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A HOXA10 Estrogen Response Element (ERE) is Differentially Regulated by 17 Beta-estradiol and Diethylstilbestrol (DES)
The molecular mechanisms by which estrogens regulate developmental gene expression are poorly understood. While 17 beta-estradiol is normally present at high concentrations in pregnancy, exposure to the estrogen diethylstilbestrol (DES) in utero induces developmental anomalies of the female reproductive tract. HOX gene expression is altered by DES, leading to abnormal Müllerian duct differentiation. The mechanism of ligand-specific regulation of HOX
G Eda Akbas; Joon Song; Hugh S Taylor
Preterm Birth, Fetal Growth, and Age at Menarche among Women Exposed Prenatally to Diethylstilbestrol (DES)
Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR) = 2.97; 95%CI=2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR=1.61; 95% CI=1.31,1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as <= 10 years (OR = 1.41 95%CI=0.97, 2.03) than defined as <= 11 years (OR=1.16; 95%CI=0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life.
Hatch, Elizabeth E.; Troisi, Rebecca; Wise, Lauren A.; Titus-Ernstoff, Linda; Hyer, Marianne; Palmer, Julie R.; Strohsnitter, William C; Robboy, Stanley J.; Anderson, Diane; Kaufman, Raymond; Adam, Ervin; Hoover, Robert N.
Diethylstilbestrol is a synthetic nonsteroidal estrogen that was used to prevent miscarriage and other pregnancy complications between 1938 and 1971 in the United States. In 1971, the U.S. Food and Drug Administration issued a warning about the use of diethylstilbestrol during pregnancy after a relationship between exposure to this synthetic estrogen and the development of clear cell adenocarcinoma of the vagina and cervix was found in young women whose mothers had taken diethylstilbestrol while they were pregnant. Although diethylstilbestrol has not been given to pregnant women in the United States for more than 30 years, its effects continue to be seen. Women who took diethylstilbestrol during pregnancy have a slightly higher risk of breast cancer than the general population and therefore should be encouraged to have regular mammography. Women who were exposed to diethylstilbestrol in utero may have structural reproductive tract anomalies, an increased infertility rate, and poor pregnancy outcomes. However, the majority of these women have been able to deliver successfully. Recommendations for gynecologic examinations include vaginal and cervical digital palpation, which may provide the only evidence of clear cell adenocarcinoma. Initial colposcopic examination should be considered; if the findings are abnormal, colposcopy should be repeated annually. If the initial colposcopic examination is normal, annual cervical and vaginal cytology is recommended. Because of the higher risk of spontaneous abortion, ectopic pregnancy, and preterm delivery, obstetric consultation may be required for pregnant women who had in utero diethylstilbestrol exposure. The male offspring of women who took diethylstilbestrol during pregnancy have an increased incidence of genital abnormalities and a possibly increased risk of prostate and testicular cancer. Routine prostate cancer screening and testicular self-examination should be encouraged. PMID:15168959
Schrager, Sarina; Potter, Beth E
Pharmacokinetics and safety profiles of novel diethylstilbestrol orally dissolving film in comparison with diethylstilbestrol capsules in healthy Chinese male subjects.
Objective: We compared the pharmacokinetic (PK) profiles of diethylstilbestrol orally dissolving film (DES ODF) and DES-capsule as well as assessing the safety, local tolerability, taste, and disintegration time of DES ODF. Materials and methods: Twelve healthy male volunteers receiving a single administration of 2.0 mg of DES ODF or DES-capsule were included in the study. The tolerability, taste, and time to dissolution of DES ODF were assessed after dosing. Safety assessments included adverse events, hematology and biochemistry tests, urinalysis, vital signs, and electrocardiography. Results: The PK parameters of DES ODF were all greater than those of DEScapsule. The Cmax values were 5.64 ± 1.1 and 3.4 ± 1.93 ng/mL for DES ODF and DES-capsule, respectively. Assessment of bioequivalence was based on the 90% CIs of the treatment ratios of the log-transformed Cmax, AUC0-t, and AUC0-? (DES ODF to DES-capsule), with the mean values being 1.93 (141 - 264), 1.24 (98 - 156), and 1.59 (121 - 207), respectively, indicating that DES ODF had a significantly high bioavailability. The mean DES ODF disintegration time was 14 ± 5 minutes. DES ODF was well tolerated and no serious adverse events or clinically relevant changes were observed. Conclusions: The DES ODF is well tolerated and better absorbed in comparison with DES-capsule. PMID:24618069
Zhang, Hong; Chen, Hong; Li, Xiao-Jiao; Zhang, Qi; Sun, Yan-Fu; Liu, Cheng-Jiao; Yang, Li-Zhi; Ding, Yan-Hua
Effects of Diethylstilbestrol in Fathead Minnows: Part 2. Concentrations in Water and Tissues
Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen, was once widely prescribed to prevent miscarriages, and was used as a growth promoter in feed for beef and poultry production. After it was determined that DES caused significant adverse effects in the offspring of mot...
Effects of Diethylstilbestrol in Fathead Minnows: Part 1. Effects on Reproductive Endocrine Function
Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen, was once widely prescribed to prevent miscarriages, and was used as a growth promoter in feed for beef and poultry production. After it was determined that DES caused significant adverse effects in the offspring of mo...
Bioactivation of diethylstilbestrol by the Syrian hamster kidney
Male Syrian golden hamsters chronically exposed to diethylstilbestrol (DES) develop renal adenocarcinomas with an incidence approaching 100%. The ability of the hamster kidney to bioactivate DES was assessed using hamster kidney slices. The male hamster renal cortex has a 2- to 5-fold greater capacity to irreversibly bind ({sup 3}H)DES as compared with female hamster renal cortex and with male hamster renal medulla. Incubation of the tissue under anaerobic conditions inhibited the metabolism and irreversible binding of ({sup 3}H)DES. Gel electrophoresis analysis of covalently modified proteins revealed several radioactive peaks indicating that specific adduct formation had occurred. The cytochrome P-450 inhibitors SKF 525-A, metyrapone, carbon monoxide, butylated hydroxytoluene, and dicumarol decreased the irreversible binding of ({sup 3}H)DES to renal cortical protein by 38 to 72%.
Adams, S.P.
Production of clenbuterol, diethylstilbestrol and trenbolone mass standards in lyophilised bovine urine
Clenbuterol (CLEN), diethylstilbestrol (DES) and trenbolone (TbOH) are xenobiotic growth promoters and have been illegally applied as repartitioning agents in meat-producing animals. In the EU, proper detection methods and control systems are established for many hormones and anabolic substances, and therefore there is a need to improve the accuracy and repeatability of quantification. In order to define a common basis
M. W Pfaffl; B Reck; R Dreher; H. H. D Meyer
The binding of steroid hormones and diethylstilbestrol to proteins of human cells in culture
The binding of 3H-labeled steroid hormones and a non-steroidal synthetic estrogen, diethylstilbestrol (DES), to proteins of cultured human embryonic lung cells (HEL 299) was studied according to the methods of Diamond et al. [Cancer Res 27:890–897 (1967)] and Kuroki and Heidelberger [Cancer Res 31:2168–2176 (1971)]. Ecdysone, estradiol, hydrocortisone, progesterone, testosterone, and DES were selected as test compounds. The aim of
Makoto Murakami; Jun-ichi Fukami
Current role of diethylstilbestrol in the management of advanced prostate cancer.
What's known on the subject? and What does the study add? Diethylstilbestrol (DES) has been found to have anti-tumour properties and clinical effectiveness in prostate cancer that is resistant to the first-line hormonal therapy. This review found that low-dose DES has anti-tumour efficacy with limited cardiovascular side effects and should be considered for secondary hormone manoeuvres. The aim of this review was to describe the most recent data from contemporary clinical trials of diethylstilbestrol (DES) to better determine its current role in advanced prostate cancer treatment as new hormonal therapies emerge. Relevant clinical studies using 1 mg of DES in castrate-resistant prostate cancer (CRPC) were identified from the literature, clinical trial databases, websites and conference abstracts. The efficacy and safety outcomes were summarized. DES in CRPC produced a biological response (change in PSA level) and improved the median survival of patients when used as a second-line hormone therapy after standard androgen deprivation with bicalutamide and LHRH analogues. These findings were for low doses of DES. The 1-mg dose is associated with a reduced toxicity, including fewer thromboembolic and cardiovascular events. Low-dose DES appears to be safe and effective for CRPC before initiating chemotherapy. The cost/efficiency ratio may encourage physicians to consider DES as a therapy option before chemotherapy in non-symptomatic CRPC. PMID:22578092
Bosset, Pierre-Olivier; Albiges, Laurence; Seisen, Thomas; de la Motte Rouge, Thibault; Phé, Véronique; Bitker, Marc-Olivier; Roupręt, Morgan
Brain Disrupting Actions of Prenatal Diethylstilbestrol Exposure in Mice — Behavioral, Neurochemical and Electrophysiological Studies
In addition to effects on the reproductive system, endocrine disruptors are thought to have brain-disrupting actions based on epidemiological and animal studies. In this review, we discuss the current state of studies on the brain-disrupting actions of diethylstilbestrol (DES), which is a prototype endocrine disruptor that has potent estro- gen-like action, focusing on our own findings. The major findings concerning
Kazuo Takahama; Taku Kaitsuka; Tetsuya Shirasaki; Fumio Soeda
Diethylstilbestrol increases the density of prolactin cells in male mouse pituitary by inducing proliferation of prolactin cells and transdifferentiation of gonadotropic cells
Diethylstilbestrol (DES) has been implicated in mammalian abnormalities. We examined the effects of DES on follicle-stimulating\\u000a hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) cells in the pituitaries of male mice treated with various doses\\u000a of DES for 20 days. DES reduced the density of FSH and LH cells in a dose-dependent manner, but increased that of PRL cells.\\u000a When the
Keiko Shukuwa; Shin-ichi Izumi; Yoshitaka Hishikawa; Kuniaki Ejima; Satoshi Inoue; Masami Muramatsu; Yasuyoshi Ouchi; Takashi Kitaoka; Takehiko Koji
Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects
Diethylstilbestrol (DES) is a potent estrogen mimic that was predominantly used from the 1940s to 1970s in hopes of preventing miscarriage in pregnant women. Decades later, DES is known to enhance breast cancer risk in exposed women, and cause a variety of birth related adverse outcomes in their daughters such as spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death. Additionally, children exposed to DES in utero suffer from sub/infertility and cancer of reproductive tissues. DES is a pinnacle compound which demonstrates the fetal basis of adult disease. The mechanisms of cancer and endocrine disruption induced by DES are not fully understood. Future studies should focus on common target tissue pathways affected and the health of the DES grandchildren.
Reed, Casey E.; Fenton, Suzanne E.
The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice
Epidemiology studies indicate that exposure to endocrine disruptors during developmental "window" contributes to adipogenesis and the development of obesity. Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated. Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) ? as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPAR? activity. Moreover, DES perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to low dose of DES significantly increased body weight, liver weight and fat mass in female offspring at postnatal day (PND) 60. In addition, serum triglyceride and glucose levels were also significantly elevated. These results suggest that perinatal exposure to DES may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders. -- Highlights: ? DES induced adipocyte differentiation in a dose-dependent manner in 3T3-L1 cells. ? DES activated adipogenic critical regulators and markers in vitro and in vivo. ? Perinatal exposure to DES led to the obese phenotype in female offspring. ? DES might be a potential chemical stressor for obesity and obesity-related disorders.
Hao, Chan-Juan; Cheng, Xue-Jia; Xia, Hong-Fei, E-mail: firstname.lastname@example.com; Ma, Xu
Effects of maternal exposure to diethylstilbestrol on epididymal development in rat offspring.
In our previous study, prenatal diethylstilbestrol (DES) exposure (days 7-21 of gestation) suppressed plasma testosterone levels and histological development in the epididymis of rat offspring. In this study, we measured cell proliferation in epididymal ductules and the expression of steroid hormone receptors and 5alpha-reductase 1 in the epididymis to assess the effect of DES on epididymal development in the offspring. Prenatal DES exposure did not alter the cell division index, but suppressed the expression of androgen receptor mRNA at 15 weeks after birth, and stimulated estrogen receptor alpha mRNA at 6 weeks. These results suggest that prenatal DES exposure results in the retardation of epididymal tissue maturation by disruption of the postnatal expression of steroid hormone receptors. PMID:19346712
Yamamoto, Masako; Kohara, Shinya; Kobayashi, Tetsuo; Shirai, Mitsuyuki; Nisikawa, Osamu; Arishima, Kazuyoshi
The Development of Cervical and Vaginal Adenosis as a Result of Diethylstilbestrol Exposure In Utero
Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed with DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Müllerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces adenosis lesions in the cervix and vagina. This review describes mouse models can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses its molecular pathogenesis.
Laronda, Monica M.; Unno, Kenji; Butler, Lindsey M.; Kurita, Takeshi
Hypospadias: a transgenerational effect of diethylstilbestrol?
BACKGROUND: In 2002, an increased risk of hypospadias was reported for sons of women exposed to diethyl- stilbestrol (DES) in utero, suggesting transgenerational effects of DES. The aim of this study was to further assess the association between parental DES exposure and hypospadias in a case-referent study. METHODS: Cases with hypospadias were retrieved from the hospital information system. Referents were
M. M. Brouwers; W. F. J. Feitz; L. A. J. Roelofs; L. A. L. M. Kiemeney; R. P. E. de Gier; N. Roeleveld
Model ecosystem evaluation of the environmental impacts of the veterinary drugs phenothiazine, sulfamethazine, clopidol, and diethylstilbestrol.
Four veterinary drugs of dissimilar chemical structures were evaluated for environmental stability and penchant for bioaccumulation. The techniques used were (1) a model aquatic ecosystem (3 days) and (2) a model feedlot ecosystem (33 days) in which the drugs were introduced via the excreta of chicks or mice. The model feedlot ecosystem was supported by metabolism cage studies to determine the amount and the form of the drug excreted by the chicks or mice. Considerable quantities of all the drugs were excreted intact or as environmentally short-lived conjugates. Diethylstilbestrol (DES) and Clopidol were the most persistent molecules, but only DES bioaccumulated to any appreciable degree. Phenothiazine was very biodegradable; sulfamethazine was relatively biodegradable and only accumulated in the organisms to very low levels. Data from the aquatic model ecosystem demonstrated a good correlation between the partition coefficients of the drugs and their accumulation in the fish. Images FIGURE 1.
Coats, J R; Metcalf, R L; Lu, P Y; Brown, D D; Williams, J F; Hansen, L G
Characterization of UDP-glucuronosyltransferases involved in glucuronidation of diethylstilbestrol in human liver and intestine.
Diethylstilbestrol (DES), a synthetic estrogen, is famous for its carcinogenic effects. Human exposure to this compound can occur frequently through dietary ingestion and medical treatment. Glucuronidation has been demonstrated to be a predominant metabolic pathway for DES in human. Therefore, glucuronidation metabolism may have a significant impact on its toxicities, and it is essential to clarify this metabolic pathway. Accordingly, this in vitro study is designed to characterize the UGTs involved in DES glucuronidation and, furthermore, to identify the roles of individual isoforms in the reaction in liver and intestine. Human liver microsomes (HLM) displayed much higher potential for DES glucuronidation than human intestinal microsomes (HIM). The intrinsic clearances in HLM and HIM were demonstrated to be 459 and 14 ?L/min/mg protein, respectively. Assays with recombinant UGTs demonstrated that UGT1A1, -1A3, -1A8, and -2B7 could catalyze DES glucuronidation, among which UGT2B7 showed the highest affinity. Chemical inhibitors of UGT2B7 and UGT1A1/1A3 both displayed similar inhibition against the reaction in UGT2B7 and HLM. In addition, DES glucuronidation in individual HLM exhibited a large individual variability and strongly correlated to UGT2B7 activity. All evidence indicates that UGT2B7 may act as a major enzyme responsible for DES glucuronidation in human liver. For HIM, both UGT2B7 inhibitor and UGT1A1/1A3/1A8 inhibitor exerted moderate inhibition. It is suggested that although UGT2B7 contributes to DES glucuronidation in intestine, other UGTs may contribute equally. In summary, this study characterizes human UGTs involved in DES glucuronidation in human liver and intestine, which may be helpful for further study about DES-related toxicities. PMID:23126256
Zhu, Liangliang; Ge, Guangbo; Liu, Yong; Guo, Zhimou; Peng, Chengcheng; Zhang, Feng; Cao, Yunfeng; Wu, Jingjing; Fang, Zhongze; Liang, Xinmiao; Yang, Ling
Perinatal exposure to diethylstilbestrol improves olfactory discrimination learning in male and female Swiss-Webster mice.
During late prenatal and early postnatal brain development, estrogen induces structural sex differences that correspond to behavioral differences in certain domains such as learning and memory. The typically superior performance of males is attributed to the action of elevated concentrations of estrogen, derived inside neurons from the aromatization of testosterone. In contrast, female performance appears dependent on minimal estrogenic activity. Rat models of the relationship between hormones and cognitive behavior predominate the field, but the advent of genetically modified mice as research tools necessitates development of analogous mouse models. This study examined how early postnatal exposure to the synthetic estrogen diethylstilbestrol (DES) affected the ability of male and female Swiss-Webster mice to learn a two-choice olfactory discrimination and three repeated reversals. Mice treated with subcutaneous injections of DES from postnatal days 1-10 learned reversals more readily than oil-treated controls, a difference that became evident after repeated testing. DES-exposed males and females learned reversals at a comparable rate, suggesting that early postnatal estrogen exposure does not influence this mode of learning through a sexually differentiated mechanism in mice. An analysis of response patterns during qualitatively different phases of reversal learning revealed that DES-induced improvements probably were not due to greater inhibitory control. Instead, DES appeared to enhance associative ability. Early postnatal estrogen exposure may have the potential to preserve certain cognitive skills in adulthood. PMID:12737934
Mihalick, Sheila M
Towards functional glycomics by localization of binding sites for tissue lectins: lectin histochemical reactivity for galectins during diethylstilbestrol-induced kidney tumorigenesis in male Syrian hamster
Endogenous lectins act as effectors of cellular activities such as growth regulation, migration, and adhesion. Following their\\u000a immunohistochemical localization in our previous study (Saussez et al. in Histochem Cell Biol 123:29–41, 2005) we purified\\u000a several galectins and used them as tools for monitoring accessible binding sites. Herein, we report the use of galectin histochemistry\\u000a for the analysis of diethylstilbestrol (DES)-induced
Sven Saussez; Francois Lorfevre; Denis Nonclercq; Guy Laurent; Sabine André; Fabrice Journé; Robert Kiss; Gérard Toubeau; Hans-Joachim Gabius
Structural insights into Resveratrol's antagonist and partial agonist actions on estrogen receptor alpha
Background Resveratrol, a naturally occurring stilbene, has been categorized as a phytoestrogen due to its ability to compete with natural estrogens for binding to estrogen receptor alpha (ER?) and modulate the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ER?) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed. Results Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ER? ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ER? monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ER? in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ER? dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ER? are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ER?. Conclusions Our Molecular Dynamics simulation of RES-ER? structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity.
Comparative study of reactions of endocrine disruptors bisphenol A and diethylstilbestrol in electrochemical treatment and chlorination.
Transformations of diethylstilbestrol (DES) and bisphenol A (BPA) in conventional chlorination and electrochemically (EC) treated solutions were examined using spectrophotometry and chromatographic analyses. EC treatment was carried out using an undivided EC cell with a PbO2 anode and a stainless steel cathode. EC-treatment and conventional chlorination caused DES and BPA to undergo a rapid degradation accompanied by the generation of low molecular weight chlorinated organic species indicative of the breakdown of DES and BPA. The identified compounds were predominated by chloroacetic acids (HAAs), but approximately 80% of the total organic halogen (TOX) was comprised by unidentified species. For EC treatment, the HAA yields were lower and HAAs were predominated by monochloroacetic acid (MCAA), while in the case of conventional chlorination, trichloroacetic acid (TCAA) was predominant and MCAA was virtually absent. The changes in the HAA speciation and yields were concluded to be caused by the EC-driven reductive dehalogenation which, however, did not affect the unidentified fraction of TOX. This indicated that the unidentified part of TOX was comprised by aromatic chlorinated forms of BPA and DES. Their resistance to degradation in EC reactors indicates that these compounds may be stable in conditions typical for drinking water treatment and distribution. PMID:16476465
Korshin, Gregory V; Kim, Jaeshin; Gan, Lili
Differential progression of neonatal diethylstilbestrol-induced disruption of the hamster testis and seminal vesicle.
The synthetic estrogen diethylstilbestrol (DES) is now recognized as the prototypical endocrine disruptor. Using a hamster experimental system, we performed a detailed temporal assessment of how neonatal DES-induced disruption progresses in the testis compared to the seminal vesicle. Both morphological and Western blot analyses confirmed that neonatal DES exposure alters androgen responsiveness in the male hamster reproductive tract. We also determined that the disruption phenomenon in the male hamster is manifest much earlier in the seminal vesicle than in the testis and that testis disruption often occurs differently between the pair of organs in a given animal. In the neonatally DES-exposed seminal vesicle, histopathological effects included: (1) general atrophy, (2) lack of exocrine products, (3) epithelial dysplasia, (4) altered organization of stromal cells and extracellular matrix, and (5) striking infiltration with polymorphonuclear leukocytes. Also, the morphological disruption phenomenon in the seminal vesicle was accompanied by a range of up-regulation and down-regulation responses in the whole organ levels of various proteins. PMID:16439099
Hendry, William J; Weaver, Benjamin P; Naccarato, Teran R; Khan, Shafiq A
Cardiac structure/function, protein expression, and DNA methylation are changed in adult female mice exposed to diethylstilbestrol in utero.
The detrimental effects of in utero exposure to the non-steroidal estrogen diethylstilbestrol (DES) are particularly marked in women. Fetal hearts express estrogen receptors, making them potentially responsive to DES. To examine whether gestational exposure to DES would impact the heart, we exposed pregnant C57bl/6n dams to DES (0.1, 1.0, and 10.0 ?g·(kg body mass)(-1)·day(-1)) on gestation days 11.5-14.5, and examined the measured cardiac structure/function and calcium homeostasis protein expression in adult females. At baseline, echocardiography revealed eccentric hypertrophy in mice treated with 10.0 ?g·(kg body mass)(-1)·day(-1) DES, and immunoblots showed increased SERCA2a in all DES-treated mice. Mice were swim-trained to assess cardiac remodeling. Swim-trained vehicle-treated mice developed eccentric hypertrophy without changing SERCA2 or calsequestrin 2 expression. In contrast, no DES-treated mice hypertrophied, and all increased in SERCA2a and calsequestrin 2 expression after training. To determine whether DES-induced changes in DNA methylation is part of the mechanism for its long-term effects, we measured DNA methyltransferase expression and DNA methylation. Global DNA methylation and DNA methyltransferase 3a expression were unchanged. However, DES-treated mice had increased DNA methylation in the calsequestrin 2 promoter. Thus, gestational exposure to DES altered female ventricular DNA, cardiac structure/function, and calcium homeostasis protein expression. We conclude that gestational exposure to estrogenizing compounds may impact cardiac structure/function in adult females. PMID:23984849
Haddad, Rami; Kasneci, Amanda; Sebag, Igal A; Chalifour, Lorraine E
Pubertal timing after neonatal diethylstilbestrol exposure in female rats: neuroendocrine vs peripheral effects and additive role of prenatal food restriction.
We studied the effects of neonatal exposure to diethylstilbestrol (DES) on pubertal timing in female rats. We examined associated neuroendocrine changes and effects of prenatal food restriction. Age at vaginal opening was advanced after exposure to 10 ?g/kg/d of DES and delayed after 1 ?g/kg/d (subcutaneous injections). Using this lower dose, pulsatile GnRH secretion was slower at 25 days of age. Both doses reduced KiSS1 mRNA levels at 15 days of age. Using functional Kisspeptin promoter assay, 1 or 10 ?M DES reduced or increased KISS1 transcription, respectively. Leptin stimulatory effect on GnRH secretion in vitro (15 days of age) was reduced after prenatal food restriction and neonatal DES exposure (higher dose), both effects being cumulative. Thus, alterations in pubertal timing by DES neonatally are not unequivocally toward precocity, the level of exposure being critical. We provide evidence of neuroendocrine disruption and interaction with prenatal food availability. PMID:24316331
Franssen, Delphine; Ioannou, Yiannis S; Alvarez-real, Alexandra; Gerard, Arlette; Mueller, Johanna K; Heger, Sabine; Bourguignon, Jean-Pierre; Parent, Anne-Simone
Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny.
Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0?g/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5-14.5. At 3months, male progeny were left sedentary or were swim trained for 4weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males. PMID:23142472
Haddad, Rami; Kasneci, Amanda; Mepham, Kathryn; Sebag, Igal A; Chalifour, Lorraine E
Mechanisms of estrogen-induced effects in avian reproduction caused by transovarian application of a xenoestrogen, diethylstilbestrol.
To clarify breeding failure in avian species caused by the estrogenicity of chemicals, alterations in the reproductive systems of Japanese quail exposed in ovo to a xenoestrogen were investigated. An injection of diethylstilbestrol (DES) into the yolk before incubation decreased, after sexual maturation, egg-laying performance of female quails, which accompanied inducing abnormal development of the oviducts. All females treated with 50 ng DES/g of egg did not lay eggs, while 0.5-5 ng DES/g reduced egg weight and eggshell strength and thickness. In the uterus (shell gland), the mRNAs for calcium regulating factors, osteopontin and calbindin D28 K, were reduced dose-dependently by DES. Scanning electron microscopy showed that shell thinning was pronounced in the mammillary and cuticular layers of the eggshell, regions where osteopontin proteins are reportedly located. These indicate that transovarian exposure to xenoestrogens causes malformation and dysfunction of the oviducts, where calcium regulating molecules could play key roles in eggshell thinning. PMID:18597071
Kamata, Ryo; Shiraishi, Fujio; Izumi, Tokukazu; Takahashi, Shinji; Shimizu, Akira; Shiraishi, Hiroaki
Developmental Exposure to Diethylstilbestrol Alters Uterine Gene Expression That May Be Associated With Uterine Neoplasia Later in Life
Previously, we described a mouse model where the well-known reproductive carcinogen with estrogenic activity, diethylstilbestrol (DES), caused uterine adenocarcinoma following neonatal treatment. Tumor incidence was dose-dependent reaching >90% by 18 mo following neonatal treatment with 1000 ?g/kg/d of DES. These tumors followed the initiation/promotion model of hormonal carcinogenesis with developmental exposure as initiator, and exposure to ovarian hormones at puberty as the promoter. To identify molecular pathways involved in DES-initiation events, uterine gene expression profiles were examined in prepubertal mice exposed to DES (1, 10, or 1000 ?g/kg/d) on days 1–5 and compared to controls. Of more than 20 000 transcripts, approximately 3% were differentially expressed in at least one DES treatment group compared to controls; some transcripts demonstrated dose–responsiveness. Assessment of gene ontology annotation revealed alterations in genes associated with cell growth, differentiation, and adhesion. When expression profiles were compared to published studies of uteri from 5-d-old DES-treated mice, or adult mice treated with 17? estradiol, similarities were seen suggesting persistent differential expression of estrogen responsive genes following developmental DES exposure. Moreover, several altered genes were identified in human uterine adenocarcinomas. Four altered genes [lactotransferrin (Ltf), transforming growth factor beta inducible (Tgfb1), cyclin D1 (Ccnd1), and secreted frizzled-related protein 4 (Sfrp4)], selected for real-time RT-PCR analysis, correlated well with the directionality of the microarray data. These data suggested altered gene expression profiles observed 2 wk after treatment ceased, were established at the time of developmental exposure and maybe related to the initiation events resulting in carcinogenesis.
Newbold, Retha R.; Jefferson, Wendy N.; Grissom, Sherry F.; Padilla-Banks, Elizabeth; Snyder, Ryan J.; Lobenhofer, Edward K.
Subchronic exposure to phytoestrogens alone and in combination with diethylstilbestrol - pituitary tumor induction in Fischer 344 rats
Background Subchronic administration of the potent pharmaceutical estrogen diethylstilbestrol (DES) to female Fischer 344 (F344) rats induces growth of large, hemorrhagic pituitaries that progress to tumors. Phytoestrogens (dietary plant estrogens) are hypothesized to be potential tumor inhibitors in tissues prone to estrogen-induced cancers, and have been suggested as "safer" estrogen replacements. However, it is unknown if they might themselves establish or exacerbate the growth of estrogen-responsive cancers, such as in pituitary. Methods We implanted rats with silastic capsules containing 5 mg of four different phytoestrogens - either coumestrol, daidzein, genistein, or trans-resveratrol, in the presence or absence of DES. We examined pituitary and other organ weights, blood levels of prolactin (PRL) and growth hormone (GH), body weights, and pituitary tissue histology. Results Blood level measurements of the administered phytoestrogens confirmed successful exposure of the animals to high levels of these compounds. By themselves, no phytoestrogen increased pituitary weights or serum PRL levels after 10 weeks of treatment. DES, genistein, and resveratrol increased GH levels during this time. Phytoestrogens neither changed any wet organ weight (uterus, ovary, cervix, liver, and kidney) after 10 weeks of treatment, nor reversed the adverse effects of DES on pituitaries, GH and PRL levels, or body weight gain after 8 weeks of co-treatment. However, they did reverse the DES-induced weight increase on the ovary and cervix. Morphometric examination of pituitaries revealed that treatment with DES, either alone or in combination with phytoestrogens, caused gross structural changes that included decreases in tissue cell density, increases in vascularity, and multiple hemorrhagic areas. DES, especially in combination with phytoestrogens, caused the development of larger and more heterogeneous nuclear sizes in pituitary. Conclusions High levels of phytoestrogens by themselves did not cause pituitary precancerous growth or change weights of other estrogen-sensitive organs, though when combined with DES, they counteracted the growth effects of DES on reproductive organs. In the pituitary, phytoestrogens did not reverse the effects of DES, but they did increase the sizes and size heterogeneity of nuclei. Therefore, phytoestrogens may oppose some but not all estrogen-responsive tissue abnormalities caused by DES overstimulation, and appear to exacerbate DES-induced nuclear changes.
Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny
Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0 ?g/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5–14.5. At 3 months, male progeny were left sedentary or were swim trained for 4 weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males. -- Highlights: ? Gestational DES changes cardiac SERCA2a and CASQ2 expression. ? Echocardiography identified systolic dysfunction and increased diastolic relaxation. ? DES increased DNMT3a expression and increased CpG DNA methylation. ? DES impacts fetal heart reducing cardiac reserve on challenge in adulthood. ? Fetal heart can be re-programmed by a non-steroidal estrogen.
Haddad, Rami, E-mail: firstname.lastname@example.com [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada) [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); Division of Experimental Medicine, Department of Medicine, McGill University, 850 Sherbrooke Street, Montréal, Québec, Canada H3A 1A2 (Canada); Kasneci, Amanda, E-mail: email@example.com [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada)] [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); Mepham, Kathryn, E-mail: firstname.lastname@example.com [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada) [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); Division of Experimental Medicine, Department of Medicine, McGill University, 850 Sherbrooke Street, Montréal, Québec, Canada H3A 1A2 (Canada); Sebag, Igal A., E-mail: email@example.com [Division of Cardiology, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); and others
Selection of Diethylstilbestrol-Specific Single-Chain Antibodies from a Non-Immunized Mouse Ribosome Display Library
Single chain variable fragments (scFvs) against diethylstilbestrol (DES) were selected from the splenocytes of non-immunized mice by ribosome display technology. A naive library was constructed and engineered to allow in vitro transcription and translation using an E. coli lysate system. Alternating selection in solution and immobilization in microtiter wells was used to pan mRNA-ribosome-antibody (ARM) complexes. After seven rounds of ribosome display, the expression vector pTIG-TRX containing the selected specific scFv DNAs were transformed into Escherichia coli BL21 (DE3) for expression. Twenty-six positive clones were screened and five clones had high antibody affinity and specificity to DES as evidenced by indirect competitive ELISA. Sequence analysis showed that these five DES-specific scFvs had different amino acid sequences, but the CDRs were highly similar. Surface plasmon resonance (SPR) analysis was used to determine binding kinetics of one clone (30-1). The measured KD was 3.79 µM. These results indicate that ribosome display technology can be used to efficiently isolate hapten-specific antibody (Ab) fragments from a naive library; this study provides a methodological framework for the development of novel immunoassays for multiple environmental pollutants with low molecular weight detection using recombinant antibodies.
Liu, Ming; Gao, Xianjun; Fan, Xianjun; Liu, Jianqing; Gao, Zhixian
Prenatal diethylstilbestrol exposure and performance on college entrance examinations.
The fetal rodent brain is permanently altered by exposure to sex hormones. Long-term effects of prenatal sex hormones on the human brain are far less clear. In order to explore such effects, we studied a measure of cognitive function among young adults who had been exposed in utero to a powerful synthetic estrogen. In a randomized clinical trial conducted at the University of Chicago in 1950-1952, 1646 pregnant women were randomly assigned to receive either high doses of diethylstilbestrol or placebo. Women in this study gave birth to 1653 liveborn infants, of whom 1603 (820 sons and 783 daughters) survived to their fifteenth birthday. College entrance examination scores were obtained for 42% of these offspring. No differences in test performance were seen among exposed daughters. Among sons, test scores were marginally higher among the exposed, probably due to chance. PMID:1398561
Wilcox, A J; Maxey, J; Herbst, A L
G Protein-Coupled Estrogen Receptor-Protein Kinase A-ERK-CREB Signaling Pathway is Involved in the Regulation of Mouse Gubernaculum Testis Cells by Diethylstilbestrol.
The etiology of testicular dysgenesis syndrome is multifactorial and involves environmental factors, such as environmental estrogens. Several studies have shown that hormonal effects on the gubernaculum may affect testicular descent. Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen that disrupts the morphology and proliferation of gubernacular cells, but the underlying mechanisms remain elusive. In this study, we aimed to determine whether DES may regulate the function of gubernaculum testis cells by way of nongenomic effects mediated by G protein-coupled estrogen receptor (GPER). We used cultured mouse gubernacular testis cells to demonstrate that GPER is expressed in gubernaculum testis cells. Erk1/2 inhibitor PD98059, PKA inhibitor H89, and Src inhibitor PP2 relieved DES-induced inhibition of gubernaculum testis cell proliferation, but ER inhibitor ICI 182780 had no effects on DES-induced inhibition of gubernaculum testis cell proliferation. In addition, we found that DES induced the activation of CREB downstream of PKA, Src, and ERK1/2 in these cells. These data suggest that the effects of DES on mouse gubernaculum testis cells are mediated at least partially by GPER-protein kinase A-ERK-CREB signaling pathway. PMID:24306628
Zhang, Xuan; Li, Jian-Hong; Duan, Shou-Xing; Lin, Qing-Jun; Ke, Song; Ma, Lian; Huang, Tian-Hua; Jiang, Xue-Wu
Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo.
Antisense transcript, long non-coding RNA HOTAIR is a key player in gene silencing and breast cancer and is transcriptionally regulated by estradiol. Here, we have investigated if HOTAIR expression is misregulated by bisphenol-A (BPA) and diethylstilbestrol (DES). Our findings demonstrate BPA and DES induce HOTAIR expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of rat. Luciferase assay showed that HOTAIR promoter estrogen-response-elements (EREs) are induced by BPA and DES. Estrogen-receptors (ERs) and ER-coregulators such as MLL-histone methylases (MLL1 and MLL3) bind to the HOTAIR promoter EREs in the presence of BPA and DES, modify chromatin (histone methylation and acetylation) and lead to gene activation. Knockdown of ERs down-regulated the BPA and DES-induced expression of HOTAIR. In summary, our results demonstrate that BPA and DES exposure alters the epigenetic programming of the HOTAIR promoters leading to its endocrine disruption in vitro and in vivo. PMID:24533973
Bhan, Arunoday; Hussain, Imran; Ansari, Khairul I; Bobzean, Samara A M; Perrotti, Linda I; Mandal, Subhrangsu S
Exposure to diethylstilbestrol during embryonic and larval stages of medaka fish (Oryzias latipes) leads to sex reversal in genetic males and reduced gonad weight in genetic females.
Molecular and cellular mechanisms involved in artificially induced ovarian differentiation were analyzed by exposing embryos of medaka (Oryzias latipes) to a potent nonsteroidal estrogen, diethylstilbestrol (DES). Embryos were exposed for short-exposure (SE) [from 0 to 8 d postfertilization (dpf)] and long-exposure (LE) periods (from 0 to 18/28 dpf) to 1 ng/ml of DES, and status of sexual differentiation in somatic and germ cells of these gonads was analyzed at 8, 18, and 28 dpf by histology, cell proliferation assays, TUNEL assay, and in situ hybridization using sex-specific somatic and germ cell markers. Additionally, gonads of exposed fry were examined after withdrawal of DES to see whether effects of DES in exposed fish were reversible or not. DES induced germ cell proliferation and meiosis in XY fry of SE and LE groups. However, SE induced only a partial reduction in expression of gonadal soma-derived factor, the male-dominant somatic cell marker, and was not sufficient to induce ovarian development after withdrawal of DES. On the contrary, LE resulted in complete loss of such male-specific gene expression in somatic cells of XY gonads, and these gonads underwent sustained ovarian development even after withdrawal of DES. Importantly, LE to DES affected germ cell proliferation in XX gonads adversely during early stages of sexual differentiation, leading to reduced gonad weight in adulthood. Interestingly, apoptosis was not the cause for reduction in germ cell number. Taken together, these results indicated that DES exposure has long-lasting effects on the gonadal development in genetic males (sex reversal) and females (reduced gonad weight) of medaka. PMID:21239430
Paul-Prasanth, Bindhu; Shibata, Yasushi; Horiguchi, Ryo; Nagahama, Yoshitaka
Analysis of the Effect of Estrogen/Androgen Perturbation on Penile Development in Transgenic and Diethylstilbestrol-Treated Mice
Because both androgens and estrogens have been implicated in penile morphogenesis, we evaluated penile morphology in transgenic mice with known imbalance of androgen and estrogen signaling using scanning electron microscopy (SEM), histology, and immunohistochemistry of androgen and estrogen receptors ?/?. Penises of adult wild-type, estrogen receptor-? knockout (?ERKO), estrogen receptor-? knockout (?ERKO), aromatase knockout (Arom-KO), and aromatase overexpression (Arom+) mice were evaluated, as well as adult mice treated with diethylstilbestrol (DES) from birth to day 10. Adult penises were examined because the adult pattern is the endpoint of development. The urethral orifice is formed by fusion of the MUMP (male urogenital mating protuberance) with the MUMP ridge, which consists of several processes fused to each other and to the MUMP. Similarly, the internal prepuce is completed ventrally by fusion of a ventral cleft. In adult murine penises the stromal processes that form the MUMP ridge are separated from their neighbors by clefts. ?ERKO, ?ERKO, and Arom-KO mice have penises with a MUMP ridge clefting pattern similar to that of wild-type mice. In contrast, Arom+ mice and neonatally DES-treated mice exhibit profound malformations of the MUMP, MUMP ridge clefting pattern, and internal prepuce. Abnormalities observed in Arom+ and neonatally DES-treated mice correlate with the expression of estrogen receptor-beta (ER?) in the affected structures. This study demonstrates that formation of the urethal orifice and internal prepuce is due to fusion of separate epithelial-surfaced mesenchymal elements, a process dependent upon both androgen and estrogen signaling, in which ER? signaling is strongly implicated.
The B1-agonist [des-Arg10]-kallidin activates transcription factor NF-kappaB and induces homologous upregulation of the bradykinin B1-receptor in cultured human lung fibroblasts.
The bradykinin B1-receptor is strongly upregulated under chronic inflammatory conditions. However, the mechanism and reason are not known. Because a better understanding of the mechanism of the upregulation will help in understanding its potential importance in inflammation, we have studied the molecular mechanism of B1-receptor upregulation in cultured human lung fibroblasts (IMR 90) in response to IL-1beta and the B1-agonist [des-Arg10]-kallidin. We show that treatment of human IMR 90 cells by IL-1beta stimulates the expression of both B1-receptor mRNA and protein. The latter was studied by Western blot analysis using antipeptide antibodies directed against the COOH-terminal part of the human B1-receptor. We furthermore report the novel observation that the B1-receptor is upregulated by its own agonist which was completely blocked by the specific B1-antagonist [des-Arg10-Leu9]-kallidin, indicating an upregulation entirely mediated through cell surface B1-receptors. The increased population of B1-receptors was functionally coupled as exemplified by an enhancement of the B1-agonist induced increase in free cytosolic calcium. Upregulation by the B1-agonist was blocked by a specific protein kinase C inhibitor. B1-agonist-induced upregulation was correlated to the induction of transcription factor nuclear factor kappaB (NF-kappaB) which efficiently bound to the NF-kappaB-like sequence located in the promoter region of the human B1-receptor gene. This correlation was further confirmed by reporter gene assays which showed that this NF-kappaB-like sequence, in the B1-receptor promoter context, could contribute to IL-1beta and DLBK-induced B1-receptor transcription activation, and by the effect of NF-kappaB inhibitor pyrrolidinedithiocarbamate which diminished both B1-receptor upregulation and NF-kappaB activation. NF-kappaB is now recognized as a key inflammatory mediator which is activated by the B1-agonist but which is also involved in B1-receptor upregulation.
Schanstra, J P; Bataille, E; Marin Castano, M E; Barascud, Y; Hirtz, C; Pesquero, J B; Pecher, C; Gauthier, F; Girolami, J P; Bascands, J L
Non-diethylstilbestrol-associated primary clear cell carcinoma of the vagina: two case reports with immunohistochemical studies and literature review.
Primary clear cell adenocarcinomas most commonly involve the genitourinary system, including the vagina. Previously, primary clear cell adenocarcinomas of the vagina have been discussed within the context of prenatal exposure to diethylstilbestrol. Due to its widely proven role in the development of this carcinoma, administration of diethylstilbestrol is prohibited. We present two cases of non-diethylstilbestrol-associated primary clear cell adenocarcinoma of the vagina from the archives of the Anatomical Pathology Department at King Abdulaziz University in order to improve our understanding of its biological behavior. Our findings suggest that primary clear cell adenocarcinoma of the vagina may be unrelated to diethylstilbestrol exposure and that non-diethylstilbestrol-associated primary clear cell adenocarcinoma of the vagina, when present at a younger age, may have a worse prognosis. PMID:24850989
Mufti, Shagufta T; Ali, Hiba Hassan
Non-Diethylstilbestrol-Associated Primary Clear Cell Carcinoma of the Vagina: Two Case Reports with Immunohistochemical Studies and Literature Review
Primary clear cell adenocarcinomas most commonly involve the genitourinary system, including the vagina. Previously, primary clear cell adenocarcinomas of the vagina have been discussed within the context of prenatal exposure to diethylstilbestrol. Due to its widely proven role in the development of this carcinoma, administration of diethylstilbestrol is prohibited. We present two cases of non-diethylstilbestrol-associated primary clear cell adenocarcinoma of the vagina from the archives of the Anatomical Pathology Department at King Abdulaziz University in order to improve our understanding of its biological behavior. Our findings suggest that primary clear cell adenocarcinoma of the vagina may be unrelated to diethylstilbestrol exposure and that non-diethylstilbestrol-associated primary clear cell adenocarcinoma of the vagina, when present at a younger age, may have a worse prognosis.
Mufti, Shagufta T.; Ali, Hiba Hassan
Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen
Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 {mu}g/pup/day) or tamoxifen (TAM; 10 {mu}g/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence in mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-{alpha}, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES.
Waalkes, Michael P. [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, PO Box 12233, Mail Drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709 (United States)]. E-mail: email@example.com; Liu Jie [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, PO Box 12233, Mail Drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709 (United States); Ward, Jerrold M. [National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892 (United States); Diwan, Bhalchandra A. [Basic Research Program, Science Applications International Corporation, National Cancer Institute at Frederick, Frederick, MD 21702-1201 (United States)
In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles
Isolated rat ovarian follicles grow and produce steroid hormones in vitro and so provide a good model for studying the effects of hormonally active compounds on follicular steroidogenesis. We have evaluated the effects of diethylstilbestrol (DES), genistein (GEN) and two alkylphenols, 4-tert-butylphenol (BP) and 4-tert-octylphenol (OP) on the growth, survival, and steroid hormone and cAMP production by isolated 14-day-old rat (Sprague-Dawley) ovarian follicles. During a 5-day culture, FSH was obligatory for follicle growth and increased estradiol and testosterone secretion in a dose-dependent manner. DES (10{sup -6} M) caused the strongest decline in estradiol and testosterone levels but did not have detectable effects on either cAMP production or aromatase enzyme activity. GEN caused a prominent decrease in cAMP and testosterone levels without significant changes in secreted estradiol. The latter, apparently, was due to a dose-dependent stimulation of aromatase enzyme activity in the presence of genistein. Both BP and OP decreased estradiol and testosterone secretion in a dose-dependent manner while no effect on aromatase activity was observed. OP, unlike BP, decreased forskolin-induced cAMP levels. Xenoestrogens at the used concentrations did not interfere with the growth and survival of the follicles. The results indicate that isolated ovarian follicles representing intact morphological and functional units offer a sensitive model system for elucidating the female-specific reproductive effects of environmental chemicals.
Myllymaeki, Sari [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland) and Departments of Physiology and Pediatrics, University of Turku, Turku (Finland)]. E-mail: email@example.com; Haavisto, Tapio [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland); Vainio, Minna [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland); Toppari, Jorma [Departments of Physiology and Pediatrics, University of Turku, Turku (Finland); Paranko, Jorma [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland)
No Increased Risk for Most Cancers Yet Observed in Daughters of Women Exposed to DES in the 1940s and 1950s
The first systematic follow-up study of a large group of women, whose mothers were given the synthetic estrogen diethylstilbestrol (DES) during pregnancy in the 1940s and 1950s, found no increase in any type of cancer except for clear cell adenocarcinoma of the vagina and cervix in women under age 30.
