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Sample records for agonist phenylephrine pe

  1. Phenylephrine

    MedlinePlus

    ... for your symptoms. Check nonprescription cough and cold product labels carefully before using two or more products at ... adults to children.Before you give a phenylephrine product to a child, check the package label to find out how much medication the child ...

  2. Phenylephrine

    MedlinePlus

    Children's Sudafed PE Nasal Decongestant® ... PediaCare Children's Decongestant® ... be giving cough and cold medications to a child.Nonprescription cough and cold combination products, including products ...

  3. Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy.

    PubMed

    Yue, T L; Gu, J L; Wang, C; Reith, A D; Lee, J C; Mirabile, R C; Kreutz, R; Wang, Y; Maleeff, B; Parsons, A A; Ohlstein, E H

    2000-12-01

    The extracellular signal-regulated kinase (ERK) pathway is activated by hypertrophic stimuli in cardiomyocytes. However, whether ERK plays an essential role or is implicated in all major components of cardiac hypertrophy remains controversial. Using a selective MEK inhibitor, U0126, and a selective Raf inhibitor, SB-386023, to block the ERK signaling pathway at two different levels and adenovirus-mediated transfection of dominant-negative Raf, we studied the role of ERK signaling in response of cultured rat cardiomyocytes to hypertrophic agonists, endothelin-1 (ET-1), and phenylephrine (PE). U0126 and SB-386023 blocked ET-1 and PE-induced ERK but not p38 and JNK activation in cardiomyocytes. Both compounds inhibited ET-1 and PE-induced protein synthesis and increased cell size, sarcomeric reorganization, and expression of beta-myosin heavy chain in myocytes with IC(50) values of 1-2 microm. Furthermore, both inhibitors significantly reduced ET-1- and PE-induced expression of atrial natriuretic factor. In cardiomyocytes transfected with a dominant-negative Raf, ET-1- and PE-induced increase in cell size, sarcomeric reorganization, and atrial natriuretic factor production were remarkably attenuated compared with the cells infected with an adenovirus-expressing green fluorescence protein. Taken together, our data strongly support the notion that the ERK signal pathway plays an essential role in ET-1- and PE-induced cardiomyocyte hypertrophy. PMID:10984495

  4. 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

  5. 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 ...

  6. 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.

  7. Investigating the degradation of the sympathomimetic drug phenylephrine by electrospray ionisation-mass spectrometry.

    PubMed

    Trommer, Hagen; Raith, Klaus; Neubert, Reinhard H H

    2010-06-01

    The frequently used sympathomimetic drug phenylephrine has been studied by electrospray ionisation-mass spectrometry. The stability of the adrenoceptor agonist was examined by investigations of the pharmaceutically used salts phenylephrine hydrochloride and phenylephrine bitartrate. Photostability has been studied by use of an irradiation equipment emitting a solar radiation spectrum. The experiments were carried out by analysis of aqueous drug solutions before and after irradiation treatment. The phenylephrine derivative with unsaturated side chain originating from the drug by loss of one water molecule has been detected as the major degradation product of both phenylephrine salts the hydrochloride and the bitartrate. Further degradation and oxidation products were detectable already in the full scan mode demonstrating a low stability of the drug. Tandem mass spectrometry and multiple stage mass spectrometry experiments enabled the establishment of fragmentation schemes of both salts for the first time. Irradiation treatment indicated that phenylephrine bitartrate is more prone to degradation than the hydrochloride because of an additional decomposition sensitivity of the tartaric acid counter ion. An interaction between phenylephrine and its counter ion degradation products via a nucleophilic addition mechanism is suggested to be the explanation for the detected ion signals after irradiation treatment of phenylephrine bitartrate. PMID:20122809

  8. Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy

    PubMed Central

    Zhong, Lin; Chiusa, Manuel; Cadar, Adrian G.; Lin, Angel; Samaras, Susan; Davidson, Jeffrey M.; Lim, Chee C.

    2015-01-01

    Aims Accumulating evidence suggest that sarcomere signalling complexes play a pivotal role in cardiomyocyte hypertrophy by communicating stress signals to the nucleus to induce gene expression. Ankyrin repeat domain 1 (ANKRD1) is a transcriptional regulatory protein that also associates with sarcomeric titin; however, the exact role of ANKRD1 in the heart remains to be elucidated. We therefore aimed to examine the role of ANKRD1 in cardiomyocyte hypertrophic signalling. Methods and results In neonatal rat ventricular myocytes, we found that ANKRD1 is part of a sarcomeric signalling complex that includes ERK1/2 and cardiac transcription factor GATA4. Treatment with hypertrophic agonist phenylephrine (PE) resulted in phosphorylation of ERK1/2 and GATA4 followed by nuclear translocation of the ANKRD1/ERK/GATA4 complex. Knockdown of Ankrd1 attenuated PE-induced phosphorylation of ERK1/2 and GATA4, inhibited nuclear translocation of the ANKRD1 complex, and prevented cardiomyocyte growth. Mice lacking Ankrd1 are viable with normal cardiac function. Chronic PE infusion in wild-type mice induced significant cardiac hypertrophy with reactivation of the cardiac fetal gene program which was completely abrogated in Ankrd1 null mice. In contrast, ANKRD1 does not play a role in haemodynamic overload as Ankrd1 null mice subjected to transverse aortic constriction developed cardiac hypertrophy comparable to wild-type mice. Conclusion Our study reveals a novel role for ANKRD1 as a selective regulator of PE-induced signalling whereby ANKRD1 recruits and localizes GATA4 and ERK1/2 in a sarcomeric macro-molecular complex to enhance GATA4 phosphorylation with subsequent nuclear translocation of the ANKRD1 complex to induce hypertrophic gene expression. PMID:25770146

  9. Endothelin-1-induced alterations in phenylephrine-induced contractile responses are largely additive in physiologically diverse rabbit vasculature.

    PubMed

    Gondré, M; Christ, G J

    1998-08-01

    Endothelin-1 (ET-1) is an important modulator of vasomotor tone that is thought to participate in the etiology of cardiovascular disease by virtue of its ability to amplify the contractile responses of vascular smooth muscle cells to the effects of other vasoactive agents. Despite this fact, few studies have quantitated the expected contribution of ET-1 to the enhanced contractile responses elicited in the presence of another spasmogen. As a first step in this direction, ET-1 and phenylephrine (PE) were used to evaluate the effects of co-activation of the ETA/B or alpha-1 adrenergic receptors, respectively, on contractile responses in isolated rings of rabbit aorta, mesenteric and femoral artery, or strips of corporal tissue. Cumulative steady-state concentration-response curves (CRCs) were constructed to PE alone before the construction of a CRC to ET-1 alone, or a mixture of PE and ET-1 using a previously described drug concentration paradigm. Computer fits of the logistic equation to CRC data revealed that in all vascular tissues examined, the partial substitution of PE with ET-1 was associated with a significant vessel-dependent approximately 3- to 30-fold leftward shift in the CRC (P < .01, Student's t test for paired samples), as judged by a significant increase in the pEC50 (negative logarithm of the concentration of drug that elicits one-half of the calculated maximal effect), in the absence of any detectable effect on the calculated maximal contractile response (Emax) or the slope factor (rho). A theoretical CRC constructed using the Pöch and Holzmann method for equiactive substitution demonstrated that the responses to mixtures of PE and ET-1 were often the result of simple additivity of agonist effects in these preparations, and thus, were "expected" based on detailed knowledge of the individual effects of these two agonists. Regardless of the precision of the Poch and Holzmann CRC in predicting the effects of this drug mixture in these vascular tissues

  10. In vivo comparison of phenylephrine and phenylephrine oxazolidine instilled in the monkey eye.

    PubMed

    Schoenwald, R D; Folk, J C; Kumar, V; Piper, J G

    1987-01-01

    The ocular and cardiovascular effects as well as aqueous humor and plasma concentrations of 10% phenylephrine HCl and 1% phenylephrine oxazolidine (prodrug) were compared in cynomolgus monkeys. A volume of 25 microliters of either drug was administered to one eye followed by blood pressure, pulse, and pupillary measurements at 10 min intervals up to 60 minutes. Careful slit lamp examinations of the anterior segment, indirect ophthalmoscopy of the vitreous and retina, and ERGs were performed at 60 minutes. Four plasma determinations of phenylephrine following administration of either drug were made between 5 and 60 minutes. Measurement of phenylephrine in aqueous humor was also determined at 60 minutes following all other measurements. The maximal pupillary dilation after administration of 1% prodrug (mean + s.d. = 4.4 + 0.5 mm, n = 12) was slightly greater than after administration of phenylephrine 10% (mean + s.d. = 3.9 + 0.8 mm, n = 12). The differences in pupillary diameter from 20 through 40 minutes were statistically greater for the prodrug. The greater pupillary diameter at the earlier times resulted in an onset of pupillary dilation approximately 15 minutes earlier for the 1% prodrug. There was no ocular toxicity from either drug. Neither drug resulted in any ERG changes compared to baseline. Significantly higher aqueous humor levels along with lower plasma levels were detected and found to be statistically different following administration of the 1% prodrug when compared to 10% phenylephrine. PMID:3503921

  11. mTOR Complexes Repress Hypertrophic Agonist-Stimulated Expression of Connective Tissue Growth Factor in Adult Cardiac Muscle Cells.

    PubMed

    Sundararaj, Kamala; Pleasant, Dorea L; Moschella, Phillip C; Panneerselvam, Kavin; Balasubramanian, Sundaravadivel; Kuppuswamy, Dhandapani

    2016-02-01

    Connective tissue growth factor (CTGF) is a fibrogenic cytokine that promotes fibrosis in various organs. In the heart, both cardiomyocytes (CM) and cardiac fibroblasts have been reported as a source of CTGF expression, aiding cardiac fibrosis. Although the mammalian target of rapamycin (mTOR) forms 2 distinct complexes, mTORC1 and mTORC2, and plays a central role in integrating biochemical signals for protein synthesis and cellular homeostasis, we explored its role in CTGF expression in adult feline CM. CM were stimulated with 10 μM phenylephrine (PE), 200 nM angiotensin (Ang), or 100 nM insulin for 24 hours. PE and Ang, but not insulin, caused an increase in CTGF mRNA expression with the highest expression observed with PE. Inhibition of mTOR with torin1 but not rapamycin significantly enhanced PE-stimulated CTGF expression. Furthermore, silencing of raptor and rictor using shRNA adenoviral vectors to suppress mTORC1 and mTORC2, respectively, or blocking phosphatidylinositol 3-kinase (PI3K) signaling with LY294002 (LY) or Akt signaling by dominant-negative Akt expression caused a substantial increase in PE-stimulated CTGF expression as measured by both mRNA and secreted protein levels. However, studies with dominant-negative delta isoform of protein kinase C demonstrate that delta isoform of protein kinase C is required for both agonist-induced CTGF expression and mTORC2/Akt-mediated CTGF suppression. Finally, PE-stimulated CTGF expression was accompanied with a corresponding increase in Smad3 phosphorylation and pretreatment of cells with SIS3, a Smad3 specific inhibitor, partially blocked the PE-stimulated CTGF expression. Therefore, a PI3K/mTOR/Akt axis plays a suppressive role on agonist-stimulated CTGF expression where the loss of this mechanism could be a contributing factor for the onset of cardiac fibrosis in the hypertrophying myocardium. PMID:26371948

  12. Local transdermal delivery of phenylephrine to the anal sphincter muscle using microneedles.

    PubMed

    Baek, Changyoon; Han, MeeRee; Min, Junhong; Prausnitz, Mark R; Park, Jung-Hwan; Park, Jung Ho

    2011-09-01

    We propose pretreatment using microneedles to increase perianal skin permeability for locally targeted delivery of phenylephrine (PE), a drug that increases resting anal sphincter pressure to treat fecal incontinence. Microneedle patches were fabricated by micromolding poly-lactic-acid. Pre-treatment of human cadaver skin with microneedles increased PE delivery across the skin by up to 10-fold in vitro. In vivo delivery was assessed in rats receiving treatment with or without use of microneedles and with or without PE. Resting anal sphincter pressure was then measured over time using water-perfused anorectal manometry. For rats pretreated with microneedles, topical application of 30% PE gel rapidly increased the mean resting anal sphincter pressure from 7±2 cm H(2)O to a peak value of 43±17 cm H(2)O after 1 h, which was significantly greater than rats receiving PE gel without microneedle pretreatment. Additional safety studies showed that topically applied green fluorescent protein-expressing E. coli penetrated skin pierced with 23- and 26-gauge hypodermic needles, but E. coli was not detected in skin pretreated with microneedles, which suggests that microneedle-treated skin may not be especially susceptible to infection. In conclusion, this study demonstrates local transdermal delivery of PE to the anal sphincter muscle using microneedles, which may provide a novel treatment for fecal incontinence. PMID:21586307

  13. Responsiveness of superficial hand veins to phenylephrine in essential hypertension. Alpha adrenergic blockade during prazosin therapy.

    PubMed

    Eichler, H G; Ford, G A; Blaschke, T F; Swislocki, A; Hoffman, B B

    1989-01-01

    Patients with essential hypertension show an increase in vascular resistance. It is unclear whether this is caused by structural changes in the arterial wall or by hyperresponsiveness of vascular smooth muscle to endogenous alpha adrenergic agonists. Using the dorsal hand vein compliance technique we compared the changes in diameter of superficial veins in response to phenylephrine, an alpha 1 adrenergic receptor agonist, and to nitroglycerin, a venorelaxant, in patients with essential hypertension and in normotensive subjects. The dose of phenylephrine that produced 50% of maximal venoconstriction (ED50) in the hypertensive subjects was 257 ng/min (geometric mean; log mean +/- SD was 2.41 +/- 0.54). In the control subjects the ED50 was 269 ng/min (geometric mean; log mean was 2.43 +/- 0.43). Maximal response (Emax) for phenylephrine was 84 +/- 13% in the hypertensive subjects and 90 +/- 6% in the control subjects. Differences in the group means of the ED50 (P = 0.92) or the Emax (P = 0.27) were not significant. There were no significant differences in the ED50 (P = 0.54) or the Emax (P = 0.08) for nitroglycerin between the two groups. These results show no evidence for a generalized change in alpha adrenergic responsiveness in hypertension and support the concept that increased blood pressure responses to alpha adrenergic stimulation in hypertensives are due to structural and geometric changes in the arterial wall rather than to an increased responsiveness of postsynaptic alpha adrenergic receptors. The phenylephrine studies were repeated in seven hypertensive patients during treatment with prazosin, an alpha 1 adrenergic antagonist. The mean dose ratio of the shift in phenylephrine ED50 (ED50 during prazosin therapy/ED50 before prazosin therapy) was 6.1. This indicates that small doses of prazosin (1-2 mg) cause significant in vivo shifts in the dose-response relationship of alpha adrenergic agonists. The dorsal hand vein compliance technique is useful in

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

    PubMed Central

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

    2014-01-01

    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 3 mM metformin for 2 hours 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. PMID:25179145

  15. 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.

  16. 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. PMID:25257714

  17. 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. PMID:25691009

  18. Evaluation of Phenylephrine Stability in Polyvinyl Chloride Bags

    PubMed Central

    Oldland, Alan R.; Kiser, Tyree H.

    2014-01-01

    Abstract Purpose: Phenylephrine hydrochloride (HCl) is commonly used to maintain adequate blood pressure during shock and shocklike states. Phenylephrine is prepared in concentrated stock vials that require further dilution prior to administration. This study evaluated the physical and chemical stability of phenylephrine in extemporaneously prepared polyvinyl chloride (PVC) bags. Methods: Phenylephrine HCl 10 mg/mL solution was diluted with 0.9% sodium chloride for injection to final concentrations of 200 µg/mL and 400 µg/mL and stored at room temperature (23°C-25°C) exposed to fluorescent light. Stability of phenylephrine HCl was evaluated by high-performance liquid chromatography on days 0, 7, 14, 21, 30, 45, and 60. Results: Phenylephrine HCl 200 and 400 µg/mL solutions in PVC bags were physically stable during the entire 60-day study period. Phenylephrine HCl retained > 95% of the original concentration. Conclusion: Phenylephrine HCl diluted to 200 or 400 µg/mL with 0.9% sodium chloride for injection is both physically and chemically stable for a period of 60 days with ≤5% degradation when stored at room temperature and exposed to fluorescent lighting. PMID:24958958

  19. 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. PMID:24895387

  20. Acute ischaemic colitis associated with oral phenylephrine decongestant use

    PubMed Central

    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. PMID:24895387

  1. 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

  2. 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

  3. Chronic activation of extracellular-signal-regulated protein kinases by phenylephrine is required to elicit a hypertrophic response in cardiac myocytes.

    PubMed Central

    Barron, Anthony J; Finn, Stephen G; Fuller, Stephen J

    2003-01-01

    Extracellular-signal-regulated protein kinases (ERKs) are activated rapidly and transiently in response to phenylephrine (PE) and endothelin-1 (ET-1) in cardiac myocytes, but whether this is linked to the subsequent development of the hypertrophic phenotype remains equivocal. To investigate this, we examined the dependence of the hypertrophic response on the length of exposure to PE in neonatal myocyte cultures. In addition to the initial transient activation of ERKs (maximum at 5-10 min), PE (10 microM) induced a second, more prolonged peak of activity several hours later. The activity of a transfected atrial natriuretic factor-luciferase reporter gene was increased 10- to 24-fold by PE. This response was inhibited by the alpha(1)-antagonist prazosin (100 nM) and by U0126 (10 microM) and PD184352 (1 microM), inhibitors of ERK activation, irrespective of whether these were added before or up to 24 h after the addition of PE. Prazosin had no effect on ET-1 (50 nM)-stimulated atrial natriuretic factor-luciferase activity. Protein synthesis was enhanced by 35+/-6% by PE, and this was blocked by prazosin added 1 h after the addition of PE, but decreased only by half when added 8 h after PE. Similarly, PE (48 h) increased myocyte area by 49% and this was prevented by prazosin added 1 h after PE, but decreased only by half when added at 24 h. These results demonstrate that prolonged exposure to PE is required to elicit alterations in gene expression, protein synthesis and cell size, characteristic of hypertrophied myocytes, and they confirm that the initial peak of ERK activity is insufficient to trigger hypertrophic responses. PMID:12513686

  4. 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.

  5. 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. PMID:20519555

  6. 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

  7. The effect of high-fructose intake on the vasopressor response to angiotensin II and adrenergic agonists in Sprague-Dawley rats.

    PubMed

    Abdulla, Mohammed Hadi; Sattar, Munavvar Abdul; Abdullah, Nor Azizan; Johns, Edward James

    2013-07-01

    Effect of losartan was assessed on systemic haemodynamic responses to angiotensin II (Ang II) and adrenergic agonists in the model of high-fructose-fed rat. Twenty-four Sprague-Dawley (SD) rats were fed for 8 weeks either 20% fructose solution (FFR) or tap water (C) ad libitum. FFR or C group received losartan (10mg/kg/day p.o.) for 1 week at the end of feeding period (FFR-L and L) respectively, then the vasopressor responses to Ang II, noradrenaline (NA), phenylephrine (PE) and methoxamine (ME) were determined. The responses (%) to NA, PE, ME and Ang II in FFR were lower (P<0.05) than C (FFR vs. C; 22±2 vs. 32±2, 30±3 vs. 40±3, 9±1 vs. 13±1, 10±1 vs. 17±1) respectively. L group had blunted (P<0.05) responses to NA, PE, ME and Ang II compared to C (L vs. C; 26±2 vs. 32±2, 30±3 vs. 40±3, 7±0.7 vs. 13±1, 5±0.4 vs. 17±1) respectively. FFR-L group had aggravated (P<0.05) response to NA and ME, but blunted response to Ang II compared to FFR (FFR-L vs. FFR; 39±3 vs. 22±2, 11±1 vs. 9±1, 3±0.4 vs. 10±1) respectively. Fructose intake for 8 weeks results in smaller vasopressor response to adrenergic agonists and Ang II. Data also demonstrated an important role played by Ang II in the control of systemic haemodynamics in FFR and point to its interaction with adrenergic neurotransmission. PMID:23811449

  8. Hemodynamic effects of ephedrine and phenylephrine bolus injection in patients in the prone position under general anesthesia for lumbar spinal surgery

    PubMed Central

    Xia, Jiangyan; Sun, Yongying; Yuan, Jing; Lu, Xinjian; Peng, Zhendan; Yin, Ning

    2016-01-01

    Ephedrine and phenylephrine (PE) are vasoconstrictors commonly used to restore the blood pressure (BP) to normal values. The aim of the present study was to investigate the effects of ephedrine and PE bolus administration on intra-arterial systolic BP (ISBP), intra-arterial diastolic BP (IDBP) and cardiac output (CO) in patients undergoing lumbar spine surgery in the prone position under general anesthesia (GA). In this prospective, randomized, and double-blind study, a total of 60 patients aged 20–60 years and undergoing elective lumbar spine surgery were administered either a single dose of ephedrine (0.1 mg/kg) or PE (1 µg/kg) through a central venous catheter as a bolus injection following the achievement of a stable hemodynamic status for ≥10 min. Following bolus injection of ephedrine or PE, a significant increase in ISBP was observed in the two experimental groups compared with pre-ephedrine and pre-PE values. The duration of the increment in ISBP however was significantly longer in the ephedrine group compared with the PE group. A similar response was observed in IDBP. A significant increase in CO began 1 min following ephedrine injection and lasted for the entire observation period, whereas the increase was only sustained for 3 min following bolus injection in the PE group. The results of the present study demonstrated that bolus ephedrine produces a more persistent pressor response and durable increase in CO and CI compared with PE when patients are in the prone position with GA for spine surgery.

  9. Intraoperative Pulseless Electrical Activity and Acute Cardiogenic Shock After Administration of Phenylephrine, Epinephrine, and Ketamine

    PubMed Central

    Kaye, Alan D.; Sabartinelli, Alecia L.; Kaye, Adam M.; Holtzman, Alan M.; Samm, Paul L.

    2010-01-01

    The use of phenylephrine has been well described as a potential cause of morbidity and mortality. A thorough literature review of phenylephrine use is presented in this article. The use of ketamine and epinephrine with phenylephrine can precipitate an even more potentially lethal and catastrophic syndrome. We present the case of a 21-year-old man with Hodgkin's lymphoma and lupus who experienced an abrupt hypertensive crisis followed by pulseless electrical activity and cardiogenic shock after application of 2.5% phenylephrine-soaked nasal pledgets prior to excision of a large nasopharyngeal tumor. This case report adds to the current literature on the potential dangers of phenylephrine in clinical practice and describes a case of reversible severe left ventricular dysfunction in the setting of excessive pharmacologically induced sympathetic stimulation. PMID:21603379

  10. 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.

  11. 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

  12. 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

  13. Intracerebral Hemorrhage Associated with Oral Phenylephrine Use: A Case Report and Review of the Literature

    PubMed Central

    Tark, Brian E; Messe, Steven R; Balucani, Clotilde; Levine, Steven R

    2014-01-01

    Background Prior reports have linked both ischemic and hemorrhagic stroke to use of sympathomimetic drugs including phenylephrine. Objective To describe the first case, to our knowledge, of intracerebral hemorrhage following oral use of phenylephrine and to systematically review the literature on phenylephrine and acute stroke. Methods A case report and review of the literature. Results A 59-year-old female presented with thunderclap headache, right hemiparesis, aphasia, and left gaze deviation. Head CT showed a left frontal intracerebral hemorrhage with intraventricular and subarachnoid extension. She had no significant past medical history. For the previous thirty days, the patient was taking multiple common cold remedies containing phenylephrine to treat sinusitis. CT and MR angiography showed no causative vascular abnormality. Catheter cerebral angiography supported reversible cerebral vasoconstriction syndrome. Phenylephrine was determined to be the most likely etiology for her hemorrhage. A review of the literature, found 7 cases describing phenylephrine use with acute stroke occurrence: female 5/7 (71%); route of administration: nasal (n=3); ophthalmic (n=2); intravenous (n=1); intracorporeal injection (n=1). Stroke types were: subarachnoid hemorrhage (n=5); ICH (n=4); ischemic (n=1). One case reported reversible cerebral vasoconstriction syndrome after phenylephrine use. Conclusion It is scientifically plausible that phenylephrine may cause strokes, consistent with the pharmacological properties and adverse event profiles of similar amphetamine-like sympathomimetics. As reversible cerebral vasoconstriction syndrome has been well-described in association with over-the-counter sympathomimetics, a likely, although not definitive, causal relationship between phenylephrine and intracerebral hemorrhage is proposed. PMID:25156786

  14. Does topical phenylephrine, tropicamide, or proparacaine affect macular blood flow?

    PubMed

    Robinson, F; Petrig, B L; Sinclair, S H; Riva, C E; Grunwald, J E

    1985-08-01

    The acute effect of topical phenylephrine HCl 10%, tropicamide 1% and proparacaine HCl 0.5% on macular capillary blood flow was studied in six healthy human volunteers using the blue field simulation technique. This technique provides a method for quantifying the velocity of leukocytes flowing in one's own retinal macular capillaries. Patients adjusted the velocity of computer simulated leukocytes moving on a CRT screen to match that of their own entoptically perceived leukocytes before instillation of each of the tested preparations and for 35 minutes immediately thereafter A 5% NaCl solution was used as a control. We found no significant difference in leukocyte velocity between the control drop and any of the tested drugs. With the six subjects tested, the calculated average minimum percentage change in leukocyte velocity detectable with this technique (P less than 0.05, paired t-test) was 9%. None of the tested drugs affected macular leukocyte velocity, and presumably blood flow, by more than this amount. PMID:4047607

  15. Comparison of phenylephrine hydrochloride and mephentermine sulphate for prevention of post spinal hypotension.

    PubMed

    Mohta, M; Janani, S Sai; Sethi, A K; Agarwal, D; Tyagi, A

    2010-12-01

    This study compared the effects of intravenous infusions of phenylephrine and mephentermine on the prevention of maternal hypotension and neonatal outcome in patients receiving spinal anaesthesia for caesarean section. Sixty ASA 1-2 patients with term, uncomplicated singleton pregnancy undergoing caesarean section under spinal anaesthesia were randomly divided into two groups of 30 each, to receive a prophylactic intravenous infusion of either phenylephrine or mephentermine. The incidence of hypotension was statistically similar in the two groups. However, in patients receiving phenylephrine, 7 (23%) developed bradycardia and 6 (20%), reactive hypertension. Neonatal outcome, in terms of Apgar scores and umbilical artery pH, was similar in both the groups. To conclude, phenylephrine and mephentermine infusions are equally effective in preventing post spinal hypotension in patients undergoing caesarean section and are associated with a similar neonatal outcome. PMID:21182601

  16. Balloon catheter injury abolishes phenylephrine-induced relaxation in the rat contralateral carotid

    PubMed Central

    Pernomian, L; Gomes, MS; de Oliveira, AM

    2011-01-01

    BACKGROUND AND PURPOSE The consequences of compensatory responses to balloon catheter injury in rat carotid artery, on phenylephrine-induced relaxation and contraction in the contralateral carotid artery were studied. EXPERIMENTAL APPROACH Relaxation and contraction concentration–response curves for phenylephrine were obtained for contralateral carotid arteries in the presence of indomethacin (COX inhibitor), SC560 (COX-1 inhibitor), SC236 (COX-2 inhibitor) or 4-hydroxytetramethyl-L-piperidine-1-oxyl (tempol; superoxide dismutase mimetic). Reactive oxygen species were measured in carotid artery endothelial cells fluorimetrically with dihydroethidium. KEY RESULTS Phenylephrine-induced relaxation was abolished in contralateral carotid arteries from operated rats (Emax= 0.01 ± 0.004 g) in relation to control (Emax= 0.18 ± 0.005 g). Phenylephrine-induced contractions were increased in contralateral arteries (Emax= 0.54 ± 0.009 g) in relation to control (Emax= 0.38 ± 0.014 g). SC236 restored phenylephrine-induced relaxation (Emax= 0.17 ± 0.004 g) and contraction (Emax= 0.34 ± 0.018 g) in contralateral arteries. Tempol restored phenylephrine-induced relaxation (Emax= 0.19 ± 0.012 g) and contraction (Emax= 0.42 ± 0.014 g) in contralateral arteries, while apocynin did not alter either relaxation (Emax= 0.01 ± 0.004 g) or contraction (Emax= 0.54 ± 0.009 g). Dihydroethidium fluorescence was increased in contralateral samples (18 882 ± 435 U) in relation to control (10 455 ± 303 U). SC236 reduced the fluorescence in contralateral samples (8250 ± 365 U). CONCLUSIONS AND IMPLICATIONS Balloon catheter injury abolished phenylephrine-induced relaxation and increased phenylephrine-induced contraction in contralateral carotid arteries, through O2− derived from COX-2. PMID:21323906

  17. 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

  18. 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.

  19. 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

  20. Enhanced bioconversion rate and released substrate inhibition in (R)-phenylephrine whole-cell bioconversion via partial acetone treatment.

    PubMed

    Kan, Shu-Chen; Zang, Chi-Zong; Yeh, Chiung-Wen; Chang, Wei-Feng; Lin, Chia-Chi; Hung, Tzu-Hsiang; Shieh, Chwen-Jen; Liu, Yung-Chuan

    2016-05-01

    An approach was developed to enhance the efficiency for the bioconversion of 1-(3-hydroxyphenyl)-2-(methyamino)-ethanone to (R)-phenylephrine. The strain Serratia marcescens N10612, giving the benefit of 99% enantiomeric excess in (R)-PE conversion, was used. The fermentation was devised to harvest cells with high hydrophobic prodigiosin content inside the cells. Then, the partial acetone extraction was applied to remove prodigiosin from the cells. The treatment was found to increase the cells conversion rate without loss of the cells NADPH redox system. When using 50% (v/v) acetone for 5min, the processed cells can give a specific conversion rate of 16.03μmol/h/g-cells. As compared the treated cells with cells under the basal medium, the maximum reaction rate (Vmax) increased from 6.69 to 10.27 (μmol/h/g-cells), the dissociation constant (Km) decreased from 0.236 to 0.167mM and the substrate inhibition constant (KSi) increased from 0.073 to 1.521mM. The 20-fold increase in substrate inhibition constant referred to a great release from the substrate inhibition for the use of S. marcescens N10612 in the bioconversion, which would greatly benefit the bioconversion to be industrialized. PMID:26992790

  1. α1 -AR agonist induced piloerection protects against the development of traction alopecia.

    PubMed

    Goren, Andy; Shapiro, Jerry; Sinclair, Rodney; Kovacevic, Maja; McCoy, John

    2016-05-01

    Traction alopecia is hair loss that occurs after persistent pulling (e.g., during cosmetic procedures) on the roots of hair over time. Unlike plucking, which is painful, persistent pulling may go unnoticed until a patient presents with either bald spots or diffuse telogen shedding. Each hair follicle in the scalp contains an arrector pili muscle that, when contracted, erects the hair. The smooth muscle in the arrector pili expresses α1 adrenergic receptors (α1 -AR). As such, we hypothesized that contraction of the arrector pili muscle via an α1 -AR agonist would increase the threshold of force required to pluck hair during cosmetic procedures. Female subjects, ages 18-40, were recruited to study the effect of topically applied phenylephrine, a selective α1 -AR agonist, on epilation force and hair shedding during cosmetic procedures. In our blinded study, 80% of subjects demonstrated reduced shedding on days using phenylephrine compared to days using a placebo solution. The average reduction in hair loss was approximately 42%. In addition, the force threshold required for epilation increased by approximately 172% following topical phenylephrine application. To our knowledge this is the first study demonstrating the utility of α1 -AR agonists in the treatment of traction alopecia and hair shedding during cosmetic procedures. PMID:26678522

  2. Bronchoconstriction following instillation of phenylephrine eye drops in premature infants with bronchopulmonary dysplasia: two cases report.

    PubMed

    Kim, Hyun Jee; Choi, Jin Guk; Kwak, Kyung-Hwa

    2015-12-01

    Premature infants requiring an ophthalmic examination or even surgery for retinopathy of prematurity (ROP) have a high prevalence of co-existing bronchopulmonary dysplasia (BPD). Reactive airway is one of the clinical presentations of BPD. We report two cases of bronchoconstriction following instillation of mydriatic eye drops. One occurred during induction of anesthesia for laser photocoagulation and the other before screening of ROP. The most likely cause in each case was phenylephrine eye drops. We recommend that the minimal dosage of phenylephrine needed to attain proper mydriasis should be instilled to infant patients, and the possibility of bronchoconstriction occurrence kept in mind, especially for infants with low body weight with BPD. PMID:26634087

  3. The transcriptional coactivator p300 plays a critical role in the hypertrophic and protective pathways induced by phenylephrine in cardiac cells but is specific to the hypertrophic effect of urocortin.

    PubMed

    Davidson, Sean M; Townsend, Paul A; Carroll, Chris; Yurek-George, Alexander; Balasubramanyam, Karanam; Kundu, Tapas K; Stephanou, Anastasis; Packham, Graham; Ganesan, A; Latchman, David S

    2005-01-01

    Anacardic acid is an alkylsalicylic acid obtained from cashew-nut-shell liquid, and is a potent inhibitor of p300 histone acetyl-transferase (HAT) activity. We have used anacardic acid to prevent the induction of hypertrophy in isolated neonatal rat cardiomyocytes. Hypertrophy was detected as an increase in cell size, the rearrangement of sarcomeres into a striated pattern, and the induction of embryonic genes beta-MHC and ANF. p300 inhibition was equally effective at preventing hypertrophy whether it was induced by treatment with the alpha1-adrenergic agonist, phenylephrine, or by treatment with urocortin, a member of the corticotrophin-releasing-factor family, which stimulates specific G protein-coupled receptors. Spiruchostatin A is a natural-product inhibitor of histone deacetylases (HDAC) similar to the depsipeptide FK228 molecule. We have recently synthesized spiruchostatin A and now show that, although HDACs act in opposition to HATs, spiruchostatin A has the same effect as anacardic acid, that is, it prevents the induction of hypertrophy in response to phenylephrine or urocortin. Pretreatment with either phenylephrine or urocortin reduced the extent of death observed after the exposure of isolated cardiomyocytes to simulated ischaemia and reoxygenation. Inhibition of p300 or HDAC activity eliminated the protection conferred by phenylephrine; however, it did not affect the protection conferred by urocortin. Therefore, it might eventually be possible to use chemical inhibitors such as these in a therapeutic setting to dissociate the protective effect and hypertrophic effect of urocortin, enhancing the survival of cardiomyocytes exposed to transient ischemia, while inhibiting the hypertrophic pathway that would otherwise be induced concurrently. PMID:15593114

  4. Bupivacaine-induced Vasodilation Is Mediated by Decreased Calcium Sensitization in Isolated Endothelium-denuded Rat Aortas Precontracted with Phenylephrine

    PubMed Central

    Ok, Seong Ho; Bae, Sung Il; Kwon, Seong Chun; Park, Jung Chul; Kim, Woo Chan; Park, Kyeong Eon; Shin, Il Woo; Lee, Heon Keun; Chung, Young Kyun; Choi, Mun Jeoung

    2014-01-01

    Background A toxic dose of bupivacaine produces vasodilation in isolated aortas. The goal of this in vitro study was to investigate the cellular mechanism associated with bupivacaine-induced vasodilation in isolated endotheliumdenuded rat aortas precontracted with phenylephrine. Methods Isolated endothelium-denuded rat aortas were suspended for isometric tension recordings. The effects of nifedipine, verapamil, iberiotoxin, 4-aminopyridine, barium chloride, and glibenclamide on bupivacaine concentration-response curves were assessed in endothelium-denuded aortas precontracted with phenylephrine. The effect of phenylephrine and KCl used for precontraction on bupivacaine-induced concentration-response curves was assessed. The effects of verapamil on phenylephrine concentration-response curves were assessed. The effects of bupivacaine on the intracellular calcium concentration ([Ca2+]i) and tension in aortas precontracted with phenylephrine were measured simultaneously with the acetoxymethyl ester of a fura-2-loaded aortic strip. Results Pretreatment with potassium channel inhibitors had no effect on bupivacaine-induced relaxation in the endothelium-denuded aortas precontracted with phenylephrine, whereas verapamil or nifedipine attenuated bupivacaine-induced relaxation. The magnitude of the bupivacaine-induced relaxation was enhanced in the 100 mM KCl-induced precontracted aortas compared with the phenylephrine-induced precontracted aortas. Verapamil attenuated the phenylephrine-induced contraction. The magnitude of the bupivacaine-induced relaxation was higher than that of the bupivacaine-induced [Ca2+]i decrease in the aortas precontracted with phenylephrine. Conclusions Taken together, these results suggest that toxic-dose bupivacaine-induced vasodilation appears to be mediated by decreased calcium sensitization in endothelium-denuded aortas precontracted with phenylephrine. In addition, potassium channel inhibitors had no effect on bupivacaine-induced relaxation

  5. 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.

  6. Prophylactic Phenylephrine for Iatrogenic Priapism: A Pilot Study With Peyronie's Patients

    PubMed Central

    Jiang, Pengbo; Christakos, Athena; Fam, Mina

    2014-01-01

    Purpose Although penile duplex Doppler ultrasonography (PDDU) is a common and integral procedure in a Peyronie's disease workup, the intracavernosal injection of vasoactive agents can carry a serious risk of priapism. Risk factors include young age, good baseline erectile function, and no coronary artery disease. In addition, patients with Peyronie's disease undergoing PDDU in an outpatient setting are at increased risk given the inability to predict optimal dosing. The present study was conducted to provide support for a standard protocol of early administration of phenylephrine in patients with a sustained erection after diagnostic intracavernosal injection of vasoactive agents to prevent the deleterious effects of iatrogenic priapism. Materials and Methods This was a retrospective review of Peyronie's disease patients who received phenylephrine reversal after intracavernosal alprostadil (prostaglandin E1) administration to look at the priapism rate. Safety was determined on the basis of adverse events reported by subjects and efficacy was determined on the basis of the rate of priapism following intervention. Results Patients with Peyronie's disease only had better hemodynamic values on PDDU than did patients with Peyronie's disease and erectile dysfunction. All of the patients receiving prophylactic phenylephrine had complete detumescence of erections without adverse events, including no priapism cases. Conclusions The reversal of erections with phenylephrine after intracavernosal injections of alprostadil to prevent iatrogenic priapism can be effective without increased adverse effects. PMID:25324950

  7. 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.

