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Sample records for m4 antagonist tropicamide

  1. Characterization of PCS1055, a novel muscarinic M4 receptor antagonist.

    Science.gov (United States)

    Croy, Carrie H; Chan, Wai Y; Castetter, Andrea M; Watt, Marla L; Quets, Anne T; Felder, Christian C

    2016-07-05

    Identification of synthetic ligands selective for muscarinic receptor subtypes has been challenging due to the high sequence identity and structural homology among the five muscarinic acetylcholine receptors. Here, we report the pharmacological characterization of PCS1055, a novel muscarinic M4 receptor antagonist. PCS1055 inhibited radioligand [(3)H]-NMS binding to the M4 receptor with a Ki=6.5nM. Though the potency of PCS1055 is lower than that of pan-muscarinic antagonist atropine, it has better subtype selectivity over previously reported M4-selective reagents such as the muscarinic-peptide toxins (Karlsson et al., 1994; Santiago and Potter, 2001a) at the M1 subtype, and benzoxazine ligand PD102807 at the M3-subtype (Bohme et al., 2002). A detailed head-to-head comparison study using [(3)H]-NMS competitive binding assays characterizes the selectivity profiles of PCS1055 to that of other potent muscarinic-antagonist compounds PD102807, tropicamide, AF-DX-384, pirenzapine, and atropine. In addition to binding studies, the subtype specificity of PCS1055 is also demonstrated by functional receptor activation as readout by GTP-γ-[(35)S] binding. These GTP-γ-[(35)S] binding studies showed that PCS1055 exhibited 255-, 69.1-, 342- and >1000-fold greater inhibition of Oxo-M activity at the M4 versus the M1-, M2(-), M3-or M5 receptor subtypes, respectively. Schild analyses indicates that PCS1055 acts as a competitive antagonist to muscarinic M4 receptor, and confirms the affinity of the ligand to be low nanomolar, Kb=5.72nM. Therefore, PCS1055 represents a new M4-preferring antagonist that may be useful in elucidating the roles of M4 receptor signaling.

  2. Evaluation of tropicamide-loaded tamarind seed xyloglucan nanoaggregates for ophthalmic delivery.

    Science.gov (United States)

    Dilbaghi, Neeraj; Kaur, Harmanmeet; Ahuja, Munish; Kumar, Sandeep

    2013-04-15

    The present study was aimed to prepare tamarind seed nanoaggregates and its evaluation for ophthalmic delivery. The preparation of tropicamide-loaded tamarind seed xyloglucan nanoaggregates was optimized using face centred central composite experimental design, employing the concentrations of tamarind seed xyloglucan and Poloxamer-407, as independent variables. The results revealed that concentration of TSX has a significant antagonistic effect on particle size, while poloxamer displayed a significant synergistic effect on encapsulation efficiency. The optimal concentrations of TSX and poloxamer were found to be 0.45% (w/v) and 0.5% (w/v) respectively. The optimized formulation of tropicamide-loaded TSX nanoaggregates showed a significantly higher corneal permeation of tropicamide across the isolated goat cornea compared to commercial conventional aqueous formulation. The results revealed excellent mucoadhesive properties of TSX nanoaggregates. Further, the tropicamide-loaded TSX nanoaggregates formulation showed excellent ocular tolerance and biocompatibility as determined by hen's egg test chorioallantoic membrane and resazurin assay on Vero cell lines.

  3. Cubic liquid crystalline nanoparticles: optimization and evaluation for ocular delivery of tropicamide.

    Science.gov (United States)

    Verma, Purnima; Ahuja, Munish

    2016-10-01

    The purpose of this study was to investigate the potential of cubic liquid crystalline nanoparticles for ocular delivery of tropicamide. Ultrasound-assisted fragmentation of cubic liquid crystalline bulk phases resulted in cubic liquid crystalline nanoparticles employing Pluronic F127 as dispersant. The effects of process variables such as sonication time, sonication amplitude, sonication depth, and pre-mixing time on particle size and polydispersity index was investigated using central composite design. The morphology of tropicamide-loaded nanoparticles was found to be nearly cubical in shape by transmission electron microscopy observation. Further, small angle X-ray scattering experiment confirmed the presence of D and P phase cubic structures in coexistence. The optimized tropicamide-loaded cubic nanoparticles showed in vitro corneal permeation of tropicamide across isolated porcine cornea comparable to its commercial preparation, Tropicacyl®. Ocular tolerance was evaluated by Hen's egg-chorioallantoic membrane test and histological studies. The results of in vivo mydriatic response study demonstrated a remarkably higher area under mydriatic response curve (AUC0→1440 min) values of cubic nanoparticles over Tropicacyl® indicating better therapeutic value of cubic nanoparticles. Furthermore, tropicamide-loaded cubic nanoparticles exhibited prolonged mydriatic effect on rabbits as compared to commercial conventional aqueous ophthalmic solution.

  4. [Objective refraction in black children: cyclopentolate and tropicamide combination, a reliable alternative to atropine?].

    Science.gov (United States)

    Ka, A M; De Medeiros, M E; Sow, A S; Ndiaye, P A; Weladji, C; Diallo, H M; Wane, A M; Diagne, J P; Kane, A; Ndiaye, J M M; Ndoye Roth, P A; Ba, E A; Ndiaye, M R

    2014-11-01

    Cycloplegia allows for an objective refraction in children. Atropine is the gold standard but causes prolonged blurred vision. Cyclopentolate is less effective but less disabling. Tropicamide is a weak cycloplegic. The purpose of this study was to evaluate a cyclopentolate and tropicamide combination (CTA) versus atropine for refraction in black children. We performed a prospective study between October 2011 and July 2012 on all children seen in consultation. Objective refraction was performed after cycloplegia with cyclopentolate 0.5% combined with tropicamide 0.5%, and then after cycloplegia with atropine. Thirty-three patients were recruited, 14 boys and 19 girls. The average age was 9.9 years. The mean age of the patients was 9.9 years. Astigmatism was found in 96.9% of cases. It was 1.34±1.32 diopters with CTA and 1.35±1.22 diopters with atropine. The mean axis was 98.15 and 99.8, respectively. Hyperopia and myopia were found in 39 and 27 eyes, respectively with ACT (average 1.73 and 5.37 diopters), and in 41 and 19 eyes with atropine (average 2.06 and 6.11 diopters). There is a good correlation of results with regards to cylindrical and spherical refractive error between the two protocols. Atropine is the best cycloplegic, however ACT provides reliable results. The cyclopentolate-tropicamide combination is satisfactory for routine cycloplegia in children. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  5. Preparation and evaluation of liposomal formulations of tropicamide for ocular delivery.

    Science.gov (United States)

    Nagarsenker, M S; Londhe, V Y; Nadkarni, G D

    1999-11-10

    Tropicamide, a mydriatic, cycloplegic drug was entrapped in liposomes. Liposomes were investigated by laser counting studies, transmission electron microscopy and differential scanning calorimetry for characterization. The precorneal clearance of liposomes was compared with solution by gamma-scintigraphy in the rabbit. The neutral liposomes failed to demonstrate significant enhancement in precorneal retention in comparison with aqueous solution. The potential of liposomes as an ophthalmic drug delivery system was investigated by comparing pupil dilatory effect of tropicamide by topical instillation, in the rabbit eye, of the solution and various drug-loaded liposomal forms, i.e. neutral liposomes, positively charged liposomes and neutral liposomes dispersed in 0.25% (w/v) polycarbophil gel. The positively charged liposomal formulation and liposomes dispersed in polycarbophil gel were found to be more effective than neutral liposomal dispersion when data were statistically treated at the 5% level of significance.

  6. Effective pupil dilatation with a mixture of 0.75% tropicamide and 2.5% phenylephrine: A randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Trinavarat Adisak

    2009-01-01

    Full Text Available Purpose: To compare the efficacy in pupil dilatation between a mixture containing 0.75% tropicamide and 2.5% phenylephrine and the alternate application of 1% tropicamide and 10% phenylephrine eye drops. Material and Methods : Patients requiring pupil dilatation were randomized to receive one drop of the mixture every 10 min for four times or our standard application of one drop of 1% tropicamide alternating with one drop of 10% phenylephrine every 10 min for two cycles. Pupil size was measured under bright light with the pupil gauge before, and every 5 min after initial application for 40 min. Application of the drops was discontinued once the pupil diameter reached 7 mm. Blood pressure and pulse rate were monitored every 15 min. Results: Of 40 patients (age 57.3±10.9 years, range 35-70 years, 22 were randomized into the mixture group and 18 into the alternate drug group. Baseline pupil sizes were 1.7±0.5 mm in the mixture group and 1.8±0.4 mm in the alternate drug group. The pupils were successfully dilated to 7 mm within 40 min in 17 patients of the mixture group compared to seven patients in the alternate drug group ( P =0.004, Log Rank test. The mean pupil sizes at 40 min were 6.6±0.8 and 6.0±0.9 mm in the mixture and alternate drug groups respectively ( P =0.050, t-test. Blood pressure and pulse rate were stable and similar in both groups. Conclusions: The mixture of 0.75% tropicamide and 2.5% phenylephrine is superior to our standard application of 1% tropicamide alternating with 10% phenylephrine. It provides faster and more successful pupil dilatation within 40 min.

  7. Variant M4 Barrel Characterization

    Science.gov (United States)

    2009-07-01

    in the button broached barrels. 6. Acknowledgments The authors are pleased to acknowledge the sample preparation provided by Mrs. A. Welty , RDAR...Rickard, C., & Welty , A. (2007). Comparison of electroplated chromium coatings applied to M4 and M16 barrels. US Army-ARDEC. 3) Smith, S. B., & Rickard

  8. Comparison of the Mydriatic Effects of Mydrin-P and Com-pound Tropicamide in the Screening of Retinopathy of Pre-maturity

    Institute of Scientific and Technical Information of China (English)

    Shuke Luo; Zhonghe Wan; Xiaofang Yin; Zuke Ye; Yan Lu

    2014-01-01

    Purpose:To observe and compare the effects of pupil dilation between Mydrin-P and compound tropicamide in the screening of retinopathy of prematurity. Methods:.The right eyes of premature infants received My-drin-P eye drops as the treatment group, whereas the left eyes were administered with compound tropicamide as the control group..The eye drops were delivered every 5 min for three times..The pupil size was observed and recorded at 10,.15, and 20 min after administering mydriasis. Results:.The mean pupil diameter did not significantly differ between the treatment and control groups at 10. (6.24 ±0.72 mm vs. 6.24±0.68 mm, t=0.00, P=1.00), 15 (6.83±0.55 mm vs. 6.78±0.54 mm, t=1.75, P=0.083) or 20 min (7.22±0.40 mm vs. 7.15±0.50 mm, t=1.62, P=0.109), respectively. How-ever, the mean pupil size at any two time points significantly differed in both groups (all P Conclusion: Both Mydrin-P and compound tropicamide exert similar clinical efficacy in the screening of retinopathy of pre-maturity..The most appropriate time for screening was at 20 min after mydriasis.

  9. Fungicin M4: a narrow spectrum peptide antibiotic from Bacillus licheniformis M-4.

    Science.gov (United States)

    Lebbadi, M; Gálvez, A; Maqueda, M; Martínez-Bueno, M; Valdivia, E

    1994-07-01

    The strain Bacillus licheniformis M-4 produces a 3.4 kDa hydrophilic peptide with antifungal activity, named fungicin M4. Analysis of the purified peptide shows that it contains the amino acids Glu (8), Arg (5), Pro (4), Tyr (8), Val (3), Met (2) and Orn (4). Its inhibitory spectrum is restricted to Microsporum canis CECT 2797, Mucor mucedo CECT 2653, Mucor plumbeus CCM 443, Sporothrix schenckii CECT 2799, Bacillus megaterium and Corynebacterium glutamicum CECT 78. Fungicin M4 exerts biocidal activity on liquid cultures of Sporothrix schenckii CECT 2799.

  10. Rotational motion of Foton M-4

    Science.gov (United States)

    Abrashkin, V. I.; Voronov, K. E.; Piyakov, I. V.; Puzin, Yu. Ya.; Sazonov, V. V.; Semkin, N. D.; Chebukov, S. Yu.

    2016-07-01

    The actual controlled rotational motion of the Foton M-4 satellite is reconstructed for the mode of single-axis solar orientation. The reconstruction was carried out using data of onboard measurements of vectors of angular velocity and the strength of the Earth's magnetic field. The reconstruction method is based on the reconstruction of the kinematic equations of the rotational motion of a solid body. According to the method, measurement data of both types collected at a certain time interval are processed together. Measurements of the angular velocity are interpolated by piecewise-linear functions, which are substituted in kinematic differential equations for a quaternion that defines the transition from the satellite instrument coordinate system to the inertial coordinate system. The obtained equations represent the kinematic model of the satellite rotational motion. A solution of these equations that approximates the actual motion is derived from the condition of the best (in the sense of the least squares method) match between the measurement data of the strength vector of the Earth's magnetic field and its calculated values. The described method makes it possible to reconstruct the actual rotational satellite motion using one solution of kinematic equations over time intervals longer than 10 h. The found reconstructions have been used to calculate the residual microaccelerations.

  11. GABAB antagonists

    DEFF Research Database (Denmark)

    Frydenvang, Karla Andrea; Hansen, J J; Krogsgaard-Larsen, P

    1994-01-01

    Phaclofen, which is the phosphonic acid analogue of the GABAB agonist (RS)-3-(4-chlorophenyl)-4-aminobutyric acid (baclofen), is a GABAB antagonist. As part of our studies on the structural requirements for activation and blockade of GABAB receptors, we have resolved phaclofen using chiral chroma...

  12. Diseño de una formulación de fenilefrina 10 % y tropicamida 1 % colirio: eyedrops Design of a 10 % Phenylephrine and 1 % Tropicamide formula

    Directory of Open Access Journals (Sweden)

    Georgy Armando Zuñiga Dedorite

    2010-06-01

    Full Text Available El colirio de fenilefrina 10 % y tropicamida 1 % se emplea en la práctica médica como antihistamínico, analgésico, midriáticos y ciclopléjico. El objetivo del presente trabajo consistió en desarrollar una formulación de fenilefrina 10 % y tropicamida 1 % que cumpliera con las especificaciones de calidad establecidas por el fabricante, que fuera estable física, química y microbiológicamente, para lo cual se realizó un diseño y los estudios de preformulación. Se estudió además, las especificaciones de calidad de la formulación seleccionada, la estabilidad del producto y el tiempo de vigencia de este. Se desarrolló y validó un método analítico para el control de la calidad y el estudio de estabilidad del producto terminado por cromatografía líquida de alta resolución. Se realizaron los resultados analíticos del estudio de estabilidad acelerado y por vida de estante, para lo cual se emplearon 3 lotes del producto a escala piloto. El colirio resultó estable física, química y microbiológicamente envasado en frascos de polietileno de baja densidad, por un tiempo de 12 meses almacenados a temperatura ambiente.The 10 % Phenylephrine and 1 % Tropicamide eyedrops is used in medical practice as antihistaminic, analgesic, mydiatric and cycloplegic. The aim of present paper was to develop a 10% Phenylephrine and 1 % Tropicamide formula fulfilling the quality specifications established by manufacturer physically, chemically and microbiologically stable with the performing of a design and pre-formula studies. Also, we studied the quality specifications of selected formula, the product stability and its expiry time. An analytical method was developed and validated to quality control and stability study of the finished product by high-performance liquid chromatography. Analytical results of accelerated stability study and by shelf life using 3 batches of product at pilot scale. Eyedrops was physically, chemically and microbiologically

  13. Responses of the Ocular Anterior Segment and Refraction to 0.5% Tropicamide in Chinese School-Aged Children of Myopia, Emmetropia, and Hyperopia.

    Science.gov (United States)

    Yuan, Ying; Zhang, Zhengwei; Zhu, Jianfeng; He, Xiangui; Du, Ergang; Jiang, Kelimu; Zheng, Wenjing; Ke, Bilian

    2015-01-01

    Purpose. To investigate the changes of anterior segment after cycloplegia and estimate the association of such changes with the changes of refraction in Chinese school-aged children of myopia, emmetropia, and hyperopia. Methods. 309 children were recruited and eligible subjects were assigned to three groups: hyperopia, emmetropia, or myopia. Cycloplegia was achieved with five cycles of 0.5% tropicamide. The Pentacam system was used to measure the parameters of interest before and after cycloplegia. Results. In the myopic group, the lenses were thinner and the lens position was significantly more posterior than that of the emmetropic and hyperopic groups in the cycloplegic status. The correlations between refraction and lens thickness (age adjusted; r = 0.26, P refraction, ACD, ACV, and ACA were significantly different among the three groups (P refraction were correlated with changes of ACD (r = 0.41, P refraction after cycloplegia when compared to emmetropia and hyperopia. Changes of anterior chamber depth were correlated with refraction changes. This may contribute to a better understanding of the relationship between anterior segment and myopia.

  14. Responses of the Ocular Anterior Segment and Refraction to 0.5% Tropicamide in Chinese School-Aged Children of Myopia, Emmetropia, and Hyperopia

    Directory of Open Access Journals (Sweden)

    Ying Yuan

    2015-01-01

    Full Text Available Purpose. To investigate the changes of anterior segment after cycloplegia and estimate the association of such changes with the changes of refraction in Chinese school-aged children of myopia, emmetropia, and hyperopia. Methods. 309 children were recruited and eligible subjects were assigned to three groups: hyperopia, emmetropia, or myopia. Cycloplegia was achieved with five cycles of 0.5% tropicamide. The Pentacam system was used to measure the parameters of interest before and after cycloplegia. Results. In the myopic group, the lenses were thinner and the lens position was significantly more posterior than that of the emmetropic and hyperopic groups in the cycloplegic status. The correlations between refraction and lens thickness (age adjusted; r=0.26, P<0.01, and lens position (age adjusted; r=-0.31, P<0.01 were found. After cycloplegia, ACD and ACV significantly increased, while ACA significantly decreased. Changes in refraction, ACD, ACV, and ACA were significantly different among the three groups (P<0.05, all. Changes of refraction were correlated with changes of ACD (r=0.41, P<0.01. Conclusions. Myopia presented thinner lenses and smaller changes of anterior segment and refraction after cycloplegia when compared to emmetropia and hyperopia. Changes of anterior chamber depth were correlated with refraction changes. This may contribute to a better understanding of the relationship between anterior segment and myopia.

  15. Topical tropicamide induced delirium and psychosis: case report Delírio e psicose induzidos por tropicamida tópica: relato de caso

    Directory of Open Access Journals (Sweden)

    Renato P. Munhoz

    2010-01-01

    Full Text Available Acute psychosis and confusional states are known complications of treatment with anticholinergic agents in the elderly. We report an 87-year-old female patient presenting with acute neurobehavioral abnormalities requiring hospitalization immediately after starting treatment for openangle glaucoma with the topic cycloplegic muscarinic receptor blocker tropicamide. Case-effect relationship was confirmed. The authors make a review of the literature trying to identify the clinical manifestations and risk factors for this complication.Tratamento com drogas anticolinérgicas é uma causa conhecida de alterações agudas do estado mental em idosos. Relata-se o caso de uma paciente de 87 anos de idade com alterações comportamentais agudas, que necessita de internamento imediatamente após início de terapia para glaucoma de ângulo aberto com tropicamida, um agente cicloplégico bloqueador de receptor muscarínico. A relação causa-efeito foi confirmada depois de a droga ter sido reiniciada durante o internamento. É apresentada uma revisão da literatura delineando as manifestações clínicas mais comuns e fatores de risco para essa complicação.

  16. Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents

    DEFF Research Database (Denmark)

    Bubser, Michael; Bridges, Thomas M; Dencker, Ditte;

    2014-01-01

    an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central...... PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801...

  17. ACTH antagonists

    Directory of Open Access Journals (Sweden)

    Adrian John Clark

    2016-08-01

    Full Text Available ACTH acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1 Cushing’s disease and ectopic ACTH syndrome – especially whilst preparing for definitive treatment of a causative tumour, or in refractory cases, or (2 congenital adrenal hyperplasia – as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role.

  18. Cycloplegic Refraction in Hyperopic Children: Effectiveness of a 0.5% Tropicamide and 0.5% Phenylephrine Addition to 1% Cyclopentolate Regimen.

    Science.gov (United States)

    Yoo, Seul Gi; Cho, Myung Jin; Kim, Ungsoo Samuel; Baek, Seung Hee

    2017-06-01

    To evaluate the effectiveness of a cycloplegic regimen using 0.5% tropicamide and 0.5% phenylephrine (Tropherine, Hanmi Pharm), in addition to 1% cyclopentolate, in hyperopic children. The medical records of hyperopic patients below the age of 14 years who had undergone cycloplegic retinoscopy were retrospectively reviewed. Cycloplegic refractions were performed using one of two cycloplegic regimens. Regimen 1 was a Tropherine-added regimen comprising the administration of one drop of 1% cyclopentolate followed by two to three drops of Tropherine added at 15-minute intervals. Regimen 2 was a cyclopentolate-only regimen comprising the administration of three to four drops of 1% cyclopentolate at 15-minute intervals. The mean difference between noncycloplegic and cycloplegic refraction was compared between the two regimens. A total of 308 eyes of 308 hyperopic children were included. The mean difference (±standard deviation) in the spherical equivalent (SE) between cycloplegic and noncycloplegic refraction was significantly larger in regimen 2 than in regimen 1, with values of +1.70 ± 1.03 diopters (D) and +1.25 ± 0.89 D, respectively (p=0.001). The SE change after cycloplegia was significantly different between the two regimens only in patients aged 5 years or younger (p=0.001), particularly in those with high hyperopia with an SE ≥5 D (p=0.005) or fully accommodative esotropia (p=0.009). There was no significant difference between the two regimens in patients older than 5 years, regardless of the presence of high hyperopia or fully accommodative esotropia. The Tropherine-added regimen exerted a weaker cycloplegic effect than the cyclopentolate-only regimen, particularly in children under the age of 5 years with high hyperopia or fully accommodative esotropia. However, the difference in refraction between the two regimens was small. A Tropherine-added regimen can be effective in hyperopic children, with less associated discomfort than the instillation of

  19. Multimedia for Art ReTrieval (M4ART)

    NARCIS (Netherlands)

    Broek, E.L. van den; Schouten, T.E.; Kok, T.; Hoenkamp, E.C.M.

    2006-01-01

    The prototype for an online Multimedia for Art ReTrieval (M4ART) system is introduced, that provides entrance to the digitized collection of the National Gallery of the Netherlands (the Rijksmuseum). The current online system of the Rijksmuseum is text-based and requires expert knowledge concerning

  20. Fast rotating Blue Stragglers in the globular cluster M4

    CERN Document Server

    Lovisi, L; Ferraro, F R; Lucatello, S; Lanzoni, B; Dalessandro, E; Beccari, G; Rood, R T; Sills, A; Pecci, F Fusi; Gratton, R; Piotto, G

    2010-01-01

    We have used high resolution spectra obtained with the spectrograph FLAMES at the ESO Very Large Telescope to determine the kinematical properties and the abundance patterns of 20 blue straggler stars (BSSs) in the globular cluster M4. We found that ~ 40% of the measured BSSs are fast rotators (with rotational velocities > 50 km/s). This is the largest frequency of rapidly rotating BSSs ever detected in a globular cluster. In addition, at odds with what has been found in 47 Tucanae, no evidence of carbon and/or oxygen depletion has been revealed in the sample of 11 BSSs for which we were able to measure the abundances. This could be due either to low statistics, or to a different BSS formation process acting in M4.

  1. Studying RR Lyrae Stars in M4 with K2

    Science.gov (United States)

    Kuehn, Charles A.; Drury, Jason; Moskalik, Pawel

    2017-01-01

    Observations by Kepler/K2 have revolutionized the study of RR Lyrae stars by allowing the detection of new phenomena, such as low amplitude additional modes and period doubling, which had not previously been seen from the ground. During its campaign 2, K2 observed the globular cluster M4, providing the first opportunity to study a sizeable group of RR Lyrae stars that belong to a single population; the other RR Lyrae stars that have been observed from space are field stars in the galactic halo and thus belong to an assortment of populations. We present the results of our study of the RR Lyrae variables in M4 from K2 photometry. We have identified additional, low amplitude pulsation modes in the two observed RRc stars. In three RRab stars we have found the Blazhko effect with periods of 16.6 days, 22.4 days, and 44.5 days.

  2. The muscarinic acetylcholine receptor agonist BuTAC mediates antipsychotic-like effects via the M4 subtype.

    Science.gov (United States)

    Watt, Marla L; Rorick-Kehn, Linda; Shaw, David B; Knitowski, Karen M; Quets, Anne T; Chesterfield, Amy K; McKinzie, David L; Felder, Christian C

    2013-12-01

    The generation of muscarinic acetylcholine receptor (mAChR) subtype-selective compounds has been challenging, requiring use of nonpharmacological approaches, such as genetically engineered animals, to deepen our understanding of the potential that members of the muscarinic receptor subtype family hold as therapeutic drug targets. The muscarinic receptor agonist 'BuTAC' was previously shown to exhibit efficacy in animal models of psychosis, although the particular receptor subtype(s) responsible for such activity was unclear. Here, we evaluate the in vitro functional agonist and antagonist activity of BuTAC using an assay that provides a direct measure of G protein activation. In addition, we employ the conditioned avoidance response paradigm, an in vivo model predictive of antipsychotic activity, and mouse genetic deletion models to investigate which presynaptic mAChR subtype mediates the antipsychotic-like effects of BuTAC. Our results show that, in vitro, BuTAC acts as a full agonist at the M2AChR and a partial agonist at the M1 and M4 receptors, with full antagonist activity at M3- and M5AChRs. In the mouse conditioned avoidance response (CAR) assay, BuTAC exhibits an atypical antipsychotic-like profile by selectively decreasing avoidance responses at doses that do not induce escape failures. CAR results using M2(-/-), M4(-/-), and M2/M4 (M2/M4(-/-)) mice found that the effects of BuTAC were near completely lost in M2/M4(-/-) double-knockout mice and potency of BuTAC was right-shifted in M4(-/-) as compared with wild-type and M2(-/-) mice. The M2/M4(-/-) mice showed no altered sensitivity to the antipsychotic effects of either haloperidol or clozapine, suggesting that these compounds mediate their actions in CAR via a non-mAChR-mediated mechanism. These data support a role for the M4AChR subtype in mediating the antipsychotic-like activity of BuTAC and implicate M4AChR agonism as a potential novel therapeutic mechanism for ameliorating symptoms associated with

  3. M4AST - A Tool for Asteroid Modelling

    Science.gov (United States)

    Birlan, Mirel; Popescu, Marcel; Irimiea, Lucian; Binzel, Richard

    2016-10-01

    M4AST (Modelling for asteroids) is an online tool devoted to the analysis and interpretation of reflection spectra of asteroids in the visible and near-infrared spectral intervals. It consists into a spectral database of individual objects and a set of routines for analysis which address scientific aspects such as: taxonomy, curve matching with laboratory spectra, space weathering models, and mineralogical diagnosis. Spectral data were obtained using groundbased facilities; part of these data are precompiled from the literature[1].The database is composed by permanent and temporary files. Each permanent file contains a header and two or three columns (wavelength, spectral reflectance, and the error on spectral reflectance). Temporary files can be uploaded anonymously, and are purged for the property of submitted data. The computing routines are organized in order to accomplish several scientific objectives: visualize spectra, compute the asteroid taxonomic class, compare an asteroid spectrum with similar spectra of meteorites, and computing mineralogical parameters. One facility of using the Virtual Observatory protocols was also developed.A new version of the service was released in June 2016. This new release of M4AST contains a database and facilities to model more than 6,000 spectra of asteroids. A new web-interface was designed. This development allows new functionalities into a user-friendly environment. A bridge system of access and exploiting the database SMASS-MIT (http://smass.mit.edu) allows the treatment and analysis of these data in the framework of M4AST environment.Reference:[1] M. Popescu, M. Birlan, and D.A. Nedelcu, "Modeling of asteroids: M4AST," Astronomy & Astrophysics 544, EDP Sciences, pp. A130, 2012.

  4. White Dwarfs in Globular Clusters HST Observations of M4

    CERN Document Server

    Richer, H B; Ibata, R A; Pryor, C E; Bell, R A; Bolte, M; Bond, H E; Harris, W E; Hesser, J E; Holland, S; Ivanans, N; Mandushev, G I; Stetson, P B; Wood, M A; Richer, Harvey B.; Fahlman, Gregory G.; Ibata, Rodrigo A.; Pryor, Carlton; Bell, Roger A.; Bolte, Michael; Bond, Howard E.; Harris, William E.; Hesser, James E.; Holland, Steve; Ivanans, Nicholas; Mandushev, Georgi; Stetson, Peter B.; Wood, Matt A.

    1997-01-01

    Using WFPC2 on the Hubble Space Telescope, we have isolated a sample of 258 white dwarfs (WDs) in the Galactic globular cluster M4. Fields at three radial distances from the cluster center were observed and sizeable WD populations were found in all three. The location of these WDs in the color-magnitude diagram, their mean mass of 0.51($ \\pm 0.03$)M$_{\\odot}$, and their luminosity function confirm basic tenets of stellar evolution theory and support the results from current WD cooling theory. The WDs are used to extend the cluster main-sequence mass function upward to stars that have already completed their nuclear evolution. The WD/red dwarf binary frequency in M4 is investigated and found to be at most a few percent of all the main-sequence stars. The most ancient WDs found are about 9 Gyr old, a level which is set solely by the photometric limits of our data. Even though this is less than the age of M4, we discuss how these cooling WDs can eventually be used to check the turnoff ages of globular clusters a...

  5. HUBBLE SPACE TELESCOPE Photometry of the Globular Cluster M4

    Science.gov (United States)

    Ibata, Rodrigo A.; Richer, Harvey B.; Fahlman, Gregory G.; Bolte, Michael; Bond, Howard E.; Hesser, James E.; Pryor, Carlton; Stetson, Peter B.

    1999-02-01

    This paper presents a detailed description of the acquisition and processing of a large body of imaging data for three fields in the globular cluster M4 taken with the Wide Field and Planetary Camera 2 aboard the Hubble Space Telescope. Analysis with the ALLFRAME package yielded the deepest photometry yet obtained for this cluster. The resulting data set for 4708 stars (positions and calibrated photometry in V, I, and, in two fields, U) spanning approximately six cluster core radii is presented. The scientific analysis is deferred to three companion papers, which investigate the significant white dwarf population discovered and the main-sequence population.

  6. The Clinical Study on the Effect of Tropicamide and Atropine Ophthalmic Solution in Mydriatic Refractometry for Children%托吡卡胺与阿托品对儿童散瞳验光效果的临床观察

    Institute of Scientific and Technical Information of China (English)

    李战梅; 黄海; 周李

    2013-01-01

    Objective:To compare the effect of tropicamide and atropine ophthalmic solution in mydriatic refractometry for children.Methods:Totally 260 cases (520 eyes) of ametropia children from 4 to 14 years without other eye disease were received optometry after using the tropicamide eye drops and 1%atropine sulfate,The results of optometry were compared by paired T-test.Results:There existed statistically significant difference between the hyperopia and myopia in 4 to 7 years old group,hyperopia in 8 to 11 years old group.But there were no significant difference between the myopia in 8 to 11 years old group,myopia and hyperopia in 12 to 14 years old group.Conclusion:Aged 8 years and older children with myopia and hyperopia in aged 12 years and above children could receive optometry after using the tropicamide eye drops.%  目的:对比托吡卡胺与阿托品眼液对儿童散瞳验光的效果。方法:用托吡卡胺眼液和1%硫酸阿托品眼膏先后分别对4~14岁260例(520只眼),无其它眼疾,眼位正常的屈光不正儿童散瞳后进行电脑验光,采用自身配对t检验对两种药物验光结果进行比较。结果:4~7岁组远视、近视和8~11岁组远视两种药物散瞳验光所得结果差异有统计学意义(P0.05)。结论:托吡卡胺散瞳验光方法适用于眼位正常的8岁及以上近视儿童和12岁及以上远视儿童。

  7. Estudo comparativo da acomodação residual após instilação de colírios de tropicamida a 1%, ciclopentolato a 1% e associação de tropicamida a 1% + ciclopentolato a 1% Comparative study of residual accommodation after the instillation of the following eye drops: 1% tropicamide, 1% cyclopentolate and 1% tropicamide + 1% cyclopentolate

    Directory of Open Access Journals (Sweden)

    Renato Klingelfus Pinheiro

    2000-12-01

    Full Text Available Objetivo:Avaliar a acomodação residual após a instilação de duas drogas cicloplégicas, o ciclopentolato a 1% e a tropicamida a 1% e a associação entre elas. Material e Método: Selecionamos pacientes de 15 a 25 anos, com íris grau 4 e 5 pela classificação de Seddon e sem nenhum tipo de doença ocular, que procuraram de maneira espontânea o ambulatório de Oftalmologia da Santa Casa de São Paulo no período de outubro de 1997 a setembro de 1998.Os 46 pacientes foram submetidos a três exames oftalmológicos completos, em que se testava o potencial de acomodação monocularmente, após a instilação de tropicamida a 1%, com tempo de espera de 20 minutos, ciclopentolato a 1% com tempo de espera de 40 minutos e tropicamida a 1% + ciclopentolato a 1% com intervalo entre as drogas de 5 minutos e com latência de 30 minutos. O intervalo entre os exames era de no mínimo 7 dias. Resultados: Não houve diferença entre os grupos dos emétropes, dos hipermétropes e dos míopes com nenhuma droga instilada (p>0,005. O ciclopentolato a 1 % e a associação entre as drogas proporcionaram menor acomodação residual estatisticamente significante, em comparação com a tropicamida a 1% no grupo dos hipermétropes e dos míopes. Conclusão: O ciclopentolato a 1% e a associação entre as drogas são seguras para o exame refratométrico estático em pacientes jovens, com íris escura e sem doença ocular, pois proporcionaram uma média da acomodação residual em todos os grupos pesquisados de no máximo 1,21 ± 0,7 dioptrias esféricas (DE.Purpose: To reevaluate the residual accomodation after instillation of two different cycloplegic drugs; 1% cyclo- pentolate, 1% tropicamide and their association. Material and Method: We selected 46 patients aged bet- ween 15 and 25 years, with iris graded 4 and 5 according to the Seddon classification and without any type of eye disease. Those patients came spontaneously to the Depart- ment of Ophthalmology

  8. Determination of benzalkonium chloride in compound tropicamide eye drops by HPLC%HPLC法测定复方托吡卡胺滴眼液中苯扎氯铵的含量

    Institute of Scientific and Technical Information of China (English)

    何丹; 杨林

    2013-01-01

    Objective :To establish an HPLC method for detecting the content of Benzalkonium Chloride in Compound Tropicamide Eye Drops .Methods :A Alltech Alltima -CN column (250cm × 4 .6mm ,5μm) was used ,and the mobile phase was 0 .1mol・L -1 NaAc solution -acetonitrile (60 :40) ,HAc was used to adjust pH to 5 ,column temperature was 30℃ ,at a flow rate of 2 .0ml・min -1 and detection wavelength of 254 nm .Results :The linear range of Benzalkonium Chloride was 0 .02~0 .5mg・mL -1 ;The correlation coefficient was 0 .9999 .The average recovery of Benzalkonium Chloride was 98 .91% (RSD=0 .44% ,n=9 ) .Conclusion :The method is accurate ,simple ,rapid and suitable for the quality control of Benzalkonium Chloride in Compound Tropicamide eye drops .%目的:建立超高效液相色谱法测定复方托吡卡胺滴眼液中苯扎氯铵的含量测定方法。方法:色谱柱为Alltech Alltima -CN(250cm ×4.6mm ,5μm),流动相为0.1mol・L -1醋酸钠溶液(用冰醋酸调节pH值至5.0)-乙腈(60:40),检测波长254nm ,流速为2.0ml・min -1,柱温30℃,进样体积50μL。结果:苯扎氯铵在0.02至0.5mg・mL -1浓度范围内线性关系良好(r=0.9999);平均回收率为98.91%,RSD=0.44%(n=9)。结论:该方法准确、简便、快速、可靠,能有效控制复方托吡卡胺滴眼液中苯扎氯铵的含量。

  9. Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline

    DEFF Research Database (Denmark)

    Dencker, Ditte; Wörtwein, Gitta; Weikop, Pia;

    2011-01-01

    studies indicate that the M(4) muscarinic cholinergic receptor subtype (mAChR) modulates the activity of the dopaminergic system and that this specific mAChR subtype is involved in mediating the antipsychotic-like effects of xanomeline. A specific neuronal subpopulation that expresses M(4) mAChRs together...... with D(1) dopamine receptors seems to be especially important in modulating dopamine-dependent behaviors. Using mutant mice that lack the M(4) mAChR only in D(1) dopamine receptor-expressing cells (D1-M4-KO), we investigated the role of this neuronal population in the antipsychotic-like effects...

  10. 26 CFR 1.401(m)-4 - Special rules for mergers, acquisitions and similar events. [Reserved

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Special rules for mergers, acquisitions and similar events. 1.401(m)-4 Section 1.401(m)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE.... § 1.401(m)-4 Special rules for mergers, acquisitions and similar events....

  11. CCR2 antagonists.

    Science.gov (United States)

    Struthers, Mary; Pasternak, Alexander

    2010-01-01

    Inhibition of CCR2 has been considered as a target for multiple therapeutic diseases including autoimmune disease, atherosclerosis, pain, and metabolic disease, based in part on the critical role this receptor plays on monocyte migration. Numerous companies have reported programs to identify CCR2 antagonists. Common challenges to the development of CCR2 agents have included poor activity at the rodent receptor and selectivity for both other chemokine receptors and ion channels. This review summarizes the rationale for targeting CCR2 in disease, the recent progress in the identification of potent and select CCR2 antagonists, and the current status of clinical trials for CCR2 agents.

  12. Opioid Antagonist Impedes Exposure.

    Science.gov (United States)

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

  13. M4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition

    Directory of Open Access Journals (Sweden)

    Koshimizu Hisatsugu

    2012-04-01

    Full Text Available Abstract Background In the central nervous system (CNS, the muscarinic system plays key roles in learning and memory, as well as in the regulation of many sensory, motor, and autonomic processes, and is thought to be involved in the pathophysiology of several major diseases of the CNS, such as Alzheimer's disease, depression, and schizophrenia. Previous studies reveal that M4 muscarinic receptor knockout (M4R KO mice displayed an increase in basal locomotor activity, an increase in sensitivity to the prepulse inhibition (PPI-disrupting effect of psychotomimetics, and normal basal PPI. However, other behaviorally significant roles of M4R remain unclear. Results In this study, to further investigate precise functional roles of M4R in the CNS, M4R KO mice were subjected to a battery of behavioral tests. M4R KO mice showed no significant impairments in nociception, neuromuscular strength, or motor coordination/learning. In open field, light/dark transition, and social interaction tests, consistent with previous studies, M4R KO mice displayed enhanced locomotor activity compared to their wild-type littermates. In the open field test, M4R KO mice exhibited novelty-induced locomotor hyperactivity. In the social interaction test, contacts between pairs of M4R KO mice lasted shorter than those of wild-type mice. In the sensorimotor gating test, M4R KO mice showed a decrease in PPI, whereas in the startle response test, in contrast to a previous study, M4R KO mice demonstrated normal startle response. M4R KO mice also displayed normal performance in the Morris water maze test. Conclusions These findings indicate that M4R is involved in regulation of locomotor activity, social behavior, and sensorimotor gating in mice. Together with decreased PPI, abnormal social behavior, which was newly identified in the present study, may represent a behavioral abnormality related to psychiatric disorders including schizophrenia.

  14. Calcium antagonists and vasospasm.

    Science.gov (United States)

    Meyer, F B

    1990-04-01

    A critical review of the clinical data supports the conclusion that nimodipine decreases the severity of neurologic deficits and improves outcome after subarachnoid hemorrhage. The mechanisms by which mortality and morbidity are reduced are still controversial. First, the frequency of vasospasm is not altered (Figs. 5 and 6). Second, the consistent reversal of vasospasm once present has not been demonstrated either angiographically or by noninvasive cerebral blood flow studies. These observations suggest that there is either modification of microcirculatory flow (i.e., dilation of pial conducting vessels or decreased platelet aggregation) or a direct neuronal protective effect. As suggested previously, support for either mechanism is not resolute, and further investigation is necessary. Currently, nimodipine has been the most thoroughly investigated calcium antagonist both from an experimental and clinical perspective. Oral administration has had few reported complications. Therefore, the benefit/risk ratio clearly supports the prophylactic use of this calcium antagonist in patients of all clinical grades after subarachnoid hemorrhage. Evidence also indicates that starting nimodipine after the onset of delayed ischemic deficits is of benefit. Finally, it can be predicted that in the future additional calcium antagonists with more selective vascular or neuronal effects will be developed for use in neurologic disorders.

  15. A selfish gene chastened: Tribolium castaneum Medea M4 is silenced by a complementary gene.

    Science.gov (United States)

    Thomson, M Scott

    2014-04-01

    Maternal-effect dominant embryonic arrest (Medea) of Tribolium castaneum are autosomal factors that act maternally to cause the death of any progeny that do not inherit them. This selfish behavior is thought to result from a maternally expressed poison and zygotically expressed antidote. Medea factors and the hybrid incompatibility factor, H, have a negative interaction consistent with complementary genes of the Dobzhansky-Muller model for post-zygotic isolation. This negative interaction may result from H suppression of Medea zygotic antidote, leaving zygotes incompletely protected from maternal poison. I report here a test of the hypothesis that H also suppresses the Medea maternal poison. Viable F1 females were generated from a cross of Medea M4 strain males to H strain females. These females, heterozygous for both M4 and H, failed to express M4 maternal lethal activity when crossed to their male sibs. Transmission of non-M4 homologues from these females was confirmed using a dominant transgenic enhanced green fluorescent protein eye color marker, tightly linked in cis to M4. M4 beetles, lacking H, were selected from the F2 population. Female descendants of these clearly expressed M4 maternal lethal activity, indicating restoration of this activity after H was segregated away. I conclude that H, or a factor tightly linked to H, suppresses Medea M4 maternal poison.

  16. Antipsychotic-induced catalepsy is attenuated in mice lacking the M4 muscarinic acetylcholine receptor

    DEFF Research Database (Denmark)

    Fink-Jensen, Anders; Schmidt, Lene S; Dencker, Ditte

    2011-01-01

    of the striatum, suggesting a role for muscarinic M4 receptors in the motor side effects of antipsychotics, and in the alleviation of these side effects by anticholinergics. Here we investigated the potential role of the muscarinic M4 receptor in catalepsy induced by antipsychotics (haloperidol and risperidone...

  17. Tetrahydroindolizinone NK1 antagonists.

    Science.gov (United States)

    Bao, Jianming; Lu, Huagang; Morriello, Gregori J; Carlson, Emma J; Wheeldon, Alan; Chicchi, Gary G; Kurtz, Marc M; Tsao, Kwei-Lan C; Zheng, Song; Tong, Xinchun; Mills, Sander G; DeVita, Robert J

    2010-04-01

    A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles.

  18. 盐酸环喷托酯滴眼液联合复方托吡卡胺滴眼液在学龄期儿童散瞳验光中的应用临床研究%combined application of Cyclopentolate hydrochloride drop eye fluid and Compound Tropicamide Eye Drops in school -age children in mydriatic optometry

    Institute of Scientific and Technical Information of China (English)

    洪茶花

    2014-01-01

    目的:观察盐酸环喷托酯滴眼液联合复方托吡卡胺滴眼液在学龄期儿童散瞳验光中的应用效果。方法60名学龄期儿童,120眼。每例先后用盐酸环喷托酯滴眼液联合复方托吡卡胺滴眼液及1%阿托品扩瞳验光取得验光数值,做自身对照。结果球镜结果相差≤0.25D的总计有115眼,占95.83%;球镜结果相差>0.25D总计有5眼,占4.17%。结论盐酸环喷托酯滴眼液联合复方托吡卡胺滴眼液用于学龄期儿童单纯近视或远视的散瞳效果好,可以替代阿托品,值得临床推广应用。%Objective To observe the ef ect of cyclopentolate hydrochloride eye drops combined with Compound Tropicamide Eye Drops in school-age children in the application ef ect of mydriasis optometry.Methods 60 school-age children,120 eyes.Each case has cyclopentolate hydrochloride eye drops combined with Compound Tropicamide Eye Drops and 1%atropine myd-riatic optometry .optometry values obtained,do their own control.Results the mirror bal result diference is less than 0.25D in 115 eyes,accounting for 95.83%;the mirror bal result difer-ence is >0.25D a total of 5 eyes,accounting for 4.17%.Conclusion cyclopentolate hydrochloride eye drops combined with Compound Tropicamide Eye Drops for school-age children simple myopia or hyperopia mydriatic ef ect is good,can replace atropine,worthy of clinical application.

  19. M4 mAChR-mediated modulation of glutamatergic transmission at corticostriatal synapses.

    Science.gov (United States)

    Pancani, Tristano; Bolarinwa, Caroline; Smith, Yoland; Lindsley, Craig W; Conn, P Jeffrey; Xiang, Zixiu

    2014-04-16

    The striatum is the main input station of the basal ganglia and is extensively involved in the modulation of motivated behavior. The information conveyed to this subcortical structure through glutamatergic projections from the cerebral cortex and thalamus is processed by the activity of several striatal neuromodulatory systems including the cholinergic system. Acetylcholine potently modulates glutamate signaling in the striatum via activation of muscarinic receptors (mAChRs). It is, however, unclear which mAChR subtype is responsible for this modulatory effect. Here, by using electrophysiological, optogenetic, and immunoelectron microscopic approaches in conjunction with a novel, highly selective M4 positive allosteric modulator VU0152100 (ML108) and M4 knockout mice, we show that M4 is a major mAChR subtype mediating the cholinergic inhibition of corticostriatal glutamatergic input on both striatonigral and striatopallidal medium spiny neurons (MSNs). This effect is due to activation of presynaptic M4 receptors, which, in turn, leads to a decrease in glutamate release from corticostriatal terminals. The findings of the present study raise the interesting possibility that M4 mAChR could be a novel therapeutic target for the treatment of neurological and neuropsychiatric disorders involving hyper-glutamatergic transmission at corticostriatal synapses.

  20. 4333M4超高压反应管的断裂韧度%Fracture Toughness of Ultrahigh Pressure Reaction Tube Made by 4333M4 Steel

    Institute of Scientific and Technical Information of China (English)

    李铜; 陈进

    2012-01-01

    The critical stress intensity factor Kit: of high strength low alloy steel 4333M4 was determinated through non-standard arch bone bending experiment, and flexibility method was used. Then the tube was assessed by the leak before break criterion. The results showed that the fracture toughness of the steel was measured up to standard of SFAC 98--01 Rev. 2 and the pipe met requirements of leak before break.%通过非标准拱形三点弯曲试样的试验,采用柔度法标定,测定了进口4333M4低合金超高强度钢管材的临界应力强度因子Kzc,并对该超高压反应管进行了先漏后破分析。结果表明:该钢材有较高的断裂韧度,符合SFAC98-01Rev.2《超高压用无缝合金钢管技术条件》的要求,且管材符合先漏后破标准。

  1. International Conference on Harmonisation; guidance on M4 common technical document; availability. Notice.

    Science.gov (United States)

    2001-10-16

    The Food and Drug Administration (FDA) is announcing the availability of guidance entitled "M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use" (M4CTD). The guidance was developed under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The guidance, which is being made available simultaneously in four parts (general organization, quality, safety, and efficacy), describes a harmonized format for new product applications (including applications for biotechnology-derived products) for submission to the regulatory authorities in the three ICH regions. The M4 CTD is intended to reduce the time and resources used to compile applications, ease the preparation of electronic submissions, facilitate regulatory reviews and communication with the applicant, and simplify the exchange of regulatory information among regulatory authorities.

  2. Voice-coil technology for the E-ELT M4 Adaptive Unit

    Science.gov (United States)

    Gallieni, D.; Tintori, M.; Mantegazza, M.; Anaclerio, E.; Crimella, L.; Acerboni, M.; Biasi, R.; Angerer, G.; Andrigettoni, M.; Merler, A.; Veronese, D.; Carel, J.-L.; Marque, G.; Molinari, E.; Tresoldi, D.; Toso, G.; Spanó, P.; Riva, M.; Mazzoleni, R.; Riccardi, A.; Mantegazza, P.; Manetti, M.; Morandini, M.; Vernet, E.; Hubin, N.; Jochum, L.; Madec, P.; Dimmler, M.; Koch, F.

    We present our design of the E-ELT M4 Adaptive Unit based on voice-coil driven deformable mirror technology. This technology was developed by INAF-Arcetri, Microgate and ADS team in the past 15 years and it has been adopted by a number of large ground based telescopes as the MMT, LBT, Magellan and lastly the VLT in the frame of the Adaptive Telescope Facility project. Our design is based on contactless force actuators made by permanent magnets glued on the back of the deformable mirror and coils mounted on a stiff reference structure. We use capacitive sensors to close a position loop co-located with each actuator. Dedicated high performance parallel processors are used to implement the local de-centralized control at actuator level and a centralized feed-forward computation of all the actuators forces. This allowed achieving in our previous systems dynamic performances well in line with the requirements of the M4 Adaptive Unit (M4AU) case. The actuator density of our design is in the order of 30-mm spacing for a figure of about 6000 actuators on the M4AU and it allows fulfilling the fitting error and corrections requirements of the E-ELT high order DM. Moreover, our contact-less technology makes the Deformable Mirror tolerant to up 5% actuators failures without spoiling system capability to reach its specified performances, besides allowing large mechanical tolerances between the reference structure and the deformable mirror. Finally, we present the Demonstration Prototype we are building in the frame of the M4AU Phase B study to measure the optical dynamical performances predicted by our design. Such a prototype will be fully representative of the M4AU features, in particular it will address the controllability of two adjacent segments of the 2-mm thick mirror and implement the actuators "brick" modular concept that has been adopted to dramatically improve the maintainability of the final unit.

  3. Correlation of the National Emergency Medicine M4 Clerkship Examination with USMLE Examination Performance

    Directory of Open Access Journals (Sweden)

    Luan E. Lawson

    2015-12-01

    Full Text Available Introduction: Assessment of medical students’ knowledge in clinical settings is complex yet essential to the learning process. Clinical clerkships use various types of written examinations to objectively test medical knowledge within a given discipline. Within emergency medicine (EM, a new national standardized exam was developed to test medical knowledge in this specialty. Evaluation of the psychometric properties of a new examination is an important issue to address during test development and use. Studies have shown that student performance on selected standardized exams will reveal students’ strengths and/or weaknesses, so that effective remedial efforts can be implemented. Our study sought to address these issues by examining the association of scores on the new EM national exam with other standardized exam scores. Methods: From August 2011 to April 2013, average National EM M4 examination scores of fourthyear medical students taken at the end of a required EM clerkship were compiled. We examined the correlation of the National EM M4 examination with the scores of initial attempts of the United States Medical Licensing Exam (USMLE Step 1 and Step 2 Clinical Knowledge (CK examinations. Correlation coefficients and 95% confidence intervals of correlation coefficients are reported. We also examined the association between the national EM M4 examination score, final grades for the EM rotation, and USMLE Step 1 and Step 2 CK scores. Results: 133 students were included in the study and achieved a mean score of 79.5 SD 8.0 on the National EM M4 exam compared to a national mean of 79.7 SD 3.89. The mean USMLE Step 1 score was 226.8 SD 19.3. The mean USMLE Step 2 CK score was 238.5 SD 18.9. National EM M4 examination scores showed moderate correlation with both USMLE Step 1 (mean score=226.8; correlation coefficient=0.50; 95% CI [0.28-0.67] and USMLE Step 2 CK (mean score=238.5; correlation coefficient=0.47; 95% CI [0.25-0.65]. Students scoring

  4. E Durans Strain M4-5 Isolated From Human Colonic Flora Attenuates Intestinal Inflammation

    DEFF Research Database (Denmark)

    Avram-Hananel, L.; Stock, J.; Parlesak, Alexandr

    2010-01-01

    inflammation, and inhibited colonic transcription of proinflammatory immune factors. The effect of therapeutic treatment alone on these parameters was more moderate but still significant. CONCLUSIONS: We conclude that E durans strain M4 to 5 and its metabolic product butyrate induce significant anti...

  5. Iconic end-users in M4H's organic area development

    NARCIS (Netherlands)

    Meijer, Michaël; Peek, Gert- Joost

    2015-01-01

    This paper present the preliminary findings of a recently started research project on the organic redevelopment strategy of the Rotterdam City Ports organization in the MerweVierhavens area (M4H) and its particular context. An overview of the area and roles of the involved actors is given from the p

  6. Terahertz and M4PP conductivity mapping of large area CVD grown graphene films

    DEFF Research Database (Denmark)

    Buron, Jonas Christian Due; Petersen, Dirch Hjorth; Bøggild, Peter;

    We demonstrate mapping of magnitude and variation of the electrical conductance of large area CVD graphene films by terahertz time-domain spectroscopy (THz-TDS) and micro four-point-probe (M4PP). Non-trivial correlations between results obtained with the two techniques are discussed in relation...

  7. Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice

    DEFF Research Database (Denmark)

    Schmidt, Lene Sørensen; Thomsen, Morgane; Weikop, Pia

    2011-01-01

    Rationale The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic M4 receptor subtype plays an important role in regulation of dopaminergic neurotransmission. Objectives Here we investigated...... of drug addiction...

  8. Studies on antagonistic marine streptomycetes

    Digital Repository Service at National Institute of Oceanography (India)

    Chandramohan, D.; Nair, S.

    Sixty nine strains of Streptomyces sp. isolated from the sediments of Andaman and Nicobar islands (Bay of Bengal) were screened for their antagonistic property against a number of test cultures (Vibrio sp., Klebsiella sp., Escherichia coli, Shigella...

  9. VizieR Online Data Catalog: M4 Core Project with HST. Radial velocities (Malavolta+, 2015)

    Science.gov (United States)

    Malavolta, L.; Piotto, G.; Bedin, L. R.; Sneden, C.; Nascimbeni, V.; Sommariva, V.

    2016-07-01

    The spectra for our project were originally used by Sommariva et al. (2009A&A...493..947S) to study the internal velocity dispersion of M4 and to search for spectroscopic binaries. A total of 2771 stars covering colour-magnitude diagram (CMD) positions from the upper RGB to about 1mag fainter than the main-sequence turnoff (TO) luminosity were observed between 2003 and 2009, including 306 new spectra obtained in 2009 and targeting MS stars already observed in the previous epochs. Determination of the M 4 velocity dispersion and binary star fraction were the prime motivators for obtaining these data. Therefore nearly all stars were observed at least twice, and three or more spectra were obtained for nearly 40 per cent of the sample. (2 data files).

  10. M4C9 +(M = Ti, V): New gas phase clusters

    Indian Academy of Sciences (India)

    R Selvan; L Gowrishankar; T Pradeep

    2001-10-01

    New metal-carbon clusters, M4C9 +(M = Ti, V), generated using a combined thermal arc discharge evaporation set-up, have been studied with quadrupole mass spectrometry. Reactivities of these clusters have been investigated by means of association reactions with H2O. Metal-carbon clusters of other compositions have also been studied. We speculate on the mechanism of formation of larger metal-carbon clusters.

  11. Hypoplastic acute myeloid leukemia-M4: A rare case report

    Directory of Open Access Journals (Sweden)

    Harsh Kumar

    2016-01-01

    Full Text Available Hypocellular acute myeloid leukemia (AML is defined as AML with bone marrow cellularity <20%. Hypocellular AML is an infrequent entity. Its frequency ranges between 5% and 12% of all cases of AML. Hypocellular variants of acute leukemia almost always have a myeloid phenotype and usually develop secondary to radiation or chemotherapy. We report a rare case of Hypocellular AML-M4 occurring in a 60-year-old woman who was incidentally found to be positive for HIV.

  12. A Business Case Analysis of the M4/AR-15 Market

    Science.gov (United States)

    2015-09-01

    market . The market analysis was conducted to fill missing gaps on the M4/AR-15 market size, customer demographics , and supplier base. Data was collected...Wesson, 2012). The article also provides data on the rapid growth in the modern sporting rifle market segment . Peters (2012) cites a Freedom Group...types of products generally manufactured in each market . The four main market segments are Small Arms (which will be considered the “Gun segment

  13. Getting ready for the real data-taking with M4

    CERN Multimedia

    Giuseppe Mornacchi

    M4 (Milestone 4), the fourth global commissioning period, took place from August 23rd to September 3rd. As for M3, this run included almost all of the ATLAS sub-detectors, with only the Pixels and Cathode Strip Chambers missing, but featured more detector hardware, new releases of offline and online software and many new functions. These are outlined below. The more mature state of systems integration called for a different organization of M4 with respect to M1-M3: following a 2-day setup time, we spent the rest of M4 running formal shifts: two shifts a day (9:00 to 17:00 and 17:00 to 24:00) with a full crew during week days, that is 13 control room desks staffed by at least one shifter each, and a single shift (9:00 to 17:00) with reduced crew of 5-7 people during weekends. While most of the time was dedicated to combined running with cosmics muons, four of the day shifts were dedicated to more technical issues such as: high rate (many kHz) runs, tests related to synchronization (Bunch Counter Reset and Eve...

  14. The M4RIE library for dense linear algebra over small fields with even characteristic

    CERN Document Server

    Albrecht, Martin R

    2011-01-01

    In this work, we present the M4RIE library which implements efficient algorithms for linear algebra with dense matrices over GF(2^e) for 2 <= 2 <= 10. As the name of the library indicates, it makes heavy use of the M4RI library both directly (i.e., by calling it) and indirectly (i.e., by using its concepts). We provide an open-source GPLv2+ C library for efficient linear algebra over GF(2^e) for e small. In this library we implemented an idea due to Bradshaw and Boothby which reduces matrix multiplication over GF(p^k) to a series of matrix multiplications over GF(p). Furthermore, we propose a caching technique - Newton-John tables - to avoid finite field multiplications which is inspired by Kronrod's method ("M4RM") for matrix multiplication over GF(2). Using these two techniques we provide asymptotically fast triangular solving with matrices (TRSM) and PLE-based Gaussian elimination. As a result, we are able to significantly improve upon the state of the art in dense linear algebra over GF(2^e) with 2 ...

  15. Abundances in a sample of turnoff and subgiant stars in NGC 6121 (M4)

    CERN Document Server

    Spite, Monique; Gallagher, Andrew J; Monaco, Lorenzo; Bonifacio, Piercarlo; Caffau, Elisabetta; Villanova, Sandro

    2016-01-01

    {The aim of this work is to investigate the relations between the abundances of different elements in the globular cluster M4, selected for its uniform deficiency of iron, to explore the best models explaining the pattern of these observed abundances. Moreover, in turnoff stars, the abundances of the elements are not suspected to be affected by internal mixing. In M4, using low and moderate resolution spectra obtained for 91 turnoff (and subgiant) stars with the ESO FLAMES-Giraffe spectrograph, we have extended previous measurements of abundances (of Li, C and Na) to other elements (C, Si, Ca, Sr and Ba), using model atmosphere analysis. We have also studied the influence of the choice of the microturbulent velocity. Firstly, the peculiar turnoff star found to be very Li-rich in a previous paper does not show any other abundance anomalies relative to the other turnoff stars in M4. ~Secondly, an anti-correlation between C and Na has been detected, the slope being significative at more than $3\\sigma$. This rela...

  16. The s-process enrichment of the globular clusters M4 and M22

    Energy Technology Data Exchange (ETDEWEB)

    Shingles, Luke J.; Karakas, Amanda I.; Fishlock, Cherie K.; Yong, David; Da Costa, Gary S.; Marino, Anna F. [Research School of Astronomy and Astrophysics, Australian National University, Canberra, ACT 2611 (Australia); Hirschi, Raphael, E-mail: luke.shingles@anu.edu.au [Institute for the Physics and Mathematics of the Universe (WPI), University of Tokyo, 5-1-5 Kashiwanoha, 277-8583 Kashiwa (Japan)

    2014-11-01

    We investigate the enrichment in elements produced by the slow neutron-capture process (s-process) in the globular clusters M4 (NGC 6121) and M22 (NGC 6656). Stars in M4 have homogeneous abundances of Fe and neutron-capture elements, but the entire cluster is enhanced in s-process elements (Sr, Y, Ba, Pb) relative to other clusters with a similar metallicity. In M22, two stellar groups exhibit different abundances of Fe and s-process elements. By subtracting the mean abundances of s-poor from s-rich stars, we derive s-process residuals or empirical s-process distributions for M4 and M22. We find that the s-process distribution in M22 is more weighted toward the heavy s-peak (Ba, La, Ce) and Pb than M4, which has been enriched mostly with light s-peak elements (Sr, Y, Zr). We construct simple chemical evolution models using yields from massive star models that include rotation, which dramatically increases s-process production at low metallicity. We show that our massive star models with rotation rates of up to 50% of the critical (break-up) velocity and changes to the preferred {sup 17}O(α, γ){sup 21}Ne rate produce insufficient heavy s-elements and Pb to match the empirical distributions. For models that incorporate asymptotic giant branch yields, we find that intermediate-mass yields (with a {sup 22}Ne neutron source) alone do not reproduce the light-to-heavy s-element ratios for M4 and M22, and that a small contribution from models with a {sup 13}C pocket is required. With our assumption that {sup 13}C pockets form for initial masses below a transition range between 3.0 and 3.5 M {sub ☉}, we match the light-to-heavy s-element ratio in the s-process residual of M22 and predict a minimum enrichment timescale of between 240 and 360 Myr. Our predicted value is consistent with the 300 Myr upper limit age difference between the two groups derived from isochrone fitting.

  17. Inversion of the Focal Mechanisms of the 2014 M4.2 and M4.0 Earthquakes in Rushan,Shandong Using the CAP Method%CAP 方法反演2014年山东乳山 M4.2、M4.0地震震源机制解

    Institute of Scientific and Technical Information of China (English)

    曲均浩; 刘瑞峰; 李金; 李永红; 张芹; 李铂; 吴丹彤

    2014-01-01

    There have been many intensive small earthquakes since the M 3.8 earthquake occurred in Rushan,Shandong on October 1,2013.Two earthquakes(M 4.2 and M 4.0)occurred separately on January 7 and April 4,2014.There have never been so many earthquakes in Rushan.A focal mechanism describes the nature and source rupture process and is an important foundation to un-derstand the stress state of the source region,earthquake faults,and for analyzing the causes of a seismic event.Therefore,seismic interpretation and post-earthquake seismogenic stress distribu-tion mechanisms play very important roles in determining earthquake focal mechanisms.In this study,using waveforms from the Shandong Seismological Network and comparing the synthetic and the observed seismograms,the focal mechanism of the Rushan M 4.2 and M 4.0 earthquakes in 2014 are inverted using the CAP(Cut and paste)method.The results show that the two earth-quakes get their best focal mechanism at 6 km depth,and that the parameters of the nodal planes are similar,belonging to the strike-slip type.At a depth of 6 km,the correlation coefficients of 40 phases of the M 4.2 earthquake greater than 0.7 that were recorded by eight stations are 37,which accounts for 93%.The correlation coefficients greater than 0.9 are 28,accounting for about 70%. Similarly,at a depth of 6 km,the correlation coefficients of 40 phases of the M 4.0 earthquake that were recorded by the eight stations are all greater than 0.7 and the correlation coefficients greater than 0.9 are 31,accounting for about 78%.Therefore,the synthetic seismograms of the two earth-quakes fit the observed seismograms well demonstrating that the inversion results are credible. The focal mechanism shows that the moment magnitude of the M 4.2 earthquake was M W =4.3;one nodal plane has a strike of 290°,rake of 84°,and dip of 22°and the other nodal plane has a strike of 189°,rake of 68°,and dip of 174°.The moment magnitude of the M 4.0 earthquake is M W=4.2,one nodal

  18. State-dependent alterations in sleep/wake architecture elicited by the M4 PAM VU0467154 - Relation to antipsychotic-like drug effects.