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Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult-type Leydig cell development in male offspring
Maternal exposure to estrogenic xenobiotics or phthalates has been implicated in the distortion of early male reproductive development, referred to in humans as the testicular dysgenesis syndrome. It is not known, however, whether such early gestational and/or lactational exposure can influence the later adult-type Leydig cell phenotype. In this study, Sprague–Dawley rats were exposed to dibutyl phthalate (DBP; from gestational day (GD) 14.5 to postnatal day (PND) 6) or diethylstilbestrol (DES; from GD14.5 to GD16.5) during a short gestational/lactational window, and male offspring subsequently analysed for various postnatal testicular parameters. All offspring remained in good health throughout the study. Maternal xenobiotic treatment appeared to modify specific Leydig cell gene expression in male offspring, particularly during the dynamic phase of mid-puberty, with serum INSL3 concentrations showing that these compounds led to a faster attainment of peak values, and a modest acceleration of the pubertal trajectory. Part of this effect appeared to be due to a treatment-specific impact on Leydig cell proliferation during puberty for both xenobiotics. Taken together, these results support the notion that maternal exposure to certain xenobiotics can also influence the development of the adult-type Leydig cell population, possibly through an effect on the Leydig stem cell population.
Ivell, Richard; Heng, Kee; Nicholson, Helen; Anand-Ivell, Ravinder
Effect of 2-week combination therapy with the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)]LHRH ethylamide and the antiandrogen flutamide on prostate structure and steroid levels in the dog.
Treatment of adult dogs for 15 days with the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)]LHRH ethylamide (50 micrograms daily, s.c.) causes a 41.6% inhibition of prostatic weight while a 55% inhibition is achieved when the antiandrogen flutamide (250 mg, twice daily) is given in association with the LHRH agonist (p less than 0.01). At histology, the glandular acini in the prostate of animals treated with the combination therapy are more atrophied than with either treatment used alone. A 2-week treatment with the LHRH agonist is characterized by two distinct phases, namely a stimulation of testicular androgen secretion between days 0 and 8 followed by an inhibition between days 9 and 15. During the inhibitory phase, the concentration of all testicular steroids progressively decreased to castration levels, thus indicating that the differences observed at the prostatic level at 2 weeks are due to the inhibition of androgen action by the antiandrogen flutamide during the period which precedes complete chemical castration by the LHRH agonist. Flutamide administered alone had no effect on plasma or prostatic steroid levels measured after 2 weeks and it did not interfere with the potent and generalized inhibitory effect of the LHRH agonist on the serum and prostatic concentration of all steroids measured.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2693158
Lacoste, D; Dubé, D; Bélanger, A; Labrie, F
Trace analysis of diethylstilbestrol, dienestrol and hexestrol in environmental water by Nylon 6 nanofibers mat-based solid-phase extraction coupled with liquid chromatography-mass spectrometry.
A simple, rapid and sensitive method for the determination of diethylstilbestrol (DES), dienestrol (DE) and hexestrol (HEX) was developed by using the Nylon 6 nanofibers mat-based solid-phase extraction (SPE) coupled with liquid chromatography-tandem mass spectrometry (LC-MS). These estrogens were separated within 8 min by LC using an ODS column and methanol/water (80/20, v/v) at a flow rate of 1.0 mL min(-1). Electrospray ionization conditions in the negative ion mode were optimized for MS detection of the estrogens. Under the optimum SPE conditions, all target analytes in 50 mL environmental water samples can be completely extracted by 1.5 mg Nylon 6 nanofibers mat at flow rate of 3.0 mL min(-1) and easily eluted by passage of 500 ?L mobile phase. By using the novel SPE-LC/MS method, good linearity of the calibration curve (r(2) ? 0.9992) was obtained in the concentration range from 0.10 ng L(-1) to 1.0 mg L(-1) (except for DE which was 0.20 ng L(-1) to 1.0 mg L(-1)) for all analytes examined. The limits of detection (S/N = 3) of the three estrogens ranged from 0.05 ng L(-1) to 0.10 ng L(-1). This method was applied successfully to the analysis of environmental water samples without any other pretreatment and interference peaks. Several water samples were collected from Jinchuan River and Xuanwu Lake, and in Jinchuan River water DES was detected at 0.13 ng L(-1). The recoveries of estrogens spiked into tap water were above 98.2%, and the relative standard deviations were below 4.78%. PMID:21994916
Xu, Qian; Wang, Min; Yu, ShuQin; Tao, Qing; Tang, Meng
Diethylstilbestrol-treated adult rats with altered epididymal sperm numbers and sperm motility parameters, but without alterations in sperm production and sperm morphology.
In this study, we characterized estrogenic effects of diethylstilbestrol (DES) on reproductive parameters in male rats to identify a minimal dose level that alters epididymal and sperm functions but has little or no effect on sperm production and/or spermatogenesis. Adult rats (five animals/group) received s.c. injections of 0.2 ml of corn oil containing DES at a rate of 1.0 mg, 200 microg, 40 microg, 8 microg, 1.6 microg, or 320 ng x rat(-1) x day(-1) for 12 days. The control group received corn oil only. DES effects were similar in the 8-microg group and higher dose groups and included significant (P < or = 0.05) reductions in 1) absolute and relative weights of the head and body of the epididymis (EP), tail of the EP, and seminal vesicle, 2) numbers of sperm in both regions of the EP, and 3) motility characteristics in sperm collected from the tail of the EP. Conversely, no significant changes were observed in relative testis weight, daily sperm production, spermatogenesis, seminiferous epithelial height in stage VII, and sperm morphology. All of the above parameters in the 1.6-microg group (except seminal vesicle weight) and 320-ng group were comparable to those of controls. Plasma testosterone (T) level was reduced to an almost undetectable level in the > or = 8-microg groups and to a very low level in the 1.6-microg group (0.35 vs. 2.36 ng/ml in controls or 320-ng group), but LH level was unaltered. In a parallel fertility study, males received DES at a rate of 40, 8, or 1.6 microg x rat(-1) x day(-1) for 12 days prior to and 12 days during cohabitation (1:1) with untreated females. Of the 15 females cohabited with treated males (5 females/dose), none in the 40-microg and 8-microg groups and 1 in the 1.6-microg group formed a copulatory plug and delivered 8 pups, in contrast to 5/5 copulatory plugs and 13-15 pups/litter in the controls. DES at a rate of 8 microg x rat(-1) x day(-1) for 12 days reduced EP weights, sperm numbers in the EP, and sperm motility patterns but caused minimal to no alterations in daily sperm production, spermatogenesis, or sperm morphology. Factors other than T, or in addition to lower T, may be responsible for DES-induced reproductive disorders (despite lower T, sperm contents and sperm motility patterns in the EP were normal in the 1.6-microg group). Deficits in EP sperm functions and/or sexual behavior (as evident from absence of copulatory plugs) probably accounted for reduced fertility in treated males. PMID:11207210
Goyal, H O; Braden, T D; Mansour, M; Williams, C S; Kamaleldin, A; Srivastava, K K
Women exposed to DES in the womb face increased cancer risk:
A large study of the daughters of women who had been given DES, the first synthetic form of estrogen, during pregnancy has found that exposure to the drug while in the womb (in utero) is associated with many reproductive problems and an increased risk of certain cancers and pre-cancerous conditions. Beginning in 1940, diethylstilbestrol, known as DES, was used clinically to prevent certain complications of pregnancy. In the 1950s, clinical studies showed DES was ineffective for this purpose. In the late 1960s, an unusual occurrence of a rare cancer of the vagina among young women, called clear cell adenocarcinoma (CCA), was observed and subsequently linked to their exposure to DES while in the womb.
We present a brief review of the literature about dopaminergic agonists. We report the five known dopaminergic receptors, where they are located, the advantages and disadvantages of the employment in parkinsonian patients. The dopaminergic agonists were introduced to control the limitations of levodopa-increasing the therapeutic window. We analyse the pharmacocynetic efficacy and the side effects of cabergoline, ropinirole and pramipexole. PMID:10412541
de Mattos, J P; Mattos, V M
Gene expression profile of terminal end buds in rat mammary glands exposed to diethylstilbestrol in neonatal period
Diethlstilbestrol (DES) is a synthetic estrogen prescribed to several millions of pregnant women worldwide. The risk for breast cancer after age 40 in women prenatally exposed to DES has been reported; however, the precise mechanism of susceptibility to breast cancer remains to be resolved. We investigated the global gene expression profile of terminal end buds (TEBs), the target of carcinogen,
Yoshihisa Umekita; Masakazu Souda; Kazuhito Hatanaka; Taiji Hamada; Takako Yoshioka; Hiroaki Kawaguchi; Akihide Tanimoto
Inhaled ?2-adrenoceptor (?2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the ?2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of ?2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and ?-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled ?2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised.
Barisione, Giovanni; Baroffio, Michele; Crimi, Emanuele; Brusasco, Vito
Melatonin agonists and insomnia.
The ability of melatonin to shift biological rhythms is well known. As a result, melatonin has been used in the treatment of various circadian rhythm sleep disorders, such as advanced and delayed sleep phase disorders, jet lag and shiftwork disorder. The current evidence for melatonin being efficacious in the treatment of primary insomnia is less compelling. The development of agents that are selective for melatonin receptors provides opportunity to further elucidate the actions of melatonin and its receptors and to develop novel treatments for specific types of sleep disorders. The agonists reviewed here - ramelteon, tasimelteon and agomelatine - all appear to be efficacious in the treatment of circadian rhythm sleep disorders and some types of insomnia. However, further studies are required to understand the mechanisms of action, particularly for insomnia. Clinical application of the agonists requires a good understanding of their phase-dependent properties. Long-term effects of melatonin should be evaluated in large-scale, independent randomized controlled trials. PMID:20136385
Ferguson, Sally A; Rajaratnam, Shantha M W; Dawson, Drew
The Nonsteroidal Effects of Diethylstilbestrol: The Rationale for Androgen Deprivation Therapy Without Estrogen Deprivation in the Treatment of Prostate Cancer
PurposeDuring the last 2 decades there has been an increase in the number of men with prostate cancer placed on luteinizing hormone releasing hormone (LH-RH) agonist therapy. In addition, the duration of individual therapy has extended from what was once only a few months to, in many cases, several years. As a result there has been an increase in the
ERIC Educational Resources Information Center
This document, intended for elementary students, contains articles and activities designed to acquaint young people with the history of Des Moines, Iowa. The articles are short, and new or difficult words are highlighted and defined for young readers. "The Raccoon River Indian Agency" discusses the archeological exploration of the indian…
Gore, Deborah, Ed.
Final Report on the Developmental Toxicity of Diethylstilbestrol (CAS No. 56-53-1) in Swiss (CD-1 (Trade Name)) Mice on Gestational Days 9 through 16.
National Technical Information Service (NTIS)
The study evaluated the potential for diethylstibestrol (DES) to alter the skeletal morphology of term mouse fetuses when administered to a limited number of pregnant animals. DES was administered during a gestational period corresponding to the period of...
B. A. Schwetz C. B. Myers C. J. Price E. S. Hunter H. A. Navarro J. D. George M. C. Marr M. D. Shelby
Histamine H4 receptor agonists.
Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes. PMID:21044842
Igel, Patrick; Dove, Stefan; Buschauer, Armin
Assurance chômage des emprunteurs
La securisation des prets pour accession a la propriete concerne les organismes de credit mais aussi la puissance publique, avec le developpement des prets a taux zero. L'assurance chomage privee des prets hypothecaires evite la budgetisation des prestations qu'entrainerait un assurance publiquepour des prets aides. L'article etudie les conditions d'assurabilite du risque chomage des emprunteurs, et en regard la theorie
Pierre-André Chiappori; Jean Pinquet
Agonists for the Chemokine Receptor CXCR4
The development of agonists for the chemokine receptor CXCR4 could provide promising therapeutic candidates. On the basis of previously forwarded two site model of chemokine–receptor interactions, we hypothesized that linking the agonistic N-terminus of SDF-1 to the T140 backbone would yield new high-affinity agonists of CXCR4. We developed chimeras with the agonistic SDF-1 N-terminus grafted to a T140 side chain and tested their binding affinity and chemotactic agonist activity. While chimeras with the peptide grafted onto position 12 of T140 remained high-affinity antagonists, those bearing the peptide on position 14 were in part agonists. One chimera was a full CXCR4 agonist with 25 nM affinity, and several chimeras showed low nanomolar affinities with partial agonist activity. Our results confirmed that we have developed high-affinity agonists of CXCR4.
Die Innervation des Dünndarmes
Zusammenfassung Bei den mit Curare vergifteten Tieren wird durch die Reizung der Medulla oblongata die Peristaltik und der Tonus des Dünndarmes vermindert. Diese Sympathicuswirkung kann jedoch durch die Durchtrennung des Rückenmarkes unterhalb der Medulla oblongata oder durch die Nicotinisierung des Ganglion coeliacum ausgeschaltet werden. Reizt man die Medulla oblongata nach einem dieser Eingriffe, so kommt es zu einer Steigerung des
B. v. Issekutz
Modulation des aides, renforcement du deuxičme pilier et répartition des subventions et des revenus agricoles
Ce texte présente trois scénarios de modulation des aides du premier pilier en vue de renforcer le deuxičme pilier. Compte tenu du poids des aides dans le revenu, une redistribution plus égalitaire des subventions ne correspond pas automatiquement ŕ une nette baisse de l'inégalité des revenus. La répartition des revenus dépend aussi trčs largement de l'évolution des prix relatifs des
Jean-Pierre Butault; Jean-Marc Rousselle
Clinical pharmacology of dopamine agonists.
With the availability of newer dopamine agonists selective for dopamine (D2) receptor subtypes, medical management of Parkinson's disease has progressed substantially. These agents can decrease the frequency of ergot-related side effects and dyskinesias. Also, when given as adjunctive therapy with levodopa, they can allow the levodopa maintenance dosage to be reduced without loss of symptom control. Based on early clinical experience, dopamine agonists can also be prescribed as initial monotherapy and can delay therapy with levodopa. Their therapeutic roles will be defined further by long-term studies. PMID:10641988
Lam, Y W
Discovery of AZD3199, An Inhaled Ultralong Acting ?2 Receptor Agonist with Rapid Onset of Action.
A series of dibasic des-hydroxy ?2 receptor agonists has been prepared and evaluated for potential as inhaled ultralong acting bronchodilators. Determination of activities at the human ?-adrenoreceptors demonstrated a series of highly potent and selective ?2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i.t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultralong acting inhaled ?2 receptor agonist with rapid onset of action. PMID:24900851
Stocks, Michael J; Alcaraz, Lilian; Bailey, Andrew; Bonnert, Roger; Cadogan, Elaine; Christie, Jadeen; Dixon, John; Connolly, Stephen; Cook, Anthony; Fisher, Adrian; Flaherty, Alice; Humphries, Alexander; Ingall, Anthony; Jordan, Stephen; Lawson, Mandy; Mullen, Alex; Nicholls, David; Paine, Stuart; Pairaudeau, Garry; Young, Alan
Dopamine agonist therapy in hyperprolactinemia.
Introduction of the dopamine agonist bromocriptine heralded a major advance in the management of hyperprolactinemic disorders. Although its side effects of nausea, dizziness and headache and its short elimination half-life are limiting factors, its efficacy established it as a reference compound against the activity of which several dopamine agonists, like pergolide, lysuride, metergoline, terguride and dihydroergocristine, fell by the wayside. More recently, two new agents, cabergoline and quinagolide, have been introduced and appear to offer considerable advantages over bromocriptine. Cabergoline, an ergoline D2 agonist, has a long plasma half-life that enables once- or twice-weekly administration. Quinagolide, in contrast, is a nonergot D2 agonist with an elimination half-life intermediate between those of bromocriptine and cabergoline, allowing the drug to be administered once daily. Comparative studies indicate that cabergoline is clearly superior to bromocriptine in efficacy (prolactin suppression, restoration of gonadal function) and in tolerability. In similar studies, quinagolide appeared to have similar efficacy and superior tolerability to that of bromocriptine. Results of a small crossover study indicate that cabergoline is better tolerated, with a trend toward activity superior to that of quinagolide. In hyperprolactinemic men and in women not seeking to become pregnant, cabergoline may be regarded as the treatment of choice. PMID:10649819
Webster, J
Effet des innovations organisationnelles et des technologies de l'information sur le rendement des entreprises
Dans ce document, on vise a determiner si les investissements dans les technologies de l'information et des communications, combines a des changements organisationnels et aux competences des travailleurs, contribuent a ameliorer le rendement des entreprises canadiennes.
Wulong Gera Surendra Gu
Agonist-induced translocation of the kinin B(1) receptor to caveolae-related rafts.
The kallikrein-kinin system, activated during inflammatory conditions and the regulation of specific cardiovascular and renal functions, includes two G protein-coupled receptors for bradykinin (BK)-related peptides. The B(1) receptor (B(1)R) subtype is not believed to undergo agonist-induced phosphorylation and endocytosis. A conjugate made of the rabbit B(1)R fused with the yellow variant of green fluorescent protein (YFP) was expressed in mammalian cells. In COS-1 or human embryonic kidney (HEK) 293 cells, the construction exhibited a nanomolar affinity for the agonist radioligand [(3)H]Lys-des-Arg(9)-BK or the antagonist ligand [(3)H]Lys-[Leu(8)]des-Arg(9)-BK and a pharmacological profile virtually identical to that of wild-type B(1)R. Lys-des-Arg(9)-BK stimulation of HEK 293 cells stably expressing B(1)R-YFP but not stimulation of untransfected cells released [(3)H]arachidonate in a phospholipase A(2) assay. B(1)R-YFP was visualized as a continuous labeling of the plasma membranes in stably transfected HEK 293 cells (confocal microscopy). Addition of Lys-des-Arg(9)-BK (1-100 nM) rapidly concentrated the receptor-associated fluorescence into multiple aggregates that remained associated with the plasma membrane (no significant internalization) and colocalized with caveolin-1. This reaction was slowly reversible upon agonist washing at 37 degrees C and prevented pretreatment with a B(1)R antagonist. beta-Cyclodextrin treatment, which extracts cholesterol from membranes and disrupts caveolae-related rafts, prevented agonist-induced redistribution of B(1)R-YFP but not the PLA(2) activation mediated by this receptor. The agonist radioligand copurified with caveolin-1 to a greater extent than the tritiated antagonist in buoyant fractions of HEK 293 cells treated with the ligands. Agonist-induced cellular translocation of the kinin B(1)R to caveolae-related rafts without endocytosis is a novel variation on the theme of G protein-coupled receptor adaptation. PMID:11854434
Sabourin, Thierry; Bastien, Luc; Bachvarov, Dimcho R; Marceau, François
Pharmacotherapy for tobacco cessation: Nicotine agonists, antagonists, and partial agonists
Nicotine replacement therapies (NRT) were the main pharmacologic option for treatment of nicotine dependence until the early\\u000a 1990s, when controlled clinical trials confirmed the efficacy of bupropion, the first treatment not based on nicotine. Varenicline,\\u000a a partial agonist at nicotine receptors, gained US regulatory approval in 2006 for smoking cessation. Although these agents\\u000a are all effective for nicotine dependence, their
Maher Karam-Hage; Paul M. Cinciripini
Standardisierte Formen des Familieninterviews
Der Beitrag stellt standardisierte und strukturierte Formen des Familien-interviews vor. Neben den "klassischen" Verfahren\\u000a des Structured Family Interviews (SFI) und des Camberwell Family Interviews (CFI) werden neuere, vorwiegend für Forschungszwecke\\u000a entwickelte Interviewmethoden beschrieben.
E. Nordmann; S. Kötter
Partage des coűts et tarification des infrastructures \\/ Partage des coűts et tarification des infrastructures
Une véritable valorisation des infrastructures communes doit reposer sur une approche rigoureuse du partage de leurs coűts et de leur tarification implicites sinon explicites. D'oů l'intéręt et la pertinence du présent ouvrage qui se veut ŕ la fois un regroupement en un seul lieu et une mise ŕjour des travaux que nous avons réalisés sur ce sujet au cours des
Marcel Boyer; Michel Moreaux; Michel Truchon
Imagerie des prolapsus périnéaux
Résumé Deux principes doivent guider l'imagerie dynamique des prolapsus des quatre étages du pelvi-périnée pour répondre ŕ l'approche\\u000a moderne d'une conception globale du plancher pelvien. C'est d'une part la prise en considération de la compétition des différents\\u000a prolapsus qui doit faire alterner la réplétion et la vidange des organes creux et le refoulement éventuel des organes pleins\\u000a dans un ordre précis.
J.-F. Lapray
The cannabinoid receptor inverse agonist AM251 regulates the expression of the EGF receptor and its ligands via destabilization of oestrogen-related receptor ? protein
BACKGROUND AND PURPOSE AM251 is an inverse agonist of the cannabinoid 1 receptor (CB1R) that can exert 'off-target' effects in vitro and in CB1R knock-out mice. AM251 is also potent at modulating tumour cell growth, suggesting that growth factor-mediated oncogenic signalling could be regulated by AM251. Since dysregulation of the EGF receptor has been associated with carcinogenesis, we examined AM251 regulation of EGF receptor (EGFR) expression and function. EXPERIMENTAL APPROACH The various biological functions of AM251 were measured in CB1R-negative human cancer cells. Pharmacological and genetic approaches were used to validate the data. KEY RESULTS The mRNA levels for EGFR and its associated ligands, including HB-EGF, were induced several fold in PANC-1 and HCT116 cells in response to AM251. This event was associated with enhanced expression of EGFR on the cell surface with concomitant increase in EGF-induced cellular responses in AM251-treated cells. Exposure to XCT790, a synthetic inverse agonist of the orphan nuclear oestrogen-related receptor ? (ERR?), also induced EGFR and HB-EGF expression to the same extent as AM251, whereas pretreatment with the ERR?-selective agonist, biochanin A, blunted AM251 actions. AM251 promoted the degradation of ERR? protein without loss of the corresponding mRNA. Knock-down of ERR? by siRNA-based approach led to constitutive induction of EGFR and HB-EGF levels, and eliminated the biological responses of AM251 and XCT790. Finally, AM251 displaced diethylstilbestrol prebound to the ligand-binding domain of ERR?. CONCLUSIONS AND IMPLICATIONS AM251 up-regulates EGFR expression and signalling via a novel non-CB1R-mediated pathway involving destabilization of ERR? protein in selected cancer cell lines.
Fiori, JL; Sanghvi, M; O'Connell, MP; Krzysik-Walker, SM; Moaddel, R; Bernier, M
NASA Astrophysics Data System (ADS)
The Dark Energy Survey Supernova program (DES SN) will discover approximately 3500 Type Ia supernovae with well-sampled multi-color light curves in the redshift range 0.2 < z < 1.2 over its five year duration. The large field of view and high z-band sensitivity of the Dark Energy Camera, combined with the precision photometry of DES and an improved handling of systematic uncertainties will allow DES SN to provide the strongest constraints on supernova cosmology to date. One of the main challenges for DES SN will be accurate classification of such a large number of faint transients. I will describe the unique spectroscopic follow-up strategy that we are employing, with emphasis on the 100 night, survey-status program at AAT which began in September. I will present preliminary supernova results obtained from the DES Science Verification period and the beginning of DES Year 1.
D'Andrea, Christopher; Dark Energy Survey, The
Zur Histophysiologie des Inselapparates
1.Der Feinbau der Langerhansschen Inseln des neugeborenen und erwachsenen Hundes wird geschildert. Das Zahlenverhältnis der betazu den alpha-Zellen in den Inseln des normalen Hundes beträgt bei Zugrundelegung nach Gomori (Azan) gefärbter Präparate 7:1, von Gros-Schultze-Präparaten 8:1. Es wird eine Einteilung der nach Gros-Schultze im Pankreas des Hundes darstellbaren verschiedenartigen Silberzellen vorgenommen. Das Vorhandensein neuroinsulärer Komplexe (Simard, 1937) wird für das
W. Creutzfeldt
Structure des bilans et types de croissance des entreprises
[fre] Structures des bilans et types de croissance des entreprises par Eric HURET. Une étude sur les structures de bilan des entreprises est réalisée ŕ partir d'un échantillon de 522 firmes fourni par la centrale des bilans du Crédit national. On étudie d'abord de maničre traditionnelle, les différences entre les moyennes sectorielles. Les conclusions économiques qui peuvent en ętre tirées
Eric Huret
Injectabilite des coulis de ciment dans des milieux fissures
Le travail presente ici est un bilan du travaux de recherche effectues sur l'injectabilite des coulis de ciment dans lu milieux fissures. Un certain nombre de coulis a base de ciment Portland et microfin ont ete selectionnes afin de caracteriser leur capacite a penetrer des milieux fissures. Une partie des essais a ete menee en laboratoire. L'etude rheologique des differents
Thameur Mnif
Elimination des noeuds dans le probleme newtonien des quatre corps
Résumé Nous appliquons la méthode des transformations canoniques ŕ variables imposées ŕ la réduction du problčme newtonien des quatre corps. L'élimination du centre de gravité étant supposée faite, le problčme est ramené ŕ celui des trois corps fictifs. Alors nous menons ŕ bien la réduction dűe aux intégrales des aires explicitement sous forme Hamiltonienne en tenant compte de l'aspect géométrique
Françoise Boigey; M. Curie
La structure des verres étudiée par diffraction des neutrons
NASA Astrophysics Data System (ADS)
La diffraction des neutrons est une méthode largement utilisée pour déterminer la structure des matériaux amorphes et en particulier des verres. L'utilisation de la méthode de substitution isotopique permet d'extraire les fonctions de distribution de paires partielles centrées autour d'un élément choisi. Nous présentons quelques exemples récents d'études par diffraction des neutrons sur des verres qui ont permis de mieux comprendre ŕ la fois le réseau polymérique de la matrice vitreuse et l'environnement local et ŕ moyenne distance autour des cations. Ces études ont révélées un ordre structural s'étendant au delŕ des premiers voisins, jusque vers de distances d'environ 10Ĺ. Le couplage avec d'autres méthodes expérimentales (diffraction anormale des rayons X) et des techniques de simulations (dynamique moléculaire, Monte Carlo Inverse ou RMC) sont indispensables pour affiner nos connaissances de la structure des verres.
Cormier, L.
NASA Astrophysics Data System (ADS)
The Dark Energy Survey (DES) is a 5 year, 5000 square degree photometric survey in 5 bands (grizY), with the primary goals of exploring the cause of cosmic acceleration and to trace the growth of structure. Probing the growth of structure via clusters of galaxies, the most massive bound structures in the Universe, is one of the key Dark Energy probes of DES as they provide one of the best ways to distinguish between a cosmological constant and deviations from General Relativity on cosmological scales. From November 2012 through February 2013 DES performed a "science verification" observing campaign (SVA1), covering over 100 deg^2 in the southern sky to full DES depth. Here we describe early results from galaxy clusters from SVA1, including a new measurement of the red galaxy conditional luminosity function to 1. We also show how these results inform our catalog simulation work for better predictions of the DES performance after the full 5 year survey.
Rykoff, Eli S.; DES Cluster Working Group
La structure des solutions aqueuses
NASA Astrophysics Data System (ADS)
En commençant par l'étude par diffraction neutronique de la structure des liquides moléculaires puis de l'hydratation des ions en solution, ce cours montrera comment les principes présentés lors des cours précédents peuvent ętre appliqués ŕ des systčmes aqueux. Des exemples tirés de la littérature seront utilisés pour illustrer les considérations expérimentales propre ŕ ce domaine et le genre d'informations que nous pouvons obtenir. Ce cours montrera également l'applicaton de la diffraction neutronique ŕ des systčmes d'intéręt biologique et environnemental et se terminera par un examen de la complémentarité fournie par la diffraction des rayons X, l'EXAFS et la RMN.
Powell, D. H.
Monoterpenoid agonists of TRPV3
Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement.
Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H
Endogenous receptor agonists: resolving inflammation.
Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A comprehensive understanding of the cellular and molecular events that control the termination of acute inflammation is needed in molecular terms given the widely held view that aberrant inflammation underlies many common diseases. This review focuses on recent advances in the understanding of the role of arachidonic acid and w-3 polyunsaturated fatty acids (PUFA)-derived lipid mediators in regulating the resolution of inflammation. Using a functional lipidomic approach employing LC-MS-MS-based informatics, recent studies, reviewed herein, uncovered new families of local-acting chemical mediators actively biosynthesized during the resolution phase from the essential fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These new families of local chemical mediators are generated endogenously in exudates collected during the resolution phase, and were coined resolvins and protectins because specific members of these novel chemical families control both the duration and magnitude of inflammation in animal models of complex diseases. Recent advances on the biosynthesis, receptors, and actions of these novel anti-inflammatory and proresolving lipid mediators are reviewed with the aim to bring to attention the important role of specific lipid mediators as endogenous agonists in inflammation resolution. PMID:17767360
Bannenberg, Gerhard; Arita, Makoto; Serhan, Charles N
Dopamine Agonists and Pathologic Behaviors
The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson's disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.
Kelley, Brendan J.; Duker, Andrew P.; Chiu, Peter
GnRH agonists and uterine leiomyomas.
Gonadotrophin-releasing hormone (GnRH) agonists are widely used in the treatment of women with symptomatic leiomyomas. The effectiveness of this treatment, as far as symptoms are concerned, is well established, and in recent years many studies have contributed to defining the optimal role for GnRH agonists. Side-effects and health risks prohibit the long-term use of these compounds. The combined use of high-dose agonists and steroids in the so-called 'add back' schedules reduces many of the disadvantages of the monotherapy. However, it is still an expensive alternative when compared with definitive surgery, and therefore should only be used in women who insist on preservation of the uterus. Low-dose agonist therapy ('draw back') has not yet been proven to be suitable for clinical application. The use of GnRH agonists and steroids in sequential schedules seems to result in a loss of both the volume reduction as well as the reduction in clinical symptoms. The use of GnRH agonists prior to myoma surgery should not become a routine measure and should be limited to cases where the size of the uterus is > 600 ml. Hysterectomy should only be preceded by GnRH agonist treatment if uterine volume decrease is expected to facilitate either the abdominal or vaginal procedure. For both operative procedures the presence of myoma-related anaemia is an indication for pretreatment. The use of GnRH agonists before endoscopic surgery is widely accepted on the basis of assumptional advantages; however, definite proof of these advantages is not yet available. PMID:9147098
Broekmans, F J
Interactions between corticosteroids and ? 2 -agonists
In vitro studies have demonstrated numerous ways in which ?2-agonists and corticosteroids may interact. Together with evidence of improved control of airway diseases using a combination\\u000a therapy of inhaled corticosteroids and long-acting ?-agonists compared with treatment with either drug alone, this suggests\\u000a that there may be a beneficial synergy between these two classes of medication. However, a positive interaction has
Robert J. Hancox
Long-term studies of dopamine agonists.
Dopamine agonists have long been used as adjunctive therapy for the treatment of Parkinson's disease (PD). In more recent years these drugs have also been proved safe and effective as initial therapy in lieu of levodopa in the treatment of PD. Long-term levodopa therapy is associated with motor complications, including fluctuating response patterns and dyskinesia. By initially introducing a dopamine agonist as symptomatic drug therapy, it may be possible to postpone the use of levodopa and delay or prevent the development of motor complications. Recently, four clinical trials have explored this hypothesis by comparing the long-term response and side effects of levodopa with dopamine agonist therapy. The drugs studied have included ropinirole, pramipexole, cabergoline, and pergolide. In each of these projects, the occurrence of motor complications, such as wearing off and dyskinesia, was significantly less in the subjects assigned to initiation of therapy with a dopamine agonist. The addition of levodopa could be postponed by many months or even several years. Therefore, these long-term studies of dopamine agonists support the initiation of a dopamine agonist instead of levodopa in an effort to postpone levodopa-related motor complications. This therapeutic approach may be particularly appropriate in PD patients with a long treatment horizon on the basis of age and general good health. The extension phase of the long-term study comparing pramipexole with levodopa is ongoing, and follow-up information may help to establish the value of this treatment strategy. PMID:11909984
Hubble, Jean P
Note des Éditeurs scientifiques
NASA Astrophysics Data System (ADS)
Cette série d'articles est une revue de résultats expérimentaux sur différents "fluides" moléculaires, dans lesquels la cohésion est due ŕ des forces de Van der Waals et ŕ des liaisons hydrogčne, l'eau étant un de ces fluides. Ces résultats sont présentés de façon ŕ justifier expérimentalement un modčle original, non extensif, des propriétés de ces fluides, et l'ensemble se présente sous la forme de trois articles décrivant le modčle, suivis chacun par un article le comparant aux résultats expérimentaux publiés par de nombreux auteurs. Le caractčre non extensif des propriétés physiques des fluides est choquant, contraire ŕ beaucoup d'idées établies, il semble n'avoir en sa faveur qu'un argument, la comparaison avec un nombre de résultats expérimentaux assez grand pour que l'effet du hasard soit difficilement soupçonnable. En particulier, les écarts entre des résultats de mesures faits par des auteurs différents dans des conditions différentes sont expliqués, le sérieux et la compétence des différents expérimentateurs ne sont plus mis en doute : mais l'interprétation de ces résultats avec un modčle extensif non adapté est seule mise en cause. Les modčles extensifs étant utilisés systématiquement, au delŕ des expériences de physiciens, dans les calculs d'ingénieurs, et dans la modélisation d'appareils qui fonctionnent et de phénomčnes naturels observés par tout le monde, il fallait expliquer pourquoi on pouvait renoncer ŕ l'extensivité. Les raisons du succčs pratique des modčles extensifs sont données, d'abord dans le cas des nématiques, puis dans celui des liquides ordinaires, et c'est ce qui rend l'ensemble cohérent, tant avec les mesures physiques fines qu'avec les observations quotidiennes. Il n'en reste pas moins que si l'interprétation donnée dans cette série d'articles est généralisable, une justification théorique du modčle utilisé devient nécessaire. Pour ce qui est des propriétés d'équilibre, une séparation de l'énergie libre en énergie libre de volume et en énergie libre de surface devrait donner les męmes résultats ; par contre les choses deviennent troublantes dčs que l'on passe aux coefficients de transport, c'est-ŕ-dire ŕ l'aspect macroscopique de la dynamique moléculaire. Il y a lŕ un écart notable avec les conceptions courantes, ce qui rend trčs surprenante la lecture de ces articles. On peut mentionner la liste des problčmes théoriques posés par la description phénoménologique qui est celle de cette série d'articles : la généralisation de lois d'échelle en dehors de zones critiques n'est pas absolument nouvelle, par contre la simplicité des lois reliant l'exposant v ŕ la température pose problčme ; le sens des temps de relaxation utilisés est sans doute également ŕ préciser. Enfin les modes considérés semblent n'intervenir dans les propriétés thermodynamiques que par un facteur par mode, comme si seulement l'énergie potentielle devait intervenir, les termes cinétiques ne participant pas vraiment aux transitions de phase. Tout cela pose donc problčme, et l'on peut se demander si un pareil modčle peut ętre compatible avec tout ce qui est connu par ailleurs en physique statistique. Mais s'il rend bien compte de beaucoup de résultats expérimentaux, ce sont ces derniers qui seraient en difficulté avec la mécanique statistique. Il a donc semblé préférable de publier le modčle, sa justification expérimentale et de poser quelques problčmes, tant aux théoriciens, qui pourraient expliquer pourquoi un tel modčle rend compte de résultats observés, qu'aux expérimentateurs, qui pourraient reprendre certaines mesures, et délimiter le caractčre plus ou moins général du modčle.
Averbuch, P.
Pharmakologie des Vasomotorenzentrums
Zusammenfassung 1.Untersuchungen an dezerebrierten Katzen mit durchschnittenen Nn. vagi und natürlicher Atmung haben gezeigt, daß die Erregbarkeit des Vasomotorenzentrums in der Medulla oblongata für den Kohlensäurereiz durch Chloroform, Äther, Chloralhydrat, Chloralose und Urethan herabgesetzt und aufgehoben werden kann.2.Bei genauen Untersuchungen über die Physiologie und Pharmakologie des Vasomotorenzentrums soll also die Verwendung von Narkoticis möglichst vermieden werden.3.Die Annahme von Itami, daß
L. W. van Esveld
Instabilite des heures de travail au Canada
Les auteurs de nombreuses etudes des heures de travail ont tire d'importantes conclusions des resultats des enquetes transversales. Par exemple, a tout moment donne, la part des personnes qui travaillent de longues heures est assez importante. En outre, elle semble avoir augmente au cours des deux dernieres decennies, faisant ressortir la necessite d'elaborer des politiques visant a reduire les divergences
Andrew Larochelle-Cote Sebastien Heisz
Pyramide des âges et gestion des ressources humaines
L'utilisation de la pyramide des âges dans les discours des directeurs de ressources humaines s'est développée au cours des années 1980. Elle renvoie au choix d'un critčre de sélection de salariés jugés en sureffectif. Derričre l'âge et ses représentations, c'est bien la question de la capacité des salariés ŕ s'adapter au changement de l'entreprise qui est posée. En définitive, il
Eric Godelier
[Dopamine agonists situation in Parkinson disease].
The development of a variety of side effects associated with long term treatment of Parkinson s disease has prompted the introduction of new drugs and new treatment strategies. The use of dopamine agonists in combination with levodopa has proved to be useful in advanced patients with motor fluctuations. Recent studies indicate that the use of dopamine agonists in monotherapy from the early stages of the disease can be as effective as levodopa for clinical improvement with the added advantage of a significant less presentation of diskinesias. Ropinirol the first dopaminergic agonist demonstrating this effect in a 5 year controlled study, has well tolerance, both in combination or in monotherapy. Although low doses can be useful for individual patients, doses of approximately 15 16 mg/day proved to be safe and effective in long term studies. PMID:11785037
Barbanoj, M; Campos Arillo, V M; Giménez-Roldán, S; Kulisevsky, J; Linazasoro Cristóbalampos, G; Luquin Piudo, M R; Vela Desojo, L
Agonist and antimineralocorticoid activities of spirolactones.
To investigate the mechanism of action of antimineralocorticoids, a series of spirolactone analogues was evaluated for both mineralocorticoid antagonist and agonist activity. Antagonist activity was assessed by inhibition of aldosterone stimulated sodium transport employing toad bladder short-circuit current (SCC) measurements. Agonist activity was assessed in the same system by the direct effect of spirolactones on SCC. Opening of the gamma-lactone ring of a spirolactone dramatically decreased antagonist activity in the compound studied. Several C-7 chi-substitutions resulted in either enhanced or diminished activity, whereas deletion of the C-10 methyl group (i.e., 19-nor compound) had only minimal effects on antagonist potency. Agonist activity was demonstrable for three of the analogues studied: the 19-nor compound, and those containing a C-7 chi-substitution with a carboxyl isopropyl ester or a C-6-7 cyclopropyl linkage. The functional activity in toad bladder was compared to previous measurements of the relative binding affinity of the same spirolactones for mineralocorticoid receptors in rat kidney. Although there was some correlation between binding to rat kidney receptors and antagonist activity in the toad bladder, the results did not coincide in the case of the three spirolactones that possessed partial agonist activity. Some of the discrepancy may have resulted from differences between mammalian and amphibian receptors; however, intrinsic agonist activity limits antagonist potency and thus may cause a divergence between binding and functional studies limited to antagonist activity alone. Binding affinity, although indicative of total activity, fails to distinguish agonist from antagonist potency. PMID:183514
Sakauye, C; Feldman, D
Increased agonist affinity at the ?-opioid receptor induced by prolonged agonist exposure.
Prolonged exposure to high-efficacy agonists results in desensitization of the ?-opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling; however, the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased after prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa594, was unaffected by similar agonist pretreatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise, the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knock-out animals increased after treatment of the cells with the desensitization protocol. Thus, opioid receptors were "imprinted" with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long-lasting but reversible conformational change in the receptor. PMID:23447620
Birdsong, William T; Arttamangkul, Seksiri; Clark, Mary J; Cheng, Kejun; Rice, Kenner C; Traynor, John R; Williams, John T
Increased agonist affinity at the mu-opioid receptor induced by prolonged agonist exposure
Prolonged exposure to high-efficacy agonists results in desensitization of the mu opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling, however the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased following prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa 594, was unaffected by similar agonist pre-treatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knockout animals increased following treatment of the cells with the desensitization protocol. Thus, opioid receptors were "imprinted" with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long lasting but reversible conformational change in the receptor.
Birdsong, William T.; Arttamangkul, Seksiri; Clark, Mary J.; Cheng, Kejun; Rice, Kenner C.; Traynor, John R.; Williams, John T.
Aspects épidémiologiques des fractures ostéoporotiques
Résumé Les fractures du col fémoral, des vertčbres et du poignet sont traditionnellement rapportées ŕ l'ostéoporose, mais la plupart\\u000a des fractures qui surviennent chez les femmes de plus de 60 ans sont liées ŕ une densité minérale osseuse (DMO) abaissée et\\u000a peuvent donc ętre considérées comme des fractures ostéoporotiques. En l'absence de mesures de prévention efficaces, des estimations\\u000a américaines indiquent que
P. Dargent-Molina
Update in TSH Receptor Agonists and Antagonists
The physiological role of the TSH receptor (TSHR) as a major regulator of thyroid function is well understood, but TSHRs are also expressed in multiple normal extrathyroidal tissues, and the physiological roles of TSHRs in these tissues are unclear. Moreover, TSHRs play a major role in several pathological conditions including hyperthyroidism, hypothyroidism, and thyroid tumors. Small molecule, "drug-like" TSHR agonists, neutral antagonists, and inverse agonists may be useful as probes of TSHR function in extrathyroidal tissues and as leads to develop drugs for several diseases of the thyroid. In this Update, we review the most recent findings regarding the development and use of these small molecule TSHR ligands.
Neumann, Susanne
Emerging adenosine receptor agonists--an update
Adenosine receptors (ARs), the major targets of caffeine and theophylline, comprise four receptor subtypes designated as A1, A2A, A2B and A3. Over a dozen AR agonists are currently in clinical trials for various conditions, including cardiac arrhythmias, neuropathic pain, myocardial perfusion imaging, cardiac ischemia, inflammatory diseases and cancer. Adenosine (non-selective), regadenoson (A2A) and dipyridamole (act indirectly via ARs) have received regulatory approval for clinical use. The present editorial will give a brief update on the current status of AR agonists in clinical trials.
Gao, Zhan-Guo; Jacobson, Kenneth A
A covalently bound photoisomerizable agonist. Comparison with reversibly bound agonists at electrophorus electroplaques
After disulphide bonds are reduced with dithiothreitol, trans-3- (?-bromomethyl)-3'-[?- (trimethylammonium)methyl]azobenzene (trans-QBr) alkylates a sulfhydryl group on receptors. The membrane conductance induced by this "tethered agonist" shares many properties with that induced by reversible agonists. Equilibrium conductance increases as the membrane potential is made more negative; the voltage sensitivity resembles that seen with 50 [mu]M carbachol. Voltage- jump relaxations follow an exponential time-course; the rate constants are about twice as large as those seen with 50 ?M carbachol and have the same voltage and temperature sensitivity. With reversible agonists, the rate of channel opening increases with the frequency of agonist-receptor collisions: with tethered trans-Qbr, this rate depends only on intramolecular events. In comparison to the conductance induced by reversible agonists, the QBr-induced conductance is at least 10-fold less sensitive to competitive blockade by tubocurarine and roughly as sensitive to "open-channel blockade" bu QX-222. Light-flash experiments with tethered QBr resemble those with the reversible photoisomerizable agonist, 3,3',bis-[?-(trimethylammonium)methyl]azobenzene (Bis-Q): the conductance is increased by cis {arrow} trans photoisomerizations and decreased by trans {arrow} cis photoisomerizations. As with Bis-Q, ligh-flash relaxations have the same rate constant as voltage-jump relaxations. Receptors with tethered trans isomer. By comparing the agonist-induced conductance with the cis/tans ratio, we conclude that each channel's activation is determined by the configuration of a single tethered QBr molecule. The QBr-induced conductance shows slow decreases (time constant, several hundred milliseconds), which can be partially reversed by flashes. The similarities suggest that the same rate-limiting step governs the opening and closing of channels for both reversible and tethered agonists. Therefore, this step is probably not the initial encounter between agonist and receptor molecules.
Lester, HA; Krouse, ME; Nass, MM; Wassermann, NH; Erlanger, BF
La diffraction des neutrons et des rayons X pour l'étude structurale des liquides et des verres
NASA Astrophysics Data System (ADS)
La compréhension de mainte propriété physique d'un verre ou d'un liquide nécessite la connaissance des facteurs de structure partiels (PSFs) qui décrivent chacun la distribution d'une espčce atomique autour d'une autre. La technique de diffraction des neutrons avec substitution isotopique (NDIS) [1,2,3], ayant bien réussi a déterminer les PSFs de certains composés [4,5], est pourtant restreinte aux isotopes présentant un contraste suffisant en longueur de diffusion. D'un autre cote, la technique de diffusion anomale des rayons X (AXS ou AXD) [6] permet de faire varier la longueur de diffusion d'une espčce atomique pourvu que son énergie d'absorption soit ŕ la fois accessible et suffisamment élevée pour donner un assez grand transfert du moment. La combinaison des techniques de diffraction des neutrons (avec ou sans substitution isotopique) et de diffraction des rayons X (avec ou sans diffusion anomale) peut donc permettre d'obtenir un meilleur contraste en longueurs de diffusion pour un systčme donné, mais exige une analyse de données plus soignée pour pouvoir bien tenir compte des erreurs systématiques qui sont différentes pour les 2 techniques [7]. Pour les atomes ayant des distributions électroniques quasi-sphériques, e.g. dans le cas d'un alliage liquide, la combinaison des techniques de NDIS et de diffraction des rayons X s'est déjŕ montrée trčs avantageuse pour la détermination des PSFs [8,9]. Dans le cas des verres ayant d'importantes liaisons covalentes, l'effective combinaison des 2 techniques peut ętre moins directe mais facilitée lorsqu'il s'agit des atomes de grand Z [10,11]. Nous présentons ici un sommaire du méthode et quelques exemples des résultats.