  8. Recombinant streptokinase vs phenylephrine-based suppositories in acute hemorrhoids, randomized, controlled trial (THERESA-3)

    PubMed Central

    Hernández-Bernal, Francisco; Castellanos-Sierra, Georgina; Valenzuela-Silva, Carmen M; Catasús-Álvarez, Karem M; Valle-Cabrera, Roselin; Aguilera-Barreto, Ana; López-Saura, Pedro A

    2014-01-01

    AIM: To compare the efficacy and safety of recombinant streptokinase (rSK) and phenylephrine-based suppositories in acute hemorrhoidal disease. METHODS: A multicenter (14 sites), randomized (1:1), open, parallel groups, active controlled trial was done. After inclusion, subjects with acute symptoms of hemorrhoids, who gave their written, informed consent to participate, were centrally randomized to receive, as outpatients, rSK (200000 IU) or 0.25% phenylephrine suppositories, which had different organoleptic characteristics. Treatment was administered by the rectal route, one unit every 6 h during 48 h for rSK, and up to a maximum of 5 d (20 suppositories) for phenylephrine. Evaluations were performed at 3, 5 and 10 d post-inclusion. The main end-point was the 5th-day complete clinical response (disappearance of pain and edema, and ≥ 70% reduction of the lesion size). Time to response and need for thrombectomy were secondary efficacy variables. Adverse events were evaluated too. RESULTS: 5th day complete response rates were 83/110 (75.5%) and 36/110 (32.7%) with rSK and phenylephrine suppositories, respectively. This 42.7% difference (95%CI: 30.5-54.2) was highly significant (P < 0.001). The advantage was detected since the early 3rd day evaluation (37.3% vs 6.4% for the rSK and active control groups, respectively; P < 0.001) and was kept even at the late 10th day assessment (83.6% vs 58.2% for rSK and phenylephrine, respectively; P < 0.001). Time for complete response was significantly shorter (P = 0.031; log-rank test) in the rSK group (median: 4.9 d; 95%CI: 4.8-5.0) with respect to the active control (median: 9.8 d; 95%CI: 9.8-10.0). Thrombectomy was necessary in 1/59 and 8/57 patients with baseline thrombosis in the rSK and phenylephrine groups, respectively (P = 0.016). There were no adverse events attributable to the experimental treatment. CONCLUSION: rSK suppositories showed a significant advantage over a widely used over-the-counter phenylephrine

  9. 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

  10. 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…

  11. 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

  12. 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

  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. 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…

  15. Nitric oxide donor beta2-agonists: furoxan derivatives containing the fenoterol moiety and related furazans.

    PubMed

    Buonsanti, M Federica; Bertinaria, Massimo; Stilo, Antonella Di; Cena, Clara; Fruttero, Roberta; Gasco, Alberto

    2007-10-01

    The structure of fenoterol, a beta2-adrenoceptor agonist used in therapy, has been joined with furoxan NO-donor moieties to give new NO-donor beta2-agonists. The furazan analogues, devoid of the property to release NO, were also synthesized for comparison. All the compounds retained beta2-agonistic activity at micromolar or submicromolar concentration when tested on guinea pig tracheal rings precontracted with carbachol. Among the furoxan derivatives, the NO contribution to trachea relaxation was evident with product 15b at micromolar concentrations. All the new NO-donor hybrids were able to dilate rat aortic strips precontracted with phenylephrine. Both furoxan and furazan derivatives displayed antioxidant activity greater than that of fenoterol. PMID:17845020

  16. 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. PMID:25982099

  17. Phenylephrine does not limit myocardial blood flow or oxygen delivery during isoflurane-induced hypotension in dogs.

    PubMed

    Abdel-Latif, M; Kim, S J; Salem, M R; Crystal, G J

    1992-06-01

    Experiments were performed on seven fentanyl-pentobarbital-anesthetized, open-chest dogs to determine whether stimulation of coronary alpha 1-adrenergic receptors by phenylephrine causes coronary vasoconstriction and impaired myocardial oxygen delivery when phenylephrine is infused to correct isoflurane-induced hypotension. Myocardial blood flow was measured with radioactive microspheres, and myocardial oxygen and lactate extraction were determined. The Fick equation was used to calculate myocardial oxygen consumption. Measurements were obtained (a) under control conditions, (b) after a 30-min inhalation of isoflurane sufficient to decrease mean aortic pressure by 30%, and (c) while maintaining administration of isoflurane, 5-10 min after restoration of mean aortic pressure by intravenous infusion of phenylephrine. Isoflurane-induced hypotension was accompanied by a baroreceptor-mediated increase in heart rate and by a decrease in myocardial oxygen consumption; however, myocardial blood flow was maintained, resulting in decreased oxygen extraction and increased coronary sinus PO2, thus implying a direct coronary vasodilating effect for isoflurane. Lactate extraction was unaffected. Phenylephrine infusion during inhalation of isoflurane returned mean aortic pressure and heart rate to their respective control values, and it did not change myocardial oxygen consumption, myocardial blood flow, myocardial oxygen extraction, coronary sinus PO2, or lactate extraction from values obtained during isoflurane alone. These latter findings are consistent with undiminished coronary vasodilation by isoflurane in the presence of phenylephrine. In conclusion, infused phenylephrine to restore aortic pressure during isoflurane administration had no vasoconstrictor effect in the coronary circulation and did not impair myocardial oxygen delivery. Apparently, the direct coronary vasodilating action of isoflurane completely nullified phenylephrine-induced vasoconstriction via local alpha

  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. Determination of phenylephrine in human plasma using ultra-performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Feng, Sheng; Zhao, Qian; Jiang, Ji; Hu, Pei

    2013-02-01

    This paper described a sensitive and rapid method based on ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) for the determination of phenylephrine in human plasma. Plasma samples were pre-purified by solid-phase extraction (SPE). The chromatographic separation was achieved with BEH HILIC column using a mixture of 10mM pH 3.5 ammonium formate and acetonitrile (10:90, v/v) under isocratic conditions at a flow rate of 0.4 mL/min. The mass spectrometry was carried out using positive electrospray ionization (ESI) and data acquisition was carried out in the multiple reaction monitoring (MRM) mode. The method was fully validated over the concentration range of 10.0-5000 pg/mL. The lower limit of quantification (LLOQ) was 10.0 pg/mL. Inter- and intra-batch precision was less than 15% and the accuracy was within 85-115%. Extraction recovery was 78.5%. Selectivity, matrix effects and stability were also validated. The method was applied to the pharmacokinetic study of phenylephrine hydrochloride in Chinese subjects. PMID:23314401

  20. 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

  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. 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…

  3. 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…

  4. 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.

  5. 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.

  6. Asymmetric membrane capsules of phenylephrine hydrochloride: an osmotically controlled drug delivery system.

    PubMed

    Kumar, Anil; Philip, Anil Kumar; Pathak, Kamla

    2011-09-01

    The aim of the current study was to develop osmotically controlled release system of freely water soluble drug phenylephrine hydrochloride by use of asymmetric membrane capsules to reduce the dosing frequency and consequently improve the patient compliance. Ethyl cellulose asymmetric membrane capsules were developed by phase inversion process and solubility modulation was accomplished by common ion effect wherein sodium chloride was included in the formulation that also served as an osmogen. The effect of formulation variables namely level of polymer (ethyl cellulose), level of pore former (glycerol) and level of osmogen (sodium chloride) on the in vitro release of the drug was evaluated by 2(3) factorial design. Effects of environmental factors on the release rate of the drug from asymmetric membrane capsules were also evaluated. Membrane characterization by scanning electron microscopy showed an outer dense region with less pores and inner porous region for the prepared asymmetric membrane. The dimensional analysis of asymmetric membrane capsule documented the capsules to be of uniform cap and body size comparable to commercial hard gelatin capsules. In vitro release studies results showed that incorporation of higher amount of osmogen not only increased the osmotic pressure but also controlled the drug release for a period of 12 hr. The drug release was inversely proportional to the level of polymer in asymmetric membrane capsule but directly related to the level of pore former in the membrane. The optimized asymmetric membrane capsule (F5) was able to provide zero order release of phenylephrine hydrochloride independent of agitation rate, intentional defect in the membrane and pH of dissolution medium but was dependent on the osmotic pressure gradient between inside and outside of the delivery system. PMID:21696358

  7. Influence of prostaglandins and adrenoceptor agonists on contractile activity in the human cervix at term.

    PubMed

    Bryman, I; Norström, A; Lindblom, B

    1986-04-01

    The influence of prostaglandins as well as adrenoceptor agonists and antagonists on contractile activity of isolated cervical smooth muscle from term pregnant women was studied. Prostaglandin E2 had an inhibitory effect at extremely low concentrations. Inhibition also was induced by prostaglandin F2 alpha, prostaglandin I2, and 6-keto-prostaglandin F1 alpha, but at considerably higher concentrations. Contractions evoked by noradrenaline or phenylephrine were blocked by the alpha-adrenoceptor antagonist phenoxybenzamine. The beta-adrenoceptor agonist terbutaline acted as an inhibitor, whereas isoprenaline in most cases stimulated contractile activity. The inhibitory action of prostaglandins and especially the high sensitivity to prostaglandin E2 point to a physiologic role of these compounds for cervical dilatation and retraction. A predominance of alpha-adrenoceptors might be of importance for the maintenance of cervical competence during pregnancy. PMID:2870450

  8. 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

  9. 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

  10. Proerectile effects of dopamine D2-like agonists are mediated by the D3 receptor in rats and mice.

    PubMed

    Collins, Gregory T; Truccone, Andrew; Haji-Abdi, Faiza; Newman, Amy Hauck; Grundt, Peter; Rice, Kenner C; Husbands, Stephen M; Greedy, Benjamin M; Enguehard-Gueiffier, Cecile; Gueiffier, Alain; Chen, Jianyong; Wang, Shaomeng; Katz, Jonathan L; Grandy, David K; Sunahara, Roger K; Woods, James H

    2009-04-01

    Dopamine D(2)-like agonists induce penile erection (PE) and yawning in a variety of species, effects that have been suggested recently to be specifically mediated by the D(4) and D(3) receptors, respectively. The current studies were aimed at characterizing a series of D(2), D(3), and D(4) agonists with respect to their capacity to induce PE and yawning in the rat and the proerectile effects of apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol hydrochloride] in wild-type and D(4) receptor (R) knockout (KO) mice. All D(3) agonists induced dose-dependent increases in PE and yawning over a similar range of doses, whereas significant increases in PE or yawning were not observed with any of the D(4) agonists. Likewise, D(2), D(3), and D(4) antagonists were assessed for their capacity to alter apomorphine- and pramipexole (N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride)-induced PE and yawning. The D(3) antagonist, PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride], inhibited the induction of PE and yawning, whereas the D(2) antagonist, L-741,626 [3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole], reversed the inhibition of PE and yawning observed at higher doses. The D(4) antagonist, L-745,870 [3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride], did not alter apomorphine- or pramipexole-induced PE or yawning. A role for the D(3) receptor was further supported because apomorphine was equipotent at inducing PE in wild-type and D(4)RKO mice, effects that were inhibited by the D(3) antagonist, PG01037, in both wild-type and D(4)R KO mice. Together, these studies provide strong support that D(2)-like agonist-induced PE and yawning are differentially mediated by the D(3) (induction) and D(2) (inhibition) receptors. These studies fail to support a role for the D(4) receptor in the regulation of PE or

  11. 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

  12. Muscarinic receptor antagonist and an alpha-adrenergic agonist are required in combination to provide stable mydriasis following intravitreal injection in mice

    PubMed Central

    Mojumder, Deb Kumar

    2010-01-01

    Tropicamide (muscarinic receptor antagonist) and phenylephrine (α-adrenergic receptor agonist) are commonly used to dilate the pupils by topical application. These two eye drops are often used, singly or in combination, to dilate the pupil and perform acute light-evoked physiological experiments (electroretinography, for example), before and after intravitreal injections of pharmacological agents, as an assay for their affect on retinal activity. This study wanted to determine whether treatment with one of these drugs, or with both, is most effective in maintaining mydriasis after intravitreal injections. Changes in pupillary dilation before and after intravitreal injection of balanced salt solution (0.5 µl) were recorded. Phenylephrine (α-adrenergic agonist) and tropicamide (muscarinic agonist) when combined, but not singly, produced full and stable pupillary dilation following intravitreal injections. Re-instillation of topical mydriatics after intravitreal injections was required for maximal pupillary dilation. A combination of a muscarinic receptor antagonist and an alpha-adrenergic agonist is required for stable mydriasis following intravitreal injection. PMID:20852745

  13. Transient supersensitivity to α-adrenoceptor agonists, and distinct hyper-reactivity to vasopressin and angiotensin II after denervation of rat tail artery

    PubMed Central

    Tripovic, Diana; Pianova, Svetlana; McLachlan, Elspeth M; Brock, James A

    2010-01-01

    Background and purpose: Vascular ‘denervation’ hyper-reactivity has generally been investigated 1–2 weeks after administration of chemicals that temporarily prevent transmitter release, but do not necessarily inactivate the neuronal noradrenaline transporters (NETs). We have investigated the reactivity of rat tail arteries over longer periods after removing the terminals by surgical denervation. Experimental approach: Two and 7 weeks after denervation, myography was used to assess contractions of isolated arterial segments to phenylephrine, methoxamine, clonidine, vasopressin and angiotensin II (AII). Denervation was confirmed by lack of tyrosine hydroxylase immunoreactive nerve terminals. Key results: The NET inhibitor, desmethylimipramine, increased the pEC50 for phenylephrine in control, but not denervated arteries after both 2 and 7 weeks. Relative to controls, pEC50s for phenylephrine (with desmethylimipramine), methoxamine, clonidine and vasopressin were increased at 2 but not 7 weeks after denervation. The pEC50 for phenylephrine in the absence of desmethylimipramine was greater than control after both 2 and 7 weeks' denervation. The maximum contraction to vasopressin was larger than in controls at 2 but not 7 weeks after denervation, whereas contractions to AII were markedly enhanced at both time points. Conclusions and implications: Increased vascular reactivity to α1- and α2-adrenoceptor agonists, and vasopressin is transient following denervation. After 7 weeks, increased reactivity to phenylephrine can be entirely accounted for by the loss of NETs. Maintained supersensitivity to AII indicates that denervation differentially and selectively affects vascular reactivity to circulating vasoconstrictor agents. This might explain persistent vasoconstriction in denervated skin of humans after nerve injuries. PMID:20002103

  14. 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

  15. Tributyltin contributes in reducing the vascular reactivity to phenylephrine in isolated aortic rings from female rats.

    PubMed

    Rodrigues, Samya Mere L; Ximenes, Carolina F; de Batista, Priscila R; Simões, Fabiana V; Coser, Pedro Henrique P; Sena, Gabriela C; Podratz, Priscila L; de Souza, Leticia N G; Vassallo, Dalton V; Graceli, Jones B; Stefanon, Ivanita

    2014-03-21

    Organotin compounds such as tributyltin (TBT) are used as antifouling paints by shipping companies. TBT inhibits the aromatase responsible for the transformation of testosterone into estrogen. Our hypothesis is that TBT modulates the vascular reactivity of female rats. Female Wistar rats were treated daily (Control; CONT) or TBT (100 ng/kg) for 15 days. Rings from thoracic aortas were incubated with phenylephrine (PHE, 10(-10)-10(-4) M) in the presence and absence of endothelium, and in the presence of N(G)-Nitro-L-Arginine Methyl Ester (L-NAME), tetraethylammonium (TEA) and apocynin. TBT decreased plasma levels of estrogen and the vascular response to PHE. In the TBT group, the vascular reactivity was increased in the absence of endothelium, L-NAME and TEA. The decrease in PHE reactivity during incubation with apocynin was more evident in the TBT group. The sensitivity to acetylcholine (ACh) and sodium nitroprusside (SNP) was reduced in the TBT group. TBT increased collagen, reduced α1-smooth muscle actin. Female rats treated with TBT for 15 days showed morphology alteration of the aorta and decreased their vascular reactivity, probably due to mechanisms dependent on nitric oxide (NO) bioavailability, K(+) channels and an increase in oxidative stress. PMID:24468273

  16. 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

  17. 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. PMID:26656357

  18. Effects of α1-adrenoceptor antagonists on phenylephrine-induced salivary secretion and intraurethral pressure elevation in anesthetized rats.

    PubMed

    Yanai-Inamura, Hiroko; Ohtake, Akiyoshi; Noguchi, Yukiko; Hatanaka, Toshiki; Suzuki, Masanori; Ueshima, Koji; Sato, Shuichi; Sasamata, Masao

    2012-03-15

    α(1)-Adrenoceptor antagonists are widely used for the treatment of voiding dysfunction associated with benign prostatic hyperplasia. Activation of α(1)-adrenoceptors is reported to induce salivary secretion in rats and humans. However, the effects of α(1)-adrenoceptor antagonists on salivary secretion remain unknown. Here, we investigated the effects of the α(1)-adrenoceptor antagonists prazosin, silodosin, tamsulosin and urapidil on phenylephrine-induced salivary secretion and compared the results with the effects on phenylephrine-induced intraurethral pressure (IUP) elevation in anesthetized rats. All antagonists inhibited phenylephrine-induced salivary secretion and IUP elevation in a dose-dependent fashion. Comparison of DR(10) values (the dose required to shift the dose-response curve 10-fold to the right) in both tissues showed that the inhibitory effect of silodosin was significantly more potent in the salivary gland than in the urethra (18-fold), but tamsulosin (2.3-fold), prazosin (1.7-fold) and urapidil (1.1-fold) did not show comparable tissue selectivity. These results suggest that α(1)-adrenoceptor antagonists inhibit not only urethral contraction but also salivary secretion, and that high tissue selectivity for the salivary gland over the urethra as shown by silodosin may contribute to the incidence of dry mouth. PMID:22314219

  19. 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. PMID:25978623

  20. 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.

  1. The Relationship between PE Biographies and PE Teaching Practices of Classroom Teachers

    ERIC Educational Resources Information Center

    Morgan, Philip J.; Hansen, Vibeke

    2008-01-01

    The current study sought to explore the relationship between personal school physical education (PE) experiences and current PE teaching practices of classroom teachers. Questionnaires were completed by 189 teachers from 38 randomly selected schools. Additionally, semi-structured interviews of 31 classroom teachers were conducted. The results…

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

    PubMed Central

    Sood, Shilpa; Messer, Zachary; Dzogbeta, Seli; Terilli, Courtney; Stewart, Julian M.

    2014-01-01

    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. PMID:25277740

  3. 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. PMID:25277740

  4. Beta-Adrenergic Agonists

    PubMed Central

    Barisione, Giovanni; Baroffio, Michele; Crimi, Emanuele; Brusasco, Vito

    2010-01-01

    Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised.

  5. Gradient HPLC-DAD determination of paracetamol, phenylephrine hydrochloride, cetirizine in tablet formulation.

    PubMed

    Dewani, A P; Shelke, P G; Bakal, R L; Jaybhaye, S S; Chandewar, A V; Patra, S

    2014-05-01

    Present work describes the development and validation of a simple and reliable high-performance liquid chromatography-diode array detection (HPLC-DAD) procedure for the analysis of phenylephrine hydrochloride (PHE), paracetamol (PAR) and cetirizine dihydrochloride (CET), in pharmaceutical mixture. The method was applied successfully on tablet dosage form. Effective chromatographic separation of PHE, PAR and CET was achieved using a Kinetex-C18 (4.6, 150 mm, 5 mm) column with gradient elution of the mobile phase composed of 10 mM phosphate buffer (pH 3.3) and acetonitrile. The elution was a 3 step gradient elution program step-1 started initially with 2% (by volume) acetonitrile and 98% phosphate buffer (pH 3.3) for first 2 min. In step-2 acetonitrile concentration changed linearly to 20% upto 12 min the analysis was concluded by step-3 changing acetonitrile to 2% upto 20 min. The reliability and analytical performance of the proposed HPLC procedure were statistically validated with respect to linearity, ranges, precision, accuracy, selectivity and robustness. Calibration curves were linear in the ranges 5-15, 250-750 and 2.5-7.5 μg/ml for PHE, PAR and CET, with correlation coefficients >0.9996. The validated HPLC method was applied to a pharmaceutical mixture of a marketed preparation tablet in which the analytes were successfully quantified with good recovery values with no interfering peaks from the excipents. PMID:24132702

  6. 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…

  7. The effect of ionophore A23187 on calcium ion fluxes and alpha-adrenergic-agonist action in perfused rat liver.

    PubMed Central

    Reinhart, P H; Taylor, W M; Bygrave, F L

    1983-01-01

    The effect of ionophore A23187 on cellular Ca2+ fluxes, glycogenolysis and respiration was examined in perfused liver. At low extracellular Ca2+ concentrations (less than 4 microM), A23187 induced the mobilization of intracellular Ca2+ and stimulated the rate of glycogenolysis and respiration. As the extracellular Ca2+ concentration was elevated, biphasic cellular Ca2+ fluxes were observed, with Ca2+ uptake preceding Ca2+ efflux. Under these conditions, both the glycogenolytic response and the respiratory response also became biphasic, allowing the differentiation between the effects of extracellular and intracellular Ca2+. Under all conditions examined the rate of Ca2+ efflux induced by A23187 was much slower than the rate of phenylephrine-induced Ca2+ efflux, although the net amounts of Ca2+ effluxed were similar for both agents. The effect of A23187 on phenylephrine-induced Ca2+ fluxes, glycogenolysis and respiration is dependent on the extracellular Ca2+ concentration. At concentrations of less than 50 microM-Ca2+, A23187 only partially inhibited alpha-agonist action, whereas at 1.3 mM-Ca2+ almost total inhibition was observed. The action of A23187 at the cellular level is complex, dependent on the experimental conditions used, and shows both differences from and similarities to the hepatic action of alpha-adrenergic agonists. PMID:6412701

  8. 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.

  9. Effects of caffeine, halothane, succinylcholine, phenylephrine and isoproterenol on myocardial force of contraction of malignant hyperthermia susceptible swine.

    PubMed

    Scholz, J; Roewer, N; Rum, U; Schmitz, W; Scholz, H; Schulte am Esch, J

    1991-05-01

    The effects of caffeine, halothane, succinylcholine, phenylephrine and isoproterenol on force of contraction were studied in electrically driven (0.2 Hz) trabeculae isolated from the right ventricles of the hearts of malignant hyperthermia susceptible (MHS) and healthy control (nMHS) swine. Caffeine (0.1-10 mmol/l) had positive inotropic effects, amounting to 275 +/- 35% of control in nMHS and 268 +/- 34% in MHS (n = 16). Halothane (0.25-4 vol%) decreased the force of contraction maximally to 52 +/- 4% in nMHS and 51 +/- 5% of control in MHS (n = 16). Propranolol did not change these effects. Succinylcholine (0.1-10000 mumol/l) had a small positive inotropic effect in both groups, which was blocked by propranolol. Phenylephrine (0.1-300 mumol/l) increased the force of contraction maximally to 188 +/- 24% of control in nMHS and to 193 +/- 23% in MHS (n = 16). The inotropic effect was blocked by prazosin but not by succinylcholine (1 mmol/l). Isoproterenol (0.01-10 mumol/l) had a positive inotropic effect of maximally 275 +/- 21% of control in nMHS and 396 +/- 31% in MHS (n = 17) (P less than 0.05). Succinylcholine potentiated this effect, and propranolol shifted the concentration-response curves to the right. We conclude that caffeine, halothane, succinylcholine and phenylephrine have similar inotropic effects in the hearts of nMHS and MHS, whereas isoproterenol has a significantly greater effect in MHS than in nMHS. PMID:1853693

  10. 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.

  11. 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

  12. 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.

  13. Marked behavioral activation from inhibitory stimulation of locus coeruleus α1-adrenoceptors by a full agonist

    PubMed Central

    Stone, Eric A.; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David

    2009-01-01

    α1-Adrenoceptors are concentrated in the locus coeruleus (LC) where they appear to regulate various active behaviors but have been difficult to stimulate effectively. The present study examined the behavioral, pharmacological and neural effects of possible stimulation of these receptors with 6-fluoronorepinephrine (6FNE), the only known selective α-agonist that has full efficacy at all brain α-receptors. Infusion of this compound in the mouse LC was found to produce extreme activation of diverse motivated behaviors of exploration, wheel running and operant approach responding in different environments consistent with a global behavioral function of the dorsal noradrenergic system. Infusion of selective antagonists of α1- (terazosin) or α2-(atipamezole) receptors or of either the partial α1-agonist, phenylephrine, or full α2-agonist, dexmedetomidine, indicated that the behavioral effects of 6FNE were due largely due to activation of LC α1-receptors consistent with the known greater density of α1-than α2-adrenoreceptors in the mouse nucleus. Immunohistochemistry of fos in tyrosine hydroxylase-positive LC neurons following IV ventricular infusions indicated that 6FNE markedly depressed whereas terazosin strongly enhanced the apparent functional activity of the nucleus. The changes in fos expression following 6FNE and terazosin were significantly greater than those following dexmedetomidine and atipamezole. It is hypothesized that the α1-receptors of the mouse LC are strongly activated by 6FNE and serve to potently inhibit its tonic or stress-induced activity which in turn disinhibits prepotent motivated behaviors. PMID:19632210

  14. 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

  15. Non-Specialist Teachers' Confidence to Teach PE: The Nature and Influence of Personal School Experiences in PE

    ERIC Educational Resources Information Center

    Morgan, Philip; Bourke, Sid

    2008-01-01

    Background: Over the past 20 years, a number of researchers have expressed concern over the lack of confidence and qualifications of primary school teachers to teach PE. Evidently, the influence of personal school PE experiences may play an important role in the development of teachers' confidence to appropriately teach PE. Most research that has…

  16. 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.

  17. 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. PMID:26957055

  18. 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…

  19. 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

  20. 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.

  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

    2016-01-01

    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

  2. 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

  3. Agonist-induced Ca2+ Sensitization in Smooth Muscle

    PubMed Central

    Artamonov, Mykhaylo V.; Momotani, Ko; Stevenson, Andra; Trentham, David R.; Derewenda, Urszula; Derewenda, Zygmunt S.; Read, Paul W.; Gutkind, J. Silvio; Somlyo, Avril V.

    2013-01-01

    Many agonists, acting through G-protein-coupled receptors and Gα subunits of the heterotrimeric G-proteins, induce contraction of smooth muscle through an increase of [Ca2+]i as well as activation of the RhoA/RhoA-activated kinase pathway that amplifies the contractile force, a phenomenon known as Ca2+ sensitization. Gα12/13 subunits are known to activate the regulator of G-protein signaling-like family of guanine nucleotide exchange factors (RhoGEFs), which includes PDZ-RhoGEF (PRG) and leukemia-associated RhoGEF (LARG). However, their contributions to Ca2+-sensitized force are not well understood. Using permeabilized blood vessels from PRG(−/−) mice and a new method to silence LARG in organ-cultured blood vessels, we show that both RhoGEFs are activated by the physiologically and pathophysiologically important thromboxane A2 and endothelin-1 receptors. The co-activation is the result of direct and independent activation of both RhoGEFs as well as their co-recruitment due to heterodimerization. The isolated recombinant C-terminal domain of PRG, which is responsible for heterodimerization with LARG, strongly inhibited Ca2+-sensitized force. We used photolysis of caged phenylephrine, caged guanosine 5′-O-(thiotriphosphate) (GTPγS) in solution, and caged GTPγS or caged GTP loaded on the RhoA·RhoGDI complex to show that the recruitment and activation of RhoGEFs is the cause of a significant time lag between the initial Ca2+ transient and phasic force components and the onset of Ca2+-sensitized force. PMID:24106280

  4. 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. PMID:19275609

  5. 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.

  6. 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.

  7. 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

  8. Influence of the dopamine receptor agonists fenoldopam and quinpirole in the rat superior mesenteric vascular bed.

    PubMed Central

    Dupont, A. G.; Lefebvre, R. A.; Vanderniepen, P.

    1987-01-01

    The effect of local administration of the dopamine 2 (DA2)-receptor agonist quinpirole and of the DA1-receptor agonist fenoldopam was studied in the in situ, constant flow autoperfused, superior mesenteric vascular bed of the rat. Local infusion of quinpirole (30 micrograms kg-1 min-1 for 5 min) had no effect on baseline perfusion pressure; it reduced the pressor responses to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial sympathetic nerves to 45.6 +/- 2.1% of its original value but did not modify similar pressor responses produced by locally administered noradrenaline. The inhibitory effect of quinpirole was antagonized by the selective DA2-receptor antagonist domperidone (10 micrograms kg-1) but not by the selective DA1-receptor antagonist SCH 23390 (50 micrograms kg-1). Local infusion of fenoldopam (30 micrograms kg-1 min-1 for 5 min) reduced baseline perfusion pressure to 89.9 +/- 1.9%, increased the pressor response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial nerves to 134.7 +/- 14.0%, but reduced the pressor response to locally administered noradrenaline to 37.2 +/- 8.2%. Similar pressor responses induced by the selective alpha 1-adrenoceptor agonist phenylephrine were also reduced by fenoldopam (to 38.4 +/- 6.4%), but responses to locally administered angiotensin II were not modified. Pretreatment with SCH 23390 (50 micrograms kg-1) antagonized the effect of fenoldopam on baseline perfusion pressure, but had no influence on the effect of fenoldopam on responses to electrical stimulation or to noradrenaline. Pretreatment with the selective alpha 2-adrenoceptor antagonist rauwolscine (100 micrograms kg-1) had no effect on the reduction in baseline perfusion pressure induced by fenoldopam nor on its inhibitory effect on the response to noradrenaline, but it antagonized the stimulatory effect of fenoldopam on the response to electrical stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2886174

  9. 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. PMID:26491100

  10. 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. PMID:21140654

  11. D-004 ameliorates phenylephrine-induced urodynamic changes and increased prostate and bladder oxidative stress in rats

    PubMed Central

    Oyarzábal, Ambar; Pérez, Yohani; Mas, Rosa; Ravelo, Yazmin; Jiménez, Sonia

    2015-01-01

    Background Lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH) mainly depend on alpha1-adrenoreceptors (α1-ADR) stimulation, but a link with oxidative stress (OS) is also involved. D-004, a lipid extract of Roystonea regia fruits, antagonizes ADR-induced responses and produces antioxidant effects. The objective of this study was to investigate whether D-004 produce antioxidant effects in rats with phenylephrine (PHE)-induced urodynamic changes. Methods Rats were randomized into eight groups (ten rats/group): a negative vehicle control and seven groups injected with PHE: a positive control, three treated with D-004 (200, 400 and 800 mg/kg) and three others with tamsulosin (0.4 mg/kg), grape seed extract (GSE) (250 mg/kg) and vitamin E (VE) (250 mg/kg), respectively. Results Effects on urinary total volume (UTV), volume voided per micturition (VM), malondialdehyde (MDA) and carbonyl groups (CG) concentrations in prostate and bladder homogenates were study outcomes. While VM and UTV lowered significantly in the positive control as compared to the negative control group, the opposite occurred with prostate and bladder MDA and CG values. D-004 (200-800 mg/kg) increased significantly both VM and UTV, lowered significantly MDA in prostate and bladder homogenates, and reduced GC levels only in the prostate. Tamsulosin increased significantly VM and UTV, but unchanged oxidative variables. GSE and VE unchanged the UTV, whereas VE, not GSE, modestly but significantly attenuated the PHE-induced decrease of VM. Conclusions Single oral administration of D-004 (200-800 mg/kg) was the only treatment that ameliorated the urodynamic changes and reduced increased oxidative variables in the prostate of rats with PHE-induced prostate hyperplasia. PMID:26816837

  12. 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

  13. Local and cellular Ca2+ transients in smooth muscle of pressurized rat resistance arteries during myogenic and agonist stimulation.

    PubMed

    Miriel, V A; Mauban, J R; Blaustein, M P; Wier, W G

    1999-08-01

    1. Confocal laser scanning microscopy was used to visualize Ca2+ transients in the vascular smooth muscle cells (VSMC) of intact, pressurized rat mesenteric resistance arteries loaded with fluorescent calcium indicators. Vasoconstriction was assessed by measuring inner arterial diameter. All arteries were studied at 70 mmHg intralumenal pressure and 37 C. 2. In the control condition of myogenic tone the arteries were constricted to 62 % (n = 10) of their passive diameter (p.d.). The [Ca2+]i in most VSMC of these arteries was constant over time. In a small percentage (< 10 %) of cells in each artery, [Ca2+]i oscillated regularly. Local calcium transients (Ca2+ sparks) were observed in five arteries studied with confocal linescan imaging. 3. Activation of alpha-adrenoceptors by phenylephrine (PE, 1.0 microM) induced further vasoconstriction of pressurized arteries (to 27 % of p.d.). In this condition, [Ca2+]i oscillations were prominent in a large percentage (83 %) of the VSMC. The Ca2+ oscillations ranged in frequency from 4 to 22 min-1, and were usually asynchronous between cells. 4. High [KCl]o (65 mM) induced nearly comparable vasoconstriction to PE (37 % of p.d.) but [Ca2+]i oscillated in only about 13 % of cells in each artery. 5. Block of L-type Ca2+ channels (with nifedipine) in arteries activated by PE caused nearly full vasodilatation, but did not abolish the Ca2+ oscillations. Subsequent block of the sarcoplasmic reticulum Ca2+ pump (with cyclopiazonic acid) abolished Ca2+ oscillations in all cells. 6. We conclude that Ca2+ entering VSMC via L-type Ca2+ channels has an obligatory role in force development, both in myogenic tone and during alpha1-adrenoceptor activation. The oscillatory pattern of [Ca2+]i that persists in the absence of Ca2+ entry via L-type Ca2+ channels is ineffective in activating contraction. PMID:10420017

  14. 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.

  15. The effects of bepridil, compared with calcium-channel inhibitors and calmodulin antagonists on both spontaneous activity and contractions induced by potassium or phenylephrine in rat portal vein.

    PubMed

    Campbell, J K; Winslow, E; Marshall, R J

    1986-12-16

    Bepridil is known to block calcium channels in some vascular tissues. Recent work has shown that bepridil also antagonises calmodulin. The present study attempted to more fully characterize the vasodilator actions of bepridil by comparing it with the known calcium channel blocking drugs, nifedipine, diltiazem, verapamil and flunarizine, the calmodulin inhibitors, trifluoperazine and W7 and propylmethylenedioxyindene, which is thought to act intracellularly, on rat portal vein. The relative activities of the test drugs were compared on spontaneous activity and on all components of the contractile responses to potassium and phenylephrine. Bepridil inhibited all components of the potassium and phenylephrine responses equally, actions similar to those of the intracellular acting drugs. The exception to this was trifluoperazine which also exerted alpha-adrenoceptor blocking actions. In contrast the calcium channel blocking drugs, with the exception of verapamil, inhibited the tonic component of both spasmogen responses more than the phasic component. Bepridil like the intracellular acting drugs, but unlike the calcium channel blockers, markedly increased the frequency of spontaneous contractions whilst reducing amplitude. It is concluded that the profile of bepridil on rat portal vein more closely resembles that of intracellularly acting drugs than that of classical calcium channel inhibitors. PMID:3493163

  16. 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...

  17. DIFFUSE PeV NEUTRINOS FROM GAMMA-RAY BURSTS

    SciTech Connect

    Liu, Ruo-Yu; Wang, Xiang-Yu

    2013-04-01

    The IceCube Collaboration recently reported the potential detection of two cascade neutrino events in the energy range 1-10 PeV. We study the possibility that these PeV neutrinos are produced by gamma-ray bursts (GRBs), paying special attention to the contribution by untriggered GRBs that elude detection due to their low photon flux. Based on the luminosity function, rate distribution with redshift and spectral properties of GRBs, we generate, using a Monte Carlo simulation, a GRB sample that reproduces the observed fluence distribution of Fermi/GBM GRBs and an accompanying sample of untriggered GRBs simultaneously. The neutrino flux of every individual GRB is calculated in the standard internal shock scenario, so that the accumulative flux of the whole samples can be obtained. We find that the neutrino flux in PeV energies produced by untriggered GRBs is about two times higher than that produced by the triggered ones. Considering the existing IceCube limit on the neutrino flux of triggered GRBs, we find that the total flux of triggered and untriggered GRBs can reach at most a level of {approx}10{sup -9} GeV cm{sup -2} s{sup -1} sr{sup -1}, which is insufficient to account for the reported two PeV neutrinos. Possible contributions to diffuse neutrinos by low-luminosity GRBs and the earliest population of GRBs are also discussed.

  18. 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…

  19. 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…

  20. "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.

  1. "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…

  2. 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

  3. 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.

  4. Behavioural evidence that different neurochemical mechanisms underly stretching-yawning and penile erection induced in male rats by SND 919, a new selective D2 dopamine receptor agonist.

    PubMed

    Ferrari, F; Pelloni, F; Giuliani, D

    1993-01-01

    The behavioural effects induced in male Wistar rats by SND 919, a new drug reputed to have selective agonistic activity at D2 dopamine (DA) receptors, were studied. The following aspects of behaviour were considered: motor activity, stretching-yawning (SY), penile erection (PE) and stereotyped behaviour (SB). Intraperitoneal injection (IP) of the drug (0.01-20 mg/kg) induced an SY syndrome in the form of a bell-shaped dose-response curve, the effect being maximal at the dose of 0.1 mg/kg and disappearing completely at 10 mg/kg. SND 919 also potently elicited PE; this latter effect, however, was not coincident with SY induction, being maximal at 1 mg/kg and persisting at 10 and 20 mg/kg. SND 919-induced SY was potently antagonized by pretreatment not only with the D2 antagonist, L-sulpiride (20 mg/kg), but also with the alpha 2 antagonist, yohimbine (1, 3 mg/kg), and the more selective alpha 2 antagonist, idazoxan (1, 2 and 5 mg/kg). While sulpiride also decreased SND 919-induced PE, idazoxan at all doses and yohimbine at 1 mg/kg did not affect this behaviour. Inhibition of motor activity was induced by the D2 agonist at low doses (0.05, 0.1 mg/kg), while at high doses (1, 10 and 20 mg/kg), it was actually replaced by a form of SB characterized by downward sniffing and licking. When, for comparison, the D2 agonist, RU 24213 (0.1-20 mg/kg IP), was tested for PE, SY, motor activity and SB, it displayed a behavioural pattern very similar to that obtained with SND 919. Idazoxan (2 mg/kg), administered before RU 24213 (10 mg/kg), significantly antagonized the drug-induced SY, but not PE.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7855178

  5. Symptomatic treatment of the common cold with a fixed-dose combination of paracetamol, chlorphenamine and phenylephrine: a randomized, placebo-controlled trial

    PubMed Central

    2013-01-01

    Background The common cold and other viral airway infections are highly prevalent in the population, and their treatment often requires the use of medications for symptomatic relief. Paracetamol is as an analgesic and antipyretic; chlorphenamine is an antihistamine; and phenylephrine, a vasoconstrictor and decongestant. This randomized, double-blind, placebo-controlled trial sought to evaluate the efficacy and safety of a fixed-dose combination of paracetamol, chlorphenamine and phenylephrine in the symptomatic treatment of the common cold and flu-like syndrome in adults. Methods This study enrolled 146 individuals aged 18 to 60 years who had moderate to severe flu-like syndrome or common cold. After clinical examination and laboratory tests, individuals were randomly assigned to receive the fixed-dose combination (73) or placebo (73), five capsules per day for 48 to 72 hours. The primary efficacy endpoint was the sum of the scores of 10 symptoms on a four-point Likert-type scale. To evaluate treatment safety, the occurrence of adverse events was also measured. Results Mean age was 33.5 (±9.5) years in the placebo group and 33.8 (±11.5) in the treatment group. There were 55 women and 18 men in the placebo group, and 46 women and 27 men in the treatment group. Comparison of overall symptom scores in the two groups revealed a significantly greater reduction in the treatment group than in the placebo group (p = 0.015). Analysis at the first 13 dose intervals (± 66 h of treatment) showed a greater reduction of symptom scores in the treatment group than in the placebo group (p < 0.05). The number and distribution of adverse events were similar in both groups. Conclusion A fixed-dose combination of paracetamol, chlorphenamine and phenylephrine was safe and more effective than placebo in the symptomatic treatment of the common cold or flu-like syndrome in adults. Trial registration NCT01389518 PMID:24261438

  6. 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

  7. 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

  8. 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.