    Science.gov (United States)

    Gould, Robert W; Nedelcovych, Michael T; Gong, Xuewen; Tsai, Erica; Bubser, Michael; Bridges, Thomas M; Wood, Michael R; Duggan, Mark E; Brandon, Nicholas J; Dunlop, John; Wood, Michael W; Ivarsson, Magnus; Noetzel, Meredith J; Daniels, J Scott; Niswender, Colleen M; Lindsley, Craig W; Conn, P Jeffrey; Jones, Carrie K

    2016-03-01

    Accumulating evidence indicates direct relationships between sleep abnormalities and the severity and prevalence of other symptom clusters in schizophrenia. Assessment of potential state-dependent alterations in sleep architecture and arousal relative to antipsychotic-like activity is critical for the development of novel antipsychotic drugs (APDs). Recently, we reported that VU0467154, a selective positive allosteric modulator (PAM) of the M4 muscarinic acetylcholine receptor (mAChR), exhibits robust APD-like and cognitive enhancing activity in rodents. However, the state-dependent effects of VU0467154 on sleep architecture and arousal have not been examined. Using polysomnography and quantitative electroencephalographic recordings from subcranial electrodes in rats, we evaluated the effects of VU0467154, in comparison with the atypical APD clozapine and the M1/M4-preferring mAChR agonist xanomeline. VU0467154 induced state-dependent alterations in sleep architecture and arousal including delayed Rapid Eye Movement (REM) sleep onset, increased cumulative duration of total and Non-Rapid Eye Movement (NREM) sleep, and increased arousal during waking periods. Clozapine decreased arousal during wake, increased cumulative NREM, and decreased REM sleep. In contrast, xanomeline increased time awake and arousal during wake, but reduced slow wave activity during NREM sleep. Additionally, in combination with the N-methyl-d-aspartate subtype of glutamate receptor (NMDAR) antagonist MK-801, modeling NMDAR hypofunction thought to underlie many symptoms in schizophrenia, both VU0467154 and clozapine attenuated MK-801-induced elevations in high frequency gamma power consistent with an APD-like mechanism of action. These findings suggest that selective M4 PAMs may represent a novel mechanism for treating multiple symptoms of schizophrenia, including disruptions in sleep architecture without a sedative profile.

  19. M4FT-15LL0806062-LLNL Thermodynamic and Sorption Data FY15 Progress Report

    Energy Technology Data Exchange (ETDEWEB)

    Zavarin, M. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Wolery, T. J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-08-31

    This progress report (Milestone Number M4FT-15LL0806062) summarizes research conducted at Lawrence Livermore National Laboratory (LLNL) within Work Package Number FT-15LL080606. The focus of this research is the thermodynamic modeling of Engineered Barrier System (EBS) materials and properties and development of thermodynamic databases and models to evaluate the stability of EBS materials and their interactions with fluids at various physicochemical conditions relevant to subsurface repository environments. The development and implementation of equilibrium thermodynamic models are intended to describe chemical and physical processes such as solubility, sorption, and diffusion.

  20. M4FT-16LL080302052-Update to Thermodynamic Database Development and Sorption Database Integration

    Energy Technology Data Exchange (ETDEWEB)

    Zavarin, Mavrik [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Glenn T. Seaborg Inst.. Physical and Life Sciences; Wolery, T. J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Akima Infrastructure Services, LLC; Atkins-Duffin, C. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Global Security

    2016-08-16

    This progress report (Level 4 Milestone Number M4FT-16LL080302052) summarizes research conducted at Lawrence Livermore National Laboratory (LLNL) within the Argillite Disposal R&D Work Package Number FT-16LL08030205. The focus of this research is the thermodynamic modeling of Engineered Barrier System (EBS) materials and properties and development of thermodynamic databases and models to evaluate the stability of EBS materials and their interactions with fluids at various physico-chemical conditions relevant to subsurface repository environments. The development and implementation of equilibrium thermodynamic models are intended to describe chemical and physical processes such as solubility, sorption, and diffusion.

  1. Abundances in a sample of turnoff and subgiant stars in NGC 6121 (M 4)

    Science.gov (United States)

    Spite, M.; Spite, F.; Gallagher, A. J.; Monaco, L.; Bonifacio, P.; Caffau, E.; Villanova, S.

    2016-10-01

    Context. The stellar abundances observed in globular clusters show complex structures, currently not yet understood. Aims: The aim of this work is to investigate the relations between the abundances of different elements in the globular cluster M 4, selected for its uniform deficiency of iron, to explore the best models explaining the pattern of these observed abundances. Moreover, in turnoff stars, the abundances of the elements are not suspected to be affected by internal mixing. Methods: In M 4, using low and moderate resolution spectra obtained for 91 turnoff (and subgiant) stars with the ESO FLAMES-Giraffe spectrograph, we have extended previous measurements of abundances (of Li, C and Na) to other elements (C, Si, Ca, Sr and Ba), using model atmosphere analysis. We have also studied the influence of the choice of the microturbulent velocity. Results: Firstly, the peculiar turnoff star found to be very Li-rich in a previous paper does not show any other abundance anomalies relative to the other turnoff stars in M 4. Secondly, an anti-correlation between C and Na has been detected, the slope being significative at more than 3σ. This relation between C and Na is in perfect agreement with the relation found in giant stars selected below the RGB bump. Thirdly, the strong enrichment of Si and of the neutron-capture elements Sr and Ba, already observed in the giants in M 4, is confirmed. Finally, the relations between Li, C, Na, Sr and Ba constrain the enrichment processes of the observed stars. Conclusions: The abundances of the elements in the turnoff stars appear to be compatible with production processes by massive AGBs, but are also compatible with the production of second generation elements (like Na) and low Li produced by, for example, fast rotating massive stars. Based on observations collected at the European Organisation for Astronomical Research in the Southern Hemisphere under ESO programme 085.D-0537(A).Full Tables 3 and 4 are only available at the

  2. [Effective method of isolating M4-lactate dehydrogenase from rat liver].

    Science.gov (United States)

    Gorbach, Z V; Maglysh, S S; Konovalenko, O V

    1984-01-01

    Lactate dehydrogenase M4-isoform in the homogeneous state was isolated from the rat liver by successive application of sulphate-ammonium fractionation, phosphocellulose ion-exchange chromatography with high-affinity elution of 1 mM NADH and subsequent hydroxyl apatite fractionation. The method permits obtaining the preparation amounts of the enzymic protein with yield 37.5%, specific activity 386.8 units per 1 mg of protein. It is established that 1 mM NAD+, 10 mM pyruvate and 100 mM lactate are also effective as agents of the selective enzyme elution.

  3. New examples of metalloaromatic Al-clusters: (Al4M4)Fe(CO)3 (M=Li, Na and K) and (Al4M4)2Ni: Rationalization for possible synthesis

    CERN Document Server

    Datta, A; Datta, Ayan; Pati, Swapan K.

    2005-01-01

    Ab-initio calculations reveal that all-metal antiaromatic molecules like Al4M4 (M=Li, Na and K) can be stabilized in half-sandwich complex: (Al4M4)Fe(CO)3 and full-sandwich complexes of the type: (Al4M4)2Ni. The formation of the full-sandwich complex [(Al4M4)2Ni] from its organometallic precursor depends on the stability of the organic-inorganic hybrid (C4H4) Ni (Al4Li4).

  4. Multiple populations along the asymptotic giant branch of the globular cluster M4

    Science.gov (United States)

    Lardo, C.; Salaris, M.; Savino, A.; Donati, P.; Stetson, P. B.; Cassisi, S.

    2017-04-01

    Nearly all Galactic globular clusters host stars that display characteristic abundance anticorrelations, like the O-rich/Na-poor pattern typical of field halo stars, together with O-poor/Na-rich additional components. A recent spectroscopic investigation questioned the presence of O-poor/Na-rich stars amongst a sample of asymptotic giant branch (AGB) stars in the cluster M4, at variance with the spectroscopic detection of a O-poor/Na-rich component along both the cluster red giant branch (RGB) and horizontal branch. This is contrary to what is expected from the cluster horizontal branch morphology and horizontal branch stellar evolution models. Here, we have investigated this issue by employing the CUBI = (U - B) - (B - I) index, that previous studies have demonstrated to be very effective in separating multiple populations along both the RGB and AGB sequences. We confirm previous results that the RGB is intrinsically broad in the V-CUBI diagram, with the presence of two components that nicely correspond to the two populations identified by high-resolution spectroscopy. We find that AGB stars are distributed over a wide range of CUBI values, in close analogy with what is observed for the RGB, demonstrating that the AGB of M4 also hosts multiple stellar populations.

  5. The discovery of an M4+T8.5 binary system

    CERN Document Server

    Burningham, Ben; Leggett, S K; Tinney, C G; Liu, M C; Homeier, D; West, A A; Day-Jones, A; Huélamo, N; Dupuy, T J; Zhang, Z; Murray, D N; Lodieu, N; Navascues, D Barrado y; Folkes, S; Galvez-Ortiz, M C; Jones, H R A; Lucas, P W; Calderon, M Morales; Tamura, M

    2009-01-01

    We report the discovery of a T8.5 dwarf, which is a companion to the M4 dwarf Wolf 940. At a distance of 12.50 (+0.75,-0.67) pc, the angular separation of 32arcsec corresponds to a projected separation of 400 AU. The M4 primary displays no Halpha emission, and we apply the age-activity relations of West et al. to place a lower limit on the age of the system of 3.5 Gyr. Weak Halpha absorption suggests some residual activity and we estimate an upper age limit of 6 Gyr. We apply the relations of Bonfils et al for V-Ks and M_Ks to determine the metallicity, [Fe/H] = -0.06 +/- 0.20 for Wolf~940A, and by extension the T8.5 secondary, Wolf 940B. We have obtained JHK NIRI spectroscopy and JHKL' photometry of Wolf 940B, and use these data, in combination with theoretical extensions, to determine its bolometric flux, Fbol = 1.75 +/- 0.18 E-16 Wm^-2 and thus its luminosity log(L*/Lsun) = -6.07 +/- 0.04. Using the age constraints for the system, and evolutionary structural models of Baraffe et al. we determine Teff = 570...

  6. An aluminium tool for multiple stellar generations in the globular clusters 47 Tuc and M 4

    CERN Document Server

    Carretta, Eugenio; Bragaglia, Angela; D'Orazi, Valentina; Lucatello, Sara

    2012-01-01

    We present aluminium abundances for a sample of about 100 red giant stars in each of the Galactic globular clusters 47 Tuc (NGC 104) and M 4 (NGC 6121). We have derived homogeneous abundances from intermediate-resolution FLAMES/GIRAFFE spectra. Aluminium abundances are from the strong doublet Al I at 8772-8773 A as in previous works done for giants in NGC 6752 and NGC 1851, and nitrogen abundances are extracted from a large number of features of the CN molecules, by assuming a suitable carbon abundance. We added previous homogeneous abundances of O and Na and newly derived abundances of Mg and Si for our samples of 83 stars in M 4 and 116 stars in 47 Tuc to obtain the full set of elements from proton-capture reactions produced by different stellar generations in these clusters. By simultaneously studying the Ne-Na and Mg-Al cycles of H-burning at high temperature our main aims are to understand the nature of the polluters at work in the first generation and to ascertain whether the second generation of cluste...

  7. Sodium-Oxygen anticorrelation among Horizontal Branch Stars in the Globular Cluster M4

    CERN Document Server

    Marino, A F; Milone, A P; Piotto, G; Lind, K; Geisler, D; Stetson, P B

    2010-01-01

    The horizontal branch (HB) morphology of globular clusters (GC) is mainly governed by metallicity. The second parameter problem, well known since the 60's, states that metallicity alone is not enough to describe the observed HB morphology of many GCs. Despite many efforts to resolve this issue, the second parameter phenomenon still remains without a satisfactory explanation. We have analyzed blue, red-HB, and RR-Lyrae stars in the GC M4 and studied their Fe, Na, and O abundances. Our goal is to investigate possible connections between the bimodal HB of M4 and the chemical signatures of the two stellar populations recently discovered among red giants of this cluster. We obtained FLAMES-UVES/GIRAFFE spectra of a sample of 22 stars covering the HB from the red to the blue region. While iron has the same abundance in both the red and blue-HB segment, the red-HB is composed of stars with scaled-solar sodium abundances, while the blue-HB stars are all sodium enhanced and oxygen depleted. The RR-Lyrae are Na-poor, a...

  8. Expression of ETV6 rearrangement in a subject with acute myeloid leukemia-M4Eo

    Institute of Scientific and Technical Information of China (English)

    GAO Na; LI Zhi-hong; DING Bu-tong; CHEN Yun; WANG Yun-shan; QIAO Ying; GUO Nong-jian

    2008-01-01

    @@ Acute myeloid leukemia (AML) M4Eo type is a hematological malignancy with abnormal eosinophilia,which is often accompanied by inv(16).The Ets variant gene 6 (ETV6),mapped to 12p13,is an ETS family transcription factor that is essential for hematopoietic processes,1 The ETV6 gene-involved chromosomal translocations have been found in many hematological malignancies characterized by fusing to a number of different partner genes;mainly coding for tyrosine kinases or transcription factors which are important for the initiation,progress and prognosis of disease.2 In particular,the ETV6 gene has been reported to be fused to ABL in acute lymphocytic leukemias (ALL),3 and chronic myeloid leukemia (CML).4 However,there have been few domestic reports of ETV6 fusion genes,especially in cases of acute leukemia.We investigated 3 cases of AML-M4Eo patients using Split-signal Fluorescence in situ hybridization (FISH) and found one case with a translocation between 12p13 and 1q25 co-occurring with an inv(16).The ETV6/ARG (ABL-related gene) fusion transcript was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR).This is the report of ARG involvement in a translocation in a human malignancy.

  9. X-ray Sources and their Optical Counterparts in the Globular Cluster M4

    CERN Document Server

    Bassa, C; Homer, L; Verbunt, F; Gaensler, B M; Lewin, W H G; Anderson, S F; Margon, B; Kaspi, V M; Van der Klis, M; Bassa, Cees; Pooley, David; Homer, Lee; Verbunt, Frank; Gaensler, Bryan M.; Lewin, Walter H. G.; Anderson, Scott F.; Margon, Bruce; Kaspi, Victoria M.; Klis, Michiel van der

    2004-01-01

    We report on the Chandra X-ray Observatory ACIS-S3 imaging observation of the Galactic globular cluster M4 (NGC 6121). We detect 12 X-ray sources inside the core and 19 more within the cluster half-mass radius. The limiting luminosity of this observation is Lx~10e29 erg/sec for sources associated with the cluster, the deepest X-ray observation of a globular cluster to date. We identify 6 X-ray sources with known objects and use ROSAT observations to show that the brightest X-ray source is variable. Archival data from the Hubble Space Telescope allow us to identify optical counterparts to 16 X-ray sources. Based on the X-ray and optical properties of the identifications and the information from the literature, we classify two (possibly three) sources as cataclysmic variables, one X-ray source as a millisecond pulsar and 12 sources as chromospherically active binaries. Comparison of M4 with 47 Tuc and NGC 6397 suggests a scaling of the number of active binaries in these clusters with the cluster (core) mass.

  10. Monte Carlo Simulations of Star Clusters - V. The globular cluster M4

    CERN Document Server

    Giersz, Mirek

    2008-01-01

    We describe Monte Carlo models for the dynamical evolution of the nearby globular cluster M4. The code includes treatments of two-body relaxation, three- and four-body interactions involving primordial binaries and those formed dynamically, the Galactic tide, and the internal evolution of both single and binary stars. We arrive at a set of initial parameters for the cluster which, after 12Gyr of evolution, gives a model with a satisfactory match to the surface brightness profile, the velocity dispersion profile, and the luminosity function in two fields. We describe in particular the evolution of the core, and find that M4 (which has a classic King profile) is actually a post-collapse cluster, its core radius being sustained by binary burning. We also consider the distribution of its binaries, including those which would be observed as photometric binaries and as radial-velocity binaries. We also consider the populations of white dwarfs, neutron stars, black holes and blue stragglers, though not all channels ...

  11. Synthesis of potential mescaline antagonists.

    Science.gov (United States)

    DeSantis, F; Nieforth, K A

    1976-10-01

    1-[2-(3,4,5-Trimethoxyphenyl)ethyl]-3-pyrroline, 2-(3,4,5-trimethoxybenzyl)-1,2,3,6-tetrahydropyridine, N-n-propylmescaline, N-cyclopropylmethylmescaline, and N-allylmescaline were synthesized as potential mescaline antagonists. The ability of these compounds to antagonize mescaline-induced disruption of swim behavior is also given.

  12. Excitatory amino acid receptor antagonists

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B

    1997-01-01

    We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation......)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments......, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation...

  13. DEVELOPMENT OF NEW LHRH ANTAGONISTS

    Institute of Scientific and Technical Information of China (English)

    PENGDun-Ren; XIAOShao-Bo

    1989-01-01

    An ideal antagonist of LHRH is one which can act on the pitutary to inhibit LHRH-stimulatod LH / FSH secretion by competitive occupying the LHRH receptor in the pitutary gland. Its action should be very specific, fast and highly effective, the durations

  14. Tracing differential reddening with Diffuse Interstellar Bands. The globular cluster M 4 as a testbed

    CERN Document Server

    Monreal-Ibero, A; Puspitarini, L; Bonifacio, P; Monaco, L

    2015-01-01

    Diffuse interstellar bands (DIBs) are weak absorption features of interstellar origin present in the optical and infrared spectra of stars. Their use as a tool to trace the structure of the Galactic ISM is gaining relevance in the recent years. Here we present an experiment to test our ability to trace differential reddening on the plane of the sky by using the information relative to the DIB at $\\lambda$6614 extracted from the spectra of cool stars. For that we made use of archive FLAMES data of the globular cluster M4, as well as WISE and Planck images for reference. We found a global positive trend between the distribution of the strength of the DIB, as traced by its equivalent width, and the amount of Galactic reddening, as traced by Planck. This result supports the use of DIBs to trace the small scale structure of the Galactic ISM.

  15. Experimental results and numerical simulations for transonic flow over the ONERA M4R model

    Directory of Open Access Journals (Sweden)

    Marius Gabriel COJOCARU

    2013-06-01

    Full Text Available This paper presents a comparison between experimental results of transonic flow over the ONERA M4R calibration model obtained in the INCAS Trisonic wind tunnel and the numerical results. The first purpose, emphasized in this paper is to compare and validate the computational fluid dynamics (CFD techniques for internal transonic flows and to try to find the most suitable numerical methodology for these flows in both accuracy and computational resources. The second purpose is to develop a general method in experimental data correction and flight Reynolds extrapolation, using numerical simulations for both global and local pressure coefficients, as a replacement for the classical vortex lattices based method. That will be developed in a future paper. Besides the computational work, the periodic wind tunnel calibration is required as a quality insurance operation and a numerical model is developed such that future hardware modifications to be included and their impact to be properly considered.

  16. Effects of dopamine D1-like and D2-like antagonists on cocaine discrimination in muscarinic receptor knockout mice.

    Science.gov (United States)

    Thomsen, Morgane; Caine, Simon Barak

    2016-04-05

    Muscarinic and dopamine brain systems interact intimately, and muscarinic receptor ligands, like dopamine ligands, can modulate the reinforcing and discriminative stimulus (S(D)) effects of cocaine. To enlighten the dopamine/muscarinic interactions as they pertain to the S(D) effects of cocaine, we evaluated whether muscarinic M1, M2 or M4 receptors are necessary for dopamine D1 and/or D2 antagonist mediated modulation of the S(D) effects of cocaine. Knockout mice lacking M1, M2, or M4 receptors, as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10mg/kg cocaine from saline in a food-reinforced drug discrimination procedure. Effects of pretreatments with the dopamine D1 antagonist SCH 23390 and the dopamine D2 antagonist eticlopride were evaluated. In intact mice, both SCH 23390 and eticlopride attenuated the cocaine discriminative stimulus effect, as expected. SCH 23390 similarly attenuated the cocaine discriminative stimulus effect in M1 knockout mice, but not in mice lacking M2 or M4 receptors. The effects of eticlopride were comparable in each knockout strain. These findings demonstrate differences in the way that D1 and D2 antagonists modulate the S(D) effects of cocaine, D1 modulation being at least partially dependent upon activity at the inhibitory M2/M4 muscarinic subtypes, while D2 modulation appeared independent of these systems.

  17. An allosteric enhancer of M(4) muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine

    DEFF Research Database (Denmark)

    Nielsen, Ditte Dencker; Weikop, Pia; Sørensen, Gunnar

    2012-01-01

    The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M(4) acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M(4) receptors could...... be a novel target for modulating psychostimulant effects of cocaine....

  18. Glutamate antagonists limit tumor growth

    OpenAIRE

    2001-01-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N...

  19. Different pharmacology of N-desmethylclozapine at human and rat M2 and M 4 mAChRs in neocortex.

    Science.gov (United States)

    Gigout, S; Wierschke, S; Dehnicke, C; Deisz, R A

    2015-05-01

    Cholinergic transmission plays a pivotal role in learning, memory and cognition, and disturbances of cholinergic transmission have been implicated in neurological disorders including Alzheimer's disease, epilepsy and schizophrenia. Pharmacological alleviation of these diseases by drugs including N-desmethylclozapine (NDMC), promising in animal models, often fails in patients. We therefore compared the effects of NDMC on glutamatergic and GABAergic transmission in slices from rat and human neocortex. We used carbachol (CCh; an established agonist at metabotropic muscarinic acetylcholine (ACh) receptors (mAChRs)) as a reference. Standard electrophysiological methods including intracellular and field potential recordings were used. In the rat neocortex, NDMC prevented the CCh-induced decrease of GABAA and GABAB receptor-mediated responses but not the CCh-induced increase of the paired-pulse depression. NDMC reduced neither the amplitude of the excitatory postsynaptic potentials (EPSP) nor antagonized the CCh-induced depression of EPSP. In the human neocortex, however, NDMC failed to prevent CCh-induced decrease of the GABAB responses and directly reduced the amplitude of EPSP. These data suggest distinct effects of NDMC in rat and human at M2 and M4 mAChRs underlying presynaptic modulation of GABA and glutamate release, respectively. In particular, NDMC might be a M2 mAChR antagonist in the rat but has no activity at this receptor in human neocortex. However, NDMC has an agonistic effect at M4 mAChR in the human but no such effect in the rat neocortex. The present study confirms that pharmacology at mAChRs can differ between species and emphasizes the need of studies in human tissue.

  20. Cosmic radiation measurements on the Foton-M4 satellite by passive detectors

    Science.gov (United States)

    Strádi, Andrea; Pálfalvi, József K.; Szabó, Julianna; Pázmándi, Tamás; Ivanova, Olga A.; Shurshakov, Vyacheslav A.

    2017-02-01

    The Russian Foton spacecraft was designed to deliver scientific experiments to low Earth orbit and return them safely to the ground for further analysis. During the 44-d Foton-M4 satellite mission in 2014 several passive cosmic ray detectors were exposed outside (in a single holder) and inside (in 4 locations) the recoverable capsule to study the radiation field. The applied thermoluminescent detectors (TLDs) are more sensitive to the particles with LET under 10 keV μm-1, while the solid state nuclear track detectors (SSNTDs) measure the particles having LET over this value. According to our measurements the average internal absorbed dose rate varied between 374-562 μGy/day for low LET radiation and 40-52 μGy/day for high LET radiation. Outside the capsule the dose rate was much higher, 1078 μGy/day for low LET radiation and 75 μGy/day for high LET radiation. Within the paper the obtained absorbed dose rates has been compared to those measured on the previous Foton-M flights, during the Bion-M1 mission and in the Columbus module of the International Space Station.

  1. Guanylpirenzepine distinguishes between neuronal ml and m4 muscarinic receptor subtypes

    Energy Technology Data Exchange (ETDEWEB)

    Monferini, E.; Cereda, E.; Ladinsky, H.; Donetti, A.; Giraldo, E. (Istituto De Angeli S.p.A., Milan (Italy))

    1990-01-01

    Guanylpirenzepine, a polar, non-quaternary analog of pirenzepine, exhibited a novel binding behavior in rat brain regions: in competition binding experiments against (3H)pirenzepine labeling the M1 receptor in membranes from cerebral cortex, hippocampus and striatum, the compound, differently from pirenzepine, displayed heterogeneous binding curves. Computer assisted analysis of these curves, evidenced the existence of two populations of binding sites: a large proportion (84-89%) of high affinity receptors (KH = 64-92 nM) and a remainder with very low affinity (KL = 19-28 microM). Like pirenzepine, guanylpirenzepine showed low affinity for the glandular M3 and the cardiac M2 receptors when (3H)N-methylscopolamine was used to label the receptors in membranes from these two tissues; affinity values for guanylpirenzepine were 1336 and 5790 nM respectively, vs 323 and 683 nM for pirenzepine. We conclude that guanylpirenzepine is able to discriminate between m1 and m4 receptor subtypes and may represent a new tool for deeper studies on muscarinic receptors classification.

  2. An extreme paucity of second population AGB stars in the normal globular cluster M4

    CERN Document Server

    MacLean, B T; De Silva, G M; Lattanzio, J; DOrazi, V; Simpson, J D; Momany, Y

    2016-01-01

    Galactic Globular clusters (GCs) are now known to harbour multiple stellar populations, which are chemically distinct in many light element abundances. It is becoming increasingly clear that asymptotic giant branch (AGB) stars in GCs show different abundance distributions in light elements compared to those in the red giant branch (RGB) and other phases, skewing toward more primordial, field-star-like abundances, which we refer to as subpopulation one (SP1). As part of a larger program targeting giants in GCs, we obtained high-resolution spectra for a sample of 106 RGB and 15 AGB stars in Messier 4 (NGC 6121) using the 2dF+HERMES facility on the Anglo-Australian Telescope. In this Letter we report an extreme paucity of AGB stars with [Na/O] > -0.17 in M4, which contrasts with the RGB that has abundances up to [Na/O] =0.55. The AGB abundance distribution is consistent with all AGB stars being from SP1. This result appears to imply that all subpopulation two stars (SP2; Na-rich, O-poor) avoid the AGB phase. Thi...

  3. [2 fatal cases of acute myeloid leukemia (M3, M4) during pregnancy].

    Science.gov (United States)

    Aragona, M; Asmundo, A

    1995-04-01

    Two cases of unexpected post-partum death of women with acute leukemia are described. In the first case (1st pregnancy) the diagnosis (acute promyelocytic leukemia: M3) was performed one week before delivery and death occurred 3 days later, because of hemorrhagic and renal DIC complication. Since one month before hospitalization, laboratory exams indicated a serious hematological pathology and no further exams were carried out by the physicians, elements of professional fault were recognized in them, considering that because of the diagnostic omission it was impossible to make an early diagnosis and thus perform to specific therapy, adopted only in the terminal phase. This specific therapy is able to determine remission from most cases of acute promyelocytic leukemia. In the second case (2nd pregnancy) the diagnosis (acute myelomonocytic leukemia: M4) was performed only postmortem because, during the whole pregnancy, no signs of disease were evident. After a few hours from the spontaneous delivery, death occurred as a result of an intractable + hemorrhagic syndrome caused by primary hyperfibrinolysis and repeated episodes of cardiac arrest, without possibility of recognizing it. The medical procedures for this case, both throughout pregnancy and terminal phases, appeared free of censure.

  4. A White Light Megaflare on the dM4.5e Star YZ CMi

    CERN Document Server

    Kowalski, Adam F; Holtzman, Jon A; Wisniewski, John P; Hilton, Eric J

    2010-01-01

    On UT 2009 January 16, we observed a white light megaflare on the dM4.5e star YZ CMi as part of a long-term spectroscopic flare-monitoring campaign to constrain the spectral shape of optical flare continuum emission. Simultaneous U-band photometric and 3350A-9260A spectroscopic observations were obtained during 1.3 hours of the flare decay. The event persisted for more than 7 hours and at flare peak, the U-band flux was almost 6 magnitudes brighter than in the quiescent state. The properties of this flare mark it as one of the most energetic and longest-lasting white light flares ever to be observed on an isolated low-mass star. We present the U-band flare energetics and a flare continuum analysis. For the first time, we show convincingly with spectra that the shape of the blue continuum from 3350A to 4800A can be represented as a sum of two components: a Balmer continuum as predicted by the Allred et al radiative hydrodynamic flare models and a T ~ 10,000K blackbody emission component as suggested by many pr...

  5. Bimodality of light and s-elements in M4 (NGC 6121)

    CERN Document Server

    Villanova, Sandro

    2011-01-01

    All Globular Clusters (GCs) studied in detail so far host two or more populations of stars. Theoretical models suggest that the second population is formed from gas polluted by processed material produced by massive stars of the first generation. However the nature of the polluter is a matter of strong debate. Several candidates have been proposed: massive main-sequence stars (fast rotating or binaries), intermediate-mass AGB stars, or SNeII. We studied red giant branch (RGB) stars in the GC M4 (NGC 6121) to measure their chemical signature. We confirm the presence of a bimodal population, first discovered by Marino et al. (2008). The two groups have different C,$^{12}$C/$^{13}$C,N,O,Na content, but share the same Li,C+N+O,Mg,Al,Si,Ca,Ti,Cr,Fe,Ni,Zr,Ba and Eu abundance. Quite surprisingly the two groups differ also in their Y abundance. The absence of a spread in $\\alpha$-elements, Eu and Ba makes SNeII and AGB stars unlikely as polluters. On the other hand, massive main-sequence stars can explain the bimodal...

  6. Hubble space telescope observations of white dwarfs in the globular cluster M4

    CERN Document Server

    Richer, H B; Ibata, R A; Stetson, P B; Bell, R A; Bolte, M; Bond, H E; Harris, W E; Hesser, J E; Mandushev, G I; Pryor, C E; Richer, Harvey B; Fahlman, Gregory G; Ibata, Rodrigo A; Stetson, Peter B; Bell, Roger A; Bolte, Michael; Bond, Howard E; Harris, William E; Hesser, James E; Mandushev, Georgi; Pryor, Carlton

    1995-01-01

    With the Wide Field Planetary Camera 2 (WFPC2) on the Hubble Space Telescope, we have discovered in M4 (NGC 6121, C 1620-264) the first extensive sequence of cooling white dwarfs seen in a globular cluster. Adopting a distance modulus of (m-M)_V = 12.65 and a reddening of E(B-V) = 0.37, we show that the sequence, which extends over 9 < M_U < 13, is comprised of white dwarfs of mass \\sim 0.5 M_{\\odot}. The total mass loss from the present turnoff to the white dwarf sequence is 0.31 M_{\\odot} and the intrinsic dispersion in the mean mass appears to be < 0.05 M_{\\odot}. Both the location of the white dwarf cooling sequence in the cluster color-magnitude diagram and the cumulative luminosity function attest to the basic correctness and completeness of the physics in theoretical models for the upper three magnitudes of the observed white dwarf cooling sequence. To test the theory in globular clusters at cooling ages beyond \\sim 3 \\times 10^8 years will require deeper and more complete data.

  7. Molecular Characterization of a Recombinant Manganese Superoxide Dismutase from Lactococcus lactis M4

    Directory of Open Access Journals (Sweden)

    Boon Hooi Tan

    2014-01-01

    Full Text Available A superoxide dismutase (SOD gene of Lactococcus lactis M4 was cloned and expressed in a prokaryotic system. Sequence analysis revealed an open reading frame of 621 bp which codes for 206 amino acid residues. Expression of sodA under T7 promoter exhibited a specific activity of 4967 U/mg when induced with 1 mM of isopropyl-β-D-thiogalactopyranoside. The recombinant SOD was purified to homogeneity by immobilised metal affinity chromatography and Superose 12 gel filtration chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot analyses of the recombinant SOD detected a molecular mass of approximately 27 kDa. However, the SOD was in dimer form as revealed by gel filtration chromatography. The purified recombinant enzyme had a pI of 4.5 and exhibited maximal activity at 25°C and pH 7.2. It was stable up to 45°C. The insensitivity of this lactococcal SOD to cyanide and hydrogen peroxide established that it was a MnSOD. Although it has 98% homology to SOD of L. lactis IL1403, this is the first elucidated structure of lactococcal SOD revealing active sites containing the catalytic manganese coordinated by four ligands (H-27, H-82, D-168, and H-172.

  8. Muscarinic Receptor Agonists and Antagonists

    Directory of Open Access Journals (Sweden)

    David R. Kelly

    2001-02-01

    Full Text Available A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes. Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

  9. 经典再出发--江淮瑞风M4上市%JAC Launch Reifne in Guangzhou

    Institute of Scientific and Technical Information of China (English)

    于占波

    2016-01-01

    Oct. 12, 2016, JAC held a grand ceremony in front of the Guangzhou Tower, the symbolic scene of Guangzhou city, to launch latest new models of Reifne M4. These new four models of Reifne were priced between 99,800 RMB to 129,800 RMB, which indicated that higher cost-effective quality is still the key to market promotion of Reifne M4.

  10. Degradation of 3-phenoxybenzoic acid by a filamentous fungus Aspergillus oryzae M-4 strain with self-protection transformation.

    Science.gov (United States)

    Zhu, Yuanting; Li, Jianlong; Yao, Kai; Zhao, Nan; Zhou, Kang; Hu, Xinjie; Zou, Likou; Han, Xinfeng; Liu, Aiping; Liu, Shuliang

    2016-11-01

    A novel filamentous fungus M-4 strain was isolated from soy sauce koji and identified as Aspergillus oryzae (Collection number: CGMCC 11645) on the basis of morphological characteristics and internal transcribed spacer sequence. M-4 could degrade 80.62 % of 3-phenoxybenzoic acid (3-PBA; 100 mg L(-1)) within 5 days. 3-PBA degradation occurred in accordance with first-order kinetics. The degradation metabolites of 3-PBA were identified through high-performance liquid chromatography-mass spectrometry (HPLC-MS). Relevant enzymatic activities and substrate utilization were also investigated, which indicated that M-4 could effectively degrade the intermediates of 3-PBA. Base on analysis of these metabolites, a novel biochemical pathway for the degradation of 3-PBA was proposed. There exists a mutual transformation between 3-phenoxy-benzyl alcohol and 3-PBA, which was firstly reported about the degradation of 3-PBA and may be attributed to self-protection transformation of M-4; subsequently, 3-PBA was gradually transformed into phenol, 3-hydroxy-5-phenoxy benzoic acid, protocatechuic acid and gallic acid. The safety of M-4 was evaluated via an acute toxicity test in vivo. The biodegradation ability of M-4 without toxic effects reveals that this fungus may be likely to be used for eliminating 3-PBA from contaminated environment or fermented foods.

  11. DEEP NEAR-IR OBSERVATIONS OF THE GLOBULAR CLUSTER M4: HUNTING FOR BROWN DWARFS

    Energy Technology Data Exchange (ETDEWEB)

    Dieball, A. [Argelander Institut für Astronomie, Helmholtz Institut für Strahlen- und Kernphysik, University of Bonn (Germany); Bedin, L. R. [INAF-Osservatorio Astronomico di Padova, Vicolo dell’Osservatorio 5, I-35122 Padova (Italy); Knigge, C. [Physics and Astronomy, University of Southampton, Southampton SO17 1BJ (United Kingdom); Rich, R. M. [Department of Physics and Astronomy, University of California at Los Angeles, Los Angeles, CA 90095-1562 (United States); Allard, F. [Centre de Recherche Astrophysique de Lyon, UMR 5574: CNRS, Université de Lyon, École Normale Supérieure de Lyon, 46 allée d’Italie, F-69364 Lyon Cedex 07 (France); Dotter, A. [Research School of Astronomy and Astrophysics, Australian National University, Canberra, ACT (Australia); Richer, H. [Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, V6T 1Z1 (Canada); Zurek, D., E-mail: adieball@astro.uni-bonn.de [Department of Astrophysics, American Museum of Natural History, New York, NY 10024 (United States)

    2016-01-20

    We present an analysis of deep Hubble Space Telescope (HST)/Wide Field Camera 3 near-IR (NIR) imaging data of the globular cluster (GC) M4. The best-photometry NIR color–magnitude diagram (CMD) clearly shows the main sequence extending toward the expected end of the hydrogen-burning limit and going beyond this point toward fainter sources. The white dwarf (WD) sequence can be identified. As such, this is the deepest NIR CMD of a GC to date. Archival HST optical data were used for proper-motion cleaning of the CMD and for distinguishing the WDs from brown dwarf (BD) candidates. Detection limits in the NIR are around F110W ≈ 26.5 mag and F160W ≈ 27 mag, and in the optical around F775W ≈ 28 mag. Comparing our observed CMDs with theoretical models, we conclude that we have reached beyond the H-burning limit in our NIR CMD and are probably just above or around this limit in our optical–NIR CMDs. Thus, any faint NIR sources that have no optical counterpart are potential BD candidates, since the optical data are not deep enough to detect them. We visually inspected the positions of NIR sources that are fainter than the H-burning limit in F110W and for which the optical photometry did not return a counterpart. We found in total five sources for which we did not get an optical measurement. For four of these five sources, a faint optical counterpart could be visually identified, and an upper optical magnitude was estimated. Based on these upper optical magnitude limits, we conclude that one source is likely a WD, one source could be either a WD or BD candidate, and the remaining two sources agree with being BD candidates. No optical counterpart could be detected for just one source, which makes this source a good BD candidate. We conclude that we found in total four good BD candidates.

  12. An image processing technique for diagnosis of Alzheimer's disease

    Science.gov (United States)

    Mahmoudian, Massoud; Ebrahimi, Soltan Ahmed; Kiani, Zahra

    2009-01-01

    BACKGROUND: Patients with Alzheimer's disease (AD) reportedly exhibit hypersensitivity to much diluted tropicamide solution (0.005%), a M4 muscarinic receptor antagonist. Therefore intraocular application of 0.005% tropicamide may be useful for screening dementia. The aim of this study was to simplify the pupil response test by using a new image analyzing system, which consists of a cheap, simple, and easy to use web-camera and a computer. METHODS: Intraocular tropicamide of 0.005% concentration was administered in 3 groups: Alzheimer's disease patients (n = 8, average age = 76 ± 5), non-Alzheimer's disease elderly (n = 6, average age = 65 ± 7), and young subjects (n = 8, average age = 28 ± 5). Every 5 minutes for 60 minutes, image of the eye's shape were taken, and the diameter of the pupils was measured. RESULTS: The results showed that differences in pupil dilation rate between Alzheimer's disease and non-Alzheimer's disease subjects were statistically significant. ROC analysis showed that after 35 minutes the sensitivity and specificity of the test were 100%. CONCLUSIONS: Based on our results, we concluded that this recording system might be an appropriate and reliable tool for pupil response diagnosis test of Alzheimer's disease. PMID:21772885

  13. An image processing technique for diagnosis of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Massoud Mahmoudian

    2009-08-01

    Full Text Available

    • BACKGROUND: Patients with Alzheimer's disease (AD reportedly hibit hypersensitivity to much diluted tropicam solution (0.005%, a M4 muscarinic receptor antagonist. Therefore aocular application of 0.005% tropicamide ma be useful for screening dementia. The aim of this study was to simplify the pupil response test by using a new image analyzing system, which consists of a cheap, simple, and easy to use web-camera and a computer.
    • METHODS: Intraocular tropicamide of 0.005% concentration was administered in 3 groups: Alzheimer's disease patients (n = 8, average age = 76 ± 5, non-Alzheimer's disease elderly (n = 6, average age = 65 ± 7, and young subjects (n = 8, average age = 28 ± 5. Every 5 minutes for 60 minutes, image of the eye's shape were taken, and the diameter of the pupils was measured.
    • RESULTS: The results showed that differences in pupil dilation rate between Alzheimer's disease and non-Alzheimer's disease subjects were statistically significant. ROC analysis showed that after 35 minutes the sensitivity and specificity of the test were 100%.
    • CONCLUSIONS: Based on our results, we concluded that this recording system might be an appropriate and reliable tool for pupil response diagnosis test of Alzheimer's disease.
    • KEYWORDS: Alzheimer’s Disease, Tropicamide, Pupil.

  14. M5-branes on S^2 x M_4: Nahm's Equations and 4d Topological Sigma-models

    CERN Document Server

    Assel, Benjamin; Wong, Jin-Mann

    2016-01-01

    We study the 6d N=(0,2) superconformal field theory, which describes multiple M5-branes, on the product space S^2 x M_4, and suggest a correspondence between a 2d N=(0,2) half-twisted gauge theory on S^2 and a topological sigma-model on the four-manifold M_4. To set up this correspondence, we determine in this paper the dimensional reduction of the 6d N=(0,2) theory on a two-sphere and derive that the four-dimensional theory is a sigma-model into the moduli space of solutions to Nahm's equations, or equivalently the moduli space of k-centered SU(2) monopoles, where k is the number of M5-branes. We proceed in three steps: we reduce the 6d abelian theory to a 5d Super-Yang-Mills theory on I x M_4, with I an interval, then non-abelianize the 5d theory and finally reduce this to 4d. In the special case, when M_4 is a Hyper-Kahler manifold, we show that the dimensional reduction gives rise to a topological sigma-model based on tri-holomorphic maps. Deriving the theory on a general M_4 requires knowledge of the met...

  15. Structural and electronic properties of reduced transition metal oxide clusters, M4O10 and M4O10- (M = Cr, W), from photoelectron spectroscopy and quantum chemical calculations.

    Science.gov (United States)

    Li, Shenggang; Zhai, Hua-Jin; Wang, Lai-Sheng; Dixon, David A

    2012-05-31

    Anion photoelectron spectroscopy and quantum chemical calculations at the density functional theory (DFT), coupled cluster theory (CCSD(T)), and complete active space self-consistent field (CASSCF) theory levels are employed to study the reduced transition metal oxide clusters M(4)O(10)(-) (M = Cr, W) and their neutrals. Photoelectron spectra are obtained at 193 and 157 nm photon energies, revealing very different electronic structures for the Cr versus W oxide clusters. The electron affinity and HOMO-LUMO gap are measured to be 3.68 ± 0.05 and 0.7 eV, respectively, for the Cr(4)O(10) neutral cluster, as compared to 4.41 ± 0.04 and 1.3 eV for W(4)O(10). A comprehensive search is performed to determine the ground-state structures for M(4)O(10) and M(4)O(10)(-), in terms of geometry and electronic states by carefully examining the calculated relative energies at the DFT, CCSD(T), and CASSCF levels. The ground states of Cr(4)O(10) and Cr(4)O(10)(-) have tetrahedral structures similar to that of P(4)O(10) with the anion having a lower symmetry due to a Jahn-Teller distortion. The ground states of W(4)O(10) and W(4)O(10)(-) have butterfly shape structures, featuring two fused five-member rings with a metal-metal multiple bond between the central metal atoms. The much stronger WW bonding than the CrCr bonding is found to be the primary cause for the different ground state structures of the reduced Cr(4)O(10)(0/-) versus W(4)O(10)(0/-) oxide clusters. The photoelectron spectra are assigned by comparing the experimental and theoretical adiabatic and vertical electron detachment energies, further confirming the determination of the ground electronic states of M(4)O(10) and M(4)O(10)(-). The time-dependent DFT method is used to calculate the excitation energies of M(4)O(10). The TD-DFT results in combination with the self-consistently calculated vertical detachment energies for some of the excited states at the DFT and CCSD(T) levels are used to assign the higher energy

  16. New antagonist agents of neuropeptide y receptors

    Directory of Open Access Journals (Sweden)

    Ignacio Aldana

    2000-12-01

    Full Text Available In the CNS, NPY has been implicated in obesity and feeding, endocrine function and metabolism. Potent and selective rNPY antagonists will be able to probe the merits of this approach for the treatment of obesity. We report the synthesis and preliminary evaluation of some hydrazide derivatives as antagonists of rNPY.

  17. A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors

    DEFF Research Database (Denmark)

    Jeon, Jongrye; Nielsen, Ditte Dencker; Wörtwein, Gitta;

    2010-01-01

    Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M(1)-M(5) mAChRs). Like other mAChR subtypes, the M(4) mAChR is widely expressed in different regions of the forebrain. Interestingly, M(4) mAChRs are coexpres....... Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance....

  18. Left-Right Symmetric Model from Geometrical Formulation of Gauge Theory in $M_{4} \\times Z_{2} \\times Z_{2}$

    CERN Document Server

    Konisi, G; Mäki, Z; Nakahara, M

    1999-01-01

    The left-right symmetric model (LRSM) with gauge group $SU(2)_{L} \\times SU(2)_{R} \\times U(1)_{B-L}$ is reconstructed from the geometric formulation of gauge theory in $M_4 \\times Z_2 \\times Z_2$ where $M_4$ is the four-dimensional Minkowski space and $Z_2 \\times Z_2$ the discrete space with four points. The geometrical structure of this model becomes clearer compared with other works based on noncommutative geometry. As a result, the Yukawa coupling terms and the Higgs potential are derived in more restricted forms than in the standard LRSM.

  19. M4/12 package project - development of a package for transport of new MOX fuel in Europe

    Energy Technology Data Exchange (ETDEWEB)

    Kaye, B.R.; Porter, I.; Ashley, P. [BNFL, Warrington, Cheshire (United Kingdom)

    2004-07-01

    BNFL has a requirement to deliver new MOX fuel from the Sellafield MOX Plant (SMP) to its customers in mainland Europe. To satisfy this requirement, a transport system has been developed which complies with national and international regulations and conventions relating to the transport of Category 1 materials. Fundamental to this system is the transport package. BNFL has designed, developed, and is manufacturing a new transport package, the M4/12, This paper gives a brief overview of the overall transport system and then goes on to describe the development of the M4/12 package with particular emphasis on the novel features of the design.

  20. Comparison of Allergenicity at Gly m 4 and Gly m Bd 30K of Soybean after Genetic Modification.

    Science.gov (United States)

    Tsai, Jaw-Ji; Chang, Ching-Yun; Liao, En-Chih

    2017-02-15

    Despite rapid growth of genetically modified (GM) crops, effective evaluations of genetic modification on allergenicity are still lacking. Gly m Bd 30K is cross-reactive with cow's milk protein casein, Gly m 4, and with birch pollen allergen Bet v 1. Here we compared the allergenicity between GM and non-GM soybeans with respect to the foci Gly m 4 and Gly m Bd 30K. Recombinant allergens of Gly m Bd 30K and Gly m 4 were generated and polyclonal antibodies raised to identify these two allergenic components in soybeans. GM soybean was first PCR-confirmed using 35S promoter. A total of 20 soybeans (half GM, half non-GM) obtained from a food market were used to assess their allergenicity based on IgE-binding and histamine release. The concentrations of Gly m Bd 30K and Gly m 4 in soybeans were then determined. Most soybean-allergic patients (9 of 10) showed IgE-positive reactions to the allergen of 30 kDa in molecular weight. That allergen turned out to be Glycine max Gly m Bd 30K based on LC-MS/MS analyses. Gly m Bd 30K is therefore the major allergen in the soybean. An increase in the transcription of both the Gly m 4 (stress-induced protein SAM22) and Gly m Bd 28K (soybean allergen precursor) was found after genetic modification. The protein concentrations of Gly m 4 and Gly m Bd 30K were not statistically significant different between non-GM and GM soybeans. There were also no statistical significances between them in the tests of IgE binding and histamine release. In conclusion, soybeans showed similar concentrations of Gly m Bd 30K and Gly m 4 regardless of genetic modification or absence thereof. The allergenicity of both Gly m Bd 30K and Gly m 4 was therefore not altered after genetic modification. Patients showing hypersensitivity to soybeans and who had pre-existing allergy to birch pollen and cow's milk casein might not further increase their allergic reactions following exposures to the GM soybeans.

  1. Cloning and characterization of a novel deletion mutant of heterogeneous nuclear ribonucleoprotein M4 from human dendritic cells

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    To identify differentially expressed genes from antigen-stimulated human dendritic cells (DC), subtractive cloning was adopted and more than ten novel genes differentially expressed were cloned. One is a deletion mutant of heterogeneous nuclear ribonucleoprotein (hnRNP) M4 in which the residues from 159 to 197 of hnRNP M4 have been absent. The deletion mutant was shown to be co-expressed with hnRNP M4 in cell lines. The mutant was expressed in antigen-stimulated DC but not in normal DC. Northern blot analysis revealed the presence of a major hnRNP M4 deletion mutant Mrna transcript of 2.4 kilobase with the highest levels in peripheral lymphocytes, lung, liver and spleen. It was also expressed in bone marrow-derived stromal cells (BMSC), BMSC treated with several cytokines but not in BMSC treated with TNF-a. The results revealed a new member of hnRNP family and suggested that hnRNP would participate in antigen process and presentation.

  2. Cloning and characterization of a novel deletion mutant of heterogeneous nuclear ribonucleoprotein M4 from human dendritic cells

    Institute of Scientific and Technical Information of China (English)

    黄欣; 赵忠良; 袁正隆; 张明徽; 朱学军; 陈国友; 曹雪涛

    2000-01-01

    To identify differentially expressed genes from antigen-stimulated human dendritic cells (DC), subtractive cloning was adopted and more than ten novel genes differentially expressed were cloned. One is a deletion mutant of heterogeneous nuclear ribonucleoprotein (hnRNP) M4 in which the residues from 159 to 197 of hnRNP M4 have been absent. The deletion mutant was shown to- be co-expressed with hnRNP M4 in cell lines. The mutant was expressed in antigen-stimulated DC but not in normal DC. Northern blot analysis revealed the presence of a major hnRNP M4 deletion mutant mRNA transcript of 2.4 kilobase with the highest levels in peripheral lymphocytes, lung, liver and spleen. It was also expressed in bone marrow-derived stromal cells (BMSC), BMSC treated with several cytokines but not in BMSC treated with TNF-a. The results revealed a new member of hnRNP family and suggested that hnRNP would participate in antigen process and presentation.

  3. Cloning and characterization of a novel deletion mutant of heterogeneous nuclear ribonucleoprotein M4 from human dendritic cells

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    To identify differentially expressed genes from antigen-stimulated human dendritic cells (DC), subtractive cloning was adopted and more than ten novel genes differentially expressed were cloned. One is a deletion mutant of heterogeneous nuclear ribonucleoprotein (hnRNP) M4 in which the residues from 159 to 197 of hnRNP M4 have been absent. The deletion mutant was shown to be co-expressed with hnRNP M4 in cell lines. The mutant was expressed in antigen-stimulated DC but not in normal DC. Northern blot analysis revealed the presence of a major hnRNP M4 deletion mutant mRNA transcript of 2.4 kilobase with the highest levels in peripheral lymphocytes, lung, liver and spleen. It was also expressed in bone marrow-derived stromal cells (BMSC), BMSC treated with several cytokines but not in BMSC treated with TNF-a. The results revealed a new member of hnRNP family and suggested that hnRNP would participate in antigen process and presentation.

  4. 8s, a numerical simulator of the challenging optical calibration of the E-ELT adaptive mirror M4

    Science.gov (United States)

    Briguglio, Runa; Pariani, Giorgio; Xompero, Marco; Riccardi, Armando; Tintori, Matteo; Lazzarini, Paolo; Spanò, Paolo

    2016-07-01

    8s stands for Optical Test TOwer Simulator (with 8 read as in italian 'otto'): it is a simulation tool for the optical calibration of the E-ELT deformable mirror M4 on its test facility. It has been developed to identify possible criticalities in the procedure, evaluate the solutions and estimate the sensitivity to environmental noise. The simulation system is composed by the finite elements model of the tower, the analytic influence functions of the actuators, the ray tracing propagation of the laser beam through the optical surfaces. The tool delivers simulated phasemaps of M4, associated with the current system status: actuator commands, optics alignment and position, beam vignetting, bench temperature and vibrations. It is possible to simulate a single step of the optical test of M4 by changing the system parameters according to a calibration procedure and collect the associated phasemap for performance evaluation. In this paper we will describe the simulation package and outline the proposed calibration procedure of M4.

  5. Quantum corrections to short folded superstring in AdS_3 x S^3 x M^4

    CERN Document Server

    Beccaria, Matteo

    2012-01-01

    We consider integrable superstring theory on AdS_3 x S^3 x M^4 where M^4=T^4 or M^4=S^3 x S^1 with generic ratio of the radii of the two 3-spheres. We compute the one-loop energy of a short folded string spinning in AdS_3 and rotating in S^3. The computation is performed by world-sheet small spin perturbation theory as well as by quantizing the classical algebraic curve characterizing the finite-gap equations. The two methods give equal results up to regularization contributions that are under control. One important byproduct of the calculation is the part of the energy which is due to the dressing phase in the Bethe Ansatz. Remarkably, this contribution E_1^{dressing} turns out to be independent on the radii ratio. In the M^4=T^4 limit, we discuss how E_1^{dressing} relates to a recent proposal for the dressing phase tested in the su(2) sector. We point out some difficulties suggesting that quantization of the AdS_3 classical finite-gap equations could be subtler than the easier AdS_5 x S^5 case.

  6. M5-branes on S 2 × M 4: Nahm's equations and 4d topological sigma-models

    Science.gov (United States)

    Assel, Benjamin; Schäfer-Nameki, Sakura; Wong, Jin-Mann

    2016-09-01

    We study the 6d N = (0 , 2) superconformal field theory, which describes multiple M5-branes, on the product space S 2 × M 4, and suggest a correspondence between a 2d N = (0 , 2) half-twisted gauge theory on S 2 and a topological sigma-model on the four-manifold M 4. To set up this correspondence, we determine in this paper the dimensional reduction of the 6d N = (0 , 2) theory on a two-sphere and derive that the four-dimensional theory is a sigma-model into the moduli space of solutions to Nahm's equations, or equivalently the moduli space of k-centered SU(2) monopoles, where k is the number of M5-branes. We proceed in three steps: we reduce the 6d abelian theory to a 5d Super-Yang-Mills theory on I × M 4, with I an interval, then non-abelianize the 5d theory and finally reduce this to 4d. In the special case, when M 4 is a Hyper-Kähler manifold, we show that the dimensional reduction gives rise to a topological sigma-model based on tri-holomorphic maps. Deriving the theory on a general M 4 requires knowledge of the metric of the target space. For k = 2 the target space is the Atiyah-Hitchin manifold and we twist the theory to obtain a topological sigma-model, which has both scalar fields and self-dual two-forms.

  7. Antagonistic formation motion of cooperative agents

    Institute of Scientific and Technical Information of China (English)

    卢婉婷; 代明香; 薛方正

    2015-01-01

    This paper investigates a new formation motion problem of a class of first-order multi-agent systems with antagonis-tic interactions. A distributed formation control algorithm is proposed for each agent to realize the antagonistic formation motion. A sufficient condition is derived to ensure that all agents make an antagonistic formation motion in a distributed manner. It is shown that all agents can be spontaneously divided into several groups, and agents in the same group collab-orate while agents in different groups compete. Finally, a numerical simulation is included to demonstrate our theoretical results.

  8. Antagonists of the kappa opioid receptor.

    Science.gov (United States)

    Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, Edward

    2014-05-01

    The research community has increasingly focused on the development of OPRK antagonists as pharmacotherapies for the treatment of depression, anxiety, addictive disorders and other psychiatric conditions produced or exacerbated by stress. Short-acting OPRK antagonists have been recently developed as a potential improvement over long-acting prototypic ligands including nor-BNI and JDTic. Remarkably the short-acting LY2456302 is undergoing phase II clinical trials for the augmentation of the antidepressant therapy in treatment-resistant depression. This Letter reviews relevant chemical and pharmacological advances in the identification and development of OPRK antagonists.

  9. Benzodiazepine receptor antagonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy....

  10. The M4.5V flare star AF Psc as seen in K2 engineering data

    CERN Document Server

    Ramsay, Gavin

    2014-01-01

    We present the light curve of the little studied flare star AF Psc (M4.5V) obtained using engineering data from the K2 mission. Data were obtained in Long Cadence mode giving an effective exposure of 29 min and nearly 9 d of coverage. A clear modulation on a period of 1.08 d was seen which is the signature of the stellar rotation period. We identify 14 flares in the light curve, with the most luminous flares apparently coming from the same active region. We compare the flare characteristics of AF Psc to two M4V flare stars studied using kepler data. The K2 mission, if given approval, will present a unique opportunity to study the rotation and flare properties of late type dwarf stars with different ages and mass.

  11. Seismicity Pattern Changes before the M = 4.8 Aeolian Archipelago (Italy) Earthquake of August 16, 2010

    Science.gov (United States)

    2014-01-01

    We investigated the seismicity patterns associated with an M = 4.8 earthquake recorded in the Aeolian Archipelago on 16, August, 2010, by means of the region-time-length (RTL) algorithm. This earthquake triggered landslides at Lipari; a rock fall on the flanks of the Vulcano, Lipari, and Salina islands, and some damages to the village of Lipari. The RTL algorithm is widely used for investigating precursory seismicity changes before large and moderate earthquakes. We examined both the spatial and temporal characteristics of seismicity changes in the Aeolian Archipelago region before the M = 4.8 earthquake. The results obtained reveal 6-7 months of seismic quiescence which started about 15 months before the earthquake. The spatial distribution shows an extensive area characterized by seismic quiescence that suggests a relationship between quiescence and the Aeolian Archipelago regional tectonics. PMID:24511288

  12. Characterization of the novel positive allosteric modulator, LY2119620, at the muscarinic M(2) and M(4) receptors.

    Science.gov (United States)

    Croy, Carrie H; Schober, Douglas A; Xiao, Hongling; Quets, Anne; Christopoulos, Arthur; Felder, Christian C

    2014-07-01

    The M(4) receptor is a compelling therapeutic target, as this receptor modulates neural circuits dysregulated in schizophrenia, and there is clinical evidence that muscarinic agonists possess both antipsychotic and procognitive efficacy. Recent efforts have shifted toward allosteric ligands to maximize receptor selectivity and manipulate endogenous cholinergic and dopaminergic signaling. In this study, we present the pharmacological characterization of LY2119620 (3-amino-5-chloro-N-cyclopropyl-4-methyl-6-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy] thieno[2,3-b]pyridine-2-carboxamide), a M(2)/M(4) receptor-selective positive allosteric modulator (PAM), chemically evolved from hits identified through a M4 allosteric functional screen. Although unsuitable as a therapeutic due to M(2) receptor cross-reactivity and, thus, potential cardiovascular liability, LY2119620 surpassed previous congeners in potency and PAM activity and broadens research capabilities through its development into a radiotracer. Characterization of LY2119620 revealed evidence of probe dependence in both binding and functional assays. Guanosine 5'-[γ-(35)S]-triphosphate assays displayed differential potentiation depending on the orthosteric-allosteric pairing, with the largest cooperativity observed for oxotremorine M (Oxo-M) LY2119620. Further [(3)H]Oxo-M saturation binding, including studies with guanosine-5'-[(β,γ)-imido]triphosphate, suggests that both the orthosteric and allosteric ligands can alter the population of receptors in the active G protein-coupled state. Additionally, this work expands the characterization of the orthosteric agonist, iperoxo, at the M(4) receptor, and demonstrates that an allosteric ligand can positively modulate the binding and functional efficacy of this high efficacy ligand. Ultimately, it was the M(2) receptor pharmacology and PAM activity with iperoxo that made LY2119620 the most suitable allosteric partner for the M(2) active-state structure recently solved

  13. Precursory signatures in the radon and geohydrological borehole data for M4.9 Kharsali earthquake of Garhwal Himalaya

    Energy Technology Data Exchange (ETDEWEB)

    Choubey, V.M., E-mail: vchoubey@wihg.res.in [Wadia Institute of Himalayan Geology, 33 General Mahadeo Singh Road, Dehradun 248001 (India); Kumar, Naresh; Arora, B.R. [Wadia Institute of Himalayan Geology, 33 General Mahadeo Singh Road, Dehradun 248001 (India)

    2009-11-01

    Continuous recording of different geophysical parameters incorporated at a single location as a unified effort for earthquake precursory through geodynamical changes initiated for the first time in the Garhwal Himalaya, India. A 68 m deep borehole, penetrating into the water table is operated for continuous radon monitoring along with meteorological/geohydrological observations at two points, one at 10 m (in the air column) and the second one at 50 m (within water column) depths from surface. Preliminary studies reveal diagnostic short duration anomalies in radon concentration recorded few days before the occurrence of a nearby moderate M4.9 earthquake at Kharsali on the 23rd of July, 2007. For nearly half of the year, radon emanation at 10 m depth in the closed air column showed definite pattern of daily variations that may be due to the influence of tidal forces, meteorological and other geodynamical phenomena. This pattern is totally missing during June and July, 2007 when few anomalies for small durations were observed out of which two are unique. These two anomalies exceed 2{sigma} (standard deviation) from average radon concentration in both positive and negative sides. However, its emanation at 50 m depth (water radon) is almost constant throughout the year 2007 except some disturbances observed to the ending of June and during July. These abnormalities in radon emanation and other parameters in the borehole may be considered precursory to the M4.9 Kharsali earthquake of July 23, 2007 having an epicenter distance of 60 km. The empirical relation used for amount of radon anomaly with the epicenter distance predicts an earthquake of M4.6 and M4.7 with the observed anomaly at 10 m and 50 m observation points respectively after taking a 60 km epicenter distance.

  14. Design of a Cortex-M4 based ultrasonic phased array detection system%基于Cortex-M4的超声相控阵探测系统的设计

    Institute of Scientific and Technical Information of China (English)

    赵连睿; 杨济民; 李振江; 李玉坤

    2013-01-01

    We design an obstacle detection system with ultrasonic phased array detection and the microcontroller Cortex-M4 as a processor. Experiments show that the actual sound field strength of the focal area is greater than that of conventional ultrasonic technology and sound energy is more convergent. Its detection distance is from 0.3 to 5.5 m, and measurement accuracy is ±1 cm. The system is therefore effective and satisfactory.%设计了一种以Cortex-M4微控制器STM32F407为核心,采用超声相控阵技术对障碍物进行探测的系统.实验结果表明,该系统聚焦探测区域的实际声场强度大于常规的超声波技术,声波能量更为集中.系统的探测范围在0.3~5.5m,探测精度±1 cm,稳定性好,准确方便.

  15. 米曲霉Aspergillus oryzae M-4降解己烯雌酚的特性研究%Degradation Characteristics of Diethylstilbestrol by Aspergillus oryzae M-4

    Institute of Scientific and Technical Information of China (English)

    胡凯弟; 邓维琴; 陈树平; 柴先杜; 刘爱平; 卓文杰; 刘书亮

    2016-01-01

    以1株分离自酱油曲的米曲霉(Aspergillus oryzae)M-4为材料,初步研究其降解己烯雌酚(diethylstilbestrol,DES)的特性.米曲霉M-4对DES的降解率与菌体生物量呈正相关,在基础盐培养基(mineral salt medium,MM)中培养9d对100mg/L的DES降解率为93%.动力学研究表明,该菌株降解DES的过程符合一级动力学方程,在所测试的培养温度、初始pH值、底物质量浓度范围内,DES半衰期为1.645~5.295d.培养温度30℃和偏酸性环境有利于其对DES的降解;底物质量浓度越高,其半衰期越长.

