tuning curves, with serotonin and the 5-HT1 receptors affecting proportionally more non-V-type neurons relative to the other agonists tested. In all, evidence suggests that the diversity of serotonin receptor subtypes in the IC is likely to account for at least some of the variability of the effects of serotonin and that receptor subtypes fulfill specialized roles in auditory processing. PMID:16870843

  4. Long-term soil moisture variability from a new P-E water budget method

    NASA Astrophysics Data System (ADS)

    Zeng, N.; Yoon, J.; Mariotti, A.; Swenson, S. C.

    2006-05-01

    Basin-scale soil moisture is traditionally estimated using either land-surface model forced by observed meteorological variables or atmospheric moisture convergence from atmospheric analysis and observed runoff. Interannual variability from such methods suffer from major uncertainties due to the sensitivity to small imperfections in the land-surface model or the atmospheric analysis. Here we introduce a novel P-E method in estimating basin-scale soil moisture, or more precisely apparent land water storage (AWS). The key input variables are observed precipitation and runoff, and reconstructed evaporation. We show the results for the tropics using the example of the Amazon basin. The seasonal cycle of diagnosed soil moisture over the Amazon is about 200mm, compares favorably with satellite estimate from the GRACE mission, thus lending confidence both in this method and the usefulness of space gravity based large-scale soil moisture estimate. This is about twice as large as estimates from several traditional methods, suggesting that current models tend to under estimate the soil moisture variability. One of the advantage of the P-E method is to retrive long-term variability of the basin-scale soil moisture (including interannual and decadal time scales), which can provide valuable information to understand climate variability and to predict future climate condition. However, validation on reconstructed evaporation is very difficult due to lack of observation. The interannual variability in AWS in the Amazon basin is about 150mm, also consistent with GRACE data, but much larger than model results. We also apply this P-E method to the midlatitude Mississippi basin and discuss the impact of major 20th century droughts such as the dust bowl period on the long-term soil moisture variability. The results suggest the existence of soil moisture memories on decadal time scales, significantly longer than typically assumed seasonal timescales.

  5. Girls' Activity Levels and Lesson Contexts in Middle School PE: TAAG Baseline

    PubMed Central

    McKENZIE, THOMAS L.; CATELLIER, DIANE J.; CONWAY, TERRY; LYTLE, LESLIE A.; GRIESER, MIRA; WEBBER, LARRY A.; PRATT, CHARLOTTE A.; ELDER, JOHN P.

    2008-01-01

    Purpose To assess girls' physical activity (PA) in middle school physical education (PE) as it relates to field site, lesson context and location, teacher gender, and class composition. Methods We observed girls' PA levels, lesson contexts, and activity promotion by teachers in 431 lessons in 36 schools from six field sites participating in the Trial of Activity for Adolescent Girls. Interobserver reliabilities exceeded 90% for all three categories. Data were analyzed using mixed-model ANOVA with controls for clustering effects by field site and school. Results Mean lesson length was 37.3 (± 9.4) min. Time (13.9 ± 7.0 min) and proportion of lessons (37.9 ± 18.5%) spent in moderate to vigorous PA (MVPA), and time (4.8 ± 4.2 min) and proportion of lessons (13.1 ± 11.7%) in vigorous PA (VPA) differed by field site (P < 0.004). Lesson time for instructional contexts differed by field site, with overall proportions as follows: game play (27.3%), management (26.1%), fitness activities (19.7%), skill drills (12.1%), knowledge (10.6%), and free play (4.4%). Coed classes were 7.9 min longer than girls-only classes (P = 0.03). Although 27 s shorter, outdoor lessons were more intense (MVPA% = 45.7 vs 33.7% of lesson, P < 0.001) and provided 4.0 more MVPA minutes (P < 0.001). MVPA, VPA, and lesson contexts did not differ by teacher gender. There was little direct promotion of PA by teachers during lessons. Conclusions Substantial variation in the conduct of PE exists. Proportion of lesson time girls spent accruing MVPA (i.e., 37.9%) fell short of the Healthy People 2010 objective of 50%. Numerous possibilities exist for improving girls' PA in PE. PMID:16826019

  6. Evaluating a moving target: Using Practical Participatory Evaluation (P-PE) in hospital settings

    PubMed Central

    Wharton, Tracy; Alexander, Neil

    2014-01-01

    This article describes lessons learned about implementing evaluations in hospital settings. In order to overcome the methodological dilemmas inherent in this environment, we used a practical participatory evaluation strategy to engage as many stakeholders as possible in the process of evaluating a clinical demonstration project. Demonstration projects, in this context, push the envelope about what is known about effectiveness in novel settings, and turnover of staff and patient populations can present challenges to gathering optimal data. By using P-PE, we built capacity in the environment while expanding possibilities for data collection. Suggestions are made based on our experience. PMID:24860251

  7. Electron attachment rate constant measurement by photoemission electron attachment ion mobility spectrometry (PE-EA-IMS)

    NASA Astrophysics Data System (ADS)

    Su, Desheng; Niu, Wenqi; Liu, Sheng; Shen, Chengyin; Huang, Chaoqun; Wang, Hongmei; Jiang, Haihe; Chu, Yannan

    2012-12-01

    Photoemission electron attachment ion mobility spectrometry (PE-EA-IMS), with a source of photoelectrons induced by vacuum ultraviolet radiation on a metal surface, has been developed to study electron attachment reaction at atmospheric pressure using nitrogen as the buffer gas. Based on the negative ion mobility spectra, the rate constants for electron attachment to tetrachloromethane and chloroform were measured at ambient temperature as a function of the average electron energy in the range from 0.29 to 0.96 eV. The experimental results are in good agreement with the data reported in the literature.

  8. Effects of 108 Days Tritium Exposure on UHMW-PE, PTFE, and Vespel(R)

    SciTech Connect

    Clark, E.A.

    2003-01-07

    Samples of three polymers, Ultra-High Molecular Weight Polyethylene (UHMW-PE), polytetrafluoroethylene (PTFE), also known as Teflon(R), and Vespel(R) polyimide were exposed to 1 atmosphere of tritium gas at ambient temperature for 108 days. Sample mass and size measurements to calculate density, spectra-colorimetry, dynamic mechanical analysis (DMA), and Fourier-transform infrared spectroscopy (FT-IR) were employed to characterize the effects of this exposure on these samples. This technical report is the first report from this research program.

  9. Heterogeneous responses of human limbs to infused adrenergic agonists: a gravitational effect?

    NASA Technical Reports Server (NTRS)

    Pawelczyk, James A.; Levine, Benjamin D.