  9. 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

  10. INsPeCT: INtegrative Platform for Cancer Transcriptomics

    PubMed Central

    Madhamshettiwar, Piyush B.; Maetschke, Stefan R.; Davis, Melissa J.; Reverter, Antonio; Ragan, Mark A.

    2014-01-01

    The emergence of transcriptomics, fuelled by high-throughput sequencing technologies, has changed the nature of cancer research and resulted in a massive accumulation of data. Computational analysis, integration, and data visualization are now major bottlenecks in cancer biology and translational research. Although many tools have been brought to bear on these problems, their use remains unnecessarily restricted to computational biologists, as many tools require scripting skills, data infrastructure, and powerful computational facilities. New user-friendly, integrative, and automated analytical approaches are required to make computational methods more generally useful to the research community. Here we present INsPeCT (INtegrative Platform for Cancer Transcriptomics), which allows users with basic computer skills to perform comprehensive in-silico analyses of microarray, ChIP-seq, and RNA-seq data. INsPeCT supports the selection of interesting genes for advanced functional analysis. Included in its automated workflows are (i) a novel analytical framework, RMaNI (regulatory module network inference), which supports the inference of cancer subtype-specific transcriptional module networks and the analysis of modules; and (ii) WGCNA (weighted gene co-expression network analysis), which infers modules of highly correlated genes across microarray samples, associated with sample traits, eg survival time. INsPeCT is available free of cost from Bioinformatics Resource Australia-EMBL and can be accessed at http://inspect.braembl.org.au. PMID:24653643

  11. INsPeCT: INtegrative Platform for Cancer Transcriptomics.

    PubMed

    Madhamshettiwar, Piyush B; Maetschke, Stefan R; Davis, Melissa J; Reverter, Antonio; Ragan, Mark A

    2014-01-01

    The emergence of transcriptomics, fuelled by high-throughput sequencing technologies, has changed the nature of cancer research and resulted in a massive accumulation of data. Computational analysis, integration, and data visualization are now major bottlenecks in cancer biology and translational research. Although many tools have been brought to bear on these problems, their use remains unnecessarily restricted to computational biologists, as many tools require scripting skills, data infrastructure, and powerful computational facilities. New user-friendly, integrative, and automated analytical approaches are required to make computational methods more generally useful to the research community. Here we present INsPeCT (INtegrative Platform for Cancer Transcriptomics), which allows users with basic computer skills to perform comprehensive in-silico analyses of microarray, ChIP-seq, and RNA-seq data. INsPeCT supports the selection of interesting genes for advanced functional analysis. Included in its automated workflows are (i) a novel analytical framework, RMaNI (regulatory module network inference), which supports the inference of cancer subtype-specific transcriptional module networks and the analysis of modules; and (ii) WGCNA (weighted gene co-expression network analysis), which infers modules of highly correlated genes across microarray samples, associated with sample traits, eg survival time. INsPeCT is available free of cost from Bioinformatics Resource Australia-EMBL and can be accessed at http://inspect.braembl.org.au. PMID:24653643

  12. Disagreement between standard transthoracic impedance cardiography and the automated transthoracic electrical bioimpedance method in estimating the cardiovascular responses to phenylephrine and isoprenaline in healthy man.

    PubMed Central

    De Mey, C; Enterling, D

    1993-01-01

    1. Impedance cardiography is a well-established noninvasive method to assess within-subject changes of cardiovascular function. We compared the standard approach (ZCG) which requires tedious signal analysis with an automated approach (TEB: NCCOM 3) with its own specific equipment, algorithms and equations in order to assess agreement of the method-specific measurements and calculations. 2. Ten healthy men were studied on two occasions with either ZCG or TEB, at rest and at the end of 5 min i.v.-infusions with 1 microgram min-1 isoprenaline and 100 micrograms min-1 phenylephrine. 3. There was good agreement for the method-independent changes (HR, SBP/DBP), but there were large differences for method-specific measurements: dZ/dtmax [TEB-ZCG] = -0.68, CI: -0.83 to -0.53 ohm s-1, PEP [TEB-ZCG] = -22.1, CI: -35.0 to -9.2 ms and QS2c [TEB-ZCG] = -16.5, CI: -32.4 to -0.6 ms and for the calculated stroke volume SV [TEB-ZCG] = 30.3, CI: 15.5 to 45.2 ml. The responses of dZ/dtmax and SV to isoprenaline and phenylephrine, although qualitatively similar, reached no quantitative agreement either. A substantial disagreement was evident for the STI responses to isoprenaline where TEB failed to detect the expected reduction of VETc and thus grossly underestimated the shortening of QS2c. 4. It is concluded that TEB-measurements and -calculations did not agree with standard ZCG, that the methods, albeit related, cannot be considered as interchangeable and that suspicion is justified that TEB might yield erroneous results under specific circumstances. PMID:8485014

  13. Western-style diet modulates contractile responses to phenylephrine differently in mesenteric arteries from senescence-accelerated prone (SAMP8) and resistant (SAMR1) mice.

    PubMed

    Jiménez-Altayó, Francesc; Onetti, Yara; Heras, Magda; Dantas, Ana P; Vila, Elisabet

    2013-08-01

    The influence of two known cardiovascular risk factors, aging and consumption of a high-fat diet, on vascular mesenteric artery reactivity was examined in a mouse model of accelerated senescence (SAM). Five-month-old SAM prone (SAMP8) and resistant (SAMR1) female mice were fed a Western-type high-fat diet (WD; 8 weeks). Mesenteric arteries were dissected, and vascular reactivity, protein and messenger RNA expression, superoxide anion (O 2 (·-) ) and hydrogen peroxide formation were evaluated by wire myography, immunofluorescence, RT-qPCR, ethidium fluorescence and ferric-xylenol orange, respectively. Contraction to KCl and relaxation to acetylcholine remained unchanged irrespective of senescence and diet. Although similar contractions to phenylephrine were observed in SAMR1 and SAMP8, accelerated senescence was associated with decreased eNOS and nNOS and increased O 2 (·-) synthesis. Senescence-related alterations were compensated, at least partly, by the contribution of NO derived from iNOS and the enhanced endogenous antioxidant capacity of superoxide dismutase 1 to maintain vasoconstriction. Administration of a WD induced qualitatively different alterations in phenylephrine contractions of mesenteric arteries from SAMR1 and SAMP8. SAMR1 showed increased contractions partly as a result of decreased NO availability generated by decreased eNOS and nNOS and enhanced O 2 (·-) formation. In contrast, WD feeding in SAMP8 resulted in reduced contractions due to, at least in part, the increased functional participation of iNOS-derived NO. In conclusion, senescence-dependent intrinsic alterations during early stages of vascular senescence may promote vascular adaptation and predispose to further changes in response to high-fat intake, which may lead to the progression of aging-related cardiovascular disease, whereas young subjects lack the capacity for this adaptation. PMID:22777652

  14. Piperidine derivatives as nonprostanoid IP receptor agonists.

    PubMed

    Hayashi, Ryoji; Sakagami, Hideki; Koiwa, Masakazu; Ito, Hiroaki; Miyamoto, Mitsuko; Isogaya, Masafumi

    2016-05-01

    The discovery of a new class of nonprostanoid prostaglandin I2 receptor (IP receptor) agonists is reported. Among them, the unique piperidine derivative 31b (2-((1-(2-(N-(4-tolyl)benzamido)ethyl)piperidin-4-yl)oxy)acetic acid) was a good IP receptor agonist and was 50-fold more selective for the human IP receptor than for other human prostanoid receptors. This compound showed good pharmacokinetic properties in dog. PMID:26996371

  15. 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…

  16. 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 =…

  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. Different contractile effects of alpha1- and alpha2-adrenergic agonists on horse isolated common digital artery smooth muscle ring preparations in vitro.

    PubMed

    Cavalli, M; Carcano, R; Beretta, C

    2002-10-01

    Despite assays on ring preparations in vitro confirmed that the vasoconstrictor sympathetic control in the horse common digital artery mainly depends on alpha(1)-adrenoceptors stimulation, selective alpha(2)-adrenoceptor agonists were investigated under the same experimental conditions. Both detomidine (DET) and UK 14304 differed from noradrenaline (NA) and phenylephrine (PHE) in provoking contractile effects which were slowly onsetting, concentrations-unrelated and unremovable by repeated washings. While prazosin (PRA) clearly antagonized the effects of NA and PHE, neither pre- nor post-treatments of the preparations with alpha(2)-antagonists succeeded in antagonizing or removing the effects of the two alpha(2)-agonists tested, which moreover were unaffectable either by lowering the organ bath temperature or by depriving the nutritive medium of Ca(2+). To explain this unusual behavior of alpha(2)-adrenoceptors stimulation it has been hypothesized that a Ca(2+) mobilization from the endoplasmic reticulum of the smooth muscle cell occurs which is followed by a hindered reuptake of them. PMID:12361691

  19. 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.

  20. 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.

  1. 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.

  2. "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…

  3. 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.

  4. 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

  5. Introduction of a single isomer beta agonist.

    PubMed

    Rau, J L

    2000-08-01

    The release of levalbuterol offers the first approved single-isomer beta agonist for oral inhalation. Data from in vitro studies support the concept that S albuterol is not inactive and may have properties antagonistic to bronchodilation. There is some variability in the results of clinical studies with the separate isomers of albuterol, which suggests the need for further study. The introduction of levalbuterol into general clinical use in managing asthma and chronic obstructive disease should begin to offer additional information on the effects of a single isomer beta agonist in comparison to previous racemic mixtures. PMID:10963321

  6. The Baculovirus PE38 Protein Augments Apoptosis Induced by Transactivator IE1

    PubMed Central

    Prikhod’ko, Elena A.; Miller, Lois K.

    1999-01-01

    While studying apoptosis induced by baculovirus transactivator IE1 in SF-21 cells, we found that the levels of IE1-induced apoptosis were increased approximately twofold upon cotransfection with the baculovirus early pe38 gene. However, no apoptotic activity was observed in cells transfected with pe38 alone, even when placed under the control of a constitutive promoter. Thus, pe38 was able to augment IE1-induced apoptosis but was unable to induce apoptosis when expressed in SF-21 cells alone. PE38, the full-length product of pe38, is a nuclear protein with RING finger and leucine zipper motifs. Deletion of the amino-terminal region, which contains a putative nuclear localization motif, resulted in cytoplasmic localization of the PE38 mutants. These N-terminal deletion mutants were unable to enhance IE1-induced apoptosis. Mutation of a single conserved leucine (L242) of the leucine zipper motif also eliminated the ability of PE38 to augment apoptosis induced by IE1. In contrast, PE38 mutants with alanine substitutions for conserved cysteine residues (C109 or C138) of the RING finger motif were able to increase IE1-induced apoptosis to levels equivalent to those of wild-type PE38. We propose that PE38 is one of at least two viral factors which collectively evoke a cellular apoptotic response during baculovirus infection. PMID:10400766

  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. 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

  9. 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. PMID:24411064

  10. Reciprocity of agonistic support in ravens

    PubMed Central

    Fraser, Orlaith N.; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim’s likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  11. 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

  12. Small molecule TSHR agonists and antagonists.

    PubMed

    Neumann, S; Gershengorn, M C

    2011-04-01

    TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies, there is a strong rationale for the design of small molecule "drug-like" ligands. Recombinant human TSH (rhTSH, Thyrogen(®)) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a small molecule ligand that is a full agonist at TSHR. Importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration. Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signalling in primary cultures of human thyrocytes. Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. We suggest that these small molecule ligands are lead compounds for the development of higher potency ligands that can be used as probes of TSHR biology with therapeutic potential. PMID:21511239

  13. Reciprocity of agonistic support in ravens.

    PubMed

    Fraser, Orlaith N; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim's likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  14. 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

  15. Cloning and stress response analysis of the PeDREB2A and PeDREB1A genes in moso bamboo (Phyllostachys edulis).

    PubMed

    Wu, H L; Li, L; Cheng, Z C; Ge, W; Gao, J; Li, X P

    2015-01-01

    Moso bamboo is a large woody bamboo with the highest ecological, economic, and cultural value among all bamboos in Asia. However, environmental stress influences its growth and development and limits its geographic distribution. Therefore, improving its resistance to environmental stress is extremely important. Dehydration responsive element binding (DREB) transcription factors perform an important role in the regulation of stress-related genes, enhancing the resistance of plants to abiotic stress. In the current study, two novel DREB genes, PeDREB2A and PeDREB1A (Gene ID No. PH01000046G1730 and PH01000668G0350), were isolated from moso bamboo and the sequences were identified and characterized (coding sequence lengths were 795 and 825 bp, respectively). The PeDREB2A and PeDREB1A proteins were estimated to have typical AP2/ERF domains, molecular weights of 28.96 and 28.84 kDa, and isoelectric points of 9.47 and 5.34, respectively. RT-PCR analysis revealed that PeDREB2A and PeDREB1A were tissue-specific genes, expressed in leaves, young stems, and roots, with similar expression levels in leaves and young stems. qRT-PCR analysis of leaves demonstrated that PeDREB2A transcription levels rapidly accumulate following exposure to drought and salt stress, peaking at 12 and 0.5 h, respectively, but only low expression levels were observed under cold stress. PeDREB1A exhibited a strong response to cold stress, reaching a peak in expression 3 h after exposure, but demonstrated only a slight response to drought and salt stress. In roots, PeDREB2A was down-regulated, and PeDREB1A was initially upregulated but then declined, under stress conditions. Two plant expression vectors, pCAMBIA2300- CaMV35S-PeDREB2A and pCAMBIA2300-CaMV35S-PeDREB1A were also successfully constructed. PMID:26345957

  16. 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}.

  17. 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

  18. PPARα Agonist WY-14643 Induces SIRT1 Activity in Rat Fatty Liver Ischemia-Reperfusion Injury

    PubMed Central

    Pantazi, Eirini; Folch-Puy, Emma; Bejaoui, Mohamed; Panisello, Arnau; Varela, Ana Teresa; Rolo, Anabela Pinto; Palmeira, Carlos Marques; Roselló-Catafau, Joan

    2015-01-01

    Ischemia-reperfusion injury (IRI) remains a frequent complication in surgery, especially in case of steatotic livers that present decreased tolerance towards IRI. Apart from its major role in metabolism, activation of peroxisome proliferator-activated receptor α (PPARα) has been related with positive effects on IRI. In addition, the deacetylase enzyme sirtuin 1 (SIRT1) has recently emerged as a promising target for preventing IRI, through its interaction with stress-related mechanisms, such as endoplasmic reticulum stress (ERS). Taking this into account, this study aims to explore whether PPARα agonist WY-14643 could protect steatotic livers against IRI through sirtuins and ERS signaling pathway. Obese Zucker rats were pretreated or not pretreated with WY-14643 (10 mg/kg intravenously) and then submitted to partial (70%) hepatic ischemia (1 hour) followed by 24 hours of reperfusion. Liver injury (ALT levels), lipid peroxidation (MDA), SIRT1 activity, and the protein expression of SIRT1 and SIRT3 and ERS parameters (IRE1α, peIF2, caspase 12, and CHOP) were evaluated. Treatment with WY-14643 reduced liver injury in fatty livers, enhanced SIRT1 activity, and prevented ERS. Together, our results indicated that PPARα agonist WY-14643 may exert its protective effect in fatty livers, at least in part, via SIRT1 induction and ERS prevention. PMID:26539534

  19. But I Like PE: Factors Associated With Enjoyment of Physical Education Class in Middle School Girls

    PubMed Central

    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 enjoyed PE class a lot. Variables positively associated with PE class enjoyment included physical activity level, perceived benefits of physical activity, self-efficacy for leisure time physical activity, and perceived school climate for girls' physical activity as influenced by teachers, while body mass index was inversely associated with PE class enjoyment. After adjusting for all variables in the model, PE class enjoyment was significantly greater in Blacks than in Whites. In model testing, with mutual adjustment for all variables, self-efficacy was the strongest correlate of PE class enjoyment, followed by perceived benefits, race/ethnicity, and teacher's support for girls' physical activity, as compared to boys, at school. The overall model explained 11% of the variance in PE class enjoyment. Findings suggest that efforts to enhance girls' self-efficacy and perceived benefits and to provide a supportive PE class environment that promotes gender equality can potentially increase PE class enjoyment among young girls. PMID:18431947

  20. 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

  1. 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. PMID:26193931

  2. 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

  3. HERG1 Channel Agonists and Cardiac Arrhythmia

    PubMed Central

    Sanguinetti, Michael

    2014-01-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  4. HERG1 channel agonists and cardiac arrhythmia.

    PubMed

    Sanguinetti, Michael C

    2014-04-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  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. 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…

  7. 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…

  8. 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

  9. 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…

  10. 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

  11. 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

  12. 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

  13. Melanocortin 1 Receptor Agonists Reduce Proteinuria

    PubMed Central

    Ebefors, Kerstin; Johansson, Martin E.; Stefánsson, Bergur; Granqvist, Anna; Arnadottir, Margret; Berg, Anna-Lena; Nyström, Jenny; Haraldsson, Börje

    2010-01-01

    Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. Recent reports suggest that treatment with adrenocorticotropic hormone (ACTH) reduces proteinuria, but the mechanism of action is unknown. Here, we identified gene expression of the melanocortin receptor MC1R in podocytes, glomerular endothelial cells, mesangial cells, and tubular epithelial cells. Podocytes expressed most MC1R protein, which colocalized with synaptopodin but not with an endothelial-specific lectin. We treated rats with passive Heymann nephritis (PHN) with MS05, a specific MC1R agonist, which significantly reduced proteinuria compared with untreated PHN rats (P < 0.01). Furthermore, treatment with MC1R agonists improved podocyte morphology and reduced oxidative stress. In summary, podocytes express MC1R, and MC1R agonism reduces proteinuria, improves glomerular morphology, and reduces oxidative stress in nephrotic rats with PHN. These data may explain the proteinuria-reducing effects of ACTH observed in patients with membranous nephropathy, and MC1R agonists may provide a new therapeutic option for these patients. PMID:20507942

  14. Intracameral phenylephrine and ketorolac injection (OMS302) for maintenance of intraoperative pupil diameter and reduction of postoperative pain in intraocular lens replacement with phacoemulsification

    PubMed Central

    Lindstrom, Richard L; Loden, James C; Walters, Thomas R; Dunn, Steven H; Whitaker, J Steven; Kim, Terry; Demopulos, Gregory A; Tjia, Khiun

    2014-01-01

    Background The purpose of this study was to evaluate the effect of OMS302 on intraoperative pupil diameter and early postoperative ocular pain when administered during intraocular lens replacement surgery. Methods Four hundred and six patients (406 study eyes; 202 in the OMS302 group and 204 in the placebo group) were entered into this randomized, double-masked, placebo-controlled, multicenter Phase III study, which was conducted at 15 centers in the USA and the Netherlands. The patients received OMS302 (60.75 mM phenylephrine HCl and 11.25 mM ketorolac tromethamine) or placebo in irrigation solution during intraocular lens replacement. No other changes in procedure were required. Coprimary endpoints were change in pupil diameter over time from surgical baseline to end of procedure and patient-reported ocular pain during the first 12 hours postoperatively. Secondary endpoints included additional measures of pupil diameter and postoperative pain. Results OMS302 was superior to placebo in maintaining intraoperative mydriasis, preventing miosis, and reducing postoperative pain. The weighted mean (standard error) difference (OMS302 – placebo) in change in the area under the curve from baseline for pupil diameter was 0.590 ([0.049]; 95% confidence interval 0.494 to 0.686; P<0.0001). For ocular pain scores, the weighted mean (standard error) difference was −4.580 ([1.192]; 95% confidence interval −6.917 to 2.244; P=0.0002). All secondary efficacy results favored OMS302. Specifically, analyses supporting prevention of miosis (patients with ≥6 mm pupil diameter at completion of cortical clean-up and those with <6 mm diameter at any time during surgery) were significant for OMS302 (95.9% versus 77.0% and 9.2% versus 38.0%, respectively; P<0.0001 for each endpoint). OMS302 was well tolerated and not associated with any unexpected adverse events. Conclusion OMS302 maintained mydriasis, prevented miosis, and reduced early postoperative pain when administered in

  15. Dopamine agonist: pathological gambling and hypersexuality.

    PubMed

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication. PMID:19536937

  16. Doubly excited 3Pe resonance states of two-electron positive ions in Debye plasmas

    NASA Astrophysics Data System (ADS)

    Hu, Xiao-Qing; Wang, Yang; Jiang, Zishi; Jiang, Pinghui; Kar, Sabyasachi

    2015-11-01

    We investigate the doubly excited 3Pe resonance states of two-electron positive ions Li+, Be2+, B3+, and C4+ by employing correlated exponential wave functions. In the framework of the stabilization method, we calculate two series (3pnp and 3dnd) of 3Pe resonances below the N = 3 threshold. The 3Pe resonance parameters (resonance energies and widths) are reported for the first time as a function of the screening parameter. For free-atomic cases, comparisons are made with the reported results and few resonance states are reported for the first time.

  17. 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

  18. Mechanisms of agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Lin, Hong; Strange, Philip G

    2004-12-01

    In this study, we investigated the biochemical mechanisms of agonist action at the G protein-coupled D2 dopamine receptor expressed in Chinese hamster ovary cells. Stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding by full and partial agonists was determined at different concentrations of [35S]GTPgammaS (0.1 and 10 nM) and in the presence of different concentrations of GDP. At both concentrations of [35S]GTPgammaS, increasing GDP decreased the [35S]GTPgammaS binding observed with maximally stimulating concentrations of agonist, with partial agonists exhibiting greater sensitivity to the effects of GDP than full agonists. The relative efficacy of partial agonists was greater at the lower GDP concentrations. Concentration-response experiments were performed for a range of agonists at the two [35S]GTPgammaS concentrations and with different concentrations of GDP. At 0.1 nM [35S]GTPgammaS, the potency of both full and partial agonists was dependent on the GDP concentration in the assays. At 10 nM [35S]GTPgammaS, the potency of full agonists exhibited a greater dependence on the GDP concentration, whereas the potency of partial agonists was virtually independent of GDP. We concluded that at the lower [35S]GTPgammaS concentration, the rate-determining step in G protein activation is the binding of [35S]GTPgammaS to the G protein. At the higher [35S]GTPgammaS concentration, for full agonists, [35S]GTPgammaS binding remains the slowest step, whereas for partial agonists, another (GDP-independent) step, probably ternary complex breakdown, becomes rate-determining. PMID:15340043

  19. Computational modeling toward understanding agonist binding on dopamine 3.

    PubMed

    Zhao, Yaxue; Lu, Xuefeng; Yang, Chao-Yie; Huang, Zhimin; Fu, Wei; Hou, Tingjun; Zhang, Jian

    2010-09-27

    The dopamine 3 (D3) receptor is a promising therapeutic target for the treatment of nervous system disorders, such as Parkinson's disease, and current research interests primarily focus on the discovery/design of potent D3 agonists. Herein, a well-designed computational protocol, which combines pharmacophore identification, homology modeling, molecular docking, and molecular dynamics (MD) simulations, was employed to understand the agonist binding on D3 aiming to provide insights into the development of novel potent D3 agonists. We (1) identified the chemical features required in effective D3 agonists by pharmacophore modeling based upon 18 known diverse D3 agonists; (2) constructed the three-dimensional (3D) structure of D3 based on homology modeling and the pharmacophore hypothesis; (3) identified the binding modes of the agonists to D3 by the correlation between the predicted binding free energies and the experimental values; and (4) investigated the induced fit of D3 upon agonist binding through MD simulations. The pharmacophore models of the D3 agonists and the 3D structure of D3 can be used for either ligand- or receptor-based drug design. Furthermore, the MD simulations further give the insight that the long and flexible EL2 acts as a "door" for agonist binding, and the "ionic lock" at the bottom of TM3 and TM6 is essential to transduce the activation signal. PMID:20695484

  20. Strategies for designing synthetic immune agonists.

    PubMed

    Wu, Tom Y-H

    2016-08-01

    Enhancing the immune system is a validated strategy to combat infectious disease, cancer and allergy. Nevertheless, the development of immune adjuvants has been hampered by safety concerns. Agents that can stimulate the immune system often bear structural similarities with pathogen-associated molecular patterns found in bacteria or viruses and are recognized by pattern recognition receptors (PRRs). Activation of these PRRs results in the immediate release of inflammatory cytokines, up-regulation of co-stimulatory molecules, and recruitment of innate immune cells. The distribution and duration of these early inflammatory events are crucial in the development of antigen-specific adaptive immunity in the forms of antibody and/or T cells capable of searching for and destroying the infectious pathogens or cancer cells. However, systemic activation of these PRRs is often poorly tolerated. Hence, different strategies have been employed to modify or deliver immune agonists in an attempt to control the early innate receptor activation through temporal or spatial restriction. These approaches include physicochemical manipulation, covalent conjugation, formulation and conditional activation/deactivation. This review will describe recent examples of discovery and optimization of synthetic immune agonists towards clinical application. PMID:27213842

  1. Proglumide exhibits delta opioid agonist properties.

    PubMed

    Rezvani, A; Stokes, K B; Rhoads, D L; Way, E L

    1987-01-01

    Recently, it was reported that proglumide, a cholecystokinin (CCK) antagonist, potentiates the analgetic effects of morphine and endogenous opioid peptides and reverses morphine tolerance by antagonizing the CCK system in the central nervous system of the rat. In order to provide additional insight into the mode of action of this agent, we assessed the effect of proglumide in the isolated guinea pig ileum and the mouse, rat and rabbit vas deferens. Furthermore, we studied the in vitro binding affinity of this substance to mouse brain synaptosomes. Our results show that proglumide inhibits, dose dependently, the electrically stimulated twitches in the mouse vas deferens and guinea pig ileum, but not in the rat or rabbit vas deferens. The inhibitory action of proglumide on the mouse vas deferens, but not on the guinea pig ileum, is antagonized by naloxone and by the selective delta-antagonist, ICI 174,864, in a competitive fashion. Other CCK antagonists were found to be devoid of such activity on the mouse vas deferens. In vitro binding studies showed that proglumide displaces D-ala-D-[leucine]5-enkephalin (DADLE), a delta agonist, but not ethylketocyclazocine (EKC), a preferentially selective kappa agonist. The effect of proglumide appeared to be elicited presynaptically since it did not alter the norepinephrine-induced contractions of the mouse vas deferens. Our results suggest that proglumide might exert its opiate-like effects by activation of delta-opioid receptors. PMID:3030338

  2. Chimpanzees Extract Social Information from Agonistic Screams

    PubMed Central

    Slocombe, Katie E.; Kaller, Tanja; Call, Josep; Zuberbühler, Klaus

    2010-01-01

    Chimpanzee (Pan troglodytes) agonistic screams are graded vocal signals that are produced in a context-specific manner. Screams given by aggressors and victims can be discriminated based on their acoustic structure but the mechanisms of listener comprehension of these calls are currently unknown. In this study, we show that chimpanzees extract social information from these vocal signals that, combined with their more general social knowledge, enables them to understand the nature of out-of-sight social interactions. In playback experiments, we broadcast congruent and incongruent sequences of agonistic calls and monitored the response of bystanders. Congruent sequences were in accordance with existing social dominance relations; incongruent ones violated them. Subjects looked significantly longer at incongruent sequences, despite them being acoustically less salient (fewer call types from fewer individuals) than congruent ones. We concluded that chimpanzees categorised an apparently simple acoustic signal into victim and aggressor screams and used pragmatics to form inferences about third-party interactions they could not see. PMID:20644722

  3. 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.

  4. Fluctuation measurements at c/{omega}{sub pe} spatial scales in a tokamak

    SciTech Connect

    Haines, E.J.; Tan, I.H.; Prager, S.C.

    1994-07-01

    Magnetic and electrostatic fluctuations have been measured at the short scale length of the collisionless skin depth (c/{omega}{sub pe} using small magnetic and electrostatic probes in the Tokapole II tokamak. For certain conditions and at high frequency (MHz range) the amplitude is observed to increase as wavelength is decreased toward the c/{omega}{sub pe} scale. Wavelength dependence is inferred from measurements with probes of varying sizes. The amplitude of the turbulence at the c/{omega}{sub pe} scale is smaller than the dominant low frequency turbulence, and is thus not relevant to transport in Tokapole II. Comparison with theoretical treatments of c/{omega}{sub pe} turbulence is discussed.

  5. 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.

  6. Molecular cloning and characterization of the glyceraldehyde-3-phosphate dehydrogenase gene from Penicillium expansum PE-12.

    PubMed

    Zhang, T; Qi, Z; Yu, Q S; Tang, K X

    2013-01-01

    Penicillium expansum produces large amounts of lipase, which is widely used in laundry detergent and leather industry. We isolated the glyceraldehyde-3-phosphate dehydrogenase gene (PeGPD) from P. expansum PE-12 through reverse transcriptase PCR and 5'-3' rapid amplification of cDNA ends (RACE-PCR). The gene is 1266 bp long, including an ORF of 1014 bp, encoding a polypeptide chain of 337 amino acids. A phylogenetic tree based on GPD proteins showed that P. expansum is close to Aspergillus species, but comparatively distant from P. marneffei. Southern blot results revealed a single copy of PeGPD, and expression analysis gave evidence of high expression levels. PeGPD genes have potential for genetic engineering of P. expansum for industrial lipase production. PMID:23420404

  7. 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.

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. 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. PMID:25684449

  14. 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)

  15. 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).

  16. Effect of PE on the structural evolution of iPP : analysis of a series of iPP-PE copolymers

    NASA Astrophysics Data System (ADS)

    Tenneti, Kishore; Tso, Chung; Li, Christopher

    2005-03-01

    The three different morphological forms of isotactic polypropylene (iPP), namely alpha, beta, and gamma, are well established. Alpha is the most common crystal phase while beta is metastable. The gamma form of iPP often exists as the minor component, intermixed with the alpha phase, during crystallization of copolymers at atmospheric pressures. A series of iPP-Polyethylene (PE) copolymers with varying percentages of PE have been investigated. Thermal and x-ray analysis reveal that as the PE content increases from 0 to 5 percent, gamma became the dominant phase. Single crystal morphology of the iPP-PE copolymers have been studied using TEM, SEM and AFM. The signature of alpha phase, the cross-hatch morphology, was observed in all the samples. Gamma single crystals were clearly observed like a ribbon shape and the center of the ribbon consisted of alpha lath. Fractal-like growth was also observed, presumably due to the thermal degradation of the polymer.

  17. 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...

  18. 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…

  19. Estrogen receptor beta agonists in neurobehavioral investigations.

    PubMed

    Choleris, Elena; Clipperton, Amy E; Phan, Anna; Kavaliers, Martin

    2008-07-01

    Neurobehavioral investigations into the functions of estrogen receptor (ER)alpha and ERbeta have utilized 'knockout' mice, phytoestrogens and, more recently, ER-specific agonists. Feeding, sexual, aggressive and social behavior, anxiety, depression, drug abuse, pain perception, and learning (and associated synaptic plasticity) are affected by ERalpha and ERbeta in a manner that is dependent upon the specific behavior studied, gender and developmental stage. Overall, ERalpha and ERbeta appear to function together to foster sociosexual behavior while inhibiting behaviors that, if occurring at the time of behavioral estrous, may compete with reproduction (eg, feeding). Recently developed pharmacological tools have limited selectivity and availability to the research community at large, as they are not commercially available. The development of highly selective, commercially available ERbeta-specific antagonists would greatly benefit preclinical and applied research. PMID:18600582

  20. Non-Benzodiazepine Receptor Agonists for Insomnia.

    PubMed

    Becker, Philip M; Somiah, Manya

    2015-03-01

    Because of proven efficacy, reduced side effects, and less concern about addiction, non-benzodiazepine receptor agonists (non-BzRA) have become the most commonly prescribed hypnotic agents to treat onset and maintenance insomnia. First-line treatment is cognitive-behavioral therapy. When pharmacologic treatment is indicated, non-BzRA are first-line agents for the short-term and long-term management of transient and chronic insomnia related to adjustment, psychophysiologic, primary, and secondary causation. In this article, the benefits and risks of non-BzRA are reviewed, and the selection of a hypnotic agent is defined, based on efficacy, pharmacologic profile, and adverse events. PMID:26055674

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. [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

  7. Risk versus benefit considerations for the beta(2)-agonists.

    PubMed

    Kelly, H William

    2006-09-01

    Short-acting beta(2)-agonists are the mainstay of therapy for acute bronchospasm associated with asthma and chronic obstructive pulmonary disease, whereas long-acting beta(2)-agonists are used in maintaining disease control in these respiratory disorders. This review describes and compares the pharmacology of the beta(2)-agonists and explains how these differences translate into differences in efficacy and beta(2)-adrenergic-mediated adverse effects. Questions commonly asked by clinicians regarding the efficacy and safety of short- and long-acting beta(2)-agonists include issues about cardiovascular effects, tolerance to their bronchodilator and bronchoprotective effects, blunting of albuterol response by long-acting beta(2)-agonists, potential masking of worsening asthma control, and the role of long-acting beta(2)-agonists as adjunctive therapy with inhaled corticosteroids in maintaining asthma control. Pharmacogenetics may play a role in determining which patients may be at risk for a reduced response to a beta(2)-agonist. The continued use of racemic albuterol, which contains a mixture of R-albuterol and S-albuterol, has been questioned because of data from preclinical and clinical studies suggesting that S-albuterol causes proinflammatory effects and may increase bronchial hyperreactivity. The preclinical and clinical effects of these two stereoisomers are reviewed. Data describing the efficacy and safety of levalbuterol (R-albuterol) and racemic albuterol are presented. PMID:16945063

  8. 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

  9. Effects of PE-TEOS process on O3-TEOS characteristics and device reliability

    NASA Astrophysics Data System (ADS)

    Jang, Syun-Ming; Lin, Yu-Min; Lee, Peter; Liu, L. M.; Yu, C. H.; Lei, Tan F.; Lin, M. S.

    1995-09-01

    This work studies the effect of PE-TEOS underlayer on O3-TEOS based intermetal dielectric (IMD) in terms of gap filling, moisture resistance, and device reliability. PE-TEOS films investigated here were formed by mixed-frequency plasma process and were differed by their reaction oxidizers and/or plasma powers. It is found that the bottom and sidewall step coverages of PE-TEOS vary with processing conditions, with both degrading as nitrogen content or film stress increases. By optimizing the underlayer thickness voidless gap fill has been achieved by O3-TEOS for 0.5 micrometers generation. To eliminate moisture absorption the deposited O3-TEOS was then integrated with SOG etchback for planarization. The integrated IMD has been evaluated by hot carrier stressing, which suggests that increasing PE-TEOS stress helps improve device reliability. For a fixed stress, the increased amount of oxygen or nitrogen also help inhibit hot carrier aging. To obtain best device reliability, a tradeoff exists between the moisture resistance and gap filling capability of PE-TEOS underlayer.

  10. 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

  11. 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

  12. Dopamine agonist withdrawal syndrome: implications for patient care.

    PubMed

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper. PMID:23686524

  13. Supra-physiological efficacy at GPCRs: superstition or super agonists?

    PubMed

    Langmead, Christopher J; Christopoulos, Arthur

    2013-05-01

    The concept of 'super agonism' has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on this phenomenon and indicate that super agonists may be more than superstition. PMID:23441648

  14. 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

  15. VelProbePE: An automated spreadsheet program for interpreting point velocity probe breakthrough curves

    NASA Astrophysics Data System (ADS)

    Schillig, P. C.

    2012-02-01

    Groundwater velocity is an important parameter for determining the fate and transport of contaminants. Recently developed point velocity probes (PVPs) were designed to provide centimeter-scale measurements of the direction and magnitude of groundwater velocity based on the injection and electrical detection of a small, saline tracer. The code reported here for velocity probe parameter estimation (VelProbePE) was designed using Visual Basic for Applications (VBA) in Microsoft Excel for processing and interpreting tracer breakthrough curves specifically for PVP applications. VelProbePE contains multiple, autoinitializing user forms that guide the user through the data-processing steps. The program allows for the rapid processing and editing of up to 16 detector signals in a single workbook. VelProbePE uses simplex optimization to calculate the intermediate parameters required for the estimation of velocity magnitude and direction.