Fischer, H. E.; Salmon, P. S.; Barnes, A. C.
FXR agonist activity of conformationally constrained analogs of GW 4064
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)
NASA Astrophysics Data System (ADS)
Last summer, the DES Collaboration installed DECam, a new 570 Megapixel CCD camera with a 3 square degree field of view, on the Blanco 4-meter telescope at CTIO. A two month long commissioning period for the instrument and the new telescope control system was followed by three weeks of science verification. Science verification was a special observing program designed to verify that the camera and the telescope meet the requirements imposed by the DES science program. In a series of tests we evaluated both image quality and operational readiness. The 23 science verification nights were split between DES and a number of community observing programs selected by NOAO to explore the wide range of science opportunities made possible by the new instrument. In this presentation we will introduce the DECam science verification program, outlines the tests that were performed and present our initial results.
Honscheid, Klaus
Reciprocity of agonistic support in ravens.
Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim's likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910
Fraser, Orlaith N; Bugnyar, Thomas
?2-adrenoceptor agonists: current and future direction
Despite the passionate debate over the use of ?2-adrenoceptor agonists in the treatment of airway disorders, these agents are still central in the symptomatic management of asthma and COPD. A variety of ?2-adrenoceptor agonists with long half-lives, also called ultra long-acting ?2-adrenoceptor agonists (ultra-LABAs; indacaterol, olodaterol, vilanterol, carmoterol, LAS100977 and PF-610355) are currently under development with the hopes of achieving once-daily dosing. It is likely that the once-daily dosing of a bronchodilator would be a significant convenience and probably a compliance-enhancing advantage, leading to improved overall clinical outcomes. As combination therapy with an inhaled corticosteroid (ICS) and a LABA is important for treating patients suffering from asthma, and a combination with an inhaled long-acting antimuscarinic agent (LAMA) is important for treating COPD patients whose conditions are not sufficiently controlled by monotherapy with a ?2-adrenoceptor agonist, some novel once-daily combinations of LABAs and ICSs or LAMAs are under development. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-1
Cazzola, Mario; Calzetta, Luigino; Matera, Maria Gabriella
Reciprocity of agonistic support in ravens
Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim's likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals.
Fraser, Orlaith N.; Bugnyar, Thomas
Biomarker Development for TLR4 Agonists.
National Technical Information Service (NTIS)
In DARPA-supported studies, we have shown that a family of novel synthetic glycolipids known as the aminoalkyl glucosaminide phosphates (AGPs) act as potent agonists of Toll-like receptor 4 (TLR4), and that administration of AGPs to the airways results in...
D. H. Persing
Multiple tyrosine metabolites are GPR35 agonists
Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including ?-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3?,5?-triiodothyronine, 3,3?,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism.
Deng, Huayun; Hu, Haibei; Fang, Ye
Bronchodilators: beta 2 agonists versus theophylline.
Beta 2 agonists are best administered by inhalation since this route provides maximum therapeutic effect with minimum side effects. Plasma levels are lower and muscle cramps, tachycardia and tremor less common. Inhalation may be carried out by use pressurised inhalers (with various modification if necessary), by a Rotahaler with Salbutamol powder, and by nebulisers. All have their uses. Apart from their immediate bronchodilator effect, it is customary to give Beta 2-agonists routinely before inhalation beclomethasone, and there is evidence that regular use of Beta 1-agonists has a useful suppressive effect. In severe chronic asthma high doses may be indicated and be effective where conventional doses have failed. The introduction of reliable sustained-release preparation of theophylline and its derivatives together with plasma assays theophylline levels has enabled therapy to be optimal and side effects to be lessened. The therapeutic range is a plasma concentration of 10-20 mg/l. There are large individual variations in hepatic clearance of theophylline, which may also be influenced by age, liver disease, drugs and viral infections. Theophyllines are less effective as bronchodilators than Beta 2-agonists but in chronic severe asthma have a place for their additive effect. They are used most frequently to suppress nocturnal asthma and early morning wheezing. PMID:2891340
Scott, G W
Agonistic ethogram of the equid bachelor band
An ethogram of agonistic and related behaviors among equid bachelor band members was developed. Several key English-language studies on equids were reviewed to derive a preliminary inventory of specific behaviors to be included in the ethogram. A bachelor band of domestic pony stallions pastured together was observed for approximately 50 daylight hours to obtain detailed descriptions of each behavior, enable
S. M. McDonnell; J. C. S. Haviland
Toxicités des chimiothérapies orales
Résumé Les effets secondaires toxiques sont indissociables de la chimiothérapie anticancéreuse. Mais aujourd'hui, nous nous trouvons\\u000a devant un phénomčne nouveauqui est l'administration orale de ces médicaments anticancéreux. Des effets secondaires qui pouvaient\\u000a passer pour anodins lors de l'administration intraveineuse de ces produits, nausées-vomissements de grades 1 ou 2 par exemple,\\u000a donc non susceptibles d'arręter le traitement, deviennent, avec la multiplication des
F. Lokiec
Agonistic CD40 antibodies and cancer therapy
Recent success in cancer immunotherapy has reinvigorated the hypothesis that the immune system can control many if not most cancers, in some cases producing durable responses in a way not seen with many small molecule drugs. Agonistic CD40 monoclonal antibodies (mAb) offer a new therapeutic option which has the potential to generate anti-cancer immunity by various mechanisms. CD40 is a tumor necrosis factor receptor superfamily member expressed broadly on antigen-presenting cells (APC) such as dendritic cells, B cells, and monocytes as well as many non-immune cells and a range of tumors. Agonistic CD40 mAb have been shown to activate APC and promote anti-tumor T cell responses and to foster cytotoxic myeloid cells with the potential to control cancer in the absence of T-cell immunity. Thus, agonistic CD40 mAb are fundamentally different from mAb which block negative immune checkpoint such as anti-CTLA-4 or anti-PD-1. Initial clinical trials of agonistic CD40 mAb have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy; however, numerous questions remain regarding dose, schedule, route of administration, and formulation. Recent findings regarding the role played by the IgG isotype and the Fc gamma receptor (Fc?R) in mAb crosslinking, together with insights into mechanisms of action, particularly with regards to the role of myeloid cells, are predicted to help design next-generation CD40 agonistic reagents with greater efficacy. Here, we will review the preclinical and clinical data and discuss the major issues facing the field.
Vonderheide, Robert H.; Glennie, Martin J.
Injectabilite des coulis de ciment dans des milieux fissures
NASA Astrophysics Data System (ADS)
Le travail presente ici est un bilan du travaux de recherche effectues sur l'injectabilite des coulis de ciment dans lu milieux fissures. Un certain nombre de coulis a base de ciment Portland et microfin ont ete selectionnes afin de caracteriser leur capacite a penetrer des milieux fissures. Une partie des essais a ete menee en laboratoire. L'etude rheologique des differents melanges a permis de tester l'influence de l'ajout de superplastifiant et/ou de fumee de silice sur la distribution granulometrique des coulis et par consequent sur leur capacite a injecter des colonnes de sable simulant un milieu fissure donne. La classe granulometrique d'un coulis, sa stabilite et sa fluidite sont apparus comme les trois facteurs principaux pour la reussite d'une injection. Un facteur de finesse a ete defini au cours de cette etude: base sur la classe granulometrique du ciment et sa stabilite, il peut entrer dans la formulation theorique du debit d'injection avant application sur chantier. La deuxieme et derniere partie de l'etude presente les resultats de deux projets de recherche sur l'injection realises sur chantier. L'injection de dalles de beton fissurees a permis le suivi de l'evolution des pressions avec la distance au point d'injection. L'injection de murs de maconnerie a caractere historique a montre l'importance de la definition de criteres de performance des coulis a utiliser pour traiter un milieu donne et pour un objectif donne. Plusieurs melanges peuvent ainsi etre predefinis et mis a disposition sur le chantier. La complementarite des ciments traditionnels et des ciments microfins devient alors un atout important. Le choix d'utilisation de ces melanges est fonction du terrain rencontre. En conclusion, cette recherche etablit une methodologie pour la selection des coulis a base de ciment et des pressions d'injection en fonction de l'ouverture des fissures ou joints de construction.
Mnif, Thameur
Chimpanzees Extract Social Information from Agonistic Screams
Chimpanzee (Pan troglodytes) agonistic screams are graded vocal signals that are produced in a context-specific manner. Screams given by aggressors and victims can be discriminated based on their acoustic structure but the mechanisms of listener comprehension of these calls are currently unknown. In this study, we show that chimpanzees extract social information from these vocal signals that, combined with their more general social knowledge, enables them to understand the nature of out-of-sight social interactions. In playback experiments, we broadcast congruent and incongruent sequences of agonistic calls and monitored the response of bystanders. Congruent sequences were in accordance with existing social dominance relations; incongruent ones violated them. Subjects looked significantly longer at incongruent sequences, despite them being acoustically less salient (fewer call types from fewer individuals) than congruent ones. We concluded that chimpanzees categorised an apparently simple acoustic signal into victim and aggressor screams and used pragmatics to form inferences about third-party interactions they could not see.
Slocombe, Katie E.; Kaller, Tanja; Call, Josep; Zuberbuhler, Klaus
1-substituted apomorphines as potent dopamine agonists.
A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5?-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands. PMID:23727194
Reinart-Okugbeni, Reet; Vonk, Argo; Uustare, Ain; Gyulai, Zsuzsanna; Sipos, Attila; Rinken, Ago
Glucagon Receptor Agonists and Antagonists Affect the Growth of the Chick Eye: A Role for Glucagonergic Regulation of Emmetropization?
Purpose In chicks, plus defocus retards eye growth, thickens the choroid, and activates glucagonergic amacrine cells, probably releasing glucagon. Glucagon receptor antagonists (expected to inhibit compensation to plus defocus) and agonists (expected to block myopia induction by form deprivation) were administered to eyes of chicks, to test the hypothesis that glucagon mediates the induction of changes in eye growth by plus defocus. Methods Seven-day-old (P7) chick eyes were injected intravitreally with peptides at concentrations of ~10?9 to 10?5 M in 20 ?L (injection volume). The glucagon-receptor antagonists [des-His1,des- Phe6,Glu9]-glucagon-NH2 (des- Phe6-antagonist) and [des-His1,Glu9]-glucagon-NH2 (Phe6-antagonist) were administered daily for 4 to 5 days to plus-defocused eyes. Agonists (porcine glucagon-[1–29] and [Lys17,18,Glu21]-glucagon-NH2) were monocularly administered daily for 5 days to form-deprived eyes. The contralateral eye remained open and received saline. After treatment, eyes were refracted, measured, and examined for histologic changes. Results The Phe6-antagonist at 10?5 M (in the syringe) inhibited changes in both refractive error and axial length compensation induced by +7-D lens wear; however, des-Phe6-antagonist (10?5 M) had weak, inconsistent effects and did not antagonize the action of exogenous glucagon. Glucagon prevented ocular elongation and myopia and induced choroidal thickening in form-deprived eyes. [Lys17,18,Glu21]-glucagon-NH2 had little effect at 1037 M, but at 10?6 to 10?5 M altered rod structure and inhibited eye growth. Conclusions Exogenous glucagon inhibited the growth of form-deprived eyes, whereas Phe6-antagonist inhibited compensation to plus defocus, as might be expected if glucagon is an endogenous mediator of emmetropization. The reason for the failure of des-Phe6-antagonist to counteract the effects of exogenous glucagon requires further investigation.
Vessey, Kirstan A.; Lencses, Kathy A.; Rushforth, David A.; Hruby, Victor J.; Stell, William K.
Treatment of pituitary tumors: dopamine agonists.
The neurotransmitter/neuromodulator dopamine plays an important role in both the central nervous system and the periphery. In the hypothalamopituitary system its function is a dominant and tonic inhibitory regulation of pituitary hormone secretion including prolactin- and proopiomelanocortin-derived hormones. It is well known that dopamine agonists, such as bromocriptine, pergolide, quinagolide, cabergoline, and lisuride, can inhibit PRL secretion by binding to the D(2) dopamine receptors located on normal as well as tumorous pituitary cells. Moreover, they can effectively decrease excessive PRL secretion as well as the size of the tumor in patients having prolactinoma. Furthermore, dopamine agonists can also be used in other pituitary tumors. The major requirement for its use is that the tumor cells should express D(2) receptors. Therefore, in addition to prolactinomas, targets of dopamine agonist therapy are somatotroph tumors, nonfunctioning pituitary tumors, corticotroph pituitary tumors, Nelson's syndrome, gonadotropinomas, and thyrotropin-secreting pituitary tumors. It is also an option for the treatment of pituitary disease during pregnancy. Differences between the effectiveness and the resistance of different dopaminergic agents as well as the future perspectives of them in the therapy of pituitary tumors are discussed. PMID:16311416
Iván, Gabriella; Szigeti-Csúcs, Nikoletta; Oláh, Márk; Nagy, György M; Góth, Miklós I
Transdermal delivery of dopamine receptor agonists.
Conceptually, continuous dopaminergic stimulation is universally accepted to be the preferred therapeutic strategy to prevent or postpone dyskinesia in Parkinson's disease (PD). L-dopa has a short half-life of 2 hours and causes dyskinesia, whereas dopamine receptor agonists usually have a much longer half-life. Of the latter agents, cabergoline has the longest half-life of 68 hours and is ideal for the prevention of dyskinesia; but this is also true for other dopamine receptor agonists such as ropinirole or pramipexole, which have a shorter half-life of about 6-8 hours. Due to the possible development of valvular fibrosis, cabergoline is, however, only approved as a second-line treatment in PD, and patch technology has therefore gained major interest. So far, rotigotine is the only dopamine receptor agonist available as a patch. There is good evidence that once-daily patch usage provides patients with constant dopaminergic stimulation, and that patches are of equal potency to other oral non-ergot derivatives such as ropinirole and pramipexole. The disadvantages of patches are skin irritation and crystallization of the drug if not kept in the refrigerator. PMID:20123566
Reichmann, Heinz
Structural analogues of ZAPA as GABAA agonists.
Structural analogues of ZAPA, Z-3-[(aminoiminomethyl)thio]prop-2-enoic acid, an isothiouronium analogue of GABA, are potent GABAA agonists as seen in the isolated guinea-pig ileum and in the facilitation of [3H]diazepam binding to rat brain membranes. Compounds with guanidino or amidine groups replacing the amino functionality of GABA were also found to be active. The highest activity was displayed by the isothiouronium salts in which the conformational flexibility of the molecule is restricted by a Z-substituted carbon-carbon double bond. A series of bis-isothiouronium compounds was prepared from aliphatic alpha, omega-bis-thioureas as mixtures of E and Z adducts. Maximum GABAA agonist activity for this series was found with a C6-C8 carbon chain, and the results were consistent with an interaction at the GABAA receptor with only one end of the molecule, rather than the more potent effect expected of a molecule bridging two active sites. GABAA antagonist/partial agonist activity was observed on the guinea pig isolated ileum for a number of different analogue types, with the most potent being bis-isothiouronium derivatives. None of the substituted derivatives of ZAPA was as active as ZAPA itself, and maximum GABAA activity was found in the n-pentyl and n-hexyl analogues. PMID:9153000
Allan, R D; Dickenson, H W; Johnston, G A; Kazlauskas, R; Mewett, K N
Zur Dampfstoßtheorie des Mondreliefs
Zusammenfassung Die Dampfstoßtheorie gründet sich auf Experimente, deren Ergebnis an Hand geologischer Erfahrungen und Anschauungen auf den Maßstab des Mondes übertragen gedacht werden kann. Das Experiment ist also keineswegs bloß ein Modellversuch.Das Mondrelief ist das letzte Bild endogener Vorgänge, die auch auf der Erde, dort aber unter anderen Bedingungen, stattfinden.Die von der Aufsturztheorie vertretene Annahme, daß Stoßwirkungen gegen die Mondoberfläche von
Georg Dahmer
Grundlagen des Tissue Engineering
NASA Astrophysics Data System (ADS)
Die Organtransplantation stellt eine verbreitete Therapie dar, um bei krankheitsoder unfallbedingter Schädigung eines Organs die Gesamtheit seiner Funktionen wieder herzustellen, indem es durch ein Spenderorgan ersetzt wird. Organtransplantationen werden für die Leber, die Niere, die Lunge, das Herz oder bei schweren grossflächigen Verbrennungen der Haut vorgenommen. Der grosse apparative, personelle und logistische Aufwand und die Risiken der Transplantationschirurgie (Abstossungsreaktionen) sowie die mangelnde Verfügbarkeit von immunologisch kompatiblen Spenderorganen führen jedoch dazu, dass der Bedarf an Organtransplantaten nur zu einem sehr geringen Teil gedeckt werden kann. Sind Spenderorgane nicht verfügbar, können in einzelnen Fällen lebenswichtige Teilfunktionen, wie beispielsweise die Filtrationsfunktion der Niere durch die Blutreinigung mittels Dialyse ersetzt oder, bei mangelnder Funktion der Bauchspeicheldrüse (Diabetes), durch die Verabreichung von Insulin ein normaler Zustand des Gesamtorganismus auch über Jahre hinweg erhalten werden. Bei der notwendigen lebenslangen Anwendung apparativer oder medikamentöser Therapie können für den Patienten jedoch häufig schwerwiegende, möglicherweise lebensverkürzende Nebenwirkungen entstehen. Daher werden in der Forschung Alternativen gesucht, um die Funktionen des ausgefallenen Organs durch die Implantation von Zellen oder in vitro gezüchteten Geweben möglichst umfassend wieder herzustellen. Dies erfordert biologisch aktive Implantate, welche die für den Stoffwechsel des Organs wichtigen Zellen enthalten und einen organtypischen Stoffwechsel entfalten.
Mayer, Jörg; Blum, Janaki; Wintermantel, Erich
Partage des coűts et tarification des infrastructures - Enjeux, problématique et pertinence du partage efficace des coűts
La plupart des organisations, sinon toutes, répartissent d'une maničre ou d'une autre des coűts communs entre leurs diverses composantes ou encore entre leurs différents partenaires. Ces problčmes de partage de coűts communs se posent avec de plus en plus d'acuité car les rčgles de partage de coűts communs sont des facteurs importants de compétitivité et de performance. Bien que leur
Marcel Boyer; Michel Moreaux; Michel Truchon
Une investigation empirique des attitudes, comportements et perceptions des produits et des formes de vente
Cette recherche a pour objectif de proposer une typologie fondée sur les orientations d'achat mesurées ŕ partir des attitudes des consommateurs envers les formes et points de vente mais aussi les produits et les marques. Puis, deux expériences sont conduites pour mettre en évidence des différences de perceptions par les consommateurs d'une offre commerciale en fonction de leurs orientations d'achat.
Blandine ANTEBLIAN-LAMBREY; Gérard FRANÇOIS
Über den Feinbau des Nebennierenmarkes des Igels ( Erinaceus europaeus L.)
Das Nebennierenmark des Igels (Erinaceus europaeus L.) wurde mit Durchlicht-, Phasenkontrast und Dunkelfeldmikroskopie untersucht. Elektronenmikroskopische Paralleluntersuchungen (Fixierung mit OsO4 und Acrolein-OsO4) sollten zunächst die Natur der sog. paranukleären Körper klären, darüber hinaus unsere Kenntnisse vom Feinbau des Markes der Nebenniere erweitern.
W. Bargmann; E. Lindner
Sports doping: emerging designer and therapeutic ?2-agonists.
Beta2-adrenergic agonists, or ?2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of ?2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel ?2-agonists molecules either by modifying the molecule of known ?2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging ?2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future. PMID:23954776
Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F
Agonist-Directed Desensitization of the ?2-Adrenergic Receptor
The ?2-adrenergic receptor (?2AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the ?2AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective ?2AR desensitization at the whole cell level.
Goral, Vasiliy; Jin, Yan; Sun, Haiyan; Ferrie, Ann M.; Wu, Qi; Fang, Ye
Compound and compositions as TGR5 agonists: WO2012082947.
The patent application WO2012082947 claims novel compounds as agonists of a plasma membrane-bound bile acid receptor TGR5. By activating TGR5, the agonists improve glycemic control and enhance energy expenditure. The basic generic claim of the patent covers pyrazole derivatives, different permutations on the core pyrazole ring are covered in the subsidiary claims. The claimed compounds are human TGR5 agonists having potency in the nM range. PMID:23409864
Raval, Saurin
Dopamine agonist: pathological gambling and hypersexuality.
(1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication. PMID:19536937
Ageismus – Sprachliche Diskriminierung des Alters
Daniel Sanders, einer der bedeutendsten Lexikografen des 19. Jahrhunderts, wertete für sein Wörterbuch Quellen seit der Lutherzeit aus und\\u000a vermerkt im Wörterbuchartikel zu alt eine "bald lobende, bald tadelnde" Bedeutung des Adjektivs. Sein Zeit- und Berufsgenosse Jacob Grimm benennt in seiner Rede über das Alter die zeitgenössischen Synonyme zu alt und Alter: "aus einheimischen schriftstellern liesze sich eine lange reihe
Undine Kramer
Discovery of selective nonpeptidergic neuropeptide FF2 receptor agonists.
We report the discovery and initial characterization of a novel class of selective NPFF2 agonists. HTS screening using R-SAT, a whole cell based functional assay, identified a class of aryliminoguanidines as NPFF1 and NPFF2 ligands. Subsequent optimization led to molecules exhibiting selective NPFF2 agonistic activity. Systemic administration showed that selective NPFF2 agonists (1 and 3) are active in various pain models in vivo, whereas administration of a nonselective NPFF1 and NPFF2 agonist (9) increases sensitivity to noxious and non-noxious stimuli. PMID:19803524
Gaubert, Gilles; Bertozzi, Fabio; Kelly, Nicholas M; Pawlas, Jan; Scully, Audra L; Nash, Norman R; Gardell, Luis R; Lameh, Jelveh; Olsson, Roger
DES Timeline Year Event 1938 Diethylstilbestrol (DES) was produced for use in pregnancy. 1940 DES was widely prescribed to women for use in threatened miscarriages and was promoted to physicians through medical publications and other communications.
Problemes aux limites en theorie des distributions
Résumé Etude de la méthode des potentiels pour résoudre des problčmes aux limites relatifs ŕ certains opérateurs différentiels. Résolution\\u000a et discussion des problčmes aux limites pour un systčme diffčrentiel elliptique lorsque les données sont des distributions\\u000a (le problčme étant elliptique ŕ droite ou ŕ gauche).
Paul Krée
Die "cortinähnliche" Wirkung des g-Strophanthins
An normalen Kaninchen bewirkten höhere Dosen des Strophanthins eine Steigerung des Blutchlorid-, Natrium- und Zuckerspiegels und eine Erniedrigung der Plasmakaliumkonzentration. An normalen Hunden wird der Chlorid- und Natriumgehalt des Blutes auf Strophanthin erhöht, der Kaliumgehalt des Plasmas gesenkt. Die mit dem Harn ausgeschiedenen Natriummengen sanken nach Strophanthinbehandlung ab und gleichzeitig nahm die Kaliumausscheidung stark zu. Im Lichte dieser auf den
E. Varga; D. Bagdy; L. Kesztyüs
Ropinirole and pramipexole, the new agonists.
Ropinirole and pramipexole are non-ergoline dopamine agonists which are relatively specific for the D2 family of dopamine receptors. They have side-effect profiles linked to peripheral and central dopaminergic stimulation, amenable to tolerance through a slow titration or the addition of domperidone in sensitive patients. They do not have the uncommon but problematic ergot-related side effects of bromocriptine and pergolide. Ropinirole and pramipexole have both been shown to be efficacious when used as monotherapy in early Parkinson's disease (PD), and have been suggested as being less likely than levodopa to lead to the early development of motor fluctuations and dyskinesias in this clinical setting. They have also been shown to be useful as adjunctive therapy to levodopa in advanced PD and to have a levodopa-sparing effect in these patients. Dose equivalents amongst the available dopamine agonists is difficult to know with certainty but has been estimated as follows: 30 mg of bromocriptine, 15 mg of ropinirole, 4.5 mg of pramipexole, and 3.0 mg of pergolide. PMID:10451757
Hobson, D E; Pourcher, E; Martin, W R
NSDL National Science Digital Library
Users can access information about educational programs and materials for teachers and students, including tours, traveling exhibits and presentations by the staff of the Des Moines Water Works. "Water Trunks", which contain water-related literature, books, science experiments, videos, games, CD-ROMs, hands-on activities, picture cards, career information, and a teacher resource book, are available to order. There are also links to other water websites, a teachers' newsletter and pollution prevention tips for classroom use and for the general public.
A propos des divergences en théorie des champs quantifiés [83
NASA Astrophysics Data System (ADS)
Comme nous le montrons ailleurs1), la causalité impose ŕ la matrice S qui décrit l'évolution d'un systčme une structure bien déterminée : lorsqu'on développe celle-ci suivant les opérateurs de translation dans l'espace des quanta, les coefficients S^{(i)} left[ {tau ''; u''../tau '; u' \\cdot \\cdot } right] sont des intégrales multiples oů n'apparaissent, ŕ cOté des champs liés ŕ un seul point de l'espace temps, que les functions*): D^c (x/y) = D^s (x/y) + _2^i D^1 (x/y) x ne y
Sécurité au-delŕ des mythes et des croyances
Présentation orale en français, support visuel en français et en anglais. La pire des failles de sécurité est l'impression de sécurité. Le décalage entre la compréhension que l?on a des technologies utilisées, et leurs potentiels réels, ainsi que l'impact potentiellement négatif qu'elles peuvent avoir sur nos vies, n'est pas toujours compris, ou pris en compte par la plupart d'entre-nous. On se contente de nos perceptions pour ne pas avoir ŕ se confronter ŕ la réalité... Alors qu'en est-il vraiment ? En matičre de sécurité qui de l'humain ou des technologies a le contrôle ?
Dopamine receptor agonists and sleep disturbances in Parkinson's disease.
Non-ergot dopamine receptor agonists, such as ropinirole, pramipexole, rotigotine and apomorphine, may alleviate some non-motor symptoms in Parkinson's disease (PD) while others may be precipitated. In this review, we discuss how dopamine receptor agonists can both ameliorate and aggravate the sleep problems in PD, a key non-motor symptom of this disease. PMID:20123546
Chaudhuri, K Ray; Logishetty, Kartik
Synthesis and SAR of Tetrahydroisoquinolines as Rev-erb? agonists
The design and synthesis of a novel series of Rev-erb? agonists is described. The development and optimization of the tetrahydroisoquinoline series was carried out from an earlier acyclic series of Rev-erb? agonists. Through the optimization of the scaffold 1, several potent compounds with good in vivo profiles were discovered.
Noel, Romain; Song, Xinyi; Shin, Youseung; Banerjee, Subhashis; Kojetin, Douglas; Lin, Li; Ruiz, Claudia H.; Cameron, Michael D.; Burris, Thomas P.
Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...
In silico discovery of novel Retinoic Acid Receptor agonist structures
BACKGROUND: Several Retinoic Acid Receptors (RAR) agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia. RESULTS: We have analysed the induced fit of
Matthieu Schapira; Bruce M Raaka; Herbert H Samuels; Ruben Abagyan
Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists
ERIC Educational Resources Information Center
Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…
King, Angela G.
GABAA agonists as targets for drug development.
1. Agents with selective actions on bicuculline-sensitive GABAA receptors have been developed by systematically restricting the conformational mobility of the GABA molecule. 2. THIP, a bicyclic isoxazole that represents GABA held in a relatively rigid and partially extended conformation, is an analgesic of potency comparable to that of morphine. THIP represents a lead compound for a novel series of analgesics acting independently of Naloxone-sensitive opiate systems. 3. ZAPA, a conformationally-restricted analogue of GABA containing an isothiouronium moiety, is a selective agonist for low affinity GABAA receptors and is a lead compound for the development of a novel series of anthelmintics. 4. (+)-TACP, a cyclopentane analogue of GABA, may activate a different subclass of GABAA receptors from THIP. 5. Pharmacological, molecular modelling and molecular biological studies provide evidence for a heterogeneity of GABAA receptors which might be exploited for drug development. PMID:1320473
Johnston, G A
[Antiarrhythmic properties of opioid receptor agonists].
Data on the antiarrhythmic properties of opioid receptor (OR) agonists have been systematized. An analysis of published works which indicate that opioids increase cardiac tolerance to arrhythmogenic influences both in vivo and in vitro has been performed. For example, occupancy of central micro- and delta-OR and also ORL1 receptors increases cardiac tolerance to arrhythmogenic action epinephrine and aconitine. In contrast, activation of central kapa-OR exacerbates arrhythmogenic action epinephrine. Stimulation of peripheral delta2- and kappa1-OR decreases an incidence of arrhythmias induced coronary artery occlusion and reperfusion in vivo. Occupancy of peripheral micro-, kappa2-, delta1-OR and also ORL1 receptors has no effect on the cardiac tolerance to arrhythmogenic action of ischemia and reperfusion but increases cardiac electrical stability in rats with post-infarction cardiosclerosis. Authors suggest that opioids which unable penetrate to blood barrier may be used for therapy of arrhythmias. PMID:16995444
Maslov, L N; Lishmanov, Iu B
[Pathological gambling induced by dopamine agonists].
Problems with impulse control and pathological gambling are known as possible side effects of dopaminergic therapy in patients with Parkinson's disease. We report 2 cases of pathological gambling induced by dopamine agonists in patients without Parkinson's disease. The first patient, a 46-year-old man, was treated with ropinirole for restless legs syndrome and had lost huge amounts of money in the context of internet-based poker game. Another 46-year-old male patient developed pathological gambling under treatment with cabergoline administered for prolactinoma. The two cases implicate pathological gambling as a possible consequence of dopaminergic treatment and support the increasing evidence regarding pathological gambling as an adverse drug reaction of dopaminergic treatment, also in patients who do not suffer from Parkinson's disease. PMID:21809260
Gahr, M; Connemann, B J; Schönfeldt-Lecuona, C J
Epidemiologie des Schmerzes – Ergebnisse des Bundes-Gesundheitssurveys 1998
Zusammenfassung \\u000a Schmerz hat als weit verbreitete Gesundheitsstörung nicht nur Konsequenzen für die Lebensqualität des einzelnen akut oder\\u000a chronisch Schmerzkranken, sondern stellt darüber hinaus Anforderungen an das Gesundheitssystem. Die Daten des Bundes-Gesundheitssurveys\\u000a ermöglichen erstmalig für die gesamte Bundesrepublik Deutschland repräsentative Aussagen zur Auftretenshäufigkeit von Schmerz,\\u000a dessen Lokalisation und Intensität. Zudem ermöglicht die Datenlage eine Differenzierung nach Alter, Geschlecht und Schichtzugehörigkeit.\\u000a Welch
B.-M. Bellach; U. Ellert; M. Radoschewski
Chimiothérapie des sarcomes des tissus mous métastatiques et localement avancés
Résumé Ŕ côté de la doxorubicine et de l'ifosfamide, aucun autre agent cytotoxique ou cytostatique a démontré une activité supérieure\\u000a ŕ 15 %, en terme de réponse objective dans les études de phase II ayant comporté plus de 30 patients. Les années 2000 marquent\\u000a clairement un tournant dans la conception des essais thérapeutiques dans les sarcomes des tissus mous localement avancés
A. Le Cesne; A. Cioffi
Dopamine agonists in dihydropteridine reductase deficiency.
The traditional treatment of severe disorders of tetrahydrobiopterin (BH4) metabolism is based on the replacement therapy with BH4, 5-hydroxytryptophan, and L-dopa. Major problems are encountered with L-dopa therapy, especially with increasing age when higher doses are necessary, because of its short half-life and adverse effects. Consequently, different L-dopa-sparing strategies have been successively introduced, with partial reduction of L-dopa dosage and amelioration of the clinical outcome. Recently, we demonstrated that the dopamine agonist pramipexole improves the therapeutic effect of L-dopa in 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency, the most common disorder of BH4 metabolism. Here we report its effectiveness in two patients (males, 7 and 22 years) with dihydropteridine reductase (DHPR) deficiency, the second most frequent cause of BH4 deficiency. Both patients experienced residual symptoms of dopamine deficiency, movement and behavioral disability, and complications of L-dopa therapy, associated with fluctuating hyperprolactinemia. They had full clinical and biochemical assessment, by an adapted Unified Parkinson's Disease Rating Scale (UPDRS) and measurement of diurnal plasma prolactin (PRL) profile before and after a trial with pramipexole. Besides allowing the reduction of L-dopa daily dosage (-58%) and administrations (from three to two) in one patient and to stop L-dopa therapy in the other, the introduction of pramipexole markedly improved and stabilized clinical and biochemical picture in both patients, as revealed by reduction of UPDRS scores and normalization of diurnal plasma prolactin profiles. Dopamine agonists can improve or even replace L-dopa therapy in disorders of synthesis and regeneration of BH4. PMID:22325981
Porta, Francesco; Mussa, Alessandro; Concolino, Daniela; Spada, Marco; Ponzone, Alberto
Asimadoline, a ?-Opioid Agonist, and Visceral Sensation
SUMMARY Asimadoline is a potent ?-opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the ? receptor, with IC50 of 5.6 nM (guinea pig) and 1.2 nM (human recombinant), and high selectively with ?: ?: ? binding ratios of 1:501:498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in IBS patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 hours post-on-demand treatment with asimadoline was not significantly reduced. Post-hoc analyses suggest asimadoline was effective in mixed IBS. In a 12-week study in 596 patients, chronic treatment with asimadoline, 0.5 mg and 1.0 mg, was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain free days in patients with IBS-D. The 1.0 mg dose was also efficacious in IBS-alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date.
Camilleri, Michael
Pharmacological characterization of the cardiovascular responses elicited by kinin B1 and B2 receptor agonists in the spinal cord of streptozotocin-diabetic rats
Kinin receptor agonists and antagonists at the B1 and B2 receptors were injected intrathecally (i.t., at T-9 spinal cord level) to conscious unrestrained rats and their effects on mean arterial pressure (MAP) and heart rate (HR) were compared in streptozotocin (STZ)-diabetic rats (65?mg?kg?1 STZ, i.p. 3 weeks earlier) and aged-matched control rats. The B1 receptor agonist, des-Arg9-Bradykinin (BK) (3.2–32.5?nmol), evoked dose-dependent increases in MAP and tachycardia during the first 10?min post-injection in STZ-diabetic rats only. The cardiovascular response to 6.5?nmol des-Arg9-BK was reversibly blocked by the prior i.t. injection of antagonists for the B1 receptor ([des-Arg10]-Hoe 140, 650?pmol or [Leu8]-des-Arg9-BK, 65?nmol) and B2 receptor (Hoe 140, 81?pmol or FR173657, 81?pmol) or by indomethacin (5?mg?kg?1, i.a.). The i.t. injection of BK (8.1–810?pmol) induced dose-dependent increases in MAP which were accompanied either by tachycardiac (STZ-diabetic rats) or bradycardiac (control rats) responses. The pressor response to BK was significantly greater in STZ-diabetic rats. The cardiovascular response to 81?pmol BK was reversibly blocked by 81?pmol Hoe 140 or 81?pmol FR173657 but not by B1 receptor antagonists nor by indomethacin in STZ-diabetic rats. The data suggest that the activation of kinin B1 receptor in the spinal cord of STZ-diabetic rats leads to cardiovascular changes through a prostaglandin mediated mechanism. Thus, this study affords an accessible model for studying the expression, the pharmacology and physiopathology of the B1 receptor in the central nervous system.
Cloutier, Frank; Couture, Rejean
Die elektrischen Eigenschaften des Bakelits
Zusammenfassung Die Arbeit erstreckt sich auf die Untersuchung der elektrischen Eigenschaften insbesondere des Bakelitproduktes C bei verschiedenen Temperaturen. In einer zweiten Versuchsreihe wird ein Überblick über das elektrische Verhalten der einzelnen Kondensationsprodukte Bakelit A, B und C zu gewinnen versucht.
O. Mannel
Targeting cannabinoid agonists for inflammatory and neuropathic pain.
The cannabinoid receptors CB(1) and CB(2) are class A G-protein-coupled receptors. It is well known that cannabinoid receptor agonists produce relief of pain in a variety of animal models by interacting with cannabinoid receptors. CB(1) receptors are located centrally and peripherally, whereas CB(2) receptors are expressed primarily on immune cells and tissues. A large body of preclinical data supports the hypothesis that either CB(2)-selective agonists or CB(1) agonists acting at peripheral sites, or with limited CNS exposure, will inhibit pain and neuroinflammation without side effects within the CNS. There has been a growing interest in developing cannabinoid agonists. Many new cannabinoid ligands have been synthesized and studied covering a wide variety of novel structural scaffolds. This review focuses on the present development of cannabinoid agonists with an emphasis on selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists for treatment of inflammatory and neuropathic pain. PMID:17594182
Cheng, Yuan; Hitchcock, Stephen A
L'endettement des entreprises industrielles françaises et allemandes : des évolutions distinctes malgré des déterminants proches
[fre] Entre 1987 et 1995, les taux d'endettement des entreprises industrielles françaises et allemandes présentent deux différences importantes. Au cours de cette période, ce taux connaît une forte baisse en France alors qu'il est relativement stable en Allemagne. Le taux d'endettement diffčre peu selon la taille de l'entreprise en France, tandis que les écarts sont significatifs entre celui des petites
Élizabeth Kremp; Elmar Stöss
Toll-like receptor agonists in cancer therapy
Toll-like receptors (TLRs) are pattern-recognition receptors related to the Drosophila Toll protein. TLR activation alerts the immune system to microbial products and initiates innate and adaptive immune responses. The naturally powerful immunostimulatory property of TLR agonists can be exploited for active immunotherapy against cancer. Antitumor activity has been demonstrated in several cancers, and TLR agonists are now undergoing extensive clinical investigation. This review discusses recent advances in the field and highlights potential opportunities for the clinical development of TLR agonists as single agent immunomodulators, vaccine adjuvants and in combination with conventional cancer therapies.
Adams, Sylvia
Reproductive responses of cattle to GnRH agonists.
The response in cattle to treatment with gonadotrophin releasing hormone (GnRH) agonist includes downregulation of GnRH receptors on gonadotrophe cells, desensitisation of the anterior pituitary gland to endogenous GnRH, and the abolition of pulsatile release of LH. In bulls, a tonic pattern of LH release is associated with increased secretion of testosterone, which persists for the duration of treatment with GnRH agonist. The mechanism for this response in bulls has not been elucidated, but clearly pulsatile release of LH is not required to stimulate the synthesis of steroidogenic enzymes that sustain elevated secretion of testosterone. In heifers, desensitisation to endogenous GnRH prevents the occurrence of the pre-ovulatory surge release of LH, thus blocking ovulation. The latter provided the opportunity to evaluate the potential of a GnRH agonist bioimplant to control fertility in heifers under extensive management. Bioimplants that contained graded amounts of GnRH agonist prevented pregnancies in heifers for periods of 3 to 12 months. Zebu crossbred heifers treated with GnRH agonist from 14 to 23 months of age failed to conceive, but showed normal conception patterns when introduced into mating herds at around 26 months of age. After treatment with GnRH agonist for 4 to 6 weeks, ovarian follicular growth in heifers is restricted to relatively small (2-4 mm) antral follicles. Suppressed follicular growth in heifers treated long-term with GnRH agonist is due to a lack of gonadotrophin support, rather than a direct action of agonist at the ovaries. This was demonstrated by the ability to induce apparently normal follicular growth and ovulation by acute treatment with FSH for 4 days, followed by an injection of LH, in heifers that had been exposed to GnRH agonist for around 6 months, and which had only small (2-4 mm) antral follicles at the start of FSH treatment. GnRH agonist bioimplants have been incorporated into new multiple ovulation and embryo transfer protocols that allow control of the time of ovulation subsequent to superstimulation of ovarian follicular growth with FSH. In these protocols, the endogenous surge release of LH is blocked by treatment with agonist and ovulation is timed by injection of exogenous LH, allowing fixed-time AI. It can be concluded from recent studies that GnRH agonist bioimplants have considerable potential for both pro-fertility and anti-fertility applications in cattle. It is likely that commercial bioimplants will be available within the next 3 to 5 years. PMID:10844213
D'Occhio, M J; Fordyce, G; Whyte, T R; Aspden, W J; Trigg, T E
Parkinson's Disease: The Proper Use of Dopamine Receptor Agonists.
Although dopamine receptor agonists are not simple to use, they are assuming increased importance in the treatment of early and advanced symptoms of Parkinson's disease (PD). The new agonists, pramipexole and ropinirole, are generally adequate without levodopa for early symptoms and carry the hope for a more acceptable profile of long-term side effects. In the patient with advanced disease, all four dopamine agonists significantly augment the response to levodopa, which reduces the problems of motor fluctuations and drug-related dyskinesia. Understanding the common pitfalls when prescribing these drugs will facilitate their safety and efficacy. PMID:11096691
[Dopaminergic agonists in the treatment of Parkinson's disease].
After levodopa, dopaminergic agonists are the most powerful agents in idiopathic Parkinson's disease treatment. Used in monotherapy or rather in early combination with levodopa, they allow a dramatic reduction of long-term motor side effects of the latter: onset and peak-dose dyskinesias, early morning dystonias. Their gastro-intestinal (nauseas) and moreover psychiatric (confusion and hallucinations) side effects limit their use, notably in geriatric populations. Superiority of so-called "second generation" agonists (ropinirole, pramipexole) on "first generation" agonists (bromocriptine, pergolide) remains to be proved. PMID:11194495
Supiot, F; Sternon, J; Zegers de Beyl, D
Röntgenologische Untersuchungen zur Lageabhängigkeit der tiefen Hirnvenen, insbesondere des Angulus venosus von der Form des Schädels
Zusammenfassung Die Lageabhängigkeit der tiefen Hirnvenen, insbesondere des Angulus venosus, von der Form des Schädels wird durch zahlreiche Streckenverhältnisse (prozentuale Unterteilung von benachbarten Strecken durch senkrechte Projektion des Angulus venosus auf diese) und durch Winkel mit verschiedenen Scheitelpunkten (an der Schädelbasis, an der Schädelkalotte und intracraniell) geprüft. — Von den Streckenverhältnismaßen eignen sich zur Lokalisation des Angulus venosus die Relationen
Erich Fischer
Modélisation des boucles d'immunisation magnétique des navires
NASA Astrophysics Data System (ADS)
This paper presents the problem of the three-dimensional modeling of degaussing coils in ships with a finite elements method. We show that these current coils are so close to the ferromagnetic sheets of the ship that they require a local very fine mesh which would be unrealistic for the whole complex structure of a real ship. We propose an alternative to the expensive mesh refinement called "reduced scalar potential jump". The idea is to previously solve the local problem by another method and to use the result in the whole FEM modelling. We present the method of implementation in the FEM software FLUX3D and comparative results on a simple geometry. Cet article présente le problčme de la modélisation en trois dimensions des boucles d'immunisation des navires par la méthode des éléments finis. Nous montrons que ces boucles de courant sont si proches des tôles ferromagnétiques du navire que leur modélisation requiert un maillage localement trčs fin, ce qui est irréaliste pour la structure complexe d'un navire réel. Nous proposons une alternative ŕ ce coűteux affinage du maillage, appelée "saut de potentiel réduit". L'idée est de résoudre au préalable le problčme local par une autre méthode que les éléments finis et d'utiliser le résultat dans la modélisation globale. Nous présentons la méthode utilisée pour l'implantation de cette technique dans le logiciel d'éléments finis FLUX3D, et des résultats comparatifs sur une géométrie simple.
Le Dorze, F.; Bongiraud, J. P.; Coulomb, J. L.; Meunier, G.; Brunotte, X.
Unique agonist-bound cannabinoid CB1 receptor conformations indicate agonist specificity in signaling
Cannabinoid drugs differ in their rank order of potency to produce analgesia versus other central nervous system effects. We propose that these differences are due to unique agonist-bound cannabinoid CB1 receptor conformations that exhibit different affinities for individual subsets of intracellular signal transduction pathways. In order to test this hypothesis, we have used plasmon-waveguide resonance (PWR) spectroscopy, a sensitive method that can provide direct information about ligand-protein and protein-protein interactions, and can detect conformational changes in lipid-embedded proteins. A recombinant epitope-tagged human cannabinoid CB1 receptor was expressed in insect Sf9 cells, solubilized and purified using two-step affinity chromatography. The purified receptor was incorporated into a lipid bilayer on the surface of the PWR resonator. PWR spectroscopy demonstrated that cannabinoid agonists exhibit high affinity (KD = 0.2 ± 0.03 nM and 2 ± 0.4 nM for CP 55,940 and WIN 55,212-2, respectively) for the purified epitope tagged hCB1 receptor. Interestingly however, these structurally different cannabinoid agonists shifted the PWR spectra in opposite directions, indicating that CP 55,940 and WIN 55,212-2 binding leads to different hCB1 receptor conformations. Furthermore, PWR experiments also indicated that these CP 55,940- and WIN 55,212 - bound hCB1 receptor conformations exhibit slightly different affinities to an inhibitory G protein heterotrimer, Gi1 (KD = 27 ± 8 nM and KD = 10.7 ± 4.7 nM, respectively), whereas they strikingly differ in their ability to activate this G protein type.
Georgieva, Teodora; Devanathan, Savitha; Stropova, Dagmar; Park, Chad K.; Salamon, Zdzislaw; Tollin, Gordon; Hruby, Victor J.; Roeske, William R.; Yamamura, Henry I.; Varga, Eva
Les problčmes économiques des régions frontičres européennes
[fre] Le développement du Marché commun tend actuellement ŕ faire reconnaître la nature spécifique de la région frontičre (région naturelle coupée par une frontičre politique) jusque-lŕ niée par les nationalismes économiques et politiques. Les problčmes communs ŕ ces régions (disparité des rythmes de croissance, émigration des frontaliers, incohérence des infrastructures et des localisations industrielles, etc.) sont envisagés d'abord sous l'angle
René Gendarme
Description d'inclusions intranuclčaires dans les cellules des tiges fasciées des Forsythia sp
Résumé Dans les cellules des pousses fasciées duForsythia sp.; nous avons observé des inclusions intranucléaires présentant des arrangements périodique trčs réguliers. Nous n'avons pas décelé de semblables inclusions intranucléaires dans les cellules de pousses prélevées sur des plants normaux. Le problčme est posé, des rapports éventuels de cause ŕ effet entre la présence de ces inclusions et l'anomalie morphologique observée.