    2002-01-01

    Unlike quadrupeds, the legs of humans are regularly exposed to elevated pressures relative to the arms. We hypothesized that this "dependent hypertension" would be associated with altered adrenergic responsiveness. Isoproterenol (0.75-24 ng x 100 ml limb volume-1 x min-1) and phenylephrine (0.025-0.8 microg x 100 ml limb volume-1 x min-1) were infused incrementally in the brachial and femoral arteries of 12 normal volunteers; changes in limb blood flow were quantified by using strain-gauge plethysmography. Compared with the forearm, baseline calf vascular resistance was greater (38.8 +/- 2.5 vs. 26.9 +/- 2.0 mmHg x 100 ml x min x ml-1; P < 0.001) and maximal conductance was lower (46.1 +/- 11.9 vs. 59.4 +/- 13.4 ml x ml-1 x min-1 x mmHg-1; P < 0.03). Vascular conductance did not differ between the two limbs during isoproterenol infusions, whereas decreases in vascular conductance were greater in the calf than the forearm during phenylephrine infusions (P < 0.001). With responses normalized to maximal conductance, the half-maximal response for phenylephrine was significantly less for the calf than the forearm (P < 0.001), whereas the half-maximal response for isoproterenol did not differ between limbs. We conclude that alpha1- but not beta-adrenergic-receptor responsiveness in human limbs is nonuniform. The relatively greater response to alpha1-adrenergic-receptor stimulation in the calf may represent an adaptive mechanism that limits blood pooling and capillary filtration in the legs during standing.

  10. Defining Nicotinic Agonist Binding Surfaces through Photoaffinity Labeling†

    PubMed Central

    Tomizawa, Motohiro; Maltby, David; Medzihradszky, Katalin F.; Zhang, Nanjing; Durkin, Kathleen A.; Presley, Jack; Talley, Todd T.; Taylor, Palmer; Burlingame, Alma L.; Casida, John E.

    2016-01-01

    Nicotinic acetylcholine (ACh) receptor (nAChR) agonists are potential therapeutic agents for neurological dysfunction. In the present study, the homopentameric mollusk ACh binding protein (AChBP), used as a surrogate for the extracellular ligand-binding domain of the nAChR, was specifically derivatized by the highly potent agonist azidoepibatidine (AzEPI) prepared as a photoaffinity probe and radioligand. One EPI-nitrene photoactivated molecule was incorporated in each subunit interface binding site based on analysis of the intact derivatized protein. Tryptic fragments of the modified AChBP were analyzed by collision-induced dissociation and Edman sequencing of radiolabeled peptides. Each specific EPI-nitrene-modified site involved either Tyr195 of loop C on the principal or (+)-face or Met116 of loop E on the complementary or (−)-face. The two derivatization sites were observed in similar frequency, providing evidence of the reactivity of the azido/nitrene probe substituent and close proximity to both residues. [3H]AzEPI binds to the α4β2 nAChR at a single high-affinity site and photoaffinity-labels only the α4 subunit, presumably modifying Tyr225 spatially corresponding to Tyr195 of AChBP. Phe137 of the β2 nAChR subunit, equivalent to Met116 of AChBP, conceivably lacks sufficient reactivity with the nitrene generated from the probe. The present photoaffinity labeling in a physiologically relevant condition combined with the crystal structure of AChBP allows development of precise structural models for the AzEPI interactions with AChBP and α4β2 nAChR. These findings enabled us to use AChBP as a structural surrogate to define the nAChR agonist site. PMID:17614369

  11. INSIGHT AGONISTES: A READING OF SOPHOCLES'S OEDIPUS THE KING.

    PubMed

    Mahon, Eugene J

    2015-07-01

    In this reading of Sophocles's Oedipus the King, the author suggests that insight can be thought of as the main protagonist of the tragedy. He personifies this depiction of insight, calling it Insight Agonistes, as if it were the sole conflicted character on the stage, albeit masquerading at times as several other characters, including gods, sphinxes, and oracles. This psychoanalytic reading of the text lends itself to an analogy between psychoanalytic process and Sophocles's tragic hero. The author views insight as always transgressing against, always at war with a conservative, societal, or intrapsychic chorus of structured elements. A clinical vignette is presented to illustrate this view of insight.

  12. Narrow SAR in odorant sensing Orco receptor agonists.

    PubMed

    Romaine, Ian M; Taylor, Robert W; Saidu, Samsudeen P; Kim, Kwangho; Sulikowski, Gary A; Zwiebel, Laurence J; Waterson, Alex G

    2014-06-15

    The systematic exploration of a series of triazole-based agonists of the cation channel insect odorant receptor is reported. The structure-activity relationships of independent sections of the molecules are examined. Very small changes to the compound structure were found to exert a large impact on compound activity. Optimal substitutions were combined using a 'mix-and-match' strategy to produce best-in-class compounds that are capable of potently agonizing odorant receptor activity and may form the basis for the identification of a new mode of insect behavior modification. PMID:24813736

  13. Clenbuterol, a beta(2)-agonist, retards atrophy in denervated muscles

    NASA Technical Reports Server (NTRS)

    Zeman, Richard J.; Ludemann, Robert; Etlinger, Joseph D.

    1987-01-01

    The effects of a beta(2) agonist, clenbuterol, on the protein content as well as on the contractile strength and the muscle fiber cross-sectional area of various denervated muscles from rats were investigated. It was found that denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, of rats treated for 2-3 weeks with clenbuterol contained 95-110 percent more protein than denervated controls. The twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area.

  14. INSIGHT AGONISTES: A READING OF SOPHOCLES'S OEDIPUS THE KING.

    PubMed

    Mahon, Eugene J

    2015-07-01

    In this reading of Sophocles's Oedipus the King, the author suggests that insight can be thought of as the main protagonist of the tragedy. He personifies this depiction of insight, calling it Insight Agonistes, as if it were the sole conflicted character on the stage, albeit masquerading at times as several other characters, including gods, sphinxes, and oracles. This psychoanalytic reading of the text lends itself to an analogy between psychoanalytic process and Sophocles's tragic hero. The author views insight as always transgressing against, always at war with a conservative, societal, or intrapsychic chorus of structured elements. A clinical vignette is presented to illustrate this view of insight. PMID:26198605

  15. Induction of depersonalization by the serotonin agonist meta-chlorophenylpiperazine.

    PubMed

    Simeon, D; Hollander, E; Stein, D J; DeCaria, C; Cohen, L J; Saoud, J B; Islam, N; Hwang, M

    1995-09-29

    Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization. There was a significant correlation between the induction of depersonalization and increase in panic, but not nervousness, anxiety, sadness, depression, or drowsiness. This report suggests that serotonergic dysregulation may in part underlie depersonalization.

  16. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    PubMed

    Wang, Si; Bovee, Toine F H

    2016-01-01

    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter. PMID:26585147

  17. Discovery of a potent and selective GPR120 agonist.

    PubMed

    Shimpukade, Bharat; Hudson, Brian D; Hovgaard, Christine Kiel; Milligan, Graeme; Ulven, Trond

    2012-05-10

    GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist.