  16. 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 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

  17. Relamorelin: A Novel Gastrocolokinetic Synthetic Ghrelin Agonist

    PubMed Central

    Camilleri, Michael; Acosta, Andres

    2015-01-01

    Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM-131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)-1a (also called the ghrelin) receptor with approximately 6-fold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin. In this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a pre-specified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders. PMID:25545036

  18. Overexpression of PeRHD3 alters the root architecture in Populus.

    PubMed

    Xu, Meng; Xie, Wenfan; Huang, Minren

    2012-07-27

    Adventitious rooting is essential for the vegetative propagation of economically important woody species. A better understanding of the genetic and physiological mechanisms that promote or hinder rooting will enhance the potential for successful commercial deployment of trees. ROOT HAIR DEFECTIVE 3 (RHD3), a large GTP-binding protein, is ubiquitously expressed in plants. Our previous microarray study identified differential expression patterns of genes belonging to the RHD3 family during adventitious root development from hardwood cuttings, and indicated that the RHD3 genes were involved in adventitious rooting in Populus. In this study, we cloned and characterized cDNAs of the two Populus RHD3 genes, designated as PeRHD3a and PeRHD3b. Transcripts encoded by the two genes were detected in roots, stems, leaves and petioles. To characterize the cellular functions of the genes, Agrobacterium tumifaciens was used to transform poplar with a vector that places expression of the target gene under the control of the strong constitutive promoter, Cauliflower Mosaic Virus 35S (Pro35S) promoter. Both PeRHD3a transgenic lines and PeRHD3b transgenic lines showed very similar phenotypic characteristics. Overexpression of PeRHD3a or PeRHD3b in poplar plants resulted in the formation of only a single prominent adventitious root with well-developed lateral roots, characteristic abnormalities in the root tip, and longer and more plentiful root hairs. These results imply that RHD3 may control adventitious and lateral root formation, as well as root hair development by regulating anisotropic cell expansion. PMID:22732403

  19. 2PE-STED microscopy with a single Ti:sapphire laser for reduced illumination.

    PubMed

    Li, Qifeng; Wang, Yang; Chen, Da; Wu, Sherry S H

    2014-01-01

    We reported a new effective approach to carry out two-photon excitation stimulated emission depletion (2PE-STED) microscopy using a single Ti:sapphire laser system. With an acoustic-optic Bragg cell, the modulated-CW 2PE STED microscope had the benefits of both CW and pulse approaches: lower input power, simple optical scheme and no complicated synchronization. Additionally, it also took advantages of fluorescence yield increasing. The sub-diffraction-limit resolution was demonstrated using ATTO 425-tagged clathrin-coated vesicles. PMID:24516661

  20. 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.

  1. Selecting agonists from single cells infected with combinatorial antibody libraries.

    PubMed

    Zhang, Hongkai; Yea, Kyungmoo; Xie, Jia; Ruiz, Diana; Wilson, Ian A; Lerner, Richard A

    2013-05-23

    We describe a system for direct selection of antibodies that are receptor agonists. Combinatorial antibody libraries in lentiviruses are used to infect eukaryotic cells that contain a fluorescent reporter system coupled to the receptor for which receptor agonist antibodies are sought. In this embodiment of the method, very large numbers of candidate antibodies expressing lentivirus and eukaryotic reporter cells are packaged together in a format where each is capable of replication, thereby forging a direct link between genotype and phenotype. Following infection, cells that fluoresce are sorted and the integrated genes encoding the agonist antibodies recovered. We validated the system by illustrating its ability to generate rapidly potent antibody agonists that are complete thrombopoietin phenocopies. The system should be generalizable to any pathway where its activation can be linked to production of a selectable phenotype. PMID:23706638

  2. Therapeutic Potential of 5-HT6 Receptor Agonists.

    PubMed

    Karila, Delphine; Freret, Thomas; Bouet, Valentine; Boulouard, Michel; Dallemagne, Patrick; Rochais, Christophe

    2015-10-22

    Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox. PMID:26099069

  3. Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

    PubMed

    Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. PMID:20579229

  4. Selective 5-HT2C agonists as potential antidepressants.

    PubMed

    Leysen, D C

    1999-02-01

    The antidepressants currently used need improvement, especially in terms of efficacy, relapse rate and onset of action. In this review the clinical and experimental data which support the rationale for 5-HT2C agonists in the treatment of depression are listed. Next, the results obtained with the non-selective 5-HT2C agonists on the market and in clinical development are described. Finally, the preclinical data on the more selective 5-HT2C agonists are summarized. These recent preclinical results reveal a greater potency and effect size compared to fluoxetine, good tolerability and no evidence of tolerance development. Selective 5-HT2C agonists might become innovative drugs for the treatment of depression, panic, obsessive-compulsive disorder (OCD), some forms of aggression and eating disorders. PMID:16160946

  5. Agonist pharmacology of two Drosophila GABA receptor splice variants.

    PubMed Central

    Hosie, A. M.; Sattelle, D. B.

    1996-01-01

    1. The Drosophila melanogaster gamma-aminobutyric acid (GABA) receptor subunits, RDLac and DRC 17-1-2, form functional homo-oligomeric receptors when heterologously expressed in Xenopus laevis oocytes. The subunits differ in only 17 amino acids, principally in regions of the N-terminal domain which determine agonist pharmacology in vertebrate ionotropic neurotransmitter receptors. A range of conformationally restricted GABA analogues were tested on the two homo-oligomers and their agonists pharmacology compared with that of insect and vertebrate iontropic GABA receptors. 2. The actions of GABA, isoguvacine and isonipecotic acid on RDLac and DRC 17-1-2 homo-oligomers were compared, by use of two-electrode voltage-clamp. All three compounds were full agonists of both receptors, but were 4-6 fold less potent agonists of DRC 17-1-2 homo-oligomers than of RDLac. However, the relative potencies of these agonists on each receptor were very similar. 3. A more complete agonist profile was established for RDLac homo-oligomers. The most potent agonists of these receptors were GABA, muscimol and trans-aminocrotonic acid (TACA), which were approximately equipotent. RDLac homo-oligomers were fully activated by a range of GABA analogues, with the order of potency: GABA > ZAPA ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid) > isoguvacine > imidazole-4-acetic acid > or = isonipecotic acid > or = cis-aminocrotonic acid (CACA) > beta-alanine. 3-Aminopropane sulphonic acid (3-APS), a partial agonist of RDLac homo-oligomers, was the weakest agonist tested and 100 fold less potent than GABA. 4. SR95531, an antagonist of vertebrate GABAA receptors, competitively inhibited the GABA responses of RDLac homo-oligomers, which have previously been found to insensitive to bicuculline. However, its potency (IC50 500 microM) was much reduced when compared to GABAA receptors. 5. The agonist pharmacology of Drosophila RDLac homo-oligomers exhibits aspects of the characteristic pharmacology of

  6. Sleep attacks in patients taking dopamine agonists: review

    PubMed Central

    Homann, Carl Nikolaus; Wenzel, Karoline; Suppan, Klaudia; Ivanic, Gerd; Kriechbaum, Norbert; Crevenna, Richard; Ott, Erwin

    2002-01-01

    Objectives To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinson's disease, the type of drugs implicated, and strategies for prevention and treatment. Design Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic-like attacks were discussed in patients with Parkinson's disease. Results 124 patients with sleep events were found in 20 publications. Overall, 6.6% of patients taking dopamine agonists who attended movement disorder centres had sleep events. Men were over-represented. Sleep events occurred at both high and low doses of the drugs, with different durations of treatment (0-20 years), and with or without preceding signs of tiredness. Sleep attacks are a class effect, having been found in patients taking the following dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists (apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32, ropinirole in 38). Reports suggest two distinct types of events: those of sudden onset without warning and those of slow onset with prodrome drowsiness. Conclusion Insufficient data are available to provide effective guidelines for prevention and treatment of sleep events in patients taking dopamine agonists for Parkinson's disease. Prospective population based studies are needed to provide this information. What is already known on this topicCar crashes in patients with Parkinson's disease have been associated with sleep attacks caused by the dopamine agonists pramipexole and ropiniroleWhether sleep attacks exist, their connection with certain agonists, prevention or treatment, and the justification of legal actions are controversialWhat this study addsSleep attacks as a phenomenon distinct from normal somnolence really do existThey are a class effect of all dopamine drugsEffective prevention and treatment

  7. Identification of M-CSF agonists and antagonists

    DOEpatents

    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.

  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. [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

  10. 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

  11. Mechanisms of inverse agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Strange, Philip G

    2005-05-01

    Mechanisms of inverse agonist action at the D2(short) dopamine receptor have been examined. Discrimination of G-protein-coupled and -uncoupled forms of the receptor by inverse agonists was examined in competition ligand-binding studies versus the agonist [3H]NPA at a concentration labelling both G-protein-coupled and -uncoupled receptors. Competition of inverse agonists versus [3H]NPA gave data that were fitted best by a two-binding site model in the absence of GTP but by a one-binding site model in the presence of GTP. K(i) values were derived from the competition data for binding of the inverse agonists to G-protein-uncoupled and -coupled receptors. K(coupled) and K(uncoupled) were statistically different for the set of compounds tested (ANOVA) but the individual values were different in a post hoc test only for (+)-butaclamol. These observations were supported by simulations of these competition experiments according to the extended ternary complex model. Inverse agonist efficacy of the ligands was assessed from their ability to reduce agonist-independent [35S]GTP gamma S binding to varying degrees in concentration-response curves. Inverse agonism by (+)-butaclamol and spiperone occurred at higher potency when GDP was added to assays, whereas the potency of (-)-sulpiride was unaffected. These data show that some inverse agonists ((+)-butaclamol, spiperone) achieve inverse agonism by stabilising the uncoupled form of the receptor at the expense of the coupled form. For other compounds tested, we were unable to define the mechanism. PMID:15735658

  12. Differential effects of AMPK agonists on cell growth and metabolism

    PubMed Central

    Vincent, Emma E.; Coelho, Paula P.; Blagih, Julianna; Griss, Takla; Viollet, Benoit; Jones, Russell G.

    2016-01-01

    As a sensor of cellular energy status, the AMP-activated protein kinase (AMPK) is believed to act in opposition to the metabolic phenotypes favored by proliferating tumor cells. Consequently, compounds known to activate AMPK have been proposed as cancer therapeutics. However, the extent to which the anti-neoplastic properties of these agonists are mediated by AMPK is unclear. Here we examined the AMPK-dependence of six commonly used AMPK agonists (metformin, phenformin, AICAR, 2DG, salicylate and A-769662) and their influence on cellular processes often deregulated in tumor cells. We demonstrate that the majority of these agonists display AMPK-independent effects on cell proliferation and metabolism with only the synthetic activator, A-769662, exerting AMPK-dependent effects on these processes. We find that A-769662 promotes an AMPK-dependent increase in mitochondrial spare respiratory capacity (SRC). Finally, contrary to the view of AMPK activity being tumor suppressive, we find A-769662 confers a selective proliferative advantage to tumor cells growing under nutrient deprivation. Our results indicate that many of the anti-growth properties of these agonists cannot be attributed to AMPK activity in cells, and thus any observed effects using these agonists should be confirmed using AMPK-deficient cells. Ultimately, our data urge caution, not only regarding the type of AMPK agonist proposed for cancer treatment, but also the context in which they are used. PMID:25241895

  13. 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

  14. 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

  15. 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…

  16. 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…

  17. 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.

  18. 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,…

  19. 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…

  20. Carex opaca (Hermann) P.E. Pothrock & Reznicek (CYPERACEAE) new to North Carolina

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Carex opaca (F. J. Hermann) P.E. Rothrock & Reznicek (CYPERACEAE) is reported from two sites in North Carolina. These are the first records of C. opaca from North Carolina and represent easternmost stations for this species in the United States. Previously C. opaca was known from Arkansas, Illino...

  1. 23 CFR 661.33 - What percentage of IRRBP funding is available for PE and construction?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 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...

  2. 23 CFR 661.33 - What percentage of IRRBP funding is available for PE and construction?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 23 Highways 1 2011-04-01 2011-04-01 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...

  3. 23 CFR 661.33 - What percentage of IRRBP funding is available for PE and construction?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 23 Highways 1 2014-04-01 2014-04-01 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...

  4. 23 CFR 661.33 - What percentage of IRRBP funding is available for PE and construction?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 23 Highways 1 2012-04-01 2012-04-01 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...

  5. 23 CFR 661.33 - What percentage of IRRBP funding is available for PE and construction?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 23 Highways 1 2013-04-01 2013-04-01 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...

  6. 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

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

    PubMed

    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

  8. 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…

  9. 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…

  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. 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…

  12. 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…

  13. 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

  14. 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.…

  15. 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...

  16. 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...

  17. 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…

  18. "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…

  19. Cloning of the Cryptochrome-Encoding PeCRY1 Gene from Populus euphratica and Functional Analysis in Arabidopsis

    PubMed Central

    Mao, Ke; Jiang, Libo; Bo, Wenhao; Xu, Fang; Wu, Rongling

    2014-01-01

    Cryptochromes are photolyase-like blue/UV-A light receptors that evolved from photolyases. In plants, cryptochromes regulate various aspects of plant growth and development. Despite of their involvement in the control of important plant traits, however, most studies on cryptochromes have focused on lower plants and herbaceous crops, and no data on cryptochrome function are available for forest trees. In this study, we isolated a cryptochrome gene, PeCRY1, from Euphrates poplar (Populus euphratica), and analyzed its structure and function in detail. The deduced PeCRY1 amino acid sequence contained a conserved N-terminal photolyase-homologous region (PHR) domain as well as a C-terminal DQXVP-acidic-STAES (DAS) domain. Secondary and tertiary structure analysis showed that PeCRY1 shares high similarity with AtCRY1 from Arabidopsis thaliana. PeCRY1 expression was upregulated at the mRNA level by light. Using heterologous expression in Arabidopsis, we showed that PeCRY1 overexpression rescued the cry1 mutant phenotype. In addition, PeCRY1 overexpression inhibited hypocotyl elongation, promoted root growth, and enhanced anthocyanin accumulation in wild-type background seedlings grown under blue light. Furthermore, we examined the interaction between PeCRY1 and AtCOP1 using a bimolecular fluorescence complementation (BiFc) assay. Our data provide evidence for the involvement of PeCRY1 in the control of photomorphogenesis in poplar. PMID:25503486

  20. "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…

  1. (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…

  2. 78 FR 56690 - PE Hydro Generation, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-13

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission PE Hydro Generation, LLC; Supplemental Notice That Initial Market-Based Rate...-referenced proceeding, of PE Hydro Generation, LLC's application for market-based rate authority, with...

  3. Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist

    PubMed Central

    Taylor, A M W; Roberts, K W; Pradhan, A A; Akbari, H A; Walwyn, W; Lutfy, K; Carroll, F I; Cahill, C M; Evans, C J

    2015-01-01

    BACKGROUND AND PURPOSE The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg−1), unmasked etorphine (3 mg·kg−1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg−1) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg−1) and diazepam (1 mg·kg−1). CONCLUSIONS AND IMPLICATIONS Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles

  4. 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

  5. Agonists and antagonists for P2 receptors

    PubMed Central

    Jacobson, Kenneth A.; Costanzi, Stefano; Joshi, Bhalchandra V.; Besada, Pedro; Shin, Dae Hong; Ko, Hyojin; Ivanov, Andrei A.; Mamedova, Liaman

    2015-01-01

    Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. PMID:16805423

  6. 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

  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. 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

  9. 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.

  10. 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

  11. 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

  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. 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

  14. Supra-physiological efficacy at GPCRs: superstition or super agonists?

    PubMed Central

    Langmead, Christopher J; Christopoulos, Arthur

    2013-01-01

    The concept of ‘super agonism’ has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on this phenomenon and indicate that super agonists may be more than superstition. Linked Article This article is a commentary on Schrage et al., pp. 357–370 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12003 PMID:23441648

  15. Principles of agonist recognition in Cys-loop receptors

    PubMed Central

    Lynagh, Timothy; Pless, Stephan A.

    2014-01-01

    Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine, and GABA. After the term “chemoreceptor” emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies, and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands. PMID:24795655

  16. Alpha-2 agonists as pain therapy in horses.

    PubMed

    Valverde, Alexander

    2010-12-01

    Alpha-2 agonists, such as xylazine, clonidine, romifidine, detomidine, medetomidine, and dexmedetomidine, are potent analgesic drugs that also induce physiologic and behavioral changes, such as hypertension, bradycardia, atrioventricular block, excessive sedation and ataxia, all of which can potentially limit their systemic use as analgesics in some clinical cases. The use of medetomidine and dexmetomidine has been introduced for equine anesthesia/analgesia, and although not approved in this species, their increased specificity for alpha-2 receptors may offer some potential advantages over the traditional alpha-2 agonists. Similarly, other routes of administration and benefits of alpha-2 agonists are recognized in the human and laboratory animal literature, which may prove useful in the equine patient if validated in the near future. This review presents this relevant information. PMID:21056297

  17. 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

  18. TANAMI blazars in the IceCube PeV-neutrino fields

    NASA Astrophysics Data System (ADS)

    Krauß, F.; Kadler, M.; Mannheim, K.; Schulz, R.; Trüstedt, J.; Wilms, J.; Ojha, R.; Ros, E.; Anton, G.; Baumgartner, W.; Beuchert, T.; Blanchard, J.; Bürkel, C.; Carpenter, B.; Eberl, T.; Edwards, P. G.; Eisenacher, D.; Elsässer, D.; Fehn, K.; Fritsch, U.; Gehrels, N.; Gräfe, C.; Großberger, C.; Hase, H.; Horiuchi, S.; James, C.; Kappes, A.; Katz, U.; Kreikenbohm, A.; Kreykenbohm, I.; Langejahn, M.; Leiter, K.; Litzinger, E.; Lovell, J. E. J.; Müller, C.; Phillips, C.; Plötz, C.; Quick, J.; Steinbring, T.; Stevens, J.; Thompson, D. J.; Tzioumis, A. K.

    2014-06-01

    The IceCube Collaboration has announced the discovery of a neutrino flux in excess of the atmospheric background. Owing to the steeply falling atmospheric background spectrum, events at PeV energies most likely have an extraterrestrial origin. We present the multiwavelength properties of the six radio-brightest blazars that are positionally coincident with these events using contemporaneous data of the TANAMI blazar sample, including high-resolution images and spectral energy distributions. Assuming the X-ray to γ-ray emission originates in the photoproduction of pions by accelerated protons, the integrated predicted neutrino luminosity of these sources is high enough to explain the two detected PeV events. Tables 1-3 are available in electronic form at http://www.aanda.org

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. Piperidine derivatives as nonprostanoid IP receptor agonists 2.

    PubMed

    Hayashi, Ryoji; Ito, Hiroaki; Ishigaki, Takeshi; Morita, Yasuhiro; Miyamoto, Mitsuko; Isogaya, Masafumi

    2016-06-15

    We searched for a strong and selective nonprostanoid IP agonist bearing piperidine and benzanilide moieties. Through optimization of substituents on the benzanilide moiety, the crucial part of the agonist, 43 (2-((1-(2-(N-(4-tolyl)benzo[d][1,3]dioxole-5-carboxamido)ethyl)piperidin-4-yl)oxy)acetic acid monohydrate monohydrochloride) was discovered and exhibited strong platelet aggregation inhibition (IC50=21nM) and 100-fold selectivity for IP receptor over other PG receptors. The systemic exposure level and bioavailability after oral administration of 43 were also good in dog. PMID:27133594

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Cortical connectivity suggests a role in limb coordination for macaque area PE of the superior parietal cortex.

    PubMed

    Bakola, Sophia; Passarelli, Lauretta; Gamberini, Michela; Fattori, Patrizia; Galletti, Claudio

    2013-04-10

    In macaques, superior parietal lobule area 5 has been described as occupying an extensive region, which includes the caudal half of the postcentral convexity as well as the medial bank of the intraparietal sulcus. Modern neuroanatomical methods have allowed the identification of various areas within this region. In the present study, we investigated the corticocortical afferent projections of one of these subdivisions, area PE. Our results demonstrate that PE, defined as a single architectonic area that contains a topographic map of the body, forms specific connections with somatic and motor fields. Thus, PE receives major afferents from parietal areas, mainly area 2, PEc, several areas in the medial bank of the intraparietal sulcus, opercular areas PGop/PFop, and the retroinsular area, frontal afferents from the primary motor cortex, the supplementary motor area, and the caudal subdivision of dorsal premotor cortex, as well as afferents from cingulate areas PEci, 23, and 24. The presence and relative strength of these connections depend on the location of injection sites, so that lateral PE receives preferential input from anterior sectors of the medial bank of intraparietal sulcus and from the ventral premotor cortex, whereas medial PE forms denser connections with area PEc and motor fields. In contrast with other posterior parietal areas, there are no projections to PE from occipital or prefrontal cortices. Overall, the sensory and motor afferents to PE are consistent with functions in goal-directed movement but also hint at a wider variety of motor coordination roles. PMID:23575861

  12. Star-forming Galaxies as the Origin of the IceCube PeV Neutrinos

    NASA Astrophysics Data System (ADS)

    Chang, Xiao-Chuan; Liu, Ruo-Yu; Wang, Xiang-Yu

    2015-06-01

    Star-forming galaxies, due to their high star formation rates, and hence large number of supernova remnants (SNRs) therein, are huge reservoirs of cosmic rays (CRs). These CRs collide with gases in galaxies and produce high-energy neutrinos through proton-proton collisions. In this paper, we calculate the neutrino production efficiency in star-forming galaxies by considering realistic galaxy properties, such as the gas density and galactic wind in star-forming galaxies. To calculate the accumulated neutrino flux, we use the infrared luminosity function of star-forming galaxies recently obtained by the Herschel PEP/HerMES survey. The intensity of CRs producing PeV neutrinos in star-forming galaxies is normalized with the observed CR flux at EeV (1 EeV = {{10}18} eV), assuming that SNR or hypernova remnants in star-forming galaxies can accelerate protons to EeV energies. Our calculations show that the accumulated neutrino emission produced by CRs in star-forming galaxies can account for the flux and spectrum of the sub-PeV/PeV neutrinos under reasonable assumptions on the CR confinement time in these galaxies.

  13. 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

  14. 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. PMID:26595505

  15. 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.

  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. 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.

  18. Mycobacterium tuberculosis PE9 protein has high activity binding peptides which inhibit target cell invasion.

    PubMed

    Díaz, Diana P; Ocampo, Marisol; Pabón, Laura; Herrera, Chonny; Patarroyo, Manuel A; Munoz, Marina; Patarroyo, Manuel E

    2016-05-01

    PE/PPE proteins are involved in several processes during Mycobacterium tuberculosis (Mtb) infection of target cells; studying them is extremely interesting as they are the only ones from the Mycobacterium genus, they abound in pathogenic species such as Mtb and their function remains yet unknown. The PE9 protein (Rv1088) was characterised, the rv1088 gene was identified by PCR in Mtb complex strains and its expression and localisation on mycobacterial surface was confirmed by Western blot and immunoelectron microscopy. Bioinformatics tools were used for predicting PE9 protein structural aspects and experimental study involved the circular dichroism of synthetic peptides. The peptides were tested in binding assays involving U937 and A549 cells; two high activity binding peptides (HABPs) were found for both cell lines (39226-(1)MSYMIATPAALTAAATDIDGI(21) and 39232-(125)YQRHFGTGGQPEFRQHSEHRR(144)), one for U937 (39231-(104)YAGAGRRQRRRRSGDGQWRLRQ(124)) and one for A549 (39230-(83)YGTGVFRRRRGRQTVTAAEHRA(103)). HABP 39232 inhibited mycobacterial entry to A549 cells (∼70%) and U937 cells (∼50%), peptides 39226 and 39231 inhibited entry to U937 cells (∼60% and 80%, respectively) and peptide 39230 inhibited entry to A549 cells (∼60%). This emphasised HABPs' functional importance in recognition between Mtb H37Rv and target cell receptors. These peptide sequences could be involved in invasion and were recognised by the host's immune system, thereby highlighting their use when designing an efficient anti-tuberculosis multiantigenic vaccine. PMID:26851205

  19. Proceedings of the Inaugural Pediatric Dermatology Research Alliance (PeDRA) Conference

    PubMed Central

    Siegel, Dawn H.; Choate, Keith; Drolet, Beth A.; Frieden, Ilona J.; Teng, Joyce M.; Tom, Wynnis; Williams, Mary; Eichenfield, Lawrence F.; Paller, Amy S.

    2014-01-01

    Abstract/Statement of the problem Skin disease research involving children currently faces several major hurdles and as a result, many therapies are only available for off-label use in children and many of the most pressing clinical needs of our pediatric population remain unsolved. A strategic planning committee of the Society for Pediatric Dermatology (SPD) identified the need for an organized, inclusive research alliance to augment the resources of individual practitioners and pre-existing smaller collaborative groups and facilitate robust, multicenter basic, translational, and clinical research and therapeutic trials. A December 2011 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Roundtable on Pediatric Dermatology further detailed the therapeutic gaps and barriers to translation of scientific advances to clinical practice. Building on these forums, in July 2012, a group of interested investigators met in Monterey, CA to develop the infrastructure for collaborative pediatric skin research, now called the Pediatric Dermatology Research Alliance (PeDRA). The vision of PeDRA is to create sustainable collaborative research networks to better understand, prevent, treat and cure dermatologic diseases in children. From that starting point, subcommittees and expert members were added, stakeholders identified, and seed funding garnered, with the first PeDRA stand-alone research meeting* realized in Chicago, IL in October 2013. PMID:25318428

  20. 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.

  1. Pyrrolo- and Pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

    PubMed Central

    Kumar, V.; Clark, M.J.; Traynor, J.R.; Lewis, J.W.; Husbands, S.M.

    2014-01-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse. PMID:24973818

  2. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    PubMed

    Kumar, V; Clark, M J; Traynor, J R; Lewis, J W; Husbands, S M

    2014-08-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse. PMID:24973818

  3. 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

  4. 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

  5. PE859, a Novel Tau Aggregation Inhibitor, Reduces Aggregated Tau and Prevents Onset and Progression of Neural Dysfunction In Vivo

    PubMed Central

    Okuda, Michiaki; Hijikuro, Ichiro; Fujita, Yuki; Wu, Xiaofeng; Nakayama, Shinichi; Sakata, Yoko; Noguchi, Yuji; Ogo, Makoto; Akasofu, Shigeru; Ito, Yoshimasa; Soeda, Yoshiyuki; Tsuchiya, Nobuhiko; Tanaka, Naoki; Takahashi, Takashi; Sugimoto, Hachiro

    2015-01-01

    In tauopathies, a neural microtubule-associated protein tau (MAPT) is abnormally aggregated and forms neurofibrillary tangle. Therefore, inhibition of the tau aggregation is one of the key approaches for the treatment of these diseases. Here, we have identified a novel tau aggregation inhibitor, PE859. An oral administration of PE859 resulted in the significant reduction of sarkosyl-insoluble aggregated tau along with the prevention of onset and progression of the motor dysfunction in JNPL3 P301L-mutated human tau transgenic mice. These results suggest that PE859 is useful for the treatment of tauopathies. PMID:25659102

  6. 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

  7. 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

  8. Development and Validation of a High-Performance Thin-Layer Chromatographic Method for the Simultaneous Determination of Two Binary Mixtures Containing Ketorolac Tromethamine with Phenylephrine Hydrochloride and with Febuxostat.

    PubMed

    El Yazbi, Fawzy A; Hassan, Ekram M; Khamis, Essam F; Ragab, Marwa A A; Hamdy, Mohamed M A

    2016-01-01

    A validated and highly selective high-performance thin-layer chromatography (HPTLC) method was developed for the determination of ketorolac tromethamine (KTC) with phenylephrine hydrochloride (PHE) (Mixture 1) and with febuxostat (FBX) (Mixture 2) in bulk drug and in combined dosage forms. The proposed method was based on HPTLC separation of the drugs followed by densitometric measurements of their spots at 273 and 320 nm for Mixtures 1 and 2, respectively. The separation was carried out on Merck HPTLC aluminum sheets of silica gel 60 F254 using chloroform-methanol-ammonia (7:3:0.1, v/v) and (7.5:2.5:0.1, v/v) as mobile phase for KTC/PHE and KTC/FBX mixtures, respectively. Linear regression lines were obtained over the concentration ranges 0.20-0.60 and 0.60-1.95 µg band(-1)for KTC and PHE (Mixture 1), respectively, and 0.10-1.00 and 0.25-2.50 µg band(-1) for KTC and FBX (Mixture 2), respectively, with correlation coefficients higher than 0.999. The method was successfully applied to the analysis of the two drugs in their synthetic mixtures and in their dosage forms. The mean percentage recoveries were in the range of 98-102%, and the RSD did not exceed 2%. The method was validated according to ICH guidelines and showed good performances in terms of linearity, sensitivity, precision, accuracy and stability. PMID:26847918

  9. Synthetic RORγt Agonists Enhance Protective Immunity.

    PubMed

    Chang, Mi Ra; Dharmarajan, Venkatasubramanian; Doebelin, Christelle; Garcia-Ordonez, Ruben D; Novick, Scott J; Kuruvilla, Dana S; Kamenecka, Theodore M; Griffin, Patrick R

    2016-04-15

    The T cell specific RORγ isoform RORγt has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of TH17 and TC17 cells, cells that have demonstrated antitumor efficacy. RORγt controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of RORγt have been shown to increase the basal activity of RORγt enhancing TH17 cell proliferation. Here, we show that activation of RORγt using synthetic agonists drives proliferation of TH17 cells while decreasing levels of the immune checkpoint protein PD-1, a mechanism that should enhance antitumor immunity while blunting tumor associated adaptive immune resistance. Interestingly, putative endogenous agonists drive proliferation of TH17 cells but do not repress PD-1. These findings suggest that synthetic agonists of RORγt should activate TC17/TH17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer). Enhanced immunity and blockage of immune checkpoints has transformed cancer treatment; thus such a molecule would provide a unique approach for the treatment of cancer. PMID:26785144

  10. Amphetamine- type reinforcement by dopaminergic agonists in the rat.

    PubMed

    Yokel, R A; Wise, R A

    1978-07-19

    Intravenous self-administration of d-amphetamine (0.25 mg/kg/injection) decreased in a dose-related fashion after injections of the dopaminergic agonists apomorphine and piribedil. The dopaminergic agonists appear to suppress amphetamine intake in the same way as do 'free' amphetamine injections, by extending drug satiation in a given interresponse period. Clonidine, an alpha noradrenergic agonist, did not have similar effects. Apomorphine and piribedil did not increase 14C-amphetamine levels in rat brains, nor did they retard disappearance of 14C-amphetamine; thus their amphetamine-like effects are not due to alterations of amphetamine metabolism. Rats responding for amphetamine continued to respond for apomorphine or peribedil when the latter drugs were substituted for the former. Rats experienced in amphetamine self-administration readily initiated and maintained responding for apomorphine and piribedil. The dopaminergic blocker (+)-butaclamol disrupted responding for apomorphine and piribedil, although it produced no marked increase in responding for the dopaminergic agonists, as it does for amphetamine. These data add to the evidence that actions in the dopaminergic synapse account for amphetamine's reinforcing properties. PMID:98800

  11. Alkaloid delta agonist BW373U86 increases hypoxic tolerance.

    PubMed

    Bofetiado, D M; Mayfield, K P; D'Alecy, L G

    1996-06-01

    Activation of delta opioid receptors increases survival time during acute, lethal hypoxia in mice. delta Agonists therefore present a promising avenue for therapeutic application to reduce the morbidity and mortality associated with clinical hypoxia in settings such as drowning, head injury apnea, and complicated childbirths. However, most delta agonists now available are peptides, and may have limited clinical utility. In the present study, we evaluate the neuroprotective ability of an alkaloid delta agonist, BW373U86. Alkaloid compounds, due to increased stability and increased systemic distribution, may be more favorable for clinical use. We found that BW373U86, like the peptide delta agonist, DPDPE ([D-Pen2, D-Pen5]-enkephalin), increases survival time of mice during lethal hypoxia. The mechanism of neuroprotection induced by delta receptor activation appears to involve decreasing body temperature. Further, using selective opioid receptor antagonists, it appears that BW373U86 exerts these neuroprotective effects by acting at delta-opioid receptors. PMID:8638797

  12. The Agonistic Approach: Reframing Resistance in Qualitative Research

    ERIC Educational Resources Information Center

    Vitus, Kathrine

    2008-01-01

    The agonistic approach--aimed at embracing opposing perspectives as part of a qualitative research process and acknowledging that process as fundamentally political--sheds light on both the construction of and the resistance to research identities. This approach involves reflexively embedding interview situations into the ethnographic context as a…

  13. [Alpha-2 adrenoreceptor agonists in anaesthesia and intensive care medicine].

    PubMed

    Mavropoulos, G; Minguet, G; Brichant, J F

    2014-02-01

    Alpha-2 adrenoreceptor agonists have long been used in the treatment of arterial hypertension. However, in that indication they have progressively been replaced by antihypertensive drugs with a more interesting therapeutic profile. Nonetheless, pharmacological activation of alpha-2 adrenoreceptors leads to a variety of clinical effects that are of major interest for anaesthesia and intensive care practice. Indeed, the sedative and analgesic properties of alpha-2 adrenoreceptor agonists allow a reduction of hypnotic and opioid needs during general anaesthesia. In addition, they induce a down-regulation of the level of consciousness comparable to that of natural slow-wave sleep during post-anaesthesia and intensive care unit stay. These drugs may also prevent some deleterious effects of the sympathetic discharge in response to surgical stress. Furthermore, alpha-2 adrenoreceptor agonists are potent adjuncts for locoregional anaesthesia. In this article, we will summarize the most frequent applications of alpha-2 adrenoreceptor agonists in anaesthesia and intensive care medicine. We will focus on the clinical data available for the two most representative molecules of this pharmacological class: clonidine and dexmedetomidine. PMID:24683831

  14. 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

  15. Physician perceptions of GLP-1 receptor agonists in the UK.

    PubMed

    Matza, Louis S; Curtis, Sarah E; Jordan, Jessica B; Adetunji, Omolara; Martin, Sherry A; Boye, Kristina S

    2016-05-01

    Objectives Glucagon-like peptide-1 (GLP-1) receptor agonists have been used to treat type 2 diabetes for almost a decade, and new treatments in this class have recently been introduced. The purpose of this study was to examine perceptions of GLP-1 receptor agonists among physicians who treat patients with type 2 diabetes in the UK. Methods A total of 670 physicians (226 diabetes specialists; 444 general practice [GP] physicians) completed a survey in 2014. Results Almost all physicians had prescribed GLP-1 receptor agonists (95.4% total sample; 99.1% specialists; 93.5% GP), most frequently to patients whose glucose levels are not adequately controlled with oral medications (85.9% of physicians) and obese/overweight patients (83.7%). Physicians' most common reasons for prescribing a GLP-1 receptor agonist were: associated with weight loss (65.8%), good efficacy (55.7%), less hypoglycemia risk than insulin (55.2%), not associated with weight gain (34.5%), and better efficacy than oral medications (32.7%). Factors that most commonly cause hesitation when prescribing this class were: not considered first line therapy according to guidelines (56.9%), injectable administration (44.6%), cost (36.7%), gastrointestinal side effects (33.4%), and risk of pancreatitis (26.7%). Almost all specialists (99.1%) believed they had sufficient knowledge to prescribe a GLP-1 receptor agonist, compared with 76.1% of GPs. Conclusions Results highlight the widespread use of GLP-1 receptor agonists for treatment of type 2 diabetes in the UK. However, almost a quarter of GPs reported that they do not have enough knowledge to prescribe GLP-1s, suggesting a need for increased dissemination of information to targeted groups of physicians. Study limitations were that the generalizability of the clinician sample is unknown; survey questions required clinicians to select answers from multiple response options rather than generating the responses themselves; and responses to this survey conducted

  16. 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

  17. Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists.

    PubMed

    Yang, Ting; Liu, Qian; Cheng, Yaobang; Cai, Wei; Ma, Yingli; Yang, Liuqing; Wu, Qianqian; Orband-Miller, Lisa A; Zhou, Ling; Xiang, Zhijun; Huxdorf, Melanie; Zhang, Wei; Zhang, Jing; Xiang, Jia-Ning; Leung, Stewart; Qiu, Yang; Zhong, Zhong; Elliott, John D; Lin, Xichen; Wang, Yonghui

    2014-01-01

    A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists. PMID:24900774

  18. 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

  19. 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

  20. 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.

  1. Glucagon-Like Peptide-1 Receptor Agonists: Beta-Cell Protection or Exhaustion?

    PubMed

    van Raalte, Daniël H; Verchere, C Bruce

    2016-07-01

    Glucagon-like peptide (GLP)-1 receptor agonists enhance insulin secretion and may improve pancreatic islet cell function. However, GLP-1 receptor (GLP-1R) agonist treatment may have more complex, and sometimes deleterious, effects on beta cells. We discuss the concepts of beta cell protection versus exhaustion for different GLP-1R agonists based on recent data. PMID:27160799

  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. Antibiofouling potential of quercetin compound from marine-derived actinobacterium, Streptomyces fradiae PE7 and its characterization.

    PubMed

    Gopikrishnan, Venugopal; Radhakrishnan, Manikkam; Shanmugasundaram, Thangavel; Pazhanimurugan, Raasaiyah; Balagurunathan, Ramasamy

    2016-07-01

    An attempt has been made to isolate, purify and characterize antifouling compound from Streptomyces fradiae PE7 isolated from Vellar estuarine sediment, Parangipettai, South India. The microbial identification was done at species level based on its phenotypic, cell wall and molecular characteristics. Strain PE7 produced high quantity of antifouling compounds in agar surface fermentation when compared to submerged fermentation. In fermentation optimization, wide range of sugars, amino acids, minerals, pH, temperature and NaCl concentration was found to influence the antifouling compound production from the strain PE7. Antifouling compound PE7-C was purified from the crude extract by preparative TLC, and its activity against biofouling bacteria was confirmed by bioautography. Based on the physico-chemical characteristics, the chemical structure of the antifouling compound PE7-C was identified as quercetin (C15H10O7), a flavonoid class of compound with the molecular weight 302.23 g/mol. The purified quercetin was active against 18 biofouling bacteria with MIC range between 1.6 and 25 μg/ml, algal spore germination and mollusc foot adherence found at 100 μg/ml and 306 ± 19.6 μg ml(-1) respectively. The present study, for the first time, reported quercetin from marine-derived Streptomyces sp. PE7 with antifouling activity. This also leads to the repurposing of quercetin for the development of antifouling agent. PMID:27032633

  4. EET agonist prevents adiposity and vascular dysfunction in rats fed a high fat diet via a decrease in Bach 1 and an increase in HO-1 levels.