  16. The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Andersen, Maibritt B; Fink-Jensen, Anders; Peacock, Linda

    2003-01-01

    Xanomeline is a muscarinic M(1)/M(4) preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects ...... that xanomeline inhibits D-amphetamine- and (-)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis....

  17. Sustainable Cost Models for mHealth at Scale: Modeling Program Data from m4RH Tanzania.

    Directory of Open Access Journals (Sweden)

    Emily R Mangone

    Full Text Available There is increasing evidence that mobile phone health interventions ("mHealth" can improve health behaviors and outcomes and are critically important in low-resource, low-access settings. However, the majority of mHealth programs in developing countries fail to reach scale. One reason may be the challenge of developing financially sustainable programs. The goal of this paper is to explore strategies for mHealth program sustainability and develop cost-recovery models for program implementers using 2014 operational program data from Mobile for Reproductive Health (m4RH, a national text-message (SMS based health communication service in Tanzania.We delineated 2014 m4RH program costs and considered three strategies for cost-recovery for the m4RH program: user pay-for-service, SMS cost reduction, and strategic partnerships. These inputs were used to develop four different cost-recovery scenarios. The four scenarios leveraged strategic partnerships to reduce per-SMS program costs and create per-SMS program revenue and varied the structure for user financial contribution. Finally, we conducted break-even and uncertainty analyses to evaluate the costs and revenues of these models at the 2014 user volume (125,320 and at any possible break-even volume.In three of four scenarios, costs exceeded revenue by $94,596, $34,443, and $84,571 at the 2014 user volume. However, these costs represented large reductions (54%, 83%, and 58%, respectively from the 2014 program cost of $203,475. Scenario four, in which the lowest per-SMS rate ($0.01 per SMS was negotiated and users paid for all m4RH SMS sent or received, achieved a $5,660 profit at the 2014 user volume. A Monte Carlo uncertainty analysis demonstrated that break-even points were driven by user volume rather than variations in program costs.These results reveal that breaking even was only probable when all SMS costs were transferred to users and the lowest per-SMS cost was negotiated with telecom partners

  18. NXP出货高速Cortex—M4及Cortex—M3微控制器

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    恩智浦半导体(NXP SemiconductorsN.V.)发布LPC4300数字信号控制器(DSC)——一款高速的ARMCortex—M4微控制器,其速度高达204MHz。LPC4300也是带有Cortex—MO协处理器的双核非对称架构DSC。恩智浦还同时将LPCI800系列的性能提升到180MHz。

  19. Functionalized Congener Approach to Muscarinic Antagonists: Analogues of Pirenzepine

    Science.gov (United States)

    Karton, Yishai; Bradbury, Barton J.; Baumgold, Jesse; Paek, Robert; Jacobson, Kenneth A.

    2012-01-01

    The M1-selective muscarinic receptor antagonist pirenzepine (5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7–10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors. PMID:2066986

  20. Auxin-Oxylipin Crosstalk: Relationship of Antagonists

    Institute of Scientific and Technical Information of China (English)

    Maik Hoffmann; Mathias Hentrich; Stephan Pollmann

    2011-01-01

    Phytohormones regulate a wide array of developmental processes throughout the life cycle of plants. Herein, the various plant hormones may interact additively, synergistically, or antagonistically. By their cooperation they create a delicate regulatory network whose net output largely depends on the action of specific phytohormone combinations rather than on the independent activities of separate hormones. While most classical studies of plant hormonal control have focused mainly on the action of single hormones or on the synergistic interaction of hormones in regulating various developmental processes, recent work is beginning to shed light on the crosstalk of nominally antagonistic plant hormones, such as gibberellins and auxins with oxylipins or abscisic acid. In this review, we summarize our current understanding of how two of the first sight antagonistic plant hormones, i.e. auxins and oxylipins,interact in controlling plant responses and development.

  1. The role of exochitinase type A1 in the fungistatic activity of the rhizosphere bacterium Paenibacillus sp. M4

    Directory of Open Access Journals (Sweden)

    Jankiewicz Urszula

    2016-01-01

    Full Text Available The aim of the study was to detect the activity and characterize potentially fungistatic chitinases synthesized by rhizosphere bacteria identified as Paenibacillus sp. M4. Maximum chitinolytic activity was achieved on the fifth day of culturing bacteria in a growth medium with 1% colloidal chitin. Analysis of a zymogram uncovered the presence of four activity bands in the crude bacterial extract. The used three-stage protein purification procedure resulted in a single band of chitinase activity on the zymogram. The purified enzyme exhibited maximum activity at pH 6.5 and temperature 45oC, and thermal stability at 40oC for 4 h. In terms of substrate specificity, it is an exochitinase (chitobiose. The amino acid sequence obtained after mass spectrometry showed similarity to chitinase A1 synthesized by Bacillus circulans. The M4 isolate demonstrated the highest growth inhibiting activity against plant pathogens belonging to the genera Fusarium, Rhizoctonia and Alternaria. Fungistatic activity, although to a somewhat lesser degree, was also demonstrated by purified chitinase. The obtained results confirm the participation of the studied exochitinase in antagonism towards pathogenic molds. However, the lower fungistatic effectiveness of the chitinases points to the synergistic action of different metabolites in biocontrol by these bacteria.

  2. High-resolution CCD spectra of stars in globular clusters. III - M4, M13, and M22

    Science.gov (United States)

    Wallerstein, George; Leep, E. Myckky; Oke, J. B.

    1987-01-01

    Spectra of 0.3 and 0.6 A resolution of stars in M4, M13 and M22 to derive abundances of various atomic species and the CN molecule. For M13, the usual Fe/H ratio and a surprisingly high aluminum abundance is found. The CN lines indicate a larger column density in the oxygen-rich star III-63 than in the oxygen-poor star II-67 by a factor of 10. It appears that II-67 is deficient in C, N, and O by about a factor 3 relative to iron for all three elements. For M4, Fe/H = -1.2 using solar f values derived via the Bell et al. (1976) model. This Fe abundance lies between earlier echelle values and photometric values. For two stars, CN data are obtained that can be understood if there was a slight excess of C/Fe and N/Fe prior to CN cycling and mixing. For M22, a large difference in CN is found between stars III-3 and IV-102. The origin of the CNO elements is discussed in terms of mass loss from an early generation of red giants and possibly Wolf-Rayet stars.

  3. 2014年河北涿鹿M4.3地震矩张量反演%Seismic Moment Tensor Inversion of 2014 Zhuolu M4.3 Earthquake

    Institute of Scientific and Technical Information of China (English)

    李冬圣; 李文军; 王艳荣; 贾炯; 蔡玲玲; 张从珍

    2016-01-01

    Using Three-component broadband digital waveform data from Hebei Digital Seismograph Net-work,we inversed the seismic moment tensor of Hebei Zhuolu M4.3 earthquake on September 6,2014 in time domain,obtain the optimum solution at the depth of 14km.The results show that the Variance (VR) is 92.2,the Double-couple (Pdc) value is 88,the Compensation linear vector dipole(CLVD) is 12 and the Residual/double-couple (RES/Pdc) is 9.54 × 10-12.The focal mechanism solution is of right-lateral strike-slip type which is consistent with the result from grid method.The seismogenic structure of the earth-quake is discussed combining with geological data and background tectonic of the Zhuolu area.%使用河北省遥测台网记录的三分量宽频带数字波形资料 ,在时间域反演2014年9月6日河北涿鹿 M4. 3地震的矩张量解 ,深度14 km时得到最佳解 ,Variance(VR)为92.2、Double-couple (Pdc)值为88、Compensation linear vector dipole(CLVD)值为12 ,Residual /double-couple(RES/Pdc)达到9.54 × 10-12 ,震源机制解呈右旋走滑 ,与格点尝试法计算结果一致 ,文章结合涿鹿地区的地质资料和构造背景对发震断层进行了讨论.

  4. THE CLUSTER AGES EXPERIMENT (CASE). V. ANALYSIS OF THREE ECLIPSING BINARIES IN THE GLOBULAR CLUSTER M4

    Energy Technology Data Exchange (ETDEWEB)

    Kaluzny, J.; Rozyczka, M.; Krzeminski, W.; Pych, W. [Nicolaus Copernicus Astronomical Center, Bartycka 18, 00-716 Warsaw (Poland); Thompson, I. B.; Burley, G. S.; Shectman, S. A. [Observatories of the Carnegie Institution of Washington, 813 Santa Barbara Street, Pasadena, CA 91101-1292 (United States); Dotter, A. [Space Telescope Science Institute, 3700 San Martin Drive, Baltimore, MD 21218 (United States); Rucinski, S. M., E-mail: jka@camk.edu.pl, E-mail: mnr@camk.edu.pl, E-mail: wk@camk.edu.pl, E-mail: batka@camk.edu.pl, E-mail: pych@camk.edu.pl, E-mail: ian@obs.carnegiescience.edu, E-mail: burley@obs.carnegiescience.edu, E-mail: shec@obs.carnegiescience.edu, E-mail: aaron.dotter@gmail.com, E-mail: rucinski@astro.utoronto.ca [Department of Astronomy and Astrophysics, David Dunlap Observatory, University of Toronto PO Box 360, Richmond Hill, ON L4C 4Y6 (Canada)

    2013-02-01

    We use photometric and spectroscopic observations of the eclipsing binaries V65, V66, and V69 in the field of the globular cluster M4 to derive masses, radii, and luminosities of their components. The orbital periods of these systems are 2.29, 8.11, and 48.19 days, respectively. The measured masses of the primary and secondary components (M{sub p} and M{sub s} ) are 0.8035 {+-} 0.0086 and 0.6050 {+-} 0.0044 M{sub Sun} for V65, 0.7842 {+-} 0.0045 and 0.7443 {+-} 0.0042 M{sub Sun} for V66, and 0.7665 {+-} 0.0053 and 0.7278 {+-} 0/0048 M{sub Sun} for V69. The measured radii (R{sub p} and R{sub s} ) are 1.147 {+-} 0.010 and 0.6110 {+-} 0.0092 R{sub Sun} for V66, 0.9347 {+-} 0.0048 and 0.8298 {+-} 0.0053 R{sub Sun} for V66, and 0.8655 {+-} 0.0097 and 0.8074 {+-} 0.0080 R{sub Sun} for V69. The orbits of V65 and V66 are circular, whereas that of V69 has an eccentricity of 0.38. Based on systemic velocities and relative proper motions, we show that all three systems are members of the cluster. We find that the distance to M4 is 1.82 {+-} 0.04 kpc-in good agreement with recent estimates based on entirely different methods. We compare the absolute parameters of V66 and V69 with two sets of theoretical isochrones in mass-radius and mass-luminosity diagrams, and for assumed [Fe/H] = -1.20, [{alpha}/Fe] = 0.4, and Y = 0.25 we find the most probable age of M4 to be between 11.2 and 11.3 Gyr. Color-magnitude diagram (CMD) fitting with the same parameters yields an age close to, or slightly in excess of, 12 Gyr. However, considering the sources of uncertainty involved in CMD fitting, these two methods of age determination are not discrepant. Age and distance determinations can be further improved when infrared eclipse photometry is obtained.

  5. Genetic factors influencing pyrimidine-antagonist chemotherapy

    NARCIS (Netherlands)

    Maring, JG; Groen, HJM; Wachters, FM; Uges, DRA; de Vries, EGE

    2005-01-01

    Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of

  6. Practical recommendations for calcium channel antagonist poisoning

    NARCIS (Netherlands)

    Rietjens, S J; de Lange, D W; Donker, D W; Meulenbelt, J

    Calcium channel antagonists (CCAs) are widely used for different cardiovascular disorders. At therapeutic doses, CCAs have a favourable side effect profile. However, in overdose, CCAs can cause serious complications, such as severe hypotension and bradycardia. Patients in whom a moderate to severe

  7. Why are mineralocorticoid receptor antagonists cardioprotective?

    NARCIS (Netherlands)

    W. Chai (Wenxia); A.H.J. Danser (Jan)

    2006-01-01

    textabstractTwo clinical trials, the Randomized ALdosterone Evaluation Study (RALES) and the EPlerenone HEart failure and SUrvival Study (EPHESUS), have recently shown that mineralocorticoid receptor (MR) antagonists reduce mortality in patients with heart failure on top of ACE inhibition. This effe

  8. Granulocytic Sarcoma by AML M4eo (inv16 after Allogeneic Stem Cell Transplantation without Bone Marrow Involvement

    Directory of Open Access Journals (Sweden)

    Stephan Zaenker

    2011-01-01

    Full Text Available Granulocytic sarcoma (GS represents a rare type of extramedullar manifestation from the acute myeloid leukaemia (AML. We report the case of a patient with recurrences of AML M4eo leukaemia in the uterus and the small intestine at 3 and 5 years, respectively, after matched related peripheral blood stem cell transplantation (PBSCT. The patient underwent the withdrawal of immunosuppression, hysterectomy, and local irradiation at first relapse, as well as systemic chemotherapy and donor lymphocyte infusions at second recurrence, inducing a second and third complete remission, respectively. At year six after transplantation, the patient experienced disease progression by meningeosis leukaemia to which she succumbed despite intrathecal chemotherapy. Following allogeneic stem cell transplantation, awareness for atypical manifestations of granulocytic sarcoma appears prudent, the cellular immunotherapy should aim at immunological disease control.

  9. The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Andersen, Maibritt B; Fink-Jensen, Anders; Peacock, Linda

    2003-01-01

    Xanomeline is a muscarinic M(1)/M(4) preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects......, stereotypies and arousal as well as apomorphine-induced stereotypies and arousal in drug-naive Cebus apella monkeys. Xanomeline did not induce EPS but vomiting occurred in some monkeys at high doses, in accordance with emetic events observed in Alzheimer patients following xanomeline administration. Even when...... that xanomeline inhibits D-amphetamine- and (-)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis....

  10. Lithium abundance in the globular cluster M4: from the turn-off to the red giant branch bump

    Science.gov (United States)

    Mucciarelli, A.; Salaris, M.; Lovisi, L.; Ferraro, F. R.; Lanzoni, B.; Lucatello, S.; Gratton, R. G.

    2011-03-01

    We present Li and Fe abundances for 87 stars in the globular cluster M4, obtained by using high-resolution spectra collected with GIRAFFE at the Very Large Telescope. The targets range from the turn-off up to the red giant branch bump. The Li abundance in the turn-off stars is uniform, with an average value equal to A(Li)= 2.30 ± 0.02 dex (σ= 0.10 dex), consistent with the upper envelope of Li content measured in other globular clusters and in the halo field stars, confirming also for M4 the discrepancy with the primordial Li abundance predicted by Wilkinson Microwave Anisotropy Probe+ big bang nucleosynthesis (WMAP+BBNS). The global behaviour of A(Li) as a function of the effective temperature allows us to identify the two main drops in the Li evolution due to the first dredge-up and to the extra-mixing episode after the red giant branch bump. The measured iron content of M4 results to [Fe/H]=-1.10 ± 0.01 dex (σ= 0.07 dex), with no systematic offsets between dwarf and giant stars. The behaviour of the Li and Fe abundances along the entire evolutionary path is incompatible with theoretical models including pure atomic diffusion, pointing out that an additional turbulent mixing below the convective region needs to be taken into account, able to inhibit the atomic diffusion. The measured value of A(Li) and its homogeneity in the turn-off stars allow us to put strong constraints on the shape of the Li profile inside the M4 turn-off stars. The global behaviour of A(Li) with the effective temperature can be reproduced with different pristine Li abundances, depending on the kind of adopted turbulent mixing. One cannot reproduce the global trend that starts from the WMAP+BBNS A(Li) and adopts the turbulent mixing described by Richard, Michaud & Richer with the same efficiency as that used by Korn et al. to explain the Li content in NGC 6397. In fact, such a solution is not able to well reproduce simultaneously the Li abundance observed in turn-off and red giant branch

  11. 英特尔蓝图大曝光 65纳米赛扬M 4XX系列

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    英特尔目前正准备发布主频为233GHz的Core Duo芯片T2700,其产品路线图包括速度更快的Core Solo芯片,快速低压的Core Duos和超低压Core Duo芯片,后者的主频为1.06GHz代号为U2500。此外,赛扬(Celoron)M 4XX也被纳入了英特尔最新的产品路线圈,这是一款从65纳米制程的Core Solo肃离下来的单核产品。

  12. Observations of the Ultraviolet-bright Star Y453 in the Globular Cluster M4 (NGC 6121)

    Science.gov (United States)

    Dixon, William V.; Chayer, Pierre; Latour, Marilyn; Miller Bertolami, Marcelo Miguel; Benjamin, Robert A.

    2017-09-01

    We present a spectral analysis of the UV-bright star Y453 in M4. Model fits to the star’s optical spectrum yield {T}{eff} ∼ 56,000 K. Fits to the star’s FUV spectrum, obtained with the Cosmic Origins Spectrograph on board the Hubble Space Telescope, reveal it to be considerably hotter, with {T}{eff} ∼ 72,000 K. We adopt {T}{eff} = 72,000 ± 2000 K and {log}g = 5.7 ± 0.2 as our best-fit parameters. Scaling the model spectrum to match the star’s optical and near-infrared magnitudes, we derive a mass {M}* =0.53+/- 0.24 {M}ȯ and luminosity {log}L/{L}ȯ =2.84+/- 0.05, consistent with the values expected of an evolved star in a globular cluster. Comparing the star with post-horizontal-branch evolutionary tracks, we conclude that it most likely evolved from the blue horizontal branch, departing the asymptotic giant branch before third dredge-up. It should thus exhibit the abundance pattern (O-poor and Na-rich) characteristic of the second-generation (SG) stars in M4. We derive the star’s photospheric abundances of He, C, N, O, Si, S, Ti, Cr, Fe, and Ni. CNO abundances are roughly 0.25 dex greater than those of the cluster’s SG stars, while the Si and S abundances match the cluster values. Abundances of the iron-peak elements (except for iron itself) are enhanced by 1–3 dex. Rather than revealing the star’s origin and evolution, this pattern reflects the combined effects of diffusive and mechanical processes in the stellar atmosphere.

  13. Combining Elements from Two Antagonists of Formyl Peptide Receptor 2 Generates More Potent Peptidomimetic Antagonists.

    Science.gov (United States)

    Skovbakke, Sarah Line; Holdfeldt, André; Nielsen, Christina; Hansen, Anna Mette; Perez-Gassol, Iris; Dahlgren, Claes; Forsman, Huamei; Franzyk, Henrik

    2017-08-24

    Structural optimization of a peptidomimetic antagonist of formyl peptide receptor 2 (FPR2) was explored by an approach involving combination of elements from the two most potent FPR2 antagonists described: a Rhodamine B-conjugated 10-residue gelsonin-derived peptide (i.e., PBP10, RhB-QRLFQVKGRR-OH) and the palmitoylated α-peptide/β-peptoid hybrid Pam-(Lys-βNspe)6-NH2. This generated an array of hybrid compounds from which a new subclass of receptor-selective antagonists was identified. The most potent representatives displayed activity in the low nanomolar range. The resulting stable and potent FPR2-selective antagonists (i.e., RhB-(Lys-βNphe)n-NH2; n = 4-6) are expected to become valuable tools in further elucidation of the physiological role of FPR2 in health and disease.

  14. Functional analysis of the stress-inducible soybean calmodulin isoform-4 (GmCaM-4) promoter in transgenic tobacco plants.

    Science.gov (United States)

    Park, Hyeong Cheol; Kim, Man Lyang; Kang, Yun Hwan; Jeong, Jae Cheol; Cheong, Mi Sun; Choi, Wonkyun; Lee, Sang Yeol; Cho, Moo Je; Kim, Min Chul; Chung, Woo Sik; Yun, Dae-Jin

    2009-04-30

    The transcription of soybean (Glycine max) calmodulin isoform-4 (GmCaM-4) is dramatically induced within 0.5 h of exposure to pathogen or NaCl. Core cis-acting elements that regulate the expression of the GmCaM-4 gene in response to pathogen and salt stress were previously identified, between -1,207 and -1,128 bp, and between -858 and -728 bp, in the GmCaM-4 promoter. Here, we characterized the properties of the DNA-binding complexes that form at the two core cis-acting elements of the GmCaM-4 promoter in pathogen-treated nuclear extracts. We generated GUS reporter constructs harboring various deletions of approximately 1.3-kb GmCaM-4 promoter, and analyzed GUS expression in tobacco plants transformed with these constructs. The GUS expression analysis suggested that the two previously identified core regions are involved in inducing GmCaM-4 expression in the heterologous system. Finally, a transient expression assay of Arabidopsis protoplasts showed that the GmCaM-4 promoter produced greater levels of GUS activity than did the CaMV35S promoter after pathogen or NaCl treatments, suggesting that the GmCaM-4 promoter may be useful in the production of conditional gene expression systems.

  15. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit+ bosentan group and Nit+ losartan group. Nitroglycerin tolerance was induced by 2-day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg- 1· d- 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg- 1· d- 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit+ losartan group and Nit+ bosentan group compared with Nit group [(31.95± 4.45 ) % vs (21.00± 3.69 ) % , P Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance .

  16. Central muscarinic receptor subtypes involved in pilocarpine-induced salivation, hypertension and water intake.

    Science.gov (United States)

    Borella, T L; De Luca, L A; Colombari, D S A; Menani, J V

    2008-12-01

    Recent evidence has suggested that pilocarpine (ACh receptor agonist) injected peripherally may act centrally producing salivation and hypertension. In this study, we investigated the effects of specific M(1) (pirenzepine), M(2)/M(4) (methoctramine), M(1)/M(3) (4-DAMP) and M(4) (tropicamide) muscarinic receptor subtype antagonists injected into the lateral cerebral ventricle (LV) on salivation, water intake and pressor responses to peripheral pilocarpine. Male Holtzman rats with stainless steel cannulae implanted in the LV were used. Salivation was measured in rats anaesthetized with ketamine (100 mg per kg body weight) and arterial pressure was recorded in unanaesthetized rats. Salivation induced by i.p. pilocarpine (4 micromol per kg body weight) was reduced only by 4-DAMP (25-250 nmol) injected into the LV, not by pirenzepine, methoctramine or tropicamide at the dose of 500 nmol. Pirenzepine (0.1 and 1 nmol) and 4-DAMP (5 and 10 nmol) injected into the LV reduced i.p. pilocarpine-induced water intake, whereas metoctramine (50 nmol) produced nonspecific effects on ingestive behaviours. Injection of pirenzepine (100 nmol) or 4-DAMP (25 and 50 nmol) into the LV reduced i.v. pilocarpine-induced pressor responses. Tropicamide (500 nmol) injected into the LV had no effect on pilocarpine-induced salivation, pressor responses or water intake. The results suggest that central M(3) receptors are involved in peripheral pilocarpine-induced salivation and M(1) receptors in water intake and pressor responses. The involvement of M(3) receptors in water intake and pressor responses is not clear because 4-DAMP blocks both M(1) and M(3) receptors.

  17. Novel benzimidazole-based MCH R1 antagonists.

    Science.gov (United States)

    Carpenter, Andrew J; Al-Barazanji, Kamal A; Barvian, Kevin K; Bishop, Michael J; Britt, Christy S; Cooper, Joel P; Goetz, Aaron S; Grizzle, Mary K; Hertzog, Donald L; Ignar, Diane M; Morgan, Ronda O; Peckham, Gregory E; Speake, Jason D; Swain, Will R

    2006-10-01

    The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.

  18. High affinity retinoic acid receptor antagonists: analogs of AGN 193109.

    Science.gov (United States)

    Johnson, A T; Wang, L; Gillett, S J; Chandraratna, R A

    1999-02-22

    A series of high affinity retinoic acid receptor (RAR) antagonists were prepared based upon the known antagonist AGN 193109 (2). Introduction of various phenyl groups revealed a preference for substitution at the para-position relative to the meta-site. Antagonists with the highest affinities for the RARs possessed hydrophobic groups, however, the presence of polar functionality was also well tolerated.

  19. Mineralocorticoid and glucocorticoid receptor antagonists in animal models of anxiety

    NARCIS (Netherlands)

    Korte, SM; KorteBouws, GAH; Koob, GF; DeKloet, ER; Bohus, B

    1996-01-01

    The behavioral effects of intracerebroventricular (ICV) administration of a specific mineralocorticoid receptor (MR) antagonist [RU28318 (10-50 ng/2 mu l)], a glucocorticoid receptor (GR) antagonist [RU38486 (1-50 ng/2 mu l)], or both antagonists (50 ng/2 mu l), were studied in two different animal

  20. Spectroscopy and Photometry of Multiple Populations along the Asymptotic Giant Branch of NGC 2808 and NGC 6121 (M4)

    Science.gov (United States)

    Marino, A. F.; Milone, A. P.; Yong, D.; Da Costa, G.; Asplund, M.; Bedin, L. R.; Jerjen, H.; Nardiello, D.; Piotto, G.; Renzini, A.; Shetrone, M.

    2017-07-01

    We present a photometric and spectroscopic study of multiple populations along the asymptotic giant branch (AGB) of the intermediate-metallicity globular clusters (GCs) NGC 2808 and NGC 6121 (M4). Chemical abundances of O, Na, Mg, Al, Si, Ca, Sc, Ti, V, Cr, Fe, Co, Ni, Zn, Y, and Ce in AGB stars from high-resolution FLAMES+UVES@VLT spectra are reported for both clusters. Our spectroscopic results have been combined with multiwavelength photometry from the Hubble Space Telescope UV survey of Galactic GCs and ground-based photometry, as well as proper motions derived by combining stellar positions from ground-based images and Gaia DR1. Our analysis reveals that the AGBs of both clusters host multiple populations with different chemical compositions. In M4, we have identified two main populations of stars with different Na/O content lying on distinct AGBs in the {m}{{F}438{{W}}} versus {C}{{F}275{{W}},{{F}}336{{W}},{{F}}438{{W}}} and the V versus {C}{{U},{{B}},{{I}}} pseudo-color-magnitude diagrams. In the more massive and complex GC NGC 2808, three groups of stars with different chemical abundances occupy different locations on the so-called “chromosome map” photometric diagram constructed for AGB stars. The spectroscopic + photometric comparison of stellar populations along the AGB and the red giants of this GC suggests that the AGB hosts stellar populations with a range in helium abundances from primordial to high contents of Y˜ 0.32. By contrast, from our data set, there is no evidence for stars with extreme helium abundance (Y˜ 0.38) on the AGB, suggesting that the most He-rich stars of NGC 2808 do not reach this phase. Based on observations collected at the European Organisation for Astronomical Research in the Southern Hemisphere under ESO programs 093.D-0789 and 094.D-0455 and on observations with the NASA/ESA Hubble Space Telescope, obtained at the Space Telescope Science Institute, which is operated by AURA, Inc., under NASA contract NAS 5-26555.

  1. [Cutaneous adverse effects of TNFalpha antagonists].

    Science.gov (United States)

    Failla, V; Sabatiello, M; Lebas, E; de Schaetzen, V; Dezfoulian, B; Nikkels, A F

    2012-01-01

    The TNFalpha antagonists, including adalimumab, etanercept and infliximab, represent a class of anti-inflammatory and immunosuppressive drugs. Although cutaneous adverse effects are uncommon, they are varied. There is no particular risk profile to develop cutaneous adverse effects. The principal acute side effects are injection site reactions and pruritus. The major long term cutaneous side effects are infectious and inflammatory conditions. Neoplastic skin diseases are exceptional. The association with other immunosuppressive agents can increase the risk of developing cutaneous adverse effects. Some adverse effects, such as lupus erythematosus, require immediate withdrawal of the biological treatment, while in other cases temporary withdrawal is sufficient. The majority of the other cutaneous adverse effects can be dealt without interrupting biologic treatment. Preclinical and clinical investigations revealed that the new biologics, aiming IL12/23, IL23 and IL17, present a similar profile of cutaneous adverse effects, although inflammatory skin reactions may be less often encountered compared to TNFalpha antagonists.

  2. The M 4 Core Project with HST - V. Characterizing the PSFs of WFC3/UVIS by focus★

    Science.gov (United States)

    Anderson, J.; Bedin, L. R.

    2017-09-01

    As part of the astrometric Hubble Space Telescope (HST) large program GO-12911, we conduct an in-depth study to characterize the point spread function (PSF) of the Uv-VISual channel of the Wide Field Camera 3 (WFC3), as a necessary step to achieve the astrometric goals of the program. We extracted a PSF from each of the 589 deep exposures taken through the F467M filter over the course of a year and find that the vast majority of the PSFs lie along a 1-D locus that stretches continuously from one side of focus, through optimal focus, to the other side of focus. We constructed a focus-diverse set of PSFs and find that with only five medium-bright stars in an exposure it is possible to pin down the focus level of that exposure. We show that the focus-optimized PSF does a considerably better job fitting stars than the average 'library' PSF, especially when the PSF is out of focus. The fluxes and positions are significantly improved over the 'library' PSF treatment. These results are beneficial for a much broader range of scientific applications than simply the program at hand, but the immediate use of these PSFs will enable us to search for astrometric wobble in the bright stars in the core of the globular cluster M 4, which would indicate a dark, high-mass companion, such as a white dwarf, neutron star or black hole.

  3. Kepler Flares. IV. A Comprehensive Analysis of the Activity of the dM4e Star GJ 1243

    Science.gov (United States)

    Silverberg, Steven M.; Kowalski, Adam F.; Davenport, James R. A.; Wisniewski, John P.; Hawley, Suzanne L.; Hilton, Eric J.

    2016-10-01

    We present a comprehensive study of the active dM4e star GJ 1243. We use previous observations and ground-based echelle spectroscopy to determine that GJ 1243 is a member of the Argus association of field stars, suggesting it is ∼ 30{--}50 {{Myr}} old. We analyze 11 months of 1 minute cadence data from Kepler, presenting Kepler flare frequency distributions, as well as determining correlations between flare energy, amplitude, duration, and decay time. We find that the exponent α of the power-law flare energy distribution varies in time, primarily due to completeness of sample and the low frequency of high-energy flares. We also find a deviation from a single power law at high energy. We use ground-based spectroscopic observations that were simultaneous with the Kepler data to provide simultaneous photometric and spectroscopic analysis of three low-energy flares, the lowest-energy dMe flares with detailed spectral analysis to date on any star. The spectroscopic data from these flares extend constraints for radiative hydrodynamic flare models to a lower energy regime than has previously been studied. We use this simultaneous spectroscopy and Kepler photometry to develop approximate conversions from the Kepler bandpass to the traditional U and B bands. This conversion will be a critical factor in comparing any Kepler flare analyses to the canon of previous ground-based flare studies.

  4. The M4 Core Project with HST - IV. Internal Kinematics from Accurate Radial Velocities of 2771 Cluster Members

    CERN Document Server

    Malavolta, L; Bedin, L R; Sneden, C; Nascimbeni, V; Sommariva, V

    2015-01-01

    We present a detailed study of the internal kinematics of the Galactic Globular Cluster M 4 (NGC 6121), by deriving the radial velocities from 7250 spectra for 2771 stars distributed from the upper part of the Red Giant Branch down to the Main Sequence. We describe new approaches to determine the wavelength solution from day-time calibrations and to determine the radial velocity drifts that can occur between calibration and science observations when observing with the GIRAFFE spectrograph at VLT. Two techniques to determine the radial velocity are compared, after a qualitative description of their advantages with respect to other commonly used algorithm, and a new approach to remove the sky contribution from the spectra obtained with fibre-fed spectrograph and further improve the radial velocity precision is presented. The average radial velocity of the cluster is $\\langle v \\rangle = 71.08 \\pm 0.08$ km s$^{-1}$ with an average dispersion of $\\mu_{v_c} = 3.97$ km s$^{-1}$. Using the same dataset and the same ...

  5. Kepler Flares IV: A Comprehensive Analysis of the Activity of the dM4e Star GJ 1243

    CERN Document Server

    Silverberg, Steven M; Davenport, James R A; Wisniewski, John P; Hawley, Suzanne L; Hilton, Eric J

    2016-01-01

    We present a comprehensive study of the active dM4e star GJ 1243. We use previous observations and ground-based echelle spectroscopy to determine that GJ 1243 is a member of the Argus association of field stars, suggesting it is $\\sim 30-50$ Myr old. We analyze eleven months of 1-minute cadence data from Kepler, presenting Kepler flare frequency distributions, as well as determining correlations between flare energy, amplitude, duration, and decay time. We find that the exponent $\\alpha$ of the power-law flare energy distribution varies in time, primarily due to completeness of sample and the low frequency of high-energy flares. We also find a deviation from a single power law at high energy. We use ground-based spectroscopic observations simultaneous with the Kepler data to provide simultaneous photometric and spectroscopic analysis of three low-energy flares, the lowest-energy dMe flares with detailed spectral analysis to date on any star. The spectroscopic data from these flares extend constraints for radi...

  6. Synthesis, structure and properties of {M4O4} cubanes containing nickel(II) and cobalt(II).

    Science.gov (United States)

    Isele, Katharina; Gigon, Fabienne; Williams, Alan F; Bernardinelli, Gérald; Franz, Patrick; Decurtins, Silvio

    2007-01-21

    A survey of the crystal structures containing simple {M4O4} cubane units is reported. It shows that the average M-M distance in these complexes is relatively constant for a given metal ion M. The structures are all distorted from the idealised cube to a T(d) structure, and most show a further distortion which, however, usually maintains some elements of symmetry. A system for classifying the different types of ligand in these complexes is proposed. Two new cubanes of cobalt(II) and nickel(II) with the ligand (R,R)-bis-1,2-(1-methylbenzimidazol-2-yl)ethane-1,2-diol, (R,R)- or its enantiomer have been isolated and the crystal structure of the cobalt(II) complex confirms the cubane structure. Electronic, CD and (1)H NMR spectra and magnetic susceptibility data are reported. The magnetic data for these and other compounds in the literature are discussed in terms of the structural parameters.

  7. Antagonistic parent-offspring co-adaptation.

    Directory of Open Access Journals (Sweden)

    Mathias Kölliker

    Full Text Available BACKGROUND: In species across taxa, offspring have means to influence parental investment (PI. PI thus evolves as an interacting phenotype and indirect genetic effects may strongly affect the co-evolutionary dynamics of offspring and parental behaviors. Evolutionary theory focused on explaining how exaggerated offspring solicitation can be understood as resolution of parent-offspring conflict, but the evolutionary origin and diversification of different forms of family interactions remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: In contrast to previous theory that largely uses a static approach to predict how "offspring individuals" and "parental individuals" should interact given conflict over PI, we present a dynamic theoretical framework of antagonistic selection on the PI individuals obtain/take as offspring and the PI they provide as parents to maximize individual lifetime reproductive success; we analyze a deterministic and a stochastic version of this dynamic framework. We show that a zone for equivalent co-adaptation outcomes exists in which stable levels of PI can evolve and be maintained despite fast strategy transitions and ongoing co-evolutionary dynamics. Under antagonistic co-adaptation, cost-free solicitation can evolve as an adaptation to emerging preferences in parents. CONCLUSIONS/SIGNIFICANCE: We show that antagonistic selection across the offspring and parental life-stage of individuals favors co-adapted offspring and parental behavior within a zone of equivalent outcomes. This antagonistic parent-offspring co-adaptation does not require solicitation to be costly, allows for rapid divergence and evolutionary novelty and potentially explains the origin and diversification of the observed provisioning forms in family life.

  8. Aminopyrimidine derivatives as adenosine antagonists / Janke Kleynhans

    OpenAIRE

    Kleynhans, Janke

    2013-01-01

    Aims of this project - The aim of this study was to design and synthesise novel 2-aminopyrimidine derivatives as potential adenosine A1 and A2A receptor antagonists. Background and rationale - Parkinson’s disease is the second most common neurodegenerative disorder (after Alzheimer’s disease) and is characterised by the selective death of the dopaminergic neurons of the nigro-striatal pathway. Distinctive motor symptoms include bradykinesia, muscle rigidity and tremor, while non-m...

  9. The Justification of Antagonistic Response to Wrongdoing

    OpenAIRE

    Goldman, David Michael

    2012-01-01

    There is a strong Western tradition of opposing angry, hostile, or antagonistic reactions to wrongdoing. In the twentieth century, leaders like Mahatma Gandhi and Dr. Martin Luther King, Jr. counseled responding to wrongdoing with forgiveness and love rather than anger, hate, or vindictiveness.This ideal has taken on an exalted status in Western culture. Gandhi and King are widely regarded as moral saints. And yet sometimes antagonism seems deeply appropriate. Consider a very serious wrong: s...

  10. Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition.

    Science.gov (United States)

    Wood, Michael R; Noetzel, Meredith J; Tarr, James C; Rodriguez, Alice L; Lamsal, Atin; Chang, Sichen; Foster, Jarrett J; Smith, Emery; Chase, Peter; Hodder, Peter S; Engers, Darren W; Niswender, Colleen M; Brandon, Nicholas J; Wood, Michael W; Duggan, Mark E; Conn, P Jeffrey; Bridges, Thomas M; Lindsley, Craig W

    2016-09-01

    This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. From the Cover: Glutamate antagonists limit tumor growth

    Science.gov (United States)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  12. Comprehensive photometric study of an extremely low mass ratio deep contact binary in the globular cluster M 4

    Science.gov (United States)

    Li, Kai; Hu, Shaoming; Chen, Xu; Guo, Difu

    2017-10-01

    A comprehensive photometric study and an investigation of the orbital period variation of V53 in the globular cluster M 4 are presented. The photometric study reveals that the mass ratio and the contact degree of V53 are q ˜ 0.078 and f ˜ 69%, respectively. The observed variation in the light curve can be explained by adjusting the spot parameters. V53 belongs to extreme mass ratio (q ≤ 0.25), deep contact (f ≥ 50%) binaries, and its mass ratio is close to the minimum mass ratio predicted by theoretical studies, making it a potential object for studying the evolution of binaries and the formation of blue stragglers and FK Com-type stars. The orbital period of V53 shows a long-term decrease at a rate of dp/dt = 5.89(±0.02) × 10-8 d yr-1. This secular period decrease may be caused by the combination of mass transfer from the more massive component to the less massive component and an angular momentum loss via magnetic braking. As this mass transfer and angular momentum loss continues, V53 will ultimately evolve into a single fast-rotation star. By studying the statistics of all the contact binaries in globular clusters that have been analyzed, we found a possible correlation between the contact degree and whether or not a contact binary is a blue straggler. A contact binary is likely to become a blue straggler when its fill-out factor is more than 46.25(±2.05)%. More samples should be introduced to confirm this preliminary result in the future.

  13. 不定方程m~4x(x+1)(x+2)(x+3)=(m~4-1)y(y+1)(y+2)(y+3)的整数解%Solutions of Diophantine Equation m~4x(x+1)(x+2)(x+3)=(m~4-1)y(y+1)(y+2)(y+3)

    Institute of Scientific and Technical Information of China (English)

    郑惠

    2012-01-01

    运用初等方法对不定方程ax(x+1)(x+2)(x+3)=by(y+1)(y+2)(y+3)的整数解进行了研究,得到了当a=m4,b=m4-1时方程的非负整数解仅有(x,y)=(0,0)。%The solution of Diophantine eqeation ax(x+1)(x+2)(x+3)=by(y+1)(y+2)(y+3) is discussed by using elementary methods.It is proved that the eqution has only non-negative integer solution(x,y)=(0,0) when a=m4,b=m4-1.

  14. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    张建梅; 陈永红; 王晓红; 唐朝枢

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n =6, each): Control group, Nitroglycerin (Nit) group, Nit + bosentan group and Nit + losartan group. Nitroglycerin tolerance was induced by 2-day treatment ofnitroglycerin patch (0. 05mg/h). Angiotensin I1 receptor antagonist losartan (10mg ·kg-1·d-1) and endothe-lin receptor antagonist bosentan ( 100 mg·kg-1· d-1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group. The effec-tive percentages of hypotensive response to SNP were increased in both Nit + losartan group and Nit + bosentangroup compared with Nit group [(31.95±4.45) % vs (21.00±3.69) %, P <0.01and (33. 18±6. 16)% vs (21.00±3.69 ) %, P < 0. 01 , respectivelyl. The maximal vessel relaxation induced by SNP was thesame in 4 different groups but the highest EC50 (concentration which produces 50% of the maximal response toSNP) was found in tolerant group[ (34 ±10) nmol/L, P < 0. 01 ]. The ET-1 amounts in plasma and vasculartissue were markedly increased by 54% and 60% in Nit group compared with those in control group( P<0. 01). The ET-1 amounts in plasma and vascular tissue were decreased by 30% and 37% in Nit + losartangroup compared with those in Nit group ( P < 0.01 ). Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance.

  15. The M4 Transmembrane α-Helix Contributes Differently to Both the Maturation and Function of Two Prokaryotic Pentameric Ligand-gated Ion Channels.

    Science.gov (United States)

    Hénault, Camille M; Juranka, Peter F; Baenziger, John E

    2015-10-09

    The role of the outermost transmembrane α-helix in both the maturation and function of the prokaryotic pentameric ligand-gated ion channels, GLIC and ELIC, was examined by Ala scanning mutagenesis, deletion mutations, and mutant cycle analyses. Ala mutations at the M4-M1/M3 interface lead to loss-of-function phenotypes in GLIC, with the largest negative effects occurring near the M4 C terminus. In particular, two aromatic residues at the M4 C terminus form a network of π-π and/or cation-π interactions with residues on M3 and the β6-β7 loop that is essential for both maturation and function. M4-M1/M3 interactions appear to be optimized in GLIC with even subtle structural changes at this interface leading to detrimental effects. In contrast, mutations along the M4-M1/M3 interface of ELIC typically lead to gain-of-function phenotypes, suggesting that these interactions in ELIC are not optimized for channel function. In addition, no cluster of interacting residues involving the M4 C terminus, M3, and the β6-β7 loop was found, suggesting that the M4 C terminus plays little role in ELIC maturation or function. This study shows that M4 makes distinct contributions to the maturation and gating of these two closely related homologs, suggesting that GLIC and ELIC exhibit divergent features of channel function. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Source parameters of a M4.8 and its accompanying repeating earthquakes off Kamaishi, NE Japan: Implications for the hierarchical structure of asperities and earthquake cycle

    Science.gov (United States)

    Uchida, N.; Matsuzawa, T.; Ellsworth, W.L.; Imanishi, K.; Okada, T.; Hasegawa, A.

    2007-01-01

    We determine the source parameters of a M4.9 ?? 0.1 'characteristic earthquake' sequence and its accompanying microearthquakes at ???50 km depth on the subduction plate boundary offshore of Kamaishi, NE Japan. The microearthquakes tend to occur more frequently in the latter half of the recurrence intervals of the M4.9 ?? 0.1 events. Our results show that the microearthquakes are repeating events and they are located not only around but also within the slip area for the 2001 M4.8 event. From the hierarchical structure of slip areas and smaller stress drops for the microearthquakes compared to the M4.8 event, we infer the small repeating earthquakes rupture relatively weak patches in and around the slip area for the M4.8 event and their activity reflects a stress concentration process and/or change in frictional property (healing) at the area. We also infer the patches for the M4.9 ?? 0.1 and other repeating earthquakes undergo aseismic slip during their interseismic period. Copyright 2007 by the American Geophysical Union.

  17. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

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

    2015-01-01

    A high degree of structural heterogeneity of the GABAA receptors (GABAARs) has been revealed and is reflected in multiple receptor subtypes. The subunit composition of GABAAR subtypes is believed to determine their localization relative to the synapses and adapt their functional properties...... to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...

  18. Elucidating the `Jekyll and Hyde' Nature of PXR: The Case for Discovering Antagonists or Allosteric Antagonists

    Science.gov (United States)

    Biswas, Arunima; Mani, Sridhar; Redinbo, Matthew R.; Krasowski, Matthew D.; Li, Hao; Ekins, Sean

    2010-01-01

    The pregnane X receptor belongs to the nuclear hormone receptor superfamily and is involved in the transcriptional control of numerous genes. It was originally thought that it was a xenobiotic sensor controlling detoxification pathways. Recent studies have shown an increasingly important role in inflammation and cancer, supporting its function in abrogating tissue damage. PXR orthologs and PXR-like pathways have been identified in several non-mammalian species which corroborate a conserved role for PXR in cellular detoxification. In summary, PXR has a multiplicity of roles in vivo and is being revealed as behaving like a “Jekyll and Hyde” nuclear hormone receptor. The importance of this review is to elucidate the need for discovery of antagonists of PXR to further probe its biology and therapeutic applications. Although several PXR agonists are already reported, virtually nothing is known about PXR antagonists. Here, we propose the development of PXR antagonists through chemical, genetic and molecular modeling approaches. Based on this review it will be clear that antagonists of PXR and PXR-like pathways will have widespread utility in PXR biology and therapeutics. PMID:19415465

  19. Sequence analysis of muscarinic receptors M2 and M4 expression by cultured rat astrocyte cells%星形胶质细胞毒蕈碱样乙酰胆碱受体M2、M4亚型基因克隆及序列分析

    Institute of Scientific and Technical Information of China (English)

    张晓娟; 汪海

    2005-01-01

    目的:克隆胶质细胞M2、M4受体亚型基因序列,并比较胶质细胞M2、 M4受体亚型基因序列和蛋白质序列与神经元细胞M2、M4受体基因序列和蛋白质序列间的差异.方法:根据神经元细胞M2、M4受体基因序列设计出针对M2、M4受体基因序列全长的特异性探针,采用RT-PCR方法扩增胶质细胞M2、M4受体亚型基因序列,并对其进行克隆测序.结果:通过RT-PCR方法扩增胶质细胞M2、M4受体亚型基因序列,与神经元细胞M2、M4受体比较,M2受体差异碱基17个,发生氨基酸改变的有8个;M4受体差异碱基3个,发生氨基酸改变的有2个.结论:胶质细胞M2、 M4受体与神经细胞M2、M4受体亚型在基因序列和氨基酸序列上具有明显差异.

  20. ETA-receptor antagonists or allosteric modulators?

    DEFF Research Database (Denmark)

    De Mey, Jo G R; Compeer, Matthijs G; Lemkens, Pieter

    2011-01-01

    The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects. In resista......The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects....... In resistance arteries, the long-lasting contractile effects can only be partly and reversibly relaxed by low-molecular-weight ET(A) antagonists (ERAs). However, the neuropeptide calcitonin-gene-related peptide selectively terminates binding of ET1 to ET(A). We propose that ET1 binds polyvalently to ET(A......) and that ERAs and the physiological antagonist allosterically reduce ET(A) functions. Combining the two-state model and the two-domain model of GPCR function and considering receptor activation beyond agonist binding might lead to better anti-endothelinergic drugs. Future studies could lead to compounds...

  1. Sexually antagonistic selection in human male homosexuality.

    Directory of Open Access Journals (Sweden)

    Andrea Camperio Ciani

    Full Text Available Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness, accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait.

  2. Activins and activin antagonists in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Alev Deli; Emanuel Kreidl; Stefan Santifaller; Barbara Trotter; Katja Seir; Walter Berger; Rolf Schulte-Hermann; Chantal Rodgarkia-Dara; Michael Grusch

    2008-01-01

    In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo-or heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic co-receptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.

  3. Sexually antagonistic selection in human male homosexuality.

    Science.gov (United States)

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-06-18

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait.

  4. The antiatherogenic potential of calcium antagonists.

    Science.gov (United States)

    Weinstein, D B

    1988-01-01

    Atherosclerosis is an arterial disease characterized by focal accumulation of collagen, elastin, lipids, and calcium at sites associated with macrophage infiltration and altered smooth muscle metabolic function. Studies in several types of animal models, especially cholesterol-fed rabbits, have shown that calcium competitors, calcium chelators, anticalcifying agents, and calcium channel blockers can reduce the accumulation of atherogenic lesion components and thus apparently decrease the progression of lesions. Although there are some conflicting data in the animal model studies using calcium channel antagonists, as a result of differences in experimental designs, it is now apparent that several classes of calcium channel blockers inhibit the progression of early arterial lesions induced by cholesterol feeding. The dihydropyridine calcium channel blockers appear to be more potent antiatherosclerotic agents than other classes of calcium channel antagonists. Several mechanisms involving regulation of endothelial cell, smooth muscle cell, and macrophage metabolic functions may be responsible for the calcium channel blocker effects on early lesion progression. For example, recent studies in cell culture model systems suggest that calcium channel blockers may significantly alter activities that regulate lipoprotein-derived cholesterol accumulation by cells. Some of these activities are independent of calcium flux across voltage-operated calcium channels. Thus, calcium channel blockers may reduce the progression of atherogenic lesions by a combination of decreasing calcium accumulation within arterial wall cells and by altering calcium-independent metabolic activities.

  5. Zebrafish phenotypic screen identifies novel Notch antagonists.

    Science.gov (United States)

    Velaithan, Vithya; Okuda, Kazuhide Shaun; Ng, Mei Fong; Samat, Norazwana; Leong, Sze Wei; Faudzi, Siti Munirah Mohd; Abas, Faridah; Shaari, Khozirah; Cheong, Sok Ching; Tan, Pei Jean; Patel, Vyomesh

    2017-04-01

    Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27(KIP1). Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

  6. Antioxidant effects of calcium antagonists in rat brain homogenates.

    Science.gov (United States)

    Yao, K; Ina, Y; Nagashima, K; Ohmori, K; Ohno, T

    2000-06-01

    We studied the antioxidant activities of calcium antagonists against autoxidation in rat brain homogenates. The homogenates were incubated for 30 min at 37 degrees C with or without a calcium antagonist and subsequently assayed for lipid peroxide content. Percent inhibition of the lipid peroxidation was used as an index of the antioxidant effect. Dihydropyridine calcium antagonists exhibited concentration-dependent (3-300 micromol/l) inhibitory effects against lipid peroxidation. The relative order of antioxidant potency and associated IC50 values (micromol/l) of the calcium antagonists for inhibition of the lipid peroxidation were as follows: nifedipine (51.5)>barnidipine (58.6)>benidipine (71.2)>nicardipine (129.3)>amlodipine (135.5)>nilvadipine (167.3)>nitrendipine (252.1)> diltiazem (>300)=verapamil (>300). These results suggest that some dihydropyridine calcium antagonists show antioxidant properties. The antioxidant effects of the calcium antagonists may contribute to their pharmacological actions.

  7. BIOLOGICAL CONTRAOL OF PHYTOPATHOGENS USING ANTAGONIST TRICHODERMA VIRIDE

    OpenAIRE

    D.S.R. RAJENDRA SINGH; SHAIK SAYEED; K. BRUNDA EVI; B. BHADRAIAH

    2006-01-01

    Antagonistic fungus i.e. Trichoderma viride was tested in vitro against seven phytopathogens viz., Aspergillus niger, A. fumigatus, Macrophimina phaseolina, Fusarium oxysporum, F. solani, Paecilomyces varoti and sclerotium rolfsii. Trichoderma viride exhibited the antagonistic effect against these phytopathogens. Under dual culture the hyphal growth of the phytopathogens was inhibited at the zone of contact with the hyphae of the antagonist. Microscopic examination revealed that hyphal tips o...

  8. Mutually-antagonistic interactions in baseball networks

    Science.gov (United States)

    Saavedra, Serguei; Powers, Scott; McCotter, Trent; Porter, Mason A.; Mucha, Peter J.

    2010-03-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit structural changes over time. We find interesting structure in the networks and examine their sensitivity to baseball’s rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to (1) compare the performance of players who competed under different conditions and (2) include information about which particular players a given player has faced. We find that a player’s position in the network does not correlate with his placement in the random walker ranking. However, network position does have a substantial effect on the robustness of ranking placement to changes in head-to-head matchups.

  9. Antagonists of IAP proteins as cancer therapeutics.

    Science.gov (United States)

    Dynek, Jasmin N; Vucic, Domagoj

    2013-05-28

    Inhibitor of apoptosis (IAP) proteins play pivotal roles in cellular survival by blocking apoptosis, modulating signal transduction, and affecting cellular proliferation. Through their interactions with inducers and effectors of apoptosis IAP proteins can effectively suppress apoptosis triggered by diverse stimuli including death receptor signaling, irradiation, chemotherapeutic agents, or growth factor withdrawal. Evasion of apoptosis, in part due to the action of IAP proteins, enhances resistance of cancer cells to treatment with chemotherapeutic agents and contributes to tumor progression. Additionally, IAP genes are known to be subject to amplification, mutation, and chromosomal translocation in human malignancies and autoimmune diseases. In this review we will discuss the role of IAP proteins in cancer and the development of antagonists targeting IAP proteins for cancer treatment.

  10. The Attractiveness of Opposites: Agonists and Antagonists.

    LENUS (Irish Health Repository)

    O'Brien, Tony

    2015-02-02

    ABSTRACT Opioid-induced bowel dysfunction, of which constipation is the most common aspect, is a major limiting factor in the use of opioids for pain management. The availability of an oral, long-acting formulation of oxycodone and naloxone represents a highly significant development in pain management. The combination of an opioid analgesic with an opioid antagonist offers reliable pain control with a significant reduction in the burden of opioid-induced constipation. This report is adapted from paineurope 2014; Issue 3, ©Haymarket Medical Publications Ltd, and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, LTD and is distributed free of charge to healthcare professionals in Europe. Archival issues can be accessed via the website: http:\\/\\/www.paineurope.com at which European health professionals can register online to receive copies of the quarterly publication.

  11. Mutually-Antagonistic Interactions in Baseball Networks

    CERN Document Server

    Saavedra, Serguei; McCotter, Trent; Porter, Mason A; Mucha, Peter J

    2009-01-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit interesting structural changes over time. We also find that these networks exhibit a significant network structure that is sensitive to baseball's rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to compare the performance of players who competed under different conditions. We find that a player's position in the network does not correlate with his success in the random walker ranking but instead has a substantial effect on its sensitivity to changes in his own aggregate performance.

  12. Plot of the distribution of the four-lepton invariant mass, m4l, for the selected candidates in the data

    CERN Multimedia

    ATLAS, Collaboration

    2013-01-01

    The distribution of the four-lepton invariant mass, m4l, for the selected candidates in the data. The estimated background, as well as the expected SM Higgs boson signal for mH = 124.3 GeV (scaled by the signal strength obtained from fits to the data), are also shown. The single-resonant peak at m4l ∼ 90 GeV includes contribu- tions from s-channel Z/γ∗ and t-channel (Z∗/γ∗)(Z∗/γ∗) production.

  13. Evaluation of Component Activity in Molten MnO-SiO2-Al2O3-CaO System with Model SELF-SReM4

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    A sub-regular solution model SE LF-SReM4 used to evaluate activity of the components in a homogeneous region of a quaternary system has been developed in Shanghai Enhanced Laboratory of Ferrometallurgy. The application of SELF-SReM4 in C-Mn-Fe-Si system without the SiC formation has been introduced in previous paper. It′s application for molten slag of MnO-SiO2-Al2O3-CaO was introduced in this paper. They provide a basis for the prediction of the metal-slag equilibrium conditions.

  14. Length and amino acid sequence of peptides substituted for the 5-HT3A receptor M3M4 loop may affect channel expression and desensitization.

    Directory of Open Access Journals (Sweden)

    Nicole K McKinnon

    Full Text Available 5-HT3A receptors are pentameric neurotransmitter-gated ion channels in the Cys-loop receptor family. Each subunit contains an extracellular domain, four transmembrane segments (M1, M2, M3, M4 and a 115 residue intracellular loop between M3 and M4. In contrast, the M3M4 loop in prokaryotic homologues is <15 residues. To investigate the limits of M3M4 loop length and composition on channel function we replaced the 5-HT3A M3M4 loop with two to seven alanine residues (5-HT3A-A(n = 2-7. Mutants were expressed in Xenopus laevis oocytes and characterized using two electrode voltage clamp recording. All mutants were functional. The 5-HT EC(50's were at most 5-fold greater than wild-type (WT. The desensitization rate differed significantly among the mutants. Desensitization rates for 5-HT3A-A(2, 5-HT3A-A(4, 5-HT3A-A(6, and 5-HT3A-A(7 were similar to WT. In contrast, 5-HT3A-A(3 and 5-HT3A-A(5 had desensitization rates at least an order of magnitude faster than WT. The one Ala loop construct, 5-HT3A-A(1, entered a non-functional state from which it did not recover after the first 5-HT application. These results suggest that the large M3M4 loop of eukaryotic Cys-loop channels is not required for receptor assembly or function. However, loop length and amino acid composition can effect channel expression and desensitization. We infer that the cytoplasmic ends of the M3 and M4 segments may undergo conformational changes during channel gating and desensitization and/or the loop may influence the position and mobility of these segments as they undergo gating-induced conformational changes. Altering structure or conformational mobility of the cytoplasmic ends of M3 and M4 may be the basis by which phosphorylation or protein binding to the cytoplasmic loop alters channel function.

  15. Antagonistic activity of marine sponges associated Actinobacteria

    Institute of Scientific and Technical Information of China (English)

    Selvakumar Dharmaraj; Dhevendaran Kandasamy

    2016-01-01

    Objective: To focus on the isolation and preliminary characterization of marine sponges associated Actinobacteria particularly Streptomyces species and also their antagonistic activities against bacterial and fungal pathogens. Methods: The sponges were collected from Kovalam and Vizhinjam port of south-west coast of Kerala, India. Isolation of strains was carried out from sponge extracts using international Streptomyces project media. For preliminary identification of the strains, morphological (mycelial colouration, soluble pigments, melanoid pigmentation, spore morphology), nutritional uptake (carbon utilisation, amonoacids influence, sodium chloride tolerance), physiological (pH, temperature) and chemotaxonomical characterization were done. Antimicrobial studies were also carried out for the selected strains. Results: With the help of the spicule structures, the collected marine sponges were identified as Callyspongia diffusa, Mycale mytilorum, Tedania anhelans and Dysidea fragilis. Nearly 94 strains were primarily isolated from these sponges and further they were sub-cultured using international Streptomyces project media. The strains exhibited different mycelial colouration (aerial and substrate), soluble and melanoid pigmentations. The strains possessed three types of sporophore morphology namely rectus flexibilis, spiral and retinaculiaperti. Among the 94 isolates, seven exhibited antibacterial and antifungal activities with maximal zone of inhibition of 30 mm. The nutritional, physiological and chemotaxonomical characteristic study helped in the conventional identification of the seven strains and they all suggest that the strains to be grouped under the genus Streptomyces. Conclusions: The present study clearly helps in the preliminary identification of the isolates associated with marine sponges. Antagonistic activities prove the production of antimicrobial metabolites against the pathogens. Marine sponges associated Streptomyces are universally well

  16. Antagonistic activity of marine sponges associated Actinobacteria

    Directory of Open Access Journals (Sweden)

    Selvakumar Dharmaraj

    2016-06-01

    Full Text Available Objective: To focus on the isolation and preliminary characterization of marine sponges associated Actinobacteria particularly Streptomyces species and also their antagonistic activities against bacterial and fungal pathogens. Methods: The sponges were collected from Kovalam and Vizhinjam port of south-west coast of Kerala, India. Isolation of strains was carried out from sponge extracts using international Streptomyces project media. For preliminary identification of the strains, morphological (mycelial colouration, soluble pigments, melanoid pigmentation, spore morphology, nutritional uptake (carbon utilisation, amonoacids influence, sodium chloride tolerance, physiological (pH, temperature and chemotaxonomical characterization were done. Antimicrobial studies were also carried out for the selected strains. Results: With the help of the spicule structures, the collected marine sponges were identified as Callyspongia diffusa, Mycale mytilorum, Tedania anhelans and Dysidea fragilis. Nearly 94 strains were primarily isolated from these sponges and further they were sub-cultured using international Streptomyces project media. The strains exhibited different mycelial colouration (aerial and substrate, soluble and melanoid pigmentations. The strains possessed three types of sporophore morphology namely rectus flexibilis, spiral and retinaculiaperti. Among the 94 isolates, seven exhibited antibacterial and antifungal activities with maximal zone of inhibition of 30 mm. The nutritional, physiological and chemotaxonomical characteristic study helped in the conventional identification of the seven strains and they all suggest that the strains to be grouped under the genus Streptomyces. Conclusions: The present study clearly helps in the preliminary identification of the isolates associated with marine sponges. Antagonistic activities prove the production of antimicrobial metabolites against the pathogens. Marine sponges associated Streptomyces are

  17. Optimisation of GnRH antagonist use in ART

    NARCIS (Netherlands)

    Hamdine, O.

    2014-01-01

    This thesis focuses on the optimisation of controlled ovarian stimulation for IVF using exogenous FSH and GnRH antagonist co-treatment, by studying the timing of the initiation of GnRH antagonist co-medication and the role of ovarian reserve markers in optimising ovarian response and reproductive ou

  18. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    Science.gov (United States)

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  19. PARTIAL AGONISTS, FULL AGONISTS, ANTAGONISTS - DILEMMAS OF DEFINITION

    NARCIS (Netherlands)

    HOYER, D; BODDEKE, HWGM

    1993-01-01

    The absence of selective antagonists makes receptor characterization difficult, and largely dependent on the use of agonists. However, there has been considerable debate as to whether certain drugs acting at G protein-coupled receptors are better described as agonists, partial agonists or antagonist

  20. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology

    NARCIS (Netherlands)

    Al-Inany, Hesham G.; Youssef, Mohamed A.; Ayeleke, Reuben Olugbenga; Brown, Julie; Lam, Wai Sun; Broekmans, Frank J.

    2016-01-01

    Background: Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-oestrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists direct

  1. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    Science.gov (United States)

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  2. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology

    NARCIS (Netherlands)

    Al-Inany, Hesham G.; Youssef, Mohamed A.; Ayeleke, Reuben Olugbenga; Brown, Julie; Lam, Wai Sun; Broekmans, Frank J.

    2016-01-01

    Background: Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-oestrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists

  3. Early gonadotropin-releasing hormone antagonist start improves follicular synchronization and pregnancy outcome as compared to the conventional antagonist protocol.

    Science.gov (United States)

    Park, Chan Woo; Hwang, Yu Im; Koo, Hwa Seon; Kang, Inn Soo; Yang, Kwang Moon; Song, In Ok

    2014-12-01

    To assess whether an early GnRH antagonist start leads to better follicular synchronization and an improved clinical pregnancy rate (CPR). A retrospective cohort study. A total of 218 infertile women who underwent IVF between January 2011 and February 2013. The initial cohort (Cohort I) that underwent IVF between January 2011 and March 2012 included a total of 68 attempted IVF cycles. Thirty-four cycles were treated with the conventional GnRH antagonist protocol, and 34 cycles with an early GnRH antagonist start protocol. The second cohort (Cohort II) that underwent IVF between June 2012 and February 2013 included a total of 150 embryo-transfer (ET) cycles. Forty-three cycles were treated with the conventional GnRH antagonist protocol, 34 cycles with the modified early GnRH antagonist start protocol using highly purified human menopause gonadotropin and an addition of GnRH agonist to the luteal phase support, and 73 cycles with the GnRH agonist long protocol. The analysis of Cohort I showed that the number of mature oocytes retrieved was significantly higher in the early GnRH antagonist start cycles than in the conventional antagonist cycles (11.9 vs. 8.2, p=0.04). The analysis of Cohort II revealed higher but non-significant CPR/ET in the modified early GnRH antagonist start cycles (41.2%) than in the conventional antagonist cycles (30.2%), which was comparable to that of the GnRH agonist long protocol cycles (39.7%). The modified early antagonist start protocol may improve the mature oocyte yield, possibly via enhanced follicular synchronization, while resulting in superior CPR as compared to the conventional antagonist protocol, which needs to be studied further in prospective randomized controlled trials.