M. Codaccioni
Ŕ la recherche des déterminants de l'investissement des entreprises
[fre] Les investissements des entreprises et la date de leur réalisation sont des éléments importants de la dynamique de court et de long terme des éco-nomies. La volatilité dans le temps des dépenses d'investissement est, en effet, la principale composante des cycles économiques de court terme de l'économie. Toutes les théories de la croissance, comme les travaux empiriques,placent par ailleurs
Anne Epaulard
L'utilisation des équipements scolaires en dehors des heures de classe
L'expérience d'un certain nombre de pays de l'OCDE montre aujourd'hui comment l'utilisation des écoles en dehors des heures de classe peut améliorer les résultats des élčves en leur donnant davantage de temps pour étudier, enrichir le programme scolaire par des activités hors programme, donner aux adultes des possibilités de développement personnel ou de formation et offrir ŕ la population en
How to succeed in using dopamine agonists in Parkinson's disease.
Dopamine receptor agonists are assuming increased importance in the treatment of both early and advanced symptoms of Parkinson's disease (PD). However, tolerability of these drugs can be a problem. Identifying patients who are at increased risk of adverse effects is central to using dopamine agonists in PD. The newer agonists, pramipexole and ropinirole, are generally adequate without levodopa for early symptoms and carry the hope for a more acceptable profile of long-term side-effects. In the patient with advanced disease, all four dopamine agonists significantly augment the response to levodopa, which reduces the problems of motor fluctuations and drug related dyskinesia. Understanding the common pitfalls when prescribing these drugs will facilitate their safety and efficacy. PMID:11054153
Shulman, L M
Agonist replacement therapy for cocaine dependence: a translational review
Cocaine use disorders are prevalent throughout the world. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. This paper reviews the translational literature, including preclinical experiments, human laboratory studies and clinical trials, to determine whether agonist-replacement therapy is a viable strategy for managing cocaine dependence. Discussion is limited to transporter blockers (i.e., methylphenidate) and releasers (i.e., amphetamine analogs) that are available for use in humans in the hope of impacting clinical research and practice more quickly. The translational review suggests that agonist-replacement therapy, especially monoamine releasers, may be effective for managing cocaine dependence. Future directions for medications development are also discussed because the viability of agonist-replacement therapy for cocaine dependence may hinge on identifying novel compounds or formulations that have less abuse and diversion potential.
Rush, Craig R; Stoops, William W
Agonist pharmacology of two Drosophila GABA receptor splice variants.
1. The Drosophila melanogaster gamma-aminobutyric acid (GABA) receptor subunits, RDLac and DRC 17-1-2, form functional homo-oligomeric receptors when heterologously expressed in Xenopus laevis oocytes. The subunits differ in only 17 amino acids, principally in regions of the N-terminal domain which determine agonist pharmacology in vertebrate ionotropic neurotransmitter receptors. A range of conformationally restricted GABA analogues were tested on the two homo-oligomers and their agonists pharmacology compared with that of insect and vertebrate iontropic GABA receptors. 2. The actions of GABA, isoguvacine and isonipecotic acid on RDLac and DRC 17-1-2 homo-oligomers were compared, by use of two-electrode voltage-clamp. All three compounds were full agonists of both receptors, but were 4-6 fold less potent agonists of DRC 17-1-2 homo-oligomers than of RDLac. However, the relative potencies of these agonists on each receptor were very similar. 3. A more complete agonist profile was established for RDLac homo-oligomers. The most potent agonists of these receptors were GABA, muscimol and trans-aminocrotonic acid (TACA), which were approximately equipotent. RDLac homo-oligomers were fully activated by a range of GABA analogues, with the order of potency: GABA > ZAPA ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid) > isoguvacine > imidazole-4-acetic acid > or = isonipecotic acid > or = cis-aminocrotonic acid (CACA) > beta-alanine. 3-Aminopropane sulphonic acid (3-APS), a partial agonist of RDLac homo-oligomers, was the weakest agonist tested and 100 fold less potent than GABA. 4. SR95531, an antagonist of vertebrate GABAA receptors, competitively inhibited the GABA responses of RDLac homo-oligomers, which have previously been found to insensitive to bicuculline. However, its potency (IC50 500 microM) was much reduced when compared to GABAA receptors. 5. The agonist pharmacology of Drosophila RDLac homo-oligomers exhibits aspects of the characteristic pharmacology of certain native insect GABA receptors which distinguish them from vertebrate GABA receptors. The high potency and efficacy of isoguvacine and ZAPA distinguishes RDLac homo-oligomers from bicuculline-insensitive vertebrate GABAC receptors, while the low potency of SR95531 and 3-APS distinguishes them from GABAA receptors. The differences in the potency of agonists on RDLac and DRC 17-1-2 homo-oligomers observed in the present study may assist in identification of further molecular determinants of GABA receptor function. PMID:8982504
Hosie, A M; Sattelle, D B
Comparative gene expression profiles induced by PPAR? and PPAR?\\/? agonists in rat hepatocytes
Species-differential toxic effects have been described with PPAR? and PPAR? agonists between rodent and human liver. PPAR? agonists (fibrates) are potent hypocholesterolemic agents in humans while they induce peroxisome proliferation and tumors in rodent liver. By contrast, PPAR? agonists (glitazones) and even dual PPAR?\\/? agonists (glitazars) have caused idiosyncratic hepatic and nonhepatic toxicities in human without evidence of any damage
Alexandra Rogue; Marie Pierre Renaud; Nancy Claude; André Guillouzo; Catherine Spire
Agonistic Properties of Cannabidiol at 5HT1a Receptors
Cannabidiol (CBD) is a major, biologically active, but psycho-inactive component of cannabis. In this cell culture-based report, CBD is shown to displace the agonist, [3H]8-OH-DPAT from the cloned human 5-HT1a receptor in a concentration-dependent manner. In contrast, the major psychoactive component of cannabis, tetrahydrocannabinol (THC) does not displace agonist from the receptor in the same micromolar concentration range. In signal
Ethan B. Russo; Andrea Burnett; Brian Hall; Keith K. Parker
Use of ?2-Agonists in Neuroanesthesia: An Overview
?2-Agonists are a novel class of drugs with mechanisms of action that differ from other commonly used anesthetic drugs. They have neuroprotective, cardioprotective, and sedative effects. These unique characteristics make them potentially useful during neuroanesthesia and intensive care. We review the effects of dexmedetomidine on cerebral blood flow and cerebral metabolism, along with recent advances in using ?2-agonists in neuroanesthesia and neurointensive care.
Farag, Ehab; Argalious, Maged; Sessler, Daniel I.; Kurz, Andrea; Ebrahim, Zeyd Y.; Schubert, Armin
Chronique des tendances de la société française
[fre] Cette chronique présente des résultats nouveaux issus d'enquętes récentes et approfondit certaines tendances de la société française déjŕ évoquées dans des articles précédents. • En deux générations, les déterminants du choix du conjoint se sont modifiés. Les anciennes générations se mariaient préférentielle- ment en fonction des positions sociales de leurs parents ; les nouvelles privilégient le diplôme du conjoint.
Philippe Bonnin; Louis Chauvel; Jean-Pierre Jaslin; Michel Forsé
Une théorie des années quatre-vingt
[fre] Les années quatre-vingt présentent, pour les analyses macroéconomiques habituelles, des énigmes majeures, dont, aux premiers rangs, la persistance d'un chômage élevé en Europe et la désynchronisation des conjonctures américaine et européennes pendant la premičre moitié de la décennie. Des «faits» nouveaux, qui distinguent la période considérée sont mal pris en compte par les modčles usuels. Cet article propose une
Jacques Le Cacheux; Jean-Paul Fitoussi
Pharmacogenetics of beta2 adrenergic receptor agonists in asthma management.
Beta2 (?2 ) adrenergic receptor agonists (beta agonists) are a commonly prescribed treatment for asthma despite the small increase in risk for life-threatening adverse responses associated with long-acting beta agonist (LABA). The concern for life-threatening adverse effects associated with LABA and the inter-individual variability of therapeutic responsiveness to LABA-containing combination therapies provide the rationale for pharmacogenetic studies of beta agonists. These studies primarily evaluated genes within the ?2 -adrenergic receptor and related pathways; however, recent genome-wide studies have identified novel loci for beta agonist response. Recent studies have identified a role for rare genetic variants in determining beta agonist response and, potentially, the risk for rare, adverse responses to LABA. Before genomics research can be applied to the development of genetic profiles for personalized medicine, it will be necessary to continue adapting to the analysis of an increasing volume of genetic data in larger cohorts with a combination of analytical methods and in vitro studies. PMID:24641588
Ortega, V E
Histamine H3-receptor inverse agonists as novel antipsychotics.
Schizophrenia (SZ) that is resistant to treatment with dopamine (DA) D2 antagonists may involve changes other than those in the dopaminergic system. Recently, histamine (HA), which regulates arousal and cognitive functions, has been suggested to act as a neurotransmitter in the central nervous system. Four HA receptors-H1, H2, H3, and H4-have been identified. Our recent basic and clinical studies revealed that brain HA improved the symptoms of SZ. The H3 receptor is primarily localized in the central nervous system, and it acts not only as a presynaptic autoreceptor that modulates the HA release but also as a presynaptic heteroreceptor that regulates the release of other neurotransmitters such as monoamines and amino acids. H3-receptor inverse agonists have been considered to improve cognitive functions. Many atypical antipsychotics are H3-receptor antagonists. Imidazole-containing H3-receptor inverse agonists inhibit not only cytochrome P450 but also hERG potassium channels (encoded by the human ether-a-go-go-related gene). Several imidazole H3-receptor inverse agonists also have high affinity for H4 receptors, which are expressed at high levels in mast cells and leukocytes. Clozapine is an H4-receptor agonist; this agonist activity may be related to the serious side effect of agranulocytosis caused by clozapine. Therefore, selective non-imidazole H3-receptor inverse agonists can be considered as novel antipsychotics that may improve refractory SZ. PMID:20021346
Ito, Chihiro
Serotonin 5-HT2C receptor homodimerization is not regulated by agonist or inverse agonist treatment
Serotonin 5-HT2C receptors represent targets for therapeutics aimed at treating anxiety, depression, schizophrenia, and obesity. Previously, we demonstrated that 5-HT2C receptors function as homodimers. Herein, we investigated the effect of agonist and inverse agonist treatment on the homodimer status of two naturally occurring 5-HT2C receptor isoforms, one without basal activity (VGV) and one with constitutive activity (INI) with respect to G?q signaling. Cyan- and yellow- fluorescent proteins were used to monitor VGV and INI homodimer formation by western blot, and in living cells using bioluminescence and fluorescence resonance energy transfer (BRET and FRET). Western blots of solubilized membrane proteins revealed equal proportions of homodimeric receptor species from HEK293 cells transfected with either the VGV or INI isoform in the absence and presence of 5-HT. BRET ratios measured in HEK293 cells transfected with the VGV or INI isoform were the same and were not modulated by 5-HT. Similarly, FRET efficiencies were the same regardless of whether measured in cells expressing the VGV or INI isoform in the absence or presence of 5-HT or clozapine. The results indicate that serotonin 5-HT2C receptors form homodimers regardless of whether they are in an inactive or active conformation and are not regulated by drug treatment.
Herrick-Davis, Katharine; Grinde, Ellinor; Weaver, Barbara A.
Serotonin 5-HT(2C) receptor homodimerization is not regulated by agonist or inverse agonist treatment.
Serotonin 5-HT(2C) receptors represent targets for therapeutics aimed at treating anxiety, depression, schizophrenia, and obesity. Previously, we demonstrated that 5-HT(2C) receptors function as homodimers. Herein, we investigated the effect of agonist and inverse agonist treatment on the homodimer status of two naturally occurring 5-HT(2C) receptor isoforms, one without basal activity (VGV) and one with constitutive activity (INI) with respect to Galpha(q) signaling. Cyan- and yellow-fluorescent proteins were used to monitor VGV and INI homodimer formation by western blot, and in living cells using bioluminescence and fluorescence resonance energy transfer (BRET and FRET). Western blots of solubilized membrane proteins revealed equal proportions of homodimeric receptor species from HEK293 cells transfected with either the VGV or INI isoform in the absence and presence of 5-HT. BRET ratios measured in HEK293 cells transfected with the VGV or INI isoform were the same and were not modulated by 5-HT. Similarly, FRET efficiencies were the same regardless of whether measured in cells expressing the VGV or INI isoform in the absence or presence of 5-HT or clozapine. The results indicate that serotonin 5-HT(2C) receptors form homodimers regardless of whether they are in an inactive or active conformation and are not regulated by drug treatment. PMID:17507008
Herrick-Davis, Katharine; Grinde, Ellinor; Weaver, Barbara A
Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12
The ADP receptor P2Y12 belongs to the superfamily of G protein–coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y12 and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y12. The potency at P2Y12 was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y12, with Y105, E188, R256, Y259, and K280 playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3?-OH of the 2?-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y12 and half of the constitutive active P2Y12 mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y12 but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands.
Schmidt, Philipp; Ritscher, Lars; Dong, Elizabeth N.; Hermsdorf, Thomas; Coster, Maxi; Wittkopf, Doreen; Meiler, Jens
Etude des Abondances de MG et de fe dans la Composante Stellaire des Disques des Galaxies Spirales
NASA Astrophysics Data System (ADS)
Je presente ici une technique d'observation par imagerie des disques stellaires des galaxies spirales. Je tente, a l'aide d'un modele evolutif multiphase, de determiner les abondances de fer et de magnesium dans les disques. Dans ce but, je mesure les indices Mg2 et Fe5270 du systeme de Lick. Ces elements representent un choix judicieux d'indicateurs car ils sont formes par des supernovae de deux types differents ayant des durees de vie differentes. Le rapport d'abondances de ces deux elements est un indicateur du taux de formation des populations stellaires. Je decris, en premier lieu, les observations, la technique de mesure, ainsi que son application. J'analyse ensuite les indices mesures. A partir du modele multiphase, j'explore differents parametres physiques des spirales comme le taux de formation stellaire, l'evolution des abondances, les effets possibles de la presence de la barre, etc.
Beauchamp, Dominique
Discovery and SAR of a Series of Agonists at Orphan G Protein-Coupled Receptor 139
GPR139 is an orphan G-protein coupled receptor (GPCR) which is primarily expressed in the central nervous system (CNS). In order to explore the biological function of this receptor, selective tool compounds are required. A screening campaign identified compound 1a as a high potency GPR139 agonist with an EC50 = 39 nM in a calcium mobilization assay in CHO-K1 cells stably expressing the GPR139 receptor. In the absence of a known endogenous ligand, the maximum effect was set as 100% for 1a. Screening against 90 diverse targets revealed no cross-reactivity issues. Assessment of the pharmacokinetic properties showed limited utility as in vivo tool compound in rat with a poor whole brain exposure of 61 ng/g and a brain/plasma (b/p) ratio of 0.03. Attempts to identify a more suitable analogue identified the des-nitrogen analogue 1s with a reduced polar surface area of 76.7 Ĺ2 and an improved b/p ratio of 2.8. The whole brain exposure remained low at 95 ng/g due to a low plasma exposure.
Discovery and SAR of a Series of Agonists at Orphan G Protein-Coupled Receptor 139.
GPR139 is an orphan G-protein coupled receptor (GPCR) which is primarily expressed in the central nervous system (CNS). In order to explore the biological function of this receptor, selective tool compounds are required. A screening campaign identified compound 1a as a high potency GPR139 agonist with an EC50 = 39 nM in a calcium mobilization assay in CHO-K1 cells stably expressing the GPR139 receptor. In the absence of a known endogenous ligand, the maximum effect was set as 100% for 1a. Screening against 90 diverse targets revealed no cross-reactivity issues. Assessment of the pharmacokinetic properties showed limited utility as in vivo tool compound in rat with a poor whole brain exposure of 61 ng/g and a brain/plasma (b/p) ratio of 0.03. Attempts to identify a more suitable analogue identified the des-nitrogen analogue 1s with a reduced polar surface area of 76.7 Ĺ(2) and an improved b/p ratio of 2.8. The whole brain exposure remained low at 95 ng/g due to a low plasma exposure. PMID:24900311
Shi, Feng; Shen, Jing Kang; Chen, Danqi; Fog, Karina; Thirstrup, Kenneth; Hentzer, Morten; Karlsson, Jens-Jakob; Menon, Veena; Jones, Kenneth A; Smith, Kelli E; Smith, Garrick
Die Mikrofossilien des jugoslawischen Perms
Zusammenfassung Die Mikrofauma-und-flora der verschiedenen Stufen und Fazies des jugoslawischen Perms wird für die einzelnen Horizonte und\\u000a einige besonders reiche Fundpunkte in Fossil-Listen dargestellt. Die Fund-Horizonte sind die unteren, mittleren und oberen\\u000a Rattendorfer Schichten, derPseudofusulina-vulgaris-Zone entsprechende mittelpermische Schichten, die Trogkofel-Schichten, Neoschwagerinen-Schichten und die Schichten der Žažar-Stufe.\\u000a \\u000a Die Morphologie und Phylogenese einiger interessanter Kalkalgen und Fusuliniden des jugoslawischen Perms wird kurz erörtert.
Vanda Kochansky-Devidé
RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists
Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates.
Cytisine-Based Nicotinic Partial Agonists as Novel Antidepressant Compounds
Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the ?2 subunit (?2*), results in antidepressant-like effects. Previous studies have shown that cytisine, a partial agonist at ?4/?2* nAChRs, and a full agonist at ?3/?4* and ?7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models. We tested cytisine and two derivatives, 5-bromo-cytisine (5-Br-Cyt) and 3-(pyridin-3?-yl)-cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at ?4/?2* nAChRS but had no agonist effects at other nAChRs normally targeted by cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly. These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.
Mineur, Yann S.; Eibl, Christoph; Young, Grace; Kochevar, Christopher; Papke, Roger L.; Gundisch, Daniela; Picciotto, Marina R.
Methamphetamine-like discriminative-stimulus effects of nicotinic agonists.
Nicotine was recently shown to engender d-methamphetamine (MA)-like discriminative-stimulus effects in rats, which may be indicative of shared psychomotor stimulant properties. To further investigate such overlapping discriminative-stimulus effects, nicotinic agonists varying in efficacy and selectivity were studied in squirrel monkeys that discriminated a moderate intramuscular dose of MA (0.1 mg/kg) from vehicle. These included ?4?2-selective ligands that may vary in efficacy from relatively high [nicotine, (+)- and (-)-epibatidine] to relatively low [isoarecolone, varenicline, (-)-cytisine, (-)-lobeline] and the ?7-selective ligands anabaseine and anabasine. Results show that nicotine, (+)-epibatidine, and (-)-epibatidine substituted fully for MA, whereas the highest doses of other nicotinic agonists produced intermediate levels of MA-like effects (isoarecolone, anabaseine, anabasine, and varenicline) or did not substitute for MA [(-)-cytisine and (-)-lobeline]. The relative potencies of nicotinic agonists, based on effective dose50 (ED50) values, corresponded more closely with their relative affinities at ?4?2 than at ?7 receptors. Regardless of selectivity or efficacy, nicotinic agonists also were observed to produce untoward effects, including salivation and emesis during or after experimental sessions. In pretreatment studies, the ?4?2-selective antagonist dihydro-?-erythroidine hydrobromide (DH?E) (0.032 and 0.1 mg/kg) and the partial agonists varenicline (0.0032-0.1 mg/kg) and (-)-cytisine (0.032 and 0.1 mg/kg) surmountably antagonized (>10-fold rightward shift) nicotine's MA-like effects but were ineffective in blocking nicotine's emetic effects. Overall, our results show that 1) MA-like discriminative-stimulus effects of nicotinic agonists likely are mediated through ?4?2 nicotinic acetylcholine receptor actions, and 2) nicotinic ?4?2 partial agonists, like the nicotinic antagonist DH?E, can reduce MA-like behavioral effects of nicotine. PMID:24389640
Desai, Rajeev I; Bergman, Jack
Transport quantique dans des nanostructures
NASA Astrophysics Data System (ADS)
Quantum transport in nanostructures This work is devoted to the design, fabrication and magnetotransport investigations of mesoscopic devices. The sample are obtain by e-beam lithography and the measurements are performed at low temperature in a dilution refrigerator in the presence of a magnetic field. We have used MBE grown AlGaAs/GaAs heterojonctions as starting material to fabricate a bipartite tiling of rhombus called mathcal{T}3 lattice. We observe for the first time large amplitude h/e oscillations in this network as compared to the one measured in square lattices of similar size. These oscillations are the signature of a recently predited localization phenomenon induced by Aharonov-Bohm interferences on this peculiar topology. For particular values of the magnetic field the propagation of the electron wave function is bounded in a small number of cells, called Aharonov-Bohm cages. More strikingly, at high magnetic field, h/2e oscillations appear whose amplitude can be much higher than the fundamental period. Their temperature dependence is similar to that of the h/e signal. These observations withdraw a simple interpretation in terms of harmonics generation. The origin of this phenomenon is still unclear and needs more investigations. The influence electrical width of the wire defining the network and so the rule of the number of channels can be studied using a gate deposited over the lattice. In particular we have measured the amplitude dependence of the h/e and h/2e signal versus the gate voltage. Ce travail est consacré ŕ la réalisation d'échantillons mésoscopiques ŕ partir de la lithographie électronique ainsi qu'ŕ leur caractérisation ŕ trčs basse température en magnétotransport. Nous avons pour cela exploité le gaz bidimensionnel d'électrons situé ŕ l'interface d'une hétérojonction AlGaAs/GaAs pour réaliser un réseau de boucle d'une géométrie particuličre baptisée la géométrie mathcal{T}3. Nous avons observé sur cette structure des oscillations de conductance en fonction du flux du champ magnétique de période h/e dont l'amplitude est beaucoup plus importante que celle mesurée sur un réseau carré de męme dimension. Cette différence constitue une signature d'un effet de localisation induit par le champ magnétique sur la topologie mathcal{T}3. Pour des valeurs spécifiques du champ magnétique, du fait des interférences destructives Aharonov-Bohm, la propagation des fonctions d'ondes est limitée ŕ un ensemble fini de cellule du réseau appelé cage. De la dépendance en température des oscillations de période h/e mesurées sur le réseau mathcal{T}3 nous avons tiré une longueur caractéristique qui peut ętre rattachée au périmčtre des cages. Un phénomčne inattendu fut l'observation, pour des champs magnétiques plus importants, d'un doublement de fréquence des oscillations. Ces oscillations de période h/2e pouvant avoir une amplitude supérieure aux oscillations de période h/e, une interprétation en terme d'harmonique n'est pas possible. Enfin, l'influence de la largeur électrique des fils constituant le réseau et donc celle du nombre de canaux par brin a été étudiée en réalisant des grilles électrostatique. Les variations de l'amplitude des signaux en h/e et h/2e en fonction de la tension de grille ont été mesurés.
Naud, C.
Proprietes optiques et mecanismes de relaxation de l'energie des porteurs dans des boites quantiques
NASA Astrophysics Data System (ADS)
L'objet de ce doctorat est l'etude des proprietes optiques, et en particulier de la relaxation de l'energie des porteurs dans des structures a boites quantiques d'InAs/GaAs. Le travail experimental a ete realise grace aux techniques de photoluminescence (PL) continue et de photoluminescence resolue dans le temps, sur des echantillons comprenant un tres grand nombre de boites. A l'aide des mesures experimentales effectuees sur une serie d'echantillons de boites quantiques interdiffusees a divers degres, et des calculs variationnels de leurs etats electroniques, nous avons demontre clairement que la largeur des raies d'emission de la PL, qui est due aux inhomogeneites dans l'ensemble de boites etudie, peut etre attribuee principalement a des fluctuations de la hauteur des boites. D'autre part, la determination des temps de montee et de decroissance des intensites de photoluminescence a montre l'importance de certains mecanismes de transport et de relaxation, en fonction des conditions experimentales. En effet, les temps caracteristiques de la capture, de la relaxation interniveaux et de la recombinaison des porteurs varient significativement, selon le mecanisme predominant, en fonction de la temperature, de la densite d'excitation et de la separation interniveaux quantiques. Ainsi, les principaux mecanismes mis en evidence sont: la localisation des porteurs dans les barrieres a basse temperature dans le cas des echantillons interdiffuses, les collisions de type Auger sous forte excitation, les processus multiphononiques et la re-emission thermique a haute temperature. Un modele de relaxation, base sur les equations d'evolution de la population de porteurs de chaque niveau quantique, a aussi ete developpe pour mieux identifier l'effet de chacun des principaux mecanismes de relaxation des porteurs considere separement. Ces simulations ont permis une analyse plus approfondie du role de ces mecanismes. Ainsi, nous avons mis en evidence l'importance de la localisation des porteurs dans la couche de mouillage, ainsi que l'importance des mecanismes de collisions Auger lors de la capture, la capture et la relaxation interniveaux des porteurs vers tous les niveaux d'energie inferieure simultanement. Finalement, les resultats experimentaux montrent que la relaxation de l'energie des porteurs est beaucoup plus rapide que cela avait ete predit initialement par la theorie du "phonon bottleneck". Nos resultats indiquent que l'intensite lumineuse emise par les boites est regie principalement par le taux de capture/relaxation interniveaux des porteurs dans les boites. Mais elle est limitee par la re-emission thermique des porteurs hors des boites, a haute temperature. (Abstract shortened by UMI.)
Perret, Nathalie Emmanuelle
Sommaire de : Instabilite des heures de travail au Canada
Le present article resume les conclusions de le document de recherche intitulee: Instabilite des heures de travail au Canada. Les auteurs de nombreuses etudes des heures de travail ont tire d'importantes conclusions des resultats des enquetes transversales. Par exemple, a tout moment donne, la part des personnes qui travaillent de longues heures est assez importante. En outre, elle semble avoir
Andrew Larochelle-Cote Sebastien Heisz
Beitrag zum Nachweis des Kohlensulfoxyds
Zusammenfassung Es wurde gezeigt, daß Kohlensulfoxyd die Jod-Azid-Reaktion beschleunigt. Diese Tatsache kann zum Nachweis des Gases herangezogen werden. Beim Vorliegen kleiner Mengen führt man eine Anreicherung über Kaliumäthylmonothiocarbonat bzw. Palladium(II)-sulfid durch. Schwefelwasserstoff und Schwefelkohlenstoff geben die gleiche Reaktion und müssen daher entfernt werden bzw. sicher abwesend sein.
H. Gamsjäger
Role of dopamine agonists in Parkinson's disease: an update.
At present, dopamine agonists play an important role in antiparkinsonian therapy since they were proved effective in the management of both advanced- and early-stage Parkinson's disease. In the latter, they are often regarded as first-choice medication to delay the introduction of levodopa therapy. Despite sharing the capacity to directly stimulate dopamine receptors, dopamine agonists show different pharmacological properties as they act on different subsets of dopamine receptors. This, in theory, provides the advantage of obtaining a different antiparkinsonian activity or safety profile with each agent. However, there is very little evidence that any of the marketed dopamine agonists should be consistently preferred in the management of patients with Parkinson's disease. Pergolide and cabergoline are now considered a second-line choice after the proven association with valvular fibrosis. Transdermal administration (rotigotine) and subcutaneous infusion (apomorphine) of dopamine receptor agonists are now available alternatives to oral administration and provide continuous dopaminergic stimulation. Continuous subcutaneous apomorphine infusion during waking hours leads to a large reduction in daily 'off' time, dyskinesias and levodopa daily dose. Almost all currently used dopamine agonists are able to provide neuroprotective effects towards dopaminergic neurons during in vitro and in vivo experiments. This neuroprotection may be the result of different mechanisms including antioxidation, scavenging of free radicals, suppression of lipid peroxidation and inhibition of apoptosis. However, the disease-modifying effect of these agents in Parkinson's disease remains to be ascertained. PMID:17939774
Bonuccelli, Ubaldo; Pavese, Nicola
Modification of opiate agonist binding by pertussis toxin
Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.
Abood, M.E.; Lee, N.M.; Loh, H.H.
A Simple Method for Quantifying Functional Selectivity and Agonist Bias
Activation of seven-transmembrane (7TM) receptors by agonists does not always lead to uniform activation of all signaling pathways mediated by a given receptor. Relative to other ligands, many agonists are "biased" toward producing subsets of receptor behaviors. A hallmark of such "functional selectivity" is cell type dependence; this poses a particular problem for the profiling of agonists in whole cell test systems removed from the therapeutic one(s). Such response-specific cell-based variability makes it difficult to guide medicinal chemistry efforts aimed at identifying and optimizing therapeutically meaningful agonist bias. For this reason, we present a scale, based on the Black and Leff operational model, that contains the key elements required to describe 7TM agonism, namely, affinity (KA–1) for the receptor and efficacy (?) in activating a particular signaling pathway. Utilizing a "transduction coefficient" term, log(?/KA), this scale can statistically evaluate selective agonist effects in a manner that can theoretically inform structure–activity studies and/or drug candidate selection matrices. The bias of four chemokines for CCR5-mediated inositol phosphate production versus internalization is quantified to illustrate the practical application of this method. The independence of this method with respect to receptor density and the calculation of statistical estimates of confidence of differences are specifically discussed.
Honokiol: A non-adipogenic PPAR? agonist from nature?
Background Peroxisome proliferator-activated receptor gamma (PPAR?) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPAR? activators. Methods We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPAR? agonists. Results The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPAR? ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPAR? ligand-binding domain (LBD) and acted as partial agonist in a PPAR?-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. Conclusion We identified honokiol as a partial non-adipogenic PPAR? agonist in vitro which prevented hyperglycemia and weight gain in vivo. General significance This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine.
Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H.
Rat Urinary Bladder Carcinogenesis by Dual-Acting PPAR? + ? Agonists
Despite clinical promise, dual-acting activators of PPAR? and ? (here termed PPAR?+? agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPAR? is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPAR? can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPAR? as well as PPAR?, making it plausible that the urothelial carcinogenicity of PPAR?+? agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPAR?+? agonist ragaglitazar, and the available literature about the role of PPAR? and ? in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPAR?+? agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.
Oleksiewicz, Martin B.; Southgate, Jennifer; Iversen, Lars; Egerod, Frederikke L.
Channel blocking properties of a series of nicotinic cholinergic agonists.
Inhibition of the nicotinic acetylcholine receptor (nAChR) by channel blockade has been demonstrated with a variety of large organic cations, including several nicotinic agonists. We have studied the kinetics of channel blocking of a series of agonists which vary systematically in size and hydrophobicity due to a hydrocarbon chain from one to six carbons in length, as well as one agonist with a tertiary isomer of one hydrocarbon chain. Single-channel recording was used in combination with three different analysis techniques for determining the kinetic and equilibrium parameters of channel blockade. With an increasing number of methylenes, the blocking rates were essentially constant and the unblocking rates decreased exponentially. This is consistent with studies of the blocking properties of alcohols at the nAChR channel. Also, a linear decrease in the depth to which the larger agonists penetrate the membrane spanning region of the channel was observed. The three smaller agonists, however, all traverse approximately 75% of the membrane field, in agreement with previous measurements of the location of the narrowest region of the channel, the selectivity filter. Images FIGURE 9
Carter, A A; Oswald, R E
La volatilité des prix sur les marchés agricoles - Etat des lieux, répercussions sur la sécurité alimentaire, réponse politiques
Les récentes périodes de forte volatilité des prix sur les marchés agricoles mondiaux présagent de l'accroissement et de la fréquence des menaces pour la sécurité alimentaire mondiale. Afin de réduire la vulnérabilité des pays, les politiques devraient améliorer le fonctionnement des marchés et préparer les pays ŕ mieux faire face aux effets néfastes de la forte volatilité des prix.
Novel delta opioid receptor agonists with oxazatricyclodecane structure.
We synthesized compounds 4a,c-f,h,i containing the oxazatricyclodecane structure from a novel rearrangement reaction product 2a. All the prepared compounds 4a,c-f,h,i exhibited full agonistic activities for the ? opioid receptor (DOR). Among them, the N-methyl derivative 4c was highly selective, and the most effective DOR agonist in functional assays. Subcutaneous administration of 4c produced dose-dependent and NTI (selective DOR antagonist)-reversible antinociception lacking any convulsive behaviors in the mice acetic acid writhing tests. The N-methyl derivative 4c is expected to be a promising lead compound for selective DOR agonists with a novel chemotype. PMID:24900842
Fujii, Hideaki; Hayashida, Kohei; Saitoh, Akiyoshi; Yokoyama, Akinobu; Hirayama, Shigeto; Iwai, Takashi; Nakata, Eriko; Nemoto, Toru; Sudo, Yuka; Uezono, Yasuhito; Yamada, Mitsuhiko; Nagase, Hiroshi
Alzheimer's Disease is characterized by the deposition of ?-amyloid within the brain parenchyma and is accompanied by the impairment of neuronal metabolism and function, leading to extensive neuronal loss. The disease involves the perturbation of synaptic function, energy and lipid metabolism. The development of amyloid plaques results in the induction of microglial-mediated inflammatory response. The nuclear receptor PPAR? is a ligand-activated transcription factor whose biological actions are to regulate glucose and lipid metabolism and suppress inflammatory gene expression. Thus, agonists of this receptor represent an attractive therapeutic target for AD. There is now an extensive body of evidence that has demonstrated the efficacy of PPAR? agonists in ameliorating disease–related pathology and improved learning and memory in animal models of AD. Recent clinical trials of the PPAR? agonist rosiglitazone have shown significant improvement in memory and cognition in AD patients. Thus, PPAR? represents an important new therapeutic target in treating AD.
Landreth, Gary; Jiang, Qingguang; Mandrekar, Shweta; Heneka, Michael
Principles of agonist recognition in Cys-loop receptors
Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine, and GABA. After the term "chemoreceptor" emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies, and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands.
Lynagh, Timothy; Pless, Stephan A.
Optimization of GPR40 Agonists for Type 2 Diabetes.
GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (1), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and identified AMG 837 (2) as a clinical candidate. Here we report our efforts in searching for structurally distinct back-ups for AMG 837. These efforts led to the identification of more polar GPR40 agonists, such as AM-4668 (10), that have improved potency, excellent pharmacokinetic properties across species, and minimum central nervous system (CNS) penetration. PMID:24900872
Liu, Jiwen Jim; Wang, Yingcai; Ma, Zhihua; Schmitt, Mike; Zhu, Liusheng; Brown, Sean P; Dransfield, Paul J; Sun, Ying; Sharma, Rajiv; Guo, Qi; Zhuang, Run; Zhang, Jane; Luo, Jian; Tonn, George R; Wong, Simon; Swaminath, Gayathri; Medina, Julio C; Lin, Daniel C-H; Houze, Jonathan B
Partager : des technologies de pointe au service de la société
Médecine, climatologie, métrologie et informatique, les techniques utilisées par le LHC trouvent déjŕ des répercussions dans d?autres domaines scientifiques. Utilisant des techniques inédites, la physique des particules en fait bénéficier la société toute entičre.
Le stress vu par les dirigeants ou tenir compte des représentations des acteurs pour améliorer la santé des salariés
La question du mal-ętre au travail, que ce soit sous l'angle du stress ou des suicides au travail récemment médiatisés, a brutalement fait irruption dans l'agenda stratégique des dirigeants. Afin d'améliorer la santé des salariés et de promouvoir leur bien ętre, il est utile de s'appuyer sur les travaux existants en matičre d'interventions de gestion du stress (notamment Brun et
Stéphan Pezé
Propogation Des Singularites pour Des Operateurs dont La Matrice Foundament contient Des Valeurs propres non Purement Imaginaires
L'objectif de ce travail est de prouver un résultat de propagation des singularité pour certains opérateurs pseudo–différentiels dont les caractéristiques doubles sont symplectiques et tels que la seule valeur propre purement imaginaire de la matrice foundamentale soit zéro. Il s'agit du probl´me du croisement symplectique. Lorsque la condimension de la variét´ des caractéeristiques dubles est 2, l'opérateur admet des directions
B. Lascar; R. Lascar
Switching cannabinoid response from CB(2) agonists to FAAH inhibitors.
A series of 3-carboxamido-5-aryl-isoxazoles designed as CB2 agonists were evaluated as FAAH inhibitors. The pharmacological results led to identify structure-activity relationships enabling to switch cannabinoid response from CB2 agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB2 activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that compounds 10 and 11 inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD. PMID:24508127
Tourteau, Aurélien; Leleu-Chavain, Natascha; Body-Malapel, Mathilde; Andrzejak, Virginie; Barczyk, Amélie; Djouina, Madjid; Rigo, Benoit; Desreumaux, Pierre; Chavatte, Philippe; Millet, Régis
Therapeutic potential of histamine H3 receptor agonists and antagonists.
The histamine H3 receptor was discovered 15 years ago, and many potent and selective H3 receptor agonists and antagonists have since been developed. Currently, much attention is being focused on the therapeutic potential of H3 receptor ligands. In this review, Rob Leurs, Patrizio Blandina, Clark Tedford and Henk Timmerman describe the available H3 receptor agonists and antagonists and their effects in a variety of pharmacological models in vitro and in vivo. The possible therapeutic applications of the various compounds are discussed. PMID:9652190
Leurs, R; Blandina, P; Tedford, C; Timmerman, H
Nature et origine des phénocristaux de quartz des laves de Martinique, Petites Antilles
Résumé Les laves de la Martiniques se répartissent en deux séries de roches volcaniques (Westercamp, 1972, 1973): la série des high-alumina basalts qui résulte d'un processus de cristallisation fractionnée et la série calc-alcaline\\u000a faiblement potassique qui résulte de la contamination du précédent magma par des roches riches en silice et alumine.\\u000a \\u000a L'étude des inclusions vitreuses et minérales des phénocristaux de quartz
R. Clocchiatti; D. Westercamp
La croissance des PME par le biais des ressources et compétences : quelles voies ?
Les PME sont des organisations particuličres, bien différentes par rapport ŕ la grande entreprise. Les PME en croissance sont vues comme des vrais leviers pour la création d'emploi et de richesse dans une économie. La croissance des PME est alimentée soit par les nouvelles ressources générées dans l'entreprise pendant le processus de croissance, soit par l'apport externe des ressources (par
A. E Popa Postariu
Partage des coűts et tarification des infrastructures : Enjeux, problématique et pertinence
La plupart des organisations, sinon toutes, répartissent d'une maničre ou d'une autre des coűts communs entre leurs diverses composantes ou encore entre leurs différents partenaires. Ces problčmes de partage de coűts communs se posent avec de plus en plus d'acuité car les rčgles de partage des coűts communs sont des facteurs importants de compétitivité et de performance. Bien que leur
Marcel Boyer; Michel Moreaux; Michel Truchon
Activation of single heteromeric GABAA receptor ion channels by full and partial agonists
The linkage between agonist binding and the activation of a GABAA receptor ion channel is yet to be resolved. This aspect was examined on human recombinant ?1?2?2S GABAA receptors expressed in human embryonic kidney cells using the following series of receptor agonists: GABA, isoguvacine, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), isonipecotic acid, piperidine-4-sulphonic acid (P4S), imidazole-4-acetic acid (IAA), 5-(4-piperidyl)-3-isothiazolol (thio-4-PIOL) and 5-(4-piperidyl)-3-isoxazolol (4-PIOL). Whole-cell concentration–response curves enabled the agonists to be categorized into four classes based upon their maximum responses. Single channel analyses revealed that the channel conductance of 25–27 pS was unaffected by the agonists. However, two open states were resolved from the open period distributions with mean open times reduced 5-fold by the weakest partial agonists. Using saturating agonist concentrations, estimates of the channel shutting rate, ?, ranged from 200 to 600 s?1. The shut period distributions were described by three or four components and for the weakest partial agonists, the interburst shut periods increased whilst the mean burst durations and longest burst lengths were reduced relative to the full agonists. From the burst analyses, the opening rates for channel activation, ?, and the total dissociation rates, k?1, for the agonists leaving the receptor were estimated. The agonist efficacies were larger for the full agonists (E ?7?9) compared to the weak partial agonists (?0.4–0.6). Overall, changes in agonist efficacy largely determined the different agonist profiles with contributions from the agonist affinities and the degree of receptor desensitization. From this we conclude that GABAA receptor activation does not occur in a switch-like manner since the agonist recognition sites are flexible, accommodating diverse agonist structures which differentially influence the opening and shutting rates of the ion channel.
Mortensen, Martin; Kristiansen, Uffe; Ebert, Bjarke; Fr?lund, Bente; Krogsgaard-Larsen, Povl; Smart, Trevor G
OzDES Spectroscopic Classification of DES transients
NASA Astrophysics Data System (ADS)
We report spectroscopic classification by OzDES of supernovae discovered by the Dark Energy Survey (ATel #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT). Object classifications were performed with SNID (Blondin & Tonry, 2007, ApJ, 666, 1024), details of which are reported in the table below.
Childress, M.; Sharp, R.; Yuan, F.; Uddin, S.; Kuehn, K.; Lidman, C.; Davis, T. M.; Parkinson, D.; Fine, S.; Martini, P.; Covarrubias, R. A.; Cane, R.; Fischer, J. A.; Gladney, L.; March, M.; Sako, M.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; D'Andrea, C.; Nichol, R.; Papadopoulos, A.; Sullivan, M.; Maartens, R.; Smith, M.; Barbary, K.; Bernstein, J. P.; Biswas, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Bloom, J. S.; Goldstein, D.; Kim, A.; Nugent, P.; Perlmutter, S.; Thomas, R. C.; Foley, R. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.
OzDES Spectroscopic Classification of DES Transients
NASA Astrophysics Data System (ADS)
We report spectroscopic classification by OzDES of supernovae discovered by the Dark Energy Survey (ATel #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT). Object classifications were performed with SNID (Blondin & Tonry, 2007, ApJ, 666, 1024), details of which are reported in the table below.
Yuan, F.; Childress, M.; Sharp, R.; Lagattuta, D. J.; Uddin, S.; Davis, T. M.; Lidman, C.; Cane, R.; Fischer, J. A.; Gladney, L.; March, M.; Sako, M.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; D'Andrea, C.; Nichol, R.; Papadopoulos, A.; Sullivan, M.; Maartens, R.; Smith, M.; Barbary, K.; Bernstein, J. P.; Biswas, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Bloom, J. S.; Goldstein, D.; Kim, A.; Nugent, P.; Perlmutter, S.; Thomas, R. C.; Foley, R. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Covarrubias, R. A.
Aktuelle Weiterentwicklungen auf dem Gebiet des UDK
1 Abstrakt Der Umweltdatenkatalog (UDK) ist ein de-facto Standard für Metadaten im Umwelt- bereich. In diesem Artikel werden die neusten Entwicklungen des UDK beschrieben. Neben einer Reihe von Verbesserungen auf dem Gebiet der Recherche wurden seit der Version 4.2 alle internen und externen Schnittstellen sowohl des Windows- als auch des WWW-UDK auf XML umgestellt. Zu diesem Zweck wurde eine eigene
Fred Kruse
Estradiol and ER? agonists enhance recognition memory, and DPN, an ER? agonist, alters brain monoamines
Effects of estradiol benzoate (EB), ER?-selective agonist, propyl pyrazole triol (PPT) and ER?-selective agonists, diarylpropionitrile (DPN) and Compound 19 (C-19) on memory were investigated in OVX rats using object recognition (OR) and placement (OP) memory tasks. Treatments were acute (behavior 4 h later) or sub chronic (daily injections for 2 days with behavior 48 h later). Objects were explored in sample trials (T1), and discrimination between sample (old) and new object/location in recognition trials (T2) was examined after 2–4 h inter-trial delays. Subjects treated sub chronically with EB, DPN, and C-19, but not PPT, discriminated between old and new objects and objects in old and new locations, suggesting that, at these doses and duration of treatments, estrogenic interactions with ER? contributes to enhancements in recognition memory. Acute injections of DPN, but not PPT, immediately after T1, also enhanced discrimination for both tasks (C19 was not investigated). Effects of EB, DPN and PPT on anxiety and locomotion, measured on elevated plus maze and open field, did not appear to account for the mnemonic enhancements. Monoamines and metabolites were measured following DPN treatment in subjects that did not receive behavioral testing. DPN was associated with alterations in monoamines in several brain areas: indexed by the metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), or the MHPG/norepinephrine (NE) ratio, NE activity was increased by 60–130% in the prefrontal cortex (PFC) and ventral hippocampus, and NE activity was decreased by 40–80% in the v. diagonal bands and CA1. Levels of the dopamine (DA) metabolite, homovanillic acid (HVA), increased 100% in the PFC and decreased by 50% in the dentate gyrus following DPN treatment. The metabolite of serotonin, 5-hydroxyindole acetic acid (5-HIAA), was increased in the PFC and CA3, by approximately 20%. No monoaminergic changes were noted in striatum or medial septum. Results suggest that ER? mediates sub chronic and acute effects of estrogens on recognition memory and that memory enhancements by DPN may occur, in part, through alterations in monoaminergic containing systems primarily in PFC and hippocampus.