    PubMed

    Sodhi, Komal; Puri, Nitin; Inoue, Kazuyoshi; Falck, John R; Schwartzman, Michal L; Abraham, Nader G

    2012-08-01

    Recent reports have shown interplay between EETs (epoxides) and the heme oxygenase (HO) system in attenuating adipogenesis in cell culture models; prompting an examination of the effectiveness of EET agonist on obesity and associated cardio-metabolic dysfunction. Patho-physiological effects of an EET agonist (NUDSA) were contrasted in the absence and in the presence of stannous mesoporphyrin (an HO inhibitor) in SD rats fed a high fat (58%, HF) for 16 weeks. Animals on HF diet exhibited enhanced oxidative stress, increased levels of inflammatory cytokines and decreased levels of adiponectin along with reduced vascular and adipose tissue levels of EETs, HO-1; as compared to control rats (11% dietary fat). Treatment with NUDSA not only reversed serum adiponectin and vascular and adipose tissue levels of EETs and HO-1, but also, decreased blood pressure, subcutaneous and visceral fat content and serum TNFα and IL-6 levels in rats on HF diet. Aortic endothelial function, peNOS expression and adipose tissue markers of energy homeostasis i.e. pAMPK, Sirt1 and FAS, impaired in rats fed a HF diet, were restored in animals treated with this EET agonist. That NUDSA enhanced HO-1 expression, was accompanied by increase in p-GSK-3β and pAKT levels along with attenuation of adipose tissue levels of Bach 1--the transcriptional suppresser of HO-1 expression. Prevention of these beneficial effects of NUDSA, in animals on HF diet and concurrently exposed to NUDSA and SnMP, supports the role of EET-HO interaction in mediating such effects. Taken together, our findings suggest that the EETs stimulate HO-1 expression via suppression of Bach 1 and interplay of these two systems affords vascular and metabolic protection in diet induced obesity. PMID:22209722

  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. 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.

  7. Search for Galactic PeV gamma rays with the IceCube Neutrino Observatory

    NASA Astrophysics Data System (ADS)

    Aartsen, M. G.; Abbasi, R.; Abdou, Y.; Ackermann, M.; Adams, J.; Aguilar, J. A.; Ahlers, M.; Altmann, D.; Andeen, K.; Auffenberg, J.; Bai, X.; Baker, M.; Barwick, S. W.; Baum, V.; Bay, R.; Beattie, K.; Beatty, J. J.; Bechet, S.; Becker Tjus, J.; Becker, K.-H.; Bell, M.; Benabderrahmane, M. L.; BenZvi, S.; Berdermann, J.; Berghaus, P.; Berley, D.; Bernardini, E.; Bertrand, D.; Besson, D. Z.; Bindig, D.; Bissok, M.; Blaufuss, E.; Blumenthal, J.; Boersma, D. J.; Bohaichuk, S.; Bohm, C.; Bose, D.; Böser, S.; Botner, O.; Brayeur, L.; Brown, A. M.; Bruijn, R.; Brunner, J.; Buitink, S.; Carson, M.; Casey, J.; Casier, M.; Chirkin, D.; Christy, B.; Clark, K.; Clevermann, F.; Cohen, S.; Cowen, D. F.; Cruz Silva, A. H.; Danninger, M.; Daughhetee, J.; Davis, J. C.; De Clercq, C.; De Ridder, S.; Descamps, F.; Desiati, P.; de Vries-Uiterweerd, G.; DeYoung, T.; Díaz-Vélez, J. C.; Dreyer, J.; Dumm, J. P.; Dunkman, M.; Eagan, R.; Eisch, J.; Ellsworth, R. W.; Engdegård, O.; Euler, S.; Evenson, P. A.; Fadiran, O.; Fazely, A. R.; Fedynitch, A.; Feintzeig, J.; Feusels, T.; Filimonov, K.; Finley, C.; Fischer-Wasels, T.; Flis, S.; Franckowiak, A.; Franke, R.; Frantzen, K.; Fuchs, T.; Gaisser, T. K.; Gallagher, J.; Gerhardt, L.; Gladstone, L.; Glüsenkamp, T.; Goldschmidt, A.; Golup, G.; Goodman, J. A.; Góra, D.; Grant, D.; Groß, A.; Grullon, S.; Gurtner, M.; Ha, C.; Haj Ismail, A.; Hallgren, A.; Halzen, F.; Hanson, K.; Heereman, D.; Heimann, P.; Heinen, D.; Helbing, K.; Hellauer, R.; Hickford, S.; Hill, G. C.; Hoffman, K. D.; Hoffmann, R.; Homeier, A.; Hoshina, K.; Huelsnitz, W.; Hulth, P. O.; Hultqvist, K.; Hussain, S.; Ishihara, A.; Jacobi, E.; Jacobsen, J.; Japaridze, G. S.; Jlelati, O.; Kappes, A.; Karg, T.; Karle, A.; Kiryluk, J.; Kislat, F.; Kläs, J.; Klein, S. R.; Köhne, J.-H.; Kohnen, G.; Kolanoski, H.; Köpke, L.; Kopper, C.; Kopper, S.; Koskinen, D. J.; Kowalski, M.; Krasberg, M.; Kroll, G.; Kunnen, J.; Kurahashi, N.; Kuwabara, T.; Labare, M.; Landsman, H.; Larson, M. J.; Lauer, R.; Lesiak-Bzdak, M.; Lünemann, J.; Madsen, J.; Maruyama, R.; Mase, K.; Matis, H. S.; McNally, F.; Meagher, K.; Merck, M.; Mészáros, P.; Meures, T.; Miarecki, S.; Middell, E.; Milke, N.; Miller, J.; Mohrmann, L.; Montaruli, T.; Morse, R.; Nahnhauer, R.; Naumann, U.; Nowicki, S. C.; Nygren, D. R.; Obertacke, A.; Odrowski, S.; Olivas, A.; Olivo, M.; O'Murchadha, A.; Panknin, S.; Paul, L.; Pepper, J. A.; Pérez de los Heros, C.; Pieloth, D.; Pirk, N.; Posselt, J.; Price, P. B.; Przybylski, G. T.; Rädel, L.; Rawlins, K.; Redl, P.; Resconi, E.; Rhode, W.; Ribordy, M.; Richman, M.; Riedel, B.; Rodrigues, J. P.; Rothmaier, F.; Rott, C.; Ruhe, T.; Ruzybayev, B.; Ryckbosch, D.; Saba, S. M.; Salameh, T.; Sander, H.-G.; Santander, M.; Sarkar, S.; Schatto, K.; Scheel, M.; Scheriau, F.; Schmidt, T.; Schmitz, M.; Schoenen, S.; Schöneberg, S.; Schönherr, L.; Schönwald, A.; Schukraft, A.; Schulte, L.; Schulz, O.; Seckel, D.; Seo, S. H.; Sestayo, Y.; Seunarine, S.; Sheremata, C.; Smith, M. W. E.; Soiron, M.; Soldin, D.; Spiczak, G. M.; Spiering, C.; Stamatikos, M.; Stanev, T.; Stasik, A.; Stezelberger, T.; Stokstad, R. G.; Stößl, A.; Strahler, E. A.; Ström, R.; Sullivan, G. W.; Taavola, H.; Taboada, I.; Tamburro, A.; Ter-Antonyan, S.; Tilav, S.; Toale, P. A.; Toscano, S.; Usner, M.; van der Drift, D.; van Eijndhoven, N.; Van Overloop, A.; van Santen, J.; Vehring, M.; Voge, M.; Vraeghe, M.; Walck, C.; Waldenmaier, T.; Wallraff, M.; Walter, M.; Wasserman, R.; Weaver, Ch.; Wendt, C.; Westerhoff, S.; Whitehorn, N.; Wiebe, K.; Wiebusch, C. H.; Williams, D. R.; Wissing, H.; Wolf, M.; Wood, T. R.; Woschnagg, K.; Xu, C.; Xu, D. L.; Xu, X. W.; Yanez, J. P.; Yodh, G.; Yoshida, S.; Zarzhitsky, P.; Ziemann, J.; Zierke, S.; Zilles, A.; Zoll, M.

    2013-03-01

    Gamma-ray induced air showers are notable for their lack of muons, compared to hadronic showers. Hence, air shower arrays with large underground muon detectors can select a sample greatly enriched in photon showers by rejecting showers containing muons. IceCube is sensitive to muons with energies above ˜500GeV at the surface, which provides an efficient veto system for hadronic air showers with energies above 1 PeV. One year of data from the 40-string IceCube configuration was used to perform a search for point sources and a Galactic diffuse signal. No sources were found, resulting in a 90% C.L. upper limit on the ratio of gamma rays to cosmic rays of 1.2×10-3 for the flux coming from the Galactic plane region (-80°≲l≲-30°; -10°≲b≲5°) in the energy range 1.2-6.0 PeV. In the same energy range, point source fluxes with E-2 spectra have been excluded at a level of (E/TeV)2dΦ/dE˜10-12-10-11cm-2s-1TeV-1 depending on source declination. The complete IceCube detector will have a better sensitivity (due to the larger detector size), improved reconstruction, and vetoing techniques. Preliminary data from the nearly final IceCube detector configuration have been used to estimate the 5-yr sensitivity of the full detector. It is found to be more than an order of magnitude better, allowing the search for PeV extensions of known TeV gamma-ray emitters.

  8. Characterization of dihydro-A2PE: an Intermediate in the A2E Biosynthetic Pathway†

    PubMed Central

    Kim, So R.; He, Jiangtao; Yanase, Emiko; Jang, Young P.; Berova, Nina; Nakanishi, Koji; Sparrow, Janet R.

    2008-01-01

    Bisretinoid lipofuscin pigments that accumulate in retinal pigment epithelial cells are implicated in the etiology of several forms of macular degeneration including juvenile onset Stargardt disease, Best vitelliform macular degeneration and age-related macular degeneration. One of these compounds, A2E, is generated by phosphate hydrolysis of a phosphatidylpyridinium bisretinoid (A2PE) that forms within photoreceptor outer segments. Here we demonstrate that the formation of the aromatic pyridinium ring of A2PE follows from the oxidation of a dihydropyridinium intermediate. Time-dependent density functional theory calculation, based on the structure of dihydro-A2E, produced a simulated UV-visible absorbance spectrum characterized by maxima of 494 and 344 nm. Subsequently, a compound exhibiting similar UV-visible absorbance maxima (λmax 490 and 330 nm) was identified in the A2E biomimetic reaction mixture. By liquid chromatography-mass spectrometry (LC-MS) this bischromophore had the expected mass of the dihydro-pyridinium bisretinoid. The compound also exhibited the behavior of a biosynthetic intermediate, since it formed in advance of the final product A2E and was consumed as A2E accumulated. Moreover, under deoxygenated conditions, conversion to the aromatic pyridinium bisretinoid was inhibited. Taken together, these findings indicate that A2E biosynthesis involves the oxidation of a dihydropyridinium intermediate dihydro-A2PE. An understanding of the biosynthetic pathways of retinal pigment epithelial lipofuscin pigments is critical to the development of therapies for macular degeneration that are based on limiting the formation of these damaging compounds. PMID:17685561

  9. PePPER: a webserver for prediction of prokaryote promoter elements and regulons

    PubMed Central

    2012-01-01

    Background Accurate prediction of DNA motifs that are targets of RNA polymerases, sigma factors and transcription factors (TFs) in prokaryotes is a difficult mission mainly due to as yet undiscovered features in DNA sequences or structures in promoter regions. Improved prediction and comparison algorithms are currently available for identifying transcription factor binding sites (TFBSs) and their accompanying TFs and regulon members. Results We here extend the current databases of TFs, TFBSs and regulons with our knowledge on Lactococcus lactis and developed a webserver for prediction, mining and visualization of prokaryote promoter elements and regulons via a novel concept. This new approach includes an all-in-one method of data mining for TFs, TFBSs, promoters, and regulons for any bacterial genome via a user-friendly webserver. We demonstrate the power of this method by mining WalRK regulons in Lactococci and Streptococci and, vice versa, use L. lactis regulon data (CodY) to mine closely related species. Conclusions The PePPER webserver offers, besides the all-in-one analysis method, a toolbox for mining for regulons, promoters and TFBSs and accommodates a new L. lactis regulon database in addition to already existing regulon data. Identification of putative regulons and full annotation of intergenic regions in any bacterial genome on the basis of existing knowledge on a related organism can now be performed by biologists and it can be done for a wide range of regulons. On the basis of the PePPER output, biologist can design experiments to further verify the existence and extent of the proposed regulons. The PePPER webserver is freely accessible at http://pepper.molgenrug.nl. PMID:22747501

  10. 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

  11. Neutrino masses and sterile neutrino dark matter from the PeV scale

    NASA Astrophysics Data System (ADS)

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

    2015-12-01

    We show that active neutrino masses and a keV-GeV mass sterile neutrino dark matter candidate can result from a modified, low energy seesaw mechanism if right-handed neutrinos are charged under a new symmetry broken by a scalar field vacuum expectation value at the PeV scale. The dark matter relic abundance can be obtained through active-sterile oscillation, freeze-in through the decay of the heavy scalar, or freeze-in via nonrenormalizable interactions at high temperatures. The low energy effective theory maps onto the widely studied ν MSM framework.

  12. 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.

  13. 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.

  14. 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

  15. A Potent and Site-Selective Agonist of TRPA1.

    PubMed

    Takaya, Junichiro; Mio, Kazuhiro; Shiraishi, Takuya; Kurokawa, Tatsuki; Otsuka, Shinya; Mori, Yasuo; Uesugi, Motonari

    2015-12-23

    TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation. PMID:26630251

  16. β2-adrenoceptor agonists in the regulation of mitochondrial biogenesis

    PubMed Central

    Peterson, Yuri K.; Cameron, Robert B.; Wills, Lauren P.; Trager, Richard E.; Lindsey, Chris C.; Beeson, Craig C.; Schnellmann, Rick G.

    2014-01-01

    The stimulation of mitochondrial biogenesis (MB) via cell surface G-protein coupled receptors is a promising strategy for cell repair and regeneration. Here we report the specificity and chemical rationale of a panel of β2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of β2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB. PMID:23954364

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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

  2. 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

  3. 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. PMID:25047939

  4. 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

  5. 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. PMID:26171608

  6. 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

  7. The PE16 (Rv1430) of Mycobacterium tuberculosis Is an Esterase Belonging to Serine Hydrolase Superfamily of Proteins

    PubMed Central

    Sultana, Rafiya; Vemula, Mani Harika; Banerjee, Sharmishta; Guruprasad, Lalitha

    2013-01-01

    The PE and PPE multigene families, first discovered during the sequencing of M. tuberculosis H37Rv genome are responsible for antigenic variation and have been shown to induce increased humoral and cell mediated immune response in the host. Using the bioinformatics tools, we had earlier reported that the 225 amino acid residue PE-PPE domain (Pfam: PF08237) common to some PE and PPE proteins has a “serine α/β hydrolase” fold and conserved Ser, Asp and His catalytic triad characteristic of lipase, esterase and cutinase activities. In order to prove experimentally that PE-PPE domain is indeed a serine hydrolase, we have cloned the full-length Rv1430 and its PE-PPE domain into pET-28a vector, expressed the proteins in E. coli and purified to homogeneity. The activity assays of both purified proteins were carried out using p-nitrophenyl esters of aliphatic carboxylic acids with varying chain length (C2–C16) to study the substrate specificity. To characterize the active site of the PE-PPE domain, we mutated the Ser199 to Ala. The activity of the protein in the presence of serine protease inhibitor- PMSF and the mutant protein were measured. Our results reveal that Rv1430 and its PE-PPE domain possess esterase activity and hydrolyse short to medium chain fatty acid esters with the highest specific activity for pNPC6 at 37°C, 38°C and pH 7.0, 8.0. The details of this work and the observed results are reported in this manuscript. PMID:23383323

  8. Delivery of dopamine transporter tracer (PE2I) through blood brain barrier with ultrasound and microbubbles

    NASA Astrophysics Data System (ADS)

    Serrière, Sophie; Escoffre, Jean-Michel; Bodard, Sylvie; Novell, Anthony; Vergote, Jackie; Vercouillie, Johnny; Thiéry, Jean-Claude; Chalon, Sylvie; Bouakaz, Ayache

    2012-10-01

    The blood-brain barrier plays a major role in controlling the delivery of therapeutic and imaging agents to the brain. The aim of this study was to investigate the use of ultrasound and microbubbles to increase its delivery through the BBB and by determining the optimal experimental conditions that achieve a transient and safe BBB disruption. First, we established the ultrasound conditions that achieved a transient BBB disruption in rats using a non-permeant marker, Evans blue. Hence SonoVue® (450 μL/kg) and Evans blue (100 mg/kg) were intravenously administered. BBB leakage was obtained using ultrasound insonation through the rat skull at 1.6 MPa, PRF 1 Hz, duty cycle 12%, burst 10 ms during 120 sec. BBB disruption was observed in all treated animals (N=4) by histological analysis. The same experimental conditions were applied to enhance brain uptake of PE2I. Biological samples were analyzed using a scintillation counter apparatus. The results showed 50% and 20% increase of 125I-PE2I uptake in the striatum and cerebral cortex, respectively, in the treated rats (N=5) versus control (N=4). Similar enhancements were observed using SonoVue® at half concentration. This innovative method provides a great potential for intracerebral delivery of molecular ligands that could be used for the therapy of brain diseases.

  9. 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

  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. 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)

  12. 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

  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. 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

  15. Improved PeT molecules for optically sensing voltage in neurons

    PubMed Central

    Woodford, Clifford R.; Frady, E. Paxon; Smith, Richard S.; Morey, Benjamin; Canzi, Gabriele; Palida, Sakina F.; Araneda, Ricardo C.; Kristan, William B.; Kubiak, Clifford P.; Miller, Evan W.; Tsien, Roger Y.

    2015-01-01

    VoltageFluor (VF) dyes have the potential to optically measure voltage in excitable membranes with the combination of high spatial and temporal resolution essential to better characterize the voltage dynamics of large groups of excitable cells. VF dyes sense voltage with high speed and sensitivity using photoinduced electron transfer (PeT) through a conjugated molecular wire. We show that tuning the driving force for PeT (ΔGPeT + w) through systematic chemical substitution modulates voltage sensitivity, estimate (ΔGPeT + w) values from experimentally measured redox potentials, and validate the voltage sensitivities in patch-clamped HEK cells for 10 new VF dyes. VF2.1(OMe).H, with a 48% ΔF/F per 100 mV, shows approximately 2-fold improvement over previous dyes in HEK cells, dissociated rat cortical neurons, and medicinal leech ganglia. Additionally, VF2.1(OMe).H faithfully reports pharmacological effects and circuit activity in mouse olfactory bulb slices, thus opening a wide range of previously inaccessible applications for voltage sensitive dyes. PMID:25584688

  16. 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.

  17. Agrobacterium tumefaciens-mediated transformation of Penicillium expansum PE-12 and its application in molecular breeding.

    PubMed

    Zhang, Tian; Qi, Zhen; Wang, Yueyue; Zhang, Fangyuan; Li, Renyong; Yu, Qingsheng; Chen, Xiangbin; Wang, Huojun; Xiong, Xin; Tang, Kexuan

    2013-03-30

    Lipase produced by Penicillium expansum is widely used in laundry detergent and leather industry; however, the absence of an efficient transformation technology sets a major obstacle for further enhancement of its lipase productivity through advanced gene engineering. In this work, Agrobacterium tumefaciens-mediated transformation (ATMT) was investigated for P. expansum PE-12 transformation, using hygromycin phosphotransferase (hph) as a selectable marker gene. As a result, we revealed that the frequency of transformation surpassed 100 transformants/10(5)condida, most of the integrated T-DNA appeared as a single copy at a random position in chromosomal DNA, and all the transformants showed mitotic stability. Facilitated by this newly established method, for the first time, P. expansum PE-12 was genetically engineered to improve the lipase yield, through a homologous expression vector carrying the endogenous lipase gene (PEL) driven by the strong constitutive promoter of the glyceraldehydes-3-phosphate dehydrogenase gene (gpdA) from Aspergillus nidulans. The highest expression level of the engineered strain reached up to 1700 U/mL, nearly 2-fold of the original industrial strain (900 U/mL). Our reproducible ATMT system has not only revealed the great potential of homologous expression-directed genetic engineering, which is more efficient and specific compared to traditional mutagenesis, but also provided new possibilities and perspectives for any other practical applications of P. expansum-related genetic engineering in the future. PMID:23265791

  18. A technique for detection of PeV neutrinos using a phased radio array

    NASA Astrophysics Data System (ADS)

    Vieregg, A. G.; Bechtol, K.; Romero-Wolf, A.

    2016-02-01

    The detection of high energy neutrinos (1015-1020 eV) is an important step toward understanding the most energetic cosmic accelerators and would enable tests of fundamental physics at energy scales that cannot easily be achieved on Earth. In this energy range, there are two expected populations of neutrinos: the astrophysical flux observed with IceCube at lower energies (~1 PeV) and the predicted cosmogenic flux at higher energies (~1018 eV) . Radio detector arrays such as RICE, ANITA, ARA, and ARIANNA exploit the Askaryan effect and the radio transparency of glacial ice, which together enable enormous volumes of ice to be monitored with sparse instrumentation. We describe here the design for a phased radio array that would lower the energy threshold of radio techniques to the PeV scale, allowing measurement of the astrophysical flux observed with IceCube over an extended energy range. Meaningful energy overlap with optical Cherenkov telescopes could be used for energy calibration. The phased radio array design would also provide more efficient coverage of the large effective volume required to discover cosmogenic neutrinos.

  19. 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.

  20. 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.

  1. 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.

  2. Hidden Cosmic-Ray Accelerators as an Origin of TeV-PeV Cosmic Neutrinos

    NASA Astrophysics Data System (ADS)

    Murase, Kohta; Guetta, Dafne; Ahlers, Markus

    2016-02-01

    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 (p γ ) 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.

  3. 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.''

  4. Covalent agonists for studying G protein-coupled receptor activation

    PubMed Central

    Weichert, Dietmar; Kruse, Andrew C.; Manglik, Aashish; Hiller, Christine; Zhang, Cheng; Hübner, Harald; Kobilka, Brian K.; Gmeiner, Peter

    2014-01-01

    Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these important drug targets. However, the crystallization of GPCRs in active states is particularly challenging, requiring the formation of stable and conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, and synthetic agonists that bind with low affinity are ineffective at stabilizing an active state for crystallogenesis. To promote structural studies on the pharmacologically highly relevant class of aminergic GPCRs, we here present the development of covalently binding molecular tools activating Gs-, Gi-, and Gq-coupled receptors. The covalent agonists are derived from the monoamine neurotransmitters noradrenaline, dopamine, serotonin, and histamine, and they were accessed using a general and versatile synthetic strategy. We demonstrate that the tool compounds presented herein display an efficient covalent binding mode and that the respective covalent ligand-receptor complexes activate G proteins comparable to the natural neurotransmitters. A crystal structure of the β2-adrenoreceptor in complex with a covalent noradrenaline analog and a conformationally selective antibody (nanobody) verified that these agonists can be used to facilitate crystallogenesis. PMID:25006259

  5. 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

  6. Biased signaling: potential agonist and antagonist of PAR2.

    PubMed

    Kakarala, Kavita Kumari; Jamil, Kaiser

    2016-06-01

    Protease activated receptor 2 (PAR2) has emerged as one of the promising therapeutic targets to inhibit rapidly metastasizing breast cancer cells. However, its elusive molecular mechanism of activation and signaling has made it a difficult target for drug development. In this study, in silico methods were used to unfold PAR2 molecular mechanism of signaling based on the concept of GPCR receptor plasticity. Although, there are no conclusive evidences of the presence of specific endogenous ligands for PAR2, the efficacy of synthetic agonist and antagonist in PAR2 signaling has opened up the possibilities of ligand-mediated signaling. Furthermore, it has been proved that ligands specific for one GPCR can induce signaling in GPCRs belonging to other subfamilies. Therefore, the aim of this study was to identify potential agonists and antagonists from the GPCR ligand library (GLL), which may induce biased signaling in PAR2 using the concept of existence of multiple ligand-stabilized receptor conformations. The results of our in silico study suggest that PAR2 may show biased signaling mainly with agonists of serotonin type 1, β-adrenergic type 1,3 and antagonists of substance K (NK1), serotonin type 2, dopamine type 4, and thromboxane receptors. Further, this study also throws light on the putative ligand-specific conformations of PAR2. Thus, the results of this study provide structural insights to putative conformations of PAR2 and also gives initial clues to medicinal chemists for rational drug design targeting this challenging receptor. PMID:26295578

  7. 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

  8. Cryptochinones from Cryptocarya chinensis act as farnesoid X receptor agonists.

    PubMed

    Lin, Hsiang-Ru; Chou, Tsung-Hsien; Huang, Din-Wen; Chen, Ih-Sheng

    2014-09-01

    Cryptochinones A-D are tetrahydroflavanones isolated from the leaves of Cryptocarya chinensis, an evergreen tree whose extracts are believed to have a variety of health benefits. The origin of their possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and for hyperglycemia. We studied whether cryptochinones A-D, which are structurally similar to known FXR ligands, may act at this target. Indeed, in mammalian one-hybrid and transient transfection reporter assays, cryptochinones A-D transactivated FXR to modulate promoter action including GAL4, SHP, CYP7A1, and PLTP promoters in dose-dependent manner, while they exhibited similar agonistic activity as chenodeoxycholic acid (CDCA), an endogenous FXR agonist. Through molecular modeling docking studies we evaluated their ability to bind to the FXR ligand binding pocket. Our results indicate that cryptochinones A-D can behave as FXR agonists. PMID:25127166

  9. Dopamine-deficient mice are hypersensitive to dopamine receptor agonists.

    PubMed

    Kim, D S; Szczypka, M S; Palmiter, R D

    2000-06-15

    Dopamine-deficient (DA-/-) mice were created by targeted inactivation of the tyrosine hydroxylase gene in dopaminergic neurons. The locomotor activity response of these mutants to dopamine D1 or D2 receptor agonists and l-3,4-dihydroxyphenylalanine (l-DOPA) was 3- to 13-fold greater than the response elicited from wild-type mice. The enhanced sensitivity of DA-/- mice to agonists was independent of changes in steady-state levels of dopamine receptors and the presynaptic dopamine transporter as measured by ligand binding. The acute behavioral response of DA-/- mice to a dopamine D1 receptor agonist was correlated with c-fos induction in the striatum, a brain nucleus that receives dense dopaminergic input. Chronic replacement of dopamine to DA-/- mice by repeated l-DOPA administration over 4 d relieved the hypersensitivity of DA-/- mutants in terms of induction of both locomotion and striatal c-fos expression. The results suggest that the chronic presence of dopaminergic neurotransmission is required to dampen the intracellular signaling response of striatal neurons. PMID:10844009

  10. Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer

    PubMed Central

    Shukla, Nikunj M.; Salunke, Deepak B.; Balakrishna, Rajalakshmi; Mutz, Cole A.; Malladi, Subbalakshmi S.; David, Sunil A.

    2012-01-01

    Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-γ induction in human PBMCs, with preservation of TLR7-driven IFN-α induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine α-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen. PMID:22952720

  11. Emerging strategies for exploiting cannabinoid receptor agonists as medicines

    PubMed Central

    Pertwee, Roger G

    2009-01-01

    Medicines that activate cannabinoid CB1 and CB2 receptor are already in the clinic. These are Cesamet® (nabilone), Marinol® (dronabinol; Δ9-tetrahydrocannabinol) and Sativex® (Δ9-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 CB2 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

  12. Highly selective agonists for substance P receptor subtypes.

    PubMed Central

    Wormser, U; Laufer, R; Hart, Y; Chorev, M; Gilon, C; Selinger, Z

    1986-01-01

    The existence of a third tachykinin receptor (SP-N) in the mammalian nervous system was demonstrated by development of highly selective agonists. Systematic N-methylation of individual peptide bonds in the C-terminal hexapeptide of substance P gave rise to agonists which specifically act on different receptor subtypes. The most selective analog of this series, succinyl-[Asp6,Me-Phe8]SP6-11, elicits half-maximal contraction of the guinea pig ileum through the neuronal SP-N receptor at a concentration of 0.5 nM. At least 60,000-fold higher concentrations of this peptide are required to stimulate the other two tachykinin receptors (SP-P and SP-E). The action of selective SP-N agonists in the guinea pig ileum is antagonized by opioid peptides, suggesting a functional counteraction between opiate and SP-N receptors. These results indicate that the tachykinin receptors are distinct entities which may mediate different physiological functions. PMID:2431898

  13. 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.

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

    SciTech Connect

    Sakolchai, S.

    1987-01-01

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

  15. 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

  16. 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

  17. Environmental Characteristics and Student Physical Activity in PE Class: Findings From Two Large Urban Areas of Texas

    PubMed Central

    Skala, Katherine A.; Springer, Andrew E.; Sharma, Shreela V.; Hoelscher, Deanna M.; Kelder, Steven H.

    2011-01-01

    Background Physical education (PE) classes provide opportunities for children to be active. This study examined the associations between specific environmental characteristics (teacher characteristics; class size, duration and location; and lesson context) and elementary school-aged children's moderate-to-vigorous activity (MVPA) during PE. Methods Environmental characteristics and student activity levels were measured in 211 3rd, 4th and 5th grade PE classes in 74 Texas public schools using SOFIT direct observation. Results Students engaged in less than half their PE class time in MVPA (38%), while approximately 25% of class time was spent in classroom management. Percent time in MVPA was significantly higher in outdoor classes compared to indoors (41.4% vs. 36.1%, p=.037). Larger (p=.044) and longer (p=.001) classes were negatively associated with percentage of MVPA and positively correlated with time spent in management (p<.001). Conclusions Findings suggest that children's activity may be influenced by environmental factors such as class size, location, and lesson contexts. These findings hold important policy implications for PE class organization and the need for strategies that maximize children's MVPA. Further research is needed to test the causal association of these factors with student MVPA. PMID:21934165

  18. 2-Triazole-Substituted Adenosines: A New Class of Selective A3 Adenosine Receptor Agonists, Partial Agonists, and Antagonists

    PubMed Central

    Cosyn, Liesbet; Palaniappan, Krishnan K.; Kim, Soo-Kyung; Duong, Heng T.; Gao, Zhan-Guo; Jacobson, Kenneth A.; Van Calenbergh, Serge

    2016-01-01

    “Click chemistry” was explored to synthesize two series of 2-(1,2,3-triazolyl)adenosine derivatives (1–14). Binding affinity at the human A1, A2A, and A3ARs (adenosine receptors) and relative efficacy at the A3AR were determined. Some triazol-1-yl analogues showed A3AR affinity in the low nanomolar range, a high ratio of A3/A2A selectivity, and a moderate-to-high A3/A1 ratio. The 1,2,3-triazol-4-yl regiomers typically showed decreased A3AR affinity. Sterically demanding groups at the adenine C2 position tended to reduce relative A3AR efficacy. Thus, several 5′-OH derivatives appeared to be selective A3AR antagonists, i.e., 10, with 260-fold binding selectivity in comparison to the A1AR and displaying a characteristic docking mode in an A3AR model. The corresponding 5′-ethyluronamide analogues generally showed increased A3AR affinity and behaved as full agonists, i.e., 17, with 910-fold A3/A1 selectivity. Thus, N6-substituted 2-(1,2,3-triazolyl)-adenosine analogues constitute a novel class of highly potent and selective nucleoside-based A3AR antagonists, partial agonists, and agonists. PMID:17149867

  19. 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

  20. Functional characterization of the ribosome biogenesis factors PES, BOP1, and WDR12 (PeBoW), and mechanisms of defective cell growth and proliferation caused by PeBoW deficiency in Arabidopsis

    PubMed Central

    Ahn, Chang Sook; Cho, Hui Kyung; Lee, Du-Hwa; Sim, Hee-Jung; Kim, Sang-Gyu; Pai, Hyun-Sook

    2016-01-01

    The nucleolar protein pescadillo (PES) controls biogenesis of the 60S ribosomal subunit through functional interactions with Block of Proliferation 1 (BOP1) and WD Repeat Domain 12 (WDR12) in plants. In this study, we determined protein characteristics and in planta functions of BOP1 and WDR12, and characterized defects in plant cell growth and proliferation caused by a deficiency of PeBoW (PES-BOP1-WDR12) proteins. Dexamethasone-inducible RNAi of BOP1 and WDR12 caused developmental arrest and premature senescence in Arabidopsis, similar to the phenotype of PES RNAi. Both the N-terminal domain and WD40 repeats of BOP1 and WDR12 were critical for specific associations with 60S/80S ribosomes. In response to nucleolar stress or DNA damage, PeBoW proteins moved from the nucleolus to the nucleoplasm. Kinematic analyses of leaf growth revealed that depletion of PeBoW proteins led to dramatically suppressed cell proliferation, cell expansion, and epidermal pavement cell differentiation. A deficiency in PeBoW proteins resulted in reduced cyclin-dependent kinase Type A activity, causing reduced phosphorylation of histone H1 and retinoblastoma-related (RBR) protein. PeBoW silencing caused rapid transcriptional modulation of cell-cycle genes, including reduction of E2Fa and Cyclin D family genes, and induction of several KRP genes, accompanied by down-regulation of auxin-related genes and up-regulation of jasmonic acid-related genes. Taken together, these results suggest that the PeBoW proteins involved in ribosome biogenesis play a critical role in plant cell growth and survival, and their depletion leads to inhibition of cell-cycle progression, possibly modulated by phytohormone signaling. PMID:27440937

  1. Functional characterization of the ribosome biogenesis factors PES, BOP1, and WDR12 (PeBoW), and mechanisms of defective cell growth and proliferation caused by PeBoW deficiency in Arabidopsis.

    PubMed

    Ahn, Chang Sook; Cho, Hui Kyung; Lee, Du-Hwa; Sim, Hee-Jung; Kim, Sang-Gyu; Pai, Hyun-Sook

    2016-09-01

    The nucleolar protein pescadillo (PES) controls biogenesis of the 60S ribosomal subunit through functional interactions with Block of Proliferation 1 (BOP1) and WD Repeat Domain 12 (WDR12) in plants. In this study, we determined protein characteristics and in planta functions of BOP1 and WDR12, and characterized defects in plant cell growth and proliferation caused by a deficiency of PeBoW (PES-BOP1-WDR12) proteins. Dexamethasone-inducible RNAi of BOP1 and WDR12 caused developmental arrest and premature senescence in Arabidopsis, similar to the phenotype of PES RNAi. Both the N-terminal domain and WD40 repeats of BOP1 and WDR12 were critical for specific associations with 60S/80S ribosomes. In response to nucleolar stress or DNA damage, PeBoW proteins moved from the nucleolus to the nucleoplasm. Kinematic analyses of leaf growth revealed that depletion of PeBoW proteins led to dramatically suppressed cell proliferation, cell expansion, and epidermal pavement cell differentiation. A deficiency in PeBoW proteins resulted in reduced cyclin-dependent kinase Type A activity, causing reduced phosphorylation of histone H1 and retinoblastoma-related (RBR) protein. PeBoW silencing caused rapid transcriptional modulation of cell-cycle genes, including reduction of E2Fa and Cyclin D family genes, and induction of several KRP genes, accompanied by down-regulation of auxin-related genes and up-regulation of jasmonic acid-related genes. Taken together, these results suggest that the PeBoW proteins involved in ribosome biogenesis play a critical role in plant cell growth and survival, and their depletion leads to inhibition of cell-cycle progression, possibly modulated by phytohormone signaling. PMID:27440937

  2. 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

  3. Coherent propagation of PeV neutrinos and the dip in the neutrino spectrum at IceCube

    NASA Astrophysics Data System (ADS)

    Kamada, Ayuki; Yu, Hai-Bo

    2015-12-01

    The energy spectrum of high-energy neutrinos reported by the IceCube Collaboration shows a dip between 400 TeV and 1 PeV. One intriguing explanation is that high-energy neutrinos scatter with the cosmic neutrino background through an ˜MeV mediator. Taking the density matrix approach, we develop a formalism to study the propagation of PeV neutrinos in the presence of the new neutrino interaction. If the interaction is flavored such as the gauged Lμ-Lτ model we consider, the resonant collision may not suppress the PeV neutrino flux completely. The new force mediator may also contribute to the number of effectively massless degrees of freedom in the early Universe and change the diffusion time of neutrinos from the supernova core. Astrophysical observations such as big bang nucleosynthesis and supernova cooling provide an interesting test for the explanation.

  4. A Single-Chip Speech Dialogue Module and Its Evaluation on a Personal Robot, PaPeRo-Mini

    NASA Astrophysics Data System (ADS)

    Sato, Miki; Iwasawa, Toru; Sugiyama, Akihiko; Nishizawa, Toshihiro; Takano, Yosuke

    This paper presents a single-chip speech dialogue module and its evaluation on a personal robot. This module is implemented on an application processor that was developed primarily for mobile phones to provide a compact size, low power-consumption, and low cost. It performs speech recognition with preprocessing functions such as direction-of-arrival (DOA) estimation, noise cancellation, beamforming with an array of microphones, and echo cancellation. Text-to-speech (TTS) conversion is also equipped with. Evaluation results obtained on a new personal robot, PaPeRo-mini, which is a scale-down version of PaPeRo, demonstrate an 85% correct rate in DOA estimation, and as much as 54% and 30% higher speech recognition rates in noisy environments and during robot utterances, respectively. These results are shown to be comparable to those obtained by PaPeRo.

  5. Measurement of anisotropy in the arrival direction distribution of PeV cosmic rays with IceTop

    NASA Astrophysics Data System (ADS)

    Westerhoff, Stefan; IceCube Collaboration

    2012-12-01

    We report on the observation of anisotropy in the arrival direction distribution of cosmic rays at PeV energies in the southern hemisphere. The analysis is based on data taken between 2009 and 2012 with the IceTop air shower array at the South Pole. We study two different energy bands with median energies of 400 TeV and 2 PeV, respectively. In both bands, we observe a strong deficit with an angular size of about 30°. The anisotropy at 400 TeV is consistent with previously reported results from cosmic-ray measurements with IceCube in the same energy range. IceTop data reveal that the anisotropy persists to at least 2 PeV.

  6. Neutron β -decay as the origin of IceCube's PeV (anti)neutrinos

    NASA Astrophysics Data System (ADS)

    Anchordoqui, Luis A.

    2015-01-01

    Motivated by the indications of a possible deficit of muon tracks in the first three-year equivalent data set of IceCube we investigate the possibility that the astrophysical (anti)neutrino flux (in the PeV energy range) could originate from β -decay of relativistic neutrons. We show that to accommodate IceCube observations it is necessary that only about 1% to 10% of the emitted cosmic rays in the energy decade 108.5≲ECR/GeV ≲109.5 , yielding antineutrinos on Earth (1 05.5≲Eν ¯/GeV ≲1 06.5 ), are observed. Such a strong suppression can be explained assuming magnetic shielding of the secondary protons which diffuse in extragalactic magnetic fields of strength 10 ≲B /nG ≲100 and coherence length ≲Mpc .