  18. Molecular Cloning and Functional Analysis of UV RESISTANCE LOCUS 8 (PeUVR8) from Populus euphratica

    PubMed Central

    Mao, Ke; Wang, Lina; Li, Yuan-Yuan; Wu, Rongling

    2015-01-01

    Ultraviolet-B (UV-B; 280–315 nm) light, which is an integral part of the solar radiation reaching the surface of the Earth, induces a broad range of physiological responses in plants. The UV RESISTANCE LOCUS 8 (UVR8) protein is the first and only light photoreceptor characterized to date that is specific for UV-B light and it regulates various aspects of plant growth and development in response to UV-B light. Despite its involvement in the control of important plant traits, most studies on UV-B photoreceptors have focused on Arabidopsis and no data on UVR8 function are available for forest trees. In this study, we isolated a homologue of the UV receptor UVR8 of Arabidopsis, PeUVR8, from Populus euphratica (Euphrates poplar) and analyzed its structure and function in detail. The deduced PeUVR8 amino acid sequence contained nine well-conserved regulator of chromosome condensation 1 (RCC1) repeats and the region 27 amino acids from the C terminus (C27) that interact with COP1 (CONSTITUTIVELY PHOTOMORPHOGENIC1). Secondary and tertiary structure analysis showed that PeUVR8 shares high similarity with the AtUVR8 protein from Arabidopsis thaliana. Using heterologous expression in Arabidopsis, we showed that PeUVR8 overexpression rescued the uvr8 mutant phenotype. In addition, PeUVR8 overexpression in wild-type background seedlings grown under UV-B light inhibited hypocotyl elongation and enhanced anthocyanin accumulation. Furthermore, we examined the interaction between PeUVR8 and AtCOP1 using a bimolecular fluorescence complementation (BiFC) assay. Our data provide evidence that PeUVR8 plays important roles in the control of photomorphogenesis in planta. PMID:26171608

  19. Molecular Cloning and Functional Analysis of UV RESISTANCE LOCUS 8 (PeUVR8) from Populus euphratica.

    PubMed

    Mao, Ke; Wang, Lina; Li, Yuan-Yuan; Wu, Rongling

    2015-01-01

    Ultraviolet-B (UV-B; 280-315 nm) light, which is an integral part of the solar radiation reaching the surface of the Earth, induces a broad range of physiological responses in plants. The UV RESISTANCE LOCUS 8 (UVR8) protein is the first and only light photoreceptor characterized to date that is specific for UV-B light and it regulates various aspects of plant growth and development in response to UV-B light. Despite its involvement in the control of important plant traits, most studies on UV-B photoreceptors have focused on Arabidopsis and no data on UVR8 function are available for forest trees. In this study, we isolated a homologue of the UV receptor UVR8 of Arabidopsis, PeUVR8, from Populus euphratica (Euphrates poplar) and analyzed its structure and function in detail. The deduced PeUVR8 amino acid sequence contained nine well-conserved regulator of chromosome condensation 1 (RCC1) repeats and the region 27 amino acids from the C terminus (C27) that interact with COP1 (CONSTITUTIVELY PHOTOMORPHOGENIC1). Secondary and tertiary structure analysis showed that PeUVR8 shares high similarity with the AtUVR8 protein from Arabidopsis thaliana. Using heterologous expression in Arabidopsis, we showed that PeUVR8 overexpression rescued the uvr8 mutant phenotype. In addition, PeUVR8 overexpression in wild-type background seedlings grown under UV-B light inhibited hypocotyl elongation and enhanced anthocyanin accumulation. Furthermore, we examined the interaction between PeUVR8 and AtCOP1 using a bimolecular fluorescence complementation (BiFC) assay. Our data provide evidence that PeUVR8 plays important roles in the control of photomorphogenesis in planta.

  20. The Co-Operonic PE25/PPE41 Protein Complex of Mycobacterium tuberculosis Elicits Increased Humoral and Cell Mediated Immune Response

    PubMed Central

    Tundup, Smanla; Pathak, Niteen; Ramanadham, M.; Mukhopadhyay, Sangita; Murthy, K. J. R.; Ehtesham, Nasreen Z.; Hasnain, Seyed E.

    2008-01-01

    Background Many of the PE/PPE proteins are either surface localized or secreted outside and are thought to be a source of antigenic variation in the host. The exact role of these proteins are still elusive. We previously reported that the PPE41 protein induces high B cell response in TB patients. The PE/PPE genes are not randomly distributed in the genome but are organized as operons and the operon containing PE25 and PPE41 genes co-transcribe and their products interact with each other. Methodology/Principal Finding We now describe the antigenic properties of the PE25, PPE41 and PE25/PPE41 protein complex coded by a single operon. The PPE41 and PE25/PPE41 protein complex induces significant (p<0.0001) B cell response in sera derived from TB patients and in mouse model as compared to the PE25 protein. Further, mice immunized with the PE25/PPE41 complex and PPE41 proteins showed significant (p<0.00001) proliferation of splenocyte as compared to the mice immunized with the PE25 protein and saline. Flow cytometric analysis showed 15–22% enhancement of CD8+ and CD4+ T cell populations when immunized with the PPE41 or PE25/PPE41 complex as compared to a marginal increase (8–10%) in the mice immunized with the PE25 protein. The PPE41 and PE25/PPE41 complex can also induce higher levels of IFN-γ, TNF-α and IL-2 cytokines. Conclusion While this study documents the differential immunological response to the complex of PE and PPE vis-à-vis the individual proteins, it also highlights their potential as a candidate vaccine against tuberculosis. PMID:18974870

  1. Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan.

    PubMed

    Inoue, Daisuke; Nakama, Koki; Sawada, Kazuko; Watanabe, Taro; Takagi, Mai; Sei, Kazunari; Yang, Min; Hirotsuji, Junji; Hu, Jianying; Nishikawa, Jun-ichi; Nakanishi, Tsuyoshi; Ike, Michihiko

    2010-04-01

    This study was conducted to investigate the agonistic activity against human retinoic acid receptor (RAR) alpha in the Lake Biwa-Yodo River and the Ina River in the Kinki region of Japan. To accomplish this, a yeast two-hybrid assay was used to elucidate the spatial and temporal variations and potential sources of RARalpha agonist contamination in the river basins. RARalpha agonistic activity was commonly detected in the surface water samples collected along two rivers at different periods, with maximum all-trans retinoic acid (atRA) equivalents of 47.6 ng-atRA/L and 23.5 ng-atRA/L being observed in Lake Biwa-Yodo River and Ina River, respectively. The results indicated that RARalpha agonists are always present and widespread in the rivers. Comparative investigation of RARalpha and estrogen receptor alpha agonistic activities at 20 stations along each river revealed that the spatial variation pattern of RARalpha agonist contamination was entirely different from that of the estrogenic compound contamination. This suggests that the effluent from municipal wastewater treatment plants, a primary source of estrogenic compounds, seemed not to be the cause of RARalpha agonist contamination in the rivers. Fractionation using high performance liquid chromatography (HPLC) directed by the bioassay found two bioactive fractions from river water samples, suggesting the presence of at least two RARalpha agonists in the rivers. Although a trial conducted to identify RARalpha agonists in the major bioactive fraction was not completed as part of this study, comparison of retention times in HPLC analysis and quantification with liquid chromatography-mass spectrometry analysis revealed that the major causative contaminants responsible for the RARalpha agonistic activity were not RAs (natural RAR ligands) and 4-oxo-RAs, while 4-oxo-RAs were identified as the major RAR agonists in sewage in Beijing, China. These findings suggest that there are unknown RARalpha agonists with high

  2. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

    SciTech Connect

    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.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  3. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064.