Jacome, Luis F.; Gautreaux, Claris; Inagaki, Tomoko; Mohan, Govini; Alves, Stephen; Lubbers, Laura S.; Luine, Victoria
Environnement des Systčmes Binaires Jeunes
NASA Astrophysics Data System (ADS)
La fréquence élevée des systčmes binaires, tant parmi les étoiles de la séquence principale que dans les régions de formation stellaire, a été largement mise en évidence au cours des dix derničres années. Cette constatation soulčve naturellement la question de la nature du processus responsable de la formation préférentielle de ces systčmes multiples. Par ailleurs, les phénomčnes d'interaction entre un compagnon et l'environnement complexe d'une étoile T Tauri sont encore trčsmal compris. C'est dans ce cadre que se place le travail conduit durant cette thčse, dont les principaux objectifs sont: i) la détermination de la fraction de binaires dans différentes populations pré-séquence principale, ii) l'étude quantitative du phénomčne d'accrétion dans les systčmes binaires T Tauri, et iii) l'observation directe et la modélisation de disques circumstellaires et circumbinaires. Dans le cadre d'une recherche de binaires visuelles ŕ l'aide du systčme d'optique adaptative du Télescope Canada-France-Hawaii, j'ai pris part ŕ l'observation de plusieurs centaines d'objets situés dans différents amas stellaires jeunes. Je détaille ici l'analyse et les résultats concernant deux amas âgés de moins de deux millions d'années. Lorsqu'on considčre l'ensemble des populations étudiées jusqu'ŕ présent, on constate que la proportion de binaires visuelles parmi les étoiles de type solaire est la męme dans les amas stellaires que sur la séquence principale. De plus, cette propriété ne dépend pas de l'âge de l'amas, ce qui implique que la fraction de binaires n'évolue pas aprčs le premier million d'années dans ces amas. A l'opposé, les zones de formation peu denses, qui sont toutes trčs jeunes, possčdent une proportion de binaires sensiblement plus élevée. Les modčles les plus ŕ męme de reproduire ces observations sont ceux selon lesquels la fraction de binaires qui résulte de l'effondrement gravitationnel est proche de 100%. Dans les amas les plus denses, cette fraction peut ensuite ętre rapidement réduite du fait des nombreuses interactions gravitationnelles destructrices entre systčmes proches. D'autres interprétations restent toutefois envisageables. Je m'intéresse ensuite au phénomčne d'accrétion dans les binaires T Tauri par la spectroscopie visible des composantes de ces systčmes. Cette approche révčle que le phénomčne d'accrétion perdure aussi longtemps sur les deux composantes d'une męme binaire. De plus, la comparaison des luminosités émises dans la raie H? montre que le primaire présente généralement le taux d'accrétion le plus élevé. Une interprétation possible de ces observations est que ces binaires possčdent des réservoirs circumbinaires de matičre, probablement sous la forme d'une vaste enveloppe, qui alimentent simultanément les deux disques circumstellaires. Enfin, je présente des images ŕ haute résolution angulaire des disques circumbinaires de GG Tau et UY Aur et des disques circumstellaires de HK Tau B et HV Tau C. Ces observations, obtenues dans le visible, le proche infrarouge et le domaine radio, permettent une description fine de l'environnement de ces binaires. Je détaille également l'analyse de cartes de polarisation des deux disques circumbinaires obtenues ŕ 1 micron. Afin de déterminer les propriétés géométriques de ces disques et celles des grains de poussičre qui s'y trouvent, j'ai entrepris une modélisation de la diffusion multiple de la lumičre en utilisant une approche Monte-Carlo. Cette étude indique que l'anneau circumbinaire de GG Tau est géométriquement épais (avec un rapport d'aspect h/r~0.18), qu'il comporte des grains de poussičre trčs petits (<1 micron) et que la masse totale de poussičre dans l'anneau est au moins 10-3 masses solaires. L'environnement de UY Aur apparaît beaucoup plus complexe que celui de GG Tau: le disque circumbinaire, dont l'inclinaison est ré-évaluée ŕ environ 60 degrés, coexiste avec un filament situé ŕ proximité mais distinct, et plusieurs "branches&qu
Duchene, Gaspard
Characterization of des-Arg9-bradykinin-induced contraction in guinea-pig gallbladder in vitro.
We have reported that bradykinin induces graded contraction in guinea-pig gallbladder in vitro through activation of bradykinin B2 receptors and prostanoid release, while des-Arg9-bradykinin, a selective bradykinin B1 receptor agonist, causes only a weak contraction, suggesting the presence of badykinin B1 receptors in this tissue. In the present study, we attempted to characterise the receptor subtype and the possible mechanism by which des-Arg9-bradykinin induces contraction in this preparation. Contractions induced by des-Arg9-bradykinin in guinea-pig gallbladder (1 pM to 1 microM) increased significantly as a function of time elapsed after setting up of the preparation, reaching the maximum after 6 h of equilibration (EC50 16.4 pM and Emax 0.6 +/- 0.08 g). Des-Arg9-bradykinin-induced contraction in guinea-pig gallbladder was totally prevented by cycloheximide (70 microM, an inhibitor of protein synthesis), indomethacin (3 microM), ibuprofen (30 microM), phenidone (30 microM) or Ca2+-free medium plus EGTA, and was partially antagonised by MK 571 ((3-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl ((3-dimethyl amino-3-oxo-propyl) thio) methyl) propanoic acid, 0.1 microM) or by nicardipine (1 microM), but was not affected by dazoxiben (30 microM), staurosporine (100 nM) or L 655,240 (240 (3-[1-(4-clorobenzil)-5-fluoro-3-metilhyindol-2il] 2,2-dimetilpropanoic acid, 1 microM). Unexpectedly, des-Arg9-bradykinin-induced contraction was unaffected by the selective bradykinin B1 receptor antagonists, des-Arg9-[Leu8]-bradykinin and des-Arg9-NPC 17761 (des-Arg0-D-Arg [Hip3, D-HipE (transtiofenil)7, Oic8]-des-Arg9-bradykinin). However, the selective bradykinin B2 receptor antagonists, HOE 140 (D-Arg0-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) and NPC 17731 (D-Arg0 [Hyp3, DHypE (transpropyl)7, Oic8]-bradykinin), completely blocked des-Arg9-bradykinin-mediated contraction. Pre-treatment of the animals with Escherichia coli endotoxin (lipopolysaccharide, 30 microg/animal, i.v., 24 h) did not significantly change the response to des-Arg9-bradykinin induction. It is concluded that des-Arg9-bradykinin-induced contractions in guinea-pig gallbladder are mediated primarily by the release of proinflammatory eicosanoid(s) derived from the cyclo-oxygenase pathway. These effects are unrelated to thromboxane A2 and do not seem to be coupled to activation of a protein kinase C-dependent mechanism. Response to des-Arg9-bradykinin increases as a function of the equilibration period of the preparation by a mechanism dependent on protein synthesis and seems to be mediated by activation of bradykinin B2 (but not B1) receptors. Finally, in contrast to that observed for bradykinin, the contraction induced by des-Arg9-bradykinin in guinea-pig gallbladder is fully dependent on the influx of extracellular Ca2+, partially through L-type Ca2+ channels. PMID:9274927
Cabrini, D A; Calixto, J B
Pheromonfallen zur Bestimmung des Apfelwicklerfluges
Zusammenfassung Pheromonfallen zur Prognose von Wicklerflügen im Obstbau werden seit 1971 in Süddeutschland verwendet. Die Fallen- und Anwendungstechniken\\u000a sowie die Ergebnisse von dreijährigen Freilandversuchen mit Lockstoffen beim ApfelwicklerLaspeyresia pomonella L. im Vergleich zu Lichtfallen werden vorgestellt. Dabei sind synthetische Lockstoffe fängiger als lebende Weibchen. Die\\u000a Fangmethode hat sich im Apfelwicklerwarndienst zur Feststellung des örtlichen und zeitlichen Flugverlaufs bewährt und kann\\u000a nun
G. Neuffer
Evaluation of PPAR? agonists on rodent endothelial cell proliferation
The PPAR? agonist troglitazone (TG) induced an increased incidence of hemangiosarcomas in mice but was not carcinogenic in rats. In contrast, pioglitazone (PIO) did not induce hemangiosarcomas or any other tumors in mice. We previously demonstrated that TG increased the proliferation of endothelial cells (ECs) in liver and adipose tissue in mice, and acted as a mitogenic stimulant and an
Satoko Kakiuchi-Kiyota; Lora L. Arnold; Masanao Yokohira; Shugo Suzuki; Karen L. Pennington; Samuel M. Cohen
FPL 63012AR: a potent D1-receptor agonist.
1. FPL 63012AR is a D1-receptor agonist in the dog kidney, 10 times as potent as dopamine, reducing renal vascular resistance by 20% with an intra-arterial dose of 0.42 nmol kg-1. 2. No prejunctional inhibitory D2-receptor agonist activity was detected in either the isolated ear artery of the rabbit or in the conscious dog as D2-receptor-mediated emesis. 3. Unlike dopamine, FPL 63012AR had no significant agonist activity at alpha 1-, alpha 2-, beta 1- or beta 2-adrenoceptors. 4. FPL 63012AR is a potent inhibitor of [3H]-noradrenaline uptake (Uptake1) into brain synaptosomes, with an IC50 of 29.5 nM, i.e. 9.2 times more potent than dopamine. 5. The ability to block Uptake1, in the anaesthetised dog was confirmed by inhibition of the tyramine-induced pressor and inotropic responses. 6. Intravenous infusion of FPL 63012AR in anaesthetized and conscious dogs (0.3 to 3 nmol kg-1 min-1) reduced vascular resistance and increased blood flow to the kidney which was accompanied by hypotension and tachycardia. 7. It is concluded that FPL 63012AR is an example of a novel class of potent agonists at the D-receptor. Such compounds may have the potential for use clinically in improving renal perfusion and reducing afterload.
Smith, G. W.; Farmer, J. B.; Ince, F.; Matu, K.; Mitchell, P. D.; Naya, I.; Springthorpe, B.
Melanocortin - 4 Receptor Agonists for the Treatment of Obesity
The melanocortin family of receptors (MC 1 - 5R) and their endogenous peptide ligands (? , ? , ? - MSH and ACTH) have been implicated in the control of a wide variety of behavioral and physiological functions including the homeostatic control of food intake and body weight. In rodent models, melanocortin agonists including the nonselective peptide MTII have been
Paul J. Emmerson; Matthew J. Fisher; Liang Zeng Yan; John P. Mayer
Effects of melanocortin 1 receptor agonists in experimental nephropathies.
Nephrotic syndrome, characterized by massive proteinuria, is caused by a large group of diseases including membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS). Although the underlying mechanisms are beginning to unravel, therapy is unspecific and far from efficient. It has been suggested that adrenocorticotropic hormone (ACTH) has beneficial effects in patients with MN and possibly in other nephrotic diseases. We have previously reported that ACTH may act directly on podocytes through the melanocortin 1 receptor (MC1R). In the present study, we evaluate the effect of highly specific MC1R agonists in two different nephrotic disease models. Experimental MN: Passive Heymann nephritis (PHN) was induced in rats that were treated for four weeks with MS05, a selective MC1R agonist, or saline. The degree of albuminuria was significantly reduced over time and the effect was sustained one week after treatment withdrawal (p<0.05). Experimental FSGS: Based on a dose-response study, two doses of adriamycin were used for induction of nephropathy in Balb/c mice. Mice were treated with either a synthetic MC1R agonist (BMS-470539), with ?-melanocyte stimulating hormone (?-MSH) or with saline. There was no beneficial effect of treatment. In summary, MC1R agonists reduce albuminuria and improve morphology in experimentally induced MN whereas they have no effect in experimental FSGS. The results illustrate the differences in these podocytopathies in terms of signaling mechanisms underlying proteinuria, and progression of disease. PMID:24498203
Lindskog Jonsson, Annika; Granqvist, Anna; Elvin, Johannes; Johansson, Martin E; Haraldsson, Börje; Nyström, Jenny
Thienopyrimidines as ?3-adrenoceptor agonists: hit-to-lead optimization.
Resulting from a vHTS based on a pharmacophore alignment on known ?3-adrenoceptor ligands, an aryloxypropanolamine scaffold comprising a thienopyrimidine moiety was further optimized as a human ?3-AR agonist, yielding a lead compound with an excellent cellular activity of EC(50)=20 pM, selectivity over h?1- and h?2-adrenoceptors and a promising safety profile. PMID:20833036
Tasler, Stefan; Baumgartner, Roland; Ammendola, Astrid; Schachtner, Josef; Wieber, Tanja; Blisse, Marcus; Rath, Sandra; Zaja, Mirko; Klahn, Philipp; Quotschalla, Udo; Ney, Peter
Pathological behaviors provoked by dopamine agonist therapy of Parkinson's disease.
The dopamine agonist medications, pramipexole and ropinirole, are commonly used to treat Parkinson's disease. These two drugs have a highly specific affinity for cerebral D3 receptors, known to be localized to the mesolimbic system. Herein is described a common side effect of these drugs, encountered in our routine clinical practice: pathological behaviors. This includes excessive gambling, hypersexuality, shopping, hyperphagia or obsessive hobbying, which may develop in up to 30% of people taking higher agonist doses. In contrast, treatment with the dopamine precursor, levodopa, in the absence of D3 agonist therapy very rarely provokes such behavioral syndromes. Although these agonist-induced behaviors have been called "impulse control disorders", the problem is not simply loss of impulse control, but rather a novel obsessive-compulsion directed at one or a few behaviors, often taking on pathological proportions. This experience points to the dopamine D3 receptor as a potential therapeutic target for gambling, sex or other addictions occurring spontaneously in the general population. PMID:21557955
Ahlskog, J Eric
Chemotype-selective modes of action of ?-opioid receptor agonists.
The crystal structures of opioid receptors provide a novel platform for inquiry into opioid receptor function. The molecular determinants for activation of the ?-opioid receptor (KOR) were studied using a combination of agonist docking, functional assays, and site-directed mutagenesis. Eighteen positions in the putative agonist binding site of KOR were selected and evaluated for their effects on receptor binding and activation by ligands representing four distinct chemotypes: the peptide dynorphin A(1-17), the arylacetamide U-69593, and the non-charged ligands salvinorin A and the octahydroisoquinolinone carboxamide 1xx. Minimally biased docking of the tested ligands into the antagonist-bound KOR structure generated distinct binding modes, which were then evaluated biochemically and pharmacologically. Our analysis identified two types of mutations: those that affect receptor function primarily via ligand binding and those that primarily affect function. The shared and differential mechanisms of agonist binding and activation in KOR are further discussed. Usually, mutations affecting function more than binding were located at the periphery of the binding site and did not interact strongly with the various ligands. Analysis of the crystal structure along with the present results provide fundamental insights into the activation mechanism of the KOR and suggest that "functional" residues, along with water molecules detected in the crystal structure, may be directly involved in transduction of the agonist binding event into structural changes at the conserved rotamer switches, thus leading to receptor activation. PMID:24121503
Vardy, Eyal; Mosier, Philip D; Frankowski, Kevin J; Wu, Huixian; Katritch, Vsevolod; Westkaemper, Richard B; Aubé, Jeffrey; Stevens, Raymond C; Roth, Bryan L
Identification of tertiary sulfonamides as RORc inverse agonists.
Screening a nuclear receptor compound subset in a RORc biochemical binding assay revealed a benzylic tertiary sulfonamide hit. Herein, we describe the identification of compounds with improved RORc biochemical inverse agonist activity and cellular potencies. These improved compounds also possessed appreciable selectivity for RORc over other nuclear receptors. PMID:24685544
Fauber, Benjamin P; René, Olivier; Burton, Brenda; Everett, Christine; Gobbi, Alberto; Hawkins, Julie; Johnson, Adam R; Liimatta, Marya; Lockey, Peter; Norman, Maxine; Wong, Harvey
Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism
Binding to helix 12 of the ligand-binding domain of PPAR{gamma} is required for full agonist activity. Previously, the degree of stabilization of the activation function 2 (AF-2) surface was thought to correlate with the degree of agonism and transactivation. To examine this mechanism, we probed structural dynamics of PPAR{gamma} with agonists that induced graded transcriptional responses. Here we present crystal structures and amide H/D exchange (HDX) kinetics for six of these complexes. Amide HDX revealed each ligand induced unique changes to the dynamics of the ligand-binding domain (LBD). Full agonists stabilized helix 12, whereas intermediate and partial agonists did not at all, and rather differentially stabilized other regions of the binding pocket. The gradient of PPAR{gamma} transactivation cannot be accounted for solely through changes to the dynamics of AF-2. Thus, our understanding of allosteric signaling must be extended beyond the idea of a dynamic helix 12 acting as a molecular switch.
Bruning, J.B.; Chalmers, M.J.; Prasad, S.; Bushby, S.A.; Kamenecka, T.A.; He, Y.; Nettles, K.W.; Griffin, P.R.
beta(3)-Adrenoceptor agonists: potential, pitfalls and progress.
beta(3)-Adrenoceptor agonists are very effective thermogenic anti-obesity and insulin-sensitising agents in rodents. Their main sites of action are white and brown adipose tissue, and muscle. beta(3)-Adrenoceptor mRNA levels are lower in human than in rodent adipose tissue, and adult humans have little brown adipose tissue. Nevertheless, beta(3)-adrenoceptors are expressed in human white as well as brown adipose tissue and in skeletal muscle, and they play a role in the regulation of energy balance and glucose homeostasis. It is difficult to identify beta(3)-adrenoceptor agonist drugs because the pharmacology of both beta(3)- and beta(1)-adrenoceptors can vary; near absolute selectivity is needed to avoid beta(1/2)-adrenoceptor-mediated side effects and selective agonists tend to have poor oral bioavailability. All weight loss is lipid and lean may actually increase, so reducing weight loss relative to energy loss. beta(3)-adrenoceptor agonists have a more rapid insulin-sensitising than anti-obesity effect, possibly because stimulation of lipid oxidation rapidly lowers intracellular long-chain fatty acyl CoA and diacylglycerol levels. This may deactivate those protein kinase C isoenzymes that inhibit insulin signalling. PMID:12007528
Arch, Jonathan R S
Discovery of Tertiary Amine and Indole Derivatives as Potent ROR?t Inverse Agonists.
A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (ROR?t) inverse agonists was discovered through agonist/inverse agonist conversion. The level of ROR?t inhibition can be enhanced by modulating the conformational disruption of H12 in ROR?t LBD. Linker exploration and rational design led to the discovery of more potent indole-based ROR?t inverse agonists. PMID:24900774
Yang, Ting; Liu, Qian; Cheng, Yaobang; Cai, Wei; Ma, Yingli; Yang, Liuqing; Wu, Qianqian; Orband-Miller, Lisa A; Zhou, Ling; Xiang, Zhijun; Huxdorf, Melanie; Zhang, Wei; Zhang, Jing; Xiang, Jia-Ning; Leung, Stewart; Qiu, Yang; Zhong, Zhong; Elliott, John D; Lin, Xichen; Wang, Yonghui
Innate Immune Responses to TLR2 and TLR4 Agonists Differ between Baboons, Chimpanzees and Humans
Background African catarrhine primates differ in bacterial disease susceptibility. Methods Human, chimpanzee, and baboon blood was stimulated with TLR-detected bacterial agonists and cytokine/chemokine induction assessed by real-time pcr. Results Humans and chimpanzees shared similar cytokine/chemokine responses, while baboon cytokine/chemokine induction differed. Generally, responses were agonist-independent. Conclusions These primates tend to generate species rather than agonist–specific responses to bacterial agonists.
Brinkworth, Jessica F.; Pechenkina, Ekaterina A.; Silver, Jack; Goyert, Sanna M.
Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists.
SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID:23916594
Gilmore, John L; Sheppeck, James E; Wang, Jim; Dhar, T G Murali; Cavallaro, Cullen; Doweyko, Arthur M; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Nadler, Steven G; Dodd, John H; Somerville, John E; Barrish, Joel C
Identification of raloxifene as a novel CB2 inverse agonist.
The purpose of the current study was to apply a high throughput assay to systematically screen a library of food and drug administration (FDA)-approved drugs as potential ligands for the cannabinoid receptor 2 (CB2). A cell-based, homogenous time resolved fluorescence (HTRF) method for measuring changes in intracellular cAMP levels was validated and found to be suitable for testing ligands that may act on CB2. Among the 640 FDA-approved drugs screened, raloxifene, a drug used to treat/prevent post-menopausal osteoporosis, was identified for the first time to be a novel CB2 inverse agonist. Our results demonstrated that by acting on CB2, raloxifene enhances forskolin-stimulated cAMP accumulation in a concentration-dependant manner. Furthermore, our data showed that raloxifene competes concentration-dependently for specific [(3)H]CP-55,940 binding to CB2. In addition, raloxifene pretreatment caused a rightward shift of the concentration-response curves of the cannabinoid agonists CP-55,940, HU-210, and WIN55,212-2. Raloxifene antagonism is most likely competitive in nature, as these rightward shifts were parallel and were not associated with any changes in the efficacy of cannabinoid agonists on CB2. Our discovery that raloxfiene is an inverse agonist for CB2 suggests that it might be possible to repurpose this FDA-approved drug for novel therapeutic indications for which CB2 is a target. Furthermore, identifying raloxifene as a CB2 inverse agonist also provides important novel mechanisms of actions to explain the known therapeutic effects of raloxifene. PMID:23611779
Kumar, Pritesh; Song, Zhao-Hui
Le gouvernement des universités françaises: transversalités des champs d'analyse et réflexion sur les compétences des managers universitaires
Le milieu de l'enseignement supérieur français se caractérise par une évolution rapide et une transformation profonde et ce depuis plusieurs décennies. Intégrées au service public de l'Etat, les universités françaises ont gagné leur autonomie institutionnelle mais le pilotage reste centralisé. Dans un contexte de modernisation des établissements universitaires, de leur autonomie et politiques de contractualisation, la question du gouvernement des
Ramzi Maamer
Analyse des impacts financiers, organisationnels et marketing des normes IFRS dans le secteur des assurances
Au détour de conférences et selon les dires de la plupart des directeurs financiers de groupes d'assurances confrontés aux normes IFRS, leur implémentation est ou a été la relčve d'un véritable défi. Outre le challenge lié ŕ la compréhension et ŕ l'application de ces normes, l'adoption du référentiel international a généré de nombreux coűts et a engendré divers changements organisationnels.
Frédéric Chandelle; Jacqueline Haverals
Interactions between ?-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration
Cannabinoid receptor agonists enhance the antinociceptive effects of ?-opioid receptor agonists, which suggests that combinations of these drugs might enhance therapeutic effectiveness (e.g., analgesia). However, it is not clear whether combinations of these drugs also enhance abuse or dependence liability. This experiment examined whether combinations of cannabinoids and opioids that enhance antinociception also increase abuse-related effects by studying the effects of the cannabinoid receptor agonists 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP 55,940) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212) on the antinociceptive, discriminative stimulus, and positive reinforcing effects of ?-opioid receptor agonists in rhesus monkeys. In one group of monkeys (n = 3), morphine (0.1–5.6 mg/kg s.c.), CP 55,940 (0.0032–0.032 mg/kg s.c.), and WIN 55,212 (0.1–1.0 mg/kg s.c.) dose-dependently increased tail withdrawal latency from 50°C water, and pretreatment with small, otherwise ineffective, doses of CP 55,940 and WIN 55,212 shifted the morphine dose-effect curve to the left. In monkeys (n = 3) discriminating 3.2 mg/kg morphine, CP 55,940 (0.01–0.032 mg/kg s.c.) and WIN 55,212 (0.1–1.78 mg/kg s.c.) attenuated the discriminative stimulus effects of morphine, shifting the dose-effect curve to the right. In monkeys (n = 4) self-administering heroin (0.32–32.0 µg/kg/infusion i.v.), CP 55,940 (0.001–0.032 mg/kg s.c.), and WIN 55,212 (0.1–1.0 mg/kg s.c.) shifted the heroin dose-effect curve rightward and downward. Cannabinoid receptor agonists CP 55,940 and WIN 55,212 enhanced the antinociceptive effects but not the discriminative stimulus or positive reinforcing effects of ?-opioid receptor agonists in rhesus monkeys, supporting the view that combining cannabinoid and opioid receptor agonists might result in enhanced treatment effectiveness for pain without similarly enhancing abuse and dependence liability.
Maguire, David R.; Yang, Wenjuan
Inhibition of dopamine neuron firing by pramipexole, a dopamine D 3 receptor-preferring agonist: comparison to other dopamine receptor agonists
Pramipexole, an amino-benzathiazole [(S)-4,5,6,7-tetrahydro-N-6-propyl-2,6-benzothiazolediamine dihydrochloride monohydrate] direct-acting dopamine receptor agonist effective in treating Parkinson's disease, bound selectively and with high affinity to dopamine D2-like receptors, with highest affinity at dopamine D3 receptors. Ergot dopamine receptor agonists (bromocriptine, lisuride, pergolide) bound to both dopamine and non-dopamine receptors. Although all agonists depressed dopamine neuron firing, only pramipexole and quinpirole completely silenced firing
Montford F. Piercey; William E. Hoffmann; Martin W. Smith; Deborah K. Hyslop
Structure des qualifications et échanges extérieurs français
[fre] Structure des qualifications et échanges extérieurs français . Selon la théorie du commerce international, les facteurs de production disponibles dans un pays déterminent la nature de ses échanges extérieurs. Dans ce cadre, et sous un certain nombre d'hypothčses, le lien entre la structure des emplois par qualifications et les échanges extérieurs est ici analysé pour la France en 1993.
Alain Gallais; Bernard Gautier
Azelluläre Matrix zur funktionellen Rekonstruktion des Urogenitaltraktes
Zusammenfassung Der Organersatz und die Rekonstruktion des Urogenitalsystem stellt noch immer ein Problem auf der Suche nach geeigneten Ersatzmaterialien dar. In der Regel werden organfremde Strukturen für die Rekonstruktion des Urogenitalsystems (Darmanteile, Wangenschleimhaut) verwandt. Diese organfremden Strukturen bedingen Nebenwirkungen, die sich aus dem Ursprungsort und der dortigen Funktion ergeben. Verschiedene Arbeitsgruppen konnten zeigen, dass azelluläre Matrices im Bereich der Harnblase
N. Schlote; J. Wefer; K.-D. Sievert
Neue Perspektiven zu den Anfängen des Aurignacien
Zusammenfassung: Zunächst werden verschiedene Modelle diskutiert, die sich mit der Ausbreitung anatomisch moderner Menschen in Europa sowie mit den Ursprüngen des Aurignacien befassen. Aus- gangspunkt für die im Anschluss daran präsentierte Sicht des Autors bilden seine technologischen Analysen frühjungpaläolithischer Steinartefaktinventare von vier wichtigen europäischen Fundplätzen: Bacho Kiro in Bulgarien, Willendorf II und Krems-Hundssteig in Österreich sowie Geißenklösterle in Deutschland. Der
Nicolas Teyssandier
Die "cortinähnliche" Wirkung des g-Strophanthins
Die Phosphatabnahme in Breien normaler Kaninchen- und Katzenmuskel blieb in Gegenwart des Strophanthins unverändert. Bei nebenniereninsuffizienten Katzen konnte die herabgesetzte Glykogenphosphorylierung durch Strophanthin nicht normalisiert werden. Das Strophanthin besitzt also das wichtigste Merkmal der Cortinwirkung nicht. Es ist also nicht berechtigt, über eine "cortinähnliche" Wirkung des Strophanthins zu sprechen.
E. Varga; E. Füzes; L. Kesztyüs
Receptor-binding and pharmacokinetic properties of dopaminergic agonists.
This review describes symptoms and pathophysiology of Parkinson's diseases (PD) and restless legs syndrome (RLS), and discusses the relationship between clinical outcome of DA agonists and their receptor-binding and pharmacokinetics. Oral DA agonists are divided into 2 classes; the ergots and the non-ergots. Both classes are in general equally effective against PD motor symptoms. Ergots (apart from bromocriptine) stimulate the DA D(1) subreceptor and increase dyskinesia. Furthermore, valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis appear to represent a class effect of 8beta-aminoergolines as cabergoline and pergolide The side effects profile therefore seems more beneficial for non-ergots than ergots. The main improvement of motor functions by DA agonists is related to D(2) agonism. However, in monotheraphy, the selective D(2)-receptor DA agonist sumanirole seemed less effective than ropinirole which is selective for D(2)-like DA-receptors (D(2), D(3) and D(4)). Given as adjunctive to L-dopa both drugs had equal efficacy on motor-symptoms, indicating that D(2)-receptor activity must be accompanied with stimulation of other DA receptors for optimizing the efficacy on motor symptoms. Striatal D(3) receptor loss may be more important than D(2) receptor loss for reduced response to dopaminergic treatment. D(3) stimulation may also be beneficial for the non-motor symptom depression/mood in PD and for neuron-protection. This makes D(3)-receptors a potential therapeutic target in PD. 5-HT(1A)-receptor agonism and alpha(2) adrenergic antagonism may contribute to prevention of dyskinesia. However, 5-HT-receptor activity is also associated with side effects. 5-HT(2B) agonism (and possibly 5-HT(1B) agonism) is associated with fibrotic reactions, and valvular heart disease (VHD). By interfering with the CYP450 system DA agonists may contribute to drug-drug interactions. Lack of CYP2D6 activity is also suggested as important for etiology and CNS-symptoms of PD. Based on current knowledge D2-like receptor activities (preferences for the D(3) receptor) seem most beneficial. 5-HT(1A)-receptor agonism (prevention of dyskinesia), 5-HT(2B) antagonism or no 5-HT(2B)-receptor activity also seems beneficial. Development of DA agonists containing these properties, without interfering with CYP2D6 may be beneficial. PMID:18691132
Kvernmo, Trond; Houben, John; Sylte, Ingebrigt
Innovation technologique, changements organisationnels et évolution des compétences
[fre] Innovation technologique, changements organisationnels et évolution des compétences . Une étude empirique sur l'industrie manufacturičre . Innovation technologique, changements dans l'organisation de la production et évolution des compétences sont fortement interdépendants. Pour dresser un état des lieux de ces différents types de changements et analyser leurs relations, cet article exploite une source originale, l'enquęte Changement organisationnel, menée auprčs des
Nathalie Greenan
Microscopic kinetics and energetics distinguish GABA(A) receptor agonists from antagonists.
Although agonists and competitive antagonists presumably occupy overlapping binding sites on ligand-gated channels, these interactions cannot be identical because agonists cause channel opening whereas antagonists do not. One explanation is that only agonist binding performs enough work on the receptor to cause the conformational changes that lead to gating. This idea is supported by agonist binding rates at GABA(A) and nicotinic acetylcholine receptors that are slower than expected for a diffusion-limited process, suggesting that agonist binding involves an energy-requiring event. This hypothesis predicts that competitive antagonist binding should require less activation energy than agonist binding. To test this idea, we developed a novel deconvolution-based method to compare binding and unbinding kinetics of GABA(A) receptor agonists and antagonists in outside-out patches from rat hippocampal neurons. Agonist and antagonist unbinding rates were steeply correlated with affinity. Unlike the agonists, three of the four antagonists tested had binding rates that were fast, independent of affinity, and could be accounted for by diffusion- and dehydration-limited processes. In contrast, agonist binding involved additional energy-requiring steps, consistent with the idea that channel gating is initiated by agonist-triggered movements within the ligand binding site. Antagonist binding does not appear to produce such movements, and may in fact prevent them.
Jones, M V; Jonas, P; Sahara, Y; Westbrook, G L
Cardiac and noncardiac fibrotic reactions caused by ergot-and nonergot-derived dopamine agonists.
There is growing evidence that the ergot-derived dopamine agonists cabergoline and pergolide can cause fibrotic cardiac valvulopathy. Data on other fibrotic reactions and nonergot-derived dopamine agonists are sparse. Aim of this study was to investigate whether there are signals that dopamine agonists are related to cardiac and other fibrotic reactions. We identified all reports of fibrotic reactions at the heart, lung, and retroperitoneal space associated with dopamine agonists within the US Adverse Event Reporting System database. Disproportionality analyses were used to calculate adjusted reporting odds ratios (RORs). For ergot-derived dopamine agonists (bromocriptine, cabergoline, pergolide), the RORs of all reactions under study were increased, whereas no such increases were observed for nonergot-derived drugs (apomorphine, pramipexole, ropinirole, rotigotine). Fibrotic reactions due to ergot-derived dopamine agonists may not be limited to heart valves. For nonergot-derived dopamine agonists, no drug safety signals were evident. PMID:19170199
Andersohn, Frank; Garbe, Edeltraut
Integrating costimulatory agonists to optimize immune-based cancer therapies
While immunotherapy for cancer has become increasingly popular, clinical benefits for such approaches remain limited. This is likely due to tumor-associated immune suppression, particularly in the advanced-disease setting. Thus, a major goal of novel immunotherapeutic design has become the coordinate reversal of existing immune dysfunction and promotion of specific tumoricidal T-cell function. Costimulatory members of the TNF-receptor family are important regulators of T-cell-mediated immunity. Notably, agonist ligation of these receptors restores potent antitumor immunity in the tumor-bearing host. Current Phase I/II evaluation of TNF-receptor agonists as single-modality therapies will illuminate their safety, mechanism(s) of action, and best use in prospective combinational immunotherapy approaches capable of yielding superior benefits to cancer patients.
Pardee, Angela D; Wesa, Amy K
Italy's electronic health record system for opioid agonist treatment.
Electronic health record systems (EHRs) play an increasingly important role in opioid agonist treatment. In Italy, an EHR called the Multi Functional Platform (MFP) is in use in 150 opioid-agonist treatment facilities in 8 of Italy's 23 regions. This report describes MFP and presents 2010 data from 65 sites that treated 8145 patients, of whom 72.3% were treated with methadone and 27.7% with buprenorphine. Patients treated with buprenorphine compared to methadone were more likely to be male (p < .01) and younger (p < .001). Methadone compared to buprenorphine patients had a higher percentage of opioid-positive urine tests (p < .001) and longer mean length of stay (p = .004). MFP has been implemented widely in Italy and has been able to track patient outcomes across treatment facilities. In the future, this EHR system can be used for performance improvement initiatives. PMID:23518287
Serpelloni, Giovanni; Gomma, Maurizio; Genetti, Bruno; Zermiani, Monica; Rimondo, Claudia; Mollica, Roberto; Gryczynski, Jan; O'Grady, Kevin E; Schwartz, Robert P
Behaviors in agonistic interaction of the butterflyfish ( Chaetodon lunulatus )
The butterflyfish (Chaetodon lunulatus) forms heterosexual pair bonds. Each pair defends a feeding territory against conspecifics. In the field, I observed the\\u000a agonistic interactions related to territoriality, and recognized nine behavioral patterns: staring, parallel swimming, rushing,\\u000a tail-up display, chasing, fleeing, encircling, TT-fighting (two-piled-tops fighting), and attacking. Almost all interactions\\u000a were conventional fighting in which attacking seldom occurred. In rare cases,
Shinji Yabuta
Development of High Affinity Selective VIP 1 Receptor Agonists
Gourlet, P., A. Vandermeers, P. Vertongen, J. Rathe, P. De Neef, J. Cnudde, M. Waelbroeck and P. Robberecht. Development of high affinity selective VIP1 receptor agonists. Peptides 18(10) 1539–1545, 1997.—The biological effects of VIP are mediated by at least two VIP receptors: the VIP1 and the VIP2 receptors that were cloned in rat, human and mice. As the mRNA coding
Philippe Gourlet; Andre Vandermeers; Pascale Vertongen; Jean Rathe; Philippe de Neef; Johnny Cnudde; Magali Waelbroeck; Patrick Robberecht
The behavioural effects of pramipexole, a novel dopamine receptor agonist
Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochloride) is a novel dopamine D2 family receptor agonist with a predominant action on D2 autoreceptors and with some D3 vs. D2 receptor preference. The central behavioural effects of pramipexole given subcutaneously to rats (male Wistar) and mice (Albino Swiss) are presented in this paper. Used in low doses (0.001–0.1 mg\\/kg), pramipexole induced locomotor hypoactivity which was
Jerzy Maj; Zofia Rogó?; Gra?yna Skuza; Krzysztof Ko?odziejczyk
Antidepressant effects of pramipexole, a novel dopamine receptor agonist
Summary Pramipexole (2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochloride), a new dopamine receptor agonist with preference for D3 compared to D2 and D4 receptors, was tested in rats in respect of its potential antidepressant activity. In the forced swimming test the drug under study, given three times in rats, reduced the immobility time. In the forced swimming test, joint treatment with antidepressants (imipramine, amitriptyline) and pramipexole
J. Maj; Z. Rogó?; G. Skuza; K. Ko?odziejczyk
T0901317 is a dual LXR\\/FXR agonist
We characterize the ability of the liver X receptor (LXR? [NR1H3] and LXR? [NR1H2]) agonist, T0901317, to activate the farnesoid X receptor (FXR [NR4H4]). Although T0901317 is a much more potent activator of LXR than FXR, this ligand actually activates FXR more potently than a natural bile acid FXR ligand, chenodeoxycholic acid. Thus, the FXR activity of T0901317 must be
Keith A. Houck; Kristen M. Borchert; Christopher D. Hepler; Jeffrey S. Thomas; Kelli S. Bramlett; Laura F. Michael; Thomas P. Burris
Nonclinical Safety Evaluation of Muraglitazar, a Novel PPAR \\/ Agonist
The toxicity of muraglitazar, an oxybenzylglycine, nonthiazo- lidinedione peroxisome proliferator-activated receptor (PPAR) a\\/g agonist, was evaluated in a comprehensive nonclinical toxicology program that included single-dose oral toxicity studies in mice, rats, and monkeys; repeat-dose toxicity studies in rats, dogs, and monkeys; a battery of in vitro and in vivo genetic toxicity studies; carcinogenicity studies in mice and rats; re- productive
Crystal R. Waites; Mark A. Dominick; Thomas P. Sanderson; Beth E. Schilling
Molecular dynamics simulations for human CAR inverse agonists.
Constitutive androstane receptor (CAR), along with pregnane x receptor (PXR), is an important metabolic sensor in the hepatocytes. Like all other nuclear receptors (NRs), CAR works in concert with coregulator proteins, coactivators, and corepressors which bind to the NRs. The main basis for the receptor to distinguish between coactivators and corepressors is the position of the C-terminal helix 12 (H12), which is determined by the bound NR ligand. CAR, having constitutive activity, can be repressed or further activated by its ligands. Crystal structure of human CAR bound to an agonist and a coactivator peptide is available, but no structural information on an inverse agonist-bound human CAR and a corepressor exists. In our previous molecular dynamics (MD) studies, no corepressor peptide was included. Therefore, probably due to the strong interactions which keep the relatively short H12 of CAR in the active position, the structural changes elicited by inverse agonists were very subtle, and H12 of CAR seemed to more or less retain its active conformation. Here, we have run a series of MD simulations to study the movement of H12 in the presence of both activating and repressing ligands as well as a corepressor peptide. The presence of the corepressor on the coregulator surface of CAR induced a clear shift of H12 of the inverse agonists-bound CAR. In general, H12 moved toward H10 and not away from the ligand binding domain, as seen in some other NRs. However, H12 of CAR is short enough that this movement seems to be adequate to accommodate the binding of the corepressor. PMID:22233089
Jyrkkärinne, Johanna; Küblbeck, Jenni; Pulkkinen, Juha; Honkakoski, Paavo; Laatikainen, Reino; Poso, Antti; Laitinen, Tuomo
Reproductive responses of cattle to GnRH agonists
The response in cattle to treatment with gonadotrophin releasing hormone (GnRH) agonist includes downregulation of GnRH receptors on gonadotrophe cells, desensitisation of the anterior pituitary gland to endogenous GnRH, and the abolition of pulsatile release of LH. In bulls, a tonic pattern of LH release is associated with increased secretion of testosterone, which persists for the duration of treatment with
M. J D'Occhio; G Fordyce; T. R Whyte; W. J Aspden; T. E Trigg
Modification of peptide interaction with MHC creates TCR partial agonists
We report the creation of TCR partial agonists by the novel approach of manipulating the interaction between immunogenic peptide and MHC. Amino acids at MHC anchor positions of the I-Ek-restricted hemoglobin (64–76) and moth cytochrome c (88–103) peptides were exchanged with MHC anchor residues from the low affinity class II invariant chain peptide (CLIP), resulting in antigenic peptides with altered
Kelli R. Ryan; Lisa K. McNeil; Chinh Dao; Peter E. Jensen; Brian D. Evavold
Improving the developability profile of pyrrolidine progesterone receptor partial agonists
The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.
Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K. (GSKPA)
In Search of Potent 5-HT6 Receptor Inverse Agonists.
A series of non-sulfonamide/non-sulfone derived potent 5-HT6 receptor inverse agonists has been disclosed. Representative compound 9 (Ki = 14 nm) displayed selectivity against a set of family members as well as brain permeability 6 h post-oral administration. In addition, the separated enantiomers of compound 9 displayed difference in activity indicating the influence of chirality on potency. PMID:24406060
Hostetler, Greg; Dunn, Derek; McKenna, Beth Ann; Kopec, Karla; Chatterjee, Sankar
Development of specific dopamine D-1 agonists and antagonists
To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo(a,d)cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo(1,2)cyclohepta(3,4,5d,e)isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC{sub 50} of compound 11 for displacement of {sup 3}H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of {sup 3}H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor.
Sakolchai, S.
Determination of beta-adrenergic agonists by hapten microarray.
The use of highly active beta-agonists as growth promoters is not appropriate because of the potential hazard for human and animal health. To investigate the residue level of these beta-agonists, hapten microarrays were employed for clenbuterol (CLB), ractopamine (RAC) and salbutamol (SAL) residue analysis. CLB, RAC and SAL conjugates were immobilized on the slides, which were precoated by agarose film to construct hapten microarrays, and then the corresponding monoclonal antibodies of these beta-agonists and the standards or samples were introduced for indirect competitive immunoassay. Finally, Cy3-labeled secondary antibody was employed to indicate the antigen-antibody complex. The fluorescence intensity of each spot was imaged and recorded, and the calibration curve of each analyte was obtained by plot fluorescence intensity against different standard concentrations. Compared to the ELISA, the hapten microarray method was more sensitive, which got the detection limits 0.09 microg/L for CLB, 0.50 microg/L for RAC, and 0.01 microg/L for SAL. What's more, with the recovery rate between 96.5% and 106.4%, and the coefficient of variation below 10%, the proposed hapten microarray method was shown to be both quantitative and reproducible. PMID:20685436
Zuo, Peng; Zhang, Yin; Liu, Jie; Ye, Bang-Ce
Retinoic acid receptor agonist activity of naturally occurring diterpenes.
Recent accumulating evidence indicates that all-trans retinoic acid (ATRA) may be useful for preventing or treating inflammation, allergy, and autoimmune diseases, despite its severe side effects. In this study, screening of 99 crude drugs for retinoic acid receptor (RAR) ligands by luciferase reporter assay demonstrated that the methanol extract of Aralia cordata Rhizoma most effectively activates the transcriptional activity of RAR?. Pimaradienoic acid (ent-pimara-8(14),15-dien-19-oic acid) was subsequently isolated as the constituent capable of activating RAR. Pimaric acid and abietic acid, which have similar structures to pimaradienoic acid, were also found to be novel RAR agonists, although abietic acid only slightly activated peroxisome proliferator-activated receptor gamma. These three natural RAR agonists with diterpene structures, while structurally different from ATRA, were able to increase the mRNA levels of the constitutive androstane receptor in HepG2 cells, induce F9 cell differentiation followed by Cyp26a1 mRNA expression, and differentiate HL-60 cells via RAR activation in a different manner from ATRA. These results demonstrate that some diterpenes exist as naturally occurring RAR agonists and that the differences in chemical structure between ATRA and these diterpenes may induce distinct gene activation and a specific cellular response. PMID:24799257
Tanabe, Hiroki; Yasui, Tomohiro; Kotani, Hitoshi; Nagatsu, Akito; Makishima, Makoto; Amagaya, Sakae; Inoue, Makoto
Fluorescent agonists for the Torpedo nicotinic acetylcholine receptor.
We have synthesized a series of fluorescent acylcholine derivatives carrying different linkers that vary in length and structure and connect the acylcholine unit to the environment-sensitive fluorophores 7-(diethylamino)coumarin-3-carbonyl (DEAC) or N-(7-nitrobenz-2-oxa-1,3-diazol-yl) (NBD). The pharmacological properties of the fluorescent analogues were investigated on heterologously expressed nicotinic acetylcholine receptor (nAChR) from Torpedo californica and on oocytes transplanted with nAChR-rich Torpedo marmorata membranes. Agonist action strongly depends on the length and the structure of the linker. One particular analogue, DEAC-Gly-C6-choline, showed partial agonist behavior with about half of the maximum response of acetylcholine, which is at least 20 times higher than those observed with previously described fluorescent dansyl- and NBD-acylcholine analogues. Binding of DEAC-Gly-C6-choline to Torpedo nAChR induces a strong enhancement of fluorescence intensity. Association and displacement kinetic experiments revealed dissociation constants of 0.5 nM for the alphadelta-binding site and 15.0 nM for the alphagamma-binding site. Both the pharmacological and the spectroscopic properties of this agonist show great promise for characterizing the allosteric mechanism behind the function of the Torpedo nAChR, as well as for drug-screening studies. PMID:18386276
Krieger, Florian; Mourot, Alexandre; Araoz, Romulo; Kotzyba-Hibert, Florence; Molgó, Jordi; Bamberg, Ernst; Goeldner, Maurice
Emerging strategies for exploiting cannabinoid receptor agonists as medicines
Medicines that activate cannabinoid CB1 and CB2 receptor are already in the clinic. These are Cesamet® (nabilone), Marinol® (dronabinol; ?9-tetrahydrocannabinol) and Sativex® (?9-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol® can also be prescribed to stimulate appetite, while Sativex® is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB2 receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed.
Pertwee, Roger G
Indacaterol: a novel long-acting ?(2) -agonist.