  7. Consequences of thermo- and photo-oxidation on end-use properties of pure PE

    SciTech Connect

    Tireau, Jonathan; Van Schoors, Laetitia; Benzarti, Karim; Colin, Xavier

    2010-06-02

    Thin films of polyethylene have been exposed to thermal and photochemical accelerated agings at different temperatures and different UV intensities. In both cases, mechanical tests performed on aged samples revealed a severe embrittlement of the PE material. However, a multi-scale analysis showed that i) under thermal oxidative conditions, such embrittlement mainly resulted from a reduction of molecular mobility of the amorphous phase due to annealing phenomena, while ii) it was rather associated to a competition between chain scission and cross-linking processes under photo-oxidative conditions. As regards the oxidation mechanisms, it was found that thermo-oxidation is clearly initiated by a bimolecular decomposition of hydroperoxides, while photo-oxidation seems rather initiated by the photolysis of ketones and hydroperoxides. Over a critical threshold of the hydroperoxide concentration, thermolysis of hydroperoxides seems to predominate and even to control the overall photo-oxidation kinetics.

  8. DSTiPE Algorithm for Fuzzy Spatio-Temporal Risk Calculation in Wireless Environments

    SciTech Connect

    Kurt Derr; Milos Manic

    2008-09-01

    Time and location data play a very significant role in a variety of factory automation scenarios, such as automated vehicles and robots, their navigation, tracking, and monitoring, to services of optimization and security. In addition, pervasive wireless capabilities combined with time and location information are enabling new applications in areas such as transportation systems, health care, elder care, military, emergency response, critical infrastructure, and law enforcement. A person/object in proximity to certain areas for specific durations of time may pose a risk hazard either to themselves, others, or the environment. This paper presents a novel fuzzy based spatio-temporal risk calculation DSTiPE method that an object with wireless communications presents to the environment. The presented Matlab based application for fuzzy spatio-temporal risk cluster extraction is verified on a diagonal vehicle movement example.

  9. Radiative transitions involving the (2p2)(3 Pe) metastable autodetaching of H(-)

    NASA Technical Reports Server (NTRS)

    Jacobs, V. L.; Bhatia, A. K.; Temkin, A.

    1974-01-01

    The absorption coefficient for the free-bound transition H (ls) + e(-)+ h omega yields H(-)(2 sq p,(3)P(e)) is calculated (together with the differential emission rate for the inverse process) using ls - 2s - 2p close coupling continuum wave functions and a Hylleraas bound state wave function. A maximum in the absorption and emission spectra is found to occur at a photon wavelength of 1219.5 A, which is 2 A closer to the Lyman alpha line than predicted by the calculations of Drake, and is in closer agreement with the stellar absorption feature identified by Heap and Stecher. The free-bound absorption process appears to be a significant source of continuous ultraviolet opacity.

  10. PeV-scale dark matter as a thermal relic of a decoupled sector

    NASA Astrophysics Data System (ADS)

    Berlin, Asher; Hooper, Dan; Krnjaic, Gordan

    2016-09-01

    In this letter, we consider a class of scenarios in which the dark matter is part of a heavy hidden sector that is thermally decoupled from the Standard Model in the early universe. The dark matter freezes-out by annihilating to a lighter, metastable state, whose subsequent abundance can naturally come to dominate the energy density of the universe. When this state decays, it reheats the visible sector and dilutes all relic abundances, thereby allowing the dark matter to be orders of magnitude heavier than the weak scale. For concreteness, we consider a simple realization with a Dirac fermion dark matter candidate coupled to a massive gauge boson that decays to the Standard Model through its kinetic mixing with hypercharge. We identify viable parameter space in which the dark matter can be as heavy as ∼1-100 PeV without being overproduced in the early universe.

  11. Temporal and Climatic Analysis of the Rio Peñasco in New Mexico

    NASA Astrophysics Data System (ADS)

    Brooks, F.

    2015-12-01

    Streamflow research usually focuses on perennial streams due to the obvious impact on water budgets and flooding forecasts as well as the readily available data due a higher quantity of gages with longer and more complete data sets. Due to this, most streamflow metrics were derived by analyzing perennial streams and may not accurately characterize streams that have intermittent flow. Even standard metrics used for intermittent streams may not accurately characterize streams that are strongly ephemeral. This study uses statistical methods to analyze the Rio Peñasco near Artesia, NM. Traditional metrics were inadequate in describing the average or variance of this ephemeral stream. This stream has been rerouted or altered numerous times in order to be used for agriculture. In the 1980s, this anthropogenic influence resulted in a drastic decline in discharge rates. ENSO was shown to alter the onset and total volume of non-zero discharge during monsoon months.

  12. Study of Raft Domains in Model Membrane of DPPC/PE/Cholesterol

    NASA Astrophysics Data System (ADS)

    Lor, Chai; Hirst, Linda

    2010-10-01

    Raft domains in bilayer membrane are thought to play an important role in many cell functions such as cell signaling or trans-membrane protein activation. Here we use a model membrane consisting of DPPC/PE/cholesterol to examine the structure of membrane rafts and phase interactions. In particular we are interested in lipids containing the highly polyunsaturated fatty acid DHA. We use both atomic force microscopy (AFM) and fluorescence microscopy to obtain information on the structural properties of raft regions and track cholesterol. As expected, we find phase separation of raft regions between saturated and unsaturated lipids. Moreover, we find that the roughness of the domains change with varying cholesterol concentration possibly due to overpacking. This model study provides further understanding of the role of cholesterol in bilayer membrane leading towards a better knowledge of cell membranes.

  13. A numerical adjoint parabolic equation (PE) method for tomography and geoacoustic inversion in shallow water

    NASA Astrophysics Data System (ADS)

    Hermand, Jean-Pierre; Berrada, Mohamed; Meyer, Matthias; Asch, Mark

    2005-09-01

    Recently, an analytic adjoint-based method of optimal nonlocal boundary control has been proposed for inversion of a waveguide acoustic field using the wide-angle parabolic equation [Meyer and Hermand, J. Acoust. Soc. Am. 117, 2937-2948 (2005)]. In this paper a numerical extension of this approach is presented that allows the direct inversion for the geoacoustic parameters which are embedded in a spectral integral representation of the nonlocal boundary condition. The adjoint model is generated numerically and the inversion is carried out jointly across multiple frequencies. The paper further discusses the application of the numerical adjoint PE method for ocean acoustic tomography. To show the effectiveness of the implemented numerical adjoint, preliminary inversion results of water sound-speed profile and bottom acoustic properties will be shown for the YELLOW SHARK '94 experimental conditions.

  14. [Epidemiological features of maternal deaths occurred in Recife, PE, Brazil (2000-2006)].

    PubMed

    Correia, Rafaella Araújo; Araújo, Hallana Cristina; Furtado, Betise Mery Alencar; Bonfim, Cristine

    2011-01-01

    This was a cross-sectional study that aimed to describe the epidemiological characteristics of maternal deaths among women living in Recife, PE, Brazil that occurred between 2000 and 2006. The data source consisted of investigation files on maternal deaths. To analyze the data, the EpiInfo 6.04d software was used. The analysis considered 111 deaths, corresponding to a maternal death ratio of 65.99/100,000 live births. The obstetric data showed that these women had had fewer than six prenatal consultations, between one and four previous pregnancies, cesarean deliveries and hospital admission in a severe condition. Hypertensive disorders were the main cause of death. Most of the deaths were considered avoidable. The results indicate the need to improve the healthcare for pregnant women prenatally, at delivery and during the puerperium. PMID:21468495

  15. Investigations on the heating effect of PE-LD induced by high-intensity focused ultrasound.

    PubMed

    Oehm, Lukas; Bach, Sascha; Majschak, Jens-Peter

    2016-08-01

    High-intensity focused ultrasound is widely applied in tissue treatment as well as for heating of solid polymer materials. Previous studies investigating the heating effect in polymer materials utilized sound transmission through water or other fluids at low HIFU power. In this study, the ultrasonic transducer possesses a solid sound conductor made of aluminum and a high HIFU power of above 100W was applied to heat solid PE-LD samples. Temperature measurements were performed by calibrated non-invasive infrared thermal imaging. A strong heating effect with heating above melting temperature and evaporation temperature within less than 1s of irradiation was observed. Furthermore, the acoustic coupling defined by the force applied by the ultrasonic applicator to the polymer material was found to be fundamental to induce the heating effect. This investigation reveals HIFU for new applications in the field of polymer processing. PMID:27208613

  16. 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.

  17. Molecular interactions of a polyaromatic surfactant C5Pe in aqueous solutions studied by a surface forces apparatus.

    PubMed

    Wang, Jing; Lu, Qingye; Harbottle, David; Sjöblom, Johan; Xu, Zhenghe; Zeng, Hongbo

    2012-09-13

    Studies on molecular mechanisms of polyaromatic surfactants in stabilizing water-in-oil (W/O) or oil-in-water (O/W) emulsions are of great scientific and practical importance. A polyaromatic surfactant N-(1-hexylheptyl)-N'-(5-carboxylicpentyl) perylene-3,4,9,10-tetracarboxylic bisimide (C5Pe) with well-defined molecular structure containing fused aromatic rings and heteroatoms similar to asphaltene molecules, was used in this study in an attempt to understand molecular interaction mechanisms of heavy oil components in aqueous solutions. A surface forces apparatus (SFA) was used to directly measure the molecular interactions of C5Pe. Solution pH, salt concentration and Ca(2+) addition showed a strong impact on molecular interactions between C5Pe adsorbed on mica surfaces. The repulsion observed between the two adsorbed C5Pe molecular layers was shown to have a steric and electrosteric origin. The force-distance profiles at short separation distances under high compression force were well fitted with the Alexander-de Gennes (AdG) model. At pH ≥ 4, the repulsive forces measured over a long separation distance under low compression force were shown to deviate from the AdG model but could be fitted with the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, indicating an electrostatic origin of the observed repulsion due to ionization of -COOH groups. Adhesion between two C5Pe surfaces was shown to decrease sharply with increasing solution pH and salt concentration, being attributed to the decrease in surface hydrophobicity and hence hydrophobic attraction. Addition of Ca(2+) ions induced the formation of large C5Pe aggregates due to strong bonding of Ca(2+) with -COOH groups, leading to a longer range steric repulsion. Our results provide a new insight into the molecular interactions of polyaromatic surfactants at oil-water interfaces and in complex aqueous solutions. PMID:22913670

  18. The Risk of Paradoxical Embolism (RoPE) Study: Initial description of the completed database

    PubMed Central

    Thaler, David E.; Angelantonio, Emanuele Di; Di Tullio, Marco R.; Donovan, Jennifer S.; Elkind, Mitchell S. V.; Griffith, John; Homma, Shunichi; Jaigobin, Cheryl; Mas, Jean-Louis; Mattle, Heinrich P.; Michel, Patrik; Mono, Marie-Luise; Nedeltchev, Krassen; Papetti, Federica; Ruthazer, Robin; Serena, Joaquín; Weimar, Christian; Kent, David M.

    2014-01-01

    Background Detecting a benefit from closure of patent foramen ovale (PFO) in patients with cryptogenic stroke (CS) is hampered by low rates of stroke recurrence and uncertainty about the causal role of PFO in the index event. A method to predict PFO-attributable recurrence risk is needed. However, individual databases generally have too few stroke recurrences to support risk modeling. Prior studies of this population have been limited by low statistical power for examining factors related to recurrence. Aims To develop a database to support modeling of PFO-attributable recurrence risk by combining extant data sets. Methods We identified investigators with extant databases including subjects with CS investigated for PFO; determined the availability and characteristics of data in each database; collaboratively specified the variables to be included in the Risk of Paradoxical Embolism (RoPE) database; harmonized the variables across databases, and collected new primary data when necessary and feasible. Results The RoPE database has individual clinical, radiologic, and echocardiographic data from 12 component databases including subjects with CS both with (n=1925) and without (n=1749) PFO. In the PFO subjects, a total of 381 outcomes (stroke, TIA, death) occurred (median follow-up = 2.2yrs). While there were substantial variations in data collection between studies, there was sufficient overlap to define a common set of variables suitable for risk modeling. Conclusion While individual studies are inadequate for modeling PFO-attributable recurrence risk, collaboration between investigators has yielded a database with sufficient power to identify those patients at highest risk for a PFO-related stroke recurrence who may have the greatest potential benefit from PFO closure. PMID:22883936

  19. Cosmogenic neutrinos: parameter space and detectabilty from PeV to ZeV

    SciTech Connect

    Kotera, K.; Olinto, A.V.; Allard, D. E-mail: allard@apc.univ-paris7.fr

    2010-10-01

    While propagating from their source to the observer, ultrahigh energy cosmic rays interact with cosmological photon backgrounds and generate to the so-called ''cosmogenic neutrinos''. Here we study the parameter space of the cosmogenic neutrino flux given recent cosmic ray data and updates on plausible source evolution models. The shape and normalization of the cosmogenic neutrino flux are very sensitive to some of the current unknowns of ultrahigh energy cosmic ray sources and composition. We investigate various chemical compositions and maximum proton acceleration energies E{sub p,max} which are allowed by current observations. We consider different models of source evolution in redshift and three possible scenarios for the Galactic to extragalactic transition. We summarize the parameter space for cosmogenic neutrinos into three regions: an optimistic scenario that is currently being constrained by observations, a plausible range of models in which we base many of our rate estimates, and a pessimistic scenario that will postpone detection for decades to come. We present the implications of these three scenarios for the detection of cosmogenic neutrinos from PeV to ZeV (10{sup 14−21} eV) with the existing and upcoming instruments. In the plausible range of parameters, the narrow flux variability in the EeV energy region assures low but detectable rates for IceCube (0.06–0.2 neutrino per year) and the Pierre Auger Observatory (0.03–0.06 neutrino per year), and detection should happen in the next decade. If EeV neutrinos are detected, PeV information can help select between competing models of cosmic ray composition at the highest energy and the Galactic to extragalactic transition at ankle energies. With improved sensitivity, ZeV neutrino observatories, such as ANITA and JEM-EUSO could explore and place limits on the maximum acceleration energy.

  20. [Anesthetic management for a patient with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome].

    PubMed

    Terada, Tadanori; Ishimura, Hiroshi; Iwagaki, Tamao; Aoyama, Kazuyoshi; Takenaka, Ichiro; Kadoya, Tatsuo

    2004-09-01

    Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome, described by McCarty et al., is a form of "seronegative rheumatoid arthritis" characterized by an acute-onset polyarthritis with pitting edema of the dorsum of both hands and/or both feet. The syndrome is prevalent in elderly men, completely remitted with a small dose of steroid over a relatively short period, and has a benign clinical course. We describe a case of RS3PE syndrome in a 61-year-old man undergoing a lobectomy of the lung and discuss anesthetic management for the syndrome. PMID:15500108

  1. Stabilisation of crosslinked ultra-high molecular weight polyethylene (UHMW-PE)-acetabular components with alpha-tocopherol.

    PubMed

    Wolf, C; Maninger, J; Lederer, K; Frühwirth-Smounig, H; Gamse, T; Marr, R

    2006-12-01

    A stabilisation of crosslinked ultra-high molecular weight polyethylene (UHMW-PE) with alpha-tocopherol (vitamin E) used for endoprostheses can increase its resistance against oxidative degradation remarkably. However, the method used for conventional UHMW-PE of adding alpha-tocopherol to the UHMW-PE powder before processing can not be applied for crosslinked UHMW-PE, since the alpha-tocopherol hinders the crosslinking process, which would be accompanied by a heavy degradation of this vitamin. The alpha-tocopherol has therefore to be added after the crosslinking process. This paper presents two methods for a stabilisation of finished products with alpha-tocopherol. In method 1, UHMW-PE-cubes (20 x 20 x 20 mm3) were stored in pure alpha-tocopherol under inert atmosphere at temperatures from 100 degrees C to 150 degrees C resulting in a high mass fraction of alpha-tocopherol in the edge zones. For further homogenisation, the cubes were stored in inert atmosphere at temperatures from 160 degrees C to 200 degrees C. In method 2, supercritical CO2 was used to incorporate the vitamin into the UHMW-PE. In an autoclave vessel, the cubes were treated with alpha-tocopherol dissolved in supercritical CO2 for several hours at temperatures from 100 degrees C to 170 degrees C. In both cases, the mass fraction of alpha-tocopherol was detected with the help of a FTIR-microscope. Both methods are well suited to stabilise crosslinked UHMW-PE with alpha-tocopherol. A stabilisation of the sensitive edge layer as well as a nearly homogenous distribution with varying alpha-tocopherol content may be realised by varying the process parameters. Using method 2, standard hip cups were stabilized nearly homogeneously with varying mass fraction of alpha-tocopherol. No oxidation of the UHMW-PE could be detected by infrared spectroscopy (FTIR) and HPLC studies showed a very low degradation of the alpha-tocopherol for both processes. PMID:17143764

  2. Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders.

    PubMed

    Geoffroy, Pierre Alexis; Etain, Bruno; Franchi, Jean-Arthur Micoulaud; Bellivier, Frank; Ritter, Philipp

    2015-01-01

    Bipolar disorders (BD) present with abnormalities of circadian rhythmicity and sleep homeostasis, even during phases of remission. These abnormalities are linked to the underlying neurobiology of genetic susceptibility to BD. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses. Exogenous melatonin has demonstrated efficacy in treating primary insomnia, delayed sleep phase disorder, improving sleep parameters and overall sleep quality, and some psychiatric disorders like autistic spectrum disorders. In order to evaluate the efficacy of melatonin among patients with BD, this comprehensive review emphasizes the abnormal melatonin function in BD, the rationale of melatonin action in BD, the available data about the exogenous administration of melatonin, and melatonin agonists (ramelteon and tasimelteon), and recommendations of use in patients with BD. There is a scientific rationale to propose melatonin-agonists as an adjunctive treatment of mood stabilizers in treating sleep disorders in BD and thus to possibly prevent relapses when administered during remission phases. We emphasized the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD that are prodromal markers of an emerging mood episode and possible targets to prevent future relapses. An additional interesting adjunctive therapeutic effect might be on preventing metabolic syndrome, particularly in patients treated with antipsychotics. Finally, melatonin is well tolerated and has little dependence potential in contrast to most available sleep medications. Further studies are expected to be able to produce stronger evidence-based therapeutic guidelines to confirm and delineate the routine use of melatonin-agonists in the treatment of BD. PMID:26088111

  3. Comparative endpoint sensitivity of in vitro estrogen agonist assays.

    PubMed

    Dreier, David A; Connors, Kristin A; Brooks, Bryan W

    2015-07-01

    Environmental and human health implications of endocrine disrupting chemicals (EDCs), particularly xenoestrogens, have received extensive study. In vitro assays are increasingly employed as diagnostic tools to comparatively evaluate chemicals, whole effluent toxicity and surface water quality, and to identify causative EDCs during toxicity identification evaluations. Recently, the U.S. Environmental Protection Agency (USEPA) initiated ToxCast under the Tox21 program to generate novel bioactivity data through high throughput screening. This information is useful for prioritizing chemicals requiring additional hazard information, including endocrine active chemicals. Though multiple in vitro and in vivo techniques have been developed to assess estrogen agonist activity, the relative endpoint sensitivity of these approaches and agreement of their conclusions remain unclear during environmental diagnostic applications. Probabilistic hazard assessment (PHA) approaches, including chemical toxicity distributions (CTD), are useful for understanding the relative sensitivity of endpoints associated with in vitro and in vivo toxicity assays by predicting the likelihood of chemicals eliciting undesirable outcomes at or above environmentally relevant concentrations. In the present study, PHAs were employed to examine the comparative endpoint sensitivity of 16 in vitro assays for estrogen agonist activity using a diverse group of compounds from the USEPA ToxCast dataset. Reporter gene assays were generally observed to possess greater endpoint sensitivity than other assay types, and the Tox21 ERa LUC BG1 Agonist assay was identified as the most sensitive in vitro endpoint for detecting an estrogenic response. When the sensitivity of this most sensitive ToxCast in vitro endpoint was compared to the human MCF-7 cell proliferation assay, a common in vitro model for biomedical and environmental monitoring applications, the ERa LUC BG1 assay was several orders of magnitude less

  4. Pharmacological properties of acid N-thiazolylamide FFA2 agonists

    PubMed Central

    Brown, Andrew J; Tsoulou, Christina; Ward, Emma; Gower, Elaine; Bhudia, Nisha; Chowdhury, Forhad; Dean, Tony W; Faucher, Nicolas; Gangar, Akanksha; Dowell, Simon J

    2015-01-01

    FFA2 is a receptor for short-chain fatty acids. Propionate (C3) and 4-chloro-α-(1-methylethyl)-N-2-thiazolyl-benzeneacetamide (4-CMTB), the prototypical synthetic FFA2 agonist, evoke calcium mobilization in neutrophils and inhibit lipolysis in adipocytes via this G-protein-coupled receptor. 4-CMTB contains an N-thiazolylamide motif but no acid group, and 4-CMTB and C3 bind to different sites on FFA2 and show allosteric cooperativity. Recently, FFA2 agonists have been described that contain both N-thiazolylamide and carboxylate groups, reminiscent of bitopic ligands. These are thought to engage the carboxylate-binding site on FFA2, but preliminary evidence suggests they do not bind to the same site as 4-CMTB even though both contain N-thiazolylamide. Here, we describe the characterization of four FFA2 ligands containing both N-thiazolylamide and carboxylate. (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid (compound 14) exhibits allosteric agonism with 4-CMTB but not C3. Three other compounds agonize FFA2 in [35S]GTPγS-incorporation or cAMP assays but behave as inverse agonists in yeast-based gene-reporter assays, showing orthosteric antagonism of C3 responses but allosteric antagonism of 4-CMTB responses. Thus, the bitopic-like FFA2 ligands engage the orthosteric site but do not compete at the site of 4-CMTB binding on an FFA2 receptor molecule. Compound 14 activates FFA2 on human neutrophils and mouse adipocytes, but appears not to inhibit lipolysis upon treatment of human primary adipocytes in spite of the presence of a functional FFA2 receptor in these cells. Hence, these new ligands may reveal differences in coupling of FFA2 between human and rodent adipose tissues. PMID:26236484

  5. 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

  6. AGONISTIC AUTOANTIBODIES AS VASODILATORS IN ORTHOSTATIC HYPOTENSION: A NEW MECHANISM

    PubMed Central

    Li, Hongliang; Kem, David C.; Reim, Sean; Khan, Muneer; Vanderlinde-Wood, Megan; Zillner, Caitlin; Collier, Daniel; Liles, Campbell; Hill, Michael A.; Cunningham, Madeleine W.; Aston, Christopher E.; Yu, Xichun

    2012-01-01

    Agonistic autoantibodies to the β-adrenergic and muscarinic receptors are a novel investigative and therapeutic target for certain orthostatic disorders. We have identified the presence of autoantibodies to β2-adrenergic and/or M3 muscarinic receptors by enzyme-linked immunosorbent assay in 75% (15 of 20) of patients with significant orthostatic hypotension. Purified serum IgG from all 20 patients and 10 healthy control subjects were examined in a receptor-transfected cell-based cAMP assay for β2 receptor activation and β-arrestin assay for M3 receptor activation. There was a significant increase in IgG-induced activation of β2 and M3 receptors in the patient group compared to controls. A dose response was observed for both IgG activation of β2 and M3 receptors and inhibition of their activation with the non-selective β blocker propranolol and muscarinic blocker atropine. The antibody effects on β2 and/or M3 (via production of nitric oxide) receptor-mediated vasodilation were studied in a rat cremaster resistance arteriole assay. Infusion of IgG from patients with documented β2 and/or M3 receptor agonistic activity produced a dose-dependent vasodilation. Sequential addition of the β blocker propranolol and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester partially inhibited IgG-induced vasodilation (% of maximal dilatory response: from 57.7±10.4 to 35.3±4.6 and 24.3±5.8, respectively, p<0.01, n=3), indicating antibody activation of vascular β2 and/or M3 receptors may contribute to systemic vasodilation. These data support the concept that circulating agonistic autoantibodies serve as vasodilators and may cause or exacerbate orthostatic hypotension. PMID:22215709

  7. Antinociceptive properties of selective MT(2) melatonin receptor partial agonists.

    PubMed

    López-Canul, Martha; Comai, Stefano; Domínguez-López, Sergio; Granados-Soto, Vinicio; Gobbi, Gabriella

    2015-10-01

    Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5-40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT2 partial agonists were blocked by the pre-treatment with the MT2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT2 melatonin receptor may be a novel target for analgesic drug development. PMID:26162699

  8. Rational diagnosis of pulmonary embolism (RADIA PE) in symptomatic outpatients with suspected PE: an improved strategy to exclude or diagnose venous thromboembolism by the sequential use of a clinical model, rapid ELISA D-dimer test, perfusion lung scan, ultrasonography, spiral CT, and pulmonary angiography.

    PubMed

    Michiels, J J

    1998-01-01

    A prospective management decision analysis for the exclusion and diagnosis of pulmonary embolism (PE) based on pre-test clinical probability (PCP) estimation for PE, a rapid ELISA D-dimer test, perfusion lungscan (P-scan), CUS, spiral CT, and pulmonary angiography is proposed. The modified PCP model for PE of Wells et al. allows reasonably accurate classification of patients with no, low, moderate, and high probability for PE. The combined rational use of the evidence-based noninvasive imaging techniques P-scan, CUS, and spiral CT with the rapid ELISA D-dimer test and PCP will reduce the need for invasive pulmonary angiography to perhaps 10 to 15% of patients, who initially presented with suspected PE. A Rational Diagnosis of Pulmonary Embolism (RADIA PE) model is proposed for testing in a large multicenter study of patients with suspected PE. PMID:9763360

  9. 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. PMID:8570768

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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

  15. Mechanisms underlying activation of transient BK current in rabbit urethral smooth muscle cells and its modulation by IP3-generating agonists

    PubMed Central

    Kyle, Barry D.; Bradley, Eamonn; Large, Roddy; Sergeant, Gerard P.; McHale, Noel G.; Thornbury, Keith D.

    2013-01-01

    We used the perforated patch-clamp technique at 37°C to investigate the mechanisms underlying the activation of a transient large-conductance K+ (tBK) current in rabbit urethral smooth muscle cells. The tBK current required an elevation of intracellular Ca2+, resulting from ryanodine receptor (RyR) activation via Ca2+-induced Ca2+ release, triggered by Ca2+ influx through L-type Ca2+ (CaV) channels. Carbachol inhibited tBK current by reducing Ca2+ influx and Ca2+ release and altered the shape of spike complexes recorded under current-clamp conditions. The tBK currents were blocked by iberiotoxin and penitrem A (300 and 100 nM, respectively) and were also inhibited when external Ca2+ was removed or the CaV channel inhibitors nifedipine (10 μM) and Cd2+ (100 μM) were applied. The tBK current was inhibited by caffeine (10 mM), ryanodine (30 μM), and tetracaine (100 μM), suggesting that RyR-mediated Ca2+ release contributed to the activation of the tBK current. When IP3 receptors (IP3Rs) were blocked with 2-aminoethoxydiphenyl borate (2-APB, 100 μM), the amplitude of the tBK current was not reduced. However, when Ca2+ release via IP3Rs was evoked with phenylephrine (1 μM) or carbachol (1 μM), the tBK current was inhibited. The effect of carbachol was abolished when IP3Rs were blocked with 2-APB or by inhibition of muscarinic receptors with the M3 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (1 μM). Under current-clamp conditions, bursts of action potentials could be evoked with depolarizing current injection. Carbachol reduced the number and amplitude of spikes in each burst, and these effects were reduced in the presence of 2-APB. In the presence of ryanodine, the number and amplitude of spikes were also reduced, and carbachol was without further effect. These data suggest that IP3-generating agonists can modulate the electrical activity of rabbit urethral smooth muscle cells and may contribute to the effects of neurotransmitters on

  16. Site of action of a pentapeptide agonist at the glucagon-like peptide-1 receptor. Insight into a small molecule agonist-binding pocket

    PubMed Central

    Dong, Maoqing; Pinon, Delia I.; Miller, Laurence J.

    2011-01-01

    The development of small molecule agonists for class B G protein-coupled receptors (GPCRs) has been quite challenging. With proof-of-concept that exenatide, the parenterally administered peptide agonist of the glucagon-like peptide-1 (GLP1) receptor, is an effective treatment for patients with diabetes mellitus, the development of small molecule agonists could have substantial advantages. We previously reported a lead for small molecule GLP1 receptor agonist development representing the pentapeptide NRTFD. In this work, we have prepared an NRTFD derivative incorporating a photolabile benzoylphenylalanine and used it to define its site of action. This peptide probe was a full agonist with potency similar to NRTFD, which bound specifically and saturably to a single, distinct site within the GLP1 receptor. Peptide mapping using cyanogen bromide and endoproteinase Lys-C cleavage of labeled wild type and M397L mutant receptor constructs identified the site of covalent attachment of NRTFD within the third extracellular loop above the sixth transmembrane segment. This region is the same as that identified using an analogous photolabile probe based on secretin receptor sequences, and has been shown in mutagenesis studies to be important for natural agonist action of several members of this family. While these observations suggest that small molecule ligands can act at a site bordering the third extracellular loop to activate this class B GPCR, the relationship of this site to the site of action of the amino-terminal end of the natural agonist peptide is unclear. PMID:22079758

  17. 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

  18. Synthesis and biological activities of indolizine derivatives as alpha-7 nAChR agonists.

    PubMed

    Xue, Yu; Tang, Jingshu; Ma, Xiaozhuo; Li, Qing; Xie, Bingxue; Hao, Yuchen; Jin, Hongwei; Wang, Kewei; Zhang, Guisen; Zhang, Liangren; Zhang, Lihe

    2016-06-10

    Human α7 nicotinic acetylcholine receptor (nAChR) is a promising therapeutic target for the treatment of schizophrenia accompanied with cognitive impairment. Herein, we report the synthesis and agonistic activities of a series of indolizine derivatives targeting to α7 nAChR. The results show that all synthesized compounds have affinity to α7 nAChR and some give strong agonistic activity, particularly most active agonists show higher potency than control EVP-6124. The docking and structure-activity relationship studies provide insights to develop more potent novel α7 nAChR agonists. PMID:26994846

  19. 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

  20. Sustained wash-resistant receptor activation responses of GPR119 agonists.

    PubMed

    Hothersall, J Daniel; Bussey, Charlotte E; Brown, Alastair J; Scott, James S; Dale, Ian; Rawlins, Philip

    2015-09-01

    G protein-coupled receptor 119 (GPR119) is involved in regulating metabolic homoeostasis, with GPR119 agonists targeted for the treatment of type-2 diabetes and obesity. Using the endogenous agonist oleoylethanolamide and a number of small molecule synthetic agonists we have investigated the temporal dynamics of receptor signalling. Using both a dynamic luminescence biosensor-based assay and an endpoint cAMP accumulation assay we show that agonist-driven desensitization is not a major regulatory mechanism for GPR119 despite robust activation responses, regardless of the agonist used. Temporal analysis of the cAMP responses demonstrated sustained signalling resistant to washout for some, but not all of the agonists tested. Further analysis indicated that the sustained effects of one synthetic agonist AR-231,453 were consistent with a role for slow dissociation kinetics. In contrast, the sustained responses to MBX-2982 and AZ1 appeared to involve membrane deposition. We also detect wash-resistant responses to AR-231,453 at the level of physiologically relevant responses in an endogenous expression system (GLP-1 secretion in GLUTag cells). In conclusion, our findings indicate that in a recombinant expression system GPR119 activation is sustained, with little evidence of pronounced receptor desensitization, and for some ligands persistent agonist responses continue despite removal of excess agonist. This provides novel understanding of the temporal responses profiles of potential drug candidates targetting GPR119, and highlights the importance of carefully examining the the mechanisms through which GPCRs generate sustained responses. PMID:26101059

  1. Mapping the agonist binding site of the nicotinic acetylcholine receptor. Orientation requirements for activation by covalent agonist.

    PubMed

    Sullivan, D A; Cohen, J B

    2000-04-28

    To characterize the structural requirements for ligand orientation compatible with activation of the Torpedo nicotinic acetylcholine receptor (nAChR), we used Cys mutagenesis in conjunction with sulfhydryl-reactive reagents to tether primary or quaternary amines at defined positions within the agonist binding site of nAChRs containing mutant alpha- or gamma-subunits expressed in Xenopus oocytes. 4-(N-Maleimido)benzyltrimethylammonium and 2-aminoethylmethanethiosulfonate acted as irreversible antagonists when tethered at alphaY93C, alphaY198C, or gammaE57C, as well as at alphaN94C (2-aminoethylmethanethiosulfonate only). [2-(Trimethylammonium)-ethyl]-methanethiosulfonate (MTSET), which attaches thiocholine to binding site Cys, also acted as an irreversible antagonist when tethered at alphaY93C, alphaN94C, or gammaE57C. However, MTSET modification of alphaY198C resulted in prolonged activation of the nAChR not reversible by washing but inhibitable by subsequent exposure to non-competitive antagonists. Modification of alphaY198C (or any of the other positions tested) by [(trimethylammonium)methyl]methanethiosulfonate resulted only in irreversible inhibition, while modification of alphaY198C by [3-(trimethylammonium)propyl]methanethiosulfonate resulted in irreversible activation of nAChR, but at lower efficacy than by MTSET. Thus changing the length of the tethering arm by less than 1 A in either direction markedly effects the ability of the covalent trimethylammonium to activate the nAChR, and agonist activation depends on a very selective orientation of the quaternary ammonium within the agonist binding site. PMID:10777557

  2. Isothiouronium compounds as gamma-aminobutyric acid agonists.

    PubMed Central

    Allan, R. D.; Dickenson, H. W.; Hiern, B. P.; Johnston, G. A.; Kazlauskas, R.

    1986-01-01

    Analogues of gamma-aminobutyric acid (GABA) incorporating an isothiouronium salt as a replacement for a protonated amino functional group have been investigated for activity on: GABA receptors in the guinea-pig ileum; [3H]-GABA and [3H]-diazepam binding to rat brain membranes; and GABA uptake and transamination. For the homologous series of omega-isothiouronium alkanoic acids, maximum GABA-mimetic activity was found at 3-[(aminoiminomethyl)thio]propanoic acid. Introduction of unsaturation into this compound gave two isomeric conformationally restricted analogues. The trans isomer was inactive at GABA receptors while the cis compound ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA)) was more potent than muscimol and GABA as a GABA agonist with respect to low affinity GABA receptor sites. Both isomers were moderately potent at inhibiting the uptake of [3H]-GABA into rat brain slices. Comparison of possible conformations of the two unsaturated isomers by interactive computer graphics modelling and comparison with muscimol has led to a plausible active conformation of ZAPA, which may be a selective and potent agonist for low affinity GABA binding sites. PMID:3015310

  3. Cold Suppresses Agonist-induced Activation of TRPV1

    PubMed Central

    Chung, M.-K.; Wang, S.

    2011-01-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction. PMID:21666106

  4. Antidiabetic Actions of an Estrogen Receptor β Selective Agonist

    PubMed Central

    Alonso-Magdalena, Paloma; Ropero, Ana B.; García-Arévalo, Marta; Soriano, Sergi; Quesada, Iván; Muhammed, Sarheed J.; Salehi, Albert; Gustafsson, Jan-Ake; Nadal, Ángel

    2013-01-01

    The estrogen receptor β (ERβ) is emerging as an important player in the physiology of the endocrine pancreas. We evaluated the role and antidiabetic actions of the ERβ selective agonist WAY200070 as an insulinotropic molecule. We demonstrate that WAY200070 enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single administration of WAY200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release and pancreatic β-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin-nicotinamide–induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic β-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic β-cell mass. We conclude that ERβ agonists should be considered as new targets for the treatment of diabetes. PMID:23349481

  5. Anti-cancer flavonoids are mouse selective STING agonists

    PubMed Central

    Kim, Sujeong; Li, Lingyin; Maliga, Zoltan; Yin, Qian; Wu, Hao; Mitchison, Timothy J.

    2013-01-01

    The flavonoids FAA and DMXAA showed impressive activity against solid tumors in mice, but failed clinical trials. They act on a previously unknown molecular target(s) to trigger cytokine release from leukocytes, which causes tumor-specific vascular damage and other anti-tumor effects. We show that DMXAA is a competitive agonist ligand for mouse STING (stimulator of interferon genes), a receptor for the bacterial PAMP cyclic-di-GMP (c-di-GMP) and an endogenous second messenger cyclic-GMP-AMP. In our structure-activity relationship studies, STING binding affinity and pathway activation activity of four flavonoids correlated with activity in a mouse tumor model measured previously. We propose that STING agonist activity accounts for the anti-tumor effects of FAA and DMXAA in mice. Importantly, DMXAA does not bind to human STING, which may account for its lack of efficacy or mechanism-related toxicity in man. We propose that STING is a druggable target for a novel innate immune activation mechanism of chemotherapy. PMID:23683494

  6. Aging changes agonist induced contractile responses in permeabilized rat bladder.

    PubMed

    Durlu-Kandilci, N Tugba; Denizalti, Merve; Sahin-Erdemli, Inci

    2015-08-01

    Aging alters bladder functions where a decrease in filling, storage and emptying is observed. These changes cause urinary incontinence, especially in women. The aim of this study is to examine how aging affects the intracellular calcium movements due to agonist-induced contractions in permeabilized female rat bladder. Urinary bladder isolated from young and old female Sprague-Dawley rats were used. Small detrusor strips were permeabilized with β-escin. The contractile responses induced with agonists were compared between young and old groups. Carbachol-induced contractions were decreased in permeabilized detrusor from old rats compared to young group. Heparin and ryanodine decreased carbachol-induced contractions in young rats where only heparin inhibited these contractions in olds. Caffeine-induced contractions but not inositol triphosphate (IP3)-induced contractions were decreased in old group compared to youngs. The cumulative calcium response curves (pCa 8-4) were also decreased in old rats. Carbachol-induced calcium sensitization responses did not alter by age where GTP-β-S and GF-109203X but not Y-27632 inhibited these responses. Carbachol-induced contractions decrease with aging in rat bladder detrusor. It can be postulated as IP3-induced calcium release (IICR) is primarily responsible for the contractions in older rats where the decrease in carbachol contractions in aging may be as a result of a decrease in calcium-induced calcium release (CICR), rather than carbachol-induced calcium sensitization. PMID:26153091

  7. A Sphingosine 1-phosphate receptor 2 selective allosteric agonist

    PubMed Central

    Satsu, Hideo; Schaeffer, Marie-Therese; Guerrero, Miguel; Saldana, Adrian; Eberhart, Christina; Hodder, Peter; Cayanan, Charmagne; Schürer, Stephan; Bhhatarai, Barun; Roberts, Ed; Rosen, Hugh; Brown, Steven J.