  4. Influence of hybridization in the magnetic circular X-ray dichroism at the Ce-M(4,5) absorption edges of Ce-Fe systems

    NARCIS (Netherlands)

    Finazzi, M; deGroot, FMF; Dias, AM; Kappler, JP; Schulte, O; Felsch, W; Krill, G

    We have performed a Magnetic Circular X-ray Dichroism (XMCD) study at the Ce-M(4,5) absorption edges on some Ce-Fe systems. We find that the dichroism signal in these systems is very sensitive to the degree of hybridization of the 4f electrons with the valence band. XMCD is able to demonstrate that

  5. Influence of hybridization in the magnetic circular X-ray dichroism at the Ce-M(4,5) absorption edges of Ce-Fe systems

    NARCIS (Netherlands)

    Finazzi, M; deGroot, FMF; Dias, AM; Kappler, JP; Schulte, O; Felsch, W; Krill, G

    1996-01-01

    We have performed a Magnetic Circular X-ray Dichroism (XMCD) study at the Ce-M(4,5) absorption edges on some Ce-Fe systems. We find that the dichroism signal in these systems is very sensitive to the degree of hybridization of the 4f electrons with the valence band. XMCD is able to demonstrate that

  6. Stable expression of human muscle-specific kinase in HEp-2 M4 cells for automatic immunofluorescence diagnostics of myasthenia gravis.

    Science.gov (United States)

    George, Sandra; Paulick, Silvia; Knütter, Ilka; Röber, Nadja; Hiemann, Rico; Roggenbuck, Dirk; Conrad, Karsten; Küpper, Jan-Heiner

    2014-01-01

    Muscle-specific kinase (MuSK) belongs to the nicotinic acetylcholine receptor complex which is targeted by pathogenic autoantibodies causing Myasthenia gravis. While up to 95% of patients with generalized Myasthenia gravis were shown to be positive for acetylcholine receptor-specific autoantibodies, up to 70% of the remaining patients develop autoantibodies against MuSK. Discrimination of the autoantibody specificity is important for therapy of Myasthenia gravis. Recently, the new automatic fluorescence assessment platform AKLIDES has been developed for immunofluorescence-based diagnostics of autoimmune diseases. In order to establish an AKLIDES procedure for the detection of MuSK-specific autoantibodies (anti-MuSK), we developed a recombinant HEp-2 cell clone expressing the human MuSK cDNA. Here we show at the mRNA and protein level that the cell clone HEp-2 M4 stably expresses human MuSK. We provide evidence for a localization of MuSK at the cell membrane. Using cell clone HEp-2 M4 on the AKLIDES system, we investigated 34 patient sera that were previously tested anti-MuSK positive by radioimmunoassay as positive controls. As negative controls, we tested 29 acetylcholine receptor-positive but MuSK-negative patient sera, 30 amytrophic lateral sclerosis (ALS) patient sera and 45 blood donors. HEp-2 M4 cells revealed a high specificity for the detection of MuSK autoantibodies from 25 patient sera assessed by a specific pattern on HEp-2 M4 cells. By using appropriate cell culture additives, the fraction of cells stained positive with anti-MuSK containing sera can be increased from 2-16% to 10-48%, depending on the serum. In conclusion, we provide data showing that the novel recombinant cell line HEp-2 M4 can be used to screen for anti-MuSK with the automatic AKLIDES system.

  7. HIGH AFFINITY ACYLATING ANTAGONISTS FOR MUSCARINIC RECEPTORS

    Science.gov (United States)

    Baumgold, Jesse; Karton, Yishai; Malka, Naftali; Jacobson, Kenneth A.

    2012-01-01

    Summary The muscarinic antagonists pirenzepine and telenzepine were derivitized as alkylamino derivatives at a site on the molecules corresponding to a region of bulk tolerance in receptor binding. The distal primary amino groups were coupled to the cross-linking reagent meta-phenylene diisothiocyanate, resulting in two isothiocyanate derivatives that were found to inhibit muscarinic receptors irreversibly and in a dose-dependent fashion. Preincubation of rat forebrain membranes with an isothiocyanate derivative followed by radioligand binding using [3H]N-methylscopolamine diminished the Bmax value, but did not affect the Kd value. The receptor binding site was not restored upon repeated washing, indicating that irreversible inhibition had occurred. IC50 values for the irreversible inhibition at rat forebrain muscarinic receptors were 0.15 nM and 0.19 nM, for derivatives of pirenzepine and telenzepine, respectively. The isothiocyanate derivative of pirenzepine was non-selective as an irreversible muscarinic inhibitor, and the corresponding derivative prepared from telenzepine was 5-fold selective for forebrain (mainly m1) vs. heart (m2) muscarinic receptors. PMID:1625525

  8. Noradrenergic antagonists mitigate amphetamine-induced recovery.

    Science.gov (United States)

    Hylin, M J; Brenneman, M M; Corwin, J V

    2017-09-15

    Brain injury, including that due to stroke, leaves individuals with cognitive deficits that can disrupt daily aspect of living. As of now there are few treatments that shown limited amounts of success in improving functional outcome. The use of stimulants such as amphetamine have shown some success in improving outcome following brain injury. While the pharmacological mechanisms for amphetamine are known; the specific processes responsible for improving behavioral outcome following injury remain unknown. Understanding these mechanisms can help to refine the use of amphetamine as a potential treatment or lead to the use of other methods that share the same pharmacological properties. One proposed mechanism is amphetamine's impact upon noradrenaline (NA). In the current, study noradrenergic antagonists were administered prior to amphetamine to pharmacologically block α- and β-adrenergic receptors. The results demonstrated that the blockade of these receptors disrupted amphetamines ability to induce recovery from hemispatial neglect using an established aspiration lesion model. This suggests that amphetamine's ability to ameliorate neglect deficits may be due in part to noradrenaline. These results further support the role of noradrenaline in functional recovery. Finally, the development of polytherapies and combined therapeutics, while promising, may need to consider the possibility that drug interactions can negate the effectiveness of treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Nalmefene: radioimmunoassay for a new opioid antagonist.

    Science.gov (United States)

    Dixon, R; Hsiao, J; Taaffe, W; Hahn, E; Tuttle, R

    1984-11-01

    A specific radioimmunoassay (RIA) has been developed for the quantitation of a new opioid antagonist, nalmefene, in human plasma. The method employs a rabbit antiserum to an albumin conjugate of naltrexone-6-(O-carboxymethyl)oxime and [3H]naltrexone as the radioligand. Assay specificity was achieved by extraction of nalmefene from plasma at pH 9 into ether prior to RIA. The procedure has a limit of sensitivity of 0.2 ng/mL of nalmefene using a 0.5-mL sample of plasma for analysis. The intra- and interassay coefficients of variation did not exceed 5.6 and 11%, respectively. The specificity of the RIA was established by demonstrating excellent agreement (r = 0.99) with a less sensitive and more time consuming HPLC procedure in the analysis of clinical plasma samples. The use of the RIA for the pharmacokinetic evaluation of nalmefene is illustrated with plasma concentration profiles of the drug in humans following intravenous and oral administration.

  10. Antagonistic Neural Networks Underlying Differentiated Leadership Roles

    Directory of Open Access Journals (Sweden)

    Richard Eleftherios Boyatzis

    2014-03-01

    Full Text Available The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950’s. Recent research in neuroscience suggests that the division between task oriented and socio-emotional oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks -- the Task Positive Network (TPN and the Default Mode Network (DMN. Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success.

  11. Fine Tuning of a Type 1 Interferon Antagonist.

    Directory of Open Access Journals (Sweden)

    Victoria Urin

    Full Text Available Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and enhanced binding to IFNAR2. Here, we further tune the IFN-1ant by producing three additional antagonists based on IFN-1ant but with altered activity profiles. We show that in all three cases the antiproliferative activity of interferons is blocked and the induction of gene transcription of immunomudolatory and antiproliferative associated genes are substantially decreased. Conversely, each of the new antagonists elicits a different degree of antiviral response, STAT phosphorylation and related gene induction. Two of the new antagonists promote decreased activity in relation to the original IFN-1ant, while one of them promotes increased activity. As we do not know the exact causes of the detrimental effects of IFNs, the four antagonists that were produced and analyzed provide the opportunity to investigate the extent of antagonistic and agonistic activity optimal for a given condition.

  12. Development of a radioligand, [(3)H]LY2119620, to probe the human M(2) and M(4) muscarinic receptor allosteric binding sites.

    Science.gov (United States)

    Schober, Douglas A; Croy, Carrie H; Xiao, Hongling; Christopoulos, Arthur; Felder, Christian C

    2014-07-01

    In this study, we characterized a muscarinic acetylcholine receptor (mAChR) potentiator, LY2119620 (3-amino-5-chloro-N-cyclopropyl-4-methyl-6-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]thieno[2,3-b]pyridine-2-carboxamide) as a novel probe of the human M2 and M4 allosteric binding sites. Since the discovery of allosteric binding sites on G protein-coupled receptors, compounds targeting these novel sites have been starting to emerge. For example, LY2033298 (3-amino-5-chloro-6-methoxy-4-methyl-thieno(2,3-b)pyridine-2-carboxylic acid cyclopropylamid) and a derivative of this chemical scaffold, VU152100 (3-amino-N-(4-methoxybenzyl)-4,6-dim​ethylthieno[2,3-b]pyridine carboxamide), bind to the human M4 mAChR allosteric pocket. In the current study, we characterized LY2119620, a compound similar in structure to LY2033298 and binds to the same allosteric site on the human M4 mAChRs. However, LY2119620 also binds to an allosteric site on the human M2 subtype. [(3)H]NMS ([(3)H]N-methylscopolamine) binding experiments confirm that LY2119620 does not compete for the orthosteric binding pocket at any of the five muscarinic receptor subtypes. Dissociation kinetic studies using [(3)H]NMS further support that LY2119620 binds allosterically to the M2 and M4 mAChRs and was positively cooperative with muscarinic orthosteric agonists. To probe directly the allosteric sites on M2 and M4, we radiolabeled LY2119620. Cooperativity binding of [(3)H]LY2119620 with mAChR orthosteric agonists detects significant changes in Bmax values with little change in Kd, suggesting a G protein-dependent process. Furthermore, [(3)H]LY2119620 was displaced by compounds of similar chemical structure but not by previously described mAChR allosteric compounds such as gallamine or WIN 62,577 (17-β-hydroxy-17-α-ethynyl-δ-4-androstano[3,2-b]pyrimido[1,2-a]benzimidazole). Our results therefore demonstrate the development of a radioligand, [(3)H]LY2119620 to probe specifically the human M2 and M4 muscarinic

  13. Identification of a novel conformationally constrained glucagon receptor antagonist.

    Science.gov (United States)

    Lee, Esther C Y; Tu, Meihua; Stevens, Benjamin D; Bian, Jianwei; Aspnes, Gary; Perreault, Christian; Sammons, Matthew F; Wright, Stephen W; Litchfield, John; Kalgutkar, Amit S; Sharma, Raman; Didiuk, Mary T; Ebner, David C; Filipski, Kevin J; Brown, Janice; Atkinson, Karen; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel

    2014-02-01

    Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.

  14. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Mohammad eKhanfar

    2016-05-01

    Full Text Available With the very recent market approval of pitolisant (Wakix®, the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  15. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists.

    Science.gov (United States)

    Khanfar, Mohammad A; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  16. Intractable pneumococcal meningoencephalitis associated with a TNF-α antagonist.

    Science.gov (United States)

    Kang, Seok-Jae; Kim, Hyun Young; Kim, Young Seo; Lee, Ha Neul; Kim, Hee Tae; Kim, Seung H

    2014-09-15

    A 34-year-old man was treated with a TNF-α antagonist for ankylosing spondylitis, and this subsequently developed a CNS infection. Magnetic resonance imaging showed diffuse subcortical white matter lesions. Streptococcus pneumoniae was cultured from the cerebrospinal fluid and blood. The patient died of multifocal widespread brain damage and subarachnoid hemorrhage, despite intensive antibacterial medication. Pneumococcal meningoencephalitis can occur in association with TNF-α antagonists. Clinicians should be aware of both the risk of fatal bacterial meningoencephalitis associated with TNF-α antagonists and the possibility of an unusual presentation of bacterial meningitis. Copyright © 2014. Published by Elsevier B.V.

  17. New potential uroselective NO-donor alpha1-antagonists.

    Science.gov (United States)

    Boschi, Donatella; Tron, Gian Cesare; Di Stilo, Antonella; Fruttero, Roberta; Gasco, Alberto; Poggesi, Elena; Motta, Gianni; Leonardi, Amedeo

    2003-08-14

    A recent uroselective alpha(1)-adrenoceptor antagonist, REC15/2739, has been joined with nitrooxy and furoxan NO-donor moieties to give new NO-donor alpha(1)-antagonists. All the compounds studied proved to be potent and selective ligands of human cloned alpha(1a)-receptor subtype. Derivatives 6 and 7 were able to relax the prostatic portion of rat vas deferens contracted by (-)-noradrenaline because of both their alpha(1A)-antagonist and their NO-donor properties.

  18. The AMPA antagonist, NBQX, protects against ischemia-induced loss of cerebellar Purkinje cells

    DEFF Research Database (Denmark)

    Balchen, T.; Diemer, Nils Henrik

    1992-01-01

    Neuropathology, NBQX, AMPA antagonist, cerebellar cells, ischemia, rats, Purkinje, neuronal death......Neuropathology, NBQX, AMPA antagonist, cerebellar cells, ischemia, rats, Purkinje, neuronal death...

  19. Search Strategy for the Standard Model Higgs Boson in the $H \\to ZZ^{(*)} \\to 4\\mu$ Decay Channel using $M(4\\mu)$-Dependent Cuts

    CERN Document Server

    Abdullin, Salavat; Bartalini, Paolo; Cavanaugh, Richard; Drozdetsky, A AN; Korytov, Andrey; Mitselmakher, Guenakh; Pakhotin, Yuriy; Scurlock, Bobby; Sherstnev, Alexander

    2007-01-01

    We present a strategy for a Higgs-boson search in its four-muon decay channel Hmu. The method is based on using optimized, smooth M(4mu)-dependent cuts that automatically ensure an optimal signal-to-background ratio for any mass at which the Higgs boson might appear. The Higgs boson then manifests itself as a 4mu resonance-like peak over the continuum M(mu) distribution and can be searched for using various statistical techniques. The most important theoretical and instrumental systematic errors as well as the fact that the search is conducted in a broad range of M(4mu) invariant masses (110-600 GeV/c^2) are taken into account.

  20. On the distance of the globular cluster M4 (NGC 6121) using RR Lyrae stars: II. Mid-infrared period-luminosity relations

    CERN Document Server

    Neeley, J R; Bono, G; Braga, V F; Dall'Ora, M; Stetson, P B; Ferraro, I; Freedman, W L; Iannicola, G; Madore, B F; Matsunaga, N; Monson, A; Persson, S E; Scowcroft, V; Seibert, M

    2015-01-01

    New mid-infrared period-luminosity (PL) relations are presented for \\rrl{} variables in the globular cluster M4 (NGC 6121). Accurate photometry was obtained for 37 \\rrl{} variables using observations from the Infrared Array Camera onboard the Spitzer Space Telescope. The dispersion of M4's PL relations is 0.056, and the uncertainty in the slope is 0.11 mag. Additionally, weestablished calibrated PL relations at 3.6 and 4.5~\\micron{} using published Hubble Space Telescopegeometric parallaxes of five Galactic \\rrl{} stars. The resulting band-averaged distance modulus for M4 is $ \\mu = 11.399 \\pm 0.007 \\textrm{(stat)} \\pm 0.080 \\textrm{(syst)} \\pm 0.015 \\textrm{(cal)} \\pm 0.020 \\textrm{(ext)}$. The systematic uncertainty will be greatly reduced when parallaxes of more stars become available from the GAIA mission. Optical and infrared period-color (PC) relations are also presented, and the lack of a MIR PC relation suggests that \\rrl{} stars are not affected by CO absorptionin the 4.5~\\micron{} band.

  1. The pharmacological properties of lipophilic calcium antagonists.

    Science.gov (United States)

    van Zwieten, P A

    1998-01-01

    Several types of calcium antagonists (CA) (verapamil, diltiazem, nifedipine and related drugs) may be used as antihypertensives. In practice, the dihydropyridines (nifedipine and related drugs) are the CA used most frequently as antihypertensives. Apart from the lowering of blood pressure CA may lead to other, theoretically beneficial, effects: regression of left ventricular and vascular hypertrophy, renal protection, weak natriuretic, weak antiplatelet, anti-ischaemic and antiatherogenic activity. Several new dihydropyridine CA have been introduced in recent years. The advantages of the newer compounds, such as amlodipine, felodipine, isradipine, lacidipine and lercanidipine, may include: vasoselectivity, hence little or no cardiodepressant activity; an improved kinetic profile, resulting in a slow onset and long duration of action, fewer side-effects such as reflex tachycardia and headache, owing to the slow onset of the antihypertensive action. For a few newer CA a predominant effect on specialized circulatory beds (renal, coronary and cerebral) has been claimed. The new CA, which are clearly lipophilic, deserve special attention. Owing to the lipophilic character of such compounds considerable concentration occurs in lipid-containing membrane depots. The CA thus concentrated are slowly released from these depots and, subsequently, reach their targets, the L-type calcium channels. This phenomenon explains both the slow onset and the long duration of action of these CA. Owing to the slow onset of action reflex tachycardia is virtually absent. The long duration of action allows satisfactory control of blood pressure in hypertensives by means of a single daily dose. A few lipophilic dihydropyridine CA are vasoselective. This property implies that at therapeutic, vasodilatory dosages no cardiodepressant activity occurs. Lercanidipine is a recently introduced example of a lipophilic and vasoselective dihydropyridine CA. It is an effective vasodilator

  2. Secondary prevention with calcium antagonists after acute myocardial infarction

    DEFF Research Database (Denmark)

    Hansen, J F

    1992-01-01

    Experimental studies have demonstrated that the 3 calcium antagonists nifedipine, diltiazem, and verapamil have a comparable effect in the prevention of myocardial damage during ischaemia. Secondary prevention trials after acute myocardial infarction, which aimed at improving survival...

  3. Structure-based drug design identifies novel LPA3 antagonists.

    Science.gov (United States)

    Fells, James I; Tsukahara, Ryoko; Liu, Jianxiong; Tigyi, Gabor; Parrill, Abby L

    2009-11-01

    Compound 5 ([5-(3-nitrophenoxy)-1,3-dioxo-1,3-dihydro-2-isoindol-2-yl]acetic acid) was identified as a weak selective LPA(3) antagonist (IC(50)=4504 nM) in a virtual screening effort to optimize a dual LPA(2 and 3) antagonist. Structure-based drug design techniques were used to prioritize similarity search matches of compound 5. This strategy rapidly identified 10 novel antagonists. The two most efficacious compounds identified inhibit activation of the LPA(3) receptor by 200 nM LPA with IC(50) values of 752 nM and 2992 nM. These compounds additionally define changes to our previously reported pharmacophore that will improve its ability to identify more potent and selective LPA(3) receptor antagonists. The results of the combined computational and experimental screening are reported.

  4. A SELECTIVE ANTAGONIST OF MINERALOCORTICOID RECEPTOR EPLERENONE IN CARDIOLOGY PRACTICE

    Directory of Open Access Journals (Sweden)

    B. B. Gegenava

    2015-09-01

    Full Text Available The role of aldosterone in pathophysiological processes is considered. The effects of the selective antagonist of mineralocorticoid receptor eplerenone are analyzed. The advantages of eplerenone compared with spironolactone are discussed.

  5. Perampanel: A Selective AMPA Antagonist for Treating Seizures

    OpenAIRE

    Krauss, Gregory L.

    2013-01-01

    Perampanel is a selective, noncompetitive AMPA receptor antagonist that has recently been approved for treating localization-related epilepsy. This article reviews the pharmacology, clinical development, efficacy, and safety/tolerability of perampanel.

  6. Complications of TNF-α antagonists and iron homeostasis

    Science.gov (United States)

    TNF-α is a central regulator of inflammation and its blockade downregulates other proinflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficia...

  7. DFT evaluation of the electronic structures and spectroscopic properties of the self-assembled [Pt_2M_4(C=CH)_8](M=Cu,Ag) clusters

    Institute of Scientific and Technical Information of China (English)

    BAI FuQuan; XIA BaoHui; ZHANG HongXing; YANG BaoZhu; WANG Jian; SUN Lei

    2009-01-01

    Electronic structures and spectroscopic properties of self-assembled[Pt_2M_4(C≡CH)_8](M=Cu,Ag) clusters have been studied by the TD-DFT (time-dependent density functional theory) calculations with the polarizable continuum model (PCM).The ground-and excited-state structures were optimized by the DFT (density functional theory) methods.The calculated structures and spectroscopic properties are in agreement with the corresponding experimental results.The[Pt_2M_4(C≡CH)_8]clusters have two stable ground state geometries (D_4 and D_(4h) symmetry).The calculated Pt-M distances suggest only very weak interactions.The Cu-Cu distances are larger than the van der Waals radii of two Cu atoms and the Ag-Ag distances are analogous with the sum of van der Waals radii of two Ag atoms.Upon excitation,the interaction of Pt…M,Ag…Ag is strengthened,while the Cu…Cu distances are shortened but they are still larger than the sum of van der Waals radii of two Cu atoms.The lowest-energy absorptions are at 450,365 and 375 nm and the emissions are at 611,431 and 435 nm for[Pt_2M_4(C≡CH)_8],[Pt_2M_4(C≡CH)_8](A) and (B),respectively.The transitions are all perturbed by the Cu or Ag composition through the UV-Vis spectra region;therefore,there are not pure ILCT or M_(pt)LCT characteristics (ILCT:intraligand charge transfer;MLCT:metal-to-ligand charge transfer) in absorptions of heteropolynuclear [Pt_2M_4(C≡CH)_8]clusters.Since the emissions and the lowest-absorptions have different transition characteristics for each complex,the emissions should not come from the lowest-energy absorptions.Because the M…M interactions in the excited state of[Pt_2Ag_4(C≡CH)_8]are augmented,the emissions of [Pt_2Ag_4(C≡CH)_8]clusters bear prominent ILCT character,which is the reason why the emission wavelengths of[Pt_2Ag_4(C≡CH)_8]have a small hypsochromic shift relative to the emission wavelength of homoleptic[Pt(C≡CH)_4]~(2-)precursor.

  8. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    OpenAIRE

    Mohammad eKhanfar; Anna eAffini; Kiril eLutsenko; Katarina eNikolic; Stefania eButini; Holger eStark

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex...

  9. Deficiency of interleukin-1 receptor antagonist responsive to anakinra.

    Science.gov (United States)

    Schnellbacher, Charlotte; Ciocca, Giovanna; Menendez, Roxanna; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Duarte, Ana M; Rivas-Chacon, Rafael

    2013-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acute-phase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy.

  10. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor...... antagonists as adjuvant single drugs to reduce trauma-, blood transfusion- and sepsis-induced immunosuppression has led to research in combined treatment regimens in major surgery, particularly, of patients operated on for malignant diseases....

  11. Structure-activity relationships of benzothiazole GPR35 antagonists.

    Science.gov (United States)

    Abdalhameed, Manahil M; Zhao, Pingwei; Hurst, Dow P; Reggio, Patricia H; Abood, Mary E; Croatt, Mitchell P

    2017-02-01

    The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound.

  12. Interleukin-2 receptor antagonists as induction therapy after heart transplantation

    DEFF Research Database (Denmark)

    Møller, Christian H; Gustafsson, Finn; Gluud, Christian;

    2008-01-01

    About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras.......About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras....

  13. Antiatherogenic properties of calcium antagonists. State of the art.

    Science.gov (United States)

    Weinstein, D B; Heider, J G

    1989-04-17

    Atherosclerosis is an arterial disease characterized by localized accumulation of collagen, elastin, lipids, and calcium at sites associated with macrophage infiltration and altered smooth muscle metabolism. Studies in several types of animal models, especially cholesterol-fed rabbits, have shown that calcium competitors, calcium chelators, anticalcifying agents, and calcium antagonists can reduce the accumulation of atherogenic lesion components and decrease the progression of lesions. Although there are some conflicting data in the animal model studies, it is now apparent that several classes of calcium antagonists inhibit the progression of early arterial lesions induced by cholesterol-feeding in animals. The dihydropyridine class of calcium antagonists may be more potent as anti-atherosclerotic agents than the other classes. Mechanisms involving regulation of endothelial cell, smooth muscle cell, and macrophage metabolism may be responsible for the effects of calcium antagonists on early lesion progression. Recent studies in cell culture-model systems suggest that calcium antagonists may significantly alter activities that regulate lipoprotein-derived cholesterol accumulation by arterial wall cells. Some of these activities are independent of calcium flux across voltage-operated calcium channels. Thus, calcium antagonists may reduce the progression of atherogenic lesions by a combination of decreasing calcium accumulation within arterial wall cells and by altering calcium channel-independent metabolic activities, which affect lesion development.

  14. Study of the photomultiplier R7600-00-M4 for the purpose of the electromagnetic calorimeter in the AMS-02 experiment

    CERN Document Server

    Kossakowski, R; Dubois, J M; Fougeron, D; Hermel-Richard; Sottile, R; Vialle, J P

    2002-01-01

    The properties of the 4-channels photomultiplier R7600-00-M4 from Hamamatsu were extensively studied for use in the AMS-02 electromagnetic calorimeter. A scan of the photocathode with a precision in position better than 0.1 mm was performed in order to measure the position dependence of the sensitivity and of the cross talk between pixels. The influence of the magnetic field applied in X, Y and Z directions was measured. The dynamic range of the photomultiplier was measured and optimized by the appropriate choice of the high voltage divider and of the value of the high voltage.

  15. Study of the photomultiplier R7600-00-M4 for the purpose of the electromagnetic calorimeter in the AMS-02 experiment

    Energy Technology Data Exchange (ETDEWEB)

    Kossakowski, Roman; Audemer, Jean Charles; Dubois, Jean Marc; Fougeron, Denis; Hermel Richard; Sottile, Rico; Vialle, Jean Pierre [Laboratoire d' Annecy-Le-Vieux de Physique des Particules, LAPP, IN2P3-CNRS, BP 110, F-74941 Annecy-Le-Vieux (France)

    2002-07-01

    The properties of the 4-channels photomultiplier R7600-00-M4 from Hamamatsu were extensively studied for use in the AMS-02 electromagnetic calorimeter. A scan of the photocathode with a precision in position better than 0.1 mm was performed in order to measure the position dependence of the sensitivity and of the cross talk between pixels. The influence of the magnetic field applied in X, Y and Z directions was measured. The dynamic range of the photomultiplier was measured and optimized by the appropriate choice of the high voltage divider and of the value of the high voltage. (authors)

  16. Crystal growth of Cd1-xZnxTe by the traveling heater method in microgravity on board of Foton-M4 spacecraft

    Science.gov (United States)

    Borisenko, E. B.; Kolesnikov, N. N.; Senchenkov, A. S.; Fiederle, M.

    2017-01-01

    Cadmium zinc telluride crystals were grown using the traveling heater method (THM) under microgravity conditions on board of Foton-M4 spacecraft, and a reference crystal was grown on Earth under gravity conditions. Structure, chemical and phase compositions of these crystals, their optical characteristics and microhardness were compared. It can be concluded that the THM growth in microgravity has a positive effect on CZT crystals, since they have more homogeneous composition and their structural perfection is improved as compared with the crystals grown under terrestrial conditions, which results in improvement of electric and optical characteristics.

  17. Binding properties of nine 4-diphenyl-acetoxy-N-methyl-piperidine (4-DAMP) analogues to M1, M2, M3 and putative M4 muscarinic receptor subtypes.

    OpenAIRE

    Waelbroeck, M.; Camus, J.; Tastenoy, M.; Christophe, J.

    1992-01-01

    1. We compared the binding properties of 4-diphenyl-acetoxy-N-methyl-piperidine methiodide (4-DAMP) and nine analogues of this compound on muscarinic receptors of human neuroblastoma NB-OK1 cells (M1 subtype), rat heart (M2 subtype), rat pancreas (M3 subtype) and to the putative M4 subtype in striatum. 2. The requirements for high affinity binding were somewhat different for the four receptor subtypes. In general, the requirements of M3 receptors were more stringent than for M1, M2 or putativ...

  18. The murine cytomegalovirus immune evasion protein m4/gp34 forms biochemically distinct complexes with class I MHC at the cell surface and in a pre-Golgi compartment.

    Science.gov (United States)

    Kavanagh, D G; Koszinowski, U H; Hill, A B

    2001-10-01

    We have recently demonstrated that the murine CMV (MCMV) gene m4 is an immune evasion gene that protects MCMV-infected targets from some virus-specific CTL clones. m4 encodes m4/gp34, a 34-kDa glycoprotein that binds to major histocompatibility complex class I in the endoplasmic reticulum and forms a detergent-stable complex that is exported to the surface of the cell. To investigate how m4/gp34 promotes CTL evasion, we analyzed the assembly and export of m4/gp34-K(b) complexes. We found that 50-70% of K(b) exported over the course of MCMV infection was m4/gp34 associated. Because these complexes are present at the cell surface, it is possible that m4 mediates CTL evasion by interfering with contact between class I and receptors on the T cell. In addition, we found that K(b) retained by the MCMV immune evasion gene m152 formed a novel type of complex with Endo H-sensitive m4/gp34; these complexes are distinguished from the exported complexes by being stable in 1% digitonin and unstable in 1% Nonidet P-40. Because this association occurs in a pre-Golgi compartment, m4/gp34 might also interfere with Ag presentation by affecting some aspect of class I assembly, such as peptide loading. Although m4/gp34 requires beta(2)-microglobulin to bind class I, there was no significant binding of m4/gp34 to beta(2)-microglobulin in the absence of class I H chain, demonstrating that m4/gp34 forms Nonidet P-40-stable complexes specifically with folded conformations of class I. We conclude that m4/gp34 promotes immune evasion by a novel mechanism involving altered assembly and/or T cell recognition of class I molecules.

  19. Optical and Near-Infrared UBVRIJHK Photometry for the RR Lyrae stars in the Nearby Globular Cluster M4 (NGC 6121)

    CERN Document Server

    Stetson, P B; Dall'Ora, M; Bono, G; Buonanno, R; Ferraro, I; Iannicola, G; Marengo, M; Neeley, J

    2014-01-01

    We present optical and near-infrared UBVRIJHK photometry of stars in the Galactic globular cluster M4 (NGC 6121) based upon a large corpus of observations obtained mainly from public astronomical archives. We concentrate on the RR Lyrae variable stars in the cluster, and make a particular effort to accurately reidentify the previously discovered variables. We have also discovered two new probable RR Lyrae variables in the M4 field: one of them by its position on the sky and its photometric properties is a probable member of the cluster, and the second is a probable background (bulge?) object. We provide accurate equatorial coordinates for all 47 stars identified as RR Lyraes, new photometric measurements for 46 of them, and new period estimates for 45. We have also derived accurate positions and mean photometry for 34 more stars previously identified as variable stars of other types, and for an additional five non-RR Lyrae variable stars identified for the first time here. We present optical and near-infrared...

  20. Relative importance of fluorescent siderophores and other factors in biological control of Gaeumannomyces graminis var. tritici by Pseudomonas fluorescens 2-79 and M4-80R.

    Science.gov (United States)

    Hamdan, H; Weller, D M; Thomashow, L S

    1991-11-01

    Pseudomonas fluorescens 2-79 suppresses take-all, a major root disease of wheat caused by Gaeumannomyces graminis var. tritici. The bacteria produce an antibiotic, phenazine-1-carboxylic acid (PCA), and a fluorescent pyoverdin siderophore. Previous studies have established that PCA has an important role in the biological control of take-all but that antibiotic production does not account fully for the suppressiveness of the strain. To define the role of the pyoverdin siderophore more precisely, mutants deficient in production of the antibiotic, the siderophore, or both factors were constructed and compared with the parental strain for control of take-all on wheat roots. In all cases, strains that produced PCA were more suppressive than those that did not, and pyoverdin-deficient mutant derivatives controlled take-all as effectively as their respective fluorescent parental strains. Thus, the phenazine antibiotic was the dominant factor in disease suppression and the fluorescent siderophore had little or no role. The siderophore also was of minor importance in a second strain, P. fluorescens M4-80R, that does not produce PCA. Strains 2-79 and M4-80R both produced substances distinct from the pyoverdin siderophore that were responsible for fungal inhibition in vitro under iron limitation, but these substances also had, at most, a minor role in disease suppression in situ.

  1. Photospheric Acne at The Bottom of the Main-Sequence: Doppler Images of M4.5 - M9V Stars

    Science.gov (United States)

    Barnes, John R.; Haswell, Carole A.; Jeffers, Sandra V.; Jones, Hugh R. A.; Pavlenko, Yakiv V.; Lohr, Marcus E.; Jenkins, James S.

    2016-07-01

    Starspots are an important manifestation of stellar activity and yet their distribution patterns on the lowest mass stars is notwell known. Time series spectra of fullyconvective M dwarfs taken in the red-optical with UVES reveal numerous line profiledistortions which are interpreted as starspots. New Doppler images of HU Del (GJ 791.2A; M4.5V), BL Ceti (GJ 65A; M5.5V)and UV Ceti (GJ 65B; M6V) attwoepochs separated by three nights are presented. We find that contrastratioscorrespondingto photosphere-spot temperature differences of only 100-400 Kare sufficient to model the time series spectra of M4.5V - M9Vstars. Starspotsare reconstructed at a range of phases and latitudes with mean spot filling factors of only a few per cent.The distribution and low-contrast of the spots/spot-groups that we recover are likely to be responsible for the low amplitudephotometric variability seen in late-M dwarfs. The stability of the spot patterns in the two sets of timeseries observationsenables us to measure the latitude dependent differential rotation, which we find to be consistent with zero.

  2. Growth Phase-Dependent Proteomes of the Malaysian Isolated Lactococcus lactis Dairy Strain M4 Using Label-Free Qualitative Shotgun Proteomics Analysis

    Directory of Open Access Journals (Sweden)

    Theresa Wan Chen Yap

    2014-01-01

    Full Text Available Lactococcus lactis is the most studied mesophilic fermentative lactic acid bacterium. It is used extensively in the food industry and plays a pivotal role as a cell factory and also as vaccine delivery platforms. The proteome of the Malaysian isolated L. lactis M4 dairy strain, obtained from the milk of locally bred cows, was studied to elucidate the physiological changes occurring between the growth phases of this bacterium. In this study, ultraperformance liquid chromatography nanoflow electrospray ionization tandem mass spectrometry (UPLC- nano-ESI-MSE approach was used for qualitative proteomic analysis. A total of 100 and 121 proteins were identified from the midexponential and early stationary growth phases, respectively, of the L. lactis strain M4. During the exponential phase, the most important reaction was the generation of sufficient energy, whereas, in the early stationary phase, the metabolic energy pathways decreased and the biosynthesis of proteins became more important. Thus, the metabolism of the cells shifted from energy production in the exponential phase to the synthesis of macromolecules in the stationary phase. The resultant proteomes are essential in providing an improved view of the cellular machinery of L. lactis during the transition of growth phases and hence provide insight into various biotechnological applications.

  3. Crystal structure determination of a neutral neurotoxin BmK M4 from Buthus martensii Karsch at 0.20 nm

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    BmK M4 is a neutral neurotoxin in the BmK toxin series.It is medially toxic and belongs to group III α-toxins.The purified sample was crystallized in rhombic space group P61.Using an X-ray diffraction technique,the crystal structure of BmK M4 was revealed by molecular replacement at 0.20 nm resolution.The model was refined.The final crystallographic R factor was 0.142 and the free R factor was 0.173.The root mean square deviation is 0.001 5 nm for the bond length and 1.753°for the bond angles.64 water molecules were added to the asymmetric unit.The refined structure showed an unusual non-prolyl cis peptide bond at residue 10.The structure was compared with group II α-toxin BmK M8 (an acidic,weak toxin).The potential structural implications of the cis peptide bond were discussed.

  4. Crystal structure determination of a neutral neurotoxin BmK M4 from Buthus martensii Karsch at 0.20 nm

    Institute of Scientific and Technical Information of China (English)

    何小林; 刘新奇; 曾宗浩; 李宏民; 王淼; 张英; 王大成

    2000-01-01

    BmK M4 is a neutral neurotoxin in the BmK toxin series. It is medially toxic and belongs to group III cc-toxins. The purified sample was crystallized in rhombic space group P6 Using an X-ray diffraction technique, the crystal structure of BmK M4 was revealed by molecular replacement at 0.20 nm resolution. The model was refined. The final crystallographic R factor was 0.142 and the free R factor was 0.173. The root mean square deviation is 0.001 5 nm for the bond length and 1.753° for the bond angles. 64 water molecules were added to the asymmetric unit. The refined structure showed an unusual non-prolyl cis peptide bond at residue 10. The structure was compared with group II a-toxin BmK M8 (an acidic, weak toxin). The potential structural implications of the cis peptide bond were discussed.

  5. HoloMonitor M4: holographic imaging cytometer for real-time kinetic label-free live-cell analysis of adherent cells

    Science.gov (United States)

    Sebesta, Mikael; Egelberg, Peter J.; Langberg, Anders; Lindskov, Jens-Henrik; Alm, Kersti; Janicke, Birgit

    2016-03-01

    Live-cell imaging enables studying dynamic cellular processes that cannot be visualized in fixed-cell assays. An increasing number of scientists in academia and the pharmaceutical industry are choosing live-cell analysis over or in addition to traditional fixed-cell assays. We have developed a time-lapse label-free imaging cytometer HoloMonitorM4. HoloMonitor M4 assists researchers to overcome inherent disadvantages of fluorescent analysis, specifically effects of chemical labels or genetic modifications which can alter cellular behavior. Additionally, label-free analysis is simple and eliminates the costs associated with staining procedures. The underlying technology principle is based on digital off-axis holography. While multiple alternatives exist for this type of analysis, we prioritized our developments to achieve the following: a) All-inclusive system - hardware and sophisticated cytometric analysis software; b) Ease of use enabling utilization of instrumentation by expert- and entrylevel researchers alike; c) Validated quantitative assay end-points tracked over time such as optical path length shift, optical volume and multiple derived imaging parameters; d) Reliable digital autofocus; e) Robust long-term operation in the incubator environment; f) High throughput and walk-away capability; and finally g) Data management suitable for single- and multi-user networks. We provide examples of HoloMonitor applications of label-free cell viability measurements and monitoring of cell cycle phase distribution.

  6. A pharmacophore model for dopamine D4 receptor antagonists

    Science.gov (United States)

    Boström, Jonas; Gundertofte, Klaus; Liljefors, Tommy

    2000-11-01

    A pharmacophore model for dopamine D4 antagonists has been developed on the basis of a previously reported dopamine D2 model. By using exhaustive conformational analyses (MM3* force field and the GB/SA hydration model) and least-squares molecular superimposition studies, a set of eighteen structurally diverse high affinity D4 antagonists have successfully been accommodated in the D4 pharmacophore model. Enantioselectivities may be rationalized by conformational energies required for the enantiomers to adopt their proposed bioactive conformations. The pharmacophore models for antagonists at the D4 and D2 receptor subtypes have been compared in order to get insight into molecular properties of importance for D2/D4 receptor selectivity. It is concluded that the bioactive conformations of antagonists at the two receptor subtypes are essentially identical. Receptor essential volumes previously identified for the D2 receptor are shown to be present also in the D4 receptor. In addition, a novel receptor essential volume in the D4 receptor, not present in the D2 receptor, has been identified. This feature may be exploited for the design of D4 selective antagonists. However, it is concluded that the major determinant for D2/D4 selectivity is the nature of the interactions between the receptor and aromatic ring systems. The effects of the electronic properties of these ring systems on the affinities for the two receptor subtypes differ substantially.

  7. The potency and efficacy of anticholinergics to inhibit haloperidol-induced catalepsy in rats correlates with their rank order of affinities for the muscarinic receptor subtypes.

    Science.gov (United States)

    Erosa-Rivero, Helena B; Bata-García, José L; Alvarez-Cervera, Fernando J; Heredia-López, Francisco J; Góngora-Alfaro, José L

    2014-06-01

    Extrapyramidal syndromes (EPS) caused by antipsychotic therapy are currently treated with anticholinergics that lack selectivity for the five muscarinic receptor subtypes. Since these receptors are heterogeneously expressed among the different classes of striatal neurons and their afferents, it can be expected that their simultaneous blockade will cause distinct, sometimes opposed, effects within the striatal circuitry. In order to test the hypothesis that the differential blockade of the muscarinic receptor subtypes would influence their potency and efficacy to prevent EPS, here we tested four anticholinergics with varying order of affinities for the muscarinic receptor subtypes, and compared their dose-response curves to inhibit haloperidol-induced catalepsy in male rats. Drugs were applied into the lateral ventricle 15 min before haloperidol (2 mg/kg, s.c.). Catalepsy was measured in the bar test at 15 min intervals during 5 h. The preferential M1/M4 antagonist pirenzepine (3, 10, 30, 100, and 300 nmol) caused a dose-dependent inhibition of catalepsy intensity: ED50 = 5.6 nmol [95% CI, 3.9-8.1], and latency: ED50 = 5.6 nmol [95% CI, 3.7-8.6]. Pirenzepine had the steepest dose-response curve, producing maximal inhibition (84 ± 5%) at the dose of 10 nmol, while its effect tended to reverse at higher doses (62 ± 11%). The purported M1/M3 antagonist 4-DAMP (30, 100, and 300 nmol) also caused a dose-dependent inhibition of catalepsy intensity: ED50 = 29.5 nmol [95% CI, 7.0 to 123.0], and latency: ED50 = 28.5 nmol [95% CI, 2.2 to 362.0]. However, the curve for 4-DAMP had a less pronounced slope, reaching its maximal effect (63 ± 14%) at the dose of 300 nmol. The M2/M4 antagonist AF-DX 116 (10, 30, and 300 nmol) only caused a partial inhibition of catalepsy (30 ± 11%) at the dose of 30 nmol, but this changed to a non-significant increment (15 ± 10%) at the dose of 100 nmol. The alleged M4 antagonist tropicamide (30, 100, 300, and

  8. Neuroprotective Effects of Glutamate Antagonists and Extracellular Acidity

    Science.gov (United States)

    Kaku, David A.; Giffard, Rona G.; Choi, Dennis W.

    1993-06-01

    Glutamate antagonists protect neurons from hypoxic injury both in vivo and in vitro, but in vitro studies have not been done under the acidic conditions typical of hypoxia-ischemia in vivo. Consistent with glutamate receptor antagonism, extracellular acidity reduced neuronal death in murine cortical cultures that were deprived of oxygen and glucose. Under these acid conditions, N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isox-azolepropionate-kainate antagonists further reduced neuronal death, such that some neurons tolerated prolonged oxygen and glucose deprivation almost as well as did astrocytes. Neuroprotection induced by this combination exceeded that induced by glutamate antagonists alone, suggesting that extracellular acidity has beneficial effects beyond the attenuation of ionotropic glutamate receptor activation.

  9. Discovery of the improved antagonistic prolactin variants by library screening.

    Science.gov (United States)

    Liu, Yun; Gong, Wei; Breinholt, Jens; Nørskov-Lauritsen, Leif; Zhang, Jinchao; Ma, Qinhong; Chen, Jianhe; Panina, Svetlana; Guo, Wei; Li, Tengkun; Zhang, Jingyuan; Kong, Meng; Liu, Zibing; Mao, Jingjing; Christensen, Leif; Hu, Sean; Wang, Lingyun

    2011-11-01

    Prolactin (PRL), a potent growth stimulator of the mammary epithelium, has been suggested to be a factor contributing to the development and progression of breast and prostate cancer. Several PRL receptor (PRLR) antagonists have been identified in the past decades, but their in vivo growth inhibitory potency was restricted by low receptor affinity, rendering them pharmacologically unattractive for clinical treatment. Thus, higher receptor affinity is essential for the development of improved PRLR antagonistic variants with improved in vivo potency. In this study, we generated Site 1 focused protein libraries of human G129R-PRL mutants and screened for those with increased affinity to the human PRLR. By combining the mutations with enhanced affinities for PRLR, we identified a novel G129R-PRL variant with mutations at Site 1 that render nearly 50-fold increase in the antagonistic potency in vitro.

  10. ANTAGONISTIC BACTERIA AGAINST SCHIZOPHYLLUM COMMUNE FR. IN PENINSULAR MALAYSIA

    Directory of Open Access Journals (Sweden)

    ANTARJO DIKIN

    2006-01-01

    Full Text Available Schizophyllum commune Fr., is one of the important fungi, causes brown germ and seed rot of oil palm. Biodiversity of antagonistic bacteria from oil palm plantations in Peninsular Malaysia is expected to support in development of biopesticide. Isolation with liquid assay and screening antagonistic bacteria using dual culture assay were carried out in the bioexploration. A total of 265 bacterial isolates from plant parts of oil palm screened 52 antagonistic bacterial isolates against 5. commune. Bacterial isolates were identified by using Biolog* Identification System i.e. Bacillus macroccanus, B. thermoglucosidasius, Burkholderia cepacia, B. gladioli, B. multivorans, B pyrrocinia, B. spinosa, Corynebacterium agropyri, C. misitidis, Enterobacter aerogenes, Microbacterium testaceum, Pseudomonas aeruginosa, P. citronellolis, Rhodococcus rhodochrous, Serratia ficaria, Serratia sp., S. marcescens, Staphylococcus sciuri, Sternotrophomonas maltophilia.

  11. First Irish birth following IVF therapy using antagonist protocol.

    LENUS (Irish Health Repository)

    Mocanu, E V

    2012-02-01

    BACKGROUND: During in vitro fertilization (IVF), the prevention of a premature LH surge was traditionally achieved using a gonadotrophin releasing hormone agonist (GnRH-a), and more recently, a GnRH antagonist. AIMS: We report a case of a 37 year old treated using the GnRH antagonist in a second completed cycle of IVF. METHODS: IVF was performed for primary infertility of 5-year duration due to frozen pelvis secondary to endometriosis. RESULTS: Following controlled ovarian hyperstimulation, oocyte recovery and fertilization, cleavage and transfer of two zygotes, a pregnancy established. A twin gestation was diagnosed at 7-weeks scan and pregnancy ended with the delivery of twin girls by emergency caesarean section. CONCLUSION: This is a first report of a delivery following IVF using the antagonist protocol in Ireland. Such therapy is patient friendly and its use should be introduced on a larger scale in clinical practice.

  12. The Apolipoprotein E Antagonistic Pleiotropy Hypothesis: Review and Recommendations

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Tuminello

    2011-01-01

    Full Text Available Research on apolipoprotein E (APOE has consistently revealed a relationship between the gene's ε4 allele and risk for development of Alzheimer's disease (AD. However, research with younger populations of ε4 carriers has suggested that the APOE ε4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area.

  13. Endothelin receptor antagonists influence cardiovascular morphology in uremic rats.

    Science.gov (United States)

    Nabokov, A V; Amann, K; Wessels, S; Münter, K; Wagner, J; Ritz, E

    1999-02-01

    In is generally held that renal failure results in blood pressure (BP)-independent structural changes of the myocardium and the vasculature. The contribution, if any, of endothelin (ET) to these changes has been unknown. We morphometrically studied random samples of the left ventricle myocardium and small intramyocardial arteries in subtotally (5/6) nephrectomized (SNx) male Sprague-Dawley rats treated with either the selective ETA receptor antagonist BMS182874 (30 mg/kg/day) or the nonselective ETA/ETB receptor antagonist Ro46-2005 (30 mg/kg/day) in comparison with either sham-operated rats, untreated SNx, or SNx rats treated with the angiotensin-converting enzyme inhibitor trandolapril (0.1 mg/kg/day). Eight weeks later, systolic BP was lower in trandolapril-treated SNx compared with untreated SNx animals. No decrease in BP was seen following either ET receptor antagonist at the dose used. A significantly increased volume density of the myocardial interstitium was found in untreated SNx rats as compared with sham-operated controls. Such interstitial expansion was prevented by trandolapril and either ET receptor antagonist. SNx caused a substantial increase in the wall thickness of small intramyocardial arteries. The increase was prevented by trandolapril or BMS182874 treatment. The arteriolar wall:lumen ratio was significantly lower in all treated groups when compared with untreated SNx. In contrast, only trandolapril, but not the ET receptor antagonists, attenuated thickening of the aortic media in SNx animals. The ETA-selective and ETA/ETB-nonselective receptor antagonists appear to prevent development of myocardial fibrosis and structural changes of small intramyocardial arteries in experimental chronic renal failure. This effect is independent of systemic BP.

  14. Development and characterization of high affinity leptins and leptin antagonists.

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-02-11

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.

  15. Development and Characterization of High Affinity Leptins and Leptin Antagonists*

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-01-01

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin. PMID:21119198

  16. Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists

    Science.gov (United States)

    2016-08-01

    swelling and pain determined, along with initial experiments on the chemokine receptor antagonist (CRA) AMD3100. Methods were established for measuring a...Presentations………………………….22 7. Inventions , Patents and Licenses……………………..………….22 8. Reportable Outcomes……………………………………………….22 9. Other Achievements...Chemokines; Chemokine receptor antagonists; Opioid analgesics; Animal models of pain; Chemokine and cytokine measurements 3. OVERALL PROJECT

  17. Interleukin-1-receptor antagonist in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan

    2007-01-01

    BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell...... proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive...

  18. Hyperglycemia of Diabetic Rats Decreased by a Glucagon Receptor Antagonist

    Science.gov (United States)

    Johnson, David G.; Ulichny Goebel, Camy; Hruby, Victor J.; Bregman, Marvin D.; Trivedi, Dev

    1982-02-01

    The glucagon analog [l-Nα-trinitrophenylhistidine, 12-homoarginine]-glucagon (THG) was examined for its ability to lower blood glucose concentrations in rats made diabetic with streptozotocin. In vitro, THG is a potent antagonist of glucagon activation of the hepatic adenylate cyclase assay system. Intravenous bolus injections of THG caused rapid decreases (20 to 35 percent) of short duration in blood glucose. Continuous infusion of low concentrations of the inhibitor led to larger sustained decreases in blood glucose (30 to 65 percent). These studies demonstrate that a glucagon receptor antagonist can substantially reduce blood glucose levels in diabetic animals without addition of exogenous insulin.

  19. Barnidipine, a long-acting slow onset calcium antagonist.

    Science.gov (United States)

    Korstanje, C

    2000-11-01

    Barnidipine is a stereochemically pure dihydropyridine calcium antagonist with a high potency. The drug showed a slow onset and long-lasting vasorelaxating effect in vitro, and strong antihypertensive activity in hypertension models. Barnidipine was shown to have a high vasoselectivity and offered protection in cardiac and renal ischaemia models. The in vitro drug:drug interaction profile suggests a low potential for clinically relevant interactions with concomitant medication. It can be anticipated that barnidipine is an attractive calcium antagonist, offering good blood pressure control without compensatory baroreflex activity.

  20. International Conference on Harmonisation; guidance on the M4 Common Technical Document--Quality: Questions and Answers/Location Issues; availability. Notice.

    Science.gov (United States)

    2004-06-09

    The Food and Drug Administration (FDA) is announcing the availability of a guidance entitled "M4: The CTD--Quality: Questions and Answers/Location Issues." The guidance was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This guidance provides further clarification for preparing the quality components of an application file in the common technical document (CTD) format. The guidance addresses the relationship between linked sections for certain parameters (such as polymorphism and particle size), and it addresses location issues (by indicating the section in which to place requested information). The guidance is intended to ease the preparation of paper and electronic submissions, facilitate regulatory reviews, and simplify the exchange of regulatory information among regulatory authorities.

  1. Behavior of the monophosphate tungsten bronzes (PO{sub 2}){sub 4}(WO{sub 3}){sub 2m} (m=4 and 6) in electrochemical lithium insertion

    Energy Technology Data Exchange (ETDEWEB)

    Longoria Rodriguez, F.E.; Martinez-de la Cruz, A.; Lopez Cuellar, E. [Division de Estudios de Posgrado, Facultad de Ingenieria Mecanica y Electrica, Universidad Autonoma de Nuevo Leon, Pedro de Alba s/n, Ciudad Universitaria, C.P. 66451, San Nicolas de los Garza, NL (Mexico)

    2006-10-06

    The electrochemical lithium insertion process has been studied in the family of monophosphate tungsten bronzes (PO{sub 2}){sub 4}(WO{sub 3}){sub 2m}, where m=4 and 6. Structural changes in the pristine oxides were followed as lithium insertion proceeded. Through potentiostatic intermittent technique, the different processes which take place in the cathode during the discharge of the cell were analysed. The nature of the bronzes Li{sub x}(PO{sub 2}){sub 4}(WO{sub 3}){sub 2m} formed was determined by in situ X-ray diffraction experiments. These results have allowed establishment of a correlation with the reversible/irreversible processes detected during the electrochemical lithium insertion. Measurements of resistivity showed that upon lithium insertion, the metallic pristine oxides become insulating. (author)

  2. DNMT3A R882 mutation is associated with elevated expression of MAFB and M4/M5 immunophenotype of acute myeloid leukemia blasts.

    Science.gov (United States)

    Yang, Li; Liu, Ya'Nan; Zhu, Li; Xiao, Min

    2015-01-01

    Researchers have recognized that aberrant methylation is an important initiating event in the pathogenesis of hematological malignancies. DNMT3A is a DNA methyltransferase that plays a vital role in de novo methylation of DNA. Somatic mutation of DNMT3A, especially at the Arg882 (R882) site of the DNMT3A coding sequence, has been identified in pre-leukemic stem cell clones as one of the driver mutations of acute myeloid leukemia (AML). Statistical analysis has indicated that patients with AML with DNMT3A mutation tend to have the M4/M5 subtype of AML according to the French-American-British classification. In this study we aimed to investigate the association between the typical immunophenotype of leukemic blasts and mutation of DNMT3A R882. In addition, we further determined the relationship between DNMT3A R882 mutation and the expression of monocytic differentiation genes, and its clinical significance.

  3. Acute and chronic effects of the M1/M4-preferring muscarinic agonist xanomeline on cocaine vs. food choice in rats.

    Science.gov (United States)

    Thomsen, Morgane; Fulton, Brian S; Caine, S Barak

    2014-02-01

    We previously showed that the M1/M4-preferring muscarinic agonist xanomeline can acutely attenuate or eliminate cocaine self-administration in mice. Medications used to treat addictions will arguably be administered in (sub)chronic or repeated regimens. Tests of acute effects often fail to predict chronic effects, highlighting the need for chronic testing of candidate medications. Rats were trained to lever press under a concurrent FR5 FR5 schedule of intravenous cocaine and food reinforcement. Once baseline behavior stabilized, the effects of 7 days once-daily injections of xanomeline were evaluated. Xanomeline pretreatment dose-dependently (1.8-10 mg/kg/day) shifted the dose-effect curve for cocaine rightward (up to 5.6-fold increase in A 50), with reallocation of behavior to the food-reinforced lever. There was no indication of tolerance, rather effects grew over days. The suppression of cocaine choice appeared surmountable at high cocaine doses, and xanomeline treatment did not significantly decrease total-session cocaine or food intake. In terms of xanomeline's potential for promoting abstinence from cocaine in humans, the findings were mixed. Xanomeline did produce reallocation of behavior from cocaine to food with a robust increase in food reinforcers earned at some cocaine/xanomeline dose combinations. However, effects appeared surmountable, and food-maintained behavior was also decreased at some xanomeline/cocaine dose combinations, suggesting clinical usefulness may be limited. These data nevertheless support the notion that chronic muscarinic receptor stimulation can reduce cocaine self-administration. Future studies should show whether ligands with higher selectivity for M1 or M1/M4 subtypes would be less limited by undesired effects and can achieve higher efficacy.

  4. Does intergenerational social mobility affect antagonistic attitudes towards ethnic minorities?

    NARCIS (Netherlands)

    Tolsma, J.; Graaf, N.D. de; Quillian, L.

    2009-01-01

    Up till now, no study satisfactorily addressed the effect of social mobility on antagonistic attitudes toward ethnic minorities. In this contribution, we investigate the effect of educational and class intergenerational mobility on ethnic stereotypes, ethnic threat, and opposition to ethnic intermar

  5. Determinants of effective, safe and convenient vitamin K antagonist use

    NARCIS (Netherlands)

    Kooistra, Hilde Afra Margaretha

    2016-01-01

    Vitamin K antagonists (VKA) are frequently used anticoagulants. They are very effective in preventing atrial fibrillation related strokes and recurrent venous thrombosis. However, it can be difficult to achieve an optimal balance between the efficacy and side effects (bleeding), as the dose response

  6. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  7. Komplikationer til langtidsbehandling med vitamin K-antagonister

    DEFF Research Database (Denmark)

    May, O; Garne, E; Mickley, H

    1990-01-01

    Long-term treatment with vitamin K antagonists (vKA) frequently involves complications. The commonest complication is haemorrhage and cases of serious haemorrhage are stated in the literature to occur with a frequency per 1,000 treatment years of 12-108, of which 2-17 are fatal. The majority...

  8. Possible site of action of CGRP antagonists in migraine

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer; Olesen, Jes

    2011-01-01

    The calcitonin gene-related peptide (CGRP) receptor antagonists olcegepant and telcagepant are very potent drugs. Both are effective in migraine but in doses much higher than would be predicted from receptor binding and other in vitro results. This could perhaps suggest an effect of CGRP antagoni...

  9. Antagonistic dielectric elastomer actuator for biologically-inspired robotics

    Science.gov (United States)

    Conn, Andrew T.; Rossiter, Jonathan

    2011-04-01

    For optimal performance, actuators designed for biologically-inspired robotics applications need to be capable of mimicking the key characteristics of natural musculoskeletal systems. These characteristics include a large output stroke, high energy density, antagonistic operation and passive compliance. The actuation properties of dielectric elastomer actuators (DEAs) make them viable for use as an artificial muscle technology. However, much like the musculoskeletal system, rigid structures are needed to couple the compliant DEA layers to a load. In this paper, a cone DEA design is developed as an antagonistic, multi-DOF actuator, viable for a variety for biologically-inspired robotics applications. The design has the advantage of maintaining pre-strain through a support structure without substantially lowering the overall mass-specific power density. Prototype cone DEAs have been fabricated with VHB 4910 acrylic elastomer and have characteristic dimensions of 49mm (strut length) and 60mm (DEA diameter). Multi-DOF kinematical outputs of the cone DEAs were measured using a custom 3D motion tracking system. Experimental tests of the prototypes demonstrate antagonistic linear (+/-10mm), rotational (+/-25°) and combined multi-DOF strokes. Overall, antagonistic cone DEAs are shown to produce a complex multi-DOF output from a mass-efficient support structure and thus are well suited for being exploited in biologically-inspired robotics.

  10. Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists.

    Science.gov (United States)

    Kim, Jeeyeon; Kim, Youngjae; Tae, Jinsung; Yeom, Miyoung; Moon, Bongjin; Huang, Xi-Ping; Roth, Bryan L; Lee, Kangho; Rhim, Hyewhon; Choo, Il Han; Chong, Youhoon; Keum, Gyochang; Nam, Ghilsoo; Choo, Hyunah

    2013-11-01

    The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7 R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7 R. Among the synthesized compounds, 1-([2'-methoxy-(1,1'-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7 R (pKi =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7 R over other serotonin receptor subtypes, such as 5-HT1 R, 5-HT2 R, 5-HT3 R, and 5-HT6 R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function.

  11. Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children

    DEFF Research Database (Denmark)

    Bisgaard, H; Nielsen, K G

    2000-01-01

    We hypothesized that a leukotriene receptor antagonist (LTRA) could provide bronchoprotection against the cold, dry air-induced response in asthmatic preschool children. In a randomized, double-blind, placebo-controlled crossover study, we examined the effect of the specific LTRA montelukast at 5...

  12. The Effect of Antagonist Muscle Sensory Input on Force Regulation.

    Directory of Open Access Journals (Sweden)

    Tanya Onushko

    Full Text Available The purpose of this study was to understand how stretch-related sensory feedback from an antagonist muscle affects agonist muscle output at different contraction levels in healthy adults. Ten young (25.3 ± 2.4 years, healthy subjects performed constant isometric knee flexion contractions (agonist at 6 torque levels: 5%, 10%, 15%, 20%, 30%, and 40% of their maximal voluntary contraction. For half of the trials, subjects received patellar tendon taps (antagonist sensory feedback during the contraction. We compared error in targeted knee flexion torque and hamstring muscle activity, with and without patellar tendon tapping, across the 6 torque levels. At lower torque levels (5%, 10%, and 15%, subjects produced greater knee torque error following tendon tapping compared with the same torque levels without tendon tapping. In contrast, we did not find any difference in torque output at higher target levels (20%, 30%, and 40% between trials with and without tendon tapping. We also observed a load-dependent increase in the magnitude of agonist muscle activity after tendon taps, with no associated load-dependent increase in agonist and antagonist co-activation, or reflex inhibition from the antagonist tapping. The findings suggest that at relatively low muscle activity there is a deficiency in the ability to correct motor output after sensory disturbances, and cortical centers (versus sub-cortical are likely involved.

  13. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

    NARCIS (Netherlands)

    Parry-Jones, A.R.; Napoli, M. Di; Goldstein, J.N.; Schreuder, F.H.; Tetri, S.; Tatlisumak, T.; Yan, B.; Nieuwenhuizen, K.M.; Dequatre-Ponchelle, N.; Lee-Archer, M.; Horstmann, S.; Wilson, D.; Pomero, F.; Masotti, L.; Lerpiniere, C.; Godoy, D.A.; Cohen, A.S.; Houben, R.; Al-Shahi Salman, R.; Pennati, P.; Fenoglio, L.; Werring, D.; Veltkamp, R.; Wood, E.; Dewey, H.M.; Cordonnier, C.; Klijn, C.J.M.; Meligeni, F.; Davis, S.M.; Huhtakangas, J.; Staals, J.; Rosand, J.; Meretoja, A.

    2015-01-01

    OBJECTIVE: There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different

  14. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

    NARCIS (Netherlands)

    Parry-Jones, Adrian R.; Di Napoli, Mario; Goldstein, Joshua N.; Schreuder, Floris H B M; Tetri, Sami; Tatlisumak, Turgut; Yan, Bernard; Van Nieuwenhuizen, Koen M.; Dequatre-Ponchelle, Nelly; Lee-Archer, Matthew; Horstmann, Solveig; Wilson, Duncan; Pomero, Fulvio; Masotti, Luca; Lerpiniere, Christine; Godoy, Daniel Agustin; Cohen, Abigail S.; Houben, Rik; Al-Shahi Salman, Rustam; Pennati, Paolo; Fenoglio, Luigi; Werring, David; Veltkamp, Roland; Wood, Edith; Dewey, Helen M.; Cordonnier, Charlotte; Klijn, Catharina J M; Meligeni, Fabrizio; Davis, Stephen M.; Huhtakangas, Juha; Staals, Julie; Rosand, Jonathan; Meretoja, Atte

    2015-01-01

    Objective There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different

  15. Pharmacoepidemiological assessment of drug interactions with vitamin K antagonists

    DEFF Research Database (Denmark)

    Pottegård, Anton; Christensen, Rene dePont; Wang, Shirley V

    2014-01-01

    PurposeWe present a database of prescription drugs and international normalized ratio (INR) data and the applied methodology for its use to assess drug-drug interactions with vitamin K antagonists (VKAs). We use the putative interaction between VKAs and tramadol as a case study. MethodsWe used...