    PubMed

    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; Parks, Derek J; Todd, Dan; Williams, Shawn P; Wisely, G Bruce

    2009-06-01

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  4. Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists.

    PubMed

    Sheppeck, James E; Gilmore, John L; Xiao, Hai-Yun; Dhar, T G Murali; Nirschl, David; Doweyko, Arthur M; Sack, Jack S; Corbett, Martin J; Malley, Mary F; Gougoutas, Jack Z; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Dodd, John H; Nadler, Steven G; Somerville, John E; Barrish, Joel C

    2013-10-01

    Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure. PMID:23953070

  5. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment

    PubMed Central

    Yang, Li; Islam, Mohammad R; Karamyan, Vardan T.; Abbruscato, Thomas J.

    2015-01-01

    To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10 nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10 nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype. PMID:25801116

  6. Quantitative ultrasound images generated by a PE-CMOS sensor array: scatter modeling and image restoration

    NASA Astrophysics Data System (ADS)

    Liu, Chu-Chuan; Lo, Shih-Chung Ben; Freedman, Matthew T.; Lasser, Marvin E.; Lasser, Bob; Kula, John; Wang, Yue Joseph

    2007-03-01

    In the projection geometry, the detected ultrasound energy through a soft-tissue is mainly attributed to the attenuated primary intensity and the scatter intensity. In order to extract ultrasound image of attenuated primary beam out of the detected raw data, the scatter component must be carefully quantified for restoring the original image. In this study, we have designed a set of apparatus to modeling the ultrasound scattering in soft-tissue. The employed ultrasound imaging device was a C-Scan (projection) prototype using a 4th generation PE-CMOS sensor array (model I400, by Imperium Inc., Silver Spring, MD) as the detector. Right after the plane wave ultrasound transmitting through a soft-tissue mimicking material (Zerdine, by CIRS Inc., Norfolk, VA), a ring aperture is used to collimate the signal before reaching the acoustic lens and the PE-CMOS sensor. Three sets of collimated ring images were acquired and analyzed to obtain the scattering components as a function of the off-center distance. Several pathological specimens and breast phantoms consisting of simulated breast tissue with masses, cysts and microcalcifications were imaged by the same C-Scan imaging prototype. The restoration of these ultrasound images were performed by using a standard deconvolution computation. Our study indicated that the resultant images show shaper edges and detailed features as compared to their unprocessed counterparts.

  7. Projection-reflection ultrasound images using PE-CMOS sensor: a preliminary bone fracture study

    NASA Astrophysics Data System (ADS)

    Lo, Shih-Chung B.; Liu, Chu-Chuan; Freedman, Matthew T.; Mun, Seong-Ki; Kula, John; Lasser, Marvin E.; Lasser, Bob; Wang, Yue Joseph

    2008-03-01

    In this study, we investigated the characteristics of the ultrasound reflective image obtained by a CMOS sensor array coated with piezoelectric material (PE-CMOS). The laboratory projection-reflection ultrasound prototype consists of five major components: an unfocused ultrasound transducer, an acoustic beam splitter, an acoustic compound lens, a PE-CMOS ultrasound sensing array (Model I400, Imperium Inc. Silver Spring, MD), and a readout circuit system. The prototype can image strong reflective materials such as bone and metal. We found this projection-reflection ultrasound prototype is able to reveal hairline bone fractures with and without intact skin and tissue. When compared, the image generated from a conventional B-scan ultrasound on the same bone fracture is less observable. When it is observable with the B-scan system, the fracture or crack on the surface only show one single spot of echo due to its scan geometry. The corresponding image produced from the projection-reflection ultrasound system shows a bright blooming strip on the image clearly indicating the fracture on the surface of the solid material. Speckles of the bone structure are also observed in the new ultrasound prototype. A theoretical analysis is provided to link the signals as well as speckles detected in both systems.

  8. PeV neutrinos from intergalactic interactions of cosmic rays emitted by active galactic nuclei.

    PubMed

    Kalashev, Oleg E; Kusenko, Alexander; Essey, Warren

    2013-07-26

    The observed very high energy spectra of distant blazars are well described by secondary gamma rays produced in line-of-sight interactions of cosmic rays with background photons. In the absence of the cosmic-ray contribution, one would not expect to observe very hard spectra from distant sources, but the cosmic ray interactions generate very high energy gamma rays relatively close to the observer, and they are not attenuated significantly. The same interactions of cosmic rays are expected to produce a flux of neutrinos with energies peaked around 1 PeV. We show that the diffuse isotropic neutrino background from many distant sources can be consistent with the neutrino events recently detected by the IceCube experiment. We also find that the flux from any individual nearby source is insufficient to account for these events. The narrow spectrum around 1 PeV implies that some active galactic nuclei can accelerate protons to EeV energies. PMID:23931348

  9. Kinetic modeling of the oxidative degradation of additive free PE in bleach disinfected water

    NASA Astrophysics Data System (ADS)

    Mikdam, Aïcha; Colin, Xavier; Billon, Noëlle; Minard, Gaëlle

    2016-05-01

    The chemical interactions between PE and bleach were studied at 60°C in immersion in bleach solutions kept at a free chlorine concentration of 100 ppm and a pH of 5 or 7.2. It was found that the polymer undergoes a severe oxidation from the earliest weeks of exposure, in a superficial layer whose thickness (of about 50-70 µm) is almost independent of the pH value, although the superficial oxidation rate is faster in acidic than in neutral medium. Oxidation leads to the formation and accumulation of a large variety of carbonyl products (mostly ketones and carboxylic acids) and, after a few weeks, to a decrease in the average molar mass due to the large predominance of chain scissions over crosslinking. A scenario was elaborated for explaining such unexpected results. According to this scenario, the non-ionic molecules (Cl2 and ClOH) formed from the disinfectant in the water phase, would migrate deeply into PE and dissociate into highly reactive radicals (Cl• and HO•) in order to initiate a radical chain oxidation. A kinetic model was derived from this scenario for predicting the general trends of the oxidation kinetics and its dependence on environmental factors such as temperature, free chlorine concentration and pH. The validity of this model was successfully checked by comparing the numerical simulations with experimental data.