    2013-01-01

    Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound. PMID:23849205

  8. 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

  9. 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.

  10. Suppression of atherosclerosis by synthetic REV-ERB agonist.

    PubMed

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M; Solt, Laura A; Burris, Thomas P

    2015-05-01

    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. PMID:25800870

  11. 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

  12. 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

  13. 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

  14. Cariprazine:New dopamine biased agonist for neuropsychiatric disorders.

    PubMed

    De Deurwaerdère, P

    2016-02-01

    Cariprazine (RGH-188, MP-214, Vraylar[TM]) is a new dopamine receptor ligand developed for the treatment of several neuropsychiatric diseases including schizophrenia and bipolar disorders. Cariprazine displays higher affinity at dopamine D3 receptors and a similar affinity at D2 and 5-HT2B receptors. At variance with some atypical antipsychotics, its affinity at 5-HT1A, 5-HT2A and histamine H1 receptors is modest compared with its three main targets. Cariprazine could correspond to a biased agonist at dopamine receptors, displaying either antagonist or partial agonist properties depending on the signaling pathways linked to D2/D3 receptors. The compound crosses the blood-brain barrier, as revealed by positron emission tomography and pharmacokinetic studies in various species. Two main metabolites result mainly from the activity of CYP34A and display properties similar to those of the parent drug. Behavioral data report that cariprazine is efficacious in animal models addressing positive, negative and cognitive symptoms of schizophrenia with no extrapyramidal side effects. In September 2015, the FDA approved the use of cariprazine for the treatment of schizophrenia and type I bipolar disorder. The efficacy of cariprazine in other neuropsychiatric diseases is currently being evaluated in preclinical and clinical studies. Side effects have been observed in humans, including extrapyramidal side effects and akathisia of mild to moderate intensity. PMID:27092339

  15. Long-Acting Beta Agonists Enhance Allergic Airway Disease.

    PubMed

    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; McMurray, John S; Corry, David B

    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

  16. Timed artificial insemination in beef cattle using GnRH agonist, PGF2alpha and estradiol benzoate (EB).

    PubMed

    Fernandes, P; Teixeira, A B; Crocci, A J; Barros, C M

    2001-04-15

    The present work evaluated low-cost protocols for timed artificial insemination (TAI) in beef cattle. In Experiment 1, cycling nonlactating Nelore cows (Bos indicus, n=98) were assigned to the following groups: GnRH-PGF (GP) and GnRH-PGF-GnRH (GPG), whereas cycling (n=328, Experiment 2) or anestrus (n = 225, Experiment 3) lactating (L) cows were divided into 3 groups: GP-L, GPG-L and GnRH-PGF-Estradiol benzoate (GPE-L). In Experiment 4, lactating cows (n=201) were separated into 3 groups: GP-L, GPE-L and G/2PE-L. Animals from Experiment 1, 3 and 4 were treated (Day 0), at random stages of the estrous cycle, with 8 microg of buserelin acetate (GnRH agonist) intramuscularly (i.m.), whereas in Experiment 2 half of the cows received 8 and the other half 12 microg of GnRH (i.m.). Seven days later (D 7) all animals were treated with 25 mg of dinoprost trometamine (PGF2alpha, i.m.) except those cows from the G/2PE-L group which received only 1/2 dose of PGF2alpha (12.5 mg) via intravulvo-submucosa (i.v.s.m.). After PGF2alpha injection the animals from the control groups (GP and GP-L) were observed twice daily to detect estrus and AI was performed 12 h afterwards. The cows from the other groups received a second GnRH injection (D 8 in GPG-L and d9 in GPG groups) or one injection of estradiol benzoate (EB, 1.0 mg, D 8 in GPE-L group). All cows from GPG and GPG-L or GPE-L groups were AI 20 to 24 or 30 to 34 h, respectively, after the last hormonal injection. Pregnancy was determined by ultrasonography or rectal palpation 30 to 50 days after AI. In the control groups (GP and GP-L) percentage of animals detected in heat (44.5 to 70.3%) and pregnancy rate (20 to 42%) varied according to the number of animals with corpus luteum (CL) at the beginning of treatment. The administration of a second dose of GnRH either 24 (Experiment 2) or 48 h (Experiment 1) after PGF2alpha resulted in 47.7 and 44.9% pregnancy rates, respectively, after TAI in cycling animals. However, in anestrus

  17. The Validity and Reliability of Turkish Version of Fair Play Questionnaire in Physical Education (FPQ-PE) and an Implementation

    ERIC Educational Resources Information Center

    Mirzeoglu, Nevzat

    2015-01-01

    The study was primarily carried out with the aim of adaptation of Fair Play in Physical Education Questionnaire (FPQ-PE). In addition, the adapted questionnaire was implemented on Turkish children and youth aged between 11 and 18 and the results were presented. The questionnaire originally adapted by Hassandra et al. for Greek students was adapted…

  18. Origin of young EAS with E[sub 0]=1--10 PeV at the mountain level

    SciTech Connect

    Adamov, D.S.; Danilova, T.V.; Erlykin, A.D. )

    1993-06-15

    It is shown, that the appearance of young showers with the high concentration of electromagnetic (e.m.) energy in cores of EAS with E[sub 0]=1--10 PeV at the mountain level, different slopes of EAS size and e.m. energy spectra and the rise of [epsilon][sub [ital e][gamma

  19. Immobilization of Firefly Luciferase on PVA-co-PE Nanofibers Membrane as Biosensor for Bioluminescent Detection of ATP.

    PubMed

    Wang, Wenwen; Zhao, Qinghua; Luo, Mengying; Li, Mufang; Wang, Dong; Wang, Yuedan; Liu, Qiongzhen

    2015-09-16

    The bioluminescent reaction catalyzed by firefly luciferase has become widely established as an outstanding analytical system for assay of adenosine triphosphate (ATP). When in solution, the luciferase is unstable and cannot be reused. The problem can be partially solved by immobilizing the luciferase on solid substrates. The poly(vinyl alcohol-co-ethylene) (PVA-co-PE) nanofibers membrane has abundant active hydroxyl groups on the surface. The PVA-co-PE nanofibers membrane was first activated by cyanuric chloride with triazinyl group. Then the activated PVA-co-PE nanofibers membrane was subsequently reacted with 1,3-propanediamine and biotin. The firefly luciferase was immobilized onto the surface of 1,3-propanediamine- and biotin-functionalized membranes. The surface chemical structure and morphologies of nanofibers membranes were characterized by FTIR-ATR spectra and SEM. The hydrophilicity of membranes was tested by water contact angle measurements. The detection of fluorescence intensity displayed that the firefly-luciferase-immobilized PVA-co-PE nanofibers membranes indicated high catalytic activity and efficiency. Especially, the firefly-luciferase-immobilized nanofiber membrane which was functionalized by biotin can be a promising candidate as biosensor for bioluminescent detection of ATP because of its high detection sensitivity. PMID:26275118

  20. Implications of a PeV neutrino spectral cut-off in gamma-ray burst models

    NASA Astrophysics Data System (ADS)

    Petropoulou, M.; Giannios, D.; Dimitrakoudis, S.

    2014-11-01

    The recent discovery of extragalactic PeV neutrinos opens a new window to the exploration of cosmic ray accelerators. The observed PeV neutrino flux is close to the Waxman-Bahcall upper bound implying that gamma-ray bursts (GRBs) may be the source of ultrahigh energy cosmic rays (UHECRs). Starting with the assumption of the GRB-UHECR connection, we show using both analytical estimates and numerical simulations that the observed neutrinos can originate at the jet as a result of photopion interactions with the following implications: the neutrino spectra are predicted to have a cut-off at energy ≲10 PeV; the dissipation responsible for the GRB emission and cosmic ray acceleration takes place at distances rdiss ≃ 3 × 1011-3 × 1013 cm from the central engine; the Thomson optical depth at the dissipation region is τT ˜ 1; the jet carries a substantial fraction of its energy in the form of Poynting flux at the dissipation region, and has a Lorentz factor Γ ≃ 100-500. The non-detection of PeV neutrinos coincident with GRBs will indicate that GRBs are either poor cosmic accelerators or the dissipation takes place at small optical depths in the jet.

  1. 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

    ... 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 HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD...

  2. 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

    ... 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 HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD...

  3. 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

    ... 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 HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD...

  4. Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons.

    PubMed

    Gunn, Adam P; Wong, Bruce X; Johanssen, Timothy; Griffith, James C; Masters, Colin L; Bush, Ashley I; Barnham, Kevin J; Duce, James A; Cherny, Robert A

    2016-03-18

    Pyroglutamate-modified amyloid-β (pE-Aβ) is a highly neurotoxic amyloid-β (Aβ) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate of Aβ oligomerization and alters the interactions of Aβ with Cu(2+) and lipids; however, a link between these properties and the toxicity of pE-Aβ peptides has not been established. We report here that Aβ3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the full-length isoform (Aβ(1-42)). In contrast, Aβ(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas Aβ3pE-42 did not. We also report that Aβ3pE-42 preferentially associates with neuronal membranes and triggers Ca(2+) influx that can be partially blocked by the N-methyl-d-aspartate receptor antagonist MK-801. Aβ3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels than Aβ(1-42) over extended incubations. Pyroglutamate formation was additionally found to increase the relative efficiency of Aβ-dityrosine oligomer formation mediated by copper-redox cycling. PMID:26697885

  5. iPE-MMR: An integrated approach to accurately assign monoisotopic precursor masses to tandem mass spectrometric data

    PubMed Central

    Jung, Hee-Jung; Purvine, Samuel O.; Kim, Hokeun; Petyuk, Vladislav A.; Hyung, Seok-Won; Monroe, Matthew E.; Mun, Dong-Gi; Kim, Kyong-Chul; Park, Jong-Moon; Kim, Su-Jin; Tolic, Nikola; Slysz, Gordon W.; Moore, Ronald J.; Zhao, Rui; Adkins, Joshua N.; Anderson, Gordon A.; Lee, Hookeun; Camp, David G.; Yu, Myeong-Hee; Smith, Richard D.; Lee, Sang-Won

    2010-01-01

    Accurate assignment of monoisotopic precursor masses to tandem mass spectrometric (MS/MS) data is a fundamental and critically important step for successful peptide identifications in mass spectrometry based proteomics. Here we describe an integrated approach that combines three previously reported methods of treating MS/MS data for precursor mass refinement. This combined method, “integrated Post-Experiment Monoisotopic Mass Refinement” (iPE-MMR), integrates steps: 1) generation of refined MS/MS data by DeconMSn; 2) additional refinement of the resultant MS/MS data by a modified version of PE-MMR; 3) elimination of systematic errors of precursor masses using DtaRefinery. iPE-MMR is the first method that utilizes all MS information from multiple MS scans of a precursor ion including multiple charge states, in an MS scan, to determine precursor mass. By combining these methods, iPE-MMR increases sensitivity in peptide identification and provides increased accuracy when applied to complex high-throughput proteomics data. PMID:20863060

  6. Pre-Service Teachers in PE Involved in an Organizational Critical Incident: Emotions, Appraisal and Coping Strategies

    ERIC Educational Resources Information Center

    Vandercleyen, François; Boudreau, Pierre; Carlier, Ghislain; Delens, Cécile

    2014-01-01

    Background: Emotions play a major role in the learning of pre-service teachers. However, there is a lack of in-depth research on emotion in the context of physical education (PE), especially during the practicum. Lazarus's model and its concepts of appraisal and coping is a salient theoretical framework for understanding the emotional…

  7. Microwave-assisted fibrous decoration of mPE surface utilizing Aloe vera extract for tissue engineering applications

    PubMed Central

    Balaji, Arunpandian; Jaganathan, Saravana Kumar; Supriyanto, Eko; Muhamad, Ida Idayu; Khudzari, Ahmad Zahran Md

    2015-01-01

    Developing multifaceted, biocompatible, artificial implants for tissue engineering is a growing field of research. In recent times, several works have been reported about the utilization of biomolecules in combination with synthetic materials to achieve this process. Accordingly, in this study, the ability of an extract obtained from Aloe vera, a commonly used medicinal plant in influencing the biocompatibility of artificial material, is scrutinized using metallocene polyethylene (mPE). The process of coating dense fibrous Aloe vera extract on the surface of mPE was carried out using microwaves. Then, several physicochemical and blood compatibility characterization experiments were performed to disclose the effects of corresponding surface modification. The Fourier transform infrared spectrum showed characteristic vibrations of several active constituents available in Aloe vera and exhibited peak shifts at far infrared regions due to aloe-based mineral deposition. Meanwhile, the contact angle analysis demonstrated a drastic increase in wettability of coated samples, which confirmed the presence of active components on glazed mPE surface. Moreover, the bio-mimic structure of Aloe vera fibers and the influence of microwaves in enhancing the coating characteristics were also meticulously displayed through scanning electron microscopy micrographs and Hirox 3D images. The existence of nanoscale roughness was interpreted through high-resolution profiles obtained from atomic force microscopy. And the extent of variations in irregularities was delineated by measuring average roughness. Aloe vera-induced enrichment in the hemocompatible properties of mPE was established by carrying out in vitro tests such as activated partial thromboplastin time, prothrombin time, platelet adhesion, and hemolysis assay. In conclusion, the Aloe vera-glazed mPE substrate was inferred to attain desirable properties required for multifaceted biomedical implants. PMID:26425089

  8. Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification.

    PubMed

    Zaware, Pandurang; Shah, Shailesh R; Pingali, Harikishore; Makadia, Pankaj; Thube, Baban; Pola, Suresh; Patel, Darshit; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Jamili, Jeevankumar; Sairam, Kalapatapu V V M; Giri, Suresh; Patel, Lala; Patel, Harilal; Sudani, Hareshkumar; Patel, Hiren; Jain, Mukul; Patel, Pankaj; Bahekar, Rajesh

    2011-01-15

    A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders. PMID:21195611

  9. Fetal Phthalate Screen: Assessment of Several Phthalate Esters (PE) on Fetal Rodent Testosterone (T) Production and Gene Expressionfollowing In Utero Exposure

    EPA Science Inventory

    PE are a large family of compounds used in a wide array of products from medical tubing to pharmaceuticals to cables. Studies have shown that in utero treatment with PE such as diethyl hexyl phthalate (DEHP) during the critical period of fetal reproductive development produced ma...

  10. Controllable Biotinylated Poly(Ethylene-co-Glycidyl Methacrylate) (PE-co-GMA) Nanofibers to Bind Streptavidin-Horseradish Peroxidase (HRP) for Potential Biosensor Applications

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Poly(ethylene-co-glycidyl methacrylate) (PE-co-GMA) nanofibers with abundant active epoxy groups on surfaces were fabricated through a novel manufacturing process. The prepared PE-co-GMA nanofibers with different average diameters ranging from 100 to 400 nm were aminated by reacting the epoxy groups...

  11. Impact of Efficacy at the μ-Opioid Receptor on Antinociceptive Effects of Combinations of μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

    PubMed Central

    Maguire, David R.

    2014-01-01

    Cannabinoid receptor agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ9-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ9-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ9-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ9-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain. PMID:25194020

  12. 1,4-Benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonists.

    PubMed

    Sherrill, R G; Berman, J M; Birkemo, L; Croom, D K; Dezube, M; Ervin, G N; Grizzle, M K; James, M K; Johnson, M F; Queen, K L; Rimele, T J; Vanmiddlesworth, F; Sugg, E E

    2001-05-01

    A series of 1,4-benzodiazepines, N-1-substituted with an N-isopropyl-N-phenylacetamide moiety, was synthesized and screened for CCK-A agonist activity. In vitro agonist activity on isolated guinea pig gallbladder along with in vivo induction of satiety following intraperitoneal administration in a rat feeding assay was demonstrated. PMID:11354363

  13. The dopamine D1 receptor agonist SKF-82958 effectively increases eye blinking count in common marmosets.

    PubMed

    Kotani, Manato; Kiyoshi, Akihiko; Murai, Takeshi; Nakako, Tomokazu; Matsumoto, Kenji; Matsumoto, Atsushi; Ikejiri, Masaru; Ogi, Yuji; Ikeda, Kazuhito

    2016-03-01

    Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson's disease and Tourette syndrome [1,2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field due to their more developed prefrontal cortex than rodents, easy handling compare to other non-human primates, and requirement for small amounts of test drugs. In this study, we evaluated the effects of dopamine D1-4 receptors agonists on eye blinking in common marmosets. Our results show that the dopamine D1 receptor agonist SKF-82958 and the non-selective dopamine receptor agonist apomorphine significantly increased common marmosets eye blinking count, whereas the dopamine D2 agonist (+)-PHNO and the dopamine D3 receptor agonist (+)-PD-128907 produced somnolence in common marmosets resulting in a decrease in eye blinking count. The dopamine D4 receptor agonists PD-168077 and A-41297 had no effect on common marmosets' eye blinking count. Finally, the dopamine D1 receptor antagonist SCH 39166 completely blocked apomorphine-induced increase in eye blinking count. These results indicate that eye blinking in common marmosets may be a useful tool for in vivo screening of novel dopamine D1 receptor agonists as antipsychotics. PMID:26675887

  14. Functional desensitization of the β2 adrenoceptor is not dependent on agonist efficacy

    PubMed Central

    Rosethorne, Elizabeth M; Bradley, Michelle E; Kent, Toby C; Charlton, Steven J

    2015-01-01

    Chronic treatment with β2 adrenoceptor agonists is recommended as a first-line maintenance therapy for chronic obstructive pulmonary disease (COPD). However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time. In this study, we have investigated the tendency of such agonists, with a range of efficacies, to develop functional desensitization to cAMP responses in primary human bronchial smooth muscle cells following prolonged agonist exposure. The data show that upon repeat exposure, all agonists produced functional desensitization to the same degree and rate. In addition, β2 adrenoceptor internalization and β-arrestin-2 recruitment were monitored using β2·eGFP visualization and the PathHunter™ β-arrestin-2 assay, respectively. All agonists were capable of causing robust receptor internalization and β-arrestin-2 recruitment, the rate of which was influenced by agonist efficacy, as measured in those assays. In summary, although a relationship exists between agonist efficacy and the rate of both receptor internalization and β-arrestin-2 recruitment, there is no correlation between agonist efficacy and the rate or extent of functional desensitization. PMID:25692019

  15. Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms.

    PubMed

    Randáková, Alena; Dolejší, Eva; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; El-Fakahany, Esam E; Jakubík, Jan

    2015-07-01

    We mutated key amino acids of the human variant of the M1 muscarinic receptor that target ligand binding, receptor activation, and receptor-G protein interaction. We compared the effects of these mutations on the action of two atypical M1 functionally preferring agonists (N-desmethylclozapine and xanomeline) and two classical non-selective orthosteric agonists (carbachol and oxotremorine). Mutations of D105 in the orthosteric binding site and mutation of D99 located out of the orthosteric binding site decreased affinity of all tested agonists that was translated as a decrease in potency in accumulation of inositol phosphates and intracellular calcium mobilization. Mutation of D105 decreased the potency of the atypical agonist xanomeline more than that of the classical agonists carbachol and oxotremorine. Mutation of the residues involved in receptor activation (D71) and coupling to G-proteins (R123) completely abolished the functional responses to both classical and atypical agonists. Our data show that both classical and atypical agonists activate hM1 receptors by the same molecular switch that involves D71 in the second transmembrane helix. The principal difference among the studied agonists is rather in the way they interact with D105 in the orthosteric binding site. Furthermore, our data demonstrate a key role of D105 in xanomeline wash-resistant binding and persistent activation of hM1 by wash-resistant xanomeline. PMID:25882246

  16. Prolonging Survival of Corneal Transplantation by Selective Sphingosine-1-Phosphate Receptor 1 Agonist

    PubMed Central

    Gao, Min; Liu, Yong; Xiao, Yang; Han, Gencheng; Jia, Liang; Wang, Liqiang; Lei, Tian; Huang, Yifei

    2014-01-01

    Corneal transplantation is the most used therapy for eye disorders. Although the cornea is somewhat an immune privileged organ, immune rejection is still the major problem that reduces the success rate. Therefore, effective chemical drugs that regulate immunoreactions are needed to improve the outcome of corneal transplantations. Here, a sphingosine-1-phosphate receptor 1 (S1P1) selective agonist was systematically evaluated in mouse allogeneic corneal transplantation and compared with the commonly used immunosuppressive agents. Compared with CsA and the non-selective sphingosine 1-phosphate (S1P) receptor agonist FTY720, the S1P1 selective agonist can prolong the survival corneal transplantation for more than 30 days with a low immune response. More importantly, the optimal dose of the S1P1 selective agonist was much less than non-selective S1P receptor agonist FTY720, which would reduce the dose-dependent toxicity in drug application. Then we analyzed the mechanisms of the selected S1P1 selective agonist on the immunosuppression. The results shown that the S1P1 selective agonist could regulate the distribution of the immune cells with less CD4+ T cells and enhanced Treg cells in the allograft, moreover the expression of anti-inflammatory cytokines TGF-β1 and IL-10 unregulated which can reduce the immunoreactions. These findings suggest that S1P1 selective agonist may be a more appropriate immunosuppressive compound to effectively prolong mouse allogeneic corneal grafts survival. PMID:25216235

  17. Interleukin 2 (IL2) PE40 is cytotoxic to cells displaying either the p55 or p70 subunit of the IL2 receptor.

    PubMed

    Lorberboum-Galski, H; Kozak, R W; Waldmann, T A; Bailon, P; FitzGerald, D J; Pastan, I

    1988-12-15

    IL2-PE40 is a chimeric protein composed of human interleukin 2 (IL2) genetically fused to the amino terminus of a modified form of pseudomonas exotoxin (PE). Internalization of IL2 via the individual p55 and p70 subunits of the IL2 receptor was studied using IL2-PE40 on several mouse and human cell lines expressing either the p55, the p70, or both IL2 receptor subunits. Internalization was assessed by measuring inhibition of protein synthesis caused by the toxin moiety of IL2-PE40. The results demonstrate that IL2 internalization is mediated by either the p55 receptor subunit or by the p70 subunit but is much more efficient when high affinity receptors composed of both subunits are present. IL2-PE40 is a powerful reagent for studying IL2 receptor interactions and for analyzing pathways of the immune response and its regulation. PMID:3143716

  18. Pinpointing the knee of cosmic rays with diffuse PeV γ-rays and neutrinos

    SciTech Connect

    Guo, Y. Q.; Hu, H. B.; Yuan, Q.; Tian, Z.; Gao, X. J.

    2014-11-01

    The origin of the knee in the cosmic ray spectrum remains to be an unsolved fundamental problem. There are various kinds of models that predict different break positions and the compositions of the knee. In this work, we suggest the use of diffuse γ-rays and neutrinos as probes to test these models. Based on several typical types of composition models, the diffuse γ-ray and neutrino spectra are calculated and show distinctive cutoff behaviors at energies from tens of TeV to multi-PeV. The expected flux will be observable by the newly upgraded Tibet-ASγ+MD (muon detector) experiment as well as more sensitive future projects, such as LHAASO and HiSCORE. By comparing the neutrino spectrum with the recent observations by the IceCube experiment, we find that the diffuse neutrinos from interactions between the cosmic rays and the interstellar medium may not be responsible to the majority of the IceCube events. Future measurements of the neutrinos may be able to identify the Galactic diffuse component and shed further light on the problem of the knee of cosmic rays.

  19. NICHE: Using Cherenkov radiation to extend Telescope Array to sub-PeV energies

    NASA Astrophysics Data System (ADS)

    Bergman, Douglas; Krizmanic, John; Tsunesada, Yoshiki; Abu-Zayyad, Tareq; Belz, John; Thomson, Gordon

    2016-03-01

    The Non-Imaging CHErenkov (NICHE) Array will measure the flux and nuclear composition evolution of cosmic rays (CRs) from below 1 PeV to 1 EeV. NICHE will be co-sited with the Telescope Array (TA) Low Energy (TALE) extension, and will observe events simultaneously with the TALE telescopes acting in imaging-Cherenkov mode. This will be the first hybrid-Cherenkov (simultaneous imaging and non-imaging Cherenkov) measurements of CRs in the Knee region of the CR energy spectrum. NICHE uses easily deployable detectors to measure the amplitude and time-spread of the air-shower Cherenkov signal to achieve an event-by-event measurement of Xmax and energy, each with excellent resolution. First generation detectors are under construction and will form an initial prototype array (j-NICHE) that will be deployed in Summer 2016. In this talk, the NICHE design, array performance, prototype development, and status will be discussed as well as NICHE's ability to measure the cosmic ray nuclear composition as a function of energy.

  20. First observation of PeV-energy neutrinos with IceCube.

    PubMed

    Aartsen, M G; Abbasi, R; Abdou, Y; Ackermann, M; Adams, J; Aguilar, J A; Ahlers, M; Altmann, D; Auffenberg, J; Bai, X; Baker, M; Barwick, S W; Baum, V; Bay, R; Beatty, J J; Bechet, S; Becker Tjus, J; Becker, K-H; Bell, M; Benabderrahmane, M L; BenZvi, S; Berdermann, J; Berghaus, P; Berley, D; Bernardini, E; Bernhard, A; Bertrand, D; Besson, D Z; Binder, G; Bindig, D; Bissok, M; Blaufuss, E; Blumenthal, J; Boersma, D J; Bohaichuk, S; Bohm, C; Bose, D; Böser, S; Botner, O; Brayeur, L; Bretz, H-P; Brown, A M; Bruijn, R; Brunner, J; Carson, M; Casey, J; Casier, M; Chirkin, D; Christov, A; Christy, B; Clark, K; Clevermann, F; Coenders, S; Cohen, S; Cowen, D F; Cruz Silva, A H; Danninger, M; Daughhetee, J; Davis, J C; De Clercq, C; De Ridder, S; Desiati, P; de With, M; DeYoung, T; Díaz-Vélez, J C; Dunkman, M; Eagan, R; Eberhardt, B; Eisch, J; Ellsworth, R W; Euler, S; Evenson, P A; Fadiran, O; Fazely, A R; Fedynitch, A; Feintzeig, J; Feusels, T; Filimonov, K; Finley, C; Fischer-Wasels, T; Flis, S; Franckowiak, A; Franke, R; Frantzen, K; Fuchs, T; Gaisser, T K; Gallagher, J; Gerhardt, L; Gladstone, L; Glüsenkamp, T; Goldschmidt, A; Golup, G; Gonzalez, J G; Goodman, J A; Góra, D; Grant, D; Groß, A; Gurtner, M; Ha, C; Haj Ismail, A; Hallen, P; Hallgren, A; Halzen, F; Hanson, K; Heereman, D; Heinen, D; Helbing, K; Hellauer, R; Hickford, S; Hill, G C; Hoffman, K D; Hoffmann, R; Homeier, A; Hoshina, K; Huelsnitz, W; Hulth, P O; Hultqvist, K; Hussain, S; Ishihara, A; Jacobi, E; Jacobsen, J; Jagielski, K; Japaridze, G S; Jero, K; Jlelati, O; Kaminsky, B; Kappes, A; Karg, T; Karle, A; Kelley, J L; Kiryluk, J; Kislat, F; Kläs, J; Klein, S R; Köhne, J-H; Kohnen, G; Kolanoski, H; Köpke, L; Kopper, C; Kopper, S; Koskinen, D J; Kowalski, M; Krasberg, M; Krings, K; Kroll, G; Kunnen, J; Kurahashi, N; Kuwabara, T; Labare, M; Landsman, H; Larson, M J; Lesiak-Bzdak, M; Leuermann, M; Leute, J; Lünemann, J; Madsen, J; Maruyama, R; Mase, K; Matis, H S; McNally, F; Meagher, K; Merck, M; Mészáros, P; Meures, T; Miarecki, S; Middell, E; Milke, N; Miller, J; Mohrmann, L; Montaruli, T; Morse, R; Nahnhauer, R; Naumann, U; Niederhausen, H; Nowicki, S C; Nygren, D R; Obertacke, A; Odrowski, S; Olivas, A; Olivo, M; O'Murchadha, A; Paul, L; Pepper, J A; Pérez de los Heros, C; Pfendner, C; Pieloth, D; Pinat, E; Pirk, N; Posselt, J; Price, P B; Przybylski, G T; Rädel, L; Rameez, M; Rawlins, K; Redl, P; Reimann, R; Resconi, E; Rhode, W; Ribordy, M; Richman, M; Riedel, B; Rodrigues, J P; Rott, C; Ruhe, T; Ruzybayev, B; Ryckbosch, D; Saba, S M; Salameh, T; Sander, H-G; Santander, M; Sarkar, S; Schatto, K; Scheel, M; Scheriau, F; Schmidt, T; Schmitz, M; Schoenen, S; Schöneberg, S; Schönwald, A; Schukraft, A; Schulte, L; Schulz, O; Seckel, D; Sestayo, Y; Seunarine, S; Sheremata, C; Smith, M W E; Soiron, M; Soldin, D; Spiczak, G M; Spiering, C; Stamatikos, M; Stanev, T; Stasik, A; Stezelberger, T; Stokstad, R G; Stößl, A; Strahler, E A; Ström, R; Sullivan, G W; Taavola, H; Taboada, I; Tamburro, A; Ter-Antonyan, S; Tešić, G; Tilav, S; Toale, P A; Toscano, S; Usner, M; van der Drift, D; van Eijndhoven, N; Van Overloop, A; van Santen, J; Vehring, M; Voge, M; Vraeghe, M; Walck, C; Waldenmaier, T; Wallraff, M; Wasserman, R; Weaver, Ch; Wellons, M; Wendt, C; Westerhoff, S; Whitehorn, N; Wiebe, K; Wiebusch, C H; Williams, D R; Wissing, H; Wolf, M; Wood, T R; Woschnagg, K; Xu, C; Xu, D L; Xu, X W; Yanez, J P; Yodh, G; Yoshida, S; Zarzhitsky, P; Ziemann, J; Zierke, S; Zilles, A; Zoll, M

    2013-07-12

    We report on the observation of two neutrino-induced events which have an estimated deposited energy in the IceCube detector of 1.04±0.16 and 1.14±0.17 PeV, respectively, the highest neutrino energies observed so far. These events are consistent with fully contained particle showers induced by neutral-current ν(e,μ,τ) (ν(e,μ,τ)) or charged-current ν(e) (ν(e)) interactions within the IceCube detector. The events were discovered in a search for ultrahigh energy neutrinos using data corresponding to 615.9 days effective live time. The expected number of atmospheric background is 0.082±0.004(stat)(-0.057)(+0.041)(syst). The probability of observing two or more candidate events under the atmospheric background-only hypothesis is 2.9×10(-3) (2.8σ) taking into account the uncertainty on the expected number of background events. These two events could be a first indication of an astrophysical neutrino flux; the moderate significance, however, does not permit a definitive conclusion at this time. PMID:23889381

  1. The origin of the p.E180 growth hormone receptor gene mutation.

    PubMed

    Ostrer, Harry

    2016-06-01

    Laron syndrome, an autosomal recessive condition of extreme short stature, is caused by the absence or dysfunction of the growth hormone receptor. A recurrent mutation in the GHR gene, p.E180, did not alter the encoded amino acid, but activated a cryptic splice acceptor resulting in a receptor protein with an 8-amino acid deletion in the extracellular domain. This mutation has been observed among Sephardic Jews and among individuals in Ecuador, Brazil and Chile, most notably in a large genetic isolate in Loja, Ecuador. A common origin has been postulated based on a shared genetic background of markers flanking this mutation, suggesting that the Lojanos (and others) may have Sephardic (Converso) Jewish ancestry. Analysis of the population structure of Lojanos based on genome-wide analysis demonstrated European, Sephardic Jewish and Native American ancestry in this group. X-autosomal comparison and monoallelic Y chromosomal and mitochondrial genetic analysis demonstrated gender-biased admixture between Native American women and European and Sephardic Jewish men. These findings are compatible with the co-occurrence of the Inquisition and the colonization of the Americas, including Converso Jews escaping the Inquisition in the Iberian Peninsula. Although not found among Lojanos, Converso Jews also brought founder mutations to contemporary Hispanic and Latino populations in the BRCA1 (c.68_69delAG) and BLM (c.2207_2212delATCTGAinsTAGATTC) genes. PMID:26277320

  2. PE-CMOS based C-scan ultrasound for foreign object detection in soft tissue.

    PubMed

    Liu, Chu-Chuan; Lo, Shih-Chung Ben; Freedman, Matthew T; Lasser, Marvin E; Kula, John; Sarcone, Anita; Wang, Yue

    2010-01-01

    In this paper, we introduce a C-scan ultrasound prototype and three imaging modalities for the detection of foreign objects inserted in porcine soft tissue. The object materials include bamboo, plastics, glass and aluminum alloys. The images of foreign objects were acquired using the C-scan ultrasound, a portable B-scan ultrasound, film-based radiography, and computerized radiography. The C-scan ultrasound consists of a plane wave transducer, a compound acoustic lens system, and a newly developed ultrasound sensor array based on the complementary metal-oxide semiconductor coated with piezoelectric material (PE-CMOS). The contrast-to-noise ratio (CNR) of the images were analyzed to quantitatively evaluate the detectability using different imaging modalities. The experimental results indicate that the C-scan prototype has better CNR values in 4 out of 7 objects than other modalities. Specifically, the C-scan prototype provides more detail information of the soft tissues without the speckle artifacts that are commonly seen with conventional B-scan ultrasound, and has the same orientation as the standard radiographs but without ionizing radiation. PMID:20036873

  3. A simplified approach for the lifetime prediction of PE in nuclear environments

    NASA Astrophysics Data System (ADS)

    Khelidj, N.; Colin, X.; Audouin, L.; Verdu, J.

    2005-07-01

    A simplified method is proposed to estimate the lifetime of thin samples of unstabilised and unfilled polyethylene (PE) exposed at low dose rates at room temperature in air. The point of departure is the observation that the "ceiling lifetime" is the lifetime due to thermal oxidation. Pure thermal oxidation predominates at very low dose rates (typically for D bar < 1. 6 ×10-7 Gy s-1) and is characterised by very long lifetimes (typically of the order of 20 years at ambient temperature). Pure radio-oxidation predominates at high dose rates (typically for D bar > 5 ×10-1 Gy s-1) and is characterised by a letal dose independent of dose rate, i.e. a lifetime proportional to the reciprocal dose rate: tF ≈ 1. 6 ×105D bar - 1 . At intermediary dose rates (typically for 1. 6 ×10-7 < D bar < 5 ×10-1 Gy s-1), a radiothermal oxidation proceeds. From a kinetic investigation, it is found that, in this latter domain, lifetime can be also estimated by a simple power law: tF ≈ 2. 3 ×105D bar - 1 / 2 .

  4. Biological, Physical, And Chemical Data From Gulf of Mexico Core PE0305-GC1

    USGS Publications Warehouse

    Osterman, Lisa E.; Swarzenski, Peter W.; Hollander, David

    2010-01-01

    This paper presents benthic foraminiferal census data, and magnetic susceptibility, 210Pb , radiocarbon, and geochemical measurements from gravity core PE0305-GC1 (=GC1). Core GC1 was collected from the Louisiana continental shelf as part of an initiative to investigate the geographic and temporal extent of hypoxia, low-oxygen water, in the Gulf of Mexico. Hypoxia (<1.4 ml/l or <2 ppm oxygen concentration) in Gulf of Mexico waters can eventually lead to death of marine species. The development of hypoxia off the Mississippi delta has increased steadily since routine and systematic measurements were begun in 1985 and has been linked to the use of fertilizer in the Mississippi basin. Benthic foraminifers provide a proxy to track the development of hypoxia prior to 1985. Previous work determined that the relative occurrence of three low-oxygen-tolerant species is highest in the hypoxia zone. The cumulative percentage of these three species (% Pseudononion atlanticum + % Epistominella vitrea, + % Buliminella morgani = PEB index of hypoxia) was used to investigate fluctuation in paleohypoxia in four cores, including the upper 60 cm of GC1. In this report, we compile all available data from GC1 as the basis for further publications.

  5. STRUCTURED JETS IN BL LAC OBJECTS: EFFICIENT PeV NEUTRINO FACTORIES?

    SciTech Connect

    Tavecchio, Fabrizio; Ghisellini, Gabriele; Guetta, Dafne

    2014-09-20

    The origin of high-energy neutrinos (0.1–1 PeV range) detected by IceCube remains a mystery. In this work, we explore the possibility that efficient neutrino production can occur in structured jets of BL Lac objects, characterized by a fast inner spine surrounded by a slower layer. This scenario has been widely discussed in the framework of the high-energy emission models for BL Lac objects and radio galaxies. One of the relevant consequences of a velocity structure is the enhancement of the inverse Compton emission caused by the radiative coupling of the two zones. We show that a similar boosting could occur for the neutrino output of the spine through the photo-meson reaction of high-energy protons scattering off the amplified soft target photon field of the layer. Assuming the local density and the cosmological evolution of γ-ray BL Lac object derived from Fermi Large Area Telescope data, we calculate the expected diffuse neutrino intensity, which can match the IceCube data for a reasonable choice of parameters.

  6. An ultra-low-voltage rectifier for PE energy harvesting applications

    NASA Astrophysics Data System (ADS)

    Jingmin, Wang; Zheng, Yang; Zhangming, Zhu; Yintang, Yang

    2016-02-01

    An ultra low voltage rectifier with high power conversion efficiency (PCE) for PE energy harvesting applications is presented in this paper. This is achieved by utilizing the DTMOS which the body terminal is connected to the gate terminal in a diode connected transistor. This implementation facilitates the rectifier with dynamic control over the threshold voltage. Moreover, we use input powered to take the place of output powered to reduce the power loss and thereby increasing the power conversion efficiency. Based on standard SMIC 0.18 μm CMOS technology, the simulation results show that the voltage conversion efficiency and the power conversion efficiency can reach up to 90.5% and 95.5% respectively, when the input voltage equals to 0.2 V @ 100 Hz with load resistance 50 kω. Input voltages with frequencies in the range of 10 Hz-1 kHz can be rectified. Project supported by the National Natural Science Foundation of China (Nos. 61234002, 61322405, 61306044, 61376033) and the National High-Tech Program of China (No. 2013AA014103).

  7. Hyperthermia induced by the dopamine D1 receptor agonist SK&F38393 in combination with the dopamine D2 receptor agonist talipexole in the rat.