  16. Voltage-Gated Calcium Channel Antagonists and Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Bruce Lyeth

    2013-06-01

    Full Text Available Traumatic brain injury (TBI is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this review provide support for further development of voltage gated calcium channel (VGCC antagonists as potential therapeutic agents. Following TBI, neurons and astrocytes experience a rapid and sometimes enduring increase in intracellular calcium ([Ca2+]i. These fluxes in [Ca2+]i drive not only apoptotic and necrotic cell death, but also can lead to long-term cell dysfunction in surviving cells. In a limited number of in vitro experiments, both L-type and N-type VGCC antagonists successfully reduced calcium loads as well as neuronal and astrocytic cell death following mechanical injury. In rodent models of TBI, administration of VGCC antagonists reduced cell death and improved cognitive function. It is clear that there is a critical need to find effective therapeutics and rational drug delivery strategies for the management and treatment of TBI, and we believe that further investigation of VGCC antagonists should be pursued before ruling out the possibility of successful translation to the clinic.

  17. Diversity, distribution, and antagonistic activities of rhizobacteria of Panax notoginseng

    Directory of Open Access Journals (Sweden)

    Ze-Yan Fan

    2016-04-01

    Conclusion: The results suggest that diverse bacteria exist in the P. notoginseng rhizosphere soil, with differences in community in the same field, and antagonistic isolates may be good potential biological control agent for the notoginseng root-rot diseases caused by F. oxysporum, Fusarium solani, and Panax herbarum.

  18. Facilitative and antagonistic interactions between plant viruses in mixed infections.

    Science.gov (United States)

    Syller, Jerzy

    2012-02-01

    Mixed infections of plant viruses are common in nature, and a number of important virus diseases of plants are the outcomes of interactions between causative agents. Multiple infections lead to a variety of intrahost virus-virus interactions, many of which may result in the generation of variants showing novel genetic features, and thus change the genetic structure of the viral population. Hence, virus-virus interactions in plants may be of crucial significance for the understanding of viral pathogenesis and evolution, and consequently for the development of efficient and stable control strategies. The interactions between plant viruses in mixed infections are generally categorized as synergistic or antagonistic. Moreover, mixtures of synergistic and antagonistic interactions, creating usually unpredictable biological and epidemiological consequences, are likely to occur in plants. The mechanisms of some of these are still unknown. This review aims to bring together the current knowledge on the most commonly occurring facilitative and antagonistic interactions between related or unrelated viruses infecting the same host plant. The best characterized implications of these interactions for virus-vector-host relationships are included. The terms 'synergism' and 'helper dependence' for facilitative virus-virus interactions, and 'cross-protection' and 'mutual exclusion' for antagonistic interactions, are applied in this article.

  19. Myofascial force transmission via extramuscular pathways occurs between antagonistic muscles.

    Science.gov (United States)

    Huijing, Peter A; Baan, Guus C

    2008-01-01

    Most often muscles (as organs) are viewed as independent actuators. To test if this is true for antagonistic muscles, force was measured simultaneously at: (1) the proximal and distal tendons of the extensor digitorum muscle (EDL) to quantify any proximo-distal force differences, as an indicator of myofascial force transmission, (2) at the distal tendons of the whole antagonistic peroneal muscle group (PER) to test if effects of EDL length changes are present and (3) at the proximal end of the tibia to test if myofascially transmitted force is exerted there. EDL length was manipulated either at the proximal or distal tendons. This way equal EDL lengths are attained at two different positions of the muscle with respect to the tibia and antagonistic muscles. Despite its relatively small size, lengthening of the EDL changed forces exerted on the tibia and forces exerted by its antagonistic muscle group. Apart from its extramuscular myofascial connections, EDL has no connections to either the tibia or these antagonistic muscles. Proximal EDL lengthening increased distal muscular forces (active PER DeltaF approximately +1.7%), but decreased tibial forces (passive from 0.3 to 0 N; active DeltaF approximately -5%). Therefore, it is concluded that these antagonistic muscles do not act independently, because of myofascial force transmission between them. Such a decrease in tibial force indicates release of pre-strained connections. Distal EDL lengthening had opposite effects (tripling passive force exerted on tibia; active PER force DeltaF approximately -3.6%). It is concluded that the length and relative position of the EDL is a co-determinant of passive and active force exerted at tendons of nearby antagonistic muscle groups. These results necessitate a new view of the locomotor apparatus, which needs to take into account the high interdependence of muscles and muscle fibres as force generators, as well as proximo-distal force differences and serial and parallel

  20. Ubiquitination profiling identifies sensitivity factors for IAP antagonist treatment.

    Science.gov (United States)

    Varfolomeev, Eugene; Izrael-Tomasevic, Anita; Yu, Kebing; Bustos, Daisy; Goncharov, Tatiana; Belmont, Lisa D; Masselot, Alexandre; Bakalarski, Corey E; Kirkpatrick, Donald S; Vucic, Domagoj

    2015-02-15

    Evasion of cell death is one crucial capability acquired by tumour cells to ward-off anti-tumour therapies and represents a fundamental challenge to sustaining clinical efficacy for currently available agents. Inhibitor of apoptosis (IAP) proteins use their ubiquitin E3 ligase activity to promote cancer cell survival by mediating proliferative signalling and blocking cell death in response to diverse stimuli. Using immunoaffinity enrichment and MS, ubiquitination sites on thousands of proteins were profiled upon initiation of cell death by IAP antagonists in IAP antagonist-sensitive and -resistant breast cancer cell lines. Our analyses identified hundreds of proteins with elevated levels of ubiquitin-remnant [K-GG (Lys-Gly-Gly)] peptides upon activation of cell death by the IAP antagonist BV6. The majority of these were observed in BV6-sensitive, but not-resistant, cells. Among these were known pro-apoptotic regulators, including CYC (cytochrome c), RIP1 (receptor-interacting protein 1) and a selection of proteins known to reside in the mitochondria or regulate NF-κB (nuclear factor κB) signalling. Analysis of early time-points revealed that IAP antagonist treatment stimulated rapid ubiquitination of NF-κB signalling proteins, including TRAF2 [TNF (tumour necrosis factor) receptor-associated factor 2], HOIL-1 (haem-oxidized iron-regulatory protein 2 ubiquitin ligase-1), NEMO (NF-κB essential modifier), as well as c-IAP1 (cellular IAP1) auto-ubiquitination. Knockdown of several NF-κB pathway members reduced BV6-induced cell death and TNF production in sensitive cell lines. Importantly, RIP1 was found to be constitutively ubiquitinated in sensitive breast-cancer cell lines at higher basal level than in resistant cell lines. Together, these data show the diverse and temporally defined roles of protein ubiquitination following IAP-antagonist treatment and provide critical insights into predictive diagnostics that may enhance clinical efficacy.

  1. Accumulation of Deleterious Mutations Near Sexually Antagonistic Genes

    Directory of Open Access Journals (Sweden)

    Tim Connallon

    2016-08-01

    Full Text Available Mutation generates a steady supply of genetic variation that, while occasionally useful for adaptation, is more often deleterious for fitness. Recent research has emphasized that the fitness effects of mutations often differ between the sexes, leading to important evolutionary consequences for the maintenance of genetic variation and long-term population viability. Some forms of sex-specific selection—i.e., stronger purifying selection in males than females—can help purge a population’s load of female-harming mutations and promote population growth. Other scenarios—e.g., sexually antagonistic selection, in which mutations that harm females are beneficial for males—inflate genetic loads and potentially dampen population viability. Evolutionary processes of sexual antagonism and purifying selection are likely to impact the evolutionary dynamics of different loci within a genome, yet theory has mostly ignored the potential for interactions between such loci to jointly shape the evolutionary genetic basis of female and male fitness variation. Here, we show that sexually antagonistic selection at a locus tends to elevate the frequencies of deleterious alleles at tightly linked loci that evolve under purifying selection. Moreover, haplotypes that segregate for different sexually antagonistic alleles accumulate different types of deleterious mutations. Haplotypes that carry female-benefit sexually antagonistic alleles preferentially accumulate mutations that are primarily male harming, whereas male-benefit haplotypes accumulate mutations that are primarily female harming. The theory predicts that sexually antagonistic selection should shape the genomic organization of genetic variation that differentially impacts female and male fitness, and contribute to sexual dimorphism in the genetic basis of fitness variation.

  2. Design, synthesis, and structure-activity relationship of novel CCR2 antagonists.

    Science.gov (United States)

    Kothandaraman, Shankaran; Donnely, Karla L; Butora, Gabor; Jiao, Richard; Pasternak, Alexander; Morriello, Gregori J; Goble, Stephen D; Zhou, Changyou; Mills, Sander G; Maccoss, Malcolm; Vicario, Pasquale P; Ayala, Julia M; Demartino, Julie A; Struthers, Mary; Cascieri, Margaret A; Yang, Lihu

    2009-03-15

    A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.

  3. M4FT-16LL080303052-State of Knowledge for Colloid Facilitated Radionuclide Transport and Update on Actinide Diffusion in Bentonite Backfill

    Energy Technology Data Exchange (ETDEWEB)

    Zavarin, Mavrik [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Glenn T. Seaborg Inst.. Physical and Life Sciences; Joseph, C. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Glenn T. Seaborg Inst.. Physical and Life Sciences

    2016-08-16

    This progress report (Level 4 Milestone Number M4FT-16LL080303052) summarizes research conducted at Lawrence Livermore National Laboratory (LLNL) within the Crystalline Disposal R&D Activity Number FT-16LL080303051 and Crystalline International Collaborations Activity Number FT-16LL080303061. The focus of this research is the interaction of radionuclides with Engineered Barrier System (EBS) and host rock materials at various physico-chemical conditions relevant to subsurface repository environments. They include both chemical and physical processes such as solubility, sorption, and diffusion. The colloid facilitated transport effort focused on preparation of a draft manuscript summarizing the state of knowledge and parameterization of colloid facilitated transport mechanisms in support of reactive transport and performance assessment models for generic crystalline repositories. This draft manuscript is being submitted as a level 3 milestone with LANL as the primary author. LLNL’s contribution to that effort is summarized only briefly in the present report. A manuscript summarizing longterm U(VI) diffusion experiments through bentonite backfill material was recently accepted for publication; the contents of that manuscript are summarized in the present report. The Np(IV) diffusion experiments were started mid-year and are ongoing. The completion of these experiments is planned for early FY17. Our progress in quantifying Np(IV) diffusion in bentonite backfill is summarized in the present report. Our involvement with the NEA TDB project was summarized in a recent Argillite Disposal activity report. It is not included in this report.

  4. Spore-Forming Thermophilic Bacterium within Artificial Meteorite Survives Entry into the Earth's Atmosphere on FOTON-M4 Satellite Landing Module.

    Science.gov (United States)

    Slobodkin, Alexander; Gavrilov, Sergey; Ionov, Victor; Iliyin, Vyacheslav

    2015-01-01

    One of the key conditions of the lithopanspermia hypothesis is that microorganisms situated within meteorites could survive hypervelocity entry from space through the Earth's atmosphere. So far, all experimental proof of this possibility has been based on tests with sounding rockets which do not reach the transit velocities of natural meteorites. We explored the survival of the spore-forming thermophilic anaerobic bacterium, Thermoanaerobacter siderophilus, placed within 1.4-cm thick basalt discs fixed on the exterior of a space capsule (the METEORITE experiment on the FOTON-M4 satellite). After 45 days of orbital flight, the landing module of the space vehicle returned to Earth. The temperature during the atmospheric transit was high enough to melt the surface of basalt. T. siderophilus survived the entry; viable cells were recovered from 4 of 24 wells loaded with this microorganism. The identity of the strain was confirmed by 16S rRNA gene sequence and physiological tests. This is the first report on the survival of a lifeform within an artificial meteorite after entry from space orbit through Earth's atmosphere at a velocity that closely approached the velocities of natural meteorites. The characteristics of the artificial meteorite and the living object applied in this study can serve as positive controls in further experiments on testing of different organisms and conditions of interplanetary transport.

  5. Detection of solar-like oscillations in relics of the Milky Way: asteroseismology of K giants in M4 using data from the NASA K2 mission

    CERN Document Server

    Miglio, A; Brogaard, K; Lund, M N; Mosser, B; Davies, G R; Handberg, R; Milone, A P; Marino, A F; Bossini, D; Elsworth, Y P; Grundahl, F; Arentoft, T; Bedin, L R; Campante, T L; Jessen-Hansen, J; Jones, C D; Kuszlewicz, J S; Malavolta, L; Nascimbeni, V; Sandquist, E L

    2016-01-01

    Asteroseismic constraints on K giants make it possible to infer radii, masses and ages of tens of thousands of field stars. Tests against independent estimates of these properties are however scarce, especially in the metal-poor regime. Here, we report the detection of solar-like oscillations in 8 stars belonging to the red-giant branch and red-horizontal branch of the globular cluster M4. The detections were made in photometric observations from the K2 Mission during its Campaign 2. Making use of independent constraints on the distance, we estimate masses of the 8 stars by utilising different combinations of seismic and non-seismic inputs. When introducing a correction to the Delta nu scaling relation as suggested by stellar models, for RGB stars we find excellent agreement with the expected masses from isochrone fitting, and with a distance modulus derived using independent methods. The offset with respect to independent masses is lower, or comparable with, the uncertainties on the average RGB mass (4-10%, ...

  6. M4FT-16LL080303052-State of Knowledge for Colloid Facilitated Radionuclide Transport and Update on Actinide Diffusion in Bentonite Backfill

    Energy Technology Data Exchange (ETDEWEB)

    Zavarin, Mavrik [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Glenn T. Seaborg Inst.. Physical and Life Sciences; Joseph, C. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Glenn T. Seaborg Inst.. Physical and Life Sciences

    2016-08-16

    This progress report (Level 4 Milestone Number M4FT-16LL080303052) summarizes research conducted at Lawrence Livermore National Laboratory (LLNL) within the Crystalline Disposal R&D Activity Number FT-16LL080303051 and Crystalline International Collaborations Activity Number FT-16LL080303061. The focus of this research is the interaction of radionuclides with Engineered Barrier System (EBS) and host rock materials at various physico-chemical conditions relevant to subsurface repository environments. They include both chemical and physical processes such as solubility, sorption, and diffusion. The colloid-facilitated transport effort focused on preparation of a draft manuscript summarizing the state of knowledge and parameterization of colloid-facilitated transport mechanisms in support of reactive transport and performance assessment models for generic crystalline repositories. This draft manuscript is being submitted as a level 3 milestone with LANL as the primary author. LLNL’s contribution to that effort is summarized only briefly in the present report. A manuscript summarizing long-term U(VI) diffusion experiments through bentonite backfill material was recently accepted for publication; the contents of that manuscript are summarized in the present report. The Np(IV) diffusion experiments were started mid-year and are ongoing. The completion of these experiments is planned for early FY17. Our progress in quantifying Np(IV) diffusion in bentonite backfill is summarized in the present report. Our involvement with the NEA TDB project was summarized in a recent Argillite Disposal activity report. It is not included in this report.

  7. Impulsive energy release and non-thermal emission in a confined M4.0 flare triggered by rapidly evolving magnetic structures

    CERN Document Server

    Kushwaha, Upendra; cho, Kyung-suk; Veronig, Astrid; Tiwari, Sanjiv Kumar; Mathew, S K

    2014-01-01

    We present observations of a confined M4.0 flare from NOAA 11302 on 2011 September 26. Observations at high temporal, spatial, and spectral resolution from Solar Dynamics Observatory, Reuven Ramaty High Energy Solar Spectroscopic Imager, and Nobeyama Radioheliograph enabled us to explore the possible triggering and energy release processes of this flare despite its very impulsive behavior and compact morphology. The flare light curves exhibit an abrupt rise of non-thermal emission with co-temporal hard X-ray (HXR) and microwave (MW) bursts that peaked instantly without any precursor emission. This stage was associated with HXR emission up to 200 keV that followed a power law with photon spectral index ($\\delta$) $\\sim$3. Another non-thermal peak, observed 32 s later, was more pronounced in the MW flux than the HXR profiles. Dual peaked structure in the MW and HXR light curves suggest a two-step magnetic reconnection process. Extreme ultraviolet (EUV) images exhibit a sequential evolution of the inner and oute...

  8. Investigating magnetic activity in very stable stellar magnetic fields: long-term photometric and spectroscopic study of the fully convective M4 dwarf V374 Peg

    CERN Document Server

    Vida, K; Oláh, K; Leitzinger, M; Odert, P; Kővári, Zs; Korhonen, H; Greimel, R; Robb, R; Csák, B; Kovács, J

    2016-01-01

    The ultrafast-rotating ($P_\\mathrm{rot}\\approx0.44 d$) fully convective single M4 dwarf V374 Peg is a well-known laboratory for studying intense stellar activity in a stable magnetic topology. As an observable proxy for the stellar magnetic field, we study the stability of the light curve, and thus the spot configuration. We also measure the occurrence rate of flares and coronal mass ejections (CMEs). We analyse spectroscopic observations, $BV(RI)_C$ photometry covering 5 years, and additional $R_C$ photometry that expands the temporal base over 16 years. The light curve suggests an almost rigid-body rotation, and a spot configuration that is stable over about 16 years, confirming the previous indications of a very stable magnetic field. We observed small changes on a nightly timescale, and frequent flaring, including a possible sympathetic flare. The strongest flares seem to be more concentrated around the phase where the light curve indicates a smaller active region. Spectral data suggest a complex CME with...

  9. The Mass-Radius Relation of Young Stars, I: UScoCTIO 5, An M4.5 Eclipsing Binary in Upper Scorpius Observed By K2

    CERN Document Server

    Kraus, Adam L; Covey, Kevin R; Rizzuto, Aaron C; Mann, Andrew W; Ireland, Michael J

    2015-01-01

    Evolutionary models of pre-main sequence stars remain largely uncalibrated, especially for masses below that of the Sun, making each new dynamical mass and radius measurement a valuable test of theoretical models. Stellar mass dependent features of star formation (such as disk evolution, planet formation, and even the IMF) are fundamentally tied to these models, which implies a systematic uncertainty that can only be improved with precise measurements of calibrator stars. We present the discovery that UScoCTIO 5, a known spectroscopic binary (P = 34 days, Mtot sin(i) = 0.64 Msun), is an eclipsing system with both primary and secondary eclipses apparent in K2 light curves obtained during Campaign 2. We have simultaneously fit the eclipse profiles from the K2 light curves and the existing RV data to demonstrate that UScoCTIO 5 consists of a pair of nearly identical M4.5 stars with M_A = 0.329 +/- 0.002 Msun, R_A = 0.834 +/- 0.006 Rsun, M_B = 0.317 +/- 0.002 Msun, and R_B = 0.810 +/- 0.006 Rsun. The radii are br...

  10. An embedded real-time red peach detection system based on an OV7670 camera, ARM cortex-M4 processor and 3D look-up tables.

    Science.gov (United States)

    Teixidó, Mercè; Font, Davinia; Pallejà, Tomàs; Tresanchez, Marcel; Nogués, Miquel; Palacín, Jordi

    2012-10-22

    This work proposes the development of an embedded real-time fruit detection system for future automatic fruit harvesting. The proposed embedded system is based on an ARM Cortex-M4 (STM32F407VGT6) processor and an Omnivision OV7670 color camera. The future goal of this embedded vision system will be to control a robotized arm to automatically select and pick some fruit directly from the tree. The complete embedded system has been designed to be placed directly in the gripper tool of the future robotized harvesting arm. The embedded system will be able to perform real-time fruit detection and tracking by using a three-dimensional look-up-table (LUT) defined in the RGB color space and optimized for fruit picking. Additionally, two different methodologies for creating optimized 3D LUTs based on existing linear color models and fruit histograms were implemented in this work and compared for the case of red peaches. The resulting system is able to acquire general and zoomed orchard images and to update the relative tracking information of a red peach in the tree ten times per second.

  11. Spore-Forming Thermophilic Bacterium within Artificial Meteorite Survives Entry into the Earth's Atmosphere on FOTON-M4 Satellite Landing Module.

    Directory of Open Access Journals (Sweden)

    Alexander Slobodkin

    Full Text Available One of the key conditions of the lithopanspermia hypothesis is that microorganisms situated within meteorites could survive hypervelocity entry from space through the Earth's atmosphere. So far, all experimental proof of this possibility has been based on tests with sounding rockets which do not reach the transit velocities of natural meteorites. We explored the survival of the spore-forming thermophilic anaerobic bacterium, Thermoanaerobacter siderophilus, placed within 1.4-cm thick basalt discs fixed on the exterior of a space capsule (the METEORITE experiment on the FOTON-M4 satellite. After 45 days of orbital flight, the landing module of the space vehicle returned to Earth. The temperature during the atmospheric transit was high enough to melt the surface of basalt. T. siderophilus survived the entry; viable cells were recovered from 4 of 24 wells loaded with this microorganism. The identity of the strain was confirmed by 16S rRNA gene sequence and physiological tests. This is the first report on the survival of a lifeform within an artificial meteorite after entry from space orbit through Earth's atmosphere at a velocity that closely approached the velocities of natural meteorites. The characteristics of the artificial meteorite and the living object applied in this study can serve as positive controls in further experiments on testing of different organisms and conditions of interplanetary transport.

  12. Oral mineralocorticoid antagonists for recalcitrant central serous chorioretinopathy

    Directory of Open Access Journals (Sweden)

    Chin EK

    2015-08-01

    Full Text Available Eric K Chin, David RP Almeida, C Nathaniel Roybal, Philip I Niles, Karen M Gehrs, Elliott H Sohn, H Culver Boldt, Stephen R Russell, James C FolkDepartment of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USAPurpose: To evaluate the effect and tolerance of oral mineralocorticoid antagonists, eplerenone and/or spironolactone, in recalcitrant central serous chorioretinopathy.Methods: Retrospective consecutive observational case series. Primary outcome measures included central macular thickness (CMT, µm, macular volume (MV, mm3, Snellen visual acuity, and prior treatment failures. Secondary outcomes included duration of treatment, treatment dosage, and systemic side effects.Results: A total of 120 patients with central serous chorioretinopathy were reviewed, of which 29 patients were treated with one or more mineralocorticoid antagonists. The average age of patients was 58.4 years. Sixteen patients (69.6% were recalcitrant to other interventions prior to treatment with oral mineralocorticoid antagonists, with an average washout period of 15.3 months. The average duration of mineralocorticoid antagonist treatment was 3.9±2.3 months. Twelve patients (52.2% showed decreased CMT and MV, six patients (26.1% had increase in both, and five patients (21.7% had negligible changes. The mean decrease in CMT of all patients was 42.4 µm (range, -136 to 255 µm: 100.7 µm among treatment-naïve patients, and 16.9 µm among recalcitrant patients. The mean decrease in MV of all patients was 0.20 mm3 (range, -2.33 to 2.90 mm3: 0.6 mm3 among treatment-naïve patients, and 0.0 mm3 among recalcitrant patients. Median visual acuity at the start of therapy was 20/30 (range, 20/20–20/250, and at final follow-up it was 20/40 (range, 20/20–20/125. Nine patients (39.1% experienced systemic side effects, of which three patients (13.0% were unable to continue therapy.Conclusion: Mineralocorticoid antagonist treatment had a positive treatment

  13. Study on mixed lineage leukemia gene rearrangement in AML-M4/M5 by interphase fluorescence in situ hybridization%急性单核系白血病M4/M5中MLL基因重排的间期荧光原位杂交研究

    Institute of Scientific and Technical Information of China (English)

    潘金兰; 薛永权; 姜海燕; 李建勇; 陈苏宁; 吴亚芳

    2004-01-01

    目的探讨间期荧光原位杂交(fluorescence in situ hybridization, FISH)技术对混合谱系白血病(mixed lineage leukemia, MLL)基因重排检测的价值;评估MLL重排在急性单核系白血病M4/M5中的发生率和预后意义.方法采用骨髓直接法或短期培养法制备染色体,应用R显带技术进行核型分析.采用地高辛标记的跨越11q23断裂位点的单色MLL探针和间期FISH技术对23例急性单核系白血病M4/M5病例进行MLL重排检测.结果 R显带揭示23例中7例有涉及11q23的易位,5例有其他核型异常,10例核型正常,1例核型分析失败.FISH研究显示12例有MLL重排,包括R显带检出11q23异常的7例.结论 FISH技术检测MLL重排的敏感性明显高于常规细胞遗传学技术;MLL重排与急性单核系白血病M4/M5高度相关,是预后不良的指标.

  14. High Expression, Purification and Characterization of cDNA Encoding M3-M4 Loop in the Essential Subuint of hNMDA Receptor%人NMDA受体主亚基M3-M4环基因片段的高效表达、纯化与鉴定

    Institute of Scientific and Technical Information of China (English)

    张玉梅; 孙长凯; 范明; 李伍举; 刘淑红; 赵杰; 韩大跃; 王嘉玺

    2003-01-01

    用基因工程方法获得人N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受体主亚基M3-M4环靶片段,以此为免疫原,用于进一步免疫原性及相关应用研究. 自人脑胶质瘤组织中提取总RNA, 采用RT-PCR扩增出人NMDA受体主亚基M3-M4环的基因片段, 并按照计算机辅助原核表达载体pBV220中外源基因高效表达的数学模型预测方法, 将其进行优化改构. 将目的基因克隆到pBV220中,转化大肠杆菌DH5α,升温诱导表达,从蛋白质水平检测重组体在大肠杆菌中的表达情况, 通过制备性SDS-PAGE 进行纯化, 从相对分子质量、免疫反应性、肽质谱指纹分析等方面进行鉴定. 结果表明,成功构建了人NMDA受体主亚基M3-M4环的原核表达载体(命名为pBV-NR1L3),通过基因优化,实现了高效表达.凝胶扫描分析表达量约占菌体总蛋白29 %,重组肽纯度达95 %以上.

  15. Design and discovery of 1,3-benzodiazepines as novel dopamine antagonists.

    Science.gov (United States)

    Zhu, Zhaoning; Sun, Zhong-Yue; Ye, Yuanzan; McKittrick, Brian; Greenlee, William; Czarniecki, Michael; Fawzi, Ahmad; Zhang, Hongtao; Lachowicz, Jean E

    2009-09-01

    A series of novel 1,3-benzodiazapine based D1 antagonists was designed according to the understanding of pharmacophore models derived from SCH 23390 (1b), a potent and selective D1 antagonist. The new design features an achiral cyclic-amidine that maintains desired basicity. Solid phase synthesis was developed for SAR development of the novel dopamine antagonists.

  16. Anti-antimicrobial peptides: folding-mediated host defense antagonists.

    Science.gov (United States)

    Ryan, Lloyd; Lamarre, Baptiste; Diu, Ting; Ravi, Jascindra; Judge, Peter J; Temple, Adam; Carr, Matthew; Cerasoli, Eleonora; Su, Bo; Jenkinson, Howard F; Martyna, Glenn; Crain, Jason; Watts, Anthony; Ryadnov, Maxim G

    2013-07-12

    Antimicrobial or host defense peptides are innate immune regulators found in all multicellular organisms. Many of them fold into membrane-bound α-helices and function by causing cell wall disruption in microorganisms. Herein we probe the possibility and functional implications of antimicrobial antagonism mediated by complementary coiled-coil interactions between antimicrobial peptides and de novo designed antagonists: anti-antimicrobial peptides. Using sequences from native helical families such as cathelicidins, cecropins, and magainins we demonstrate that designed antagonists can co-fold with antimicrobial peptides into functionally inert helical oligomers. The properties and function of the resulting assemblies were studied in solution, membrane environments, and in bacterial culture by a combination of chiroptical and solid-state NMR spectroscopies, microscopy, bioassays, and molecular dynamics simulations. The findings offer a molecular rationale for anti-antimicrobial responses with potential implications for antimicrobial resistance.

  17. Lead optimization studies of cinnamic amide EP2 antagonists.

    Science.gov (United States)

    Ganesh, Thota; Jiang, Jianxiong; Yang, Myung-Soon; Dingledine, Ray

    2014-05-22

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role.

  18. Churg-Strauss syndrome associated with leukotriene receptor antagonists (LTRA).

    Science.gov (United States)

    Cuchacovich, R; Justiniano, M; Espinoza, L R

    2007-10-01

    Churg-Strauss syndrome (CSS) is a rare vasculitic disorder that generally occurs in patients with bronchial asthma. CSS is being increasingly recognized in asthmatic patients treated with leukotriene receptor antagonists. However, the nature of this relationship remains to be elucidated. The present report describes three asthmatic patients who developed clinical manifestations highly suggestive of CSS, although one patient lacked the presence of eosinophilia. The patient, however, exhibited biopsy-proven cutaneous necrotizing vasculitis, which improved after withdrawal of montelukast. The second patient presented with systemic constitutional signs including fever, malaise, arthralgias, clinical jaundice, peripheral blood eosinophilia, and biopsy-proven eosinophilic hepatitis. The third patient also had circulating eosinophilia, scleritis, and arthritis. All patients improved after discontinuation of the leukotriene receptor antagonist (montelukast).

  19. Are peripheral opioid antagonists the solution to opioid side effects?

    LENUS (Irish Health Repository)

    Bates, John J

    2012-02-03

    Opioid medication is the mainstay of therapy for severe acute and chronic pain. Unfortunately, the side effects of these medications can affect patient comfort and safety, thus limiting their proven therapeutic potential. Whereas the main analgesic effects of opioids are centrally mediated, many of the common side effects are mediated via peripheral receptors. Novel peripheral opioid antagonists have been recently introduced that can block the peripheral actions of opioids without affecting centrally mediated analgesia. We review the clinical and experimental evidence of their efficacy in ameliorating opioid side effects and consider what further information might be useful in defining their role. IMPLICATIONS: The major analgesic effects of opioid medication are mediated within the brain and spinal cord. Many of the side effects of opioids are caused by activation of receptors outside these areas. Recently developed peripherally restricted opioid antagonists have the ability to block many opioid side effects without affecting analgesia.

  20. Potential Clinical Implications of the Urotensin II Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Emilie Kane

    2011-07-01

    Full Text Available Urotensin-II (UII, which binds to its receptor UT, plays an important role in the heart, kidneys, pancreas, adrenal gland and CNS. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, this constriction-dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in ACAT-1 activity leading to SMC proliferation and foam cell infiltration, insulin resistance (DMII, as well as inflammation, high blood pressure and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino-isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases.

  1. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn

    2011-01-01

    Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered......: Preclinical, clinical and post-mortem studies of the serotonin 5-HT2A system in schizophrenia are reviewed. The implications of a combined D2 and 5-HT2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT2A...... receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...

  2. Non-imidazole histamine NO-donor H3-antagonists.

    Science.gov (United States)

    Tosco, Paolo; Bertinaria, Massimo; Di Stilo, Antonella; Cena, Clara; Fruttero, Roberta; Gasco, Alberto

    2005-01-01

    Recently a series of H3-antagonists related to Imoproxifan was realised (I); in these products the oxime substructure of the lead was constrained in NO-donor furoxan systems and in the corresponding furazan derivatives. In this paper, a new series of compounds derived from I by substituting the imidazole ring with the ethoxycarbonylpiperazino moiety present in the non-imidazole H3-ligand A-923 is described. For all the products synthesis and preliminary pharmacological characterisation, as well as their hydrophilic-lipophilic balance, are reported. The imidazole ring replacement generally results in a decreased H3-antagonist activity with respect to the analogues of series I and, in some cases, induces relaxing effects on the electrically contracted guinea-pig ileum, probably due to increased affinity for other receptor systems.

  3. Drug discovery and chemokine receptor antagonists: eppur si muove!

    Science.gov (United States)

    Terricabras, Emma; Benjamim, Claudia; Godessart, Nuria

    2004-11-01

    The blockade of leukocyte migration has been demonstrated to be a valid option for the treatment of several autoimmune diseases. Chemokines play an active role in regulating cell infiltration into inflammatory sites and disrupting chemokine-receptor interactions has emerged as an alternative therapeutic approach. Pharmaceutical companies have developed an intense activity in the drug discovery of chemokine receptor antagonists in the last 10 years. Potent and selective compounds have been obtained and some of them are currently being evaluated in the clinic. The success of these trials will demonstrate whether the blockade of a single receptor is of therapeutic benefit. Alternative approaches, such as pan-receptor antagonists or inhibitors of the signalling pathways evoked by chemokines, are also being explored. In the meantime, new relationships between chemokines and receptors will be revealed, increasing our knowledge of such a fascinating field.

  4. The Mass-Radius Relation of Young Stars. I. USco 5, an M4.5 Eclipsing Binary in Upper Scorpius Observed by K2

    Science.gov (United States)

    Kraus, Adam L.; Cody, Ann Marie; Covey, Kevin R.; Rizzuto, Aaron C.; Mann, Andrew W.; Ireland, Michael J.

    2015-07-01

    We present the discovery that UScoCTIO 5, a known spectroscopic binary in the Upper Scorpius star-forming region (P = 34 days, {M}{tot}{sin}(i)=0.64 {M}⊙ ), is an eclipsing system with both primary and secondary eclipses apparent in K2 light curves obtained during Campaign 2. We have simultaneously fit the eclipse profiles from the K2 light curves and the existing RV data to demonstrate that UScoCTIO 5 consists of a pair of nearly identical M4.5 stars with {M}A=0.329+/- 0.002 {M}⊙ , {R}A=0.834+/- 0.006 {R}⊙ , {M}B=0.317+/- 0.002 {M}⊙ , and {R}B=0.810+/- 0.006 {R}⊙ . The radii are broadly consistent with pre-main-sequence ages predicted by stellar evolutionary models, but none agree to within the uncertainties. All models predict systematically incorrect masses at the 25%-50% level for the HR diagram position of these mid-M dwarfs, suggesting significant modifications to mass-dependent outcomes of star and planet formation. The form of the discrepancy for most model sets is not that they predict luminosities that are too low, but rather that they predict temperatures that are too high, suggesting that the models do not fully encompass the physics of energy transport (via convection and/or missing opacities) and/or a miscalibration of the SpT-{T}{eff} scale. The simplest modification to the models (changing {T}{eff} to match observations) would yield an older age for this system, in line with the recently proposed older age of Upper Scorpius (τ ˜ 11 Myr).

  5. Calmodulin antagonists promote TRA-8 therapy of resistant pancreatic cancer.

    Science.gov (United States)

    Yuan, Kaiyu; Yong, Sun; Xu, Fei; Zhou, Tong; McDonald, Jay M; Chen, Yabing

    2015-09-22

    Pancreatic cancer is highly malignant with limited therapy and a poor prognosis. TRAIL-activating therapy has been promising, however, clinical trials have shown resistance and limited responses of pancreatic cancers. We investigated the effects of calmodulin(CaM) antagonists, trifluoperazine(TFP) and tamoxifen(TMX), on TRA-8-induced apoptosis and tumorigenesis of TRA-8-resistant pancreatic cancer cells, and underlying mechanisms. TFP or TMX alone did not induce apoptosis of resistant PANC-1 cells, while they dose-dependently enhanced TRA-8-induced apoptosis. TMX treatment enhanced efficacy of TRA-8 therapy on tumorigenesis in vivo. Analysis of TRA-8-induced death-inducing-signaling-complex (DISC) identified recruitment of survival signals, CaM/Src, into DR5-associated DISC, which was inhibited by TMX/TFP. In contrast, TMX/TFP increased TRA-8-induced DISC recruitment/activation of caspase-8. Consistently, caspase-8 inhibition blocked the effects of TFP/TMX on TRA-8-induced apoptosis. Moreover, TFP/TMX induced DR5 expression. With a series of deletion/point mutants, we identified CaM antagonist-responsive region in the putative Sp1-binding domain between -295 to -300 base pairs of DR5 gene. Altogether, we have demonstrated that CaM antagonists enhance TRA-8-induced apoptosis of TRA-8-resistant pancreatic cancer cells by increasing DR5 expression and enhancing recruitment of apoptotic signal while decreasing survival signals in DR5-associated DISC. Our studies support the use of these readily available CaM antagonists combined with TRAIL-activating agents for pancreatic cancer therapy.

  6. Exploration of a new series of PAR1 antagonists.

    Science.gov (United States)

    Planty, Bruno; Pujol, Chantal; Lamothe, Marie; Maraval, Catherine; Horn, Clemens; Le Grand, Bruno; Perez, Michel

    2010-03-01

    Two series of new PAR1 antagonists have been identified. The first incorporates a cinnamoylpiperidine motif and the second a cinnamoylpyridine pattern. The synthesis, biological activity and structure-activity relationship of these compounds are presented. In each series, one analog showed potent in vivo antithrombotic activity in a rat AV shunt model, with up to 53% inhibition at 1.25mpk iv for compound 30.

  7. Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine

    OpenAIRE

    Funder JW

    2013-01-01

    John W FunderPrince Henry's Institute, Clayton, Victoria, AustraliaAbstract: Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor (MR) antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more MR-specific. From a marginal role as a potassium-sparing diuretic, spironolactone was shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure, as ...

  8. Epiminocyclohepta[b]indole analogs as 5-HT6 antagonists

    DEFF Research Database (Denmark)

    Henderson, Alan J; Guzzo, Peter R; Ghosh, Animesh;

    2012-01-01

    A new series of epiminocyclohepta[b]indoles with potent 5-HT(6) antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT(6) receptor occupancy studies. The compound was found...... to have excellent oral absorption, a highly favorable PK profile and demonstrated pharmacodynamic interaction with the 5-HT(6) receptor as shown by ex vivo autoradiography....

  9. Potent and orally efficacious benzothiazole amides as TRPV1 antagonists.

    Science.gov (United States)

    Besidski, Yevgeni; Brown, William; Bylund, Johan; Dabrowski, Michael; Dautrey, Sophie; Harter, Magali; Horoszok, Lucy; Hu, Yin; Johnson, Dean; Johnstone, Shawn; Jones, Paul; Leclerc, Sandrine; Kolmodin, Karin; Kers, Inger; Labarre, Maryse; Labrecque, Denis; Laird, Jennifer; Lundström, Therese; Martino, John; Maudet, Mickaël; Munro, Alexander; Nylöf, Martin; Penwell, Andrea; Rotticci, Didier; Slaitas, Andis; Sundgren-Andersson, Anna; Svensson, Mats; Terp, Gitte; Villanueva, Huascar; Walpole, Christopher; Zemribo, Ronald; Griffin, Andrew M

    2012-10-01

    Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.

  10. μ Opioid receptor: novel antagonists and structural modeling

    Science.gov (United States)

    Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

    2016-02-01

    The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.

  11. Receptor discrimination and control of agonist-antagonist binding.

    Science.gov (United States)

    Tallarida, R J

    1995-08-01

    The law of mass action is the common model for the interaction of agonist and antagonist compounds with cellular receptors. Parameters of the interaction, obtained from functional and radioligand-binding studies, allow discrimination and subtyping of receptors and aid in understanding specific mechanisms. This article reviews the theory and associated mathematical models and graphical transformations of data that underlie the determination of receptor parameters. The main theory assumes that agonist and antagonist compounds bind to cells that have a fixed number of receptors and provides the framework for obtaining drug-receptor parameters from data and their graphical transformations. Conditions that produce a change in receptor number, a newer concept in pharmacology, can have an important effect on the parameter values derived in the usual way. This review concludes with a discussion of the quantitative study of receptor-mediated feedback control of endogenous ligands, a very new topic with potentially important implications for understanding antagonist effectiveness, loss of control, and chaos in regulated mass action binding.

  12. Histamine H1 antagonists and clinical characteristics of febrile seizures

    Directory of Open Access Journals (Sweden)

    Zolaly MA

    2012-03-01

    Full Text Available Mohammed A ZolalyDepartment of Pediatrics, College of Medicine, Taibah University, Al-Madinah Al-Munawarah, Kingdom of Saudi ArabiaBackground: The purpose of this study was to determine whether seizure susceptibility due to antihistamines is provoked in patients with febrile seizures.Methods: The current descriptive study was carried out from April 2009 to February 2011 in 250 infants and children who visited the Madinah Maternity and Children's Hospital as a result of febrile convulsions. They were divided into two groups according to administration of antihistamines at the onset of fever.Results: Detailed clinical manifestations were compared between patients with and without administration of antihistamines. The time from fever detection to seizure onset was significantly shorter in the antihistamine group than that in the nonantihistamine group, and the duration of seizures was significantly longer in the antihistamine group than in the nonantihistamine group. No significant difference was found in time from fever detection to seizure onset or seizure duration between patients who received a first-generation antihistamine and those who received a second-generation antihistamine.Conclusion: Due to their central nervous system effects, H1 antagonists should not be administered to patients with febrile seizures and epilepsy. Caution should be exercised regarding the use of histamine H1 antagonists in young infants, because these drugs could potentially disturb the anticonvulsive central histaminergic system.Keywords: antihistamine, nonantihistamine, histamine H1 antagonist, febrile seizures

  13. Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.

    Directory of Open Access Journals (Sweden)

    Sachiko Yamada

    Full Text Available Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7 in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1, a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.

  14. Twisted Gastrulation, a BMP Antagonist, Exacerbates Podocyte Injury

    Science.gov (United States)

    Yamada, Sachiko; Nakamura, Jin; Asada, Misako; Takase, Masayuki; Matsusaka, Taiji; Iguchi, Taku; Yamada, Ryo; Tanaka, Mari; Higashi, Atsuko Y.; Okuda, Tomohiko; Asada, Nariaki; Fukatsu, Atsushi; Kawachi, Hiroshi; Graf, Daniel; Muso, Eri; Kita, Toru; Kimura, Takeshi; Pastan, Ira; Economides, Aris N.; Yanagita, Motoko

    2014-01-01

    Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury. PMID:24586548

  15. Newer calcium channel antagonists and the treatment of hypertension.

    Science.gov (United States)

    Cummins, D F

    1999-07-01

    Calcium channel antagonists have become popular medications for the management of hypertension. These agents belong to the diphenylalkylamine, benzothiazepine, dihydropyridine, or tetralol chemical classes. Although the medications share a common pharmacological mechanism in reducing peripheral vascular resistance, clinical differences between the sub-classes can be linked to structural profiles. This heterogeneity is manifested by differences in vascular selectivity, effects on cardiac conduction and adverse events. The lack of differentiation between calcium channel antagonists in clinical trials has contributed to uncertainty associated with their impact on morbidity and mortality. Data from more recent studies in specific patient populations underscores the importance of investigating these antihypertensives as individual agents. A proposed therapeutic classification system suggests that newer agents should share the slow onset and long-acting antihypertensive effect of amlodipine. Additionally, a favourable trough-to-peak ratio has been recommended as an objective measurement of efficacy. The newer drugs, barnidipine and lacidipine, have a therapeutic profile similar to amlodipine, but trough-to-peak ratios are not substantially greater than the recommended minimum of 0.50. Aranidipine, cilnidipine and efonidipine have unique pharmacological properties that distinguish them from traditional dihydropyridines. Although clinical significance is unconfirmed, these newer options may be beneficial for patients with co-morbid conditions that preclude use of older antagonists.

  16. IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

    Science.gov (United States)

    Shekhar, Tanmay M.; Miles, Mark A.; Gupte, Ankita; Taylor, Scott; Tascone, Brianna; Walkley, Carl R.; Hawkins, Christine J.

    2016-01-01

    Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors. PMID:27129149

  17. Synergistic and antagonistic drug combinations depend on network topology.

    Science.gov (United States)

    Yin, Ning; Ma, Wenzhe; Pei, Jianfeng; Ouyang, Qi; Tang, Chao; Lai, Luhua

    2014-01-01

    Drug combinations may exhibit synergistic or antagonistic effects. Rational design of synergistic drug combinations remains a challenge despite active experimental and computational efforts. Because drugs manifest their action via their targets, the effects of drug combinations should depend on the interaction of their targets in a network manner. We therefore modeled the effects of drug combinations along with their targets interacting in a network, trying to elucidate the relationships between the network topology involving drug targets and drug combination effects. We used three-node enzymatic networks with various topologies and parameters to study two-drug combinations. These networks can be simplifications of more complex networks involving drug targets, or closely connected target networks themselves. We found that the effects of most of the combinations were not sensitive to parameter variation, indicating that drug combinational effects largely depend on network topology. We then identified and analyzed consistent synergistic or antagonistic drug combination motifs. Synergistic motifs encompass a diverse range of patterns, including both serial and parallel combinations, while antagonistic combinations are relatively less common and homogenous, mostly composed of a positive feedback loop and a downstream link. Overall our study indicated that designing novel synergistic drug combinations based on network topology could be promising, and the motifs we identified could be a useful catalog for rational drug combination design in enzymatic systems.

  18. Approaches to the rational design of selective melanocortin receptor antagonists

    Science.gov (United States)

    Hruby, Victor J; Cai, Minying; Nyberg, Joel; Muthu, Dhanasekaran

    2015-01-01

    Introduction When establishing the physiological roles of specific receptors in normal and disease states, it is critical to have selective antagonist ligands for each receptor in a receptor system with several subtypes. The melanocortin receptors have five subtypes referred to as the melanocortin 1 receptor, melanocortin 2 receptor, melanocortin 3 receptor, melanocortin 4 receptor and melanocortin 5 receptor, and they are of critical importance for many aspects of human health and disease. Areas covered This article reviews the current efforts to design selective antagonistic ligands for the five human melanocortin receptors summarizing the currently published orthosteric and allosteric antagonists for each of these receptors. Expert opinion Though there has been progress, there are still few drugs available that address the many significant biological activities and diseases that are associated with these receptors, which is possibly due to the lack of receptor selectivity that these designed ligands are currently showing. The authors believe that further studies into the antagonists’ 3D conformational and topographical properties in addition to future mutagenesis studies will provide greater insight into these ligands which could play a role in the treatment of various diseases in the future. PMID:22646078

  19. A synthetic peptide derivative that is a cholecystokinin receptor antagonist.

    Science.gov (United States)

    Lignon, M F; Galas, M C; Rodriguez, M; Laur, J; Aumelas, A; Martinez, J

    1987-05-25

    So far, there are no known peptidic effective receptor antagonists of both peripheral and central effects of cholecystokinin (CCK). Here, we describe a synthetic peptide derivative of CCK, t-butyloxycarbonyl-Tyr(SO3-)-Met-Gly-D-Trp-Nle-Asp 2-phenylethyl ester 1 (where Nle is norleucine), which is a potent CCK receptor antagonist. In rat and guinea pig dispersed pancreatic acini, this peptide derivative did not alter amylase secretion, but was able to antagonize the stimulation caused by cholecystokinin-related agonists. It caused a parallel rightward shift in the dose-response curve for the stimulation of amylase secretion with half-maximal inhibition of CCK-8-stimulated amylase release at a concentration of about 0.1 microM. Compound 1 was able to inhibit the binding of labeled CCK-9 (the C-terminal nonapeptide of CCK) to rat and guinea pig pancreatic acini (IC50 = 5 X 10(-8) M) as well as to guinea pig cerebral cortical membranes (IC50 = 5 X 10(-7) M). These results indicate that Compound 1 is a potent competitive CCK receptor antagonist.

  20. Kappa opioid receptor antagonist and N-methyl-D- aspartate receptor antagonist affect dynorphin- induced spinal cord electrophysiologic impairment

    Institute of Scientific and Technical Information of China (English)

    Yu Chen; Liangbi Xiang; Jun Liu; Dapeng Zhou; Hailong Yu; Qi Wang; Wenfeng Han; Weijian Ren

    2012-01-01

    The latencies of motor- and somatosensory-evoked potentials were prolonged to different degrees, and wave amplitude was obviously decreased, after injection of dynorphin into the rat subarachnoid cavity.The wave amplitude and latencies of motor- and somatosensory-evoked potentials were significantly recovered at 7 and 14 days after combined injection of dynorphin and either the kappa opioid receptor antagonist nor-binaltorphimine or the N-methyl-D-aspartate receptor antagonist MK-801.The wave amplitude and latency were similar in rats after combined injection of dynorphin and nor-binaltorphimine or MK-801.These results suggest that intrathecal injection of dynorphin causes damage to spinal cord function.Prevention of N-methyl-D-aspartate receptor or kappa receptor activation lessened the injury to spinal cord function induced by dynorphin.

  1. 毒蕈碱乙酰胆碱M2/M4受体亚型在调节脊髓背角神经元谷氨酸能递质释放中的作用%Role of muscarinic cholinergic receptor subtypes in regulating glutamatergic synaptic transmission in rat spinal dorsal horn

    Institute of Scientific and Technical Information of China (English)

    杜威; 郭英; 袁维秀

    2013-01-01

    Objective To investigate the role of muscarinic cholinergic receptor (mAChR) subtypes in the regulation of glutamatergic input to the spinal dorsal horn neurons and the possible mechanism.Methods Whole-cell voltage-clamp recordings on acute spinal slice was utilized to investigate the effect of activation of mAChRs and blockade of M2/M4 subtypes on glutamatergic synaptic transmission in rat spinal dorsal horn neurons.Results The nonselective mAChRs agonist oxotremorine-M concentration-dependently decreased the amplitude of monosynaptic and polysynaptic evoked glutamate-mediated excitatory postsynaptic currents (eEPSCs) in most of the neurons.The M2/M4 antagonist himbacine completely blocked the inhibitory effect of oxotremorine-M in 92.3% of monosynaptic and 75% of polysynaptic neurons in the spinal cord slices.In the remaining 16% neurons,himbacine partially blocked the inhibitory effect of oxotremorine-M.Conclusions Activation of mAChRs in the spinal cord attenuates synaptic glutamate release to the dorsal horn neurons mainly through M2 and M4 receptor subtypes,indicating that a presynaptic inhibition in the spinal cord may be involved in the regulation of nociception by the cholinergic system and mAChRs.%目的 研究毒蕈碱胆碱能受体(mAChRs)亚型对脊髓背角感觉神经元谷氨酸能突触传递的调节机制.方法 在急性切取的腰段脊髓切片上,利用全细胞膜片钳法记录mAChRs非特异性激动剂氢化震颤素M(Oxo-M)对脊髓背角浅层神经元谷氨酸能兴奋性突触后电流(eEPSCs)的影响,给予M2/M4受体特异性拮抗剂喜巴辛,观察mAChRs在脊髓背角浅层神经元谷氨酸能递质释放调节过程中的作用.结果 不同浓度Oxo-M使脊髓背角神经元单突触和多突触eEPSCs的幅度显著降低,其抑制强度呈浓度依赖性,喜巴辛可以拮抗Oxo-M对刺激诱发eEPSCs幅度的抑制作用,在记录的25个细胞中,92.3%的单突触细胞和75%的多突触细胞表现为Oxo-M

  2. Anti free radical action of calcium antagonists and H1 and H2 receptors antagonists in neoplastic disease.

    Science.gov (United States)

    della Rovere, F; Broccio, M; Granata, A; Zirilli, A; Brugnano, L; Artemisia, A; Broccio, G

    1996-01-01

    The blood of the subjects suffering from Neoplastic Disease (ND) shows phenomena of membrane peroxidation due to the presence of Free Radicals (FRs), in a quantity much greater than the one observed in the blood of healthy subjects. This can be detected either by calculating the time necessary for the formation of "Heinz bodies" (Hbs), (p < 0.00001) after oxidative stress of the blood in vitro with acetylphenylidrazine (APH), or by calculating the methemoglobin (metHb) quantity that forms after the same treatment (P < 0.00001). The statistical analyses we carried out showed that metHb formation was not affected by age, sex, smoking habits, red blood cell number, Hb, Ht or tumor staging. In this study, by using equal parameters of investigation, we noted that the blood of the subjects with ND who were previously treated with calcium-antagonists drugs and with antagonists of H1 and H2 receptors, gave results completely superimposable on the results obtained from healthy subjects, implying that the treatment had avoided the increase of FRs. Therefore we concluded that calcium-antagonists and the antagonists of the H1 and H2 receptors behave as antioxidant substances, having decreased the FRs damaging activity on the cellular membranes, thus controlling, although to a limited degree, the pejorative evolution of the disease. It is also important to remember that investigations into the ND, even possible screenings, must take into account the above said data, submitting the subjects under investigation to a pharmacological wash out, particularly with those substances which, are considered to be scavengers of FRs. Some of these substances are investigated in this work.

  3. Conformational studies of 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists leading to new spirocyclic antagonists.

    Science.gov (United States)

    Pasternak, Alexander; Goble, Stephen D; Doss, George A; Tsou, Nancy N; Butora, Gabor; Vicario, Pasquale P; Ayala, Julia Marie; Struthers, Mary; Demartino, Julie A; Mills, Sander G; Yang, Lihu

    2008-02-15

    In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold.

  4. Spectroscopic Properties of Novel Aromatic Metal Clusters: NaM4 (M=Al, Ga, In) and their Cations and Anions

    Energy Technology Data Exchange (ETDEWEB)

    Balasubramanian, K; Zhao, C

    2004-03-17

    The ground and several excited states of metal aromatic clusters, namely NaM4 and NaM{sub 4}{sup {+-}} (M=Al, Ga, In) clusters have been investigated by employing complete activespace self-consistent-field (CASSCF) followed by Multi-reference singles and doubles configuration interaction (MRSDCI) computations that included up to 10 million configurations and other methods. The ground states NaM{sub 4}{sup -} of aromatic anions are found to be symmetric C{sub 4v} ({sup 1}A{sub 1}) electronic states with ideal square pyramid geometries. While the ground state of NaIn4 is also predicted to be a symmetric C{sub 4v} ({sup 2}A{sub 1}) square pyramid, the ground state of the NaAl4 cluster is found to have a C{sub 2v} ({sup 2}A{sub 1}) pyramid with a rhombus base and the ground state of NaGa{sub 4} possesses a C{sub 2v} ({sup 2}A{sub 1}) pyramid with a rectangle base. In general these structures exhibit 2 competing geometries, viz., an ideal C{sub 4v} structure and a distorted rhomboidal or rectangular pyramid structure (C{sub 2v}). All of the ground states of the NaM{sub 4}{sup +} (M= Al, Ga, In) cations are computed to be C{sub 2v} ({sup 3}A{sub 2}) pyramids with rhombus bases. The equilibrium geometries, vibrational frequencies, dissociation energies, adiabatic ionization potentials, adiabatic electron affinities for the electronic states of NaM{sub 4} (M=Al, Ga, In) and their ions are computed and compared with experimental results and other theoretical calculations. On the basis of our computed excited states energy separations, we have tentatively suggested assignments to the observed X and A states in the anion photoelectron spectra of Al{sub 4}Na{sup -} reported by Li et al. The X state can be assigned to a C{sub 2v} ({sup 2}A{sub 1}) rhomboidal pyramid. The A state observed in the anion spectrum is assigned to the first excited state ({sup 2}B{sub 1}) of the neutral NaAl{sub 4} with the C{sub 4v} symmetry. The assignments of the excited states are consistent with

  5. Microearthquake detection at 2012 M4.9 Qiaojia earthquake source area , the north of the Xiaojiang Fault in Yunnan, China

    Science.gov (United States)

    Li, Y.; Yang, H.; Zhou, S.; Yan, C.

    2016-12-01

    We perform a comprehensive analysis in Yunnan area based on continuous seismic data of 38 stations of Qiaojia Network in Xiaojiang Fault from 2012.3 to 2015.2. We use an effective method: Match and Locate (M&L, Zhang&Wen, 2015) to detect and locate microearthquakes to conduct our research. We first study dynamic triggering around the Xiaojiang Fault in Yunnan. The triggered earthquakes are identified as two impulsive seismic arrivals in 2Hz-highpass-filtered velocity seismograms during the passage of surface waves of large teleseismic earthquakes. We only find two earthquakes that may have triggered regional earthquakes through inspecting their spectrograms: Mexico Mw7.4 earthquake in 03/20/2012 and El Salvador Mw7.3 earthquake in 10/14/2014. To confirm the two earthquakes are triggered instead of coincidence, we use M&L to search if there are any repeating earthquakes. The result of the coefficients shows that it is a coincidence during the surface waves of El Salvador earthquake and whether 2012 Mexico have triggered earthquake is under discussion. We then visually inspect the 2-8Hz-bandpass-filterd velocity envelopes of these years to search for non-volcanic tremor. We haven't detected any signals similar to non-volcanic tremors yet. In the following months, we are going to study the 2012 M4.9 Qiaojia earthquake. It occurred only 30km west of the epicenter of the 2014 M6.5 Ludian earthquake. We use Match and Locate (M&L) technique to detect and relocate microearthquakes that occurred 2 days before and 3 days after the mainshock. Through this, we could obtain several times more events than listed in the catalogs provided by NEIC and reduce the magnitude of completeness Mc. We will also detect microearthquakes along Xiaojiang Fault using template earthquakes listed in the catalogs to learn more about fault shape and other properties of Xiaojiang Fault. Analyzing seismicity near Xiaojiang Fault systematically may cast insight on our understanding of the features of

  6. Reproduction and appraisal of an animal model of acute myelomonocytic leukemia in the CB6F1 generation nice%CB6F1小鼠急性粒单核细胞白血病M4(AML-M4)模型的建立及鉴定

    Institute of Scientific and Technical Information of China (English)

    左洪莉; 彭恩兰; 刘铁强; 黄珊; 李玉芳; 姚晓兰; 尚世臣; 艾辉胜

    2011-01-01

    Objective To reproduce an acute myelomonocytic leukemia M4 (AML-M4) animal model with the CB6F1 generation mice Methods The CB6F1 (BALB/c C57BL/6) mice were inoculated intravenously with different amounts (1×l06, 2×l06, 5×l06, 1 × 107 ) of WEHI-3 cells, a cell line of myelomonocyfic leukemia. The correlation between the animal survival and the inoculated amount was analyzed. The mice, inoculated with 1× l06 cells, were selected for observation of leukemia onset, and sampled for rourine blood test.Four weeks after inoculation, the peripheral blood was collected from moribund mice, morphological observation was made in blood smears, and irranunophenotype and major histocompatibility complex (MHC) was determined; the marrow cells were collected for morphological observation, and immunochemical and karyotype analysas were made. The liver, spleen, kidney, lung, heart and brain were obtained for pathological observation. The results of all the observations and determinations were then comprehensively analyzed to evaluate the authenticity of the established AML-M4 mice model Ara-C, in a dosage of 50 mg/kg or 100mg/kg, was intraperitoneally injected to the model mice for observation of the disease course and survival of the animals, and to evaluate the sensitivity of model mice to the ehemotherapeutics Normal mice were selected to serve as control in all the experiments. Results Mice inoculated with different amount of WEHI-3 cells died of leukemia 17 to 33 days after inoculation, and a negative correlation between the inoculated amount and the survival time of animals was observed (r=-0.936, P<0.01). Those inoculated with 1×106 cells survived for 25~33 (28. 50±1. 87) days Four weeks after inoculation, the WBC counts of peripheral blood increased obviously with a peak value of 81× 109/L, in the moribund leukemic mice, which was significantly different from that of normal control (P<0.05). Leukemia ceils with larger size and irregular shape were observed

  7. Selective agonists and antagonists of formylpeptide receptors: duplex flow cytometry and mixture-based positional scanning libraries.

    Science.gov (United States)

    Pinilla, Clemencia; Edwards, Bruce S; Appel, Jon R; Yates-Gibbins, Tina; Giulianotti, Marc A; Medina-Franco, Jose L; Young, Susan M; Santos, Radleigh G; Sklar, Larry A; Houghten, Richard A

    2013-09-01

    The formylpeptide receptor (FPR1) and formylpeptide-like 1 receptor (FPR2) are G protein-coupled receptors that are linked to acute inflammatory responses, malignant glioma stem cell metastasis, and chronic inflammation. Although several N-formyl peptides are known to bind to these receptors, more selective small-molecule, high-affinity ligands are needed for a better understanding of the physiologic roles played by these receptors. High-throughput assays using mixture-based combinatorial libraries represent a unique, highly efficient approach for rapid data acquisition and ligand identification. We report the superiority of this approach in the context of the simultaneous screening of a diverse set of mixture-based small-molecule libraries. We used a single cross-reactive peptide ligand for a duplex flow cytometric screen of FPR1 and FPR2 in color-coded cell lines. Screening 37 different mixture-based combinatorial libraries totaling more than five million small molecules (contained in 5,261 mixture samples) resulted in seven libraries that significantly inhibited activity at the receptors. Using positional scanning deconvolution, selective high-affinity (low nM K(i)) individual compounds were identified from two separate libraries, namely, pyrrolidine bis-diketopiperazine and polyphenyl urea. The most active individual compounds were characterized for their functional activities as agonists or antagonists with the most potent FPR1 agonist and FPR2 antagonist identified to date with an EC₅₀ of 131 nM (4 nM K(i)) and an IC₅₀ of 81 nM (1 nM K(i)), respectively, in intracellular Ca²⁺ response determinations. Comparative analyses of other previous screening approaches clearly illustrate the efficiency of identifying receptor selective, individual compounds from mixture-based combinatorial libraries.

  8. Predictions of in vivo prolactin levels from in vitro k I values of d 2 receptor antagonists using an agonist-antagonist interaction model

    NARCIS (Netherlands)

    Petersson, K.J.; Vermeulen, A.M.J.; Friberg, L.E.

    2013-01-01

    Prolactin elevation is a side effect of all currently available D2 receptor antagonists used in the treatment of schizophrenia. Prolactin elevation is the result of a direct antagonistic D2 effect blocking the tonic inhibition of prolactin release by dopamine. The aims of this work were to assess th

  9. Interaction of the M4 Segment with Other Transmembrane Segments Is Required for Surface Expression of Mammalian α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors*

    Science.gov (United States)

    Salussolia, Catherine L.; Corrales, Alexandra; Talukder, Iehab; Kazi, Rashek; Akgul, Gulcan; Bowen, Mark; Wollmuth, Lonnie P.

    2011-01-01

    Ionotropic glutamate receptors (GluRs) are ligand-gated ion channels with a modular structure. The ion channel itself shares structural similarity, albeit an inverted membrane topology, with P-loop channels. Like P-loop channels, prokaryotic GluR subunits (e.g. GluR0) have two transmembrane segments. In contrast, eukaryotic GluRs have an additional transmembrane segment (M4), located C-terminal to the ion channel core. However, the structural/functional significance of this additional transmembrane segment is poorly defined. Although topologically similar to GluR0, mammalian AMPA receptor (GluA1) subunits lacking the M4 segment do not display surface expression. This lack of expression is not due to the M4 segment serving as an anchor to the ligand-binding domain because insertion of an artificial polyleucine transmembrane segment does not rescue surface expression. Specific interactions between M4 and the ligand-binding domain are also unlikely because insertion of polyglycines into the linker connecting them has no deleterious effects on function or surface expression. However, tryptophan and cysteine scanning mutagenesis of the M4 segment, as well as recovery of function in the polyleucine background, defined a unique face of the M4 helix that is required for GluR surface expression. In the AMPA receptor structure, this face forms intersubunit contacts with the transmembrane helices of the ion channel core (M1 and M3) from another subunit within the homotetramer. Thus, our experiments show that a highly specific interaction of the M4 segment with an adjacent subunit is required for surface expression of AMPA receptors. This interaction may represent a mechanism for regulating AMPA receptor biogenesis. PMID:21930708

  10. Sexually antagonistic "zygotic drive" of the sex chromosomes.

    Directory of Open Access Journals (Sweden)

    William R Rice

    2008-12-01

    Full Text Available Genomic conflict is perplexing because it causes the fitness of a species to decline rather than improve. Many diverse forms of genomic conflict have been identified, but this extant tally may be incomplete. Here, we show that the unusual characteristics of the sex chromosomes can, in principle, lead to a previously unappreciated form of sexual genomic conflict. The phenomenon occurs because there is selection in the heterogametic sex for sex-linked mutations that harm the sex of offspring that does not carry them, whenever there is competition among siblings. This harmful phenotype can be expressed as an antagonistic green-beard effect that is mediated by epigenetic parental effects, parental investment, and/or interactions among siblings. We call this form of genomic conflict sexually antagonistic "zygotic drive", because it is functionally equivalent to meiotic drive, except that it operates during the zygotic and postzygotic stages of the life cycle rather than the meiotic and gametic stages. A combination of mathematical modeling and a survey of empirical studies is used to show that sexually antagonistic zygotic drive is feasible, likely to be widespread in nature, and that it can promote a genetic "arms race" between the homo- and heteromorphic sex chromosomes. This new category of genomic conflict has the potential to strongly influence other fundamental evolutionary processes, such as speciation and the degeneration of the Y and W sex chromosomes. It also fosters a new genetic hypothesis for the evolution of enigmatic fitness-reducing traits like the high frequency of spontaneous abortion, sterility, and homosexuality observed in humans.