  10. Interaction of High Flash Point Electrolytes and PE-Based Separators for Li-Ion Batteries.

    PubMed

    Hofmann, Andreas; Kaufmann, Christoph; Müller, Marcus; Hanemann, Thomas

    2015-01-01

    In this study, promising electrolytes for use in Li-ion batteries are studied in terms of interacting and wetting polyethylene (PE) and particle-coated PE separators. The electrolytes are characterized according to their physicochemical properties, where the flow characteristics and the surface tension are of particular interest for electrolyte-separator interactions. The viscosity of the electrolytes is determined to be in a range of η = 4-400 mPa∙s and surface tension is finely graduated in a range of γL = 23.3-38.1 mN∙m(-1). It is verified that the technique of drop shape analysis can only be used in a limited matter to prove the interaction, uptake and penetration of electrolytes by separators. Cell testing of Li|NMC half cells reveals that those cell results cannot be inevitably deduced from physicochemical electrolyte properties as well as contact angle analysis. On the other hand, techniques are more suitable which detect liquid penetration into the interior of the separator. It is expected that the results can help fundamental researchers as well as users of novel electrolytes in current-day Li-ion battery technologies for developing and using novel material combinations. PMID:26343636

  11. Hidden Cosmic-Ray Accelerators as an Origin of TeV-PeV Cosmic Neutrinos.

    PubMed

    Murase, Kohta; Guetta, Dafne; Ahlers, Markus

    2016-02-19

    The latest IceCube data suggest that the all-flavor cosmic neutrino flux may be as large as 10^{-7}  GeV cm^{-2} s^{-1} sr^{-1} around 30 TeV. We show that, if sources of the TeV-PeV neutrinos are transparent to γ rays with respect to two-photon annihilation, strong tensions with the isotropic diffuse γ-ray background measured by Fermi are unavoidable, independently of the production mechanism. We further show that, if the IceCube neutrinos have a photohadronic (pγ) origin, the sources are expected to be opaque to 1-100 GeV γ rays. With these general multimessenger arguments, we find that the latest data suggest a population of cosmic-ray accelerators hidden in GeV-TeV γ rays as a neutrino origin. Searches for x-ray and MeV γ-ray counterparts are encouraged, and TeV-PeV neutrinos themselves will serve as special probes of dense source environments.

  12. Fuel loading of PeBR for a long operation life on the lunar surface

    SciTech Connect

    Schriener, T. M.; El-Genk, M. S.

    2012-07-01

    The Pellet Bed Reactor (PeBR) power system could provide 99.3 kW e to a lunar outpost for 66 full power years and is designed for no single point failures. The core of this fast energy spectrum reactor consists of three sectors that are neutronically and thermally coupled, but hydraulically independent. Each sector has a separate Closed Brayton Cycle (CBC) loop for energy conversion and separate water heat-pipes radiator panels for heat rejection. He-Xe (40 g/mole) binary gas mixture serves as the reactor coolant and CBC working fluid. On the lunar surface, the emplaced PeBR below grade is loaded with spherical fuel pellets (1-cm in dia.). It is launched unfueled and the pellets are launched in separate subcritical canisters, one for each core sector. This paper numerically simulates the transient loading of a core sector with fuel pellets on the Moon. The simulation accounts for the dynamic interaction of the pellets during loading and calculates the axial and radial distributions of the volume porosity in the sector. The pellets pack randomly with a volume porosity of 0.39 - 0.41 throughout most of the sector, except near the walls the local porosity is higher. (authors)

  13. Hidden Cosmic-Ray Accelerators as an Origin of TeV-PeV Cosmic Neutrinos.

    PubMed

    Murase, Kohta; Guetta, Dafne; Ahlers, Markus

    2016-02-19

    The latest IceCube data suggest that the all-flavor cosmic neutrino flux may be as large as 10^{-7}  GeV cm^{-2} s^{-1} sr^{-1} around 30 TeV. We show that, if sources of the TeV-PeV neutrinos are transparent to γ rays with respect to two-photon annihilation, strong tensions with the isotropic diffuse γ-ray background measured by Fermi are unavoidable, independently of the production mechanism. We further show that, if the IceCube neutrinos have a photohadronic (pγ) origin, the sources are expected to be opaque to 1-100 GeV γ rays. With these general multimessenger arguments, we find that the latest data suggest a population of cosmic-ray accelerators hidden in GeV-TeV γ rays as a neutrino origin. Searches for x-ray and MeV γ-ray counterparts are encouraged, and TeV-PeV neutrinos themselves will serve as special probes of dense source environments. PMID:26943524

  14. Heat Tolerance in Curraleiro Pe-Duro, Pantaneiro and Nelore Cattle Using Thermographic Images

    PubMed Central

    Cardoso, Caio Cesar; Lima, Flávia Gontijo; Fioravanti, Maria Clorinda Soares; do Egito, Andrea Alves; Silva, Flávia Cristina de Paula e; Tanure, Candice Bergmann; Peripolli, Vanessa; McManus, Concepta

    2016-01-01

    The objective of this study was to compare physiological and thermographic responses to heat stress in three breeds of cattle. Fifteen animals of each of the Nelore, Pantaneiro and Curraleiro Pe-Duro breeds, of approximately two years of age, were evaluated. Heart and respiratory rates, rectal and surface temperature of animals as well as soil temperature were recorded at 8:30 and 15:30 on six days. Variance, correlation, principal factors and canonical analyses were carried out. There were significant differences in the rectal temperature, heart and respiratory rate between breeds (p < 0.001). Nelore and Pantaneiro breeds had the highest rectal temperatures and the lowest respiratory rate (p < 0.001). Breed was also significant for surface temperatures (p < 0.05) showing that this factor significantly affected the response of the animal to heat tolerance in different ways. The Curraleiro Pe-Duro breed had the lowest surface temperatures independent of the period evaluated, with fewer animals that suffered with the climatic conditions, so this may be considered the best adapted when heat challenged under the experimental conditions. Thermography data showed a good correlation with the physiological indexes, and body area, neck and rump were the main points. PMID:26840335

  15. Heat Tolerance in Curraleiro Pe-Duro, Pantaneiro and Nelore Cattle Using Thermographic Images.

    PubMed

    Cardoso, Caio Cesar; Lima, Flávia Gontijo; Fioravanti, Maria Clorinda Soares; Egito, Andrea Alves do; Silva, Flávia Cristina de Paula E; Tanure, Candice Bergmann; Peripolli, Vanessa; McManus, Concepta

    2016-01-29

    The objective of this study was to compare physiological and thermographic responses to heat stress in three breeds of cattle. Fifteen animals of each of the Nelore, Pantaneiro and Curraleiro Pe-Duro breeds, of approximately two years of age, were evaluated. Heart and respiratory rates, rectal and surface temperature of animals as well as soil temperature were recorded at 8:30 and 15:30 on six days. Variance, correlation, principal factors and canonical analyses were carried out. There were significant differences in the rectal temperature, heart and respiratory rate between breeds (p < 0.001). Nelore and Pantaneiro breeds had the highest rectal temperatures and the lowest respiratory rate (p < 0.001). Breed was also significant for surface temperatures (p < 0.05) showing that this factor significantly affected the response of the animal to heat tolerance in different ways. The Curraleiro Pe-Duro breed had the lowest surface temperatures independent of the period evaluated, with fewer animals that suffered with the climatic conditions, so this may be considered the best adapted when heat challenged under the experimental conditions. Thermography data showed a good correlation with the physiological indexes, and body area, neck and rump were the main points.