Bronchodilator drugs are the foundation for the treatment of chronic obstructive pulmonary disease. The principal inhaled bronchodilator treatments used are ?(2) -agonists and anticholinergics, either alone or in combination. Currently available ?(2) -agonists are of either short duration and used multiple times/day, or of long duration, which requires twice-daily administration. Indacaterol is considered an ultra-long-acting ?(2) -agonist and was recently approved for use in the United States. Its duration of action is approximately 24 hours, allowing for once-daily administration. Cough was the most commonly reported adverse effect with use of indacaterol. Cough usually occurred within 15 seconds of inhalation of the drug, lasted around 6 seconds, was not associated with bronchospasm, and did not cause discontinuation of the drug. Otherwise, the drug's safety profile was similar to that of other bronchodilators. Based on similar improvement in spirometric measurements compared with other bronchodilator drugs and the convenience of its once-daily dosing, indacaterol may be beneficial in the management of mild-to-moderate chronic obstructive pulmonary disease, either alone or in combination with anticholinergic drugs administered once/day. PMID:22499359
Ray, Shaunta' M; McMillen, James C; Treadway, Sarah A; Helmer, Robert S; Franks, Andrea S
LHRH Agonists for the Treatment of Prostate Cancer: 2012
The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge ("clinical flare") and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT.
Lepor, Herbert; Shore, Neal D
Structure of the agonist-bound neurotensin receptor
Summary Neurotensin (NT) is a 13 amino acid peptide that functions as both a neurotransmitter and a hormone through activation of the neurotensin receptor NTS1, a G protein-coupled receptor (GPCR). In the brain, NT modulates activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake, and in the gut NT regulates a range of digestive processes. Here we present the structure at 2.8 Ĺ resolution of NTS1 in an active-like state, bound to NT8-13, the C terminal portion of NT responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTS1 in an extended conformation nearly perpendicular to the membrane plane with the C-terminus oriented towards the receptor core. Our findings provide the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity.
White, Jim F.; Noinaj, Nicholas; Shibata, Yoko; Love, James; Kloss, Brian; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Shiloach, Joseph; Tate, Christopher G.; Grisshammer, Reinhard
Structure of the agonist-bound neurotensin receptor.
Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8?Ĺ resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity. PMID:23051748
White, Jim F; Noinaj, Nicholas; Shibata, Yoko; Love, James; Kloss, Brian; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Shiloach, Joseph; Tate, Christopher G; Grisshammer, Reinhard
Treatment of Parkinson's disease should begin with a dopamine agonist.
The occurrence of side effects with long-term levodopa therapy, such as fluctuations in motor performance or abnormal movements, led to a search for new antiparkinsonian drugs. Dopamine agonists include ergot derivatives such as bromocriptine, lisuride, pergolide, and cabergoline and other agents which do not possess the ergot structure such as pramipexole and ropinirole. They all are powerful stimulators of the D2 dopamine receptor which probably underlies their therapeutic effects. The clinical consequences of their binding to other dopamine receptor subtypes (D1 or D3) remains unknown. They are usually prescribed in combination with levodopa when late side effects begin to occur. This review summarizes the available pharmacologic and clinical data to support the early use of dopamine agonists in Parkinson's disease. Several strategies can be used, such as monotherapy or "early" or "late" combination with levodopa. Results of recent well-performed, modern clinical trials show that early use of the new dopamine agonists is able to effectively control the clinical symptoms for more than 3 years thereby offering the possibility of delaying the occurrence of levodopa-induced late motor side effects. PMID:10495032
Montastruc, J L; Rascol, O; Senard, J M
TLR agonists: our best frenemy in cancer immunotherapy
Various TLR agonists are currently under investigation in clinical trials for their ability to orchestrate antitumor immunity. The antitumor responses are largely attributed to their aptitude to stimulate APCs such as DCs which in turn, activate tumor-specific T cell responses. However, there is a potential for TLR signaling to occur on cells other than professional APCs that could negate antitumor responses or even worse, promote tumor growth. The impetus for this review is twofold. First, there is accumulating data demonstrating that the engagement of TLRs on different T cell subsets and different cancer types could promote tumor growth or conversely, contribute to antitumor responses. Second, the efficacy of TLR agonists as monotherapies to treat cancer patients has been limited. In this review, we discuss how TLR signaling within different T cell subsets and cancer cells can potentially impact the generation of antitumor responses. Based on evidence from preclinical models and clinical trials, we draw attention to several criteria that we believe must be considered when selecting TLR agonists for developing effective immunotherapeutic strategies against cancer.
Kaczanowska, Sabina; Joseph, Ann Mary; Davila, Eduardo
Lipopolysaccharide is a Direct Agonist for Platelet RNA Splicing
Platelets express TLR4 receptors, but its ligand lipopolysaccharide (LPS) does not directly activate thrombotic functions nor, obviously, transcription by these anucleate cells. Platelets, however, store information that changes their phenotype over a few hours in the form of unprocessed RNA transcripts. We show even low concentrations of LPS in the presence of soluble CD14 initiated splicing of unprocessed IL-1? RNA, with translation and accumulation of IL-1? protein. LPS was a more robust agonist for this response than thrombin. Platelets also contained cyclooxygenase-2 pre-mRNA, which also was spliced and translated after LPS stimulation. Flow cytometry and immunocytochemistry of platelets extensively purified by negative immunodepletion showed platelets contained IL-1?, and quantitative assessment of white blood cell contamination by CD14 real time PCR confirms that leukocytes were not the IL-1? source, nor were they required for platelet stimulation. LPS did not initiate rapid platelet responses, but over time did prime platelet aggregation to soluble agonists, induced actin rearrangement, and initiated granule secretion with P-selectin expression that resulted the coating of quiescent leukocytes with activated platelets. LPS is a direct agonist for platelets that allows these cells to directly participate in the innate immune response to bacteria.
Shashkin, Pavel N.; Brown, G. Thomas; Ghosh, Arundhati; Marathe, Gopal K.; McIntyre, Thomas M.
Importance and prospects for design of selective muscarinic agonists.
There are five subtypes of muscarinic receptors that serve various important physiological functions in the central nervous system and the periphery. Mental functions like attention, learning, and memory are attributed to the muscarinic M1 subtype. These functions decline during natural aging and an early deficit is typical for Alzheimer s disease. In addition, stimulation of the M1 receptor increases non-amyloidogenic processing of the amyloid precursor protein and thus prevents accumulation of noxious beta-amyloid fragments. The selectivity of classical muscarinic agonists among receptor subtypes is very low due to the highly conserved nature of the orthosteric binding site among receptor subtypes. Herein we summarize some recent studies with the functionally-selective M1 agonist xanomeline that indicate complex pharmacological profile of this drug that includes interactions with and activation of receptor from both orthosteric and ectopic binding sites, and the time-dependent changes of ligand binding and receptor activation. These findings point to potential profitability of exploitation of ectopic ligands in the search for truly selective muscarinic receptor agonists. PMID:18481916
Jakubík, J; Michal, P; Machová, E; Dolezal, V
Science gone translational: the OX40 agonist story
Summary OX40 (CD134) is a tumor necrosis factor (TNF) receptor expressed primarily on activated CD4+ and CD8+ T cells and transmits a potent costimulatory signal when engaged. OX40 is transiently expressed after T-cell receptor engagement and is upregulated on the most recently antigen-activated T cells within inflammatory lesions (e.g. sites of autoimmune destruction and on tumor-infiltrating lymphocytes). Hence, it is an attractive target to modulate immune responses: OX40 blocking agents to inhibit undesirable inflammation or OX40 agonists to enhance immune responses. In regards to this review, OX40 agonists enhance anti-tumor immunity, which leads to therapeutic effects in mouse tumor models. A team of laboratory and clinical scientists at the Providence Cancer Center has collaborated to bring the preclinical observations in cancer models from the bench to the bedside. This review describes the journey from in vitro experiments through preclinical mouse models to the successful translation of the first OX40 agonist to the clinic for the treatment of patients with cancer.
Weinberg, Andrew D.; Morris, Nicholas P.; Kovacsovics-Bankowski, Magdalena; Urba, Walter J.; Curti, Brendan D.
Controlled, reversible suppression of estrous cycles in beef heifers and cows using agonists of gonadotropin-releasing hormone.
Agonists of GnRH were examined for their potential to achieve controlled, reversible suppression of estrous cycles in beef cattle. In Exp. 1, cyclic heifers received two (Group B2) or four (Group B4) buserelin (D-Ser[Bu(t)]6-Pro9-LHRH[1-9] nonapeptide ethylamide) implants and degree of cessation of estrous cycles was monitored. Treatment with buserelin caused estrous cycles to cease, as indicated by basal (.2 ng/mL) concentrations of progesterone, for 48.4 +/- 3.8 d (mean +/- SEM) in Group B2, which was less (P = .6) than the 87.4 +/- 17.4 d in Group B4. In Exp. 2, heifers treated with one (Group D1) or two (Group D2) implants of deslorelin (D-Trp6-Pro9-des-Gly10-LHRH ethylamide) had basal progesterone concentrations for 203 +/- 26 d (Group D1) and 170 +/- 28 d (Group D2; P > .05). In Exp. 3, stage of the estrous cycle was synchronized in cows, and, on d 7 of the ensuing cycle, cows received four deslorelin implants for 28 (Group D28) or 56 d (Group D56). Treatment with deslorelin induced an acute increase in plasma concentrations of immunoactive and bioactive LH, which remained increased over 7 d of observation. Based on profiles of progesterone, cows did not develop a functional corpus luteum during deslorelin treatment. Days to first and second estrus after implant removal were similar for cows in Group D28 (23.6 +/- 2.1 and 40.2 +/- 4.2 d, respectively) and Group D56 (21.5 +/- 3.3 and 44.3 +/- 2.9 d). The findings indicated that GnRH agonists block estrous cycles in cattle. Also, estrous cycles returned after discontinuation of treatment. Furthermore, the consistent and predictable responses detected in cows after implant removal indicated that agonists should be suitable for achieving a controlled, reversible suppression of estrous cycles in cattle. PMID:8778103
D'Occhio, M J; Aspden, W J; Whyte, T R
Switching from ergot to nonergot dopamine agonists in Parkinson's disease: a clinical series and five-drug dose conversion table.
Of 99 patients on ergot-derived dopamine agonists informed about possible long-term side effects, switching to a nonergot was undertaken in 88 (89%). There were adverse events in 26%. After 11 months, 82% were on their switch agonist and 93% were on any agonist. Switching dopamine agonists is feasible in this population. PMID:15389984
Grosset, Katherine; Needleman, Fiona; Macphee, Graeme; Grosset, Donald
Structure et dynamique des systčmes désordonnés
NASA Astrophysics Data System (ADS)
Définis par leur "absence" d'ordre, les systčmes désordonnés ne forment pas ŕ proprement parler une famille. La notion de désordre est elle-męme assez difficile ŕ définir. Aussi, dans ce type d'étude, le type de systčmes, les techniques et les concepts sont-ils particuličrement diversifiés. Aprčs avoir énoncé quelques grandes généralités sur la définition du désordre et fait une tentative de classification des systčmes désordonnés, cette revue a été principalement orientée sur les moyens d'études de la structure et de la dynamique des fluides et des verres. Une insistance particuličre est mise sur les moyens mis ŕ disposition par la physique statistique aussi bien pour élaborer des modčles que pour analyser les résultats d'expériences spectroscopiques ou de diffraction. En effet, le nombre de configurations locales des atomes et molécules dans ces systčmes est tellement important que les résultats expérimentaux et les modčles ne décrivent en général que des moyennes d'ensemble qui n'apportent que des informations partielles sur la réalité microscopique.
Damay, P.
["Sleep attacks" in Parkinson patients. A side effect of nonergoline dopamine agonists or a class effect of dopamine agonists?].
Recently, sudden "sleep attacks" have been described in parkinsonian patients taking the nonergoline dopamine agonists pramipexole and ropinirole. Due to this possible side effect, patients must be instructed not to drive vehicles and to refrain from other activities carrying the risk of self-injury. However, the very existence of sleep attacks remains controversial in sleep medicine, since a gradual transition from wakefulness to sleep is normally observed. Accordingly, sudden onset of sleep, e.g., in narcolepsy or sleep apnea syndrome, is usually associated with excessive daytime sleepiness. Prevalence of sleep disorders and daytime sleepiness have been shown to be increased in Parkinson's disease. Nonergoline dopamine agonists are already known to induce somnolence. Currently, it is not predictable whether sleep attacks represent a sudden transition from wakefulness to sleep or result from an increased propensity to fall asleep, with patients perceiving a sudden onset. Possible pathophysiological mechanisms and legal implications of sleep attacks are discussed. PMID:10996919
Möller, J C; Stiasny, K; Cassel, W; Peter, J H; Krüger, H P; Oertel, W H
Opposite effects of agonist and inverse agonist ligands of benzodiazepine receptor on self-defensive and submissive postures in the rat
The effects of benzodiazepine receptor ligands on different types of defensive behaviours were examined in intruder male rats confronted with offensive residents. Chronic administration, via a subcutaneous silastic pellet, of a full agonist (diazepam) for 15 days increased self-defensive postures as well as social and non-social behaviour whereas submissive postures and flight were reduced. Acute administration of a partial agonist
Bertrand Piret; Antoine Depaulis; Marguerite Vergnes
Impact environnemental des cultures transgéniques II. L'impact des caractčres recombinants
La publication d'un article scientifique sur les effets néfastes d'un hybride de maďs transgénique expri- mant une ? -endotoxine du Bacillus thuringiensis contre des larves du papillon monarque causait, il y a quelques années, une controverse sans précédent sur l'impact environnemental des caractčres recom- binants introduits au bagage génétique des cultures agricoles. Le présent article de synthčse, complé- mentaire ŕ
Dominique Michaud
Placements des ménages en Europe : le rôle des intermédiaires financiers se transforme en profondeur
[fre] L'adoption de bases comptables communes pour la présentation des statistiques financičres des pays européens ouvre un large éventail de possibilités en matičre d'études comparatives. Pour ce qui concerne l'épargne des ménages, on relčve de profondes disparités dans les comportements, mais également un certain nombre d'évolutions communes. D'un point de vue structurel, l'affectation initiale du patrimoine financier entre les différentes
Nathalie Lévy; Auguste Mpacko Priso; Michel Boutillier; Stéphane Justeau; Christine Lagoutte; Bruno Séjourné; Valérie Oheix; Agnčs Labye
Enhancement of D2 receptor agonist-induced inhibition by D1 receptor agonist in the ventral tegmental area.
1. A microiontophoretic study was performed on chloral hydrate-anaesthetized rats to examine the role of D1 receptors in the ventral tegmental area (VTA) neurones, which are inhibited by autoreceptor and D2 receptor agonists. 2. Inhibition by microiontophoretic application of quinpirole (a D2 agonist) of antidromic spikes elicited by stimulation of the nucleus accumbens in dopaminergic neurones of the VTA, was significantly enhanced by simultaneous application of SKF 38393 (D1 agonist), although SKF 38393 alone had little effect on the neurones. 3. In addition, quinpirole-induced inhibition was antagonized by iontophoretic application of domperidone (D2 antagonist), but was not affected by SCH 23390 (D1 antagonist). 4. Furthermore, SKF 38393-induced enhancement of inhibition by quinpirole was antagonized by simultaneous application of SCH 23390. 5. These results suggest that activation of D1 receptors located on the VTA dopaminergic neurones or on non-dopaminergic nerve terminals is not essential for inducing inhibition of the dopaminergic neurones, but enhances D2 receptor-mediated inhibition directly or indirectly via inhibitory neurones. Images Figure 1
Momiyama, T.; Sasa, M.; Takaori, S.
Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer
Androgen deprivation therapy (ADT) resulting in testosterone suppression is central to the management of prostate cancer (PC). As PC incidence increases, ADT is more frequently prescribed, and for longer periods of time as survival improves. Initial approaches to ADT included orchiectomy or oral estrogen (diethylstilbestrol [DES]). DES reduces PC-specific mortality, but causes substantial cardiovascular (CV) toxicity. Currently, luteinizing hormone-releasing hormone agonists (LHRHa) are mainly used; they produce low levels of both testosterone and estrogen (as estrogen in men results from the aromatization of testosterone), and many toxicities including osteoporosis, fractures, hot flashes, erectile dysfunction, muscle weakness, increased risk for diabetes, changes in body composition, and CV toxicity. An alternative approach is parenteral estrogen, it suppresses testosterone, appears to mitigate the CV complications of oral estrogen by avoiding first-pass hepatic metabolism, and avoids complications caused by estrogen deprivation. Recent research on the toxicity of ADT and the rationale for revisiting parenteral estrogen is discussed.
Phillips, Iain; Shah, Syed I A; Duong, Trinh; Abel, Paul; Langley, Ruth E
Agonist-promoted trafficking of human bradykinin receptors: arrestin- and dynamin-independent sequestration of the B2 receptor and bradykinin in HEK293 cells.
In this study, we analysed the agonist-promoted trafficking of human B(2) (B(2)R) and B(1) (B(1)R) bradykinin (BK) receptors using wild-type and green fluorescent protein (GFP)-tagged receptors in HEK293 cells. B(2)R was sequestered to a major extent upon exposure to BK, as determined by the loss of cell-surface B(2)R using radioligand binding and by imaging of B(2)R-GFP using laser-scanning confocal fluorescence microscopy. Concurrent BK sequestration was revealed by the appearance of acid-resistant specific BK receptor binding. The same techniques showed that B(1)R was sequestered to a considerably lesser extent upon binding of des-Arg(10)-kallidin. B(2)R sequestration was rapid (half-life approximately 5 min) and reached a steady-state level that was significantly lower than that of BK sequestration. B(2)R sequestration was minimally inhibited by K44A dynamin (22.4+/-3.7%), and was insensitive to arrestin-(319-418), which are dominant-negative mutants of dynamin I and beta-arrestin respectively. Furthermore, the B(2)R-mediated sequestration of BK was completely insensitive to both mutants, as was the association of BK with a caveolae-enriched fraction of the cells. On the other hand, agonist-promoted sequestration of the beta(2)-adrenergic receptor was dramatically inhibited by K44A dynamin (81.2+/-16.3%) and by arrestin-(319-418) (36.9+/-4.4%). Our results show that B(2)R is sequestered to a significantly greater extent than is B(1)R upon agonist treatment in HEK293 cells. Furthermore, B(2)R appears to be recycled in the process of sequestering BK, and this process occurs in a dynamin- and beta-arrestin-independent manner and, at least in part, involves caveolae.
Lamb, M E; De Weerd, W F; Leeb-Lundberg, L M
Antagonist, partial agonist and antiproliferative actions of B-9870 (CU201) as a function of the expression and density of the bradykinin B1 and B2 receptors
Background and purpose: A bradykinin (BK) B2 receptor (B2R) antagonist, B-9870 (CU201), has been proposed to behave as a 'biased agonist' at B2Rs and to exert anti-neoplasic effects. It was unclear whether these effects were determined by the activation of B2Rs by the drug. B-9870 was evaluated for antagonism or stimulation of several responses mediated by the rabbit B2R or B1 receptor (B1R); its anti-proliferative activity was also characterized. Experimental approach and key results: B-9870 was an insurmountable B2R antagonist in the rabbit jugular vein contractility assay, but a partial agonist in HEK 293 cells expressing the rabbit B2R or a green fluorescent protein (GFP) conjugate of the latter (ERK1/2 phosphorylation, [Ca2+]i, [3H]-arachidonate release, endocytosis). The agonist-like effects of B-9870 were inhibited by the B2R antagonist LF 16.0687 and absent in untransfected cells. In addition, B-9870 was a surmontable antagonist of the rabbit B1R in the aorta contractility assay, and blocked Lys-des-Arg9-BK-induced ERK1/2 phosphorylation in HEK 293 cells expressing a fluorescent B1R conjugate. B-9870 inhibited the growth of MDA-MB-231 cells. The latter effect was not influenced by B1R or B2R antagonists and was not apoptotic. MDA-MB-231 cells expressed a small population of B2Rs but no B1Rs; they responded to BK (small calcium transients) and B-9870 behaved as an antagonist. Conclusion and implications: B-9870 is a dual B1R and B2R antagonist with confirmed stimulating effects at the B2R in high expression systems only. Its cell type-specific anti-proliferative effect occurs at a high concentration, independently from kinin receptors and apoptosis.
Morissette, G; Houle, S; Gera, L; Stewart, J M; Marceau, F
Antinociceptive Interactions between Mu-Opioid Receptor Agonists and the Serotonin Uptake Inhibitor Clomipramine in Rhesus Monkeys: Role of Mu Agonist Efficacy
Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine < morphine < methadone). Clomipramine and each mu agonist were studied alone and in fixed-proportion mixtures in assays of schedule-controlled responding, thermal nociception, and capsaicin-induced thermal allodynia. In the assay of schedule-controlled responding, all mu agonists dose-dependently decreased response rates. Clomipramine was inactive alone and did not alter the effects of mu agonists. In the assay of thermal nociception, all mu agonists produced dose-dependent antinociception. Clomipramine was inactive alone but produced a proportion-dependent enhancement of the antinociceptive effects of nalbuphine > morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine.
Banks, Matthew L.; Rice, Kenner C.
L'impact des politiques de croissance externe : l'expérience des entreprises françaises au cours des années quatre-vingt
[fre] Les entreprises industrielles françaises ont considérablement accru leur effort de développement par croissance externe depuis le milieu des années quatre-vingt. Cette tendance, particuličrement nette entre 1986 et 1988, semble se confirmer en 1989 au vu des réalisations d'acquisition d'actifs financiers. . Les grandes entreprises développent des stratégies sur longue période afin d'atteindre une dimension ŕ l'échelle des marchés internationaux.
François Bavay; Denis Beau
Zur Physiologie des Labyrinthes der Tanzmaus
Zusammenfassung 1.Die Tanzmäuse reagiren auf keinerlei Schalleindrücke.2.Sie besitzen ein mangelhaftes Vermögen, das Körpergleichgewicht zu erhalten.3.Sie haben keinen Drehschwindel.4.Sie verhalten sich der galvanischen Durchströmung des Kopfes gegenüber wie normale Thiere.
G. Alexander; Alois Kreidl
Caracterisation des proprietes acoustiques des materiaux poreux a cellules ouvertes et a matrice rigide ou souple
NASA Astrophysics Data System (ADS)
L'objectif global vise par les travaux de cette these est d'ameliorer la caracterisation des proprietes macroscopiques des materiaux poreux a structure rigide ou souple par des approches inverses et indirectes basees sur des mesures acoustiques faites en tube d'impedance. La precision des approches inverses et indirectes utilisees aujourd'hui est principalement limitee par la qualite des mesures acoustiques obtenues en tube d'impedance. En consequence, cette these se penche sur quatre problemes qui aideront a l'atteinte de l'objectif global precite. Le premier probleme porte sur une caracterisation precise de la porosite ouverte des materiaux poreux. Cette propriete en est une de passage permettant de lier la mesure des proprietes dynamiques acoustiques d'un materiau poreux aux proprietes effectives de sa phase fluide decrite par les modeles semi-phenomenologiques. Le deuxieme probleme traite de l'hypothese de symetrie des materiaux poreux selon leur epaisseur ou un index et un critere sont proposes pour quantifier l'asymetrie d'un materiau. Cette hypothese est souvent source d'imprecision des methodes de caracterisation inverses et indirectes en tube d'impedance. Le critere d'asymetrie propose permet ainsi de s'assurer de l'applicabilite et de la precision de ces methodes pour un materiau donne. Le troisieme probleme vise a mieux comprendre le probleme de transmission sonore en tube d'impedance en presentant pour la premiere fois un developpement exact du probleme par decomposition d'ondes. Ce developpement permet d'etablir clairement les limites des nombreuses methodes existantes basees sur des tubes de transmission a 2, 3 ou 4 microphones. La meilleure comprehension de ce probleme de transmission est importante puisque c'est par ce type de mesures que des methodes permettent d'extraire successivement la matrice de transfert d'un materiau poreux et ses proprietes dynamiques intrinseques comme son impedance caracteristique et son nombre d'onde complexe. Enfin, le quatrieme probleme porte sur le developpement d'une nouvelle methode de transmission exacte a 3 microphones applicable a des materiaux ou systemes symetriques ou non. Dans le cas symetrique, on montre que cette approche permet une nette amelioration de la caracterisation des proprietes dynamiques intrinseques d'un materiau. Mots cles. materiaux poreux, tube d'impedance, transmission sonore, absorption sonore, impedance acoustique, symetrie, porosite, matrice de transfert.
Salissou, Yacoubou
Contraception épididymaire: état des recherches et perspectives
Resume Le développement de nouvelles stratégies contraceptives est un enjeu économique important. L'épididyme, sičge de la maturation\\u000a post-testiculaire des spermatozoďdes est depuis peu sous les feux de la recherche comme un organe cible pour le développement\\u000a de nouvelles approches contraceptives chez les mammifčres. En effet, cet organe dans lequel transitent et sont stockés les\\u000a permatozoďdes (chez la plupart des mammifčres) est,
Joël R. Drevet
Sedimentologie des Lias der Berchtesgadener Kalkalpen
Zusammenfassung Ausgehend von der herrschenden Vorstellung einer Transgression roter Liaskalke zur Zeit des oberen Unterlias über ein subaerisch verkarstetes Dachsteinkallerelief, untersuchte ich die Liassedimente in den Berchtesgadener Alpen eingehender und unternahm vergleichende Begehungen im östlichen Hagengebirge, im Steinernen Meer und in den Steinbrüchen von Adnet.Die Sedimente des Lias liegen in einer Graukalk- und einer abwechslungsreicheren Rotkalk-Fazies (F.Fabricius 1962) vor. Ammoniten zeigten,
Hermann Jurgan
Discovery of AM-1638: A Potent and Orally Bioavailable GPR40/FFA1 Full Agonist
GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1.
A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency
Receptor agonism remains poorly understood at the molecular and mechanistic level. In this study, we identified a fully human anti-Fas antibody that could efficiently trigger apoptosis and therefore function as a potent agonist. Protein engineering and crystallography were used to mechanistically understand the agonistic activity of the antibody. The crystal structure of the complex was determined at 1.9?Ĺ resolution and provided insights into epitope recognition and comparisons with the natural ligand FasL (Fas ligand). When we affinity-matured the agonist antibody, we observed that, surprisingly, the higher-affinity antibodies demonstrated a significant reduction, rather than an increase, in agonist activity at the Fas receptor. We propose and experimentally demonstrate a model to explain this non-intuitive impact of affinity on agonist antibody signalling and explore the implications for the discovery of therapeutic agonists in general.
Chodorge, M; Zuger, S; Stirnimann, C; Briand, C; Jermutus, L; Grutter, M G; Minter, R R
Roulement des entreprises et croissance de la productivite dans le secteur canadien du commerce de detail
La presente etude se penche sur le roulement des entreprises et sur la croissance de la productivite dans le secteur canadien du commerce de detail. Le roulement des entreprises a lieu lorsque, en raison du processus concurrentiel, des entreprises sortantes et des entreprises existantes en declin voient diminuer leur part de marche au profit des nouvelles entreprises et des entreprises
John R. Gu Wulong Baldwin
Endomorphin-2: a biased agonist at the ?-opioid receptor.
Previously we correlated the efficacy for G protein activation with that for arrestin recruitment for a number of agonists at the ?-opioid receptor (MOPr) stably expressed in HEK293 cells. We suggested that the endomorphins (endomorphin-1 and -2) might be biased toward arrestin recruitment. In the present study, we investigated this phenomenon in more detail for endomorphin-2, using endogenous MOPr in rat brain as well as MOPr stably expressed in HEK293 cells. For MOPr in neurons in brainstem locus ceruleus slices, the peptide agonists [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) and endomorphin-2 activated inwardly rectifying K(+) current in a concentration-dependent manner. Analysis of these responses with the operational model of pharmacological agonism confirmed that endomorphin-2 had a much lower operational efficacy for G protein-mediated responses than did DAMGO at native MOPr in mature neurons. However, endomorphin-2 induced faster desensitization of the K(+) current than did DAMGO. In addition, in HEK293 cells stably expressing MOPr, the ability of endomorphin-2 to induce phosphorylation of Ser375 in the COOH terminus of the receptor, to induce association of arrestin with the receptor, and to induce cell surface loss of receptors was much more efficient than would be predicted from its efficacy for G protein-mediated signaling. Together, these results indicate that endomorphin-2 is an arrestin-biased agonist at MOPr and the reason for this is likely to be the ability of endomorphin-2 to induce greater phosphorylation of MOPr than would be expected from its ability to activate MOPr and to induce activation of G proteins. PMID:22553358
Rivero, Guadalupe; Llorente, Javier; McPherson, Jamie; Cooke, Alex; Mundell, Stuart J; McArdle, Craig A; Rosethorne, Elizabeth M; Charlton, Steven J; Krasel, Cornelius; Bailey, Christopher P; Henderson, Graeme; Kelly, Eamonn
Endomorphin-2: A Biased Agonist at the ?-Opioid Receptor
Previously we correlated the efficacy for G protein activation with that for arrestin recruitment for a number of agonists at the ?-opioid receptor (MOPr) stably expressed in HEK293 cells. We suggested that the endomorphins (endomorphin-1 and -2) might be biased toward arrestin recruitment. In the present study, we investigated this phenomenon in more detail for endomorphin-2, using endogenous MOPr in rat brain as well as MOPr stably expressed in HEK293 cells. For MOPr in neurons in brainstem locus ceruleus slices, the peptide agonists [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and endomorphin-2 activated inwardly rectifying K+ current in a concentration-dependent manner. Analysis of these responses with the operational model of pharmacological agonism confirmed that endomorphin-2 had a much lower operational efficacy for G protein-mediated responses than did DAMGO at native MOPr in mature neurons. However, endomorphin-2 induced faster desensitization of the K+ current than did DAMGO. In addition, in HEK293 cells stably expressing MOPr, the ability of endomorphin-2 to induce phosphorylation of Ser375 in the COOH terminus of the receptor, to induce association of arrestin with the receptor, and to induce cell surface loss of receptors was much more efficient than would be predicted from its efficacy for G protein-mediated signaling. Together, these results indicate that endomorphin-2 is an arrestin-biased agonist at MOPr and the reason for this is likely to be the ability of endomorphin-2 to induce greater phosphorylation of MOPr than would be expected from its ability to activate MOPr and to induce activation of G proteins.
Rivero, Guadalupe; Llorente, Javier; McPherson, Jamie; Cooke, Alex; Mundell, Stuart J.; McArdle, Craig A.; Rosethorne, Elizabeth M.; Charlton, Steven J.; Krasel, Cornelius; Bailey, Christopher P.; Henderson, Graeme
Adjunctive ?2-agonists reverse neuromuscular involvement in murine Pompe disease
Pompe disease has resisted enzyme replacement therapy with acid ?-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated ?2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<2×10?5). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wirehang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive ?2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain.—Li, S., Sun, B., Nilsson, M. I., Bird, A., Tarnopolsky, M. A., Thurberg, B. L., Bali, D., Koeberl, D. D. Adjunctive ?2-agonists reverse neuromuscular involvement in murine Pompe disease.
Li, Songtao; Sun, Baodong; Nilsson, Mats I.; Bird, Andrew; Tarnopolsky, Mark A.; Thurberg, Beth L.; Bali, Deeksha; Koeberl, Dwight D.
The ?-blocker Nebivolol Is a GRK/?-arrestin Biased Agonist
Nebivolol, a third generation ?-adrenoceptor (?-AR) antagonist (?-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another ?-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of G?s and involves G protein-coupled receptor kinase (GRK)/?-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/?-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express ?2-ARs, and HL-1 cardiac myocytes that express ?1- and ?2-ARs and no detectable ?3-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of ?-ARs indicating that nebivolol is also not a classical ?-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective ?-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from ?-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of ?-arrestin 1/2. Additionally, nebivolol induced redistribution of ?-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a ?2-AR, and likely ?1-AR, GRK/?-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at ?1- and/or ?2-ARs.
Blessing, Christopher P.; Nguyen, Jenny; Liu, Tammy; Pulakat, Lakshmi; Bastepe, Murat; Jackson, Edwin K.; Andresen, Bradley T.
Variations in cell signaling pathways for different vasoconstrictor agonists in renal circulation of the rat
Variations in cell signaling pathways for different vasoconstrictor agonists in renal circulation of the rat.BackgroundMajor cell signaling pathways involved in agonist-induced vasoconstriction are recognized to be Ca2+ mobilization via inositol-1,4,5 triphosphate (IP3), Ca2+ influx through L-type channels, activation of protein kinase C (PKC), and of Rho-associated kinase (ROK). However, their contribution for renal vasoconstriction induced by different agonists is not
Johannes Bauer; Niranjan Parekh
Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064
Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)
Effect of Cannabinoid Receptor Agonists on Streptozotocin-Induced Hyperalgesia in Diabetic Neuropathy
The effect of CB-1 and CB-2 receptor agonists, as well as an influence of a non-selective inhibitor of nitric oxide synthase (NOS), L-NOArg, and an inhibitor acting preferentially on cyclooxygenase-1 (COX-1), indomethacin, on the action of cannabinoid receptor agonists in a streptozotocin (STZ)-induced neuropathic model was investigated. When administered alone, a non-selective cannabinoid receptor agonist, WIN 55,212-2, a potentially selective
Magdalena Bujalska
Serotonergic influences on male sexual behavior of rhesus monkeys: effects of serotonin agonists
Although numerous studies in rats have demonstrated an influence of serotonin (5-HT) on male copulation, no studies have yet to demonstrate whether such a relationship exists in primate species. The present study sought to characterize 5-HT influences on male copulatory behavior of rhesus monkeys by using three different 5-HT agonists: a full 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT); a partial 5-HT1A agonist,
Steven M. Pomerantz; Bert C. Hepner; Joan M. Wertz
Sites of Action of some Partial Agonists on the Isolated Guineapig Ileum
IT is well known that if in a homologous series of drugs a special group is changed by heavier ones, they gradually change from agonists through partial agonists into competitive antagonists1. It has been reported that isoamyl acetate, its analogues2 and pilocarpine3, some of which are partial agonists, contract the isolated guinea-pig ileum through the liberation of acetylcholine on the
K. Takagi; I. Takayanagi; F. Taga; K. Nishino
Ghrelin and motilin receptor agonists: time to introduce bias into drug design.
Ghrelin and motilin receptor agonists increase gastric motility and are attractive drug targets. However, 14 years after the receptors were described (18-24 years since ligands became available) the inactivity of the ghrelin agonist TZP-102 in patients with gastroparesis joins the list of unsuccessful motilin agonists. Fundamental questions must be asked. Pustovit et al., have now shown that the ghrelin agonist ulimorelin evokes prolonged increases in rat colorectal propulsion yet responses to other ghrelin agonists fade. Similarly, different motilin agonists induce short- or long-lasting effects in a cell-dependent manner. Together, these and other data create the hypothesis that the receptors can be induced to preferentially signal ('biased agonism') via particular pathways to evoke different responses with therapeutic advantages/disadvantages. Biased agonism has been demonstrated for ghrelin. Are motilin agonists which cause long-lasting facilitation of human stomach cholinergic function (compared with motilin) biased agonists (e.g., camicinal, under development for patients with gastric hypo-motility)? For ghrelin, additional complications exist because the therapeutic aims/mechanisms of action are uncertain, making it difficult to select the best (biased) agonist. Will ghrelin agonists be useful treatments of nausea and/or as suggested by Pustovit et al., chronic constipation? How does ghrelin increase gastric motility? As gastroparesis symptoms poorly correlate with delayed gastric emptying (yet gastro-prokinetic drugs can provide relief: e.g., low-dose erythromycin), would low doses of ghrelin and motilin agonists relieve symptoms simply by restoring neuromuscular rhythm? These questions on design and functions need addressing if ghrelin and motilin agonists are to reach patients as drugs. PMID:24438586
Sanger, G J
Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists.
Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure. PMID:23953070
Sheppeck, James E; Gilmore, John L; Xiao, Hai-Yun; Dhar, T G Murali; Nirschl, David; Doweyko, Arthur M; Sack, Jack S; Corbett, Martin J; Malley, Mary F; Gougoutas, Jack Z; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Dodd, John H; Nadler, Steven G; Somerville, John E; Barrish, Joel C
Muscarinic and nicotinic cholinergic agonists: structural analogies and discrepancies.
Acetylcholine, the first identified neurotransmitter acts on both types of cholinergic receptors. Both rigid and flexible derivatives of acetylcholine could either be selective muscarinic or selective nicotinic agonists while some compounds show activity at both receptor subclasses. Earlier structure-activity considerations are revisited. Ligand and receptor based calculations have been applied in the hope to identify characteristic geometrical and steric requirements for the activity on the receptor subtypes. Results are treated critically and applied cautiously for predicting selective structural requirements by the cholinergic receptor subclasses. PMID:14529475
Bikádi, Zsolt; Simonyi, Miklós
Discovery of a highly potent series of TLR7 agonists.
The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed. PMID:21885277
Jones, Peter; Pryde, David C; Tran, Thien-Duc; Adam, Fiona M; Bish, Gerwyn; Calo, Frederick; Ciaramella, Guiseppe; Dixon, Rachel; Duckworth, Jonathan; Fox, David N A; Hay, Duncan A; Hitchin, James; Horscroft, Nigel; Howard, Martin; Laxton, Carl; Parkinson, Tanya; Parsons, Gemma; Proctor, Katie; Smith, Mya C; Smith, Nicholas; Thomas, Amy
GLP-1 Agonists and Dipeptidyl-Peptidase IV Inhibitors
\\u000a Novel therapeutic options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1)\\u000a were introduced in 2005. Incretin-based therapies consist of two classes: (1) the injectable GLP-1 receptor agonists solely\\u000a acting on the GLP-1 receptor and (2) dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) as oral medications raising endogenous\\u000a GLP-1 and other hormone levels by inhibiting the degrading
Baptist Gallwitz
Narrow SAR in odorant sensing Orco receptor agonists.
The systematic exploration of a series of triazole-based agonists of the cation channel insect odorant receptor is reported. The structure-activity relationships of independent sections of the molecules are examined. Very small changes to the compound structure were found to exert a large impact on compound activity. Optimal substitutions were combined using a 'mix-and-match' strategy to produce best-in-class compounds that are capable of potently agonizing odorant receptor activity and may form the basis for the identification of a new mode of insect behavior modification. PMID:24813736
Romaine, Ian M; Taylor, Robert W; Saidu, Samsudeen P; Kim, Kwangho; Sulikowski, Gary A; Zwiebel, Laurence J; Waterson, Alex G
A 3 Adenosine Receptor Agonists: History and Future Perspectives
\\u000a IB-MECA, the first selective A3 adenosine receptor (A3AR) agonist, was reported in 1993, and since then numerous adenosine derivatives have been modified to optimize their interaction\\u000a with the A3AR. IB-MECA (CF101) and its 2-chloro analogue, Cl-IB-MECA (CF102) are in Phase II clinical trials for treatment of autoimmune\\u000a inflammatory diseases and cancer, respectively. Additional structural modifications made at the N\\u000a 6
Kenneth A. Jacobson; Zhan-Guo Gao; Dilip K. Tosh; Gangadhar J. Sanjayan; Sonia de Castro
Thermodynamic analysis of antagonist and agonist interactions with dopamine receptors.
The binding of [3H]spiperone to dopamine D-2 receptors and its inhibition by antagonists and agonists were examined in microsomes derived from the sheep caudate nucleus, at temperatures between 37 and 1 degree C, and the thermodynamic parameters of the binding were evaluated. The affinity of the receptor for the antagonists, spiperone and (+)-butaclamol, decreased as the incubation temperature decreased; the affinity for haloperidol did not further decrease at temperatures below 15 degrees C. The binding of the antagonists was associated with very large increases in entropy, as expected for hydrophobic interactions. The enthalpy and entropy changes associated with haloperidol binding were dependent on temperature, in contrast to those associated with spiperone and (+)-butaclamol. The magnitude of the entropy increase associated with the specific binding of the antagonists did not correlate with the degree of lipophilicity of these drugs. The data suggest that, in addition to hydrophobic forces, other forces are also involved in the antagonist-dopamine receptor interactions, and that a conformational change of the receptor could occur when the antagonist binds. Agonist binding data are consistent with a two-state model of the receptor, a high-affinity state (RH) and a low-affinity state (RL). The affinity of dopamine binding to the RH decreased with decreasing temperatures below 20 degrees C, whereas the affinity for the RL increased at low temperatures. In contrast, the affinity of apomorphine for both states of receptor decreased as the temperature decreased from 30 to 8 degrees C. A clear distinction between the energetics of high-affinity and low-affinity agonist binding was observed. The formation of the high-affinity complex was associated with larger increases in enthalpy and entropy than the interaction with the low-affinity state was. The results suggest that the interaction of the receptor with the G-proteins, induced or stabilized by the binding of agonist, leads to an increase in entropy and to negative heat capacity changes in the system. PMID:2452751
Duarte, E P; Oliveira, C R; Carvalho, A P
PPAR-? agonistic metabolites from the ascidian Herdmania momus.
Seven new amino acid derivatives (1-4 and 6-8) were isolated from MeOH extracts of the marine ascidian Herdmania momus. Planar structures were established on the basis of NMR, IR, and MS spectroscopic analyses. Absolute configurations of these compounds were derived from specific rotation and CD analysis. The peroxisome proliferator-activated receptor (PPAR)-? agonistic activities of the compounds were investigated due to the similarity of the structural motif to that of the antidiabetic drug rosiglitazone. Analogues with indoleglyoxyl moieties (5, 6, and 8) showed significant PPAR-? activation in Ac2F rat liver cells. PMID:23189988
Li, Jian Lin; Xiao, Bin; Park, Minhi; Yoo, Eun Sook; Shin, Sook; Hong, Jongki; Chung, Hae Young; Kim, Hyung Sik; Jung, Jee H
Identification of dissociated non-steroidal glucocorticoid receptor agonists.
A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. To identify compounds with an improved side effect profile over marketed steroids the functional activity of compounds was evaluated in cell based assays for transactivation (aromatase) and transrepression (IL-6). Through this effort, 36 has been identified as a partial agonist with a dissociated profile in these cell based assays. PMID:17692519
Kuzmich, Daniel; Kirrane, Tom; Proudfoot, John; Bekkali, Younes; Zindell, Renee; Beck, Laura; Nelson, Richard; Shih, Cheng-Kon; Kukulka, Alison J; Paw, Zofia; Reilly, Patty; Deleon, Rodney; Cardozo, Mario; Nabozny, Gerald; Thomson, David
Diffusion des Metaux et Evolution Stellaire
NASA Astrophysics Data System (ADS)
Nous presentons dans cette these des modeles d'evolution stellaire incorporant la diffusion microscopique de maniere consistante. Pour la premiere fois, on a calcule l'evolution d'etoiles en tenant compte en detail de l'impact des variations d'abondances sur leur structure. Nous utilisons des spectres monochromatiques pour chacun des elements les plus abondants dans un melange solaire pour recalculer l'opacite pour les abondances et les conditions locales dans l'interieur d'une etoile au cours de son evolution. Nos modeles montrent que la diffusion atomique des metaux a un effet important sur les opacites dan les etoiles de plus de 1.3Msolar ou l'abondance du fer et des autres elements du pic du fer varient substantiellement. Ces etoiles, sans rotation ou champ magnetique, sont proches des etoiles de type Fm-Am dans lesquelles on observe une legere surabondance d'elements du pic du fer en plus d'une sous-abondance de calcium, sous-abondance que l'on obtient egalement. Nous obtenons cependant des surabondances depassant un facteur 10 pour les etoiles de plus de 1.4Msolar ce qui suggere qu'il existe un ou plusieurs mecanismes limitant la diffusion microscopique. La surabondance du fer en surface cause une augmentation, qui peut atteindre un facteur sept, de l'opacite a la limite de la zone convective. Ceci cause un accroissement de la temperature effective et de la masse de la zone convective comparativement aux modeles n'incluant que la diffusion de l'helium. Il s'agit la du principal effet de la diffusion sur la structure interne de ces etoiles. La diffusions n'a pas d'influence sur l'evolution de coeur stellaire dans les etoiles significativement plus massives quie le Soleil. Nous avons verife que l'utilisation de modeles consistants avec diffusion n'apporte pas d'amelioration sensible aux modeles solaires. Les forces radiatives calculees a partir des spectres d'OPAL pour les elements du pic du fer representent une fraction importante de la gravite. On obtient des forces de 40% la gravite a la base de la zone convective. Ces forces radiatives sont assez grandes pour avoir un impact significatif sur les variations d'abondance de ces elements. Cet effet est neglige dans les modeles solaires publies. Nos modeles solaires montrent que les donnees du projet OPACITE pour le fer sont trop deficientes dans leur etat actuel pour pouvoir etre utilisees dans des calculs evolutifs. Nous confirmons que la diffusion doit etre prise en compte pour reproduire les donnes helioseismologiques. Nous discutons en detail de la manipulation des donnees monochromatiques. Il en ressort que les donnees d'OPAL sont superieures aux donnees tirees de OP. Les donnees de OP sont utiles pour les forces radiatives dans deux applications. Premierement pour determiner les corrections a apporter aux accelerations radiatives de OPAL pour tenir compte de la redistribution de l'impulsion lors de la photoionisation, puis parce que le sampling de OPAL perd de sa validite a basse temperature et pour les metaux tres peu abondants. Finalement nous avons calcule des modeles d'etoiles de population II de faible metallicite. Nous montrons dans un premier temps que la diffusion des metaux n'a pas d'effet significatif sur l'evolution de ces etoiles. Nous montrons egalement que l'incertitude sur l'age des amas globulaires associe a la diffusion est sous-estimee. Quoique la difference s'amenuise il existe toujours un desaccord avec l'age de l'Univers tel que determine a partir de la loi de Hubble.
Turcotte, Sylvain
Influence de la dépendance en température des propriétés optiques des matériaux sur la force de Casimir
NASA Astrophysics Data System (ADS)
Nous évaluons la force de Casimir entre deux surfaces planes métalliques constituées d'argent. Nous prenons, pour effectuer cette évaluation, des propriétés optiques de l'argent ŕ différentes températures [1]. Nous montrons que cette dépendance en température modifie la force de Casimir (de 0.2%) y compris ŕ des distances inférieures ŕ la longueur d'onde thermique.
Joulain, K.; Henkel, C.; Greffet, J.-J.