  11. Classification and virtual screening of androgen receptor antagonists.

    Science.gov (United States)

    Li, Jiazhong; Gramatica, Paola

    2010-05-24

    Computational tools, such as quantitative structure-activity relationship (QSAR), are highly useful as screening support for prioritization of substances of very high concern (SVHC). From the practical point of view, QSAR models should be effective to pick out more active rather than inactive compounds, expressed as sensitivity in classification works. This research investigates the classification of a big data set of endocrine-disrupting chemicals (EDCs)-androgen receptor (AR) antagonists, mainly aiming to improve the external sensitivity and to screen for potential AR binders. The kNN, lazy IB1, and ADTree methods and the consensus approach were used to build different models, which improve the sensitivity on external chemicals from 57.1% (literature) to 76.4%. Additionally, the models' predictive abilities were further validated on a blind collected data set (sensitivity: 85.7%). Then the proposed classifiers were used: (i) to distinguish a set of AR binders into antagonists and agonists; (ii) to screen a combined estrogen receptor binder database to find out possible chemicals that can bind to both AR and ER; and (iii) to virtually screen our in-house environmental chemical database. The in silico screening results suggest: (i) that some compounds can affect the normal endocrine system through a complex mechanism binding both to ER and AR; (ii) new EDCs, which are nonER binders, but can in silico bind to AR, are recognized; and (iii) about 20% of compounds in a big data set of environmental chemicals are predicted as new AR antagonists. The priority should be given to them to experimentally test the binding activities with AR.

  12. Does protein binding modulate the effect of angiotensin II receptor antagonists?

    Directory of Open Access Journals (Sweden)

    Marc P Maillard

    2001-03-01

    Full Text Available IntroductionAngiotensin II AT 1-receptor antagonists are highly bound to plasma proteins (≥ 99%. With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists.MethodsA radio-receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II antagonists to block AT1-receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin.ResultsThe in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists.ConclusionAlthough the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors.

  13. Discovery of dopamine D₄ receptor antagonists with planar chirality.

    Science.gov (United States)

    Sanna, Fabrizio; Ortner, Birgit; Hübner, Harald; Löber, Stefan; Tschammer, Nuska; Gmeiner, Peter

    2013-04-01

    Employing the D4 selective phenylpiperazine 2 as a lead compound, planar chiral analogs with paracyclophane substructure were synthesized and evaluated for their ability to bind and activate dopamine receptors. The study revealed that the introduction of a [2.2]paracyclophane moiety is tolerated by dopamine receptors of the D2 family. Subtype selectivity for D4 and ligand efficacy depend on the absolute configuration of the test compounds. Whereas the achiral single-layered lead 2 and the double-layered paracyclophane (R)-3 showed partial agonist properties, the enantiomer (S)-3 behaved as a neutral antagonist.

  14. Discovery and pharmacological effects of a novel GPR142 antagonist.

    Science.gov (United States)

    Murakoshi, Michiko; Kuwabara, Harumi; Nagasaki, Miyuki; Xiong, Yu Mei; Reagan, Jeff D; Maeda, Hiroaki; Nara, Futoshi

    2017-06-01

    GPR142 is a G-protein-coupled receptor (GPCR), whose most potent and efficacious ligand has been reported as being the natural amino acid l-tryptophan. GPR142 is highly expressed in pancreatic β-cells and immune cells, suggesting the receptor may play a role in the pathogenesis and development of diabetes or inflammatory diseases. In a previous report, we developed GPR142 agonists as insulin secretagogues. In this report, we show the discovery of a selective, potent small-molecule GPR142 antagonist, CLP-3094, and its pharmacological characteristics. These data support targeting this receptor for the treatment of chronic inflammatory diseases.

  15. Antagonistic action of pitrazepin on human and rat GABAA receptors

    Science.gov (United States)

    Demuro, Angelo; Martinez-Torres, Ataulfo; Francesconi, Walter; Miledi, Ricardo

    1999-01-01

    Pitrazepin, 3-(piperazinyl-1)-9H-dibenz(c,f) triazolo(4,5-a)azepin is a piperazine antagonist of GABA in a variety of electrophysiological and in vitro binding studies involving GABA and glycine receptors. In the present study we have investigated the effects of pitrazepin, and the GABAA antagonist bicuculline, on membrane currents elicited by GABA in Xenopus oocytes injected with rat cerebral cortex mRNA or cDNAs encoding α1β2 or α1β2γ2S human GABAA receptor subunits.The three types of GABAA receptors expressed were reversibly antagonized by bicuculline and pitrazepin in a concentration-dependent manner. GABA dose-current response curves for the three types of receptors were shifted to the right, in a parallel manner, by increasing concentrations of pitrazepin.Schild analyses gave pA2 values of 6.42±0.62, n=4, 6.41±1.2, n=5 and 6.21±1.24, n=6, in oocytes expressing rat cerebral cortex, α1β2 or α1β2γ2S human GABAA receptors respectively (values are given as means±s.e.mean), and the Hill coefficients were all close to unity. All this is consistent with the notion that pitrazepin acts as a competitive antagonist of these GABAA receptors; and that their antagonism by pitrazepin is not strongly dependent on the subunit composition of the receptors here studied.Since pitrazepin has been reported to act also at the benzodiazepine binding site, we studied the effect of the benzodiazepine antagonist Ro 15-1788 (flumazenil) on the inhibition of α1β2γ2S receptors by pitrazepin. Co-application of Ro 15-1788 did not alter the inhibiting effect of pitrazepin. Moreover, pitrazepin did not antagonize the potentiation of GABA-currents by flunitrazepam. All this suggests that pitrazepin does not affect the GABA receptor-chloride channel by interacting with the benzodiazepine receptor site. PMID:10369456

  16. The opiate antagonist, naltrexone, in the treatment of trichotillomania

    DEFF Research Database (Denmark)

    Grant, Jon E; Odlaug, Brian Lawrence; Schreiber, Liana R N;

    2014-01-01

    Trichotillomania (TTM) is characterized by repetitive hair pulling resulting in hair loss. Data on the pharmacological treatment of TTM are limited. This study examined the opioid antagonist, naltrexone, in adults with TTM who had urges to pull their hair. Fifty-one individuals with TTM were...... improved with naltrexone (P = 0.026). Subjects taking naltrexone with a family history of addiction showed a greater numerical reduction in the urges to pull, although it was not statistically significant. Future studies will have to examine whether pharmacological modulation of the opiate system may...

  17. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    Science.gov (United States)

    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.

  18. Lymphocyte homing antagonists in the treatment of inflammatory bowel diseases.

    Science.gov (United States)

    Saruta, Masayuki; Papadakis, Konstantinos A

    2014-09-01

    Lymphocyte homing antagonists represent promising therapeutic agents for the treatment of idiopathic inflammatory bowel disease (IBD). Several critical molecules involved in the recruitment of inflammatory cells in the intestine, including integrins and chemokine receptors, have been successfully targeted for the treatment of IBD. These agents have shown great promise for the induction and maintenance of remission for both Crohn disease and ulcerative colitis. This article discusses currently approved prototypic agents for the treatment of IBD (natalizumab, anti-α4 integrin; vedolizumab, anti-α4β7 integrin), and several other agents in the same class currently under development. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Kinetic expression analysis of the cluster mdv1-mir-M9-M4, genes meq and vIL-8 differs between the lytic and latent phases of Marek's disease virus infection.

    Science.gov (United States)

    Coupeau, D; Dambrine, G; Rasschaert, D

    2012-07-01

    Marek's disease virus (GaHV-2) is an alphaherpesvirus that induces T-cell lymphoma in chickens. The infection includes both lytic and latent stages. GaHV-2 encodes three clusters of microRNAs (miRNAs) located in the internal (I)/terminal (T) repeat (R) regions. We characterized transcripts encompassing the mdv1-mir-M9-M4 and mir-M11-M1 clusters located in the IR(L)/TR(L) region, upstream and downstream from the meq oncogene, respectively. By 5'- and 3'-RACE-PCR and targeted RT-PCR, we showed that mdv1-mir-M9-M4 could be transcribed from an unspliced transcript or from at least 15 alternatively spliced transcripts covering the IR(L)/TR(L) region, encompassing the meq and vIL-8 genes and localizing the mdv1-mir-M9-M4 cluster to the first intron at the 5'-end. However, all these transcripts, whether spliced or unspliced, seemed to start at the same transcriptional start site, their transcription being driven by a single promoter, prmiRM9M4. We demonstrated alternative promoter usage for the meq and vIL-8 genes, depending on the phase of GaHV-2 infection. During the latent phase, the prmiRM9M4 promoter drove transcription of the meq and vIL-8 genes and the mdv1-mir-M9-M4 cluster in the first intron of the corresponding transcripts. By contrast, during the lytic phase, this promoter drove the transcription only of the mdv1-mir-M9-M4 cluster to generate unspliced mRNA, the meq and vIL-8 genes being transcribed principally from their own promoters. Despite the expression of meq and the mdv1-mir-M9-M4 cluster under two different transcriptional processes during the latent and lytic phases, our data provide an explanation for meq expression and mdv1-mir-M4-5P overexpression in miRNA libraries from GaHV-2-infected cells, regardless of the phase of infection.

  20. NMDA receptor antagonists extend the sensitive period for imprinting.

    Science.gov (United States)

    Parsons, C H; Rogers, L J

    2000-03-01

    Filial imprinting in the domestic chick occurs during a sensitive period of development. The exact timing of this period can vary according to the methods used to measure imprinting. Using our imprinting paradigm, we have shown that normal, dark-reared chicks lose the ability to imprint after the second day post-hatching. Further, we reported that chicks treated 10 h after hatching with a mixture of the noncompetitive NMDA receptor antagonist ketamine (55 mg/kg) and the alpha(2)-adrenergic receptor agonist xylazine (6 mg/kg) were able to imprint on day 8 after hatching, whereas controls treated with saline did not imprint. We now show that the effect of the ketamine-xylazine mixture can be mimicked by treating chicks with ketamine alone or with another noncompetitive NMDA receptor antagonist, MK-801 (5 mg/kg). Treating chicks with a single dose of ketamine (55 mg/kg) or with a single dose of xylazine (6 mg/kg) failed to produce the effect on the sensitive period. However, prolonging the action of ketamine by treating chicks with two doses of ketamine (at 10 and 12 h after hatching) did allow imprinting on day 8. In contrast, prolonging the action of xylazine had no effect on the sensitive period for imprinting. Chicks treated with MK-801 were also able to imprint on day 8. Thus, we have evidence that the NMDA receptor system is involved in the mechanisms that control the sensitive period for imprinting.

  1. CGRP antagonists and antibodies for the treatment of migraine.

    Science.gov (United States)

    Vécsei, László; Szok, Délia; Csáti, Anett; Tajti, János

    2015-01-01

    Introduction: Migraine is a highly devastating neurovascular disorder that affects up to 16% of the population worldwide. In spite of intensive research, its origin remains enigmatic with no therapeutic option appropriate for all migraine patients. One of the leading hypotheses is related to the function of the calcitonin gene-related peptide (CGRP). Regardless, the pharmaceutical options currently applied for the acute and prophylactic treatment of migraine are not appropriate for all migraine patients. Areas covered: This article is based on a literature review using the PubMed database and highlights the CGRP theory of the pathomechanism of migraine. Expert opinion: Since migraine is a CGRP-related disorder, it appeared obvious to develop CGRP receptor antagonists that exert high efficacy, both intravenously and orally. Unfortunately, the frequent use of these antagonists results in an elevated liver transaminase level. In an attempt to bypass these harmful side effects, efforts should be made to modify these pharmacons. The use of fully humanized monoclonal antibodies (mAbs) that target CGRP and its receptors may also be possible. However, while Phase I and II clinical trials are promising, a long-term follow-up of these therapies is still needed.

  2. Human Homosexuality: A Paradigmatic Arena for Sexually Antagonistic Selection?

    Science.gov (United States)

    Ciani, Andrea Camperio; Battaglia, Umberto; Zanzotto, Giovanni

    2015-01-01

    Sexual conflict likely plays a crucial role in the origin and maintenance of homosexuality in our species. Although environmental factors are known to affect human homosexual (HS) preference, sibling concordances and population patterns related to HS indicate that genetic components are also influencing this trait in humans. We argue that multilocus, partially X-linked genetic factors undergoing sexually antagonistic selection that promote maternal female fecundity at the cost of occasional male offspring homosexuality are the best candidates capable of explaining the frequency, familial clustering, and pedigree asymmetries observed in HS male proband families. This establishes male HS as a paradigmatic example of sexual conflict in human biology. HS in females, on the other hand, is currently a more elusive phenomenon from both the empirical and theoretical standpoints because of its fluidity and marked environmental influence. Genetic and epigenetic mechanisms, the latter involving sexually antagonistic components, have been hypothesized for the propagation and maintenance of female HS in the population. However, further data are needed to truly clarify the evolutionary dynamics of this trait. PMID:25635045

  3. CCR9 Antagonists in the Treatment of Ulcerative Colitis

    Directory of Open Access Journals (Sweden)

    Pirow Bekker

    2015-01-01

    Full Text Available While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a−/− mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a−/− mice. In the mdr1a−/− mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.

  4. Implications of hedgehog signaling antagonists for cancer therapy

    Institute of Scientific and Technical Information of China (English)

    Jingwu Xie

    2008-01-01

    The hedgehog(Hh)pathway,initially discovered inDrosophila by two Nobel laureates,Dr.Eric Wieschaus and Dr.Christiane Nusslein-Volhard,is a major regulator for cell differentiation,tissue polarity and cell proliferation.Studies from many laboratories,including ours,reveal activation of this pathway in most basal cell carcinomas and in approximately 30% of extracutaneous human cancers,including medulloblastomas,gastrointestinal,lung,breast and prostate cancers.Thus,it is believed that targeted inhibition of Hh signaling may be effective in treating and preventing many types of human cancers.Even more exciting is the discovery and synthesis of specific signaling antagonists for the Hh pathway,which have significant clinical implications in novel cancer therapeutics.This review discusses the major advances in the current understanding of Hh signaling activation in different types of human cancers,the molecular basis of Hh signaling activation,the major antagonists for Hh signaling inhibition and their potential clinical application in human cancer therapy.

  5. Rogue sperm indicate sexually antagonistic coevolution in nematodes.

    Directory of Open Access Journals (Sweden)

    Ronald E Ellis

    2014-07-01

    Full Text Available Intense reproductive competition often continues long after animals finish mating. In many species, sperm from one male compete with those from others to find and fertilize oocytes. Since this competition occurs inside the female reproductive tract, she often influences the outcome through physical or chemical factors, leading to cryptic female choice. Finally, traits that help males compete with each other are sometimes harmful to females, and female countermeasures may thwart the interests of males, which can lead to an arms race between the sexes known as sexually antagonistic coevolution. New studies from Caenorhabditis nematodes suggest that males compete with each other by producing sperm that migrate aggressively and that these sperm may be more likely to win access to oocytes. However, one byproduct of this competition appears to be an increased probability that these sperm will go astray, invading the ovary, prematurely activating oocytes, and sometimes crossing basement membranes and leaving the gonad altogether. These harmful effects are sometimes observed in crosses between animals of the same species but are most easily detected in interspecies crosses, leading to dramatically lowered fitness, presumably because the competitiveness of the sperm and the associated female countermeasures are not precisely matched. This mismatch is most obvious in crosses involving individuals from androdioecious species (which have both hermaphrodites and males, as predicted by the lower levels of sperm competition these species experience. These results suggest a striking example of sexually antagonistic coevolution and dramatically expand the value of nematodes as a laboratory system for studying postcopulatory interactions.

  6. Suppression of Aldosterone Synthesis and Secretion by Channel Antagonists

    Directory of Open Access Journals (Sweden)

    Keiichi Ikeda

    2012-01-01

    Full Text Available Aldosterone, a specific mineralocorticoid receptor (MR agonist and a key player in the development of hypertension, is synthesized as a final product of renin-angiotensin-aldosterone system. Hypertension can be generally treated by negating the effects of angiotensin II through the use of angiotensin-converting enzyme inhibitors (ACE-Is or angiotensin II type 1 receptor antagonists (ARBs. However, the efficacy of angiotensin II blockade by such drugs is sometimes diminished by the so-called “aldosterone breakthrough” effect, by which ACE-Is or ARBs (renin-angiotensin system (RAS inhibitors gradually lose their effectiveness against hypertension due to the overproduction of aldosterone, known as primary aldosteronism. Although MR antagonists are used to antagonize the effects of aldosterone, these drugs may, however, give rise to life-threatening adverse actions, such as hyperkalemia, particularly when used in conjunction with RAS inhibitors. Recently, several groups have reported that some dihydropyridine Ca2+ channel blockers (CCBs have inhibitory actions on aldosterone production in in vitro and in the clinical setting. Therefore, the use of such dihydropyridine CCBs to treat aldosterone-related hypertension may prove beneficial to circumvent such therapeutic problems. In this paper, we discuss the mechanism of action of CCBs on aldosterone production and clinical perspectives for CCB use to inhibit MR activity in hypertensive patients.

  7. Evodiamine as a novel antagonist of aryl hydrocarbon receptor

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Hui [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China); Department of Laboratory Medicine, The Affiliated Tenth People' s Hospital, Tongji University, Shanghai 200072 (China); Tu, Yongjiu; Zhang, Chun; Fan, Xia; Wang, Xi [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China); Wang, Zhanli [College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014 (China); Liang, Huaping, E-mail: huaping_liang@yahoo.com.cn [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China)

    2010-11-05

    Research highlights: {yields} Evodiamine interacted with the AhR. {yields} Evodiamine inhibited the specific binding of [{sup 3}H]-TCDD to the AhR. {yields} Evodiamine acts as an antagonist of the AhR. -- Abstract: Evodiamine, the major bioactive alkaloid isolated from Wu-Chu-Yu, has been shown to interact with a wide variety of proteins and modify their expression and activities. In this study, we investigated the interaction between evodiamine and the aryl hydrocarbon receptor (AhR). Molecular modeling results revealed that evodiamine directly interacted with the AhR. Cytosolic receptor binding assay also provided the evidence that evodiamine could interact with the AhR with the K{sub i} value of 28.4 {+-} 4.9 nM. In addition, we observed that evodiamine suppressed the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced nuclear translocation of the AhR and the expression of CYP1A1 dose-dependently. These results suggested that evodiamine was able to bind to the AhR as ligand and exhibit antagonistic effects.

  8. The evolution of histamine H₃ antagonists/inverse agonists.

    Science.gov (United States)

    Lebois, Evan P; Jones, Carrie K; Lindsley, Craig W

    2011-01-01

    This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H₃ antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H₃R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimer's disease, neuropathic pain and ADHD. Within the two main classes of H₃ ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H₃ ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H₃R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H₃R antagonists/inverse agonists.

  9. Human homosexuality: a paradigmatic arena for sexually antagonistic selection?

    Science.gov (United States)

    Camperio Ciani, Andrea; Battaglia, Umberto; Zanzotto, Giovanni

    2015-01-29

    Sexual conflict likely plays a crucial role in the origin and maintenance of homosexuality in our species. Although environmental factors are known to affect human homosexual (HS) preference, sibling concordances and population patterns related to HS indicate that genetic components are also influencing this trait in humans. We argue that multilocus, partially X-linked genetic factors undergoing sexually antagonistic selection that promote maternal female fecundity at the cost of occasional male offspring homosexuality are the best candidates capable of explaining the frequency, familial clustering, and pedigree asymmetries observed in HS male proband families. This establishes male HS as a paradigmatic example of sexual conflict in human biology. HS in females, on the other hand, is currently a more elusive phenomenon from both the empirical and theoretical standpoints because of its fluidity and marked environmental influence. Genetic and epigenetic mechanisms, the latter involving sexually antagonistic components, have been hypothesized for the propagation and maintenance of female HS in the population. However, further data are needed to truly clarify the evolutionary dynamics of this trait.

  10. Comparative proteome analysis of two antagonist Bacillus subtilis strains.

    Science.gov (United States)

    Zhang, C X; Zhao, X; Han, F; Yang, M F; Chen, H; Chida, T; Shen, S H

    2009-04-01

    Natural wild-type strains of Bacillus subtilis are extensively used in agriculture as biocontrol agents for plants. This study examined two antagonist B. subtilis strains, KB-1111 and KB-1122, and the results illustrated that KB-1122 was a more potent inhibitor of the indicator pathogen than KB- 1111. Thus, to investigate the intrinsic differences between the two antagonist strains under normal culture conditions, samples of KB-1111 and KB-1122 were analyzed using MALDI-TOF-MS. The main differences were related to 20 abundant intracellular and 17 extracellular proteins. When searching the NCBI database, a number of the differentially expressed proteins were identified, including 11 cellular proteins and 10 secretory proteins. Among these proteins, class III stress-response-related ATPase, aconitate hydratase, alpha-amylase precursor, and a secretory protein, endo-1, 4-beta-glucanase, were differentially expressed by the two strains. These results are useful to comprehend the intrinsic differences between the antagonism of KB-1111 and KB-1122.

  11. Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core.

    Science.gov (United States)

    Wood, Michael R; Noetzel, Meredith J; Engers, Julie L; Bollinger, Katrina A; Melancon, Bruce J; Tarr, James C; Han, Changho; West, Mary; Gregro, Alison R; Lamsal, Atin; Chang, Sichen; Ajmera, Sonia; Smith, Emery; Chase, Peter; Hodder, Peter S; Bubser, Michael; Jones, Carrie K; Hopkins, Corey R; Emmitte, Kyle A; Niswender, Colleen M; Wood, Michael W; Duggan, Mark E; Conn, P Jeffrey; Bridges, Thomas M; Lindsley, Craig W

    2016-07-01

    This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma Kp=0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma Kp>10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.

  12. Actions of dopamine antagonists on stimulated striatal and limbic dopamine release: an in vivo voltammetric study.

    OpenAIRE

    Stamford, J. A.; Kruk, Z L; Millar, J.

    1988-01-01

    1. Fast cyclic voltammetry at carbon fibre microelectrodes was used to study the effects of several dopamine antagonists upon stimulated dopamine release in the rat striatum and nucleus accumbens. 2. In both nuclei, stimulated dopamine release was increased by D2-receptor-selective and mixed D1/D2-receptor antagonists. The D1-selective antagonist SCH 23390 had no effect. 3. Striatal and limbic dopamine release were elevated by cis- but not trans-flupenthixol. 4. The 'atypical' neuroleptics (c...

  13. Synthesis and Dual Histamine H1 and H2 Receptor Antagonist Activity of Cyanoguanidine Derivatives

    OpenAIRE

    2013-01-01

    Premedication with a combination of histamine H1 receptor (H1R) and H2 receptor (H2R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H1R and H2R antagonistic activity, a series of cyanoguanidines 14–35 was synthesized by linking mepyramine-type H1R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H2R antagonist moieties. N-desmethylmepyramine was connected via a poly-met...

  14. Oral Administration of a Retinoic Acid Receptor Antagonist Reversibly Inhibits Spermatogenesis in Mice

    OpenAIRE

    Chung, Sanny S. W.; Wang, Xiangyuan; Roberts, Shelby S.; Stephen M Griffey; Reczek, Peter R.; Wolgemuth, Debra J.

    2011-01-01

    Meeting men's contraceptive needs, orally administered retinoic acid receptor antagonists represent new lead molecules in developing non-hormonal, reversible male contraceptives without adverse side effects.

  15. Clinical experience in Europe with uroselective alpha1-antagonists.

    Science.gov (United States)

    Debruyne, F M; Van der Poel, H G

    1999-01-01

    alpha1-Adrenoreceptors are thought to be involved in prostate smooth muscle contractions and could hence play a role in the dynamic component of intravesical obstruction associated with symptomatic BPH. Consequently, since the mid-eighties alpha receptor blocking agents have been used for the treatment of BPH. Non-selective alpha blockers are usually associated with systemic side-effects which resulted in an exclusion or withdrawal of many patients from this form of treatment. With the availability of so-called uroselective alpha blockers the management picture has changed since it was anticipated that these compounds cause lesser side-effects with at least the same, or even better, efficacy. Comparative clinical studies are essential for determining the eventual advantages of the uroselective alpha1-antagonists and a large number of such studies have been performed worldwide studying the various available compounds. European studies with terazosin showed clear superiority of the drug over the placebo while causing only limited side-effects. Various other studies using alpha-blocking agents such as doxazosin, tamsulosin and alfuzosin yielded identical results. Especially with tamsulosin and alfuzosin, the side-effects were comparable with those encountered in the placebo group. About 7% of the patients using tamsulosin experienced retrograde ejaculation in one study which did not occur in the alfuzosin studies. Important studies in Europe have also investigated the value of a combination of an alpha blocker with a 5alpha-reductase inhibitor. Comparable studies in which both alfuzosin and doxazosin were combined with the 5alpha-reductase inhibitor Proscar have shown that a combination is not superior to a blocker monotherapy and especially in the ALFIN study the results show that alfuzosin monotherapy is superior to Proscar in the management of symptomatic BPH. European studies have evaluated Quality of Life, sexuality as well as socio-economical outcome of the

  16. Discovery and characterization of carbamothioylacrylamides as EP2 selective antagonists.

    Science.gov (United States)

    Ganesh, Thota; Jiang, Jianxiong; Shashidharamurthy, Rangaiah; Dingledine, Ray

    2013-07-11

    Prostanoid receptor EP2 is emerging as a novel target for development of anti-inflammatory drugs for the treatment of chronic neurodegenerative and peripheral diseases; however, the availability of EP2 antagonist probes for exploration of peripheral disease models is very limited. We now report identification and characterization of a novel chemical class of compounds that show nanomolar potency and competitive antagonism of the EP2 receptor. A compound in this class, TG6-129, showed prolonged plasma half-life and did not cross the blood brain barrier. This compound also suppressed the induction of inflammatory mRNA markers in a macrophage cell line upon activation of EP2. Thus, this compound could be useful as a probe for a variety of peripheral chronic inflammatory diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease, in which EP2 appears to play a pathogenic role.

  17. [Antifibrillatory activity of dipeptide antagonist of nerve growth factor].

    Science.gov (United States)

    Kryzhanovskiĭ, S A; Stoliarchuk, V N; Vititnova, M B; Tsorin, I B; Pekel'dina, E S; Gudasheva, T A

    2012-01-01

    In experiments on anesthetized rats were assessed antifibrillatoty action of dipeptide GK-1. This compound is the fragment of fourth loop of nerve growth factor (NGF) and manifests antagonistic activity in respect to TrkA receptor, that specified for NGF. It is shown that this compound is able to significantly increase the threshold of electrical fibrillation of the heart and its effectiveness is not inferior to the reference antiarrhythmics I and III class on Vaughan Williams classification. However, unlike the latter, antifibrillatory action of dipeptide GK-1 was delayed and realized within 40-60 minutes after its administration. It is discussed possible mechanisms underlying antifibrillatory action of dipeptide GK-1, that, to some extent, may be associated with its ability to change the reactivity of beta-adrenergic structures of the heart.

  18. M sub 1 muscarinic antagonists interact with. sigma. recognition sites

    Energy Technology Data Exchange (ETDEWEB)

    Hudkins, R.L. (Virginia Commonwealth Univ., Richmond (United States)); DeHaven-Hudkins, D.L. (Sterling Research Group, Malvern, PA (United States))

    1991-01-01

    The M{sub 1}-selective muscarinic antagonists aprophen, caramiphen, carbetapentane, 2-DAEX, dicyclomine, hexahydrosiladifenidol, iodocaramiphen, nitrocaramiphen, oxybutynin and trihexyphenidyl potently inhibited binding to {sigma} sites in brain. Both basic ester and non-ester structural type compounds which exhibit affinity for the muscarinic receptor also demonstrated affinity for the {sigma} site, while the classical antimuscarinic agents atropine and QNB, and the tricyclic pirenzepine, were ineffective in binding to this site. The authors also observed a significant correlation between the K{sub i} values for {sigma}compounds to inhibit ({sup 3}H)pirenzepine binding and their IC{sub 50} values to inhibit carbachol-stimulated phosphoinositide turnover. These observations may aid in elucidating the relationship of {sigma} binding to inhibition of phosphoinositide turnover stimulated by cholinergic agonists.

  19. Pharmacoepidemiological assessment of drug interactions with vitamin K antagonists

    DEFF Research Database (Denmark)

    Pottegård, Anton; Christensen, R. D.; Wang, S. V.;

    2014-01-01

    PurposeWe present a database of prescription drugs and international normalized ratio (INR) data and the applied methodology for its use to assess drug-drug interactions with vitamin K antagonists (VKAs). We use the putative interaction between VKAs and tramadol as a case study. MethodsWe used...... a self-controlled case series to estimate the incidence rate ratio (IRR) comparing the rate of INR measurements of 4.0 in concomitant tramadol and VKA-exposed periods to VKA-only-exposed periods. Secondary analyses considered specific subgroups, alternative exposure criteria, alternative outcome...... definitions, and other drugs. ResultsWe identified 513 VKA users with at least 1 INR measurement 4.0 and concomitant tramadol and VKA exposure during the observation period. The overall IRR was 1.80 (95% confidence interval [CI], 1.53-2.10), with a stronger association among users of phenprocoumon compared...

  20. 1/f scaling in heart rate requires antagonistic autonomic control

    Science.gov (United States)

    Struzik, Zbigniew R.; Hayano, Junichiro; Sakata, Seiichiro; Kwak, Shin; Yamamoto, Yoshiharu

    2004-11-01

    We present systematic evidence for the origins of 1/f -type temporal scaling in human heart rate. The heart rate is regulated by the activity of two branches of the autonomic nervous system: the parasympathetic (PNS) and the sympathetic (SNS) nervous systems. We examine alterations in the scaling property when the balance between PNS and SNS activity is modified, and find that the relative PNS suppression by congestive heart failure results in a substantial increase in the Hurst exponent H towards random-walk scaling 1/f2 and a similar breakdown is observed with relative SNS suppression by primary autonomic failure. These results suggest that 1/f scaling in heart rate requires the intricate balance between the antagonistic activity of PNS and SNS.

  1. Pathological gambling induced by dopamine antagonists: a case report.

    Science.gov (United States)

    Grötsch, Philipp; Lange, Claudia; Wiesbeck, Gerhard A; Lang, Undine

    2015-03-01

    Pathological gambling is defined as inappropriate, persistent, and maladaptive gambling behaviour. It is a non-pharmacological addiction classified as an impulse control disorder. However, pathological gambling has been associated with dopamine agonist use. Here we report of a 28-year-old man with a first major depressive episode and a post-traumatic stress disorder who has been treated with a combination of the serotonine/noradrenaline reuptake inhibitor duloxetine and the tricyclic antidepressant maprotiline. The administration of antipsychotic flupentixole (up to 7 mg) turned this slight online poker gambler into an excessive gambler. Only after the discontinuation of the antidopaminergic agents and the switch to bupropion did this gambling behaviour stop which suggests a causal relationship between dopamine antagonists and pathological gambling.

  2. Suvorexant: The first orexin receptor antagonist to treat insomnia

    Directory of Open Access Journals (Sweden)

    Ashok K Dubey

    2015-01-01

    Full Text Available Primary insomnia is mainly treated with drugs acting on benzodiazepine receptors and a few other classes of drugs used for different co-morbidities. A novel approach to treat insomnia has been introduced recently, with the approval of suvorexant, the first in a new class of orexin receptor antagonists. Orexin receptors in the brain have been found to play an important role in the regulation of various aspects of arousal and motivation. The drugs commonly used for insomnia therapy to date, have often been associated with adverse effects, such as, day-time somnolence, amnesia, confusion, and gait disturbance, apart from the risk of dependence on chronic use. Suvorexant has not shown these adverse effects because of its unique mechanism of action. It also appears to be suitable as a chronic therapy for insomnia, because of minimal physical dependence. The availability of this new drug as an effective and safe alternative is an important and welcome development in insomnia management.

  3. Precise Determination of the Focal Depth of Jiangsu Gaoyou-Baoying M4.9 Earthquake by sPn Phase%利用sPn震相精确测定江苏高邮、宝应交界M4.9地震震源深度

    Institute of Scientific and Technical Information of China (English)

    王俊; 缪发军; 詹小艳; 瞿旻; 高景春

    2013-01-01

    In this paper,the authors select 16 broadband stations recorded data from digital seismic network in Jiangsu Province,in which the epicentral distance ranges about 280~380 km.Then using the sliding window cross-correlation overlay technique to extract sPn phase,the focal depth of Gaoyou-Baoying M4.9 earthquake on July 20,2012 by sPn-Pn,is exactly determined to be 9.4 km,the total error range less than 1.2 km.In addition,in order to validate the calculation results,we used time-domain moment tensor inverse method,which has not arrival time of phases.By inversion of the different focal depth (5~25 km) models of the moment tensor solution,we find that when focal depth is 9,10 km,the inversion results of the correlation coefficient reaches the maximum,i.e.about 0.93,0.92.This indicates that 9~10 km is the best of focal depth range.Positioning result by the method of double-difference location with waveform cross-correlation is about 10.2 km.The difference is only 0.8 km.%从江苏省数字地震台网中选取16个宽频带台站的记录资料(震中距范围约为280~380 km),利用滑动窗互相关叠加技术提取出sPn震相,并通过sPn与Pn的到时差准确地测定出2012年7月20日江苏高邮、宝应交界M4.9地震的震源深度为9.4 km,总的误差小于1.2 km.为了验证计算结果,采用与震相走时无关的时域矩张量反演方法(Time-Domain Moment Tensor Inverse),通过反演不同震源深度(5~25 km)模型下的矩张量解来进行逆向佐证.结果显示:在震源深度为9、10 km时,反演结果的相关系数达到最大,分别约为0.93、0.92,表明9~10 km是此次地震的最佳震源深度范围.另外,利用波形互相关的双差定位法得到的震源深度为10.2 km,两者相差仅为0.8 km.

  4. Agonistic and antagonistic estrogens in licorice root (Glycyrrhiza glabra).

    Science.gov (United States)

    Simons, Rudy; Vincken, Jean-Paul; Mol, Loes A M; The, Susan A M; Bovee, Toine F H; Luijendijk, Teus J C; Verbruggen, Marian A; Gruppen, Harry

    2011-07-01

    The roots of licorice (Glycyrrhiza glabra) are a rich source of flavonoids, in particular, prenylated flavonoids, such as the isoflavan glabridin and the isoflavene glabrene. Fractionation of an ethyl acetate extract from licorice root by centrifugal partitioning chromatography yielded 51 fractions, which were characterized by liquid chromatography-mass spectrometry and screened for activity in yeast estrogen bioassays. One third of the fractions displayed estrogenic activity towards either one or both estrogen receptors (ERs; ERα and ERβ). Glabrene-rich fractions displayed an estrogenic response, predominantly to the ERα. Surprisingly, glabridin did not exert agonistic activity to both ER subtypes. Several fractions displayed higher responses than the maximum response obtained with the reference compound, the natural hormone 17β-estradiol (E(2)). The estrogenic activities of all fractions, including this so-called superinduction, were clearly ER-mediated, as the estrogenic response was inhibited by 20-60% by known ER antagonists, and no activity was found in yeast cells that did not express the ERα or ERβ subtype. Prolonged exposure of the yeast to the estrogenic fractions that showed superinduction did, contrary to E(2), not result in a decrease of the fluorescent response. Therefore, the superinduction was most likely the result of stabilization of the ER, yeast-enhanced green fluorescent protein, or a combination of both. Most fractions displaying superinduction were rich in flavonoids with single prenylation. Glabridin displayed ERα-selective antagonism, similar to the ERα-selective antagonist RU 58668. Whereas glabridin was able to reduce the estrogenic response of E(2) by approximately 80% at 6 × 10(-6) M, glabrene-rich fractions only exhibited agonistic responses, preferentially on ERα.

  5. SP 01-3 ALDOSTERONE ANTAGONISTS IN HEART FAILURE.

    Science.gov (United States)

    Johnston, Colin

    2016-09-01

    Aldosterone's deleterious pathophysiological effects on the cardiovascular system if blocked by mineralcorticord antagonists (MRAs) logically should lead to improvement in heart function and outcomes in heart failure (HF). The first trial to test this hypothesis was tthe RALES trial in 1999 which treated patients with class III-IV HF with spironolactone. It showed significant reduction in mortality and cardiovascular hospitalzation rates. This was confirmed & extended in EMHASIS-HF RCT with classs II-III being treated with ACEIs & BB who received placebo or elperinone (a MRA) with again a statistically significant fall in mortality & hospitalization.The possible cardioprotective effects of MRA post acute myocardial infarct (MI) is less clear. The EPHESUS RCT in 2003 demostrated that elperinone given 3-14 days AMI in patients with early signs of HF reduced mortality & morbidity. However in the ALBTROSS trial using spironolactone 2 days after AMI showed no benfit in patients without HF but in a subgroup with ST elevation there was a 80% reduction in mortality after 6 months. However a recent meta-analysis from 25 RCT with data invovling 19,333 patients with either HF or post MI assigned aldosterone antagonists (AA)or placebo showed a 18% reduction in mortality including a 20% fall in CV mortality and a 19% reduction in SCD.The role of AA in HFPEF is even even more contraversial. The TOPCAT RCT of 3445 patients with symptomatc HFPEF randomised to spironolactone failed to meet the primary composite end point of death, aborted cardiac arrest or hospitalization although there was a reduction in hospitalization for HF (HR 0.83 P = 0.04).The differences between selective or non-selective MRAs, their ADRs & off target effects will also be discussed.

  6. Alpha antagonists and intraoperative floppy iris syndrome: A spectrum

    Directory of Open Access Journals (Sweden)

    Sharif A Issa

    2008-07-01

    Full Text Available Sharif A Issa, Omar H Hadid, Oliver Baylis, Margaret DayanDepartment of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UKBackground: To determine occurrence of features of intraoperative floppy iris syndrome (IFIS during cataract surgery in patients taking systemic alpha-antagonists (AA.Methods: We prospectively studied patients on AA and who underwent phacoemulsification. The following were recorded: pupil diameter preoperatively, iris flaccidity, iris prolapse and peroperative miosis.Results: We studied 40 eyes of 31 subjects. Mean age was 78 years. Overall, 14 eyes (13 patients showed signs of IFIS: 9/13 (69% eyes of patients on tamsulosin, 1/18 (6% eyes in the doxazosin group, 2/2 prazosin patients, 1/4 eyes in the indoramin group, and 1/2 eyes in two patients on a combination of doxazosin and tamsulosin. Most cases (92% had only one or two signs of IFIS. Bilateral cataract surgery was undertaken in 9 patients but only one patient (on tamsulosin had features of IFIS in both eyes, while 4 patients (2 on tamsulosin and 2 on other AA showed signs of IFIS in one eye only, and 4 patients did not show IFIS in either eye.Conclusion: Most AA were associated with IFIS, but it tends to present as a spectrum of signs rather than full triad originally described. Tamsulosin was most likely to be associated with IFIS; however, its intake does not necessarily mean that IFIS will occur. For patients on AA, the behavior of the iris intraoperatively in one eye is a poor predictor of the other eye. Surgeons should anticipate the occurrence of IFIS in any patient on AA.Keywords: alpha blocker, alpha antagonist, cataract surgery, intraoperative floppy iris syndrome, tamsulosin.

  7. Anticonvulsive effect of nonimidazole histamine H3 receptor antagonists.

    Science.gov (United States)

    Sadek, Bassem; Kuder, Kamil; Subramanian, Dhanasekaran; Shafiullah, Mohamed; Stark, Holger; Lażewska, Dorota; Adem, Abdu; Kieć-Kononowicz, Katarzyna

    2014-06-01

    To determine the potential of histamine H3 receptor (H3R) ligands as new antiepileptic drugs (AEDs), aromatic ether, and diether derivatives (1-12) belonging to the nonimidazole class of ligands, with high in-vitro binding affinity at human H3R, were tested for their in-vivo anticonvulsive activity in the maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in rats. The anticonvulsive effects of a systemic injection of 1-12 on MES-induced and PTZ-kindled seizures were evaluated against the reference AED phenytoin (PHT) and the structurally related H3R antagonist/inverse agonist pitolisant (PIT). Among the most promising ligands 2, 4, 5, and 11, there was a significant and dose-dependent reduction in the duration of tonic hind limb extension (THLE) in MES-induced seizure subsequent to administration of 4 and 5 [(5, 10, and 15 mg/kg, intraperitoneally (i.p.)]. The protective effects observed for the 1-(3-(3-(4-chlorophenyl)propoxy)propyl)-3-methylpiperidine derivative 11 at 10 mg/kg, i.p. were significantly greater than those of PIT, and were reversed by pretreatment with the central nervous system penetrant H1R antagonist pyrilamine (PYR) (10 mg/kg). Moreover, the protective action of the reference AED PHT, at a dose of 5 mg/kg (without considerable protection in the MES model), was significantly augmented when coadministered with derivative 11 (5 mg/kg, i.p.). Surprisingly, pretreatment with derivative 7 (10 mg/kg, i.p.), an ethylphenoxyhexyl-piperidine derivative without considerable protection in the MES model, potently altered PTZ-kindled seizure, significantly prolonged myoclonic latency time, and clearly shortened the total seizure time when compared with control, PHT, and PIT. These interesting results highlight the potential of H3R ligands as new AEDs or as adjuvants to available AED therapeutics.

  8. Concentric agonist-antagonist robots for minimally invasive surgeries

    Science.gov (United States)

    Oliver-Butler, Kaitlin; Epps, Zane H.; Rucker, Daniel Caleb

    2017-03-01

    We present a novel continuum robot design concept, Concentric Agonist-Antagonist Robots (CAAR), that uses push-pull, agonist-antagonist action of a pair of concentric tubes. The CAAR tubes are designed to have noncentral, offset neutral axes, and they are fixed together at their distal ends. Axial base translations then induce bending in the device. A CAAR segment can be created by selectively cutting asymmetric notches into the profile of two stock tubes, which relocates the neutral bending plane away from the center of the inner lumen. Like conventional concentric-tube robots (CTRs) based on counter-rotating precurved tubes, a CAAR can be made at very small scales and contain a large, open lumen. In contrast with CTRs, the CAAR concept has no elastic stability issues, offers a larger range of motion, and has lower overall stiffness. Furthermore, by varying the position of the neutral axes along the length of each tube, arbitrary, variable curvature actuation modes can be achieved. Precurving the tubes can additionally increase the workspace of a single segment. A single two-tube assembly can be used to create 3 degree-of-freedom (DOF) robot segments, and multiple segments can be deployed concentrically. Both additive manufacturing and traditional machining of stock tubes can create and customize the geometry and performance of the CAAR. In this paper, we explore the CAAR concept, provide kinematic and static models, and experimentally evaluate the model with a both a straight and a precurved CAAR. We conclude with a discussion of the significance and our plans for future work.

  9. Cytochrome P450 enzymes involved in the metabolic pathway of the histamine 2 (H2)-receptor antagonist roxatidine acetate by human liver microsomes.

    Science.gov (United States)

    Sasaki, M; Nakayama, M; Numazawa, S; Oguro, T; Honma, S; Iwamura, S; Tsukamoto, K; Yoshida, T

    2001-01-01

    Roxatidine acetate hydrochloride (ROX, 2-acetoxy-N-[3-[m-(1-piperidinylmethyl)phenoxy]propyl]acetamide hydrochloride, CAS 78273-80-0), a histamine 2 (H2)-receptor antagonist, has been clinically applied for the treatment of gastritis, gastric and duodenal ulcers. There is no report on the identification of the metabolic enzyme of M-1 (2-hydroxy-N-[3-[m-(1-piperidinylmethyl)phenoxy]propyl]acetamide), the pharmacologically active metabolite, in humans. In this study, the Cytochrome P450 (CYP or P450) enzymes which participate in the metabolism of ROX were identified using human liver microsomes and S9 fractions. M-1 was converted to M-4 (3-[m-(1-piperidinyl-methyl)phenoxy]propylamine) by the enzyme reaction with the S9 but not with microsomes. M-4 was further metabolized to M-5 (3-[m-(1-piperidinylmethyl)phenoxy]propanol) by microsomes. The metabolism was inhibited by coumarin and anti-CYP2A1 serum. (3-[m-(1-piperidinylmethyl)-phenoxy]propionic acid) and M-3 (m-(1-piperidinylmethyl) phenol) formation from M-5 were inhibited by quinidine and anti-CYP2D6 serum. Moreover, M-5 was converted to M-2 and M-3 by cDNA-expressed CYP2D6. In conclusion, this study shows that microsomal enzymes do not participate in the clearance of the active metabolite M-1, CYP2A6 primarily catalyzes M-5 formation from M-4, and CYP2D6 primarily catalyzes M-2 and M-3 formation from M-5 in humans.

  10. Comparison of GnRH Agonist, GnRH Antagonist, and GnRH Antagonist Mild Protocol of Controlled Ovarian Hyperstimulation in Good Prognosis Patients

    Directory of Open Access Journals (Sweden)

    Martin Stimpfel

    2015-01-01

    Full Text Available The reports on how to stimulate the ovaries for oocyte retrieval in good prognosis patients are contradictory and often favor one type of controlled ovarian hyperstimulation (COH. For this reason, we retrospectively analyzed data from IVF/ICSI cycles carried out at our IVF Unit in good prognosis patients (aged <38 years, first and second attempts of IVF/ICSI, more than 3 oocytes retrieved to elucidate which type of COH is optimal at our condition. The included patients were undergoing COH using GnRH agonist, GnRH antagonist or GnRH antagonist mild protocol in combination with gonadotrophins. We found significant differences in the average number of retrieved oocytes, immature oocytes, fertilized oocytes, embryos, transferred embryos, embryos frozen per cycle, and cycles with embryo freezing between studied COH protocols. Although there were no differences in live birth rate (LBR, miscarriages, and ectopic pregnancies between compared protocols, pregnancy rate was significantly higher in GnRH antagonist mild protocol in comparison with both GnRH antagonist and GnRH agonist protocols and cumulative LBR per cycle was significantly higher in GnRH antagonist mild protocol in comparison to GnRH agonist protocol. Our data show that GnRH antagonist mild protocol of COH could be the best method of choice in good prognosis patients.

  11. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity.

    Science.gov (United States)

    Brents, Lisa K; Gallus-Zawada, Anna; Radominska-Pandya, Anna; Vasiljevik, Tamara; Prisinzano, Thomas E; Fantegrossi, William E; Moran, Jeffery H; Prather, Paul L

    2012-04-01

    K2 and several similar purported "incense products" spiked with synthetic cannabinoids are abused as cannabis substitutes. We hypothesized that metabolism of JWH-073, a prevalent cannabinoid found in K2, contributes to toxicity associated with K2 use. Competition receptor binding studies and G-protein activation assays, both performed by employing mouse brain homogenates, were used to determine the affinity and intrinsic activity, respectively, of potential monohydroxylated (M1, M3-M5) and monocarboxylated (M6) metabolites at cannabinoid 1 receptors (CB1Rs). Surprisingly, M1, M4 and M5 retain nanomolar affinity for CB1Rs, while M3 displays micromolar affinity and M6 does not bind to CB1Rs. JWH-073 displays equivalent efficacy to that of the CB1R full agonist CP-55,940, while M1, M3, and M5 act as CB1R partial agonists, and M4 shows little or no intrinsic activity. Further in vitro investigation by Schild analysis revealed that M4 acts as a competitive neutral CB1R antagonist (K(b)∼40nM). In agreement with in vitro studies, M4 also demonstrates CB1R antagonism in vivo by blunting cannabinoid-induced hypothermia in mice. Interestingly, M4 does not block agonist-mediated responses of other measures in the cannabinoid tetrad (e.g., locomotor suppression, catalepsy or analgesia). Finally, also as predicted by in vitro results, M1 exhibits agonist activity in vivo by inducing significant hypothermia and suppression of locomotor activity in mice. In conclusion, the present study indicates that further work examining the physiological effects of synthetic cannabinoid metabolism is warranted. Such a complex mix of metabolically produced CB1R ligands may contribute to the adverse effect profile of JWH-073-containing products.

  12. Draft genome sequence of the antagonistic rhizosphere bacterium Serratia plymuthica strain PRI-2C.

    Science.gov (United States)

    Garbeva, P; van Elsas, J D; de Boer, W

    2012-08-01

    Serratia plymuthica strain PRI-2C is a rhizosphere bacterial strain with antagonistic activity against different plant pathogens. Here we present the 5.39-Mb (G+C content, 55.67%) draft genome sequence of S. plymuthica strain PRI-2C with the aim of providing insight into the genomic basis of its antagonistic activity.

  13. Survivin mRNA antagonists using locked nucleic acid, potential for molecular cancer therapy

    DEFF Research Database (Denmark)

    Fisker, Niels; Westergaard, Majken; Hansen, Henrik Frydenlund;

    2007-01-01

    synergistic effect when combining the mRNA antagonists against Survivin with the chemotherapeutic Taxol. This effect was demonstrated at concentrations of antagonists far lower than any previously demonstrated, indicating the high potential of locked nucleic acid for therapeutic use. Further characterisations...

  14. Inhibition of tryptase release from human colon mast cells by histamine receptor antagonists.

    Science.gov (United States)

    He, Shao-Heng; Xie, Hua; Fu, Yi-Ling

    2005-03-01

    The main objective of this study was to investigate the ability of histamine receptor antagonists to modulate tryptase release from human colon mast cells induced by histamine. Enzymatically dispersed cells from human colon were challenged with histamine in the absence or presence of the histamine receptor antagonists, and the tryptase release was determined. It was found that histamine induced tryptase release from colon mast cells was inhibited by up to approximately 61.5% and 24% by the H1 histamine receptor antagonist terfenadine and the H2 histamine receptor antagonist cimetidine, respectively, when histamine and its antagonists were added to cells at the same time. The H3 histamine receptor antagonist clobenpropit had no effect on histamine induced tryptase release from colon mast cells at all concentrations tested. Preincubation of terfenadine, cimetidine or clobenpropit with cells for 20 minutes before challenging with histamine did not enhance the ability of these antihistamines to inhibit histamine induced tryptase release. Apart from terfenadine at 100 microg/ml, the antagonists themselves did not stimulate tryptase release from colon mast cells following both 15 minutes and 35 minutes incubation periods. It was concluded that H1 and H2 histamine receptor antagonists were able to inhibit histamine induced tryptase release from colon mast cells. This not only added some new data to our hypothesis of self-amplification mechanisms of mast cell degranulation, but also suggested that combining these two types of antihistamine drugs could be useful for the treatment of inflammatory bowel disease (IBD).

  15. Anti-inflammatory properties of a novel peptide interleukin 1 receptor antagonist

    DEFF Research Database (Denmark)

    Klementiev, Boris; Li, Shizhong; Korshunova, Irina

    2014-01-01

    Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide.......Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide....

  16. Discovery and mapping of an intracellular antagonist binding site at the chemokine receptor CCR2

    DEFF Research Database (Denmark)

    Zweemer, Annelien J M; Bunnik, Julia; Veenhuizen, Margo

    2014-01-01

    The chemokine receptor CCR2 is a G protein-coupled receptor that is involved in many diseases characterized by chronic inflammation, and therefore a large variety of CCR2 small molecule antagonists has been developed. On the basis of their chemical structures these antagonists can roughly be divi...

  17. INCREASED PLASMA-CONCENTRATIONS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST IN NEONATAL SEPSIS

    NARCIS (Netherlands)

    DEBONT, ESJM; DELEIJ, LHFM; OKKEN, A; BAARSMA, R; KIMPEN, JLL

    Newborns are prone to severe infections and sepsis. Cytokines such as tumor necrosis factor-alpha and IL-1 beta play a major role in the initiation of the host response to infections. IL-1 receptor antagonist (IL-1ra) is a naturally occurring antagonist of IL-1 beta. we hypothesized that low IL-1ra

  18. Discovery of the CCR1 antagonist, BMS-817399, for the treatment of rheumatoid arthritis.

    Science.gov (United States)

    Santella, Joseph B; Gardner, Daniel S; Duncia, John V; Wu, Hong; Dhar, Murali; Cavallaro, Cullen; Tebben, Andrew J; Carter, Percy H; Barrish, Joel C; Yarde, Melissa; Briceno, Stephanie W; Cvijic, Mary Ellen; Grafstrom, R Robert; Liu, Richard; Patel, Sima R; Watson, Andrew J; Yang, Guchen; Rose, Anne V; Vickery, Rodney D; Caceres-Cortes, Janet; Caporuscio, Christian; Camac, Daniel M; Khan, Javed A; An, Yongmi; Foster, William R; Davies, Paul; Hynes, John

    2014-09-25

    High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.

  19. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview

    OpenAIRE

    Soltani, Hoda; Pardakhty, Abbas

    2016-01-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of “new drug delivery systems” is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  20. Transitions between male and female heterogamety caused by sex-antagonistic selection

    NARCIS (Netherlands)

    van Doorn, G. Sander; Kirkpatrick, Mark

    2010-01-01

    Many animal taxa show frequent and rapid transitions between male heterogamety (XY) and female heterogamety (ZW). We develop a model showing how these transitions can be driven by sex-antagonistic selection. Sex-antagonistic selection acting on loci linked to a new sex-determination mutation can cau

  1. Agar composition affects in vitro screening of biocontrol activity of antagonistic microorganisms.

    Science.gov (United States)

    Bosmans, L; De Bruijn, I; De Mot, R; Rediers, H; Lievens, B

    2016-08-01

    Agar-based screening assays are the method of choice when evaluating antagonistic potential of bacterial biocontrol-candidates against pathogens. We showed that when using the same medium, but different agar compositions, the activity of a bacterial antagonist against Agrobacterium was strongly affected. Consequently, results from in vitro screenings should be interpreted cautiously.

  2. Agar composition affects in vitro screening of biocontrol activity of antagonistic microorganisms

    NARCIS (Netherlands)

    Bosmans, Lien; De Bruijn, I.; de Mot, Rene; Readers, Hans; Lievens, Bart

    2016-01-01

    Agar-based screening assays are the method of choice when evaluating antagonistic potential of bacterial biocontrol-candidates against pathogens.Weshowed thatwhen using the samemedium, but different agar compositions, the activity of a bacterial antagonist against Agrobacteriumwas strongly affected.

  3. Screening of Fungus Antagonists against Six Main Disease Pathogens in Crops

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    28 soil samples were collected from the rhizosphere of 16 plant species in six different districts in Hunan. As a result of isolation and purification, 122 fungus strains were obtained of which the antagonistic activity was tested against six fungus pathogens in tomato, cotton, cucumber, chilli, rice and rape, and 17 strains were found antagonistic to one or more pathogenic fungi.

  4. Agar composition affects in vitro screening of biocontrol activity of antagonistic microorganisms

    NARCIS (Netherlands)

    Bosmans, Lien; De Bruijn, I.; de Mot, Rene; Readers, Hans; Lievens, Bart

    2016-01-01

    Agar-based screening assays are the method of choice when evaluating antagonistic potential of bacterial biocontrol-candidates against pathogens.Weshowed thatwhen using the samemedium, but different agar compositions, the activity of a bacterial antagonist against Agrobacteriumwas strongly affected.

  5. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview.

    Science.gov (United States)

    Soltani, Hoda; Pardakhty, Abbas

    2016-04-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of "new drug delivery systems" is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  6. Antagonistic activity of autosimbionts А. viridans, B. subtilis and their probiotic association to conditionally microflora

    Directory of Open Access Journals (Sweden)

    Stepansky D.A.

    2015-03-01

    Full Text Available In this research the data on examination of antagonist qualities of bioassotiantes A. viridans and strain B. subtilis 3 towards pathogenic and opportunistic pathogenic microflora isolated from oropharynx and nasopharynx of children who were in contact with patients with pulmonary tuberculosis (MBT + are submitted. The expressed antagonist activity of autosimbionts A. viridans towards pathogenic and opportunistic pathogenic microflora was shown. Common antagonist activity of A. viridans (k N 1 and B. subtilis 3 towards diverse strains of test-cultures is 1,5-2 times higher, than separate antagonist activity of A. viridans (k №1 and B. subtilis 3. Received research data showed the possibility of continuing work on development of probiotic associations, that contain representatives of normal microflora - bioassociants A. viridans and probiotic strains B. subtilis 3 with broadspectrum of antagonistic activity in relation to the various groups of bacterium.

  7. Screening of antagonistic bacteria for biological control of nursery wilt of black pepper (Piper nigrum).

    Science.gov (United States)

    Anith, K N; Radhakrishnan, N V; Manomohandas, T P

    2003-01-01

    Bacterial antagonists of Phytophthora capsici were isolated from underground shoot portions of rooted cuttings of black pepper. Initially isolates were screened by dual culture on potato dextrose agar and carrot agar. Further, a screening was done on black pepper shoots for supression of lesion caused by the pathogen. Most of the antagonists showed varying levels of antagonism in the dual culture and the shoot assay. Isolate PN-026, showing the highest suppression of lesion development in the shoot assay was found to be the most efficient antagonist in reducing Phytophthora capsici induced nursery wilt of black pepper. This screening involving the host, pathogen, and the antagonist, performed on black pepper shoot (the planting material for this vegetatively propagated crop), could be used as a rapid and reliable method for the isolation of efficient bacterial antagonists of P. capsici.

  8. 地西他滨联合丙戊酸钠对一例AML-M4复发患者原始细胞体外的分化凋亡影响%Synergistic effect of decitabine and valproic acid on differentiation and apoptosis of stem cells of an AML - M4 patient in vitro

    Institute of Scientific and Technical Information of China (English)

    安明和; 王晔恺; 周吉航; 李翊卫; 曾芳

    2012-01-01

    Objective:To investigate the synergistic effect of decitabine(DCA) and valproic acid(VPA) on differentiation and apoptosis of stem cells of an AML - M4 patient in vitro. Methods; The groups were set as follows: control group; DCA alone group A ( 1. 0 μmol/L); DCA alone group B (4. 0 μmol/L); VPA alone group (2.0 nunol/L); combination group A ( DCA 1. 0 μmol/L + VPA 2. 0 mmol/L) ; combination group B ( DCA 4.0 μmol/L + VPA 2.0 mmol/L) . The cells were treated by drug for 48 hours. Then the apoptosis rates, CD117 and CD14 expressions were detected by flow cytometry. Results; Compared with corresponding single drug group,the apoptosis rates and CD14 expressions of the combination group A and combination group B were significantly higher(P <0.01) while CD117 expressions were significantly lower(P< 0.01). Conclusion; Combination of DCA and VPA in vitro can remarkably enhance anti - leukemia effect.%目的:探讨地西他滨( decitabine,DCA)和丙戊酸钠(valproic acid,VPA)联用对AML患者原始细胞体外的影响.方法:设立分组如下:对照组,DCA单药A组(1.0 μmol/L),DCA单药B组(4.0 μmol/L),VPA单药组(2.0 mmol/L),联合用药A组(DCA 1.0 mol/L+VPA 2.0 mmol/L),联合用药B组(DCA4.0 μmol/L+ VPA 2.0 mmol/L),作用48 h.应用流式细胞术检测早期凋亡率和CD117、CD14表达率.结果:相对于各自的单药组,联合用药A组和联合用药B组均能显著提高早期凋亡率和CD14表达,抑制CD117的表达(P<0.01).结论:体外DCA联合VPA能显著加强抗白血病效应.

  9. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

    Directory of Open Access Journals (Sweden)

    Sadek B

    2016-11-01

    , in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-ylpropoxyphenylmethanol, and its (S-enantiomer (4 significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R-enantiomer (3 in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H3R agonist R-(α-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1–6 revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1–6 showed stereoselectivity in different convulsion models in male adult rats. Keywords: histamine, H3 receptor, isomeric antagonists, anticonvulsant activity, stereo­selectivity

  10. The NK1 receptor antagonist L822429 reduces heroin reinforcement.

    Science.gov (United States)

    Barbier, Estelle; Vendruscolo, Leandro F; Schlosburg, Joel E; Edwards, Scott; Juergens, Nathan; Park, Paula E; Misra, Kaushik K; Cheng, Kejun; Rice, Kenner C; Schank, Jesse; Schulteis, Gery; Koob, George F; Heilig, Markus

    2013-05-01

    Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared with heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects.

  11. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists.

    Science.gov (United States)

    Sadek, Bassem; Saad, Ali; Schwed, Johannes Stephan; Weizel, Lilia; Walter, Miriam; Stark, Holger

    2016-01-01

    Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%-80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its (S)-enantiomer (4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R)-enantiomer (3) in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and

  12. Dopamine D(3) receptor antagonists: The quest for a potentially selective PET ligand. Part two: Lead optimization.

    Science.gov (United States)

    Micheli, Fabrizio; Holmes, Ian; Arista, Luca; Bonanomi, Giorgio; Braggio, Simone; Cardullo, Francesca; Di Fabio, Romano; Donati, Daniele; Gentile, Gabriella; Hamprecht, Dieter; Terreni, Silvia; Heidbreder, Christian; Savoia, Chiara; Griffante, Cristiana; Worby, Angela

    2009-08-01

    The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.

  13. Antagonistic and Biocontrol Potential of Trichoderma asperellum ZJSX5003 Against the Maize Stalk Rot Pathogen Fusarium graminearum

    National Research Council Canada - National Science Library

    Li, Yaqian; Sun, Ruiyan; Yu, Jia; Saravanakumar, Kandasamy; Chen, Jie

    2016-01-01

    ...) the causal agent of corn stalk rot of maize were in vitro for their antagonistic properties followed by statistical model of principal compound analysis to identify the beneficial antagonist T. asperellum strain...

  14. XAS spectra of Ce-2[MnN3] at the Ce-M-4,M-5, Ce-L-3, Mn-L-2,L-3 and N-K thresholds

    NARCIS (Netherlands)

    Niewa, R; Hu, Z; Grazioli, C; Rossler, U; Golden, MS; Knupfer, M; Fink, J; Giefers, H; Wortmann, G; de Groot, FMF; DiSalvo, FJ

    2002-01-01

    The X-ray absorption spectroscopy at the Ce-M-4.5, Ce-L-3, Mn-L-2,L-3 and N-K thresholds was used to study the electronic and magnetic structure of the recently obtained Ce-2[MnN3]. Manganese is found to be in a state similar to that in eta-Mn3N2, with strong covalency between Mn and N. The multiple

  15. Programmable self-assembly of water-soluble organo-heterometallic cages [M12M'4L12] using 3-(3,5-dimethyl-1H-pyrazol-4-yl)pentane-2,4-dione (H2L).

    Science.gov (United States)

    Chen, Zi-Man; Cui, Yu; Jiang, Xuan-Feng; Tong, Jin; Yu, Shu-Yan

    2017-04-11

    A bifunctional ligand H2L featuring primary (pyrazole) and secondary (acetylacetone) coordination sites was preferentially reacted with dimetallic [M2(NO3)2](NO3)2 linkers at the pyrazolyl end of H2L, giving rise to dimetallic corners. Subsequently, the corners serve as the secondary site with M' to form water-soluble organo-heterometallic [M12M'4L12] cages in a stepwise mode.