  16. PE-CMOS-based C-mode ultrasound: signal acquisition and time gating

    NASA Astrophysics Data System (ADS)

    Lo, Shih-Chung B.; Liu, Chu-Chuan; Freedman, Matthew T.; Mun, Seong-Ki; Kula, John; Lasser, Marvin E.; Lasser, Bob; Wang, Yue Joseph

    2009-02-01

    Two types of signal acquisition methods using CMOS sensor array coated with piezoelectric material (PE-CMOS) were studied. The laboratory projection-reflection ultrasound prototypes featuring a PE-CMOS ultrasound sensing array and an acoustic compound lens were employed to image pork bones with fractures in vitro. We found that the projection-reflection ultrasound prototypes are capable of revealing hairline bone fractures with skin in tact. However, the image characteristics generated from these C-scan prototypes are somewhat different because they were equipped with two different senor array models. The signal acquired by the first sensor model is based on an integrated signal (IS) at a given time interval. But the signal acquired by the second sensor model is based on peak signal (PS) with a time gating function controllable by the user. We found that both systems can detect bone fracture as small as 0.5mm shown as a strip of ultrasound signal. However, images obtained from the IS sensor show more speckles with a greater blooming effect on the fractures. On the other hand, images obtained from the PS sensor show less contrast with less speckles. When the beam position is slightly tilted from the normal direction, the blooming effect of the ultrasound image would become dark on the fracture region with both acquisition modes.

  17. Interaction of High Flash Point Electrolytes and PE-Based Separators for Li-Ion Batteries.

    PubMed

    Hofmann, Andreas; Kaufmann, Christoph; Müller, Marcus; Hanemann, Thomas

    2015-08-27

    In this study, promising electrolytes for use in Li-ion batteries are studied in terms of interacting and wetting polyethylene (PE) and particle-coated PE separators. The electrolytes are characterized according to their physicochemical properties, where the flow characteristics and the surface tension are of particular interest for electrolyte-separator interactions. The viscosity of the electrolytes is determined to be in a range of η = 4-400 mPa∙s and surface tension is finely graduated in a range of γL = 23.3-38.1 mN∙m(-1). It is verified that the technique of drop shape analysis can only be used in a limited matter to prove the interaction, uptake and penetration of electrolytes by separators. Cell testing of Li|NMC half cells reveals that those cell results cannot be inevitably deduced from physicochemical electrolyte properties as well as contact angle analysis. On the other hand, techniques are more suitable which detect liquid penetration into the interior of the separator. It is expected that the results can help fundamental researchers as well as users of novel electrolytes in current-day Li-ion battery technologies for developing and using novel material combinations.

  18. COMET-PE as an Alternative to Monte Carlo for Photon and Electron Transport

    NASA Astrophysics Data System (ADS)

    Hayward, Robert M.; Rahnema, Farzad

    2014-06-01

    Monte Carlo methods are a central component of radiotherapy treatment planning, shielding design, detector modeling, and other applications. Long calculation times, however, can limit the usefulness of these purely stochastic methods. The coarse mesh method for photon and electron transport (COMET-PE) provides an attractive alternative. By combining stochastic pre-computation with a deterministic solver, COMET-PE achieves accuracy comparable to Monte Carlo methods in only a fraction of the time. The method's implementation has been extended to 3D, and in this work, it is validated by comparison to DOSXYZnrc using a photon radiotherapy benchmark. The comparison demonstrates excellent agreement; of the voxels that received more than 10% of the maximum dose, over 97.3% pass a 2% / 2mm acceptance test and over 99.7% pass a 3% / 3mm test. Furthermore, the method is over an order of magnitude faster than DOSXYZnrc and is able to take advantage of both distributed-memory and shared-memory parallel architectures for increased performance.

  19. The Lipid domain Phase diagram in a Dipalmitoyl-PC/Docosahaexnoic Acid-PE/Cholesterol System

    NASA Astrophysics Data System (ADS)

    Lor, Chai; Hirst, Linda

    2011-03-01

    Lipid domains in bilayer membrane and polyunsaturated fatty acids (PUFAs) are thought to play an important role in cellular activities. In particular, lipids containing docosahaexnoic acid are an interesting class of PUFAs due to their health benefits. In this project, we perform oxidation measurements of DHA-PE to determine the rate of oxidation in combination with antioxidants. A ternary diagram of DPPC/DHA-PE/cholesterol is mapped out to identify phase separation phenomena using atomic force microscope (AFM). Fluorescence microscopy is also used to image lipid domains in a flat bilayer with fluorescent labels. As expected, we observe the phase, shape, and size of lipid domains changes with varying composition. Moreover, we find that the roughness of the domains changes possibly due to overpacking of cholesterol in domains. This model study provides further understanding of the role of cholesterol in the bilayer membrane leading towards a better understanding of cell membranes. NSF award # DMR 0852791, ``CAREER: Self-Assembly of Polyunsaturated Lipids and Cholesterol In The Cell Membrane.''

  20. Interaction of High Flash Point Electrolytes and PE-Based Separators for Li-Ion Batteries

    PubMed Central

    Hofmann, Andreas; Kaufmann, Christoph; Müller, Marcus; Hanemann, Thomas

    2015-01-01

    In this study, promising electrolytes for use in Li-ion batteries are studied in terms of interacting and wetting polyethylene (PE) and particle-coated PE separators. The electrolytes are characterized according to their physicochemical properties, where the flow characteristics and the surface tension are of particular interest for electrolyte–separator interactions. The viscosity of the electrolytes is determined to be in a range of η = 4–400 mPa∙s and surface tension is finely graduated in a range of γL = 23.3–38.1 mN∙m−1. It is verified that the technique of drop shape analysis can only be used in a limited matter to prove the interaction, uptake and penetration of electrolytes by separators. Cell testing of Li|NMC half cells reveals that those cell results cannot be inevitably deduced from physicochemical electrolyte properties as well as contact angle analysis. On the other hand, techniques are more suitable which detect liquid penetration into the interior of the separator. It is expected that the results can help fundamental researchers as well as users of novel electrolytes in current-day Li-ion battery technologies for developing and using novel material combinations. PMID:26343636

  1. Coordinated field study for CaPE: Analysis of energy and water budgets

    NASA Technical Reports Server (NTRS)

    Goodman, Steven J.; Duchon, Claude; Kanemasu, Edward T.; Smith, Eric A.; Crosson, William; Laymon, Chip; Luvall, Jeff

    1993-01-01

    The objectives of this hydrologic cycle study are to understand and model (1) surface energy and land-atmosphere water transfer processes, and (2) interactions between convective storms and surface energy fluxes. A surface energy budget measurement campaign was carried out by an interdisciplinary science team during the period July 8 - August 19, 1991 as part of the Convection and Precipitation/Electrification Experiment (CaPE) in the vicinity of Cape Canaveral, FL. Among the research themes associated with CaPE is the remote estimation of rainfall. Thus, in addition to surface radiation and energy budget measurements, surface mesonet, special radiosonde, precipitation, high-resolution satellite (SPOT) data, geosynchronous (GOES) and polar orbiting (DMSP SSM/I, OLS; NOAA AVHRR) satellite data, and high altitude airplane data (AMPR, MAMS, HIS) were collected. Initial quality control of the seven surface flux station data sets has begun. Ancillary data sets are being collected and assembled for analysis. Browsing of GOES and radar data has begun to classify days as disturbed/undisturbed to identify the larger scale forcing of the pre-convective environment, convection storms and precipitation. The science analysis plan has been finalized and tasks assigned to various investigators.