Equations de transport relatives ŕ des champs de vecteurs non-lipschitziens et mécanique des fluides
Le but de cet article est l'étude des équations de transport relatives ŕ des champs de vecteurs non-lipschitziens, mais seulement logarithmiquement lipschitziens. Ces champs possčdent un flot dont la régularité hölderienne est exponentiellement décroissante. On exhibe une solution de l'équation d'Euler bidimensionnelle présentant effectivement ce phénomčne.
H. Bahouri; J.-Y. Chemin
Developpement des betons semi autoplacants a rheologie adaptee pour des infrastructures
NASA Astrophysics Data System (ADS)
Au cours des derničres décennies, les infrastructures canadiennes et québécoises comportent plusieurs structures en béton armé présentant des problčmes de durabilité dus aux conditions climatiques sévčres, ŕ la mauvaise conception des structures, ŕ la qualité des matériaux, aux types des bétons choisis, aux systčmes de construction ou ŕ l'existence d'événements incontrôlables. En ce qui concerne le choix du béton pour la construction des infrastructures, une vaste gamme de béton divisée en deux principaux types peut ętre utilisée: le béton conventionnel vibré (BCV) et le béton autoplaçant (BAP). Dans le cas d'un BCV, la consolidation inadéquate par vibration a été un problčme récurrent, occasionnant des dommages structuraux. Ceci a conduit ŕ une réduction de la durabilité et ŕ une augmentation du coűt d'entretien et de réparation des infrastructures. Rien que l'utilisation d'un BAP a des avantages tels que l'élimination de la vibration, la réduction des coűts de main d'oeuvre et l'amélioration de la qualité des structures, néanmoins, le coűt initial d'un BAP par rapport ŕ un BCV ne permet pas encore de généraliser son utilisation dans l'industrie de la construction. Ce mémoire présente la conception d'une nouvelle gamme de béton semi-autoplaçant pour la construction des infrastructures (BSAP-I) exigeant une vibration minimale. Il s'agit de trouver un équilibre optimal entre la rhéologie et le coűt initial du nouveau béton pour conférer une bonne performance structurale et économique aux structures. Le programme expérimental établi a premičrement permis d'évaluer la faisabilité d'utilisation des BSAP-I pour la mise en place des piliers d'une infrastructure de pont ŕ Sherbrooke. En plus, l'utilisation d'un plan d'expériences a permis l'évaluation de trois paramčtres de formulation sur les propriétés des mélanges de BSAP-I ŕ l'état frais et durci. Finalement, l'évaluation de la performance des BSAP-I optimisés ŕ travers une caractérisation complčte des propriétés mécaniques et de la durabilité a été réalisée. A la suite de cette étude, les résultats obtenus nous permettent de conclure que : (1) L'utilisation d'un BSAP-I avec un gros granulat de 5 - 14 mm, des rapports E/L = 0,37 et S/G = 0,52 et une teneur en air de 6 ŕ 9% a été possible en conférant un équilibre optimal fluidité / stabilité ŕ l'état frais, ainsi qu'un niveau de thixotropie adéquate au chantier permettant d'optimiser la conception du coffrage des piliers de pont et de conférer des qualités de surfaces trčs acceptables de ces infrastructures. (2) La méthode adaptée pour l'essai L-Box contenant 2 barres et une vibration de 5 secondes a permis de bien caractériser la capacité de remplissage d'un BSAP-I. (3) L'utilisation d'un plan factoriel 23 a permis d'obtenir des modčles statistiques fiables, capables de prédire les propriétés rhéologiques ŕ l'état frais et les résistances en compression des BSAP-I avec des dosages en liant entre 370 et 420 kg/m3, des rapports E/L entre 0,34 et 0,40 et S/G entre 0,47 et 0,53. (4) Des mesures de vitesse d'écoulement T40 d'un BSAP-I sont trčs semblables ŕ celles d'un BAP. En plus, des valeurs T40 montrent une bonne corrélation linéaire avec celles de T400 mesurés dans la boîte L-Box. (5) Ŕ la frontičre du BAP et du BCV, une bande rhéologique possédant un ?0 entre 30 et 320 Pa et un ? entre 10 et 140 Pa.s a été trouvée pour la conception optimale des BSAP-I. (6) Les BSAP-I optimisés ont également conféré une trčs bonne performance ŕ l'état frais, en permettant maintenir un bon équilibre entre la rhéologie et la stabilité dans le temps, lorsqu'on utilise une énergie de vibration minimale pour amorcer son écoulement. (7) Ŕ l'état durci Les BSAP-I ont conféré une bonne performance présentant des résistances mécaniques élevées et des niveaux négligeables de pénétration aux ions chlores, de perte de masse par écaillage et des attaques par le gel/dégel. (8) L'utilisation des cim
Sotomayor Cruz, Cristian Daniel
Salvinorin A: A potent naturally occurring nonnitrogenous ? opioid selective agonist
Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited 3H-bremazocine binding to cloned ? opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent ? opioid agonist at cloned ? opioid receptors expressed in human embryonic kidney-293 cells and at native ? opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT2A serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for ? opioid receptors, ? opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that ? opioid receptors play a prominent role in the modulation of human perception.
Roth, Bryan L.; Baner, Karen; Westkaemper, Richard; Siebert, Daniel; Rice, Kenner C.; Steinberg, SeAnna; Ernsberger, Paul; Rothman, Richard B.
Pindolol--the pharmacology of a partial agonist.
1 Pindolol is a non-selective beta-adrenoceptor blocking agent; its affinity to adrenoceptors in guinea pig atria (beta 1) is not significantly different from that in guinea pig trachea (beta 1 + beta 2) and canine vascular smooth muscle (beta 2). 2 Pindolol displays a striking diversity of agonist activities in isolated tissues. Stimulant effects correspond to 40--50% of the maximum effects of isoprenaline in isolated kitten atria and guinea pig trachea and to only 10% in guinea pig atria. Effects in canine isolated mesenteric vessels are those of a full agonist, maximum responses equaling those of isoprenaline. These findings suggest that the stimulant effects of pindolol are exerted principally on beta 2-adrenoceptors. 3 Cardiac stimulation produced by pindolol in the dog is sufficient to compensate for the cardiac depression resulting from blockade of beta-adrenoceptors in the heart. Reductions in cardiac output and compensatory increases in total peripheral resistance do not occur or are much smaller than those produced by beta-adrenoceptor blocking agents lacking sympathomimetic activity. 4 Pindolol-induced relaxation of bronchial smooth muscle prevents or minimizes the bronchoconstrictor effects of injected spasmogens in the cat. 5 Pindolol has marked vasodilator activity, small doses reducing femoral and mesenteric vascular resistance by approximately 30%. Doses comparable to those used in hypertensive patients lower blood pressure by 20 mmHg in non-anaesthetized dogs.
Clark, B J; Menninger, K; Bertholet, A
Computational study of synthetic agonist ligands of ionotropic glutamate receptors.
Neurological glutamate receptors are among the most important and intensely studied protein ligand binding systems in humans. They are crucial for the functioning of the central nervous system and involved in a variety of pathologies. Apart from the neurotransmitter glutamate, several artificial, agonistic and antagonistic ligands are known. Of particular interest here are novel photoswitchable agonists that would open the field of optogenetics to glutamate receptors. The receptor proteins are complex, membrane-bound multidomain oligomers that undergo large scale functional conformational changes, making detailed studies of their atomic structure challenging. Therefore, a thorough understanding of the microscopic details of ligand binding and receptor activation remains elusive in many cases. This topic has been successfully addressed by theoretical studies in the past and in this paper, we present extensive molecular dynamics simulation and free energy calculation results on the binding of AMPA and an AMPA derivative, which is the basis for designing light-sensitive ligands. We provide a two-step model for ligand binding domain activation and predict binding free energies for novel compounds in good agreement to experimental observations. PMID:23536824
Wolter, Tino; Steinbrecher, Thomas; Elstner, Marcus
Computational Study of Synthetic Agonist Ligands of Ionotropic Glutamate Receptors
Neurological glutamate receptors are among the most important and intensely studied protein ligand binding systems in humans. They are crucial for the functioning of the central nervous system and involved in a variety of pathologies. Apart from the neurotransmitter glutamate, several artificial, agonistic and antagonistic ligands are known. Of particular interest here are novel photoswitchable agonists that would open the field of optogenetics to glutamate receptors. The receptor proteins are complex, membrane-bound multidomain oligomers that undergo large scale functional conformational changes, making detailed studies of their atomic structure challenging. Therefore, a thorough understanding of the microscopic details of ligand binding and receptor activation remains elusive in many cases. This topic has been successfully addressed by theoretical studies in the past and in this paper, we present extensive molecular dynamics simulation and free energy calculation results on the binding of AMPA and an AMPA derivative, which is the basis for designing light-sensitive ligands. We provide a two-step model for ligand binding domain activation and predict binding free energies for novel compounds in good agreement to experimental observations.
Wolter, Tino; Steinbrecher, Thomas; Elstner, Marcus
Isothiouronium compounds as gamma-aminobutyric acid agonists.
Analogues of gamma-aminobutyric acid (GABA) incorporating an isothiouronium salt as a replacement for a protonated amino functional group have been investigated for activity on: GABA receptors in the guinea-pig ileum; [3H]-GABA and [3H]-diazepam binding to rat brain membranes; and GABA uptake and transamination. For the homologous series of omega-isothiouronium alkanoic acids, maximum GABA-mimetic activity was found at 3-[(aminoiminomethyl)thio]propanoic acid. Introduction of unsaturation into this compound gave two isomeric conformationally restricted analogues. The trans isomer was inactive at GABA receptors while the cis compound ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA)) was more potent than muscimol and GABA as a GABA agonist with respect to low affinity GABA receptor sites. Both isomers were moderately potent at inhibiting the uptake of [3H]-GABA into rat brain slices. Comparison of possible conformations of the two unsaturated isomers by interactive computer graphics modelling and comparison with muscimol has led to a plausible active conformation of ZAPA, which may be a selective and potent agonist for low affinity GABA binding sites. PMID:3015310
Allan, R D; Dickenson, H W; Hiern, B P; Johnston, G A; Kazlauskas, R
Muscarinic Receptor Agonists and Antagonists: Effects on Cancer
Many epithelial and endothelial cells express a cholinergic autocrine loop in which acetylcholine acts as a growth factor to stimulate cell growth. Cancers derived from these tissues similarly express a cholinergic autocrine loop and ACh secreted by the cancer or neighboring cells interacts with M3 muscarinic receptors expressed on the cancer cells to stimulate tumor growth. Primary proliferative pathways involve MAPK and Akt activation. The ability of muscarinic agonists to stimulate, and M3 antagonists to inhibit tumor growth has clearly been demonstrated for lung and colon cancer. The ability of muscarinic agonists to stimulate growth has been shown for melanoma, pancreatic, breast, ovarian, prostate and brain cancers, suggesting that M3 antagonists will also inhibit growth of these tumors as well. As yet no clinical trials have proven the efficacy of M3 antagonists as cancer therapeutics, though the widespread clinical use and low toxicity of M3 antagonists support the potential role of these drugs as adjuvants to current cancer therapies.
Agonistic induction of PPAR? reverses cigarette smoke-induced emphysema.
The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator-activated receptor ? (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPAR? in APCs using Cd11c-Cre Pparg(flox/flox) mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Pparg(flox/flox) mice required OPN, suggesting an antiinflammatory mechanism in which PPAR? negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPAR? agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPAR? agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPAR? activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema. PMID:24569375
Shan, Ming; You, Ran; Yuan, Xiaoyi; Frazier, Michael V; Porter, Paul; Seryshev, Alexander; Hong, Jeong-Soo; Song, Li-zhen; Zhang, Yiqun; Hilsenbeck, Susan; Whitehead, Lawrence; Zarinkamar, Nazanin; Perusich, Sarah; Corry, David B; Kheradmand, Farrah
Anticancer flavonoids are mouse-selective STING agonists.
The flavonoids FAA and DMXAA showed impressive activity against solid tumors in mice but failed clinical trials. They act on a previously unknown molecular target(s) to trigger cytokine release from leukocytes, which causes tumor-specific vascular damage and other antitumor effects. We show that DMXAA is a competitive agonist ligand for mouse STING (stimulator of interferon genes), a receptor for the bacterial PAMP cyclic-di-GMP (c-di-GMP) and an endogenous second messenger cyclic-GMP-AMP. In our structure-activity relationship studies, STING binding affinity and pathway activation activity of four flavonoids correlated with activity in a mouse tumor model measured previously. We propose that STING agonist activity accounts for the antitumor effects of FAA and DMXAA in mice. Importantly, DMXAA does not bind to human STING, which may account for its lack of efficacy or mechanism-related toxicity in man. We propose that STING is a druggable target for a novel innate immune activation mechanism of chemotherapy. PMID:23683494
Kim, Sujeong; Li, Lingyin; Maliga, Zoltan; Yin, Qian; Wu, Hao; Mitchison, Timothy J
A novel PPARgamma agonist monascin's potential application in diabetes prevention.
Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways. PMID:24752777
Hsu, Wei-Hsuan; Pan, Tzu-Ming
Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets
The metabolism of inositol phospholipids in response to serotonergic agonists was investigated in rabbit platelets. In platelets prelabelled with (/sup 3/H)-inositol, in a medium containing 10 mM LiCl which blocks the enzyme inositol-1-phosphatase, 5-hydroxytryptamine (5-HT) caused a dose-dependent accumulation of inositol phosphates (IP). This suggests a phospholipase-C-mediated breakdown of phosphoinositides. Ketanserin, a selective 5-HT/sub 2/ antagonist, was a potent inhibitor of the 5-HT response, with a Ki of 28 nM, indicating that 5-HT is activating receptors of the 5-HT/sub 2/ type in the platelet. Lysergic acid diethylamide (LSD) and quipazine also caused dose-related increases in inositol phosphate levels, though these were considerably less than those produced by 5-HT. These results show that relatively small changes in phosphoinositide metabolism induced by serotonergic agonists can be investigated in the rabbit platelet, and this cell may therefore be a useful model for the study of some 5-HT receptors. 30 references, 4 figures.
Schaechter, M.; Godfrey, P.P.; Minchin, M.C.W.; McClue, S.J.; Young, M.M.
Nicotinic acetylcholine receptor agonists: a milestone for modern crop protection.
The destruction of crops by invertebrate pests is a major threat against a background of a continuously rising demand in food supply for a growing world population. Therefore, efficient crop protection measures in a vast range of agricultural settings are of utmost importance to guarantee sustainable yields. The discovery of synthetic agonists selectively addressing the nicotinic acetylcholine receptors (nAChRs), located in the central nervous system of insects, for use as insecticides was a major milestone in applied crop protection research. These compounds, as a result of their high target specificity and versatility in application methods, opened a new innovative era in the control of some of the world's most devastating insect pests. These insecticides also contributed massively to extending our knowledge of the biochemistry of insect nicotinic acetylcholine receptors. The global economic success of synthetic nAChR agonists as insecticides renders the nicotinic acetylcholine receptor still one of the most attractive target sites for exploration in insecticide discovery. PMID:23934864
Jeschke, Peter; Nauen, Ralf; Beck, Michael Edmund
La variabilité des canaux semi-circulaires osseux
Résumé Depuis le début du sičcle les observations anatomiques ont révélé la variabilité de la disposition des canaux semi-circulaires osseux (canales semi-circulares ossei) et celle des appareils vestibulaires droit et gauche pris dans leur ensemble.
M. Caix; G. Outrequin
Bedeutung des Debitorenratings für das Working Capital Management
\\u000a Wie die folgende Darstellung veranschaulicht, versteht sich Debitorenrating als ein Baustein des Debitorenmanagements. Letzteres\\u000a ist wiederum eine der drei Komponenten des Working Capital Managements.
Bianca Heyke; Michael Stahl
Politique des déchets : l'approche du Royaume-Uni
[fre] Politique des déchets : l'approche du Royaume-Uni . L'évolution récente de la réglementation européenne en dématičre de déchets risque d'entraîner des coűts importants pour les États membres. L'exemple britannique est d'autant plus intéressant pour la France que les deux pays présentent des similitudes : quantité presque identique de déchets ménagers (environ 20 millions de tonnes), faible capacité des incinérateurs
David Litvan
La construction de réponses ŕ des problčmes impossibles
Résumé — Cet article se propose d'illustrer la dynamique de construction de réponses ŕ des problčmes impossibles. En fonction du cadre conceptuel, situé ŕ l'articulation de problématiques psychologiques et didactiques, un modčle d'analyse des différents plans de rationalité en jeu dans la fabrication des réponses des élčves est présenté et discuté. Le choix de problčmes impossibles de différentes complexités s'avčre
Maria Luisa Schubauer-Leoni; Ladislas Ntamakiliro
Théâtre et entreprise, état des lieux et une approche globale
Voilŕ quinze ans environ, démarraient les premičres expériences du théâtre dit d'entreprise (Michel Fustier, 1996). Deux grandes orientations se sont développées, le théâtre au service des hommes de l'entreprise et le théâtre au service de l'organisation d'entreprise. Au service des hommes, la pratique des techniques théâtrales contribuent au développement personnel, au travers des formations ŕ la prise de parole en
Laurent Lesavre
Conformational analysis and molecular modelling of a partial GABAA agonist and a glycine antagonist related to the GABAA agonist, THIP.
A series of 3-hydroxyisoxazoles (3-isoxazoles) substituted in the 5-position by piperidyl moieties (2-, 3-, and 4-PIOL) were studied by molecular modelling and computer graphics methods. Whereas 2-PIOL is pharmacologically inactive, 3-PIOL is a glycine antagonist and 4-PIOL a low-efficacy partial GABAA agonist. A conformational analysis of the isomeric PIOLs was performed on the basis of molecular mechanics calculations. The conformational analysis revealed a large degree of conformational freedom for all three compounds, especially of conformers having the 3-hydroxyisoxazole moiety in equatorial positions. By comparison of the PIOLs with the semi-rigid GABAA agonist THIP and the conformationally restricted glycine antagonist THAZ, the conformations relevant for GABAA and glycine receptor recognition were determined. For 2-PIOL a predicted active conformation is energetically favourable, but it exhibits considerable extra volume as compared to THIP, which may explain its lack of affinity for GABAA receptors. 3-PIOL is capable of adopting a conformation resembling that of THAZ. The GABAA receptor affinity of 4-PIOL may be explained by its ability to orientate the functional groups in space in a manner that allows a comparison with THIP. The low efficacy and affinity of 4-PIOL may reflect that not all atoms are directly involved in receptor binding. Certain steric requirements for binding to the GABAA receptor site have been identified and discussed. PMID:8268393
Buur, J R; Hjeds, H; Krogsgaard-Larsen, P; Jřrgensen, F S
Small molecules with similar structures exhibit agonist, neutral antagonist or inverse agonist activity toward angiotensin II type 1 receptor.
Small differences in the chemical structures of ligands can be responsible for agonism, neutral antagonism or inverse agonism toward a G-protein-coupled receptor (GPCR). Although each ligand may stabilize the receptor conformation in a different way, little is known about the precise conformational differences. We synthesized the angiotensin II type 1 receptor blocker (ARB) olmesartan, R239470 and R794847, which induced inverse agonism, antagonism and agonism, respectively, and then investigated the ligand-specific changes in the receptor conformation with respect to stabilization around transmembrane (TM)3. The results of substituted cysteine accessibility mapping studies support the novel concept that ligand-induced changes in the conformation of TM3 play a role in stabilizing GPCR. Although the agonist-, neutral antagonist and inverse agonist-binding sites in the AT(1) receptor are similar, each ligand induced specific conformational changes in TM3. In addition, all of the experimental data were obtained with functional receptors in a native membrane environment (in situ). PMID:22719858
Miura, Shin-ichiro; Kiya, Yoshihiro; Hanzawa, Hiroyuki; Nakao, Naoki; Fujino, Masahiro; Imaizumi, Satoshi; Matsuo, Yoshino; Yanagisawa, Hiroaki; Koike, Hiroyuki; Komuro, Issei; Karnik, Sadashiva S; Saku, Keijiro
Small Molecules with Similar Structures Exhibit Agonist, Neutral Antagonist or Inverse Agonist Activity toward Angiotensin II Type 1 Receptor
Small differences in the chemical structures of ligands can be responsible for agonism, neutral antagonism or inverse agonism toward a G-protein-coupled receptor (GPCR). Although each ligand may stabilize the receptor conformation in a different way, little is known about the precise conformational differences. We synthesized the angiotensin II type 1 receptor blocker (ARB) olmesartan, R239470 and R794847, which induced inverse agonism, antagonism and agonism, respectively, and then investigated the ligand-specific changes in the receptor conformation with respect to stabilization around transmembrane (TM)3. The results of substituted cysteine accessibility mapping studies support the novel concept that ligand-induced changes in the conformation of TM3 play a role in stabilizing GPCR. Although the agonist-, neutral antagonist and inverse agonist-binding sites in the AT1 receptor are similar, each ligand induced specific conformational changes in TM3. In addition, all of the experimental data were obtained with functional receptors in a native membrane environment (in situ).
Hanzawa, Hiroyuki; Nakao, Naoki; Fujino, Masahiro; Imaizumi, Satoshi; Matsuo, Yoshino; Yanagisawa, Hiroaki; Koike, Hiroyuki; Komuro, Issei; Karnik, Sadashiva S.; Saku, Keijiro
Zur Kanülierung des Ductus thoracicus beim Pfortaderhochdruck der Lebercirrhose
Zusammenfassung Bei 24 Patienten wurde der Ductus thoracicus im Bereich des Angulus veno-lymphaticus freigelegt. Vier Patienten hatten davon eine intakte Leber. Kaliber und Lymphfluß des Ductus thoracicus entsprachen hier den schon bekannten Normalwerten. Bei den 20 Patienten mit Lebercirrhose war der Lymphfluß in 18 Fällen erhöht, eine Erweiterung des Ductus thoracicus fand sich aber nur in der Hälfte der Fälle.
A. Fritsch; K. Mach
Financement, investissement et performances des entreprises industrielles françaises
Les interrogations nombreuses au sujet des PME en restent généralement ŕ un constat d' insuffisance de fonds propre, confondant ainsi problčme de financement et nature de celui-ci. En outre elles trouvent leur origine dans une comparaison abusive avec les grandes entreprises, ignorant des traits distinctifs déterminants liés ŕ l' effort d' accumulation et ŕ la nature des contraintes selon la
Bernard Paranque
Fair diagnosability in PN-based DES models
Failure diagnosability has been widely studied for discrete event system (DES) models because of modeling simplicity and computational efficiency due to abstraction. Frameworks based on FSMs, process algebra, Petri nets (PN) etc. have been used for modeling and diagnosability analysis of DES. DES failure diagnosability algorithms work successfully for systems where fairness is not a part of the model. They
A. Khan; K. Misra; S. Biswas; J. Deka; H. Kapoor
Die Verhütung von Erschöpfungszuständen des Herzens durch Digitalissubstanzen
Zusammenfassung Durch erschöpfendes Schwimmen bzw. Lauftraining wird bei Ratten eine Herzund Nebennierenhypertrophie erzeugt. Durch Injektion von g-Strophanthin bzw. k-Strophanthin jeweils vor Beginn des Trainings ist es möglich, die Hypertrophie des Herzens und der Nebennieren zu vermindern. Daraus ist zu schließen, daß Strophanthin die Leistung des Herzens so verbessert, daß einer Erschöpfung, d. h. relativen Insuffizienz vorgebeugt wird.
Gustav Kuschinsky
Investigation of D1 Receptor-Agonist Interactions and D1/D2 Agonist Selectivity Using a Combination of Pharmacophore and Receptor Homology Modeling
The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D1 receptor agonism and D1/D2 agonist selectivity. A 3D structure model of the D1 receptor in its agonist-bound state was constructed with a full D1 agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D1 agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor-based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D1 and D2 receptors revealed differences in shape and ligand-interacting features that determine selectivity of D1 and D2 receptor agonists. A hydrogen bond pharmacophoric feature (Ser-TM5) was shown to contribute most to the selectivity. Non-conserved residues in the binding pocket that strongly contribute to D1/D2 receptor agonist selectivity were also identified; those were Ser/Cys3.36, Tyr/Phe5.38, Ser/Tyr5.41, and Asn/His6.55 in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D1 and D2 agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand–protein interactions for which experimental information is limited.
Malo, Marcus; Brive, Lars; Luthman, Kristina; Svensson, Peder
Étude expérimentale des micro-mécanismes d'endommagement et de rupture des zircaloy hydrurés
NASA Astrophysics Data System (ADS)
Afin de mieux comprendre les mécanismes d'endommagement et de rupture des Zircaloy, des essais de traction sur anneaux ont été réalisés in-situ sous MEB sur des éprouvettes de tube de gainage de combustible, contenant environ 150ppm d'hydrogčne et avec différentes orientations d'hydrures: de circonférentielle ŕ radiale. Ces essais ont mis en évidence deux modes de rupture selon l'orientation des hydrures. Les éprouvettes avec hydrures radiaux (perpendiculaires ŕ la sollicitation) rompent brutalement par propagation d'une fissure suivant un chemin d'hydrures radiaux alignés. Les niveaux de déformation au voisinage de la fissure, estimés par des techniques de micro-électrolithographie associées ŕ celle d'analyse par corrélation d'images, sont trčs faibles, de l'ordre du %. En revanche, dans celles avec hydrures circonférentiels (suivant l'axe de sollicitation), les effets de structure prédominent: des bandes de cisaillement macroscopique apparaissent, dans lesquelles la déformation se localise. En dehors de ces zones de localisation intense, la déformation reste inférieure ŕ 10% et trčs peu d'endommagement par germination de cavités ou fissuration d'hydrures a été observé. Les hétérogénéités du champ local de déformation, corrélées ŕ la présence des hydrures, semblent établir l'influence de ceux-ci sur le mode de déformation local, mais ces observations nécessitent d'ętre confirmées.
Racine, A.; Bornert, M.; Sainte Catherine, C.; Caldemaison, D.
Profil epidemiologique des brulures d'enfants admis au Centre National des Brules, Maroc
Summary Ce travail rétrospectif analyse les particularités épidémiologiques de 543 cas de brűlures d'enfants, représentant 45,7% des admissions de notre centre, en vue de déterminer les éléments pouvant contribuer ŕ renforcer la prévention, qui reste le traitement de choix de cette pathologie. La moyenne d'âge est de 4,25 ans avec une prédilection pour la tranche d'âge d'un ŕ cinq ans, avec 42,5% des cas. Une atteinte masculine est retrouvée dans 63,5% des cas. La brűlure survient ŕ domicile dans 85,1% et accidentellement dans 95% des cas. Les brűlures thermiques représentent 96,5% des causes dominées par les liquides dans 69,3% des cas. La surface cutanée brűlée est ? 20% dans 52,3%. La brűlure intéresse essentiellement les membres supérieurs (79,1%). 56,8% des enfants sont transférés par d'autres hôpitaux et le délai de prise en charge hospitaličre est supérieur ŕ 6 heures dans 65,5%. Le taux de mortalité a été de 13,2%.
Zahid, A.; Atannaz, J.; Alaoui, M.; Rafik, A.; Ezzoubi, M.; Diouri, M.; Chlihi, A.; Bahechar, N.; Boukind, E.H.
Information content of male agonistic displays in the territorial tawny dragon ( Ctenophorus decresii )
Two potential signals used during male–male agonistic encounters were examined for signal content in the territorial agamid lizard Ctenophorus decresii, or tawny dragon. Males have black chest patches, which are apparent when they posture during agonistic encounters. Patches are not condition or size dependent. The area of the patches is positively associated with levels of aggression and likelihood of winning
Louise Osborne
Inhalation of ?2 agonists impairs the clearance of nontypable Haemophilus influenzae from the murine respiratory tract
BACKGROUND: Nontypable Haemophilus influenzae (NTHi) is a common bacterial pathogen causing human respiratory tract infections under permissive conditions such as chronic obstructive pulmonary disease. Inhalation of ?2-receptor agonists is a widely used treatment in patients with chronic obstructive pulmonary disease. The aim of this study was to determine the effect of inhalation of ?2 agonists on the host immune response
Nico A Maris; Sandrine Florquin; Cornelis van't Veer; Vos F. de Alex; Wim Buurman; Jansen M. Henk; Tom van der Poll
In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2 receptor?
Background and purpose: The CB2 receptor has been proposed as a novel target for the treatment of pain, and CB2 receptor agonists defined in in vitro assays have demonstrated analgesic activity in animal models. Based on its in vivo analgesic efficacy, AM1241 has been classified as a CB2-selective agonist. However, in vitro characterization of AM1241 in functional assays has not been reported. Experimental approach: In this study, AM1241 was characterized across multiple in vitro assays employing heterologous recombinant receptor expression systems to assess its binding potencies at the human CB2 and CB1 receptors and its functional efficacies at the human CB2 receptor. Key results: AM1241 exhibited distinct functional properties depending on the assay conditions employed, a unique profile in contrast to those of the agonist CP 55,940 and the inverse agonist SR144528. AM1241 displayed neutral antagonist activities in FLIPR and cyclase assays. However, when cyclase assays were performed using lower forskolin concentrations for stimulation, AM1241 exhibited partial agonist efficacy. In addition, it behaved as a partial agonist in ERK (or MAP) kinase assays. Conclusions and implications: The unusual phenomenon of inconsistent functional efficacies suggests that AM1241 is a protean agonist at the CB2 receptor. We postulate that functional efficacies displayed by protean agonists in various assay systems may depend on the levels of receptor constitutive activities exhibited in the assay systems, and therefore, efficacies observed in in vitro assays may not predict in vivo activities.
Yao, B B; Mukherjee, S; Fan, Y; Garrison, T R; Daza, A V; Grayson, G K; Hooker, B A; Dart, M J; Sullivan, J P; Meyer, M D
Cooperative Activation of Gene Expression by Agonists and Antagonists Mediated by Estrogen Receptor Heteroligand Dimer Complexes
Estrogen receptor (ER) antagonists are generally thought to inhibit estrogen action through competitive inhibition, resulting in receptor binding to antagonist rather than agonist. However, microarray analyses reveal a group of genes for which ER agonist and antagonist cooperatively regulate expression, suggesting additional models of combined agonist/antagonist action must exist. In conjunction with a chimeric reporter gene and two modified ERs, one [ER?(GSCKV)] with a mutation in the DNA-binding domain and the other (ER?-G521R) with a ligand-binding specificity mutation, we herein demonstrate that ER agonist and antagonist cooperatively activate gene expression through an ER heteroligand dimer complex (ER-HLD) consisting of one subunit of the receptor dimer bound to agonist and another occupied by antagonist. Coimmunoprecipitation experiments confirmed interaction between the agonist-bound and antagonist-bound receptors. This cooperative activation of gene expression was enhanced by steroid receptor coactivator 3 coactivator, and required each ligand-bound subunit of the dimer to bind to DNA, as well as both activation function 1 domains for maximal transcriptional activity. Ligand combinations able to induce ER-HLD transcriptional activity include the agonists 17?-estradiol or conjugated estrogens with the antagonists tamoxifen, raloxifene, bazedoxifene, or fulvestrant. Moreover, ER-HLD can activate transcription in the context of a natural promoter. Taken together, these findings broaden our understanding of the complex relationship between ER agonist and antagonist, and suggest a novel model by which cell and tissue selective effects of antiestrogens may be achieved.
Liu, Shuang; Han, Sang Jun
Synthesis, photolysis studies and in vitro photorelease of caged TRPV1 agonists and antagonists.
The synthesis of a range of caged TRPV1 agonists and antagonists is reported. The photolysis characteristics of these compounds, when irradiated with a 355 nm laser, have been studied and in all cases the desired compound was produced. Photolysis of a caged TRPV1 agonist in cultured trigeminal neurons produced responses that were consistent with the activation of TRPV1 receptors. PMID:19865707
Van Ryssen, Michael P; Avlonitis, Nicolaos; Giniatullin, Rashid; McDougall, Craig; Carr, James L; Stanton-Humphreys, Megan N; Borgström, Emma L A; Brown, C Tom A; Fayuk, Dmitriy; Surin, Alexander; Niittykoski, Minna; Khiroug, Leonard; Conway, Stuart J
Dominance relations and agonistic behaviour of Tundra Swans ( Cygnus columbianus columbianus ) during fall and spring migration
Social interactions and agonistic activities of Tundra Swans (Cygnus columbianus columbianus ) were docu- mented at Long Point, Ontario, to determine (i) dominance relations among social groups and (ii) the frequency and in- tensity of agonistic acts by swans. Families were involved in one-third as many interactions as were nonfamily groups. Nonfamily groups initiated interactions with other nonfamily groups more
Shannon S. Badzinski
Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120).
The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein. PMID:24881566
Sparks, Steven M; Chen, Grace; Collins, Jon L; Danger, Dana; Dock, Steven T; Jayawickreme, Channa; Jenkinson, Stephen; Laudeman, Christopher; Leesnitzer, M Anthony; Liang, Xi; Maloney, Patrick; McCoy, David C; Moncol, David; Rash, Vincent; Rimele, Thomas; Vulimiri, Padmaja; Way, James M; Ross, Sean
The Effect of the Melanocortin Agonist, MT-II, on the Defended Level of Body Adiposity
A wide range of experimental evidence implicates a critical role for melanocortin signaling in the control of food intake and body adiposity. Melanocortin receptor agonists such as MT-II potently reduce food intake and body weight, making such agonists potential therapeutics for obesity. The critical concept addressed by the present experiments is whether the homeostaticeffectsofmelanocortinagonistsdirectlyregulate food intake or whether the effects
Randy J. Seeley; Melissa L. Burklow; Kihmberly A. Wilmer; Colette C. Matthews; Ofer Reizes; Charles C. McOsker; Darren P. Trokhan; Marla C. Gross; Russell J. Sheldon
Design driven HtL: The discovery and synthesis of new high efficacy ??-agonists.
The design and synthesis of a new series of high efficacy ?(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious ?(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of ?(2)-adrenoceptor crystal structure, other biophysical data and modeling studies. PMID:21652207
Stocks, Michael J; Alcaraz, Lilian; Bailey, Andrew; Bonnert, Roger; Cadogan, Elaine; Christie, Jadeen; Connolly, Stephen; Cook, Anthony; Fisher, Adrian; Flaherty, Alice; Hill, Stephen; Humphries, Alexander; Ingall, Anthony; Jordan, Stephen; Lawson, Mandy; Mullen, Alex; Nicholls, David; Paine, Stuart; Pairaudeau, Garry; St-Gallay, Stephen; Young, Alan
From libraries to candidate: The discovery of new ultra long-acting dibasic ? 2-adrenoceptor agonists
Libraries of dibasic compounds designed around the molecular scaffold of the DA2\\/?2 dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious ?2-agonist with high selectivity and a
Lilian Alcaraz; Andrew Bailey; Elaine Cadogan; Stephen Connolly; Robert Jewell; Stephen Jordan; Nicholas Kindon; Andrew Lister; Mandy Lawson; Alexander Mullen; Ian Dainty; David Nicholls; Stuart Paine; Garry Pairaudeau; Michael J. Stocks; Phillip Thorne; Alan Young
Design driven HtL: The discovery and synthesis of new high efficacy ? 2-agonists
The design and synthesis of a new series of high efficacy ?2-agonists devoid of the key benzylic alcohol present in previously described highly efficacious ?2-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of ?2-adrenoceptor crystal structure, other biophysical data and modeling studies.
Michael J. Stocks; Lilian Alcaraz; Andrew Bailey; Roger Bonnert; Elaine Cadogan; Jadeen Christie; Stephen Connolly; Anthony Cook; Adrian Fisher; Alice Flaherty; Stephen Hill; Alexander Humphries; Anthony Ingall; Stephen Jordan; Mandy Lawson; Alex Mullen; David Nicholls; Stuart Paine; Garry Pairaudeau; Stephen St-Gallay; Alan Young
PPAR agonists stimulate adipogenesis at the expense of osteoblast differentiation while inhibiting osteoclast formation and activity.
Drugs used in the treatment of type 2 diabetes and cardiovascular disease, specifically peroxisome proliferator-activated receptor (PPAR) agonists, have been reported to affect bone cell function and fracture risk. In this study, we assessed the direct effects of PPAR-? agonists (rosiglitazone and troglitazone), used in the treatment of diabetes, and a PPAR-? agonist (fenofibrate), used to treat hyperlipidaemia, on the function of primary osteoblasts and osteoclasts. Formation of 'trabecular' bone structures by rat calvarial osteoblasts was reduced by up to 85% in cultures treated with rosiglitazone and by 45% in troglitazone-treated or fenofibrate-treated cultures; at the same time, lipid droplet formation was increased by 40-70%. The expression of key osteogenic markers was similarly downregulated in cultures treated with PPAR agonists, whereas adipogenesis markers were upregulated. Formation of osteoclasts in cultures derived from mouse marrow diminished with fenofibrate treatment, whereas both glitazones reduced resorptive activity without affecting osteoclast number. Metformin, although not a PPAR agonist, is also commonly used in the treatment of type 2 diabetes. Here, metformin was found to have no effect on bone cell function. Taken together, these data suggest that PPAR-? agonists may enhance bone loss via increased adipogenesis at the expense of osteoblast formation. In contrast, PPAR-? agonists may prevent bone loss. Given that the prevalence of diabetes and cardiovascular disease is expected to rise significantly, greater attention may need to be paid to the effects of PPAR agonists on bone homeostasis. Copyright © 2014 John Wiley & Sons, Ltd. PMID:24615887
Patel, Jessal J; Butters, Oliver R; Arnett, Timothy R
PPAR-Alpha Agonists as Novel Antiepileptic Drugs: Preclinical Findings
Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in ?4 or ?2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-? (PPAR?), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing ?2 subunits. On these bases, we tested whether PPAR? agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ?100% of mice. A single dose of the synthetic PPAR? agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPAR? antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPAR? agonists abolished nicotine-induced sIPSC increases. PPAR? within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.
Melis, Miriam; Lecca, Salvatore; Marrosu, Francesco; De Montis, Maria Graziella; Scheggi, Simona; Carta, Gianfranca; Murru, Elisabetta; Aroni, Sonia; Muntoni, Anna Lisa; Pistis, Marco
Differential effects of micro-opioid, delta-opioid and kappa-opioid receptor agonists on dopamine receptor agonist-induced climbing behavior in mice.
Interactions between the dopaminergic system and opioids have not been adequately clarified. The present study was designed to investigate the effects of micro-opioid (morphine), delta-opioid (SNC80) and kappa-opioid (U50 488H) receptor agonists on dopamine receptor agonist-induced climbing behavior in mice. Apomorphine (dopamine-receptor agonist) increased stereotyped climbing behavior, unlike methamphetamine, morphine, U-50 488H and (+/-)7-hydroxy-N,N-di-n-propyl-2-aminotetralin hydrobromide (D2-like receptor agonist). Furthermore, SKF81297 (D1 receptor agonist) and SNC80 caused climbing behavior. In addition, while morphine (20 mg/kg), but not U50 488H or SNC80, significantly attenuated high-dose apomorphine (2.0 mg/kg)-induced climbing behavior, it significantly potentiated low-dose apomorphine (0.5 mg/kg)-induced climbing behavior. These results suggest that morphine may have dual effects on the behavioral effects induced by apomorphine. Furthermore, we interestingly showed that the combination of apomorphine or SKF81297 and SNC80 enhanced frequent nonstereotypic climbing behavior, suggesting that delta/D1 interactions may play a prominent role in the expression of certain types of behavior in mice. Thus, micro-opioid, delta-opioid and kappa-opioid receptor agonists induce possible differential effects on the dopaminergic system in mice. PMID:17110795
Ito, Shinobu; Mori, Tomohisa; Sawaguchi, Toshiko
De l'hypothčse de revenu permanent en politique de distribution des profits des sociétés : une polémique
[fre] La transposition, en politique de distribution des profits des sociétés, de l'hypothčse de revenu permanent met en évidence certaines implications financičres intéressantes de cette politique de ventilation. Toutefois, les comportements différents du consommateur et de la firme appellent certaines réserves quant ŕ la transposition directe. Aussi une approche alternative fut envisagée, consistant ŕ examiner la réceptivité des formulations traditionnelles
Jean-Pierre Chateau
Discovery of substituted sulfonamides and thiazolidin-4-one derivatives as agonists of human constitutive androstane receptor.
The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor responsible for the recognition of potentially toxic endo- and exogenous compounds whose elimination from the body is accelerated by the CAR-mediated inducible expression of metabolizing enzymes and transporters. Despite the importance of CAR, few human agonists are known so far. Following a sequential virtual screening procedure using a 3D pharmacophore and molecular docking approach, we identified 17 novel agonists that could activate human CAR in vitro and enhance its association with the nuclear receptor co-activator SRC1. Selected agonists also increased the expression of the human CAR target CYP2B6 mRNA in primary hepatocytes. Composed of substituted sulfonamides and thiazolidin-4-one derivatives, these agonists represent two novel chemotypes capable of human CAR activation, thus broadening the agonist spectrum of CAR. PMID:18786510
Küblbeck, Jenni; Jyrkkärinne, Johanna; Poso, Antti; Turpeinen, Miia; Sippl, Wolfgang; Honkakoski, Paavo; Windshügel, Björn
Dihydroergocriptine in Parkinson's disease: clinical efficacy and comparison with other dopamine agonists.
The present paper reviews clinical studies on the use of dihydroergocriptine (DHEC), an ergot derivative with dopamine agonist activity, for the treatment of Parkinson's disease. This compound is a hydrogenated ergot derivative structurally quite similar to bromocriptine, from which it differs because of the hydrogenation in C9 C10 and the lack of bromine in C2. DHEC has a potent D2-like receptor agonist and a partial D1-like receptor agonist activity; because of this biochemical profile, it has been suggested that DHEC may produce fewer side-effects and have clinical efficacy equal to that of a classical dopamine agonist. Several open-label and double-blind studies indicate that DHEC is an efficacious remedy for parkinsonian signs and symptoms. Further studies are necessary to compare DHEC to new dopamine agonists (pergolide, cabergoline, ropinirole, and pramipexole) which have been more recently marketed. PMID:12713527
Albanese, A; Colosimo, C
Rate constants of agonist binding to muscarinic receptors in rat brain medulla. Evaluation by competition kinetics
The method of competition kinetics, which measures the binding kinetics of an unlabeled ligand through its effect on the binding kinetics of a labeled ligand, was employed to investigate the kinetics of muscarinic agonist binding to rat brain medulla pons homogenates. The agonists studied were acetylcholine, carbamylcholine, and oxotremorine, with N-methyl-4-(TH)piperidyl benzilate employed as the radiolabeled ligand. Our results suggested that the binding of muscarinic agonists to the high affinity sites is characterized by dissociation rate constants higher by 2 orders of magnitude than those of antagonists, with rather similar association rate constants. Our findings also suggest that isomerization of the muscarinic receptors following ligand binding is significant in the case of antagonists, but not of agonists. Moreover, it is demonstrated that in the medulla pons preparation, agonist-induced interconversion between high and low affinity bindings sites does not occur to an appreciable extent.
Schreiber, G.; Henis, Y.I.; Sokolovsky, M.
Identification, Optimization, and Pharmacology of Acylurea GHS-R1a Inverse Agonists.
Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a. PMID:24967667
McCoull, William; Barton, Peter; Brown, Alastair J H; Bowker, Suzanne S; Cameron, Jennifer; Clarke, David S; Davies, Robert D M; Dossetter, Alexander G; Ertan, Anne; Fenwick, Mark; Green, Clive; Holmes, Jane L; Martin, Nathaniel; Masters, David; Moore, Jane E; Newcombe, Nicholas J; Newton, Claire; Pointon, Helen; Robb, Graeme R; Sheldon, Christopher; Stokes, Stephen; Morgan, David
New Guidelines for Cervical Cancer Screening
... with human immunodeficiency virus (HIV) , have a weakened immune system , or who were exposed to diethylstilbestrol (DES) before ... anus, and throat. Hysterectomy: Removal of the uterus. Immune System: The body's natural defense system against foreign substances ...
La structure des systčmes désordonnés et sa mesure par diffraction
NASA Astrophysics Data System (ADS)
La compréhension de mainte propriété physique d'un verre ou d'un liquide nécessite la connaissance des facteurs de structure partiels (PSFs) qui décrivent chacun la distribution d'une espčce atomique autour d'une autre. La technique de diffraction des neutrons avec substitution isotopique (NDIS) [1,2,3], ayant bien réussi a déterminer les PSFs de certains composés [4,5], est pourtant restreinte aux isotopes présentant un contraste suffisant en longueur de diffusion. D'un autre cote, la technique de diffusion anomale des rayons X (AXS ou AXD) [6] permet de faire varier la longueur de diffusion d'une espčce atomique pourvu que son énergie d'absorption soit ŕ la fois accessible et suffisamment élevée pour donner un assez grand transfert de moment. La combinaison des techniques de diffraction des neutrons (avec ou sans substitution isotopique) et de diffraction des rayons X (avec ou sans diffusion anomale) peut donc permettre d'obtenir un meilleur contraste en longueurs de diffusion pour un systčme donné, mais exige une analyse de données plus soignée pour pouvoir bien tenir compte des erreurs systématiques qui sont différentes pour les 2 techniques [7]. Pour les atomes ayant des distributions électroniques quasi-sphériques, e.g. dans le cas d'un alliage liquide, la combinaison des techniques de NDIS et de diffraction des rayons X s'est déjŕ montrée trčs avantageuse pour la détermination des PSFs [8,9]. Dans le cas des verres ayant d'importantes liaisons covalentes, l'effective combinaison des 2 techniques peut ętre moins directe mais facilitée lorsqu'il s'agit des atomes de grand Z [10,11]. Nous présentons ici un sommaire du méthode et quelques exemples des résultats.
Barnes, A. C.; Fischer, H. E.; Salmon, P. S.
Optimization of isochromanone based urotensin II receptor agonists.