  16. Antagonistic evolution in an aposematic predator-prey signaling system.

    Science.gov (United States)

    Speed, Michael P; Franks, Daniel W

    2014-10-01

    Warning signals within species, such as the bright colors of chemically defended animals, are usually considered mutualistic, monomorphic traits. Such a view is however increasingly at odds with the growing empirical literature, showing nontrivial levels of signal variation within prey populations. Key to understanding this variation, we argue, could be a recognition that toxicity levels frequently vary within populations because of environmental heterogeneity. Inequalities in defense may undermine mutualistic monomorphic signaling, causing evolutionary antagonism between loci that determine appearance of less well-defended and better defended prey forms within species. In this article, we apply a stochastic model of evolved phenotypic plasticity to the evolution of prey signals. We show that when toxicity levels vary, then antagonistic interactions can lead to evolutionary conflict between alleles at different signaling loci, causing signal evolution, "red queen-like" evolutionary chase, and one or more forms of signaling equilibria. A key prediction is that variation in the way that predators use information about toxicity levels in their attack behaviors profoundly affects the evolutionary characteristics of the prey signaling systems. Environmental variation is known to cause variation in many qualities that organisms signal; our approach may therefore have application to other signaling systems.

  17. Agonists and Antagonists of TGF-β Family Ligands.

    Science.gov (United States)

    Chang, Chenbei

    2016-08-01

    The discovery of the transforming growth factor β (TGF-β) family ligands and the realization that their bioactivities need to be tightly controlled temporally and spatially led to intensive research that has identified a multitude of extracellular modulators of TGF-β family ligands, uncovered their functions in developmental and pathophysiological processes, defined the mechanisms of their activities, and explored potential modulator-based therapeutic applications in treating human diseases. These studies revealed a diverse repertoire of extracellular and membrane-associated molecules that are capable of modulating TGF-β family signals via control of ligand availability, processing, ligand-receptor interaction, and receptor activation. These molecules include not only soluble ligand-binding proteins that were conventionally considered as agonists and antagonists of TGF-β family of growth factors, but also extracellular matrix (ECM) proteins and proteoglycans that can serve as "sink" and control storage and release of both the TGF-β family ligands and their regulators. This extensive network of soluble and ECM modulators helps to ensure dynamic and cell-specific control of TGF-β family signals. This article reviews our knowledge of extracellular modulation of TGF-β growth factors by diverse proteins and their molecular mechanisms to regulate TGF-β family signaling.

  18. Histamine and histamine receptor antagonists in cancer biology.

    Science.gov (United States)

    Blaya, Bruno; Nicolau-Galmés, Francesca; Jangi, Shawkat M; Ortega-Martínez, Idoia; Alonso-Tejerina, Erika; Burgos-Bretones, Juan; Pérez-Yarza, Gorka; Asumendi, Aintzane; Boyano, María D

    2010-07-01

    Histamine has been demonstrated to be involved in cell proliferation, embryonic development, and tumour growth. These various biological effects are mediated through the activation of specific histamine receptors (H1, H2, H3, and H4) that differ in their tissue expression patterns and functions. Although many in vitro and in vivo studies of the modulatory roles of histamine in tumour development and metastasis have been reported, the effect of histamine in the progression of some types of tumours remains controversial; however, recent findings on the role of histamine in the immune system have shed new light on this question. This review focuses on the recent advances in understanding the roles of histamine and its receptors in tumour biology. We report our recent observations of the anti-tumoural effect of H1 histamine antagonists on experimental and human melanomas. We have found that in spite of exogenous histamine stimulated human melanoma cell proliferation, clonogenic ability and migration activity in a dose-dependent manner, the melanoma tumour growth was not modulated by in vivo histamine treatment. On the contrary, terfenadine-treatment in vitro induced melanoma cell death by apoptosis and in vivo terfenadine treatment significantly inhibited tumour growth in murine models. These observations increase our understanding of cancer biology and may inspire novel anticancer therapeutic strategies.

  19. Effect of antagonist muscle fatigue on knee extension torque.

    Science.gov (United States)

    Beltman, J G M; Sargeant, A J; Ball, D; Maganaris, C N; de Haan, A

    2003-09-01

    The effect of hamstring fatigue on knee extension torque was examined at different knee angles for seven male subjects. Before and after a dynamic flexion fatigue protocol (180 degrees s(-1), until dynamic torque had declined by 50%), maximal voluntary contraction extension torque was measured at four knee flexion angles (90 degrees, 70 degrees, 50 degrees and 30 degrees ). Maximal torque generating capacity and voluntary activation of the quadriceps muscle were determined using electrical stimulation. Average rectified EMG of the biceps femoris was determined. Mean dynamic flexion torque declined by 48+/-11%. Extensor maximal voluntary contraction torque, maximal torque generating capacity, voluntary activation and average rectified EMG at the four knee angles were unaffected by the hamstring fatigue protocol. Only at 50 degrees knee angle was voluntary activation significantly lower (15.7%) after fatigue ( P<0.05). In addition, average rectified EMG before fatigue was not significantly influenced by knee angle. It was concluded that a fatigued hamstring muscle did not increase the maximal voluntary contraction extension torque and knee angle did not change coactivation. Three possible mechanisms may explain the results: a potential difference in recruited fibre populations in antagonist activity compared with the fibres which were fatigued in the protocol, a smaller loss in isometric torque generating capacity of the hamstring muscle than was expected from the dynamic measurements and/or a reduction in voluntary activation.

  20. Locomotor adaptation to a soleus EMG-controlled antagonistic exoskeleton.

    Science.gov (United States)

    Gordon, Keith E; Kinnaird, Catherine R; Ferris, Daniel P

    2013-04-01

    Locomotor adaptation in humans is not well understood. To provide insight into the neural reorganization that occurs following a significant disruption to one's learned neuromuscular map relating a given motor command to its resulting muscular action, we tied the mechanical action of a robotic exoskeleton to the electromyography (EMG) profile of the soleus muscle during walking. The powered exoskeleton produced an ankle dorsiflexion torque proportional to soleus muscle recruitment thus limiting the soleus' plantar flexion torque capability. We hypothesized that neurologically intact subjects would alter muscle activation patterns in response to the antagonistic exoskeleton by decreasing soleus recruitment. Subjects practiced walking with the exoskeleton for two 30-min sessions. The initial response to the perturbation was to "fight" the resistive exoskeleton by increasing soleus activation. By the end of training, subjects had significantly reduced soleus recruitment resulting in a gait pattern with almost no ankle push-off. In addition, there was a trend for subjects to reduce gastrocnemius recruitment in proportion to the soleus even though only the soleus EMG was used to control the exoskeleton. The results from this study demonstrate the ability of the nervous system to recalibrate locomotor output in response to substantial changes in the mechanical output of the soleus muscle and associated sensory feedback. This study provides further evidence that the human locomotor system of intact individuals is highly flexible and able to adapt to achieve effective locomotion in response to a broad range of neuromuscular perturbations.

  1. Antagonistic functions of two stardust isoforms in Drosophila photoreceptor cells.

    Science.gov (United States)

    Bulgakova, Natalia A; Rentsch, Michaela; Knust, Elisabeth

    2010-11-15

    Membrane-associated guanylate kinases (MAGUKs) are scaffolding proteins that organize supramolecular protein complexes, thereby partitioning the plasma membrane into spatially and functionally distinct subdomains. Their modular organization is ideally suited to organize protein complexes with cell type- or stage-specific composition, or both. Often more than one MAGUK isoform is expressed by one gene in the same cell, yet very little is known about their individual in vivo functions. Here, we show that two isoforms of Drosophila stardust, Sdt-H (formerly called Sdt-B2) and Sdt-D, which differ in their N terminus, are expressed in adult photoreceptors. Both isoforms associate with Crumbs and PATJ, constituents of the conserved Crumbs-Stardust complex. However, they form distinct complexes, localized at the stalk, a restricted region of the apical plasma membrane. Strikingly, Sdt-H and Sdt-D have antagonistic functions. While Sdt-H overexpression increases stalk membrane length and prevents light-dependent retinal degeneration, Sdt-D overexpression reduces stalk length and enhances light-dependent retinal degeneration. These results suggest that a fine-tuned balance of different Crumbs complexes regulates photoreceptor homeostasis.

  2. Discovery and Characterization of an Endogenous CXCR4 Antagonist

    Directory of Open Access Journals (Sweden)

    Onofrio Zirafi

    2015-05-01

    Full Text Available CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.

  3. Nalmefene: intravenous safety and kinetics of a new opioid antagonist.

    Science.gov (United States)

    Dixon, R; Howes, J; Gentile, J; Hsu, H B; Hsiao, J; Garg, D; Weidler, D; Meyer, M; Tuttle, R

    1986-01-01

    In a placebo-controlled, double-blind study we evaluated the safety and kinetics of a new narcotic antagonist, nalmefene, after 2, 6, 12, and 24 mg intravenous doses to healthy men. At each dose level four subjects received active drug and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, the most common of which was lightheadedness. The plasma concentration-time data were best fit with a triexponential equation, and the terminal elimination phase had a harmonic mean t1/2 of 8 to 9 hours. Only about 5% of the dose was excreted in the urine as intact nalmefene, with up to 60% excreted as nalmefene glucuronide. Although intersubject differences were noted, mean or dose-normalized mean kinetic parameters such as clearance, steady-state volume of distribution, terminal t1/2, and AUC showed no consistent trends related to increasing doses, indicating that nalmefene has linear pharmacokinetics.

  4. Preliminary investigations into triazole derived androgen receptor antagonists.

    Science.gov (United States)

    Altimari, Jarrad M; Niranjan, Birunthi; Risbridger, Gail P; Schweiker, Stephanie S; Lohning, Anna E; Henderson, Luke C

    2014-05-01

    A range of 1,4-substituted-1,2,3-N-phenyltriazoles were synthesized and evaluated as non-steroidal androgen receptor (AR) antagonists. The motivation for this study was to replace the N-phenyl amide portion of small molecule antiandrogens with a 1,2,3-triazole and determine effects, if any, on biological activity. The synthetic methodology presented herein is robust, high yielding and extremely rapid. Using this methodology a series of 17 N-aryl triazoles were synthesized from commercially available starting materials in less than 3h. After preliminary biological screening at 20 and 40 μM, the most promising three compounds were found to display IC50 values of 40-50 μM against androgen dependent (LNCaP) cells and serve as a starting point for further structure-activity investigations. All compounds in this work were the focus of an in silico study to dock the compounds into the human androgen receptor ligand binding domain (hARLBD) and compare their predicted binding affinity with known antiandrogens. A comparison of receptor-ligand interactions for the wild type and T877A mutant AR revealed two novel polar interactions. One with Q738 of the wild type site and the second with the mutated A877 residue.

  5. Spatial working memory in rats: effects of monoaminergic antagonists.

    Science.gov (United States)

    Beatty, W W; Rush, J R

    1983-01-01

    To assess the possible involvement of the monoaminergic neurotransmitters norepinephrine, dopamine and serotonin in the maintenance of spatial working memory rats were treated with antagonists 0 or 2 hr after completing the first 4 choices in an 8 arm maze. Haloperidol (0.25-1 mg/kg), when administered 2 hr after Choice 4, produced a small but consistent impairment in performance on retention tests given 5 hr after the first 4 choices. This deficit closely resembled natural forgetting in terms of the type of errors committed. By contrast, haloperidol in the same doses given 0 hr after Choice 4 or 3 hr before the first 4 choices did not affect retention. Likewise treatment with propranolol (10-20 mg/kg), phentolamine (5-20 mg/kg) or methysergide (5-15 mg/kg) did not impair spatial memory, regardless of when these drugs were injected within the session. Evidently dopaminergic neuronal systems are important in the maintenance of normal spatial working memory.

  6. Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.

    Science.gov (United States)

    Hong, Seoung-Soo; Bavadekar, Supriya A; Lee, Sang-Il; Patil, Popat N; Lalchandani, S G; Feller, Dennis R; Miller, Duane D

    2005-11-01

    The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.

  7. Blood flow distribution with adrenergic and histaminergic antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Baker, C.H.; Davis, D.L.; Sutton, E.T.

    1989-03-01

    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects.

  8. [Vascular calcifications, the hidden side effects of vitamin K antagonists].

    Science.gov (United States)

    Bennis, Youssef; Vengadessane, Subashini; Bodeau, Sandra; Gras, Valérie; Bricca, Giampiero; Kamel, Saïd; Liabeuf, Sophie

    2016-09-01

    Despite the availability of new oral anticoagulants, vitamin K antagonists (VKA, such as fluindione, acenocoumarol or warfarin) remain currently the goal standard medicines for oral prevention or treatment of thromboembolic disorders. They inhibit the cycle of the vitamin K and its participation in the enzymatic gamma-carboxylation of many proteins. The VKA prevent the activation of the vitamin K-dependent blood clotting factors limiting thus the initiation of the coagulation cascade. But other proteins are vitamin K-dependent and also remain inactive in the presence of VKA. This is the case of matrix Gla-protein (MGP), a protein that plays a major inhibitory role in the development of vascular calcifications. Several experimental and epidemiological results suggest that the use of the VKA could promote the development of vascular calcifications increasing thus the cardiovascular risk. This risk seems to be higher in patients with chronic kidney disease or mellitus diabetes who are more likely to develop vascular calcifications, and may be due to a decrease of the MGP activity. This review aims at summarizing the data currently available making vascular calcifications the probably underestimated side effects of VKA.

  9. CALCIUM ANTAGONISTS IN THE TREATMENT OF ARTERIAL HYPERTENSION DURING PREGNANCY

    Directory of Open Access Journals (Sweden)

    R. I. Striuk

    2006-01-01

    Full Text Available According to WHO data, arterial hypertension (HT is revealed in 15-20% of pregnant women. In different regions of Russia the incidence of pregnancy HT varies from 7 to 29%. In women with HT started before pregnancy , perinatal losses are observed in 3, 8%, premature births – in 15, 3% and intrauterine growth retardation - in 16, 6%. Physiological gestational changes of hemodynamics are described. Hypertensive pregnant patients of high and low risk are defined. Non-pharmacological treatment of pregnant women with HT is presented in details. Antihypertensive therapy may not be used in hypertensive patients of low risk with blood pressure (BP of 140-160\\90-110 mm Hg. If BP is higher antihypertensive therapy should be used immediately. Dihydropyridine calcium antagonists (CA is drugs of choice for HT treatment during pregnancy , especially “advanced” CA of the third generation. They have predictable efficacy. It is possible to use short-acting nifedipine for treatment of acute HT in pregnant patients.

  10. Iontophoresis of endothelin receptor antagonists in rats and men.

    Directory of Open Access Journals (Sweden)

    Matthieu Roustit

    Full Text Available INTRODUCTION: The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis. METHODS: Cathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA was subsequently performed on the forearm skin of healthy men (n = 5. RESULTS: In rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC(0-20 were 44032.2 ± 12277 and 14957.5 ± 23818.8 %BL.s, respectively; P = 0.01. In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans. CONCLUSIONS: This study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.

  11. Montelukast: More than a Cysteinyl Leukotriene Receptor Antagonist?

    Directory of Open Access Journals (Sweden)

    Gregory R. Tintinger

    2010-01-01

    Full Text Available The prototype cysteinyl leukotriene receptor antagonist, montelukast, is generally considered to have a niche application in the therapy of exercise- and aspirin-induced asthma. It is also used as add-on therapy in patients whose asthma is poorly controlled with inhaled corticosteroid monotherapy, or with the combination of a long-acting β(2-agonist and an inhaled corticosteroid. Recently, however, montelukast has been reported to possess secondary anti-inflammatory properties, apparently unrelated to conventional antagonism of cysteinyl leukotriene receptors. These novel activities enable montelukast to target eosinophils, monocytes, and, in particular, the corticosteroid-insensitive neutrophil, suggesting that this agent may have a broader spectrum of anti-inflammatory activities than originally thought. If so, montelukast is potentially useful in the chemotherapy of intermittent asthma, chronic obstructive pulmonary disease, cystic fibrosis, and viral bronchiolitis, which, to a large extent, involve airway epithelial cell/neutrophil interactions. The primary objective of this mini-review is to present evidence for the cysteinyl leukotrien–independent mechanisms of action of montelukast and their potential clinical relevance.

  12. Effect of platelet activating factor antagonist treatment on gentamicin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    A. Rodriguez-Barbero

    1992-01-01

    Full Text Available To assess whether PAF could be involved in the gentamicin-induced nephrotoxicity, we have studied the effect of PAF antagonist BN-52021 on renal function in rats after gentamicin (GENTA treatment. Experiments were completed in 21 Wistar rats divided into three groups: group GENTA was injected with gentamicin 100 mg kg−1 body wt/day s.c. for 6 days. Group GENTA + BN received gentamicin and BN-52021 i.p. 5 mg kg−1 body wt/day. A third group served as control. Rats were placed in meta-bolic cages and plasma creatinine and creatinine clearance were measured daily. GENTA group showed a progressive increase in plasma creatinine, a drop in creatinine clearance and an increase in urinary excretion of N-acetyl-β-D-glucosaminidase and alkaline phosphatase. GENTA + BN group showed a lesser change in plasma creatinine and a creatinine clearance, but no difference with GENTA group in urinary excretion of NAG and AP were observed. Histological examination revealed a massive cortical tubular necrosis in rats treated with gentamicin, whereas in BN-52021 injected animals tubular damage was markedly attenuated. The present results suggest a role for PAF in the gentamicininduced nephro-toxicity.

  13. Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure.

    Science.gov (United States)

    Sica, Domenic A

    2015-01-01

    Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered.

  14. A new class of NO-donor H3-antagonists.

    Science.gov (United States)

    Tosco, Paolo; Bertinaria, Massimo; Di Stilo, Antonella; Marini, Elisabetta; Rolando, Barbara; Sorba, Giovanni; Fruttero, Roberta; Gasco, Alberto

    2004-05-01

    Synthesis and pharmacological characterisation of a series of compounds obtained by joining, through appropriate spacers, NO-donor furoxan and nitrooxy moieties to the imidazole ring, as well as their structurally related analogues devoid of NO-donating properties are described. All the products were studied for their capacity to interact with H3-receptors present on the guinea-pig ileum and with H2-receptors present on guinea-pig right atrium. The whole series of products displayed reversible H3-antagonistic activity. No activity on H2-receptors was observed when the products were tested at 10 microM concentration. Many of the products were also able to induce partial relaxation when added to the bath after electrical contraction of the guinea-pig ileum during the study of their H3-antagonism. This phenomenon seems to be dependent on various factors; for some compounds it proved to be dependent on NO-mediated sGC activation, for other products it could be due to their weak M3-antagonism. The investigation of the lipophilic-hydrophilic balance of all the products indicates, for many of them, an ideal value to cross the blood-brain barrier.

  15. Orexin receptor antagonists as therapeutic agents for insomnia

    Directory of Open Access Journals (Sweden)

    Ana Clementina Equihua

    2013-12-01

    Full Text Available Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning.Currently, treatment for insomnia involves a combination of cognitive behavioral therapy and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine receptor agonist drugs (GABAA receptor, although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects.Orexin (hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g. impaired cognition, disturbed arousal, and motor balance difficulties. However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.

  16. Survey of H2-antagonist usage in acute upper gastrointestinal hemorrhage.

    Science.gov (United States)

    Bhatt, B D; Meriano, F V; Phipps, T L; Ho, H; Zuckerman, M J

    1990-02-01

    H2-antagonists are frequently used in the management of upper gastrointestinal (UGI) hemorrhage despite their lack of proven efficacy. In order to determine the pattern of H2-antagonist usage for this indication, we retrospectively reviewed the charts of 137 patients admitted with acute UGI bleeding over a 1-year period at two teaching hospitals in West Texas. An H2-antagonist was ordered in 89% of patients (77%) intravenous, 12% oral). It was administered within 2 h of admission in 25% of these patients, within 4 h in 54%, and within 8 h in 78%. An H2-antagonist was ordered among the initial six orders in 49% and among the initial 10 orders in 77% of patients. Considering orders for specific therapies, an H2-antagonist was in the initial three orders in 60% of patients and among the initial six orders in 97%. Of the patients who were prescribed an H2-antagonist and who also had upper endoscopy, the drug was ordered prior to endoscopy in 86%. This review of H2-antagonist usage in the management of acute UGI bleeding has identified a prescribing pattern of writing for these drugs early in the sequence of order writing, with the drugs being given early in the course of hospitalization.

  17. FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yi [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu (China); Xie, Xiaoyan; Li, Xinyi; Wang, Peiqi [State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University (China); Jing, Qian; Yue, Jiaqi; Liu, Yang [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Cheng, Zhong [Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu (China); Li, Jingyi, E-mail: li--jingyi@hotmail.com [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Song, Haixing [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Li, Guoyu, E-mail: liguoyulisa@163.com [School of Pharmacy, Shihezi University, Shihezi 832003 (China); Liu, Rui, E-mail: liurui_scu@hotmail.com [State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University (China); Wang, Jinhui [School of Pharmacy, Shihezi University, Shihezi 832003 (China)

    2016-05-20

    Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.

  18. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

    Directory of Open Access Journals (Sweden)

    Mallory Batty

    2016-08-01

    Full Text Available This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa. Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers.

  19. Angiotensin II AT1 receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release.

    Science.gov (United States)

    Kalinowski, Leszek; Matys, Tomasz; Chabielska, Ewa; Buczko, Włodzimierz; Malinski, Tadeusz

    2002-10-01

    This study investigated the process of nitric oxide (NO) release from platelets after stimulation with different angiotensin II type 1 (AT1)-receptor antagonists and its effect on platelet adhesion and aggregation. Angiotensin II AT1-receptor antagonist-stimulated NO release in platelets was compared with that in human umbilical vein endothelial cells by using a highly sensitive porphyrinic microsensor. In vitro and ex vivo effects of angiotensin II AT1-receptor antagonists on platelet adhesion to collagen and thromboxane A2 analog U46619-induced aggregation were evaluated. Losartan, EXP3174, and valsartan alone caused NO release from platelets and endothelial cells in a dose-dependent manner in the range of 0.01 to 100 micro mol/L, which was attenuated by NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. The angiotensin II AT1-receptor antagonists had more than 70% greater potency in NO release in platelets than in endothelial cells. The degree of inhibition of platelet adhesion (collagen-stimulated) and aggregation (U46619-stimulated) elicited by losartan, EXP3174, and valsartan, either in vitro or ex vivo, closely correlated with the NO levels produced by each of these drugs alone. The inhibiting effects of angiotensin II AT1-receptor antagonists on collagen-stimulated adhesion and U46619-stimulated aggregation of platelets were significantly reduced by pretreatment with N(G)-nitro-L-arginine methyl ester. Neither the AT2 receptor antagonist PD123319, the cyclooxygenase synthase inhibitor indomethacin, nor the selective thromboxane A2/prostaglandin H2 receptor antagonist SQ29,548 had any effect on angiotensin II AT1-receptor antagonist-stimulated NO release in platelets and endothelial cells. The presented studies clearly indicate a crucial role of NO in the arterial antithrombotic effects of angiotensin II AT1-receptor antagonists.

  20. Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy.

    Science.gov (United States)

    Löscher, W

    1998-04-01

    It is widely accepted that excitatory amino acid transmitters such as glutamate are involved in the initiation of seizures and their propagation. Most attention has been directed to synapses using NMDA receptors, but more recent evidence indicates potential roles for ionotropic non-NMDA (AMPA/kainate) and metabotropic glutamate receptors as well. Based on the role of glutamate in the development and expression of seizures, antagonism of glutamate receptors has long been thought to provide a rational strategy in the search for new, effective anticonvulsant drugs. Furthermore, because glutamate receptor antagonists, particularly those acting on NMDA receptors, protect effectively in the induction of kindling, it was suggested that they may have utility in epilepsy prophylaxis, for example, after head trauma. However, first clinical trials with competitive and uncompetitive NMDA receptor antagonists in patients with partial (focal) seizures, showed that these drugs lack convincing anticonvulsant activity but induce severe neurotoxic adverse effects in doses which were well tolerated in healthy volunteers. Interestingly, the only animal model which predicted the unfavorable clinical activity of competitive NMDA antagonists in patients with chronic epilepsy was the kindling model of temporal lobe epilepsy, indicating that this model should be used in the search for more effective and less toxic glutamate receptor antagonists. In this review, results from a large series of experiments on different categories of glutamate receptor antagonists in fully kindled rats are summarized and discussed. NMDA antagonists, irrespective whether they are competitive, high- or low-affinity uncompetitive, glycine site or polyamine site antagonists, do not counteract focal seizure activity and only weakly, if at all, attenuate propagation to secondarily generalized seizures in this model, indicating that once kindling is established, NMDA receptors are not critical for the expression of

  1. ASSESSMENT OF EFFICACY OF LEUKOTRIENE RECEPTOR ANTAGONISTS IN THERAPY OF BRONCHIAL ASTHMA IN CHILDREN

    Directory of Open Access Journals (Sweden)

    Yu.G. Levina

    2009-01-01

    Full Text Available The article provides data regarding the clinical efficacy and safety of leukotriene receptor antagonists in treatment of bronchial asthma in children. The only representative of this group that is allowed in Russia for treatment of children over 6 years of age is Montelukast. Approval of new 4 mg dosage of Montelukast for children from 2 years of age is expected in Russia in July 2009. Leukotriene receptor antagonists have a high safety profile and can be used as an alternative first-line therapy for persistent asthma.Key words: leukotriene receptor antagonists, montelukast, bronchial asthma, children.

  2. Development of selective agonists and antagonists of P2Y receptors

    OpenAIRE

    2008-01-01

    Although elucidation of the medicinal chemistry of agonists and antagonists of the P2Y receptors has lagged behind that of many other members of group A G protein-coupled receptors, detailed qualitative and quantitative structure–activity relationships (SARs) were recently constructed for several of the subtypes. Agonists selective for P2Y1, P2Y2, and P2Y6 receptors and nucleotide antagonists selective for P2Y1 and P2Y12 receptors are now known. Selective nonnucleotide antagonists were report...

  3. [Comparative pharmacophore analysis of dual dopamine D2/5-HT(2A) receptor antagonists].

    Science.gov (United States)

    Guo, Yan-shen; Guo, Zong-ru

    2009-03-01

    Dual dopamine D2/5-HT2A receptor antagonists have potent activity and are referred to atypical antipsychotics due to their lower propensity to elicit EPS and their moderate efficacy toward negative symptoms. However, an on-going challenge in developing atypical antipsychotics drugs is to maintain the favorable profiles and avoid of cardiovascular risk. In this paper, comparative pharmacophore analysis of dual dopamine D2/5-HT2A receptor antagonists, hERG K+ channel blockers, and alA adrenoceptor antagonists is carried out, and the results could give some insight into multi-target drug design.

  4. Structural insight into inactivation of plasminogen activator inhibitor-1 by a small-molecule antagonist

    DEFF Research Database (Denmark)

    Lin, Zhonghui; Jensen, Jan Kristian; Hong, Zebin

    2013-01-01

    and cancer. Several types of PAI-1 antagonist have been developed, but the structural basis for their action has remained largely unknown. Here we report X-ray crystal structure analysis of PAI-1 in complex with a small-molecule antagonist, embelin. We propose a mechanism for embelin-induced rapid conversion...... of PAI-1 into a substrate for its target proteases and the subsequent slow conversion of PAI-1 into an irreversibly inactivated form. Our work provides structural clues to an understanding of PAI-1 inactivation by small-molecule antagonists and an important step toward the design of drugs targeting PAI-1....

  5. Stereospecific reduction by narcotic antagonists of clonidine-induced food intake.

    Science.gov (United States)

    Katz, N L; Schlemmer, R F; Waller, D P

    1985-04-01

    The present study examined the effect of opiate antagonists on clonidine-induced feeding in rabbits. The change in food intake induced by clonidine was blocked by naltrexone. The active (-)-isomer of the antagonist 5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan had an effect similar to naltrexone. Similar doses of the (+)-isomer were inactive, except at the highest dose used in the study. The results suggest that opiate antagonists block feeding elicited by a specific noradrenoreceptor agonist and that this inhibition is due to a direct interaction with opiate systems.

  6. Activation of muscarinic acetylcholine receptors elicits pigment granule dispersion in retinal pigment epithelium isolated from bluegill

    Science.gov (United States)

    González, Alfredo; Crittenden, Elizabeth L; García, Dana M

    2004-01-01

    Background In fish, melanin pigment granules in the retinal pigment epithelium disperse into apical projections as part of the suite of responses the eye makes to bright light conditions. This pigment granule dispersion serves to reduce photobleaching and occurs in response to neurochemicals secreted by the retina. Previous work has shown that acetylcholine may be involved in inducing light-adaptive pigment dispersion. Acetylcholine receptors are of two main types, nicotinic and muscarinic. Muscarinic receptors are in the G-protein coupled receptor superfamily, and five different muscarinic receptors have been molecularly cloned in human. These receptors are coupled to adenylyl cyclase, calcium mobilization and ion channel activation. To determine the receptor pathway involved in eliciting pigment granule migration, we isolated retinal pigment epithelium from bluegill and subjected it to a battery of cholinergic agents. Results The general cholinergic agonist carbachol induces pigment granule dispersion in isolated retinal pigment epithelium. Carbachol-induced pigment granule dispersion is blocked by the muscarinic antagonist atropine, by the M1 antagonist pirenzepine, and by the M3 antagonist 4-DAMP. Pigment granule dispersion was also induced by the M1 agonist 4-[N-(4-chlorophenyl) carbamoyloxy]-4-pent-2-ammonium iodide. In contrast the M2 antagonist AF-DX 116 and the M4 antagonist tropicamide failed to block carbachol-induced dispersion, and the M2 agonist arecaidine but-2-ynyl ester tosylate failed to elicit dispersion. Conclusions Our results suggest that carbachol-mediated pigment granule dispersion occurs through the activation of Modd muscarinic receptors, which in other systems couple to phosphoinositide hydrolysis and elevation of intracellular calcium. This conclusion must be corroborated by molecular studies, but suggests Ca2+-dependent pathways may be involved in light-adaptive pigment dispersion. PMID:15251036

  7. Activation of muscarinic acetylcholine receptors elicits pigment granule dispersion in retinal pigment epithelium isolated from bluegill

    Directory of Open Access Journals (Sweden)

    Crittenden Elizabeth L

    2004-07-01

    Full Text Available Abstract Background In fish, melanin pigment granules in the retinal pigment epithelium disperse into apical projections as part of the suite of responses the eye makes to bright light conditions. This pigment granule dispersion serves to reduce photobleaching and occurs in response to neurochemicals secreted by the retina. Previous work has shown that acetylcholine may be involved in inducing light-adaptive pigment dispersion. Acetylcholine receptors are of two main types, nicotinic and muscarinic. Muscarinic receptors are in the G-protein coupled receptor superfamily, and five different muscarinic receptors have been molecularly cloned in human. These receptors are coupled to adenylyl cyclase, calcium mobilization and ion channel activation. To determine the receptor pathway involved in eliciting pigment granule migration, we isolated retinal pigment epithelium from bluegill and subjected it to a battery of cholinergic agents. Results The general cholinergic agonist carbachol induces pigment granule dispersion in isolated retinal pigment epithelium. Carbachol-induced pigment granule dispersion is blocked by the muscarinic antagonist atropine, by the M1 antagonist pirenzepine, and by the M3 antagonist 4-DAMP. Pigment granule dispersion was also induced by the M1 agonist 4-[N-(4-chlorophenyl carbamoyloxy]-4-pent-2-ammonium iodide. In contrast the M2 antagonist AF-DX 116 and the M4 antagonist tropicamide failed to block carbachol-induced dispersion, and the M2 agonist arecaidine but-2-ynyl ester tosylate failed to elicit dispersion. Conclusions Our results suggest that carbachol-mediated pigment granule dispersion occurs through the activation of Modd muscarinic receptors, which in other systems couple to phosphoinositide hydrolysis and elevation of intracellular calcium. This conclusion must be corroborated by molecular studies, but suggests Ca2+-dependent pathways may be involved in light-adaptive pigment dispersion.

  8. Development of psoriasis in IBD patients under TNF-antagonist therapy is associated neither with anti-TNF-antagonist antibodies nor trough levels.

    Science.gov (United States)

    Protic, Marijana; Schoepfer, Alain; Yawalkar, Nikhil; Vavricka, Stephan; Seibold, Frank

    2016-12-01

    The cause of anti-TNF-induced psoriasis is still unknown. We aimed to evaluate if the appearance of psoriasis under anti-TNF therapy is associated with anti-TNF antibody levels and TNF-antagonist trough levels. In this case-control study we identified 23 patients (21 with Crohn's disease [CD], two with ulcerative colitis [UC]) who developed psoriasis under infliximab (IFX, n = 20), adalimumab (ADA, n = 2), and certolizumab pegol (CZP, n= 1) and compared them regarding the anti-TNF-antagonist antibody levels with 85 IBD patients (72 with CD, 13 with UC) on anti-TNF therapy without psoriasis. Median disease duration was not different between the two groups (7 years in the group with psoriasis under TNF-antagonists vs. 10 years in the control group, p = 0.072). No patient from the psoriasis group had antibodies against TNF-antagonists compared to 10.6% in the control group (p = 0.103). No difference was found in IFX trough levels in the group of patients with psoriasis compared to the control group (2.6 μg/mL [IQR 0.9-5.5] vs. 3.4 μg/mL [IQR 1.4-8.1], p = 0.573). TNF-antagonist therapy could be continued in 91.3% of patients with TNF-antagonist related psoriasis and most patients responded to topical therapies. Anti-TNF-induced psoriasis seems to be independent of anti-TNF antibodies and trough levels. Interruption of Anti-TNF therapy is rarely necessary.

  9. 甘肃马家塬战国墓地M4出土硅酸盐珠饰的科学分析研究%Analysis of the Decorated Silicate Beads Excavated f rom Tomb M4 of the Ma-Jia-Yuan Warring States Cemetery,Gansu Province

    Institute of Scientific and Technical Information of China (English)

    黄晓娟; 严静; 王辉

    2015-01-01

    结合X射线荧光光谱、拉曼光谱和X射线衍射分析,对甘肃马家塬战国墓地M 4出土的11件装饰性硅酸盐珠饰进行了无损分析研究。依据分析结果将这些样品划分为钠钙硅酸盐玻璃、铅钡硅酸盐玻璃和釉砂三种类型。化学成分分析结果表明:钠钙硅酸盐蜻蜓眼玻璃珠的蓝色眼珠部分采用Co2+着色。拉曼光谱分析在铅钡体系硅酸盐样品中检测到了人工合成的硅酸钡铜系中国蓝和中国紫颜料,在钠钙蜻蜓眼玻璃的白色区域检测到了锑酸钙(CaSb2 O6)乳浊剂/着色剂。结合已有的研究结果,探讨了所分析样品的可能来源及其反映的早期文化和技术交流状况。含有中国蓝、中国紫的装饰性珠子的制作材料和工艺应当是受到当时秦人的影响。而钠钙蜻蜓眼珠的成分特点,又与新疆等西北地区出土的同类珠子有相似之处。可见西戎人在玻璃制作技术方面同时受到北方草原民族文化和秦文化的共同影响。这批样品中以泥芯和玻璃化材料共同组成的装饰珠子,可能是从釉砂珠向玻璃珠的过渡类型,这对于研究我国玻璃的起源问题提供了新的参考资料。%This paper reports the analysis results of 11 decorated silicate beads samples excavated from Ma Jia‐yuan Warring State Cemetery ,Gan Su Province with the portable X‐ray fluorescence spectrometer ,laser Raman spectrometer and X‐ray dif‐fraction spectrometer .It is includes 3 types among these samples on the basis of their chemical composition ,NaO‐CaO‐SiO2 , PbO‐BaO‐SiO2 glass system ,and glassy faience .The blue part of the NaO‐CaO‐SiO2 glass sample was colored by Co2+ ,and Sb2O5 was discovered as opacifier .The results of Laser Raman analysis shows in some circle beads exits Chinese blue and Chinese purple .Combined with the existing research results the early cultural factors and technical exchange reflected from these

  10. A new series of photoactivatable and iodinatable linear vasopressin antagonists.

    Science.gov (United States)

    Carnazzi, E; Aumelas, A; Barberis, C; Guillon, G; Seyer, R

    1994-06-10

    A series of new linear photoactivatable and iodinatable antagonists of the neuropeptidic hormone vasopressin was designed and synthesized by a combination of PyBOP-mediated Boc/solid-phase peptide synthesis and solution synthesis approaches. These were based on modifications of a previously reported potent and selective antagonist of the vasopressor response (V1a receptor) to [arginine]vasopressin, phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2. (Azidophenyl)alkyl substitutions, of the general structure N3-C6H4(CH2)nCO (n = 0, 1, 2, or 3), were employed in position 1. The seven new analogues are 4-N3-C6H4CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (3), 3-N3-C6H4CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (12), 4-N3-C6H4CH2-CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (13), 3-N3-C6H4CH2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (14), 4-N3-C6H4(CH2)2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (15), 3-N3-C6H4(CH2)2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (16), 4-N3-C6H4-(CH2)3CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (17). All analogues were tested for their affinity of the rat hepatic V1a receptor. Analogues 3 and 12 have a low affinity (Ki approximately 20 nM) and analogues 13-17 show a high affinity (Ki between 0.04 and 0.3 nM). The affinity values appear to be mainly a function of the alkyl chain length and to a lesser extent of the meta or para position of the azido group on the aromatic ring. Analogues 13-17 were iodinated on the Tyr-9 residue, giving compounds 18-22. All these five iodinated derivatives exhibited Ki values of 0.2-1 nM for rat liver membranes. Their affinities for oxytocin and renal V2 vasopressin receptors were much lower. Moreover, all analogues completely antagonized the vasopressin-stimulated inositol phosphates production in WRK1 cells and were devoided of any agonistic potency. Preliminary covalent binding studies showed improved covalent yields as compared to any previously reported results. They are very promising

  11. Challenges to antagonist blockade during sustained-release naltrexone treatment.

    Science.gov (United States)

    Kunøe, Nikolaj; Lobmaier, Philipp; Vederhus, John Kåre; Hjerkinn, Bjørg; Gossop, Michael; Hegstad, Solfrid; Kristensen, Øistein; Waal, Helge

    2010-09-01

    Naltrexone is a competitive opioid antagonist that effectively blocks the action of heroin and other opioid agonists. Sustained-release naltrexone formulations are now available that provide long-acting opioid blockade. This study investigates the use of heroin and other opioids among opioid-dependent patients receiving treatment with long-acting naltrexone implants, their subjective experience of drug 'high' after opioid use, and factors associated with opioid use. Participants (n = 60) were opioid-dependent patients receiving treatment with naltrexone implants. Outcome data on substance use, drug 'high', depression and criminal activity were collected over a 6-month period. Blood samples were taken to monitor naltrexone plasma levels, and hair samples to verify self-reported opioid use. More than half [n = 34 or 56%; 95% confidence interval (CI) 44-68%)] the patients challenged the blockade with illicit opioids during the 6-month treatment period; 44% (n = 26; 95% CI 32-56%) were abstinent from opioids. Mean opioid use was reduced from 18 [standard deviation (SD)13] days during the month preceding treatment to 6 days (SD 11) after 6 months. Of the respondents questioned on opioid 'high' (n = 31), nine patients (30%; 95% CI 16-47%) reported partial drug 'high' following illicit opioid use, and three (12%; 95% CI 3-26%) reported full 'high'. Opioid use was associated with use of non-opioid drugs and criminal behaviour. Challenging naltrexone blockade with heroin on at least one occasion is common among sustained-release naltrexone patients, but only a minority of patients use opioids regularly. Challenges represent a warning sign for poor outcomes and often occur in the context of polydrug use and social adjustment problems.

  12. Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension

    Directory of Open Access Journals (Sweden)

    Borst Mathias M

    2009-12-01

    Full Text Available Abstract Background In idiopathic pulmonary arterial hypertension (IPAH, peripheral airway obstruction is frequent. This is partially attributed to the mediator dysbalance, particularly an excess of endothelin-1 (ET-1, to increased pulmonary vascular and airway tonus and to local inflammation. Bosentan (ET-1 receptor antagonist improves pulmonary hemodynamics, exercise limitation, and disease severity in IPAH. We hypothesized that bosentan might affect airway obstruction. Methods In 32 IPAH-patients (19 female, WHO functional class II (n = 10, III (n = 22; (data presented as mean ± standard deviation pulmonary vascular resistance (11 ± 5 Wood units, lung function, 6 minute walk test (6-MWT; 364 ± 363.7 (range 179.0-627.0 m, systolic pulmonary artery pressure, sPAP, 79 ± 19 mmHg, and NT-proBNP serum levels (1427 ± 2162.7 (range 59.3-10342.0 ng/L were measured at baseline, after 3 and 12 months of oral bosentan (125 mg twice per day. Results and Discussion At baseline, maximal expiratory flow at 50 and 25% vital capacity were reduced to 65 ± 25 and 45 ± 24% predicted. Total lung capacity was 95.6 ± 12.5% predicted and residual volume was 109 ± 21.4% predicted. During 3 and 12 months of treatment, 6-MWT increased by 32 ± 19 and 53 ± 69 m, respectively; p Conclusion This study gives first evidence in IPAH, that during long-term bosentan, improvement of hemodynamics, functional parameters or serum biomarker occur independently from persisting peripheral airway obstruction.

  13. Pediatric heart failure therapy with beta-adrenoceptor antagonists.

    Science.gov (United States)

    Foerster, Susan R; Canter, Charles E

    2008-01-01

    Management of chronic heart failure in pediatrics has been altered by the adult literature showing improvements in mortality and hospitalization rates with the use of beta-adrenoceptor antagonists (beta-blockers) for routine therapy of all classes of ischemic and non-ischemic heart failure. Many pediatric heart failure specialists have incorporated these agents into their routine management of pediatric heart failure related to dilated cardiomyopathy or ventricular dysfunction in association with congenital heart disease. Retrospective and small prospective case series have shown encouraging improvements in cardiac function and symptoms, but interpretation has been complicated by the high rate of spontaneous recovery in pediatric patients. A recently completed pediatric double-blind, randomized, placebo-controlled clinical trial showed no difference between placebo and two doses of carvedilol over a 6-month period of follow-up, with significant improvement of all three groups over the course of evaluation. Experience with adults has suggested that only certain beta-blockers, including carvedilol, bisoprolol, nebivolol, and metoprolol succinate, should be used in the treatment of heart failure and that patients with high-grade heart failure may derive the most benefit. Other studies surmise that early or prophylactic use of these medications may alter the risk of disease progression in some high-risk subsets, such as patients receiving anthracyclines or those with muscular dystrophy. This article reviews these topics using experience as well as data from all the recent pediatric studies on the use of beta-blockers to treat congestive heart failure, especially when related to systolic ventricular dysfunction.

  14. Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy.

    Science.gov (United States)

    Stern, Michael

    2017-06-01

    The antagonistic pleiotropy (AP) theory posits that aging occurs because alleles that are detrimental in older organisms are beneficial to growth early in life and thus are maintained in populations. Although genes of the insulin signaling pathway likely participate in AP, the insulin-regulated cellular correlates of AP have not been identified. The mitochondrial quality control process called mitochondrial autophagy (mitophagy), which is inhibited by insulin signaling, might represent a cellular correlate of AP. In this view, rapidly growing cells are limited by ATP production; these cells thus actively inhibit mitophagy to maximize mitochondrial ATP production and compete successfully for scarce nutrients. This process maximizes early growth and reproduction, but by permitting the persistence of damaged mitochondria with mitochondrial DNA mutations, becomes detrimental in the longer term. I suggest that as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy, leading to a further decrease in ATP output in a classic death spiral. I suggest that this increasing ATP deficit is communicated by progressive increases in mitochondrial ROS generation, which signals inhibition of mitophagy via ROS-dependent activation of insulin signaling. This hypothesis clarifies a role for ROS in aging, explains why insulin signaling inhibits autophagy, and why cells become progressively more oxidized during aging with increased levels of insulin signaling and decreased levels of autophagy. I suggest that the mitochondrial death spiral is not an error in cell physiology but rather a rational approach to the problem of enabling successful growth and reproduction in a competitive world of scarce nutrients. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  15. ANTAGONISTIC ACTIVITY OF SERRATIA MARCESCENS AGAINST PYRICULARIA ORYZAE

    Directory of Open Access Journals (Sweden)

    V. JAIGANESH

    2007-08-01

    Full Text Available Rice is an important crop, widely affected by quite a number of diseases that results in higher yield losses. Among the fungal diseases, blast incited by Pyricularia oryzae is a major disease. The biological method of plant disease management seems to be an alternative to chemical fungicides in managing the blast disease. A new bio control agent viz., Serratia marcescens appears to be an ideal agent for the control of P. oryzae, because it produces chitinolytic enzymes which causes degradation of the fungal cell walls, induction of plant defence reaction and certain antifungal low molecular weight molecules. A study was undertaken to investigate the effect of a new bio control agent like S. marcescens against P. oryzae. The talc based formulation of S. marcescens (@ 1.0, 1.5, 2.0 and 2.5 kg/ha was sprayed on old IR 50 rice plants in fields. Out of the six-bio protectants tested, S. marcescens was found very effective against P. oryzae under in vitro conditions. S. marcescens could be isolated from shoots as well as roots emerging from the treated seeds and the plant parts from treated seeds inhibited P. oryzae. The antagonist S. marcescens survived in the phyllosphere even 80 days after spray. The results revealed that rice blast control was achieved by spraying S. marcescens @ 1.0 kg/ha. The increasing dose of talc-based inoculum when applied on foliage increased the phyllosphere population of S. marcescens and controlled rice blast. The maximum disease control was achieved when inoculum was applied at 2.5 kg/ha.

  16. Hepcidin antagonists for potential treatments of disorders with hepcidin excess

    Directory of Open Access Journals (Sweden)

    Poli eMaura

    2014-04-01

    Full Text Available The discovery of hepcidin clarified the basic mechanism of the control of systemic iron homeostasis. Hepcidin is mainly produced by the liver as a propeptide and processed by furin into the mature active peptide. Hepcidin binds ferroportin, the only cellular iron exporter, causing the internalization and degradation of both. Thus hepcidin blocks iron export from the key cells for dietary iron absorption (enterocytes, recycling of haemoglobin iron (the macrophages and the release of storage iron from hepatocytes, resulting in the reduction of systemic iron availability. The BMP/HJV/SMAD pathway is the major regulator of hepcidin expression that responds to iron status. Also inflammation stimulates hepcidin via the IL6/STAT3 pathway with a support of an active BMP/HJV/SMAD pathway. In some pathological conditions hepcidin level is inadequately elevated and reduces iron availability in the body, resulting in anemia. These conditions occur in the genetic Iron Refractory Iron Deficiency Anemia (IRIDA and the common Anemia of Chronic Disease (ACD or Anemia of Inflammation. Currently, there is no definite treatment for ACD. Erythropoiesis stimulating agents and intravenous iron have been proposed in some cases but they are scarcely effective and may have adverse effects. Alternative approaches aimed to a pharmacological control of hepcidin expression have been attempted, targeting different regulatory steps. They include hepcidin sequestering agents (antibodies, anticalins and aptamers, inhibitors of BMP/SMAD or of IL6/STAT3 pathway or of hepcidin transduction (siRNA/shRNA or ferroportin stabilizers. In this review we summarized the biochemical interactions of the proteins involved in the BMP/HJV/SMAD pathway and its natural inhibitors, the murine and rat models with high hepcidin levels currently available and finally the progresses in the development of hepcidin antagonists, with particular attention to the role of heparins and heparin sulphate

  17. Update on leukotriene receptor antagonists in preschool children wheezing disorders

    Directory of Open Access Journals (Sweden)

    Montella Silvia

    2012-06-01

    Full Text Available Abstract Asthma is the most common chronic disease in young children. About 40% of all preschool children regularly wheeze during common cold infections. The heterogeneity of wheezing phenotypes early in life and various anatomical and emotional factors unique to young children present significant challenges in the clinical management of this problem. Anti-inflammatory therapy, mainly consisting of inhaled corticosteroids (ICS, is the cornerstone of asthma management. Since Leukotrienes (LTs are chemical mediators of airway inflammation in asthma, the leukotriene receptor antagonists (LTRAs are traditionally used as potent anti-inflammatory drugs in the long-term treatment of asthma in adults, adolescents, and school-age children. In particular, montelukast decreases airway inflammation, and has also a bronchoprotective effect. The main guidelines on asthma management have confirmed the clinical utility of LTRAs in children older than five years. In the present review we describe the most recent advances on the use of LTRAs in the treatment of preschool wheezing disorders. LTRAs are effective in young children with virus-induced wheeze and with multiple-trigger disease. Conflicting data do not allow to reach definitive conclusions on LTRAs efficacy in bronchiolitis or post-bronchiolitis wheeze, and in acute asthma. The excellent safety profile of montelukast and the possibility of oral administration, that entails better compliance from young children, represent the main strengths of its use in preschool children. Montelukast is a valid alternative to ICS especially in poorly compliant preschool children, or in subjects who show adverse effects related to long-term steroid therapy.

  18. A novel antagonistic role of natural compound icariin on neurotoxicity of amyloid β peptide

    Directory of Open Access Journals (Sweden)

    Jianhui Liu

    2015-01-01

    Interpretation & conclusions: The results indicated a novel antagonistic role of icariin in the neurotoxicity of Aβ1-42 via inhibiting its aggregation, suggesting that icariin might have potential therapeutic benefits to delay or modify the progression of AD.

  19. Melanin concentrating hormone receptor 1 (MCHR1) antagonists - Still a viable approach for obesity treatment?

    DEFF Research Database (Denmark)

    Högberg, T.; Frimurer, T.M.; Sasmal, P.K.

    2012-01-01

    Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes...

  20. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment : a randomized controlled trial

    NARCIS (Netherlands)

    De Jong, Cor A J; Laheij, Robert J F; Krabbe, Paul F M

    AIM: Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without

  1. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment: a randomized controlled trial.

    NARCIS (Netherlands)

    Jong, C.A.J. de; Laheij, R.J.F.; Krabbe, P.F.M.

    2005-01-01

    AIM: Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without

  2. HETEROGENEOUS RECEPTOR-BINDING OF CLASSICAL QUATERNARY MUSCARINIC ANTAGONISTS .1. BOVINE TISSUE DISTRIBUTION

    NARCIS (Netherlands)

    ROFFEL, AF; ENSING, K; INTHOUT, WG; DEZEEUW, RA; ZAAGSMA, J

    1991-01-01

    In competition experiments with the teritiary radioligand [H-3]dexetimide, classical quaternary muscarinic antagonists like ipratropium bromide and N-methylscopolamine bromide distinguished two muscarinic binding sites in bovine brain (total brain minus cerebellum) membranes, in contrast to their

  3. Antagonist muscle moment is increased in ACL deficient subjects during maximal dynamic knee extension

    DEFF Research Database (Denmark)

    Alkjær, Tine; Simonsen, Erik B; Magnusson, S Peter

    2012-01-01

    INTRODUCTION: Coactivation of the hamstring muscles during dynamic knee extension may compensate for increased knee joint laxity in anterior cruciate ligament (ACL) deficient subjects. This study examined if antagonist muscle coactivation during maximal dynamic knee extension was elevated...... in subjects with anterior cruciate ligament (ACL) deficiency compared to age-matched healthy controls. METHODS: Electromyography (EMG) and net knee joint moments were recorded during maximal concentric quadriceps and eccentric hamstring contractions, performed in an isokinetic dynamometer (ROM: 90......-10°, angular speed: 30°/s). Hamstring antagonist EMG recorded during concentric quadriceps contraction was converted into antagonist moment based on the EMG-moment relationship observed during eccentric agonist contractions. RESULTS: The magnitude of antagonist hamstring EMG was 65.5% higher in ACL deficient...

  4. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement

    DEFF Research Database (Denmark)

    Solovic, I.; Sester, M.; Gomez-Reino, J.J.

    2010-01-01

    a history of bacille Calmette-Guerin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test......Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased...... risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-gamma release assays or, as an alternative in individuals without...

  5. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement

    DEFF Research Database (Denmark)

    Solovic, I; Sester, M; Gomez-Reino, J J

    2010-01-01

    of bacille Calmette-Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test......Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased...... risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-¿ release assays or, as an alternative in individuals without a history...

  6. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction : integrating evidence into clinical practice

    NARCIS (Netherlands)

    Zannad, Faiez; Stough, Wendy Gattis; Rossignol, Patrick; Bauersachs, Johann; McMurray, John J. V.; Swedberg, Karl; Struthers, Allan D.; Voors, Adriaan A.; Ruilope, Luis M.; Bakris, George L.; O'Connor, Christopher M.; Gheorghiade, Mihai; Mentz, Robert J.; Cohen-Solal, Alain; Maggioni, Aldo P.; Beygui, Farzin; Filippatos, Gerasimos S.; Massy, Ziad A.; Pathak, Atul; Pina, Ileana L.; Sabbah, Hani N.; Sica, Domenic A.; Tavazzi, Luigi; Pitt, Bertram

    2012-01-01

    Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HFREF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These

  7. Epimuscular myofascial force transmission between antagonistic and synergistic muscles can explain movement limitation in spastic paresis

    NARCIS (Netherlands)

    Huijing, Peter A.

    2007-01-01

    Details and concepts of intramuscular, extramuscular and intermuscular myofascial force transmission are reviewed. Some new experimental data are added regarding myofascial force transmission between antagonistic muscles across the interosseal membrane of the lower hind limb of the rat. Combined wit

  8. Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles

    DEFF Research Database (Denmark)

    Arce, Joan-Carles; La Marca, Antonio; Mirner Klein, Bjarke

    2013-01-01

    To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol.......To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol....

  9. Population pharmacokinetic modeling of a subcutaneous depot for GnRH antagonist degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;

    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone (GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose...... depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles....

  10. Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;

    2004-01-01

    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone ( GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose...... depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles....

  11. Data on the oral CRTh2 antagonist QAW039 (fevipiprant) in patients with uncontrolled allergic asthma

    OpenAIRE

    2016-01-01

    This article contains data on clinical endpoints (Peak Flow Expiratory Rate, fractional exhaled nitric oxide and total IgE serum levels) and plasma pharmacokinetic parameters concerning the use of the oral CRTh2 antagonist QAW039 (fevipiprant) in mild to moderate asthma patients. Information on experimental design and methods on how this data was obtained is also described. Further interpretation and discussion of this data can be found in the article “The oral CRTh2 antagonist QAW039 (fevipi...

  12. The Effect of Sympathetic Antagonists on the Antidepressant Action of Alprazolam

    Directory of Open Access Journals (Sweden)

    Gorash ZM

    2008-01-01

    Full Text Available Alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam–induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a β1-selective adrenoceptor antagonist; propranolol, a non selective β-adrenoceptor antagonist; and prazocin, an α1-adrenoceptor antagonist. Results confirmed the antidepressant action of alprazolam and imipramine. Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. Atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. Propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments. In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates β2 receptors to produce an antidepressant action. Imipramine may act by activating β2 receptors by blocking or down-regulating β1 receptors.

  13. Biological Control of Chickpea Collar Rot by Co-inoculation of Antagonistic Bacteria and Compatible Rhizobia

    OpenAIRE

    Hameeda, B.; Harini, G.; Rupela, O. P.; Kumar Rao, J. V. D. K.; Reddy, Gopal

    2010-01-01

    Two hundred and seven bacteria were isolated from composts and macrofauna and screened for plant growth promoting and antagonistic traits. Seven of the 207 isolates showed antagonistic activity against Sclerotium rolfsii in plate culture. Inhibition of S. rolfsii by the bacterial isolates ranged between 61 and 84%. Two of the seven isolates were Bacillus sp. and rest belonged to Pseudomonas sp. Two isolates, Pseudomonas sp. CDB 35 and Pseudomonas sp. BWB 21 was compatible with chickpea Rhizob...

  14. The discovery of the benzazepine class of histamine H3 receptor antagonists.

    Science.gov (United States)

    Wilson, David M; Apps, James; Bailey, Nicholas; Bamford, Mark J; Beresford, Isabel J; Briggs, Michael A; Calver, Andrew R; Crook, Barry; Davis, Robert P; Davis, Susannah; Dean, David K; Harris, Leanne; Heightman, Tom D; Panchal, Terry; Parr, Christopher A; Quashie, Nigel; Steadman, Jon G A; Schogger, Joanne; Sehmi, Sanjeet S; Stean, Tania O; Takle, Andrew K; Trail, Brenda K; White, Trevor; Witherington, Jason; Worby, Angela; Medhurst, Andrew D

    2013-12-15

    This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.

  15. Histamine H3 receptor antagonist decreases cue-induced alcohol reinstatement in mice.

    Science.gov (United States)

    Nuutinen, Saara; Mäki, Tiia; Rozov, Stanislav; Bäckström, Pia; Hyytiä, Petri; Piepponen, Petteri; Panula, Pertti

    2016-07-01

    We have earlier found that the histamine H3 receptor (H3R) antagonism diminishes motivational aspects of alcohol reinforcement in mice. Here we studied the role of H3Rs in cue-induced reinstatement of alcohol seeking in C57BL/6J mice using two different H3R antagonists. Systemic administration of H3R antagonists attenuated cue-induced alcohol seeking suggesting that H3R antagonists may reduce alcohol craving. To understand how alcohol affects dopamine and histamine release, a microdialysis study was performed on C57BL/6J mice and the levels of histamine, dopamine and dopamine metabolites were measured in the nucleus accumbens. Alcohol administration was combined with an H3R antagonist pretreatment to reveal whether modulation of H3R affects the effects of alcohol on neurotransmitter release. Alcohol significantly increased the release of dopamine in the nucleus accumbens but did not affect histamine release. Pretreatment with H3R antagonist ciproxifan did not modify the effect of alcohol on dopamine release. However, histamine release was markedly increased with ciproxifan. In conclusion, our findings demonstrate that H3R antagonism attenuates cue-induced reinstatement of alcohol seeking in mice. Alcohol alone does not affect histamine release in the nucleus accumbens but H3R antagonist instead increases histamine release significantly suggesting that the mechanism by which H3R antagonist inhibits alcohol seeking found in the present study and the decreased alcohol reinforcement, reward and consumption found earlier might include alterations in the histaminergic neurotransmission in the nucleus accumbens. These findings imply that selective antagonists of H3Rs could be a therapeutic strategy to prevent relapse and possibly diminish craving to alcohol use. This article is part of the Special Issue entitled 'Histamine Receptors'.

  16. Synthesis and dual histamine H₁ and H₂ receptor antagonist activity of cyanoguanidine derivatives.

    Science.gov (United States)

    Sadek, Bassem; Alisch, Rudi; Buschauer, Armin; Elz, Sigurd

    2013-11-15

    Premedication with a combination of histamine H₁ receptor (H₁R) and H₂ receptor (H₂R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H₁R and H₂R antagonistic activity, a series of cyanoguanidines 14-35 was synthesized by linking mepyramine-type H₁R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H₂R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the "urea equivalent" of the H₂R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H₁R) and the isolated spontaneously beating right atrium (H₂R) of the guinea pig. The results indicate that, depending on the nature of the H₂R antagonist partial structure, the highest H₁R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21), and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33), N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl)-N-(pyridyl)-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H₁R, ileum) and 7.73 (H₂R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H₁R) and 6.61 (H₂R) were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H₁R and H₂R pharmacophoric moieties with mutually affinity-enhancing properties.

  17. Synthesis and Dual Histamine H1 and H2 Receptor Antagonist Activity of Cyanoguanidine Derivatives

    Directory of Open Access Journals (Sweden)

    Bassem Sadek

    2013-11-01

    Full Text Available Premedication with a combination of histamine H1 receptor (H1R and H2 receptor (H2R antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H1R and H2R antagonistic activity, a series of cyanoguanidines 14–35 was synthesized by linking mepyramine-type H1R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H2R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the “urea equivalent” of the H2R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H1R and the isolated spontaneously beating right atrium (H2R of the guinea pig. The results indicate that, depending on the nature of the H2R antagonist partial structure, the highest H1R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21, and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33, N-cyano-N'-[2-[[(2-guanidino-4-thiazolylmethyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl-N-(pyridyl-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H1R, ileum and 7.73 (H2R, atrium and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H1R and 6.61 (H2R were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H1R and H2R pharmacophoric moieties with mutually affinity-enhancing properties.

  18. Action of CB1 and CB2 antagonists/inverse agonists on mantle cell lymphoma

    OpenAIRE

    Chui, Daniel

    2011-01-01

    In this study, the effects of antagonists to the cannabinoid receptors in MCL cell lines were studied. Results presented in this study show that signalling through cannabinoid receptor with antagonists such as SR141716, SR144528 decreases cell viability but hemopressin when analyzing with XTT. The decrease in cell viability by SR141716 is caused by apoptosis triggered after 5 hours of treatment. The CB1 expression was confirmed in all MCL cell lines tested via western blotting but the express...

  19. Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model

    DEFF Research Database (Denmark)

    Chan, K Y; Gupta, S; de Vries, R;

    2010-01-01

    studies have shown that glutamate receptor antagonists affect the pathophysiology of migraine. This study investigated whether antagonists of NMDA (ketamine and MK801), AMPA (GYKI52466) and kainate (LY466195) glutamate receptors affected dural vasodilatation induced by alpha-CGRP, capsaicin......During migraine, trigeminal nerves may release calcitonin gene-related peptide (CGRP), inducing cranial vasodilatation and central nociception; hence, trigeminal inhibition or blockade of craniovascular CGRP receptors may prevent this vasodilatation and abort migraine headache. Several preclinical...

  20. Three years in vivo wear: core-ceramic, veneers, and enamel antagonists.

    Science.gov (United States)

    Esquivel-Upshaw, Josephine F; Rose, William F; Barrett, Allyson A; Oliveira, Erica R; Yang, Mark C K; Clark, Arthur E; Anusavice, Kenneth J

    2012-06-01

    Test the hypotheses that there are equivalent wear rates for enamel-versus-enamel and ceramic-versus-enamel, analyzing the in vivo wear of crown ceramics, their natural enamel antagonists, and the corresponding two contralateral teeth; and, that bite force does not correlate with the wear. A controlled, clinical trial was conducted involving patients needing full coverage crowns opposing enamel antagonists. Bite forces were measured using a bilateral gnathodynamometer. Single-unit restorations of metal/ceramic (Argedent 62, Argen Corp/IPS d.SIGN veneer); or, core-ceramic/veneer from either, Empress2/Eris, or e.max Press core/e.max Ceram glaze (ceramics: Ivoclar Vivadent, USA) were randomly assigned, fabricated and cemented. Impressions were made of the ceramic crowns, as well as each maxillary and mandibular quadrant at one week (baseline) and one, two and three years. Resulting models were scanned (3D laser scanner). Maximum wear was calculated by superimposing baseline with annual images. There were a total of thirty-six crowns required for thirty-one patients. Each restoration had three associated enamel teeth: crown, (1) antagonist, (2) contralateral and (3) contralateral-antagonist. SAS PROC MIXED (α=0.05) indicated no statistical significance for mean maximum wear among crown ceramics, enamel antagonists and contralaterals. However, enamel wear was statistically significant in relation to intraoral location (p=0.04) and among years (p<0.02). Analyzed alone, the enamel contralateral-antagonist exhibited significantly greater wear (p<0.001). Considering all wear sites, there was no correlation with bite force (p=0.15). The ceramics and their antagonists exhibited in vivo wear rates within the range of normal enamel. Future studies should examine the wear implications of the contralateral-antagonist enamel. Copyright © 2012 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

  1. Partial characterization of antagonistic substance produced by a Clostridium butyricum strain

    OpenAIRE

    Nely Cristina Medeiros Caires; Aline Magalhães Matos; Luiz Macedo Farias; Maria Auxiliadora Roque Carvalho; Regina Maria Nardi Drummond; Jacques Robert Nicoli; Antônio Paulino Ribeiro Sobrinho

    2007-01-01

    The production of antagonistic substance by bacterium present in the infected root canal system (RCS) probably is an important ecological factor for its successful colonization of the local. The objective of this study was to partially characterize an antagonistic substance produced by a Clostridium butyricum isolated from infected RCS.Production of inhibitory compound was evaluated by the agar double layer diffusion technique using Fusobacterium nucleatum and Bifidobacterium adolescentis as ...