  2. Effects of LAAM and methadone utilization in an opiate agonist treatment program.

    PubMed

    Valdivia, J F; Khattak, S

    2000-01-01

    The development and approval of levo-alpha-acetylmethadol (LAAM) as a pharmacotherapeutic agent in opioid agonist therapy provided an alternative to methadone. Clinicians recognized the potential benefits that LAAM, a synthetic mu agonist with pharmacological properties which differ from those of methadone,could have in the treatment management of addicts in opioid agonist therapy. We report our experience utilizing LAAM from 1995 to 1999 at the Hines VA opioid agonist therapy clinic. The addition of LAAM to the clinic's treatment armamentarium has resulted in management options that have improved the areas of patient recruitment, patient retention, patient traffic, take-home medication, detoxification, and treatment outcomes.

  3. Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy

    PubMed Central

    Iribarren, Kristina; Bloy, Norma; Buqué, Aitziber; Cremer, Isabelle; Eggermont, Alexander; Fridman, Wolf Hervé; Fucikova, Jitka; Galon, Jérôme; Špíšek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2016-01-01

    ABSTRACT Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy. PMID:27141345

  4. Dopamine agonist-induced substance addiction: the next piece of the puzzle.

    PubMed

    Evans, Andrew

    2011-02-01

    Traditional antiparkinson treatment strategies strive to balance the antiparkinson effects of dopaminergic drugs with the avoidance of motor response complications. Dopamine agonists have an established role in delaying the emergence of motor response complications or reducing motor "off" periods. The recent recognition of a range of "behavioural addictions" that are linked to dopamine agonist use has highlighted the role of dopamine in brain reward function and addiction disorders in general. Dopamine agonists have now even been linked occasionally to new substance addictions. The challenge now for the Parkinsonologist is to also balance the net benefits of using dopamine agonists for their motor effects with avoiding the harm from behavioural compulsions. PMID:20980151

  5. Analysis of agonist dissociation constants as assessed by functional antagonism in guinea pig left atria

    SciTech Connect

    Molenaar, P.; Malta, E.

    1986-04-01

    In electrically driven guinea pig left atria, positive inotropic responses to (-)-isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were obtained in the absence and in the presence of the functional antagonists adenosine, carbachol, gallopamil, nifedipine, and Ro 03-7894. Each of the functional antagonists reduced the maximum response to both agonists and produced nonparallel rightward shifts in the cumulative concentration effect curves. For both agonists, dissociation constants (KA) were calculated using the equation described by Furchgott (1966) for irreversible antagonism. For RO363, which is a partial agonist with high agonist activity, the equations outlined for functional interaction by Mackay (1981) were also employed to calculate KA values. The KA values obtained by each method were compared with the dissociation constants (KD) for the two agonists determined from their ability to displace the radioligand (-)-(/sup 125/I)iodocyanopindolol from beta 1-adrenoceptors in guinea pig left atrial membrane preparations. The estimates of KA varied substantially from KD values. The KD values were taken as more accurate estimates of the true values for the dissociation constants because a high degree of correlation exists between pKD and pD2 values for a number of other beta-adrenoceptor agonists that behave as partial agonists and between pKD and pKB values for a number of beta-adrenoceptor antagonists. Thus, it appears that there are serious limitations in the current theory for using functional antagonism as a means of obtaining agonist dissociation constants.

  6. Structural complexes of the agonist, inverse agonist and antagonist bound C5a receptor: insights into pharmacology and signaling.

    PubMed

    Rana, Soumendra; Sahoo, Amita Rani; Majhi, Bharat Kumar

    2016-04-26

    The C5a receptor (C5aR) is a pharmacologically important G-protein coupled receptor (GPCR) that interacts with (h)C5a, by recruiting both the "orthosteric" sites (site1 at the N-terminus and site2 at the ECS, extra cellular surface) on C5aR in a two site-binding model. However, the complex pharmacological landscape and the distinguishing chemistry operating either at the "orthosteric" site1 or at the functionally important "orthosteric" site2 of C5aR are still not clear, which greatly limits the understanding of C5aR pharmacology. One of the major bottlenecks is the lack of an experimental structure or a refined model structure of C5aR with appropriately defined active sites. The study attempts to understand the pharmacology at the "orthosteric" site2 of C5aR rationally by generating a highly refined full-blown model structure of C5aR through advanced molecular modeling techniques, and further subjecting it to automated docking and molecular dynamics (MD) studies in the POPC bilayer. The first series of structural complexes of C5aR respectively bound to a linear native peptide agonist ((h)C5a-CT), a small molecule inverse agonist (NDT) and a cyclic peptide antagonist (PMX53) are reported, apparently establishing the unique pharmacological landscape of the "orthosteric" site2, which also illustrates an energetically distinct but coherent competitive chemistry ("cation-π" vs. "π-π" interactions) involved in distinguishing the established ligands known for targeting the "orthosteric" site2 of C5aR. Over a total of 1 μs molecular dynamics (MD) simulation in the POPC bilayer, it is evidenced that while the agonist prefers a "cation-π" interaction, the inverse agonist prefers a "cogwheel/L-shaped" interaction in contrast to the "edge-to-face/T-shaped" type π-π interactions demonstrated by the antagonist by engaging the F275(7.28) of the C5aR. In the absence of a NMR or crystallographically guided model structure of C5aR, the computational model complexes not only

  7. Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets

    SciTech Connect

    Schaechter, M.; Godfrey, P.P.; Minchin, M.C.W.; McClue, S.J.; Young, M.M.

    1985-10-28

    The metabolism of inositol phospholipids in response to serotonergic agonists was investigated in rabbit platelets. In platelets prelabelled with (/sup 3/H)-inositol, in a medium containing 10 mM LiCl which blocks the enzyme inositol-1-phosphatase, 5-hydroxytryptamine (5-HT) caused a dose-dependent accumulation of inositol phosphates (IP). This suggests a phospholipase-C-mediated breakdown of phosphoinositides. Ketanserin, a selective 5-HT/sub 2/ antagonist, was a potent inhibitor of the 5-HT response, with a Ki of 28 nM, indicating that 5-HT is activating receptors of the 5-HT/sub 2/ type in the platelet. Lysergic acid diethylamide (LSD) and quipazine also caused dose-related increases in inositol phosphate levels, though these were considerably less than those produced by 5-HT. These results show that relatively small changes in phosphoinositide metabolism induced by serotonergic agonists can be investigated in the rabbit platelet, and this cell may therefore be a useful model for the study of some 5-HT receptors. 30 references, 4 figures.