    PubMed

    Nagashima, M; Yamada, K; Kimura, H; Matsumoto, S; Furukawa, T

    1992-12-01

    The present experiments were performed to investigate the effects of dopamine D1 receptor agonists given alone or in combination with dopamine D2 receptor agonists on body temperature in rats. The selective dopamine D1 receptor agonist, 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SK&F38393), produced hyperthermia. However, the dopamine D2 receptor agonist, B-HT 920 (talipexole), and the newly synthesized dopamine D2 receptor agonist, (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (SND 919), did not change the temperature. Interestingly, the SK&F38393-induced hyperthermia was enhanced by talipexole and SND 919. The drastic hyperthermia induced by combined administration of dopamine D1 and D2 receptor agonists was blocked by either the dopamine D1 receptor antagonist, SCH23390, or the dopamine D2 receptor antagonist, spiperone. On the other hand, treatment with prazosin, yohimbine, propranolol, scopolamine, or methysergide failed to affect the marked hyperthermia. The present results suggest that a functional link between dopamine D1 and D2 receptors may be synergistic in the regulation of body temperature and that concurrent stimulation of both dopamine D1 and D2 receptors thereby produces marked hyperthermia in the rat. PMID:1361996

  8. CD4+ T Cells Recognizing PE/PPE Antigens Directly or via Cross Reactivity Are Protective against Pulmonary Mycobacterium tuberculosis Infection.

    PubMed

    Sayes, Fadel; Pawlik, Alexandre; Frigui, Wafa; Gröschel, Matthias I; Crommelynck, Samuel; Fayolle, Catherine; Cia, Felipe; Bancroft, Gregory J; Bottai, Daria; Leclerc, Claude; Brosch, Roland; Majlessi, Laleh

    2016-07-01

    Mycobacterium tuberculosis (Mtb), possesses at least three type VII secretion systems, ESX-1, -3 and -5 that are actively involved in pathogenesis and host-pathogen interaction. We recently showed that an attenuated Mtb vaccine candidate (Mtb Δppe25-pe19), which lacks the characteristic ESX-5-associated pe/ppe genes, but harbors all other components of the ESX-5 system, induces CD4+ T-cell immune responses against non-esx-5-associated PE/PPE protein homologs. These T cells strongly cross-recognize the missing esx-5-associated PE/PPE proteins. Here, we characterized the fine composition of the functional cross-reactive Th1 effector subsets specific to the shared PE/PPE epitopes in mice immunized with the Mtb Δppe25-pe19 vaccine candidate. We provide evidence that the Mtb Δppe25-pe19 strain, despite its significant attenuation, is comparable to the WT Mtb strain with regard to: (i) its antigenic repertoire related to the different ESX systems, (ii) the induced Th1 effector subset composition, (iii) the differentiation status of the Th1 cells induced, and (iv) its particular features at stimulating the innate immune response. Indeed, we found significant contribution of PE/PPE-specific Th1 effector cells in the protective immunity against pulmonary Mtb infection. These results offer detailed insights into the immune mechanisms underlying the remarkable protective efficacy of the live attenuated Mtb Δppe25-pe19 vaccine candidate, as well as the specific potential of PE/PPE proteins as protective immunogens. PMID:27467705

  9. CD4+ T Cells Recognizing PE/PPE Antigens Directly or via Cross Reactivity Are Protective against Pulmonary Mycobacterium tuberculosis Infection

    PubMed Central

    Sayes, Fadel; Pawlik, Alexandre; Frigui, Wafa; Gröschel, Matthias I.; Crommelynck, Samuel; Fayolle, Catherine; Cia, Felipe; Bancroft, Gregory J.; Bottai, Daria; Leclerc, Claude; Brosch, Roland; Majlessi, Laleh

    2016-01-01

    Mycobacterium tuberculosis (Mtb), possesses at least three type VII secretion systems, ESX-1, -3 and -5 that are actively involved in pathogenesis and host-pathogen interaction. We recently showed that an attenuated Mtb vaccine candidate (Mtb Δppe25-pe19), which lacks the characteristic ESX-5-associated pe/ppe genes, but harbors all other components of the ESX-5 system, induces CD4+ T-cell immune responses against non-esx-5-associated PE/PPE protein homologs. These T cells strongly cross-recognize the missing esx-5-associated PE/PPE proteins. Here, we characterized the fine composition of the functional cross-reactive Th1 effector subsets specific to the shared PE/PPE epitopes in mice immunized with the Mtb Δppe25-pe19 vaccine candidate. We provide evidence that the Mtb Δppe25-pe19 strain, despite its significant attenuation, is comparable to the WT Mtb strain with regard to: (i) its antigenic repertoire related to the different ESX systems, (ii) the induced Th1 effector subset composition, (iii) the differentiation status of the Th1 cells induced, and (iv) its particular features at stimulating the innate immune response. Indeed, we found significant contribution of PE/PPE-specific Th1 effector cells in the protective immunity against pulmonary Mtb infection. These results offer detailed insights into the immune mechanisms underlying the remarkable protective efficacy of the live attenuated Mtb Δppe25-pe19 vaccine candidate, as well as the specific potential of PE/PPE proteins as protective immunogens. PMID:27467705

  10. Pharmacology and clinical potential of guanylyl cyclase C agonists in the treatment of ulcerative colitis

    PubMed Central

    Pitari, Giovanni M

    2013-01-01

    Agonists of the transmembrane intestinal receptor guanylyl cyclase C (GCC) have recently attracted interest as promising human therapeutics. Peptide ligands that can specifically induce GCC signaling in the intestine include endogenous hormones guanylin and uroguanylin, diarrheagenic bacterial enterotoxins (ST), and synthetic drugs linaclotide, plecanatide, and SP-333. These agonists bind to GCC at intestinal epithelial surfaces and activate the receptor’s intracellular catalytic domain, an event initiating discrete biological responses upon conversion of guanosine-5′-triphosphate to cyclic guanosine monophosphate. A principal action of GCC agonists in the colon is the promotion of mucosal homeostasis and its dependent barrier function. Herein, GCC agonists are being developed as new medications to treat inflammatory bowel diseases, pathological conditions characterized by mucosal barrier hyperpermeability, abnormal immune reactions, and chronic local inflammation. This review will present important concepts underlying the pharmacology and therapeutic utility of GCC agonists for patients with ulcerative colitis, one of the most prevalent inflammatory bowel disease disorders. PMID:23637522

  11. Voltage dependence of agonist effectiveness at the frog neuromuscular junction: resolution of a paradox.

    PubMed Central

    Dionne, V E; Stevens, C F

    1975-01-01

    1. End-plate currents produced by nerve-released acetylcholine and iontophoretically applied acetylcholine and carbachol have been recorded from voltage-clamped frog cutaneous pectoris neuromuscular junctions made visible with Nomarski differential interference contrast optics. 2. The effectiveness of agonists - that is, the end-plate conductance change produced by a given dose-has been determined as a function of post-junctional membrane potential. 3. As the post-junctional membrane potential is made more negative, nerve-released acetylcholine becomes less effective whereas iontophoretically-applied agonists become more effective. 4. This voltage dependence of agonist effectiveness is mediated neither by end-plate current iontophoresis of agonist into the cleft nor through electric field effects on the esterase. 5. Influences of membrane potential on the opening and closing of end-plate channel gates can account quantitatively for the voltage-dependent effectiveness of both nerve-released and iontophoretically applied agonist. PMID:1081139

  12. The link between non-ergot-derived dopamine agonists and heart failure: how strong is it?

    PubMed

    Lockett, Katrina; DeBacker, Danielle; Cauthon, Kimberly A B

    2015-03-01

    Dopamine agonists are commonly used as initial monotherapy and adjunct treatment for Parkinson's disease. However, the Food and Drug Administration recently linked pramipexole use with an increased risk of heart failure (HF). Several case-control studies demonstrate a possible increased risk of the development of HF in patients taking non-ergot-derived dopamine agonists compared with patients not taking dopamine agonists. In patients taking non-ergot-derived dopamine agonists, the studies associated the risk of increased HF with pramipexole. These studies did not find a possible increased risk with ropinirole, but to date no randomized, controlled trials have been conducted to directly compare ropinirole with pramipexole and the risk of HF. The mechanism by which HF occurs is unknown, but the development of edema after dopamine agonist use could increase the risk of HF. If patients with a history of cardiovascular disease or edema are prescribed pramipexole, additional monitoring for HF signs and symptoms is recommended. PMID:25760663

  13. [Is the LHRH Agonist Recommended for Fertility Preservation ?].

    PubMed

    Kimura, Kosei; Iwamoto, Mitsuhiko; Tanaka, Satoru; Watanabe, Toru; Aihara, Tomohiko; Sugimoto, Takeki; Miyara, Kyuichiro; Hayashi, Mitsuhiro; Kouno, Tsutomu; Baba, Shinichi; Kawashima, Hiroaki; Hashimoto, Naoki; Uchiyama, Kazuhisa

    2015-08-01

    The POEMS reportedan effect of goserelin for fertility preservation. The Clinical Practice Guideline for Breast Cancer by The Japanese Breast Cancer Society indicates that the use of the LHRH agonist (LHRHa) for preventing chemotherapy-induced early menopause is a grade C-1 recommendation, and its use for fertility preservation is a grade C-2 recommendation. Results from previous studies on the effects of LHRHa for fertility preservation have varied owing to differences in chemotherapy regimens, definitions of ovarian failure, and dosages of tamoxifen. In the POEMS, the primary endpoint of ovarian failure at 2 years was significantly lower, and the secondary endpoint of pregnancy outcomes was better in the combination group; however, precise interpretation is difficult because many cases were excluded. Currently, it is not necessary to revise The Clinical Practice Guideline; however, desirable results from future studies may allow the recommendation of a specific dosage of LHRHa for fertility preservation. PMID:26321722

  14. The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity

    PubMed Central

    Crane, James; McGowan, Barbara

    2015-01-01

    There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity. PMID:26977279

  15. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist.

    PubMed

    Kühnen, Peter; Clément, Karine; Wiegand, Susanna; Blankenstein, Oliver; Gottesdiener, Keith; Martini, Lea L; Mai, Knut; Blume-Peytavi, Ulrike; Grüters, Annette; Krude, Heiko

    2016-07-21

    Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2). PMID:27468060

  16. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis

    PubMed Central

    Dietrich, Johannes W.; Landgrafe, Gabi; Fotiadou, Elisavet H.

    2012-01-01

    This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of thyroid homeostasis. Explicit usage of this information with mathematical methods promises to deliver a better understanding of thyrotropic feedback control and new options for personalised diagnosis of thyroid dysfunction and targeted therapy, also by permitting a new perspective on the conundrum of the TSH reference range. PMID:23365787

  17. The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity.

    PubMed

    Crane, James; McGowan, Barbara

    2016-03-01

    There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity. PMID:26977279

  18. Saralasin and Sarile Are AT2 Receptor Agonists

    PubMed Central

    2014-01-01

    Saralasin and sarile, extensively studied over the past 40 years as angiotensin II (Ang II) receptor blockers, induce neurite outgrowth in a NG108-15 cell assay to a similar extent as the endogenous Ang II. In their undifferentiated state, these cells express mainly the AT2 receptor. The neurite outgrowth was inhibited by preincubation with the AT2 receptor selective antagonist PD 123,319, which suggests that the observed outgrowth was mediated by the AT2 receptor. Neither saralasin nor sarile reduced the neurite outgrowth induced by Ang II proving that the two octapeptides do not act as antagonists at the AT2 receptor and may be considered as AT2 receptor agonists. PMID:25313325

  19. Use of Thrombopoietin Receptor Agonists in Childhood Immune Thrombocytopenia

    PubMed Central

    Garzon, Angelica Maria; Mitchell, William Beau

    2015-01-01

    Most children with immune thrombocytopenia (ITP) will have spontaneous remission regardless of therapy, while about 20% will go on to have chronic ITP. In those children with chronic ITP who need treatment, standard therapies for acute ITP may have adverse effects that complicate their long-term use. Thus, alternative treatment options are needed for children with chronic ITP. Thrombopoietin receptor agonists (TPO-RA) have been shown to be safe and efficacious in adults with ITP, and represent a new treatment option for children with chronic ITP. One TPO-RA, eltrombopag, is now approved for children. Clinical trials in children are ongoing and data are emerging on safety and efficacy. This review will focus on the physiology of TPO-RA, their clinical use in children, as well as the long-term safety issues that need to be considered when using these agents. PMID:26322297

  20. Antiinfective applications of toll-like receptor 9 agonists.

    PubMed

    Krieg, Arthur M

    2007-07-01

    The innate immune system detects pathogens by the presence of highly conserved pathogen-expressed molecules, which trigger host immune defenses. Toll-like receptor (TLR) 9 detects unmethylated CpG dinucleotides in bacterial or viral DNA, and can be stimulated for therapeutic applications with synthetic oligodeoxynucleotides containing immune stimulatory "CpG motifs." TLR9 activation induces both innate and adaptive immunity. The TLR9-induced innate immune activation can be applied in the prevention or treatment of infectious diseases, and the adaptive immune-enhancing effects can be harnessed for improving vaccines. This article highlights the current understanding of the mechanism of action of CpG oligodeoxynucleotides, and provides an overview of the preclinical data and early human clinical trial results, applying these TLR9 agonists in the field of infectious diseases. PMID:17607015

  1. Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist

    PubMed Central

    Tai, Sherrica; Nikas, Spyros P.; Shukla, Vidyanand G.; Vemuri, Kiran; Makriyannis, Alexandros; Järbe, Torbjörn U.C.

    2015-01-01

    Rationale Previous reports shows rimonabant's inverse properties may be a limiting factor for treating cannabinoid dependence. To overcome this limitation neutral antagonists were developed, to address mechanisms by which an inverse agonist and neutral antagonist elicit withdrawal. Objective Introduces an animal model to study cannabinoid dependence by incorporating traditional methodologies and profiling novel cannabinoid ligands with distinct pharmacological properties/modes of action by evaluating their pharmacological effects on CB1-receptor (CB1R) related physiological/behavioral endpoints. Methods The cannabinergic AM2389 was acutely characterized in the tetrad (locomotor activity, analgesia, inverted screen/catalepsy bar test and temperature); with some comparisons made to Δ9-tetrahydrocannabinol (THC). Tolerance was measured in mice repeatedly administered AM2389. Antagonist-precipitated withdrawal was characterized in cannabinoid-adapted mice induced by either centrally acting antagonists, rimonabant and AM4113, or an antagonist with limited brain penetration, AM6545. Results In the tetrad, AM2389 was more potent and longer acting than THC, suggesting a novel approach for inducing dependence. Repeated administration of AM2389 led to tolerance by attenuating hypothermia that was induced by acute AM2389 administration. Antagonist-precipitated withdrawal signs were induced by rimonabant or AM4113, but not by AM6545. Antagonist-precipitated withdrawal was reversed by reinstating AM2389 or THC. Conclusions These findings suggest cannabinoid-precipitated withdrawal may not be ascribed to the inverse properties of rimonabant, but rather to rapid competition with the agonist at the CB1R. This withdrawal syndrome is likely centrally-mediated, since only the centrally acting CB1R antagonists elicited withdrawal, i.e., such responses were absent after the purported peripherally selective CB1R antagonist AM6545. PMID:25772338

  2. RS 30026: a potent and effective calcium channel agonist.

    PubMed Central

    Patmore, L.; Duncan, G. P.; Clarke, B.; Anderson, A. J.; Greenhouse, R.; Pfister, J. R.

    1990-01-01

    1. A series of dihydropyridine derivatives has been evaluated for calcium channel agonist activity using reversal of nisoldipine-induced inhibition of beating of aggregates of embryonic chick myocytes. This test appears to be specific for calcium channel agonists since isoprenaline and cardiac glycosides are inactive. 2. RS 30026 was the most potent of the series, was significantly more potent than CGP 28392 and of similar potency to Bay K 8644 (pEC50 = 7.45, 6.16 and 7.20, respectively). RS 30026 increased edge movement of individual aggregates, in the absence of nisoldipine, by 50% at 2 nM. 3. Compounds were also evaluated for their effects on guinea-pig papillary muscle and porcine coronary artery rings. RS 30026 displayed positive inotropism at concentrations between 10(-9) and 10(-6) M (pEC200 = 8.21), but was a much more powerful inotrope than Bay K 8644, increasing contractility to 1300% of control at 10(-6) M (compared to 350% of control for Bay K 8644). RS 30026 caused vasoconstriction at concentrations between 10(-10) and 10(-7) M. 4. Calcium channel currents in single embryonic chick myocytes were recorded by whole-cell voltage clamp techniques. RS 30026 (100 nM-500 nM) produced large increases in peak current amplitude and shifted the voltage for threshold and maximal currents to more negative values. RS 30026 (500 nM) also produced large increases in the inward tail currents evoked upon repolarization. The effects of Bay K 8644 (50 and 500 nM) were much less marked.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1694461

  3. Asimadoline, a κ-Opioid Agonist, and Visceral Sensation

    PubMed Central

    Camilleri, Michael

    2009-01-01

    SUMMARY Asimadoline is a potent κ-opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the κ receptor, with IC50 of 5.6 nM (guinea pig) and 1.2 nM (human recombinant), and high selectively with κ: μ: δ binding ratios of 1:501:498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in IBS patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 hours post-on-demand treatment with asimadoline was not significantly reduced. Post-hoc analyses suggest asimadoline was effective in mixed IBS. In a 12-week study in 596 patients, chronic treatment with asimadoline, 0.5 mg and 1.0 mg, was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain free days in patients with IBS-D. The 1.0 mg dose was also efficacious in IBS-alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date. PMID:18715494

  4. Agonist and antagonist effects of cytisine in vivo.

    PubMed

    Radchenko, Elena V; Dravolina, Olga A; Bespalov, Anton Y

    2015-08-01

    Varenicline, the most successful smoking cessation aid, is a selective partial agonists at α4β2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including cytisine. The present study aimed to characterize behavioral effects of cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self-administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1-3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05-0.4 mg/kg), but not cytisine (0.3-3 mg/kg), lowered ICSS thresholds and cytisine dose-dependently reversed effects of nicotine. Nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), stimulated locomotor activity and cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), reinstated extinguished nicotine self-administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline. Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects. PMID:25839895

  5. Could dopamine agonists aid in drug development for anorexia nervosa?

    PubMed

    Frank, Guido K W

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  6. Gonadotropin-Releasing Hormone Agonist Therapy and Obesity in Girls

    PubMed Central

    Shiasi Arani, Kobra; Heidari, Fatemeh

    2015-01-01

    Background: Depot preparations of gonadotropin-releasing hormone agonists (GnRHa) are the gold standard drugs for the treatment of central precocious puberty. A concern about these drugs is obesity. Objectives: This study aimed to investigate the effect of gonadotropin-releasing hormone agonists (GnRHa) therapy on body mass index (BMI) in girls with central precocious puberty (CPP). Patients and Methods: The girls with onset of puberty before eight years of age or menarche before nine years of age were studied. The weight, height, BMI, and pubertal stage were determined before and at sixth and 12th months of treatment. The GnRHa (Triptorelin) was administered intramuscularly for patients with rapidly progressive forms of CPP. Patients with slowly progressive forms of CPP were considered as control group. Results: From 110 subjects with CPP, 46 girls (41.8%) were considered as intervention and 64 (58.2%) as control groups. The mean age at initial visit was 7.46 ± 1.03 years. The BMI standard deviation scores in both groups was not significantly different at sixth and 12th months of treatment compared with baseline (P = 0.257 and P = 0.839, respectively). The prevalence of obesity was not significantly different between study groups at baseline and at and sixth and 12th months of therapy (P = 0.11, P = 0.068, and P = 0.052, respectively). Conclusions: The GnRHa therapy has no effect on BMI and the prevalence of obesity. PMID:26401141

  7. Recent advances in the development of farnesoid X receptor agonists

    PubMed Central

    Carey, Elizabeth J.; Lindor, Keith D.

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  8. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    PubMed Central

    Frank, Guido K. W.

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  9. Recent advances in the development of farnesoid X receptor agonists.

    PubMed

    Ali, Ahmad H; Carey, Elizabeth J; Lindor, Keith D

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  10. Interaction of a radiolabeled agonist with cardiac muscarinic cholinergic receptors

    SciTech Connect

    Harden, T.K.; Meeker, R.B.; Martin, M.W.

    1983-12-01

    The interaction of a radiolabeled muscarinic cholinergic receptor agonist, (methyl-/sup 3/H)oxotremorine acetate ((/sup 3/H)OXO), with a washed membrane preparation derived from rat heart, has been studied. In binding assays at 4 degrees C, the rate constants for association and dissociation of (/sup 3/H)OXO were 2 X 10(7) M-1 min-1 and 5 X 10(-3) min-1, respectively, Saturation binding isotherms indicated that binding was to a single population of sites with a Kd of approximately 300 pM. The density of (/sup 3/H)OXO binding sites (90-100 fmol/mg of protein) was approximately 75% of that determined for the radiolabeled receptor antagonist (/sup 3/H)quinuclidinyl benzilate. Both muscarinic receptor agonists and antagonists inhibited the binding of (/sup 3/H)OXO with high affinity and Hill slopes of approximately one. Guanine nucleotides completely inhibited the binding of (/sup 3/H)OXO. This effect was on the maximum binding (Bmax) of (/sup 3/H)OXO with no change occurring in the Kd; the order of potency for five nucleotides was guanosine 5'-O-(3-thio-triphosphate) greater than 5'-guanylylimidodiphosphate greater than GTP greater than or equal to guanosine/diphosphate greater than GMP. The (/sup 3/H)OXO-induced interaction of muscarinic receptors with a guanine nucleotide binding protein was stable to solubilization. That is, membrane receptors that were prelabeled with (/sup 3/H)OXO could be solubilized with digitonin, and the addition of guanine nucleotides to the soluble, (/sup 3/H)OXO-labeled complex resulted in dissociation of (/sup 3/H)OXO from the receptor. Pretreatment of membranes with relatively low concentrations of N-ethylmaleimide inhibited (/sup 3/H)OXO binding by 85% with no change in the Kd of (/sup 3/H)OXO, and with no effect on (/sup 3/H)quinuclidinyl benzilate binding.

  11. GITR agonist enhances vaccination responses in lung cancer

    PubMed Central

    Zhu, Li X; Davoodi, Michael; Srivastava, Minu K; Kachroo, Puja; Lee, Jay M; St. John, Maie; Harris-White, Marni; Huang, Min; Strieter, Robert M; Dubinett, Steven; Sharma, Sherven

    2015-01-01

    An immune tolerant tumor microenvironment promotes immune evasion of lung cancer. Agents that antagonize immune tolerance will thus aid the fight against this devastating disease. Members of the tumor necrosis factor receptor (TNFR) family modulate the magnitude, duration and phenotype of immune responsiveness to antigens. Among these, GITR expressed on immune cells functions as a key regulator in inflammatory and immune responses. Here, we evaluate the GITR agonistic antibody (DTA-1) as a mono-therapy and in combination with therapeutic vaccination in murine lung cancer models. We found that DTA-1 treatment of tumor-bearing mice increased: (i) the frequency and activation of intratumoral natural killer (NK) cells and T lymphocytes, (ii) the antigen presenting cell (APC) activity in the tumor, and (iii) systemic T-cell specific tumor cell cytolysis. DTA-1 treatment enhanced tumor cell apoptosis as quantified by cleaved caspase-3 staining in the tumors. DTA-1 treatment increased expression of IFNγ, TNFα and IL-12 but reduced IL-10 levels in tumors. Furthermore, increased anti-angiogenic chemokines corresponding with decreased pro-angiogenic chemokine levels correlated with reduced expression of the endothelial cell marker Meca 32 in the tumors of DTA-1 treated mice. In accordance, there was reduced tumor growth (8-fold by weight) in the DTA-1 treatment group. NK cell depletion markedly inhibited the antitumor response elicited by DTA-1. DTA-1 combined with therapeutic vaccination caused tumor rejection in 38% of mice and a 20-fold reduction in tumor burden in the remaining mice relative to control. Mice that rejected tumors following therapy developed immunological memory against subsequent re-challenge. Our data demonstrates GITR agonist antibody activated NK cell and T lymphocyte activity, and enhanced therapeutic vaccination responses against lung cancer. PMID:26137407

  12. Immobilized thrombin receptor agonist peptide accelerates wound healing in mice.

    PubMed

    Strukova, S M; Dugina, T N; Chistov, I V; Lange, M; Markvicheva, E A; Kuptsova, S; Zubov, V P; Glusa, E

    2001-10-01

    To accelerate the healing processes in wound repair, attempts have been repeatedly made to use growth factors including thrombin and its peptide fragments. Unfortunately, the employment of thrombin is limited because of its high liability and pro-inflammatory actions at high concentrations. Some cellular effects of thrombin in wound healing are mediated by the activation of protease activated receptor-1 (PAR-1). The thrombin receptor agonist peptide (TRAP:SFLLRN) activates this receptor and mimics the effects of thrombin, but TRAP is a relatively weak agonist. We speculated that the encapsulated peptide may be more effective for PAR-1 activation than nonimmobilized peptide and developed a novel method for TRAP encapsulation in hydrogel films based on natural and synthetic polymers. The effects of an encapsulated TRAP in composite poly(N-vinyl caprolactam)-calcium alginate (PVCL) hydrogel films were investigated in a mouse model of wound healing. On day 7 the wound sizes decreased by about 60% under TRAP-chitosan-containing PVCL films, as compared with control films without TRAP. In the case of TRAP-polylysine-containing films no significant decrease in wound sizes was found. The fibroblast/macrophage ratio increased under TRAP-containing films on day 3 and on day 7. The number of proliferating fibroblasts increased to 150% under TRAP-chitosan films on day 7 as compared with control films. The number of [3H]-thymidine labeled endothelial and epithelial cells in granulation tissues was also enhanced. Thus, the immobilized TRAP to PVCL-chitosan hydrogel films were found to promote wound healing following the stimulation of fibroblast and epithelial cell proliferation and neovascularization. Furthermore, TRAP was shown to inhibit the secretion of the inflammatory mediator PAF from stimulated rat peritoneal mast cells due to augmentation of NO release from the mast cells. The encapsulated TRAP is suggested to accelerate wound healing due to the anti-inflammatory effects

  13. Maternal Treatment with Agonistic Autoantibodies against Type-1 Angiotensin II Receptor in Late Pregnancy Increases Apoptosis of Myocardial Cells and Myocardial Susceptibility to Ischemia-Reperfusion Injury in Offspring Rats

    PubMed Central

    Wang, Xiaofang; Zheng, Yanqian; Zhang, Qiaoyan; Zhi, Jianming

    2013-01-01

    Epidemiological studies have demonstrated that offspring born to mothers preeclampsia (PE) are at increased risk for developing cardiovascular diseases after birth, but the underlying mechanism is unknown. Angiotensin II receptor type 1 autoantibody (AT1-AA), an agonist acting via activation of the AT1 receptor, is believed to be involved in the pathogenesis of both PE and fetal growth restriction. The aim of the present study was to confirm the hypothesis that prenatal AT1-AA exposure increases the heart susceptibility to ischemia/reperfusion injury (IRI) in the offspring in an AT1-AA-induced animal model of PE, and determine whether or not the increase of maternal AT1-AA level is a factor contributing to sustained abnormalities of the heart structure during infancy. The hearts of 45-day-old offspring rats were studied using Langendorff preparation to determine the susceptibility of the heart to IRI. The results showed that the body weight of the maternal rats was not significantly different between the study and control groups, but the body weight of their offspring in AT1-AA group was decreased slightly at day 21 of gestational age, and at day 3 after birth. Although the heart weight index was not significantly affected at all ages examined, AT1-AA significantly increased the size of myocardial cells of the left ventricle (LV) at the age of 45 days. AT1-AA gained access to fetal circulation via the placenta and induced apoptosis of fetal myocardial cells. AT1-AA also significantly delayed recovery from IRI and affected the LV function of 45-day-old offspring. This was associated with a significant increase in IRI-induced LV myocardial infarct size. These results suggest that AT1-AA induced abnormal apoptosis of fetal myocardial cells during the fetal period and increased the cardiac susceptibility to IRI in adult offspring. PMID:24278308

  14. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.

    PubMed

    Yu, Shan; Li, Sijia; Henke, Adam; Muse, Evan D; Cheng, Bo; Welzel, Gustav; Chatterjee, Arnab K; Wang, Danling; Roland, Jason; Glass, Christopher K; Tremblay, Matthew

    2016-07-01

    Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR-mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol-based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol-based LXR agonists in mice significantly reduces dextran sulfate sodium colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti-inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol-based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for chronic inflammatory diseases.-Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. PMID:27025962

  15. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs.

    PubMed

    DeVree, Brian T; Mahoney, Jacob P; Vélez-Ruiz, Gisselle A; Rasmussen, Soren G F; Kuszak, Adam J; Edwald, Elin; Fung, Juan-Jose; Manglik, Aashish; Masureel, Matthieu; Du, Yang; Matt, Rachel A; Pardon, Els; Steyaert, Jan; Kobilka, Brian K; Sunahara, Roger K

    2016-07-01

    G-protein-coupled receptors (GPCRs) remain the primary conduit by which cells detect environmental stimuli and communicate with each other. Upon activation by extracellular agonists, these seven-transmembrane-domain-containing receptors interact with heterotrimeric G proteins to regulate downstream second messenger and/or protein kinase cascades. Crystallographic evidence from a prototypic GPCR, the β2-adrenergic receptor (β2AR), in complex with its cognate G protein, Gs, has provided a model for how agonist binding promotes conformational changes that propagate through the GPCR and into the nucleotide-binding pocket of the G protein α-subunit to catalyse GDP release, the key step required for GTP binding and activation of G proteins. The structure also offers hints about how G-protein binding may, in turn, allosterically influence ligand binding. Here we provide functional evidence that G-protein coupling to the β2AR stabilizes a ‘closed’ receptor conformation characterized by restricted access to and egress from the hormone-binding site. Surprisingly, the effects of G protein on the hormone-binding site can be observed in the absence of a bound agonist, where G-protein coupling driven by basal receptor activity impedes the association of agonists, partial agonists, antagonists and inverse agonists. The ability of bound ligands to dissociate from the receptor is also hindered, providing a structural explanation for the G-protein-mediated enhancement of agonist affinity, which has been observed for many GPCR–G-protein pairs. Our data also indicate that, in contrast to agonist binding alone, coupling of a G protein in the absence of an agonist stabilizes large structural changes in a GPCR. The effects of nucleotide-free G protein on ligand-binding kinetics are shared by other members of the superfamily of GPCRs, suggesting that a common mechanism may underlie G-protein-mediated enhancement of agonist affinity. PMID:27362234

  16. An Update of the International Society of Sexual Medicine's Guidelines for the Diagnosis and Treatment of Premature Ejaculation (PE)

    PubMed Central

    Althof, Stanley E; McMahon, Chris G; Waldinger, Marcel D; Serefoglu, Ege Can; Shindel, Alan W; Adaikan, P Ganesan; Becher, Edgardo; Dean, John; Giuliano, Francois; Hellstrom, Wayne JG; Giraldi, Annamaria; Glina, Sidney; Incrocci, Luca; Jannini, Emmanuele; McCabe, Marita; Parish, Sharon; Rowland, David; Segraves, R Taylor; Sharlip, Ira; Torres, Luiz Otavio

    2014-01-01

    Introduction In 2009, the International Society for Sexual Medicine (ISSM) convened a select panel of experts to develop an evidence-based set of guidelines for patients suffering from lifelong premature ejaculation (PE). That document reviewed definitions, etiology, impact on the patient and partner, assessment, and pharmacological, psychological, and combined treatments. It concluded by recognizing the continually evolving nature of clinical research and recommended a subsequent guideline review and revision every fourth year. Consistent with that recommendation, the ISSM organized a second multidisciplinary panel of experts in April 2013, which met for 2 days in Bangalore, India. This manuscript updates the previous guidelines and reports on the recommendations of the panel of experts. Aim The aim of this study was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts. Method A comprehensive literature review was performed. Results This article contains the report of the second ISSM PE Guidelines Committee. It offers a new unified definition of PE and updates the previous treatment recommendations. Brief assessment procedures are delineated, and validated diagnostic and treatment questionnaires are reviewed. Finally, the best practices treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with PE, in facilitating treatment of their patients. Conclusion Development of guidelines is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to a more complete understanding of the pathophysiology as well as new efficacious and safe treatments for this sexual dysfunction. We again recommend that these guidelines be reevaluated and updated by the ISSM in 4 years. Althof SE, McMahon CG, Waldinger MD, Serefoglu EC, Shindel AW, Adaikan PG

  17. Peştera cu Oase 2 and the cranial morphology of early modern Europeans.

    PubMed

    Rougier, Hélène; Milota, Stefan; Rodrigo, Ricardo; Gherase, Mircea; Sarcina, Laurentiu; Moldovan, Oana; Zilhão, João; Constantin, Silviu; Franciscus, Robert G; Zollikofer, Christoph P E; Ponce de León, Marcia; Trinkaus, Erik

    2007-01-23

    Between 2003 and 2005, the Peştera cu Oase, Romania yielded a largely complete early modern human cranium, Oase 2, scattered on the surface of a Late Pleistocene hydraulically displaced bone bed containing principally the remains of Ursus spelaeus. Multiple lines of evidence indicate an age of approximately 40.5 thousand calendar years before the present (approximately 35 ka 14C B.P.). Morphological comparison of the adolescent Oase 2 cranium to relevant Late Pleistocene human samples documents a suite of derived modern human and/or non-Neandertal features, including absence of a supraorbital torus, subrectangular orbits, prominent canine fossae, narrow nasal aperture, level nasal floor, angled and anteriorly oriented zygomatic bones, a high neurocranium with prominent parietal bosses and marked sagittal parietal curvature, superiorly positioned temporal zygomatic root, vertical auditory porous, laterally bulbous mastoid processes, superiorly positioned posterior semicircular canal, absence of a nuchal torus and a suprainiac fossa, and a small occipital bun. However, these features are associated with an exceptionally flat frontal arc, a moderately large juxtamastoid eminence, extremely large molars that become progressively larger distally, complex occlusal morphology of the upper third molar, and relatively anteriorly positioned zygomatic arches. Moreover, the featureless occipital region and small mastoid process are at variance with the large facial skeleton and dentition. This unusual mosaic in Oase 2, some of which is paralleled in the Oase 1 mandible, indicates both complex population dynamics as modern humans dispersed into Europe and significant ongoing human evolution once modern humans were established within Europe. PMID:17227863

  18. Electron electric dipole moment as a sensitive probe of PeV scale physics

    NASA Astrophysics Data System (ADS)

    Ibrahim, Tarek; Itani, Ahmad; Nath, Pran

    2014-09-01

    We give a quantitative analysis of the electric dipole moments as a probe of high scale physics. We focus on the electric dipole moment of the electron since the limit on it is the most stringent. Further, theoretical computations of it are free of QCD uncertainties. The analysis presented here first explores the probe of high scales via electron electric dipole moment (EDM) within minimal supersymmetric standard model where the contributions to the EDM arise from the chargino and the neutralino exchanges in loops. Here it is shown that the electron EDM can probe mass scales from tens of TeV into the PeV range. The analysis is then extended to include a vectorlike generation which can mix with the three ordinary generations. Here new CP phases arise and it is shown that the electron EDM now has not only a supersymmetric (SUSY) contribution from the exchange of charginos and neutralinos but also a nonsupersymmetric contribution from the exchange of W and Z bosons. It is further shown that the interference of the supersymmetric and the nonsupersymmetric contribution leads to the remarkable phenomenon where the electron EDM as a function of the slepton mass first falls and become vanishingly small and then rises again as the slepton mass increases. This phenomenon arises as a consequence of cancellation between the SUSY and the non-SUSY contribution at low scales while at high scales the SUSY contribution dies out and the EDM is controlled by the non-SUSY contribution alone. The high mass scales that can be probed by the EDM are far in excess of what accelerators will be able to probe. The sensitivity of the EDM to CP phases both in the SUSY and the non-SUSY sectors are also discussed.

  19. Photoelectronic-Digital Radiology (PE-DL-R) At The University Of Arizona

    NASA Astrophysics Data System (ADS)

    Nudelman, S.; Capp, M. P.; Fisher, H. D.; Ouimette, D.; Ovitt, T. W.; Roehrig, H.

    1982-01-01

    System designs for PE-DI-R are being evaluated relative to the optimum configuration to meet the needs of diagnostic radiology at the University of Arizona. It is clear that the system can be examined in terms of sub-systems broadly delineated as image acquisition, processing, display and archival storage. Its architecture is influenced by the diverse imaging requirements of different radiological exams; the extent of processing desired in terms of complexity and speed; the degree of sophistication for displays serving a reading room as compared to clinics, conference rooms and offices; and the instrumentation available for archival storage. Issues have risen pertaining to system architecture, particularly in questioning the advantages of systems stressing a strong computer center versus a distribution of "stand alone" systems utilizing microprocessors. These appear to be resolvable at least in part on the basis of hospital size. The hospital carrying out in excess of 200,000 procedures per year has different requirements than those of a hospital performing only 10,000 exams/year, The University of Arizona Health Sciences Center is a 300 bed hospital which performs 67,000 radiological procedures per year. Its size and activity suggest a mix of computer and microprocessors will be needed to carry out its multiplicity of tasks, We anticipate completing the design and essentially install most components of the system over the next four years. Features of the system that have evolved to date and deemed most pertinent to the interests of the participants will be discussed at the symposium.

  20. Photoelectronic-Digital Radiology (PE-DI-R) At The University Of Arizona

    NASA Astrophysics Data System (ADS)

    Nudelman, S.; Capp, M. P.; Fisher, H. D.; Ouimette, D.; Ovitt, T. W.; Roehrig, H.

    1982-01-01

    System designs for PE-DI-R are being evaluated relative to the optimum configuration to meet the needs of diagnostic radiology at the University of Arizona. It is clear that the system can be examined in terms of sub-systems broadly delineated as image acquisition, processing, display and archival storage. Its architecture is influenced by the diverse imaging requirements of different radiological exams; the extent of processing desired in terms of complexity and speed; the degree of sophistication for displays serving a reading room as compared to clinics, conference rooms and offices; and the instrumentation available for archival storage. Issues have risen pertaining to system architecture, particularly in questioning the advantages of systems stressing a strong computer center versus a distribution of "stand alone" systems utilizing microprocessors. These appear to be resolvable at least in part on the basis of hospital size. The hospital carrying out in excess of 200,000 procedures per year has different requirements than those of a hospital performing only 10,000 exams/year, The University of Arizona Health Sciences Center is a 300 bed hospital which performs 67,000 radiological procedures per year. Its size and activity suggest a mix of computer and microprocessors will be needed to carry out its multiplicity of tasks, We anticipate completing the design and essentially install most components of the system over the next four years. Features of the system that have evolved to date and deemed most pertinent to the interests of the participants will be discussed at the symposium.