  2. Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg

    2004-01-01

    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone ( GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose...... depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles....

  3. Effects of H1–receptor antagonists in antidepressant tests in rats

    OpenAIRE

    Chitra C. Khanwelkar

    2008-01-01

    : Considering the vast data suggesting the role of brain histamine(HA) in behaviour,emotions,anxiety and depression;four H1-receptor antagonists; promethazine, diphenhydramine, cyclizine and pheniramine were subjected to antidepressant tests in rats. All H1 – antagonists behaved like antidepressants in animal tests. They antagonized reserpine induced catalepsy, potentiated methamphetamine induced stereotypy and reduced the period of immobility in Porsolt’s behavioural despair test. It is sug...

  4. The molecular marker of antagonistic genes of biological bacteria against rice sheath blight by RAPD

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    @@Forrty-one isolates of Bacillus amyloliquefaciens were differentiated from 184 G + bacterial strains having genetic similarities over 75%based on BOX-PCR fingerprint. Antagonism against to Rhizotonia solani in vitro was tested.Four isolates of B. arayloliquefaciens (2 isolates with antagonistic ability, G 396 + and G229 +, and 2 isolates without antagonistic ability, G433-and G434-) were selected to screen effective primers for RAPD analysis. Of 124 random primers (AA, AB, AC, AD, AE, AM, and AL) tested.

  5. Ondansetron, a selective 5-HT3 antagonist, antagonizes methamphetamine-induced anorexia in mice.

    Science.gov (United States)

    Ginawi, O T; Al-Majed, A A; Al-Suwailem, A K

    2005-03-01

    Effects of some selective serotonergic (5-HT) antagonists on methamphetamine-induced anorexia were investigated in male mice. The least possible dose of methamphetamine alone that caused significant anorectic activity was 11 micromolkg(-1), i.p. (2 mgkg(-1)). Various doses of some selective serotonergic receptor antagonists were administered half an hour before the above mentioned dose of methamphetamine. Methiothepin potentiated, whereas NAN-190, methysergide, mianserin and ondansetron antagonized methamphetamine-induced anorectic activity. The least possible doses of these antagonists which modified methamphetamine-induced anorexia were as follows: methiothepin (1.1 micromolkg(-1), i.p.), NAN-190 (4.2 micromolkg(-1), i.p.), methysergide (2.1 micromolkg(-1), i.p.), mianserin (3.3 micromolkg(-1), i.p.) and ondansetron (0.003 micromolkg(-1), i.p.). The serotonergic antagonists at the above mentioned doses did not modify the food intake of animals not treated with methamphetamine, except for methiothepin, which produced a significant reduction, and mianserin, which produced a significant increase in food intake. The results of the present study indicated that the anorectic activity induced by methamphetamine is related to the interactions of methamphetamine with 5-HT receptor. Since a very small dose (0.003 micromolkg(-1)) of ondansetron (the 5-HT(3) antagonist), as compared with the other antagonists used in this study, antagonized the anorexia induced by methamphetamine, the 5-HT(3) receptor is likely to be the site for this interaction.

  6. Molecular Gymnastics: Mechanisms of HIV-1 Resistance to CCR5 Antagonists and Impact on Virus Phenotypes.

    Science.gov (United States)

    Roche, Michael; Borm, Katharina; Flynn, Jacqueline K; Lewin, Sharon R; Churchill, Melissa J; Gorry, Paul R

    2016-01-01

    Human immunodeficiency virus type 1 (HIV-1) enters host cells through the binding of its envelope glycoproteins (Env) to the host cell receptor CD4 and then subsequent binding to a chemokine coreceptor, either CCR5 or CXCR4. CCR5 antagonists are a relatively recent class addition to the armamentarium of anti-HIV-1 drugs. These compounds act by binding to a hydrophobic pocket formed by the transmembrane helices of CCR5 and altering the conformation of the extracellular domains, such that they are no longer recognized by Env. Maraviroc is the first drug within this class to be licenced for use in HIV-1 therapy regimens. HIV resistance to CCR5 antagonists occurs either through outgrowth of pre-existing CXCR4-using viruses, or through acquisition of the ability of CCR5-using HIV-1 to use the antagonist bound form of CCR5. In the latter scenario, the mechanism underlying resistance is through complex alterations in the way that resistant Envs engage CCR5. These significant changes are unlikely to occur without consequence to the viral entry phenotype and may also open up new avenues to target CCR5 antagonist resistant viruses. This review discusses the mechanism of action of CCR5 antagonists, how HIV resistance to CCR5 antagonists occurs, and the subsequent effects on Env function.

  7. The variability of co-activation pattern of antagonist muscles in human infant crawling.

    Science.gov (United States)

    Xiong, Qi L; Wu, Xiao Y; Nong Xiao; Zeng, Si Y; Zheng, Xiao L; Di Wu; Hou, Wen S

    2016-08-01

    Infant crawling is part of normal human gross motor development, and a 4-beat gait that involves rhythmical flexion and extension of limbs and the underlying muscle co-activation of antagonist muscle around the joint. However, detection the co-activation pattern of antagonist muscle are sparse due to the general difficulty of measuring locomotion in human infants. In this paper, sEMG of antagonist muscles and the corresponding kinematics data of limbs were collected when infants were crawling on hands and knees at their self-selected speed. The infant's gross motor developmental status was assessed by the global Gross Motor Function Measure Scale (GMFM-88) as well. The method based on EMG-EMG plots was used to quantify the variability of co-activation pattern of antagonist muscle. After that, we observed that antagonist muscles of upper limb (triceps brachii and biceps brachii) showed less variability of co-activation pattern of muscles than lower limb(quadriceps femoris and hamstrings) during crawling, and this variability was also varied in different crawling phases (stance and swing). Furthermore, we found some varied behaviors in the co-activation patterns of antagonist muscles when gross motor developmental level increased. The preliminary work suggests that such adaptive changes may be related to the adjustment of neuromuscular in the early stage of gross motor development.

  8. Anti-idiotypic antibody: A new strategy for the development of a growth hormone receptor antagonist.

    Science.gov (United States)

    Lan, Hainan; Zheng, Xin; Khan, Muhammad Akram; Li, Steven

    2015-11-01

    In general, traditional growth hormone receptor antagonist can be divided into two major classes: growth hormone (GH) analogues and anti-growth hormone receptor (GHR) antibodies. Herein, we tried to explore a new class of growth hormone receptor (GHR) antagonist that may have potential advantages over the traditional antagonists. For this, we developed a monoclonal anti-idiotypic antibody growth hormone, termed CG-86. A series of experiments were conducted to characterize and evaluate this antibody, and the results from a competitive receptor-binding assay, Enzyme Linked Immunosorbent Assays (ELISA) and epitope mapping demonstrate that CG-86 behaved as a typical Ab2β. Next, we examined its antagonistic activity using in vitro cell models, and the results showed that CG-86 could effectively inhibit growth hormone receptor-mediated signalling and effectively inhibit growth hormone-induced Ba/F3-GHR638 proliferation. In summary, these studies show that an anti-idiotypic antibody (CG-86) has promise as a novel growth hormone receptor antagonist. Furthermore, the current findings also suggest that anti-idiotypic antibody may represent a novel strategy to produce a new class of growth hormone receptor antagonist, and this strategy may be applied with other cytokines or growth factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Novel antagonists of alcohol inhibition of l1-mediated cell adhesion: multiple mechanisms of action.

    Science.gov (United States)

    Wilkemeyer, Michael F; Menkari, Carrie E; Charness, Michael E

    2002-11-01

    1-Octanol antagonizes ethanol inhibition of L1-mediated cell adhesion and prevents ethanol teratogenesis in mouse whole embryo culture. Herein, we identify a new series of alcohol antagonists and study their mechanism of action. Cell aggregation assays were carried out in ethanol-sensitive, human L1-transfected NIH/3T3 cells in the absence and presence of 100 mM ethanol or 2 mM 1-butanol and candidate antagonists. Antagonist potency for 1-alcohols increased progressively over 5 log orders from 1-pentanol (C5) to 1-dodecanol (C12). Antagonist potency declined from 1-dodecanol (C12) to 1-tridecanol (C13), and 1-tetradecanol (C14) and 1-pentadecanol (C15) were inactive. The presence and position of a double bond in the 1-butanol molecule determined whether a compound was a full agonist (1-butanol), a mixed agonist-antagonist (2-buten-1-ol), or an antagonist (3-buten-1-ol). Increasing the concentration of agonist (1-butanol or ethanol) overcame the antagonism of 3-buten-1-ol, benzyl alcohol, cyclopentanol, and 3-pentanol, but not that of 4-methyl-1-pentanol, 2-methyl-2-pentanol, 1-pentanol, 2-pentanol, 1-octanol, and 2,6-di-isopropylphenol (propofol), suggesting that the mechanisms of antagonism may differ between these groups of compounds. These findings suggest that selective straight, branched, and cyclic alcohols may act at multiple, discrete sites to antagonize the actions of ethanol and 1-butanol on L1-mediated cell-cell adhesion.

  10. Penicillium expansum versus antagonist yeasts and patulin degradation in vitro

    Directory of Open Access Journals (Sweden)

    Alexandre Rodrigo Coelho

    2007-07-01

    Full Text Available Taking into account the preliminary antagonistic/biodegradation property showed by Pichia membranifaciens and Sporobolomyces roseus, which decreased the initial patulin concentration of 588.4 to 290.0 µg/mL, ability of P. ohmeri 158 in biocontrol against Penicillium expansum and patulin decrease in vitro was performed. The culture supernatant of P. ohmeri 158 was effective against 66.17% micelial growth, indicating antibiosis related with the killer phenomenon. The initial patulin concentration of 223 µg in the presence of P. ohmeri 158 cells was decreased over 83% of the original concentration, when incubated at 25ºC/2 days and > 99% after 5 days incubation time, with undetectable patulin level after 15 days. The initial pH 4.0 decreased to pH 3.3 along 15 days experiment, suggesting that patulin decrease was an active process and a consequence of yeast metabolism. The results suggested that P. ohmeri 158 could be a promising alternative for the inhibition of P. expansum growth and patulin degradation.Considerando o antagonismo e degradação de patulina detectados em Pichia membranifaciens e Sporobolomyces roseus no estudo preliminar, este trabalho avaliou o efeito antagônico de Pichia ohmeri 158 no desenvolvimento de Penicillium expansum e a degradação de patulina "in vitro". O sobrenadante do cultivo de P. ohmeri 158 inibiu 66,17% do desenvolvimento micelial, indicando antibiose relacionada ao fator killer. A concentração inicial de patulina (223 µg na presença de células íntegras de P. ohmeri foi reduzida em mais de 83% após dois dias de incubação a 25ºC e superior a 99% após 5 dias, com níveis indetectáveis no 15º dia. O decréscimo do pH 4,0 inicial para pH 3,3 sugeriu que a eliminação de patulina é um processo ativo e uma conseqüência do metabolismo da levedura. Os resultados obtidos concluem que P. ohmeri 158 é uma alternativa promissora na inibição do desenvolvimento de P. expansum e na degradação de

  11. Isolation and Characterisation of Antagonistic Actinobacteria from Mangrove Soil

    Directory of Open Access Journals (Sweden)

    Venkata Raghava Rao

    2012-04-01

    Full Text Available 1024x768 The aim of the present study was to isolate and screen actinobacteria having antagonistic activities against pathogenic microorganisms. A total of twenty actinobacteria strains were isolated from the mangrove sediment. Of these four active isolates were identified as Streptomyces species by means of morphological, physiological, biochemical and cultural characteristics. These isolates were subjected to shake flask fermentation and the secondary metabolites were extracted with ethyl acetate and screened for their antimicrobial activities against selected bacterial and fungal pathogens. The results showed that among the active isolates, four isolates (BC 01, BC 02, BC 03 and BC 04 showed promising activities against the selected test pathogens. These four extracted isolates were analyzed for UV Spectrophotometric and HPLC. Spectral data of the extracted compound revealed its antimicrobial nature. The UV spectrum of the methanol extracts for the active isolates showed absorbance peaks ranging between 207-223 nm. Two to three bioactive regions were detected on the HPLC. The results indicate that Streptomyces strains isolated from mangrove sediment produce potential antibacterial, antifungal and broad spectrum antibiotic compounds. Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}

  12. Haplotypes of the interleukin-1 receptor antagonist gene, interleukin-1 receptor antagonist mRNA levels and the risk of myocardial infarction

    NARCIS (Netherlands)

    van Minkelen, Rick; Wettinger, Stephanie Bezzina; de Visser, Marieke C.H.; Vos, Hans L.; Reitsma, Pieter H.; Rosendaal, Frits R.; Bertina, Rogier M.; Doggen, Catharina Jacoba Maria

    2009-01-01

    Background The overall effect of the major pro-inflammatory cytokine interleukin-1 (IL-1) on coagulation and fibrinolysis is prothrombotic. We recently found that haplotype 5 (H5) of the gene (IL1RN) coding for the interleukin-1 receptor antagonist (IL-1Ra), the natural inhibitor of IL-1, is

  13. Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists.

    Science.gov (United States)

    Hansen, Kasper B; Mullasseril, Praseeda; Dawit, Sara; Kurtkaya, Natalie L; Yuan, Hongjie; Vance, Katie M; Orr, Anna G; Kvist, Trine; Ogden, Kevin K; Le, Phuong; Vellano, Kimberly M; Lewis, Iestyn; Kurtkaya, Serdar; Du, Yuhong; Qui, Min; Murphy, T J; Snyder, James P; Bräuner-Osborne, Hans; Traynelis, Stephen F

    2010-06-01

    N-Methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca(2+)-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism.

  14. Genetic determinants of response and adverse effects following vitamin K antagonist oral anticoagulants

    Directory of Open Access Journals (Sweden)

    Parameshwar S.

    2016-06-01

    Full Text Available Background: Vitamin K antagonist anticoagulants (warfarin/acenocoumarol are commonly used anticoagulants that require careful clinical management to balance the risks of over anticoagulation and bleeding with those of under anticoagulation and clotting. Genetic variants of the enzyme that metabolizes vitamin K antagonist anticoagulant, cytochrome P-450 2C9 (CYP2C9, and of a key pharmacologic target of vitamin K antagonists anticoagulant, vitamin K epoxide reductase (VKORC1, contribute to differences in patients responses to various anticoagulant doses. Methods: In thirty patients on oral vitamin K antagonist anticoagulant therapy, presented with either clotting manifestations (valve thrombosis, pulmonary embolism and DVT or prolonged INR/bleeding manifestations, we assessed CYP2C9 genotypes, VKORC1 haplotypes, clinical characteristics, response to therapy (as determined by the international normalized ratio [INR], and bleeding events. Results: Of the thirty patients, thirteen patients INR was high and four patients presented with major bleeding and four with minor bleeding manifestations. Out of thirteen patients with high INR, ten patients showed CYP2C9 polymorphism ( 1/ 3 and 2/ 3 of poor metabolizer genotype. Most of the high INR patients were recently started on oral vitamin K antagonist anticoagulant. Most patients presented with clotting manifestations with below therapeutic INR are noncompliant with anticoagulants. Conclusions: The results of this study suggest that the CYP2C9 polymorphisms are associated with an increased risk of over anticoagulation and of bleeding events among patients on vitamin K antagonists' anticoagulant setting. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving vitamin K antagonist anticoagulants. However the cost-effectiveness of genotyping of patients must be considered. [Int J Res Med Sci

  15. Cloning and analysis of the antagonistic related genes of Enterobacter cloacae B8

    Institute of Scientific and Technical Information of China (English)

    YU Xuping; ZHU Junli; YAO Xunping; HE Shicheng; HUANG Haining; CHEN Weiliang; LI Debao

    2004-01-01

    To understand the antagonistic mechanism of the broad spectrum antagonistic Enterobacter cloacae B8,Tn5 transposon-mediated mutagenesis is performed using suicide plasmid pZJ25. Two mutant strains that lost antagonistic character are isolated. Tagging with kanr gene on Tn5,an antagonistic related DNA fragment, the F fragment, right of the Tn5 insertion site is cloned in a plasmid named pTLF,from one of the mutant strains B8F. The 735 bp F fragment is then sequenced after subcloning. Genomic DNA of the original B8 strain is isolated, digested with Pst I and ligated to Pst I cassette. DNA fragments left and right of the F fragment are amplified from the Pst I cassette library using cassette primer and specific primers designed according to known sequence. 1106 bp sequence left of the F fragment and 664bp sequence right of the F fragment are finally obtained. Bioinformatics analysis shows that the contig assembled from the sequences of the cloned antagonistic related DNA fragments of B8 encodes three ORFs and is homogeneous to admM,admN and admO genes of Pantoea agglomerans andrimid biosynthetic gene cluster (AY192157). The ORF, named anrF gene which encodes a polyketide synthase, knocked out by Tn5 insertion, is a homology of admM and the insertion site of Tn5 is at 214 bp upstream of the stop codon. It is concluded that the anrF gene is a gene related to the antagonistic activity of E. cloacae B8, and speculated that the antagonistic substance produced by B8 is an andrimid.

  16. Evaluation of antagonist coactivation strategies elicited from electrically stimulated muscles under load-moving conditions.

    Science.gov (United States)

    Zhou, B H; Katz, S R; Baratta, R V; Solomonow, M; D'Ambrosia, R D

    1997-07-01

    Muscle coactivation strategies that produce ankle dorsiflexion and plantar flexion were elicited by electrical stimulation of the tibialis anterior (TA) and soleus (SOL) muscles of the cat, and examined under several loading conditions. Four different load types were used: free-limb motion (no load), fly-wheel, and two pendulums, each with a different lever arm. Three types of coactivation strategies were considered. The first coactivation strategy consisted of antagonist activity that decreased as the agonist activity increased. The second strategy consisted of increasing antagonist activity with increasing agonist activity. And, in the third strategy, antagonist coactivation decreased at low force levels, then increased at high force levels. The three strategies were evaluated based on the joint angle's peak-to-peak movement and its ability to track a linear input command given by the correlation coefficient of the output signal versus linear input. Results showed that increasing antagonist activity resulted in decreasing peak-to-peak angle and a decreased signal tracking capability for each load condition. The latter, however, was not as obvious in the flywheel load (as compared with free-moving and pendulum conditions). A decreasing peak-to-peak torque for pendulum loads was also observed with increasing antagonist activity. In all loading conditions, maximal peak-to-peak angle and torque were present when a moderate degree of antagonist activity was engaged, and signal tracking capability improved with earlier engagement of the antagonist muscles. It is suggested that strategies using a combination of low-level coactivation, as described in the physiological literature and previous functional electrical stimulation (FES) studies, could satisfactorily address the issues of controllability and efficiency while maintaining long-term joint integrity.

  17. Structure-Based Design of a Periplasmic Binding Protein Antagonist that Prevents Domain Closure

    Energy Technology Data Exchange (ETDEWEB)

    Borrok, M. Jack; Zhu, Yimin; Forest, Katrina T.; Kiessling, Laura L.; (UW)

    2009-07-31

    Many receptors undergo ligand-induced conformational changes to initiate signal transduction. Periplasmic binding proteins (PBPs) are bacterial receptors that exhibit dramatic conformational changes upon ligand binding. These proteins mediate a wide variety of fundamental processes including transport, chemotaxis, and quorum sensing. Despite the importance of these receptors, no PBP antagonists have been identified and characterized. In this study, we identify 3-O-methyl-D-glucose as an antagonist of glucose/galactose-binding protein and demonstrate that it inhibits glucose chemotaxis in E. coli. Using small-angle X-ray scattering and X-ray crystallography, we show that this antagonist acts as a wedge. It prevents the large-scale domain closure that gives rise to the active signaling state. Guided by these results and the structures of open and closed glucose/galactose-binding protein, we designed and synthesized an antagonist composed of two linked glucose residues. These findings provide a blueprint for the design of new bacterial PBP inhibitors. Given the key role of PBPs in microbial physiology, we anticipate that PBP antagonists will have widespread uses as probes and antimicrobial agents.

  18. Evaluation of the protagonist-antagonist dichotomy in Spanish television content targeting children

    Directory of Open Access Journals (Sweden)

    José A. García-Castillo, Ph.D.

    2010-01-01

    Full Text Available The goal of this study is to analyse the profile of the protagonist-antagonist dichotomy in all children’s television content, of all genres, offered by Spanish television channels. The analysis of protagonist and antagonist characters focuses on variables such as: type and number, age, gender, nationality, skills, relationship between the characters, characterisation, means used to achieve goals, consequences of the action of the antagonist over the antagonist and vice versa. The sample consists of 168 series that were analysed using descriptive content analysis and multivariate analysis. The results showed that over 50% of the series do not have an antagonist and that when there is one the most common type is a single human, which appears in more than 15% of the analysed series, followed by the fantastic creature type, which is present in just 10%. In 80% of the series the skills of the protagonists are social and human, and in 45.24% the exhibited skill is intelligence.

  19. Dual action of neurokinin-1 antagonists on Mas-related GPCRs

    Science.gov (United States)

    Azimi, Ehsan; Reddy, Vemuri B.; Shade, Kai-Ting C.; Anthony, Robert M.; Pereira, Paula Juliana Seadi; Lerner, Ethan A.

    2016-01-01

    The challenge of translating findings from animal models to the clinic is well known. An example of this challenge is the striking effectiveness of neurokinin-1 receptor (NK-1R) antagonists in mouse models of inflammation coupled with their equally striking failure in clinical investigations in humans. Here, we provide an explanation for this dichotomy: Mas-related GPCRs (Mrgprs) mediate some aspects of inflammation that had been considered mediated by NK-1R. In support of this explanation, we show that conventional NK-1R antagonists have off-target activity on the mouse receptor MrgprB2 but not on the homologous human receptor MRGPRX2. An unrelated tripeptide NK-1R antagonist has dual activity on MRGPRX2. This tripeptide both suppresses itch in mice and inhibits degranulation from the LAD-2 human mast cell line elicited by basic secretagogue activation of MRGPRX2. Antagonists of Mrgprs may fill the void left by the failure of NK-1R antagonists. PMID:27734033

  20. Heterogeneity of binding of muscarinic receptor antagonists in rat brain homogenates

    Energy Technology Data Exchange (ETDEWEB)

    Lee, J.H.; el-Fakahany, E.E.

    1985-06-01

    The binding properties of (-)-(/sup 3/H)quinuclidinyl benzilate and (/sup 3/H) N-methylscopolamine to muscarinic acetylcholine receptors have been investigated in rat brain homogenates. The binding of both antagonists demonstrated high affinity and saturability. Analysis of the binding data resulted in linear Scatchard plots. However, (-)-(/sup 3/H)quinuclidinyl benzilate showed a significantly higher maximal binding capacity than that of (/sup 3/H)N-methylscopolamine. Displacement of both ligands with several muscarinic receptor antagonists resulted in competition curves in accordance with the law of mass-action for quinuclidinyl benzilate, atropine and scopolamine. A similar profile was found for the quaternary ammonium analogs of atropine and scopolamine when (/sup 3/H)N-methylscopolamine was used to label the receptors. However, when these hydrophilic antagonists were used to displace (-)-(/sup 3/H) quinuclidinyl benzilate binding, they showed interaction with high- and low-affinity binding sites. On the other hand, the nonclassical muscarinic receptor antagonist, pirenzepine, was able to displace both ligands from two binding sites. The present data are discussed in terms of the relationship of this anomalous heterogenity of binding of these hydrophilic muscarinic receptor antagonists and the proposed M1 and M2 receptor subtypes.

  1. Antagonistic interactions between endophytic cultivable bacterial communities isolated from the medicinal plant Echinacea purpurea.

    Science.gov (United States)

    Maida, Isabel; Chiellini, Carolina; Mengoni, Alessio; Bosi, Emanuele; Firenzuoli, Fabio; Fondi, Marco; Fani, Renato

    2016-09-01

    In this work we have studied the antagonistic interactions existing among cultivable bacteria isolated from three ecological niches (rhizospheric soil, roots and stem/leaves) of the traditional natural medicinal plant Echinacea purpurea. The three compartments harboured different taxonomic assemblages of strains, which were previously reported to display different antibiotic resistance patterns, suggesting the presence of differential selective pressure due to antagonistic molecules in the three compartments. Antagonistic interactions were assayed by the cross-streak method and interpreted using a network-based analysis. In particular 'within-niche inhibition' and 'cross-niche inhibition' were evaluated among isolates associated with each compartment as well as between isolates retrieved from the three different compartments respectively. Data obtained indicated that bacteria isolated from the stem/leaves compartment were much more sensitive to the antagonistic activity than bacteria from roots and rhizospheric soil. Moreover, both the taxonomical position and the ecological niche might influence the antagonistic ability/sensitivity of different strains. Antagonism could play a significant role in contributing to the differentiation and structuring of plant-associated bacterial communities. © 2015 Society for Applied Microbiology and John Wiley & Sons Ltd.

  2. Wear Behavior of Ceramic CAD/CAM Crowns and Natural Antagonists

    Directory of Open Access Journals (Sweden)

    Ella A. Naumova

    2017-02-01

    Full Text Available Objective: Evaluation of wear behavior of computer-aided design/computer-aided manufacturing (CAD/CAM crowns from various restorative materials and natural antagonists. Method: Full CAD/CAM crowns fabricated with nanoceramic resin (Lava Ultimate (LU, a glass ceramic in a resin interpenetrating matrix (Vita Enamic (VE and a lithium silicate reinforced ceramic enriched with zirconia (Vita Suprinity (VS were cemented on human molars. The crown and antagonists were subjected to simulated chewing. 3D data sets, before and after the chewing simulation, were generated and matched. Occlusal surface roughness, vertical and volume loss of the crowns and antagonists were analyzed. Results: Crown roughness was significantly different between the LU and VE groups after chewing simulation. Crown vertical loss differed in all groups. The highest crown volume loss was found in the LU group, and the lowest in the VE group. Comparisons between the LU and VE groups and the LU and VS groups were significantly different. The highest antagonist volume loss was reached in the VE group, the lowest was in the LU group. Conclusion: Roughness increased after chewing simulation. LU crowns are the most natural antagonist-friendly; these were the most susceptible to vertical and volume loss. Of the tested materials, the VE crowns are the most stable regarding occlusion.

  3. A long-acting GH receptor antagonist through fusion to GH binding protein.

    Science.gov (United States)

    Wilkinson, Ian R; Pradhananga, Sarbendra L; Speak, Rowena; Artymiuk, Peter J; Sayers, Jon R; Ross, Richard J

    2016-10-12

    Acromegaly is a human disease of growth hormone (GH) excess with considerable morbidity and increased mortality. Somatostatin analogues are first line medical treatment but the disease remains uncontrolled in up to 40% of patients. GH receptor (GHR) antagonist therapy is more effective but requires frequent high-dose injections. We have developed an alternative technology for generating a long acting potent GHR antagonist through translational fusion of a mutated GH linked to GH binding protein and tested three candidate molecules. All molecules had the amino acid change (G120R), creating a competitive GHR antagonist and we tested the hypothesis that an amino acid change in the GH binding domain (W104A) would increase biological activity. All were antagonists in bioassays. In rats all antagonists had terminal half-lives >20 hours. After subcutaneous administration in rabbits one variant displayed a terminal half-life of 40.5 hours. A single subcutaneous injection of the same variant in rabbits resulted in a 14% fall in IGF-I over 7 days.

  4. 5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure

    Directory of Open Access Journals (Sweden)

    Wiebke Janssen

    2015-01-01

    Full Text Available Objective. The serotonin (5-HT pathway was shown to play a role in pulmonary hypertension (PH, but its functions in right ventricular failure (RVF remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist or SB204741 (5-HT2B receptor antagonist on right heart function and structure upon pulmonary artery banding (PAB in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid or SB204741 (5 mg/kg day. Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI, and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.

  5. 5-HT2B receptor antagonists inhibit fibrosis and protect from RV heart failure.

    Science.gov (United States)

    Janssen, Wiebke; Schymura, Yves; Novoyatleva, Tatyana; Kojonazarov, Baktybek; Boehm, Mario; Wietelmann, Astrid; Luitel, Himal; Murmann, Kirsten; Krompiec, Damian Richard; Tretyn, Aleksandra; Pullamsetti, Soni Savai; Weissmann, Norbert; Seeger, Werner; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo

    2015-01-01

    The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid) or SB204741 (5 mg/kg day). Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.

  6. Novel pyrazole derivatives as neutral CB₁ antagonists with significant activity towards food intake.

    Science.gov (United States)

    Manca, Ilaria; Mastinu, Andrea; Olimpieri, Francesca; Falzoi, Matteo; Sani, Monica; Ruiu, Stefania; Loriga, Giovanni; Volonterio, Alessandro; Tambaro, Simone; Bottazzi, Mirko Emilio Heiner; Zanda, Matteo; Pinna, Gérard Aimè; Lazzari, Paolo

    2013-04-01

    In spite of rimonabant's withdrawal from the European market due to its adverse effects, interest in the development of drugs based on CB1 antagonists is revamping on the basis of the peculiar properties of this class of compounds. In particular, new strategies have been proposed for the treatment of obesity and/or related risk factors through CB1 antagonists, i.e. by the development of selectively peripherally acting agents or by the identification of neutral CB1 antagonists. New compounds based on the lead CB1 antagonist/inverse agonist rimonabant have been synthesized with focus on obtaining neutral CB1 antagonists. Amongst the new derivatives described in this paper, the mixture of the two enantiomers (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(2-cyclohexyl-1-hydroxyethyl)-4-methyl-1H-pyrazole ((±)-5), and compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-[(Z)-2-cyclohexyl-1-fluorovinyl]-4-methyl-1H-pyrazole ((Z)-6), showed interesting pharmacological profiles. According to the preliminary pharmacological evaluation, these novel pyrazole derivatives showed in fact both neutral CB1 antagonism behaviour and significant in vivo activity towards food intake.

  7. Orexin 1 receptor antagonists in compulsive behaviour and anxiety: possible therapeutic use.

    Directory of Open Access Journals (Sweden)

    Emilio eMerlo-Pich

    2014-02-01

    Full Text Available Fifteen years after the discovery of hypocretin/orexin a large body of evidence has been collected supporting its critical role in the modulation of several regulatory physiological functions. While reduced levels of hypocretin/orexin were early on associated with narcolepsy, increased levels have been linked in recent years to pathological states of hypervigilance and, in particular, to insomnia. The filing to FDA of the dual-activity orexin receptor antagonist (DORA suvorexant for the indication of insomnia further corroborates the robustness of such evidences. However, as excessive vigilance is also typical of anxiety and panic episodes, as well as of abstinence and craving in substance misuse disorders, in this review we briefly discuss the evidence supporting the development of hypocretin/orexin receptor 1 (OX1 antagonists for these indications. Experiments using the OX1 antagonist SB-334867 and mutant mice have involved the OX1 receptor in mediating the compulsive reinstatement of drug seeking for ethanol, nicotine, cocaine, cannabinoids and morphine. More recently, data have been generated with the novel selective OX1 antagonists GSK1059865 and ACT-335827 on behavioural and cardiovascular response to stressors and panic-inducing agents in animals. Concluding, while waiting for pharmacologic data to become available in humans, risks and benefits for the development of an OX1 receptor antagonist for Binge Eating and Anxiety Disorders are discussed.

  8. 1.3-μm, 4 × 25-Gbit/s, EADFB laser array module with large-output-power and low-driving-voltage for energy-efficient 100GbE transmitter.

    Science.gov (United States)

    Fujisawa, Takeshi; Kanazawa, Shigeru; Takahata, Kiyoto; Kobayashi, Wataru; Tadokoro, Takashi; Ishii, Hiroyuki; Kano, Fumiyoshi

    2012-01-02

    A 1.3-μm, 4 × 25-Gbit/s, EADFB laser array module with large output power and low driving voltage is developed for 100GbE. A novel rear grating DFB laser is introduced to increase the output power of the laser while keeping the single mode lasing, which is desirable for a monolithic integration. Also, InGaAlAs-based electroabsorption modulators make very-low-driving-voltage operation possible due to their steep extinction curves. With the module, very clear 25-Gbit/s eye openings are obtained for four wavelengths with the driving voltage of only 0.5 V while securing the dynamic extinction ratio required by the system. These results indicate that the presented module is a promising candidate for energy-efficient future 100GbE transmitter.

  9. Antagonistic and Biocontrol Potential of Trichoderma asperellum ZJSX5003 Against the Maize Stalk Rot Pathogen Fusarium graminearum

    OpenAIRE

    Li, Yaqian; Sun, Ruiyan; Yu, Jia; Saravanakumar, Kandasamy; Chen, Jie

    2016-01-01

    The efficacy of seven strains of Trichodermaasperellum collected from the fields in Southern China was assessed against Fusarium graminearum (FG) the causal agent of corn stalk rot of maize were in vitro for their antagonistic properties followed by statistical model of principal compound analysis to identify the beneficial antagonist T.asperellum strain. The key factors of antagonist activity were attributed to a total of 13 factors including cell wall degrading enzymes (chitnase, protease a...

  10. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists

    DEFF Research Database (Denmark)

    Ebert, B; Thorkildsen, C; Andersen, S;

    1998-01-01

    Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However......, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA...... receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence...

  11. Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia.

    Science.gov (United States)

    Roecker, Anthony J; Cox, Christopher D; Coleman, Paul J

    2016-01-28

    Since its discovery in 1998, the orexin system, composed of two G-protein coupled receptors, orexins 1 and 2, and two neuropeptide agonists, orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the treatment of obesity, anxiety, and sleep/wake disorders. Genetic evidence in rodents, dogs, and humans was revealed between 1999 and 2000, demonstrating a causal link between dysfunction or deletion of the orexin system and narcolepsy, a disorder characterized by hypersomnolence during normal wakefulness. These findings encouraged efforts to discover agonists to treat narcolepsy and, alternatively, antagonists to treat insomnia. This perspective will focus on the discovery and development of structurally diverse orexin antagonists suitable for preclinical pharmacology studies and human clinical trials. The work described herein culminated in the 2014 FDA approval of suvorexant as a first-in-class dual orexin receptor antagonist for the treatment of insomnia.

  12. GnRH antagonist in in vitro fertilization: where we are now.

    Science.gov (United States)

    Shapiro, D B; Mitchell-Leef, D

    2003-10-01

    This review focuses on the recent literature concerning the use of GnRH antagonists in ovulation induction for in vitro fertilization (IVF). The GnRH antagonists, ganirelix acetate (Orgalutran/Antagon) and cetrorelix (Cetrotide), have come into increasingly common use since their release in the last 3 years. This class of GnRH analogue has several potential advantages over GnRH agonists. Among these advantages are: 1) shorter duration of injectable drug treatment, 2) decreased gonadotropin requirement per cycle, 3) improved patient convenience and 4) lower overall treatment cost. As clinicians gain experience with these drugs, optimal treatment paradigms will likely emerge. This review will discuss current strategies and potential applications for the GnRH antagonists.

  13. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease

    DEFF Research Database (Denmark)

    Currie, Gemma; Taylor, Alison H M; Fujita, Toshiro

    2016-01-01

    BACKGROUND: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease. Hyperkalaemia...... is a concern with the use of mineralocorticoid receptor antagonists. We aimed to determine whether the renal protective benefits of mineralocorticoid antagonists outweigh the risk of hyperkalaemia associated with this treatment in patients with chronic kidney disease. METHODS: We conducted a meta......-analysis investigating renoprotective effects and risk of hyperkalaemia in trials of mineralocorticoid receptor antagonists in chronic kidney disease. Trials were identified from MEDLINE (1966-2014), EMBASE (1947-2014) and the Cochrane Clinical Trials Database. Unpublished summary data were obtained from investigators...

  14. Using a pharmacophore representation concept to elucidate molecular similarity of dopamine antagonists

    Science.gov (United States)

    Atlamazoglou, V.; Thireou, T.; Eliopoulos, E.

    2007-05-01

    The pharmacophoric concept plays an important role in ligand-based drug design methods to describe the similarity and diversity of molecules, and could also be exploited as a molecular representation scheme. A three-point pharmacophore method was used as a molecular representation perception. This procedure was implemented for dopamine antagonists of the D2 receptor subtype. The molecular structures of the antagonists included in this analysis were categorized into two structurally distinct classes. Using structural superposition with internal energy minimization, two pharmacophore models were deduced. Based on these two models other D2 antagonists that fulfil them were derived and studied. This procedure aided the identification of the common 3D patterns present in diverse molecules that act at the same biological target and the extraction of a common molecular framework for the two structural classes. The pharmacophoric information was found to be suitable for guiding superposition of structurally diverse molecules, using a more biologically meaningful selection of the targeting points.

  15. Role of leukotriene antagonists and antihistamines in the treatment of allergic rhinitis.

    Science.gov (United States)

    Cobanoğlu, Bengü; Toskala, Elina; Ural, Ahmet; Cingi, Cemal

    2013-04-01

    Allergic rhinitis is the most common atopic disorder seen in ENT clinics. It is diagnosed by history, physical exam and objective testing. Patient education, environmental control measures, pharmacotherapy, and allergen-specific immunotherapy are the cornerstones of allergic rhinitis treatment and can significantly reduce the burden of disease. Current treatment guidelines include antihistamines, intranasal corticosteroids, oral and intranasal decongestants, intranasal anticholinergics, intranasal cromolyn, and leukotriene receptor antagonists. In the mechanism of allergic rhinitis, histamine is responsible for major allergic rhinitis symptoms such as rhinorrhea, nasal itching and sneezing. Its effect on nasal congestion is less evident. In contrast, leukotrienes result in increase in nasal airway resistance and vascular permeability. Antihistamines and leukotriene receptor antagonists are commonly used in the treatment of allergic rhinitis. The published literature about combined antihistamines and leukotriene antagonists in mono- or combination therapy is reviewed and presented.

  16. Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands.

    Science.gov (United States)

    Vardanyan, Ruben; Kumirov, Vlad K; Nichol, Gary S; Davis, Peg; Liktor-Busa, Erika; Rankin, David; Varga, Eva; Vanderah, Todd; Porreca, Frank; Lai, Josephine; Hruby, Victor J

    2011-10-15

    Newly designed bivalent ligands-opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials-carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds-amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited μ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.

  17. Dicentrine is preferentially antagonistic to rat aortic than splenic α1-adrenoceptor stimulation

    Institute of Scientific and Technical Information of China (English)

    MUSTAFA Mohd Rais; ACHIKE Francis Ifejika

    2000-01-01

    AIM: Dicentrine is a known α1-adrenoceptor antagonist, but its α1-adrenoceptor subtype selectivity has not yet been determined. We therefore, investigated the putative α1-adrenoceptor subtype selectivity of this agent. METHODS: Graded isometric contractile responses of rat aortic rings and spleen to phenylephrine were observed in the absence or presence of various concentrations of dicentrine. The pA2 values for dicentrine were determined.RESULTS: Aortic tissues were more sensitive to phenylephrine-induced connaction than the spleen tissues. Dicentrine was approximately 100 times more potent as an antagonist to the aortic contraction, than it was to the splenic contractions. CONCLUSION: Dicenuine is an a1-adrenoceptor antagonist which is more selective towards the putative α1D-adrenoceptor subtype of the rat aorta than the α1s-adrenoceptor of the spleen.

  18. Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma

    DEFF Research Database (Denmark)

    Bisgaard, H

    2001-01-01

    Cysteinyl leukotrienes, synthesized de novo from cell membrane phospholipids, are proinflammatory mediators that play an important role in the pathophysiology of asthma. These mediators are among the most potent of bronchoconstrictors and cause vasodilation, increased microvascular permeability, ...... antagonists are additive with those of beta agonists. These data provide strong support for the use of leukotriene receptor antagonists for treating asthma.......Cysteinyl leukotrienes, synthesized de novo from cell membrane phospholipids, are proinflammatory mediators that play an important role in the pathophysiology of asthma. These mediators are among the most potent of bronchoconstrictors and cause vasodilation, increased microvascular permeability...... ciliary motility, which may hinder mucociliary clearance. Asthmatic patients demonstrate increased production of cysteinyl leukotrienes during naturally occurring asthma and acute asthma attacks as well as after allergen and exercise challenge. The leukotriene receptor antagonists montelukast, zafirlukast...

  19. Effects of calmodulin antagonists on radiation-induced lipid peroxidation in microsomes

    Energy Technology Data Exchange (ETDEWEB)

    Varshney, R.; Kale, R.K. (Jawaharlal Nehru Univ., New Delhi (India). School of Life Sciences)

    1990-11-01

    Rat liver microsomes were irradiated with {gamma}-rays at a dose of 1.31 Gy s{sup -1}. The extent of lipid peroxidation, measured in terms of malondialdehyde (MDA) formed, increased with radiation dose. The presence of calmodulin antagonists during irradiation decreased lipid peroxidation. The order of their protective efficiency was: chlorpromazine (CPZ)>promethazine (PMZ)>trimeprazine (TMZ). Their protective effect was diminished in the presence of ferrous (Fe{sup 2+}) ions and was restored on addition of EDTA. However, calmodulin antagonists considerably inhibited radiation-induced lipid peroxidation in the presence of ferric (Fe{sup 3+}) ions. Calmodulin antagonists also decreased the cytochrome P-450 content of microsomes. These results are discussed with respect to their applicability to radiotherapy. A possible mechanism for the inhibition of radiation-induced lipid peroxidation is suggested. (author).

  20. Optimizing subcutaneous injection of the gonadotropin-releasing hormone receptor antagonist degarelix.

    Science.gov (United States)

    Barkin, Jack; Burton, Shelley; Lambert, Carole

    2016-02-01

    The gonadotropin-releasing hormone (GnRH) receptor antagonist degarelix has several unique characteristics compared to luteinizing hormone-releasing hormone (LHRH) analogs used in the management of prostate cancer. Notable differences of GnRH receptor antagonists include no flare reaction, and a more rapid suppression of testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prostate-specific antigen (PSA) compared to LHRH analogs. Despite emerging evidence supporting the use of GnRH receptor antagonists over the more widely used LHRH analogs in the management of prostate cancer, physicians may be reluctant to prescribe degarelix. They may be concerned about patient complaints about injection-site reactions (ISRs). The subcutaneous injection of degarelix has been associated with a higher rate of ISRs compared with the intramuscular injections of LHRH analogs. This "How I Do It" article describes techniques and strategies that have been developed by physicians and nurses to reduce the discomfort associated with the subcutaneous delivery of degarelix.

  1. Growth Hormone Receptor Antagonist Treatment Reduces Exercise Performance in Young Males

    DEFF Research Database (Denmark)

    Goto, K.; Doessing, S.; Nielsen, R.H.

    2009-01-01

    period, they exercised to determine exercise performance and hormonal and metabolic responses. Participants: Twenty healthy males participated in the study. Intervention: Subjects were treated with the GHR antagonist (n = 10; 10 mg/d) or placebo (n = 10). After the treatment period, they performed...... a maximal oxygen uptake ((V) over dotO(2max)) test and a prolonged exercise test, consisting of 60 min of submaximal cycling followed by exercise to fatigue at 90% of (V) over dotO(2max). Main Outcome Measures: (V) over dotO(2max) was measured before and after the treatment period. Hormonal and metabolic......Context: The effects of GH on exercise performance remain unclear. Objective: The aim of the study was to examine the effects of GH receptor (GHR) antagonist treatment on exercise performance. Design: Subjects were treated with the GHR antagonist pegvisomant or placebo for 16 d. After the treatment...

  2. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.

    Science.gov (United States)

    Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Beneton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodeme, Edwige; Grillot, Didier; Martres, Paul

    2014-02-15

    Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat).

  3. Synthesis and Biological Evaluation of Substituted Desloratadines as Potent Arginine Vasopressin V2 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Shuai Mu

    2014-02-01

    Full Text Available Twenty-one non-peptide substituted desloratadine class compounds were synthesized as novel arginine vasopressin receptor antagonists from desloratadine via successive acylation, reduction and acylation reactions. Their structures were characterized by 1H-NMR and HRMS, their biological activity was evaluated by in vitro and in vivo studies. The in vitro binding assay and cAMP accumulation assay indicated that these compounds are potent selective V2 receptor antagonists. Among them compounds 1n, 1t and 1v exhibited both high affinity and promising selectivity for V2 receptors. The in vivo diuretic assay demonstrated that 1t presented remarkable diuretic activity. In conclusion, 1t is a potent novel AVP V2 receptor antagonist candidate.

  4. Therapeutic potential of CRF receptor antagonists: a gut-brain perspective.

    Science.gov (United States)

    Heinrichs, S C; Taché, Y

    2001-04-01

    Activation of the corticotropin-releasing factor (CRF) family of neuropeptide receptors in the brain and periphery appears to mediate stress-related changes in a variety of physiological and functional domains. Comparative pharmacology of CRF receptor agonists suggests that CRF, urocortin, sauvagine and urotensin consistently mimic, and conversely peptide CRF receptor antagonists lessen, the functional consequences of stressor exposure. Together with the development of novel non-peptide CRF receptor antagonists, a growing number of CRF receptor selective ligands are available to elucidate the neurobiology and physiological role of CRF systems. The present review considers available preclinical evidence as well as results from one Phase II clinical trial which address the hypothesis that CRF receptor antagonists may represent a new option for pharmacotherapy of stress-related disorders.

  5. Bradykinin as a pain mediator: receptors are localized to sensory neurons, and antagonists have analgesic actions

    Energy Technology Data Exchange (ETDEWEB)

    Steranka, L.R.; Manning, D.C.; DeHaas, C.J.; Ferkany, J.W.; Borosky, S.A.; Connor, J.R.; Vavrek, R.J.; Stewart, J.M.; Snyder, S.H.

    1988-05-01

    Autoradiographic studies localize (/sup 3/H)bradykinin receptor binding sites to the substantia gelatinosa, dorsal root, and a subset of small cells in both the dorsal root and trigeminal ganglia of the guinea pig. (/sup 3/H)Bradykinin labeling is also observed over myocardinal/coronary visceral afferent fibers. The localization of (/sup 3/H)bradykinin receptors to nociceptive pathways supports a role for bradykinin in pain mediation. Several bradkykinin antagonists block bradykinin-induced acute vascular pain in the rat. The bradykinin antagonists also relieve bradykinin- and urate-induced hyperalgesia in the rat paw. These results indicate that bradykinin is a physiologic mediator of pain and that bradykinin antagonists have analgesic activity in both acute and chronic pain models.

  6. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

    2014-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  7. 7-Chloroarctinone-b as a new selective PPARγ antagonist potently blocks adipocyte differentiation

    Institute of Scientific and Technical Information of China (English)

    Yong-tao LI; Li LI; Jing CHEN; Tian-cen HU; Jin HUANG; Yue-wei GUO; Hua-liang JIANG; Xu SHEN

    2009-01-01

    Aim: Peroxisome proliferator-activated receptor gamma (PPARy) is a therapeutic target for obesity, cancer and diabetes mellitus. In order to develop potent lead compounds for obesity treatment, we screened a natural product library for novel PPARy antagonists with inhibitory effects on adipocyte differentiation. Methods: Surface plasmon resonance (SPR) technology and cell-based transactivation assay were used to screen for PPARy antago-nists. To investigate the antagonistic mechanism of the active compound, we measured its effect on PPARy/RXRα heterodimerization and PPARy co-activator recruitment using yeast two-hybrid assay, Gal4/UAS cell-based assay and SPR based assay. The 3T3-L1 cell differentiation assay was used to evaluate the effect of the active compound on adipocyte differentiation. Results: A new thiophene-acetylene type of natural product, 7-chloroarctinone-b (CAB), isolated from the roots of Rhaponticum uniflo-rum, was discovered as a novel PPARγ antagonist capable of inhibiting rosiglitazone-induced PPARγ transcriptional activity. SPR analy-sis suggested that CAB bound tightly to PPARγ and considerably antagonized the potent PPARy agonist rosigtitazone-stimulated PPARγ-LBD/RXRα-LBD binding. Gal4/UAS and yeast two-hybrid assays were used to evaluate the antagonistic activity of CAB on rosiglitazone-induced recruitment of the coactivator for PPARy. CAB could efficiently antagonize both hormone and rosiglitazone-induced adipocyte differentiation in cell culture. Conclusion: CAB shows antagonistic activity to PPARγ and can block the adipocyte differentiation, indicating it may be of potential use as a lead therapeutic compound for obesity.

  8. Serotonin (5-HT3 receptor antagonists for the reduction of symptoms of low anterior resection syndrome

    Directory of Open Access Journals (Sweden)

    Itagaki R

    2014-03-01

    Full Text Available Ryohei Itagaki, Keiji Koda, Masato Yamazaki, Kiyohiko Shuto, Chihiro Kosugi, Atsushi Hirano, Hidehito Arimitsu, Risa Shiragami, Yukino Yoshimura, Masato Suzuki Department of Surgery, Teikyo University Chiba Medical Center, Anesaki, Ichihara, Chiba, Japan Purpose: Serotonin (5-hydroxytryptamine [5-HT]3 receptor antagonists are effective for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D, in which exaggerated intestinal/colonic hypermotility is often observed. Recent studies have suggested that the motility disorder, especially spastic hypermotility, seen in the neorectum following sphincter-preserving operations for rectal cancer may be the basis of the postoperative defecatory malfunction seen in these patients. We investigated the efficacy of 5-HT3 receptor antagonists in patients suffering from severe low anterior resection syndrome. Patients and methods: A total of 25 male patients with complaints of uncontrollable urgency or fecal incontinence following sphincter-preserving operations were enrolled in this study. Defecatory status, assessed on the basis of incontinence score (0–20, urgency grade (0–3, and number of toilet visits per day, was evaluated using a questionnaire before and 1 month after the administration of the 5-HT3 antagonist ramosetron. Results: All the parameters assessed improved significantly after taking ramosetron for 1 month. The effect was more prominent in cases whose anastomotic line was lower, ie, inside the anal canal. Defecatory function was better in patients who commenced ramosetron therapy within 6 months postoperatively, as compared to those who were not prescribed ramosetron for more than 7 months postoperatively. Conclusion: These results suggest that 5-HT3 antagonists are effective for the treatment of low anterior resection syndrome, as in diarrhea-predominant irritable bowel syndrome. The improvement in symptoms is not merely time dependent, but it is related to treatment with 5

  9. Microglial inhibition of neuroprotection by antagonists of the EP1 prostaglandin E2 receptor

    Directory of Open Access Journals (Sweden)

    Rojas Monica A

    2009-02-01

    Full Text Available Abstract Background The EP1 receptor for the prostanoid PGE2 is a G-protein coupled receptor that has been shown to contribute to excitotoxic neuronal death. In this study we examined the influence of non-neuronal cells on neuroprotective properties of EP1 receptor antagonists (Ono 8711 and SC 51089. Methods Primary neuronal cultures systems with or without non-neuronal cells were used to examine how the neuroprotective properties of EP1 antagonists were influenced by non-neuronal cells. The influence of astrocytes or microglia were individually tested in excitotoxicity assays using a co-culture system with these cells grown on permeable transwell inserts above the neuronal-enriched cultures. The influence of microglia on PGE2 synthesis and EP1 receptor expression was examined. Results EP1 antagonists were neuroprotective in neuronal-enriched cultures (> 90% neurons but not in mixed cultures (30% neurons plus other non-neuronal cells. Co-cultures of microglia on permeable transwell inserts above neuronal-enriched cultures blocked neuroprotection by EP1 antagonists. Incubation of microglia with neuronal-enriched cultures for 48 hours prior to NMDA challenge was sufficient to block neuroprotection by EP1 antagonists. The loss of neuroprotection by EP1 antagonists was accompanied by a decrease of neuronal EP1 expression in the nucleus in cultures with microglia present. Conclusion These findings demonstrate microglial modulation of neuronal excitotoxicity through interaction with the EP1 receptor and may have important implications in vivo where microglia are associated with neuronal injury.

  10. Discovery of antagonists of tick dopamine receptors via chemical library screening and comparative pharmacological analyses.

    Science.gov (United States)

    Ejendal, Karin F K; Meyer, Jason M; Brust, Tarsis F; Avramova, Larisa V; Hill, Catherine A; Watts, Val J

    2012-11-01

    Ticks transmit a wide variety of disease causing pathogens to humans and animals. Considering the global health impact of tick-borne diseases, there is a pressing need to develop new methods for vector control. We are exploring arthropod dopamine receptors as novel targets for insecticide/acaricide development because of their integral roles in neurobiology. Herein, we developed a screening assay for dopamine receptor antagonists to further characterize the pharmacological properties of the two D₁-like dopamine receptors (Isdop1 and Isdop2) identified in the Lyme disease vector, Ixodes scapularis, and develop a screening assay for receptor antagonists. A cell-based, cyclic AMP luciferase reporter assay platform was implemented to screen the LOPAC(1280) small molecule library for Isdop2 receptor antagonists, representing the first reported chemical library screen for any tick G protein-coupled receptor. Screening resulted in the identification of 85 "hit" compounds with antagonist activity at the Isdop2 receptor. Eight of these chemistries were selected for confirmation assays using a direct measurement of cAMP, and the effects on both Isdop1 and Isdop2 were studied for comparison. Each of these eight compounds showed antagonistic activity at both Isdop1 and Isdop2, although differences were observed regarding their relative potencies. Furthermore, comparison of the pharmacological properties of the tick dopamine receptors with that of the AaDOP2 receptor from the yellow fever mosquito and the human dopamine D₁ receptor (hD₁) revealed species-specific pharmacological profiles of these receptors. Compounds influencing dopaminergic functioning, such as the dopamine receptor antagonists discovered here, may provide lead chemistries for discovery of novel acaricides useful for vector control

  11. Isolation, identification, and biocontrol of antagonistic bacterium against Botrytis cinerea after tomato harvest.

    Science.gov (United States)

    Shi, Jun-Feng; Sun, Chang-Qing

    2017-06-03

    Tomato is one of the most important vegetables in the world. Decay after harvest is a major issue in the development of tomato industry. Currently, the most effective method for controlling decay after harvest is storage of tomato at low temperature combined with usage of chemical bactericide; however, long-term usage of chemical bactericide not only causes pathogen resistance but also is harmful for human health and environment. Biocontrol method for the management of disease after tomato harvest has great practical significance. In this study, antagonistic bacterium B-6-1 strain was isolated from the surface of tomato and identified as Enterobacter cowanii based on morphological characteristics and physiological and biochemical features combined with sequence analysis of 16SrDNA and ropB gene and construction of dendrogram. Effects of different concentrations of antagonistic bacterium E. cowanii suspension on antifungal activity after tomato harvest were analyzed by mycelium growth rate method. Results revealed that antifungal activity was also enhanced with increasing concentrations of antagonistic bacterium; inhibitory rates of 1×10(5) colony-forming units (cfu)/mL antagonistic bacterial solution on Fusarium verticillioides, Alternaria tenuissima, and Botrytis cinerea were 46.31%, 67.48%, and 75.67%, respectively. By using in vivo inoculation method, it was further confirmed that antagonistic bacterium could effectively inhibit the occurrence of B. cinerae after tomato harvest, biocontrol effect of 1×10(9)cfu/mL zymotic fluid reached up to 95.24%, and antagonistic bacterium E. cowanii has biocontrol potential against B. cinerea after harvest of fruits and vegetables. Copyright © 2017 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

  12. Antagonists of the human A(2A) receptor. Part 6: Further optimization of pyrimidine-4-carboxamides.

    Science.gov (United States)

    Gillespie, Roger J; Bamford, Samantha J; Clay, Alex; Gaur, Suneel; Haymes, Tim; Jackson, Philip S; Jordan, Allan M; Klenke, Burkhard; Leonardi, Stefania; Liu, Jeanette; Mansell, Howard L; Ng, Sean; Saadi, Mona; Simmonite, Heather; Stratton, Gemma C; Todd, Richard S; Williamson, Douglas S; Yule, Ian A

    2009-09-15

    Antagonists of the human A(2A) receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson's disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure-activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson's disease.

  13. Data on the oral CRTh2 antagonist QAW039 (fevipiprant) in patients with uncontrolled allergic asthma.

    Science.gov (United States)

    Erpenbeck, Veit J; Popov, Todor A; Miller, David; Weinstein, Steven F; Spector, Sheldon; Magnusson, Baldur; Osuntokun, Wande; Goldsmith, Paul; Weiss, Markus; Beier, Jutta

    2016-12-01

    This article contains data on clinical endpoints (Peak Flow Expiratory Rate, fractional exhaled nitric oxide and total IgE serum levels) and plasma pharmacokinetic parameters concerning the use of the oral CRTh2 antagonist QAW039 (fevipiprant) in mild to moderate asthma patients. Information on experimental design and methods on how this data was obtained is also described. Further interpretation and discussion of this data can be found in the article "The oral CRTh2 antagonist QAW039 (fevipiprant): a phase II study in uncontrolled allergic asthma" (Erpenbeck et al., in press) [1].

  14. Data on the oral CRTh2 antagonist QAW039 (fevipiprant in patients with uncontrolled allergic asthma

    Directory of Open Access Journals (Sweden)

    Veit J. Erpenbeck

    2016-12-01

    Full Text Available This article contains data on clinical endpoints (Peak Flow Expiratory Rate, fractional exhaled nitric oxide and total IgE serum levels and plasma pharmacokinetic parameters concerning the use of the oral CRTh2 antagonist QAW039 (fevipiprant in mild to moderate asthma patients. Information on experimental design and methods on how this data was obtained is also described. Further interpretation and discussion of this data can be found in the article “The oral CRTh2 antagonist QAW039 (fevipiprant: a phase II study in uncontrolled allergic asthma” (Erpenbeck et al., in press [1].

  15. DAS-28-based EULAR response and HAQ improvement in rheumatoid arthritis patients switching between TNF antagonists

    Directory of Open Access Journals (Sweden)

    Barcelo Mireia

    2009-07-01

    Full Text Available Abstract Introduction No definitive data are available regarding the value of switching to an alternative TNF antagonist in rheumatoid arthritis patients who fail to respond to the first one. The aim of this study was to evaluate treatment response in a clinical setting based on HAQ improvement and EULAR response criteria in RA patients who were switched to a second or a third TNF antagonist due to failure with the first one. Methods This was an observational, prospective study of a cohort of 417 RA patients treated with TNF antagonists in three university hospitals in Spain between January 1999 and December 2005. A database was created at the participating centres, with well-defined operational instructions. The main outcome variables were analyzed using parametric or non-parametric tests depending on the level of measurement and distribution of each variable. Results Mean (± SD DAS-28 on starting the first, second and third TNF antagonist was 5.9 (± 2.0, 5.1 (± 1.5 and 6.1 (± 1.1. At the end of follow-up, it decreased to 3.3 (± 1.6; Δ = -2.6; p > 0.0001, 4.2 (± 1.5; Δ = -1.1; p = 0.0001 and 5.4 (± 1.7; Δ = -0.7; p = 0.06. For the first TNF antagonist, DAS-28-based EULAR response level was good in 42% and moderate in 33% of patients. The second TNF antagonist yielded a good response in 20% and no response in 53% of patients, while the third one yielded a good response in 28% and no response in 72%. Mean baseline HAQ on starting the first, second and third TNF antagonist was 1.61, 1.52 and 1.87, respectively. At the end of follow-up, it decreased to 1.12 (Δ = -0.49; p Conclusion A clinically significant effect size was seen in less than half of RA patients cycling to a second TNF antagonist.

  16. 5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure

    OpenAIRE

    Wiebke Janssen; Yves Schymura; Tatyana Novoyatleva; Baktybek Kojonazarov; Mario Boehm; Astrid Wietelmann; Himal Luitel; Kirsten Murmann; Damian Richard Krompiec; Aleksandra Tretyn; Soni Savai Pullamsetti; Norbert Weissmann; Werner Seeger; Hossein Ardeschir Ghofrani; Ralph Theo Schermuly

    2015-01-01

    Objective. The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg b...

  17. Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects

    Science.gov (United States)

    Jin, Yifeng; Han, Younho; Khadka, Daulat Bikram; Zhao, Chao; Lee, Kwang Youl; Cho, Won-Jea

    2016-01-01

    Conformational change in helix 12 can alter ligand-induced PPARγ activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPARγ antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form hydrogen bonds with the Cys285 and Arg288 residues of PPARγ. Furthermore, SPR results demonstrated strong binding affinity of isoquinolinoquinazolinones towards PPARγ. Additionally, biological assays showed that this new series of PPARγ antagonists more strongly inhibit adipocyte differentiation and PPARγ2-induced transcriptional activity than GW9662. PMID:27695006

  18. Antianxiety actions of Ca2+ channel antagonists with Vogel-type conflict test in rats.

    Science.gov (United States)

    Matsumoto, Y; Kataoka, Y; Watanabe, Y; Miyazaki, A; Taniyama, K

    1994-10-13

    We examined the effects of various derivatives of Ca2+ channel antagonists in a modified rat Vogel-type conflict model. Flunarizine (10 and 20 mg/kg), nicardipine (20 mg/kg), and verapamil (20 mg/kg), given as single i.p. injections, significantly increased punished lickings by 50-110%. Chronic administration of diltiazem, at 20 mg/kg i.p. for 8 days, a dose ineffective with a single i.p. injection, produced a significant anticonflict action. The possibility that Ca2+ channel antagonists have anxiolytic action should be considered.

  19. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, Lars

    2015-01-01

    Recently developed calcitonin gene-related peptide (CGRP) receptor antagonistic molecules have shown promising results in clinical trials for acute treatment of migraine attacks. Drugs from the gepant class of CGRP receptor antagonists are effective and do not cause vasoconstriction, one...... for treatment of chronic migraine (attacks >15 days/month). Initial results from phase I and II clinical trials have revealed promising results with minimal side effects and significant relief from chronic migraine as compared with placebo. The effectiveness of these various molecules raises the question...... to understand the localization of CGRP and the CGRP receptor components in these possible sites of migraine-related regions and their relation to the BBB....

  20. Unprecedented NES non-antagonistic inhibitor for nuclear export of Rev from Sida cordifolia.

    Science.gov (United States)

    Tamura, Satoru; Kaneko, Masafumi; Shiomi, Atsushi; Yang, Guang-Ming; Yamaura, Toshiaki; Murakami, Nobutoshi

    2010-03-15

    Bioassay-guided separation from the MeOH extract of the South American medicinal plant Sida cordifolia resulted in isolation of (10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid (1) as an unprecedented NES non-antagonistic inhibitor for nuclear export of Rev. This mechanism of action was established by competitive experiment by the biotinylated probe derived from leptomycin B, the known NES antagonistic inhibitor. Additionally, structure-activity relationship analysis by use of the synthesized analogs clarified cooperation of several functionalities in the Rev-export inhibitory activity of 1. Copyright 2010 Elsevier Ltd. All rights reserved.