  8. Long-Acting Beta Agonists Enhance Allergic Airway Disease

    PubMed Central

    Knight, John M.; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O.; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A.; Milner, Joshua D.; Zhang, Yuan; Mandal, Pijus K.; Luong, Amber; Kheradmand, Farrah

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  9. Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

    PubMed Central

    Shan, Ming; You, Ran; Yuan, Xiaoyi; Frazier, Michael V.; Porter, Paul; Seryshev, Alexander; Hong, Jeong-Soo; Song, Li-zhen; Zhang, Yiqun; Hilsenbeck, Susan; Whitehead, Lawrence; Zarinkamar, Nazanin; Perusich, Sarah; Corry, David B.; Kheradmand, Farrah

    2014-01-01

    The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator–activated receptor γ (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARγ in APCs using Cd11c-Cre Ppargflox/flox mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Ppargflox/flox mice required OPN, suggesting an antiinflammatory mechanism in which PPARγ negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARγ agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARγ agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARγ activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema. PMID:24569375

  10. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways. PMID:24752777

  11. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity

    PubMed Central

    Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel; Sankaranarayanan, Ishwarya; Aron, Jennifer L.; Maazi, Hadi; Chen, Lin; Akbari, Omid

    2016-01-01

    Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma. PMID:27752043

  12. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways.

  13. Mood disorders, circadian rhythms, melatonin and melatonin agonists.

    PubMed

    Quera Salva, M A; Hartley, S

    2012-01-01

    Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC). Melatonin (N-acetyl-5-hydroxytryptamine) is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD) and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light) or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse.

  14. Pindolol--the pharmacology of a partial agonist.

    PubMed Central

    Clark, B J; Menninger, K; Bertholet, A

    1982-01-01

    1 Pindolol is a non-selective beta-adrenoceptor blocking agent; its affinity to adrenoceptors in guinea pig atria (beta 1) is not significantly different from that in guinea pig trachea (beta 1 + beta 2) and canine vascular smooth muscle (beta 2). 2 Pindolol displays a striking diversity of agonist activities in isolated tissues. Stimulant effects correspond to 40--50% of the maximum effects of isoprenaline in isolated kitten atria and guinea pig trachea and to only 10% in guinea pig atria. Effects in canine isolated mesenteric vessels are those of a full agonist, maximum responses equaling those of isoprenaline. These findings suggest that the stimulant effects of pindolol are exerted principally on beta 2-adrenoceptors. 3 Cardiac stimulation produced by pindolol in the dog is sufficient to compensate for the cardiac depression resulting from blockade of beta-adrenoceptors in the heart. Reductions in cardiac output and compensatory increases in total peripheral resistance do not occur or are much smaller than those produced by beta-adrenoceptor blocking agents lacking sympathomimetic activity. 4 Pindolol-induced relaxation of bronchial smooth muscle prevents or minimizes the bronchoconstrictor effects of injected spasmogens in the cat. 5 Pindolol has marked vasodilator activity, small doses reducing femoral and mesenteric vascular resistance by approximately 30%. Doses comparable to those used in hypertensive patients lower blood pressure by 20 mmHg in non-anaesthetized dogs. PMID:7049208

  15. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    PubMed

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists. PMID:19832688

  16. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    PubMed

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

  17. Identification of agonists for a group of human odorant receptors

    PubMed Central

    Gonzalez-Kristeller, Daniela C.; do Nascimento, João B. P.; Galante, Pedro A. F.; Malnic, Bettina

    2015-01-01

    Olfaction plays a critical role in several aspects of the human life. Odorants are detected by hundreds of odorant receptors (ORs) which belong to the superfamily of G protein-coupled receptors. These receptors are expressed in the olfactory sensory neurons of the nose. The information provided by the activation of different combinations of ORs in the nose is transmitted to the brain, leading to odorant perception and emotional and behavioral responses. There are ~400 intact human ORs, and to date only a small percentage of these receptors (~10%) have known agonists. The determination of the specificity of the human ORs will contribute to a better understanding of how odorants are discriminated by the olfactory system. In this work, we aimed to identify human specific ORs, that is, ORs that are present in humans but absent from other species, and their corresponding agonists. To do this, we first selected 22 OR gene sequences from the human genome with no counterparts in the mouse, rat or dog genomes. Then we used a heterologous expression system to screen a subset of these human ORs against a panel of odorants of biological relevance, including foodborne aroma volatiles. We found that different types of odorants are able to activate some of these previously uncharacterized human ORs. PMID:25784876

  18. How does agonistic behaviour differ in albino and pigmented fish?

    PubMed Central

    Horký, Pavel; Wackermannová, Marie

    2016-01-01

    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics. PMID:27114883

  19. Study of incorporation of silver nanoparticles onto PE-g-PAAc nonwoven fabric by γ-irradiation for water treatment

    NASA Astrophysics Data System (ADS)

    Phu, Dang Van; Quoc, Le Anh; Duy, Nguyen Ngoc; Hien, Nguyen Quoc

    2013-07-01

    Polyethylene nonwoven (PE) fabric was grafted with acrylic acid (PE-g-PAAc) by the γ-ray pre-irradiation process. The effect of dose and acrylic acid concentration on the grafting degree was investigated. The dose of about 20-30 kGy, acrylic acid concentration of 20-30%, and the reaction time of about 2 h at ˜90 °C were selected as suitable parameters for grafting. The PE-g-PAAc fabric was then impregnated in colloidal silver nanoparticles (AgNPs) solution for incorporating AgNPs. The resultant PE-g-PAAc/AgNPs fabric containing ˜10,000 ppm AgNPs exhibits high antimicrobial activity (η>99%) against Escherichia coli in water. The release of silver into water filtrate determined by ICP-MS was less than 0.1 mg/L. The PE-g-PAAc/AgNPs fabric can be potentially applied for water and/or air treatment as an antimicrobial membrane filter.

  20. Identifying Cognate Binding Pairs among a Large Set of Paralogs: The Case of PE/PPE Proteins of Mycobacterium tuberculosis

    PubMed Central

    Riley, Robert; Pellegrini, Matteo; Eisenberg, David

    2008-01-01

    We consider the problem of how to detect cognate pairs of proteins that bind when each belongs to a large family of paralogs. To illustrate the problem, we have undertaken a genomewide analysis of interactions of members of the PE and PPE protein families of Mycobacterium tuberculosis. Our computational method uses structural information, operon organization, and protein coevolution to infer the interaction of PE and PPE proteins. Some 289 PE/PPE complexes were predicted out of a possible 5,590 PE/PPE pairs genomewide. Thirty-five of these predicted complexes were also found to have correlated mRNA expression, providing additional evidence for these interactions. We show that our method is applicable to other protein families, by analyzing interactions of the Esx family of proteins. Our resulting set of predictions is a starting point for genomewide experimental interaction screens of the PE and PPE families, and our method may be generally useful for detecting interactions of proteins within families having many paralogs. PMID:18787688