A series of novel isochromanone based urotensin II receptor agonists have been synthesized and evaluated for their activity using a functional cell based assay (R-SAT). Several potent and efficacious derivatives were identified, with 3-(3,4-dichlorophenyl)-6,7-dimethyl-3-(2-dimethylaminoethyl)isochroman-1-one being the most potent compound showing an EC??-value of 51 nM, thereby being the most potent compound so far within the isochromanone series. In addition, two other heterocyclic systems (isochromanes and tetrahydroisoquinolinones) were investigated and these derivatives were found to be both potent and efficacious. The activity of the isochromane derivatives implies that the carbonyl group of the isochromanone is not necessary for activity. Furthermore it was found that the geometry of the heterocycles was more important for receptor interaction than the composition of the heteroatoms present. PMID:20570157
Lehmann, Fredrik; Currier, Erika A; Olsson, Roger; Ma, Jian-Nong; Burstein, Ethan S; Hacksell, Uli; Luthman, Kristina
?7-nicotinic acetylcholine receptor agonists for cognitive enhancement in schizophrenia.
?7-Nicotinic acetylcholine receptors have emerged as a potential therapeutic target for the treatment of neurocognitive dysfunctions in schizophrenia that are often resistant to existing antipsychotic drugs. Molecular evidence for involvement in schizophrenia of CHRNA7, the gene for the receptor subunit, in the neurobiology of deficits in attention is a critical rationale for the clinical study of ?7-nicotinic receptor agonists to improve neurocognition. Initial clinical trials show enhancement of inhibitory neuron function related to sensory gating and increased attention and working memory, as well as improvement in negative symptoms such as anhedonia and alogia. Further development of this therapeutic strategy requires assessment of interactions with patients' heavy cigarette smoking and the relationship of this mechanism to the therapeutic effects of clozapine and olanzapine, both highly effective therapeutics with significant side effects. PMID:24111888
Freedman, Robert
TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis
This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of thyroid homeostasis. Explicit usage of this information with mathematical methods promises to deliver a better understanding of thyrotropic feedback control and new options for personalised diagnosis of thyroid dysfunction and targeted therapy, also by permitting a new perspective on the conundrum of the TSH reference range.
Dietrich, Johannes W.; Landgrafe, Gabi; Fotiadou, Elisavet H.
Development of TLR9 agonists for cancer therapy
In vertebrates, the TLRs are a family of specialized immune receptors that induce protective immune responses when they detect highly conserved pathogen-expressed molecules. Synthetic agonists for several TLRs, including TLR3, TLR4, TLR7, TLR8, and TLR9, have been or are being developed for the treatment of cancer. TLR9 detects the unmethylated CpG dinucleotides prevalent in bacterial and viral DNA but not in vertebrate genomes. As discussed in this Review, short synthetic oligodeoxynucleotides containing these immune stimulatory CpG motifs activate TLR9 in vitro and in vivo, inducing innate and adaptive immunity, and are currently being tested in multiple phase II and phase III human clinical trials as adjuvants to cancer vaccines and in combination with conventional chemotherapy and other therapies.
Krieg, Arthur M.
Second generation of dopamine agonists: pros and cons.
Dopamine agonists (DAGs) were first used in patients with moderate or advanced Parkinson's disease (PD). At that time, it was thought that DAGs could replace levodopa (LD) with fewer side effects. However, it soon became clear that while they could not replace LD, they did allow reduction of the dose of LD and diminished its side effects. Since the use of DAGs reduces response fluctuations as well as dyskinesias, there is a tendency to introduce them in the first stages of the disease, trying to delay motor fluctuations. While many DAGs have been developed, only four have been marketed and are used extensively for the treatment of Parkinson's disease: apomorphine, bromocriptine, lisuride and pergolide. In the present chapter, following a review of the "old" DAGs, the experience with three new promising DAGs is reported: cabergoline, ropinirole and pramipexole. PMID:8748628
Rabey, J M
Characterization of the hypothermic effects of imidazoline I2 receptor agonists in rats
BACKGROUND AND PURPOSE Imidazoline I2 receptors have been implicated in several CNS disorders. Although several I2 receptor agonists have been described, no simple and sensitive in vivo bioassay is available for studying I2 receptor ligands. This study examined I2 receptor agonist-induced hypothermia as a functional in vivo assay of I2 receptor agonism. EXPERIMENTAL APPROACH Different groups of rats were used to examine the effects of I2 receptor agonists on the rectal temperature and locomotion. The pharmacological mechanisms were investigated by combining I2 receptor ligands and different antagonists. KEY RESULTS All the selective I2 receptor agonists examined (2-BFI, diphenyzoline, phenyzoline, CR4056, tracizoline, BU224 and S22687, 3.2–56 mg·kg–1, i.p.) dose-dependently and markedly decreased the rectal temperature (hypothermia) in rats, with varied duration of action. Pharmacological mechanism of the observed hypothermia was studied by combining the I2 receptor agonists (2-BFI, BU224, tracizoline and diphenyzoline) with imidazoline I2 receptor/ ?2 adrenoceptor antagonist idazoxan, selective I1 receptor antagonist efaroxan, ?2 adrenoceptor antagonist/5-HT1A receptor agonist yohimbine. Idazoxan but not yohimbine or efaroxan attenuated the hypothermic effects of 2-BFI, BU224, tracizoline and diphenyzoline, supporting the I2 receptor mechanism. In contrast, both idazoxan and yohimbine attenuated hypothermia induced by the ?2 adrenoceptor agonist clonidine. Among all the I2 receptor agonists studied, only S22687 markedly increased the locomotor activity in rats. CONCLUSIONS AND IMPLICATIONS Imidazoline I2 receptor agonists can produce hypothermic effects, which are primarily mediated by I2 receptors. These data suggest that I2 receptor agonist-induced hypothermia is a simple and sensitive in vivo assay for studying I2 receptor ligands.
Thorn, David A; An, Xiao-Fei; Zhang, Yanan; Pigini, Maria; Li, Jun-Xu
L'article porte sur la répartition des profits bruts des filiales étrangčres entre les impôts prélevés par le pays hôte, les dividendes et les profits retenus. Cette question est d'une importance considérable pour l'evaluation des avantages des investissements étrangers pour le pays hôte ainsi que pour la distribution des avantages. L'un des objectifs principaux de l'analyse est de comparer les fonctions
Donald J. Brean
L'article analyse le rôle des instituts d'épargne dans l'évolution des marchés mobiliers par rapport aux exigences des pays en voie de développement sur la base de l'expérience des pays développés. Les instituts d'épargne contribuent au développement des marchés mobiliers du fait qu'ils engendrent une demande de titres différents d'aprčs leurs besoins de portefeuille. L'offre de titres, d'autre part, depend des
Anand G. Chandavarkar
Atypical nicotinic agonist bound conformations conferring subtype selectivity
The nicotinic acetylcholine (ACh) receptor (nAChR) plays a crucial role in excitatory neurotransmission and is an important target for drugs and insecticides. Diverse nAChR subtypes with various subunit combinations confer differential selectivity for nicotinic drugs. We investigated the subtype selectivity of nAChR agonists by comparing two ACh-binding proteins (AChBPs) as structural surrogates with distinct pharmacological profiles [i.e., Lymnaea stagnalis (Ls) AChBP of low neonicotinoid and high nicotinoid sensitivities and Aplysia californica (Ac) AChBP of high neonicotinoid sensitivity] mimicking vertebrate and insect nAChR subtypes, respectively. The structural basis of subtype selectivity was examined here by photoaffinity labeling. Two azidoneonicotinoid probes in the Ls-AChBP surprisingly modified two distinct and distant subunit interface sites: loop F Y164 of the complementary or (?)-face subunit and loop C Y192 of the principal or (+)-face subunit, whereas three azidonicotinoid probes derivatized only Y192. Both the neonicotinoid and nicotinoid probes labeled Ac-AChBP at only one position at the interface between loop C Y195 and loop E M116. These findings were used to establish structural models of the two AChBP subtypes. In the Ac-AChBP, the neonicotinoids and nicotinoids are nestled in similar bound conformations. Intriguingly, for the Ls-AChBP, the neonicotinoids have two bound conformations that are inverted relative to each other, whereas nicotinoids appear buried in only one conserved conformation as seen for the Ac-AChBP subtype. Accordingly, the subtype selectivity is based on two disparate bound conformations of nicotinic agonists, thereby establishing an atypical concept for neonicotinoid versus nicotinoid selectivity between insect and vertebrate nAChRs.
Tomizawa, Motohiro; Maltby, David; Talley, Todd T.; Durkin, Kathleen A.; Medzihradszky, Katalin F.; Burlingame, Alma L.; Taylor, Palmer; Casida, John E.
Mutations affecting agonist sensitivity of the nicotinic acetylcholine receptor.
The nicotinic acetylcholine receptor (AChR) is a pentameric transmembrane protein (alpha 2 beta gamma delta) that binds the neurotransmitter acetylcholine (ACh) and transduces this binding into the opening of a cation selective channel. The agonist, competitive antagonist, and snake toxin binding functions of the AChR are associated with the alpha subunit (Kao et al., 1984; Tzartos and Changeux, 1984; Wilson et al., 1985; Kao and Karlin, 1986; Pederson et al., 1986). We used site-directed mutagenesis and expression of AChR in Xenopus oocytes to identify amino acid residues critical for ligand binding and channel activation. Several mutations in the alpha subunit sequence were constructed based on information from sequence homology and from previous biochemical (Barkas et al., 1987; Dennis et al., 1988; Middleton and Cohen, 1990) and spectroscopic (Pearce and Hawrot, 1990; Pearce et al., 1990) studies. We have identified one mutation, Tyr190 to Phe (Y190F), that had a dramatic effect on ligand binding and channel activation. These mutant channels required more than 50-fold higher concentrations of ACh for channel activation than did wild type channels. This functional change is largely accounted for by a comparable shift in the agonist binding affinity, as assessed by the ability of ACh to compete with alpha-bungarotoxin binding. Other mutations at nearby conserved positions of the alpha subunit (H186F, P194S, Y198F) produce less dramatic changes in channel properties. Our results demonstrate that ligand binding and channel gating are separable properties of the receptor protein, and that Tyr190 appears to play a specific role in the receptor site for acetylcholine.
Tomaselli, G F; McLaughlin, J T; Jurman, M E; Hawrot, E; Yellen, G
Immobilized thrombin receptor agonist peptide accelerates wound healing in mice.
To accelerate the healing processes in wound repair, attempts have been repeatedly made to use growth factors including thrombin and its peptide fragments. Unfortunately, the employment of thrombin is limited because of its high liability and pro-inflammatory actions at high concentrations. Some cellular effects of thrombin in wound healing are mediated by the activation of protease activated receptor-1 (PAR-1). The thrombin receptor agonist peptide (TRAP:SFLLRN) activates this receptor and mimics the effects of thrombin, but TRAP is a relatively weak agonist. We speculated that the encapsulated peptide may be more effective for PAR-1 activation than nonimmobilized peptide and developed a novel method for TRAP encapsulation in hydrogel films based on natural and synthetic polymers. The effects of an encapsulated TRAP in composite poly(N-vinyl caprolactam)-calcium alginate (PVCL) hydrogel films were investigated in a mouse model of wound healing. On day 7 the wound sizes decreased by about 60% under TRAP-chitosan-containing PVCL films, as compared with control films without TRAP. In the case of TRAP-polylysine-containing films no significant decrease in wound sizes was found. The fibroblast/macrophage ratio increased under TRAP-containing films on day 3 and on day 7. The number of proliferating fibroblasts increased to 150% under TRAP-chitosan films on day 7 as compared with control films. The number of [3H]-thymidine labeled endothelial and epithelial cells in granulation tissues was also enhanced. Thus, the immobilized TRAP to PVCL-chitosan hydrogel films were found to promote wound healing following the stimulation of fibroblast and epithelial cell proliferation and neovascularization. Furthermore, TRAP was shown to inhibit the secretion of the inflammatory mediator PAF from stimulated rat peritoneal mast cells due to augmentation of NO release from the mast cells. The encapsulated TRAP is suggested to accelerate wound healing due to the anti-inflammatory effects and earlier development of the proliferative phase of wound healing. PMID:11697718
Strukova, S M; Dugina, T N; Chistov, I V; Lange, M; Markvicheva, E A; Kuptsova, S; Zubov, V P; Glusa, E
Synergism between the contractile effect of epidermal growth factor and that of des-Arg9-bradykinin or of alpha-thrombin in rabbit aortic rings.
1. Rabbit aortic rings were used to test the possible contractile effects of growth factors and their interaction with other stimuli. A rapid potentiation of kinin-induced contraction by epidermal growth factor (EGF) has been previously observed in this preparation. 2. EGF (5-1500 ng ml-1) and the isoform BB of platelet-derived growth factor (PDGF-BB; 1-126 ng ml-1) exerted modest but sustained contractile effects in rabbit aortic rings. 3. EGF pretreatment (100 ng ml-1) potentiated the contractile responses to des-Arg9-bradykinin (des-Arg9-BK), an agonist of the B1 receptors for kinin found in this preparation, and to human alpha-thrombin but not to several other contractile stimuli. The interaction appeared also relatively selective for the growth factor, because PDGF-BB pretreatment potentiated neither des-Arg9-BK nor alpha-thrombin-induced contraction. 4. EGF, applied on a contraction plateau induced by des-Arg9-BK or alpha-thrombin, exerted a synergistic contractile effect, with a time course and a half-maximal concentration for EGF-induced contraction similar to the ones recorded in resting tissues (between 67 and 220 ng ml-1, depending on the series of experiments). 5. The direct or synergistic contractile effects of EGF were not modified by the removal of the endothelium or by treatment with indomethacin. However, the tyrosine kinase inhibitors, erbstatin or genistein, inhibited the synergistic effect of EGF with des-Arg9-BK. The small direct contractile effect of EGF was significantly reduced by genistein. The synergistic effect of EGF with alpha-thrombin was comparatively more resistant to the tested tyrosine kinase inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
deBlois, D.; Drapeau, G.; Petitclerc, E.; Marceau, F.
Specific Activation of Estrogen Receptor Alpha and Beta Enhances Male Sexual Behavior and Neuroplasticity in Male Japanese Quail
Two subtypes of estrogen receptors (ER), ER? and ER?, have been identified in humans and numerous vertebrates, including the Japanese quail. We investigated in this species the specific role(s) of each receptor in the activation of male sexual behavior and the underlying estrogen-dependent neural plasticity. Castrated male Japanese quail received empty (CX) or testosterone-filled (T) implants or were daily injected with the ER general agonist diethylstilbestrol (DES), the ER?-specific agonist PPT, the ER?-specific agonist DPN or the vehicle, propylene glycol. Three days after receiving the first treatment, subjects were alternatively tested for appetitive (rhythmic cloacal sphincter movements, RCSM) and consummatory aspects (copulatory behavior) of male sexual behavior. 24 hours after the last behavioral testing, brains were collected and analyzed for aromatase expression and vasotocinergic innervation in the medial preoptic nucleus. The expression of RCSM was activated by T and to a lesser extent by DES and PPT but not by the ER?agonist DPN. In parallel, T fully restored the complete sequence of copulation, DES was partially active and the specific activation of ER? or ER? only resulted in a very low frequency of mount attempts in few subjects. T increased the volume of the medial preoptic nucleus as measured by the dense cluster of aromatase-immunoreactive cells and the density of the vasotocinergic innervation within this nucleus. DES had only a weak action on vasotocinergic fibers and the two specific ER agonists did not affect these neural responses. Simultaneous activation of both receptors or treatments with higher doses may be required to fully activate sexual behavior and the associated neurochemical events.
Seredynski, Aurore L.; Ball, Gregory F.; Balthazart, Jacques; Charlier, Thierry D.
Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent [N?-Bodipy]-des-Arg9-bradykinin
Background The kinin B1 receptor (B1R) is upregulated by pro-inflammatory cytokines, bacterial endotoxins and hyperglycaemia-induced oxidative stress. In animal models of diabetes, it contributes to pain polyneuropathy. This study aims at defining the cellular localization of B1R in thoracic spinal cord of type 1 diabetic rats by confocal microscopy with the use of a fluorescent agonist, [N?-Bodipy]-des-Arg9-BK (BdABK) and selective antibodies. Methods Diabetes was induced by streptozotocin (STZ; 65 mg/kg, i.p.). Four days post-STZ treatment, B1R expression was confirmed by quantitative real-time PCR and autoradiography. The B1R selectivity of BdABK was determined by assessing its ability to displace B1R [125I]-HPP-desArg10-Hoe140 and B2R [125I]-HPP-Hoe 140 radioligands. The in vivo activity of BdABK was also evaluated on thermal hyperalgesia. Results B1R was increased by 18-fold (mRNA) and 2.7-fold (binding sites) in the thoracic spinal cord of STZ-treated rats when compared to control. BdABK failed to displace the B2R radioligand but displaced the B1R radioligand (IC50 = 5.3 nM). In comparison, IC50 values of B1R selective antagonist R-715 and B1R agonist des-Arg9-BK were 4.3 nM and 19 nM, respectively. Intraperitoneal BdABK and des-Arg9-BK elicited dose-dependent thermal hyperalgesia in STZ-treated rats but not in control rats. The B1R fluorescent agonist was co-localized with immunomarkers of microglia, astrocytes and sensory C fibers in the spinal cord of STZ-treated rats. Conclusion The induction and up-regulation of B1R in glial and sensory cells of the spinal cord in STZ-diabetic rats reinforce the idea that kinin B1R is an important target for drug development in pain processes.
Talbot, Sebastien; Theberge-Turmel, Patrick; Liazoghli, Dalinda; Senecal, Jacques; Gaudreau, Pierrette; Couture, Rejean
Agonist-stimulated Cl- efflux from human neutrophils. A common phenomenon during neutrophil activation.
When human peripheral blood neutrophils were stimulated with various agonists which activate and/or prime neutrophils, we found that Cl- efflux was enhanced with a dramatic (50%) loss of intracellular Cl-. Interestingly, the Cl- efflux was enhanced by both agonists which induce a rapid transient increase in intracellular Ca2+ concentration ([Ca2+]i) [class I, e.g. N-formyl-methionyl-leucyl-phenylalanine (fMLP), interleukin-8 (IL8), platelet-activating factor, leukotriene B4 and C5a] and those which do not induce such an [Ca2+]i elevation [class II, e.g. tumor necrosis factor alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF)]. The time course of agonist-stimulated Cl- efflux differed depending on the agonist. Class I agonists such as IL8 and fMLP exhibited a 1 min lag phase before the onset of Cl- efflux; class II agonists such as GM-CSF and TNF displayed a 2 and 5 min lag phase, respectively. Both IL8 (class I)- and TNF (class II)-stimulated Cl- efflux exhibited similar sensitivity to inhibition by different types of ion transport inhibitors [ethacrynic acid (EA), amiloride, 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid, anthracene-9-carboxylic acid, and 4-4'-diisothiocyanatostilbene-2,2'-disulfonic acid]. On the other hand, natural Cl- efflux, which is thought to be mainly mediated by Cl-/Cl- self exchange, was not inhibited by EA (0.5 mM) or amiloride (0.3 mM). These results imply that both class I and class II agonist-stimulated Cl- efflux occurs via a common Cl- transporter which is different from that reported previously in resting human neutrophils. Although all agonists which induced a Cl- efflux also induced shape change of neutrophils, there did not appear to be a causal relationship between shape change and agonist-stimulated Cl- efflux. However, a temporal correlation was found to exist between agonist-stimulated Cl- efflux and intracellular alkalinization following agonist stimulation. Agonist-stimulated Cl- efflux therefore seems to be a common phenomenon activated by several agonists which act through different signal transduction pathways. PMID:8494532
Shimizu, Y; Daniels, R H; Elmore, M A; Finnen, M J; Hill, M E; Lackie, J M
Effects of Trecadrine®, a ?3-adrenergic agonist, on leptin secretion, glucose and lipid metabolism in isolated rat adipocytes
Objective: Leptin, a hormone produced in adipocytes, is a key signal in the regulation of food intake and energy expenditure. ?-Adrenergic agonists have been shown to inhibit leptin gene expression and leptin secretion. The mechanisms underlying the inhibitory effects of ?-adrenergic agonists have not been established. In this study, we examined the effects of Trecadrine®, a novel ?3-adrenergic agonist, on
MJ Moreno-Aliaga; JA Martínez; KL Stanhope; MP Fernández-Otero; PJ Havel; PJ Harvel
Both estrogen receptor ? and estrogen receptor ? agonists enhance cell proliferation in the dentate gyrus of adult female rats
This study investigated the involvement of estrogen receptors ? and ? in estradiol-induced enhancement of hippocampal neurogenesis in the adult female rat. Subtype selective estrogen receptor agonists, propyl-pyrazole triol (estrogen receptor ? agonist) and diarylpropionitrile (estrogen receptor ? agonist) were examined for each receptor's contribution, individual and cooperative, for estradiol-enhanced hippocampal cell proliferation. Estradiol increases hippocampal cell proliferation within 4
C. A. Mazzucco; S. E. Lieblich; B. I. Bingham; M. A. Williamson; V. Viau; L. A. M. Galea
Rôle des hyrates dans la formation de Titan et des satellites réguliers
NASA Astrophysics Data System (ADS)
Cette these est dediee a l'etude de l'origine de Titan et de son atmosphere. Dans l'hypothese ou la subnebuleuse de Saturne etait geometriquement mince, le modele de disque turbulent utilise, derive des travaux de Dubrulle (1993), est moins dense que le modele de Prinn et Fegley (1981). De ce fait, les conversions de Co en CH4 et de N2 en NH3 ont ete inhibees dans la subnebuleuse, contrairement a ce qui est couramment admis pour interpreter la presence du methane dans l'atmosphere de Titan. C'est pourquoi nous avons developpe un nouveau scenario de la formation de titan, qui tient compte simultanement des contraintes resultant de la chimie de la subnebuleuse et des abondances de CH4, N2 et CH3D mesurees dans l'atmosphere du satellite. Nous faisons l'hypothese que ces gaz proviennent initialement de la vaporisation du nuage presolaire, qui s'effondra et forma le Soleil et son disque environnant. Lors du refroidissement de la nebuleuse, les volatils auraient ete pieges sous formes de clathrates d'hydrates dans les grains, puis dans les planetesimaux qu'ils formerent. Les planetesimaux hydrates a l'origine de la formation de Titan seraient alors des rescapes de l'effondrement hydsrodynamique de la feeding zone de Saturne. Ce scenario a ete applique aux subnebuleuses de Jupiter et d'Uranus, et a apporte un certain nombre de contraintes sur la formation des satellites reguliers de ces planetes. Le temps et la zone de formation des grains cometaires ont egalement ete estimes dans la nebuleuse solaire. Enfin, l'etude experimentale de la temperature de fusion du dihydrate d'ammoniac dans la gamme des hautes pressions a apporte des nouvelles donnees thermodynamiques qui permettront d'ameliorer les modeles de l'interieur de Titan.
Mousis, O.
Régimes transitoires des photopiles: durée de vie des porteurs et vitesse de recombinaison
NASA Astrophysics Data System (ADS)
A detailed analysis of a new experimental practice of the open circuit voltage decay method and of the short circuit current decay method for determining the base minority carrier lifetime and the back surface recombination velocity in solar cells has been performed. The measurements have been made by using the monitoring of a single transient of an operating cell at any level of injection; no power supply is required and a constant illumination level imposes the carrier injection level for normal operating conditions. The theory considers the complete continuity equation including generation and recombination rates of carriers. Precision and sensitivity of the method have been compared. The necessity of a precise knowledge of cell structural parameters have been shown to impose a limitation of the practical use of short-circuit current decay method, to low illumination levels. Cette étude développe une nouvelle méthode expérimentale pour mesurer la durée de vie des porteurs minoritaires dans la base d'une photopile ainsi que la vitesse de recombinaison ŕ son interface arričre. Au cours de la mesure, la photopile est maintenue sous un éclairement constant qui impose le niveau d'injection souhaité. Cette méthode permet d'éliminer les effets néfastes ŕ la mesure, provenant des impédances, propres au composant. Un régime transitoire, provoqué par une variation d'impédance, est étudié au cours de fonctionnements dans des conditions de court-circuit ou de circuit ouvert. L'étude théorique souligne la prise en compte de l'ensemble des phénomčnes de recombinaison. L'obtention d'une bonne précision des mesures nécessite, avec une expérimentation rigoureuse, une connaissance précise des paramčtres de structure de la photopile étudié. Pour la mesure de la durée de vie des porteurs, la plus grande sensibilité de la méthode en régime transitoire de court-circuit, comparée au régime de circuit ouvert, impose des mesures sous faible illumination.
Mialhe, P.; Sissoko, G.; Pelanchon, F.; Salagnon, J. M.
Correlations entre les proprietes physico-mecaniques des roches et le comportement des granulats manufactures
\\u000aRsum La revue des essais d'acceptation des granulats, quant leur qualit mcanique ou leur rsistance aux agents atmosphriques,\\u000a montre qu'il existe de trs nombreux essais empiriques en usage dans le monde mais pratiquement aucun n'est employ universellement.\\u000a Dans cette communication il est pass en revue les divers modes de sollicitation imposs au granulat depuis sa production\\u000a en carrire jusqu' son emploi,
Ballivy Gérard; Dayre Michel
Die Beurteilung des Schlaf-Wachzustands aus dem EEG und dem photisch evozierten Rindenpotential des Kaninchens
1.Beim Kaninchen ist im Gegensatz zu Katze und Ratte der deep sleep (sommeil rapide) nicht nachweisbar. Das Schlaf-EEG des Kaninchens ist gegenüber dem Wach-EEG nicht durch Frequenzsenkung, sondern durch Erhöhung der Frequenzaktivität im ganzen EEG-Frequenzbereich charakterisiert. Der spontane Wechsel des Schlaf-Wachzustands wird durch die Änderung der EEG-Frequenzaktivität etwa ebenso gut wiedergegeben wie durch die Änderung der Spindelaktivität.2.Die photisch evozierte Rindenantwort
Otto Vatter
De la légitimité d'une géographie des réseaux sociaux : la géographie des réseaux sociaux au service d'une géographie des conflits
Résumé.— Les réseaux sociaux en géographie structurent les territoires, influencent les actions d'aménagement et de gestion de l'espace, et participent au dynamisme des systčmes spatiaux. Au cśur de la géographie sociale, les réseaux sociaux aident notamment ŕ la compréhension des processus conflictuels des espaces en mutation. Une étude de cas qualitative, relative au conflit lié ŕ l'urbanisme sauvage sur le
Anne Cadoret
Simulation et détermination par rayons X des contraintes dans des micro-composants modčles
NASA Astrophysics Data System (ADS)
Dans les composants de la microélectronique, du fait de l'existence de singularités géométriques, de trčs fortes contraintes sont générées. Des micro-composants modčles, formés de lignes réguličres déposées sur un substrat mono-cristallin sont utilisés pour mettre au point une méthode générique de détermination des contraintes mécaniques locales dans la ligne et dans le substrat. Pour cela, des mesures par diffraction des rayons X et des simulations sont mises au point. Le dispositif expérimental est décrit. Les simulations sont réalisées ŕ l'aide de deux types d'approche: le modčle de Hu, analytique, et la méthode des éléments finis. Ces deux approches sont comparées entre elles, et une courbe universelle est établie, donnant la contrainte moyenne dans une ligne en fonction d'un paramčtre incluant sa forme et les propriétés élastiques du substrat et de la ligne. Enfin, le couplage entre les mesures par diffraction de rayons X ŕ haute résolution (HRXRD) et les simulations par éléments finis ouvrent une voie pour la détermination de contraintes locales.
Loubens, A.; Fillit, R. Y.; Fortunier, R.; Thomas, O.
Apport des neutrons ŕ l'analyse structurale des composés partiellement désordonnés
NASA Astrophysics Data System (ADS)
La cristallographie est un outil extręmement puissant qui pourrait ętre utilisé par de nombreux scientifiques dont les sujets de recherche sont en fait trčs éloignés. L'évolution des techniques ces derničres années a relégué par exemple la cristallographie des rayons X des petites molécules ŕ un rôle mineur, un rôle de service. Certains ont męme le sentiment semble-t-il que toutes les connaissances sont contenues dans de multiples logiciels capables par eux-męmes de conduire une analyse structurale ŕ un résultat correct unique. Il est souhaitable que chacun soit capable de réaliser l'étude structurale du composé qui l'intéresse et bien entendu nécessaire de comprendre ce que l'on fait, la qualité des résultats et leur analyse en dépend. L'objet de cette présentation est de montrer l'apport spécifique de la diffraction de neutrons sur monocristaux ŕ l'étude du désordre, en particulier des atomes d'hydrogčne, et ses conséquences sur la compréhension des propriétés physiques, ŕ partir de développements et d'exemples récents.
Cousson, A.
Vents stellaires chauds et nébuleuses éjectées des étoiles chaudes: nécessaire inclusion des phénomčnes radiatifs dans les simulations hydrodynamiques
NASA Astrophysics Data System (ADS)
Nous décrivons, ŕ l'instar de la formation et de l'évolution des nébuleuses planétaires, comment l'histoire des vents stellaires issus d'une męme étoile chaude (massive ou non) détermine la morphologie des nébuleuses éjectées. Ensuite, nous présentons sommairement la structure et la dynamique des vents accélérés radiativement au sein des étoiles massives (O, Wolf-Rayet) et des étoiles centrales de nébuleuses planétaires de type [WC]. Enfin, nous tâchong d'illustrer en quoi la prise en compte des phénomčnes radiatifs est nécessaire pour effectuer toute simulation hydrodynamique sensée reproduire les observations dans les deux contextes, i.e. les vents stellaires chauds eux-męmes, la persistance de surdensités en leur sein, et les nébuleuses éjectées qui en résultent.
Grosdidier, Y.; Garcia-Segura, G.; Acker, A.; Moffat, A. F. J.
Computational investigation of interactions between human H2 receptor and its agonists.
Type 2 histamine receptor (H(2)R) is widely distributed in the body. Its main function is modulating the secretion of gastric acid. Most gastric acid-related diseases are closely associated with it. In this study, a combination of pharmacophore modeling, homology modeling, molecular docking and molecular dynamics methods were performed on human H(2)R and its agonists to investigate interaction details between them. At first, a pharmacophore model of H(2)R agonists was developed, which was then validated by QSAR and database searching. Afterwards, a model of the H(2)R was built utilizing homology modeling method. Then, a reference agonist was docked into the receptor model by induced fit docking. The 'induced' model can dramatically improve the recovery ratio from 46.8% to 69.5% among top 10% of the ranked database in the simulated virtual screening. The pharmocophore model and the receptor model matched very well each other, which provided valuable information for future studies. Asp98, Asp186 and Tyr190 played key roles in the binding of H(2)R agonists, and direct interactions were observed between the three residues and agonists. Residue Tyr250 could also form a hydrogen bond with H(2)R agonists. These findings would be very useful for the discovery of novel and potent H(2)R agonists. PMID:21212009
Sun, Xianqiang; Li, Yaozong; Li, Weihua; Xu, Zhejun; Tang, Yun
Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers
RXR permissive heterodimers are reported to be activated differently depending upon the chemical structure of RXR agonists, but the relationship of agonist structure to differential heterodimer activation has not been explored in detail. In this study, we performed systematic conversion of the alkoxy side chain of 5a (6-[ethyl-(3-isopropoxy-4-isopropylphenyl)amino]nicotinic acid, NEt-3IP) and evaluated the RXR-, PPAR/RXR-, and LXR/RXR-agonist activities of the products. The cyclopropylmethoxy analogue (5c) showed similar RXR- and LXR/RXR-agonistic activities to the benzyloxy analogue (5i) and n-propoxy analogue (5k) but exhibited more potent PPAR/RXR-agonistic activity than 5i or 5k. Differential modulation of RXR heterodimer-activating ability by conversion of the alkoxy group located in the lipophilic domain of the RXR-agonist common structure is expected be a useful approach in the design of new RXR agonists for the treatment of hyperlipidemia or type 2 diabetes.
Cannabinoid Discrimination and Antagonism by CB1 Neutral and Inverse Agonist Antagonists
Cannabinoid receptor 1 (CB1) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB1 neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB1 inverse agonist SR141716A (rimonabant) and the CB1 neutral antagonist AM4113 were compared for their ability to modify CB1 receptor–mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB1 full agonist AM4054. Results indicate that AM4054 serves as an effective CB1 discriminative stimulus, with an onset and time course of action comparable with that of the CB1 agonist ?9-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA2 values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB1 neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB1 receptors.
Delatte, Marcus S.; Vemuri, V. Kiran; Thakur, Ganesh A.; Nikas, Spyridon P.; Subramanian, Kumara V.; Shukla, Vidyanand G.; Makriyannis, Alexandros; Bergman, Jack
Risk of Cardiac Events in Patients with Asthma and Long QT Syndrome Treated with ?2-agonists
The clinical course and risk factors associated with ?2-agonist therapy for asthma have not been investigated previously in patients with the Long QT Syndrome (LQTS). The risk of a first LQTS-related cardiac event due to ?2-agonist therapy was examined in 3,287 patients enrolled in the International LQTS Registry with QTc?450msec. The Cox proportional hazards model was used to assess the independent contribution of clinical factors for first cardiac events (syncope, aborted cardiac arrest, or sudden death) from birth through age 40. Time-dependent ?2-agonist therapy for asthma was associated with an increased risk for cardiac events (hazard ratio (HR) = 2.00, 95% confidence interval 1.26–3.15, p = 0.003) after adjustment for relevant covariates including time-dependent ?-blocker use, sex, QTc, and history of asthma. This risk was augmented within the first year after the initiation of ?2-agonist therapy (HR = 3.53; p = 0.006). The combined use of ?2-agonist and anti-inflammatory steroids was associated with an elevated risk for cardiac events (HR = 3.66; p < 0.01). ?-blocker therapy was associated with a reduction in cardiac events in those using ?2-agonists (HR = 0.14; P = 0.05). In conclusion, ?2-agonist therapy was associated with an increased risk for cardiac events in asthmatic patients with LQTS, and this risk was diminished in patients receiving ?-blockers.
Thottathil, Princy; Acharya, Jay; Moss, Arthur J.; Jons, Christian; McNitt, Scott; Goldenberg, Ilan; Zareba, Wojciech; Kaufman, Elizabeth; Qi, Ming; Robinson, Jennifer L.
Agonist and blocking actions of choline and tetramethylammonium on human muscle acetylcholine receptors
Choline has been used widely as an agonist for the investigation of gain-of-function mutants of the nicotinic acetylcholine receptor. It is useful because it behaves like a partial agonist. The efficacy of choline is difficult to measure because choline blocks the channel at concentrations about four times lower than those that activate it. We have fitted activation mechanisms to single-channel activity elicited from HEK-expressed human recombinant muscle nicotinic receptors by choline and by tetramethylammonium (TMA). Channel block by the agonist was incorporated into the mechanisms that were fitted, and block was found not to be selective for the open state. The results also suggest that channel block is very fast and that the channel can shut almost as fast as normal when the blocker was bound. Single-channel data are compatible with a mechanism in which choline is actually a full agonist, its maximum response being limited only by channel block. However, they are also compatible with a mechanism incorporating a pre-opening conformation change ('flip') in which choline is a genuine partial agonist. The latter explanation is favoured by concentration jump experiments, and by the fact that only this mechanism fits the TMA data. We propose that choline, like TMA, is a partial agonist because it is very ineffective (approximately 600-fold less than acetylcholine) at eliciting the initial, pre-opening conformation change. Once flipping has occurred, all agonists, even choline, open the channel with similar efficiency.
Lape, Remigijus; Krashia, Paraskevi; Colquhoun, David; Sivilotti, Lucia G
Effects of yohimbine on the antinociceptive and place conditioning effects of opioid agonists in rodents
The pharmacological modulation of opioid actions by drugs acting on heterologous mechanisms could be useful to overcome some of the main problems associated with the use of opiate agonists. Based on previous findings on the interactions between yohimbine and opioid drugs, we have further studied the effects of yohimbine on the antinociceptive and positive-negative reinforcing effects of morphine (? opioid receptor-preferring agonist), U-50,488 (? agonist) and SNC80 (? agonist). Pretreatment with yohimbine completely blocked the antinociception provided by the three opioid agonists in the mouse tail-immersion test. A similar blockade of SNC80 and U-50,488-induced antinociception was observed with yohimbine in the mouse hot plate test at the same doses. In this paradigm, the effect of the ? agonist was very slight and the actions of yohimbine rather variable. In place conditioning experiments with SD (Sprague?–?Dawley) male rats, yohimbine alone was inactive but it limited the preference induced by morphine and SNC80 and the aversive effect of U-50,488. Impaired novelty preference was also observed with the combination of yohimbine and U-50,488. It is concluded that yohimbine tends to limit opioid antinociception and the addictive potential of ? and ? opioid agonists. More selective drugs could help to understand the mechanisms involved in these actions.
Morales, Lydia; Perez-Garcia, Carmen; Alguacil, Luis F
Anti-inflammatory effects of ?2 adrenergic receptor agonists in experimental acute lung injury
These studies were undertaken to extend emerging evidence that ?2 adrenergic receptor (?2AR) agonists, in addition to their bronchorelaxing effects, may have broad anti-inflammatory effects in the lung following onset of experimental acute lung injury (ALI). Young male C57BL/6 mice (25 g) developed ALI following airway deposition of bacterial LPS or IgG immune complexes in the absence or presence of appropriate stereoisomers (enantiomers) of ?2AR agonists, albuterol or formoterol. Endpoints included albumin leak into lung and buildup of polymorphonuclear neutrophils and cytokines/chemokines in bronchoalveolar fluids. Both ?2AR agonists suppressed lung inflammatory parameters (IC50=10?7 M). Similar effects of ?2AR agonists on mediator release were found when mouse macrophages were stimulated in vitro with LPS. The protective effects were associated with reduced activation (phosphorylation) of JNK but not of other signaling proteins. Collectively, these data suggest that ?2AR agonists have broad anti-inflammatory effects in the setting of ALI. While ?2AR agonists suppress JNK activation, the extent to which this can explain the blunted lung inflammatory responses in the ALI models remains to be determined.—Bosmann, M., Grailer, J. J., Zhu, K., Matthay, M A., Vidya Sarma, J., Zetoune, F. S., Ward, P. A. Anti-inflammatory effects of ?2 adrenergic receptor agonists in experimental acute lung injury.
Bosmann, Markus; Grailer, Jamison J.; Zhu, Ketong; Matthay, Michael A.; Sarma, J. Vidya; Zetoune, Firas S.; Ward, Peter A.
Endocrine and reproductive responses of male and female cattle to agonists of gonadotrophin-releasing hormone.
The pituitary response in cattle to treatment with GnRH agonist has two phases. In the acute phase secretion of LH is increased, while the chronic phase is characterized by a downregulation of GnRH receptors and insensitivity of gonadotrophs to natural sequence GnRH. After long-term treatment with GnRH agonist, cattle do not have pulsatile secretion of LH but maintain basal LH. This is associated with reduced pituitary contents of LH, LH mRNA, FSH and FSH mRNA. Long-term treatment of bulls with GnRH agonist results in an increase in testicular LH receptors and high plasma testosterone. Heifers treated with a GnRH agonist from early in the oestrous cycle develop a larger corpus luteum and secrete more progesterone. Increased steroidogenesis is reflected in increased steroid acute regulatory (StAR) protein and steroidogenic enzymes in the testes and corpus luteum. GnRH agonists have potential as novel strategies for reproductive management in cattle. A GnRH agonist bioimplant was recently used to block the LH surge after FSH stimulation of follicle growth in heifers. Ovulation was induced by injection of LH, and heifers were inseminated relative to the LH injection. This GnRH agonist-LH protocol provides a model for studying the gonadotrophin requirements for follicular growth and oocyte maturation in cattle, and will enable controlled in vivo maturation of oocytes before recovery for in vitro procedures. PMID:10692848
D'Occhio, M J; Aspden, W J
The glycine transport inhibitor sarcosine is an NMDA receptor co-agonist that differs from glycine
Sarcosine is an amino acid involved in one-carbon metabolism and a promising therapy for schizophrenia because it enhances NMDA receptor (NMDAR) function by inhibiting glycine uptake. The structural similarity between sarcosine and glycine led us to hypothesize that sarcosine is also an agonist like glycine. We examined this possibility using whole-cell recordings from cultured embryonic mouse hippocampal neurons. We found that sarcosine is an NMDAR co-agonist at the glycine binding site. However, sarcosine differed from glycine because less NMDAR desensitization occurred with sarcosine than with glycine as the co-agonist. This finding led us to examine whether the physiological effects of NMDAR activation with these two co-agonists are the same. The difference in desensitization probably accounts for rises in intracellular Ca2+, as assessed by the fluorescent indicator fura-FF, being larger when NMDAR activation occurred with sarcosine than with glycine. In addition, Ca2+-activated K+ currents following NMDAR activation were larger with sarcosine than with glycine. Compared to glycine, NMDAR-mediated autaptic currents decayed faster with sarcosine suggesting that NMDAR deactivation also differs with these two co-agonists. Despite these differences, NMDAR-dependent neuronal death as assessed by propidium iodide was similar with both co-agonists. The same was true for neuronal bursting. Thus, sarcosine may enhance NMDAR function by more than one mechanism and may have different effects from other NMDAR co-agonists.
Zhang, Hai Xia; Hyrc, Krzysztof; Thio, Liu Lin
Withdrawal of GnRH agonist decreases oestradiol and VEGF concentrations in high responders.
This study evaluated whether the withdrawal of a gonadotrophin-releasing hormone (GnRH) agonist before triggering ovulation reduces the incidence of ovarian hyperstimulation syndrome (OHSS) in high-risk infertility patients who were treated with gonadotrophins. GnRH agonist was withdrawn for 2 or 3 days when dominant follicles were ?14 mm in diameter, according to the GnRH agonist long protocol. Non-withdrawal of GnRH agonist was used as control. The serum concentration of oestradiol on the ovulation trigger day was significantly decreased in the GnRH agonist withdrawal group compared with the control group (5750.78 ± 2344.77 pg/ml versus 8076.43 ± 1981.67 pg/ml); however, the number of retrieved oocytes and the fertilization rate were similar between the groups. In addition, the concentrations of vascular endothelial growth factor in plasma on day of human chorionic gonadotrophin administration and follicular fluid on the oocyte retrieval day were decreased following GnRH agonist withdrawal. In fresh embryo transfer cycles, rates of clinical pregnancy, implantation and OHSS were not different between the groups. When GnRH agonist withdrawal was followed by total embryos cryopreserved, the rate of OHSS was decreased compared with the control group (0% versus 8.70%). Clinical pregnancy rates in cryopreserved embryo transfer cycles were comparable between the two groups. PMID:23764202
Ding, Li-Jun; Wang, Bin; Shen, Xiao-Yue; Yan, Gui-Jun; Zhang, Ning-Yuan; Hu, Ya-Li; Sun, Hai-Xiang
Ascorbic acid enables reversible dopamine receptor /sup 3/H-agonist binding
The effects of ascorbic acid on dopaminergic /sup 3/H-agonist receptor binding were studied in membrane homogenates of bovine anterior pituitary and caudate, and rat striatum. In all tissues virtually no stereospecific binding (defined using 1uM (+)butaclamol) of the /sup 3/H-agonists N-propylnorapomorphine (NPA), apomorphine, or dopamine could be demonstrated in the absence of ascorbic acid. Although levels of total /sup 3/H-agonist binding were three to five times greater in the absence than in the presence of 0.1% ascorbic acid, the increased binding was entirely non-stereospecific. Greater amounts of dopamine-inhibitable /sup 3/H-NPA binding could be demonstrated in the absence of 0.1% ascorbic acid, but this measure of ''specific binding'' was demonstrated not to represent dopamine receptor binding since several other catecholamines and catechol were equipotent with dopamine and more potent than the dopamine agonist (+/-)amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene (ADTN) in inhibiting this binding. High levels of dopamine-displaceable /sup 3/H-agonist binding were detected in fresh and boiled homogenates of cerebellum, an area of brain which receives no dopaminergic innervation, further demonstrating the non-specific nature of /sup 3/H-agonist binding in the absence of ascorbic acid. These studies emphasize that under typical assay conditions ascorbic acid is required in order to demonstrate reversible and specific /sup 3/H-agonist binding to dopamine receptors.
Leff, S.; Sibley, D.R.; Hamblin, M.; Creese, I.
Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve
Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-?-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.
Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi, E-mail: email@example.com
Modélisation macroscopique des milieux stratifiés conducteurs
NASA Astrophysics Data System (ADS)
Many laminated structures are recognised in Electrotechnics : magnetic cores, flat conductors windings, slotted surfaces... These structures exhibit macroscopic properties, as magnetic than electric ones. This paper shows how these characteristics can be obtained by homogenisation. It deals with linear materials but taking into account the effect of eddy currents, as well on the macroscopic magnetic permeability as on the macroscopic electric conductivity, which become then complex numbers. An example of use of the macroscopic properties is provided. On peut identifier en électrotechnique de nombreuses structures stratifiées: noyaux magnétiques, bobinages formés de conducteurs plats, surfaces encochées... Ces structures présentent des propriétés macroscopiques tant magnétiques qu'électriques. Cet article montre comment ces caractéristiques peuvent ętre obtenues par homogénéisation. Il se limite au cas de matériaux linéaires mais en prenant en compte l'effet des courants de Foucault aussi bien sur la perméabilité magnétique macroscopique que sur la conductivité électrique macroscopique, grandeurs qui deviennent alors des nombres complexes. Un exemple d'utilisation des caractéristiques macroscopiques est fourni.
Matagne, E.; Conard, J. Ph.
The "Conservatoire National des Arts et Metiers"
ERIC Educational Resources Information Center
The overall mission of the Conservatoire national des arts et metiers--(CNAM) [National Conservatory of Industrial Arts and Trades] is outlined. One of its centers, the "Centre national de l'entrepreneuriat"--(CNE) [National Center for Entrepreneurship] is described in greater detail. In particular, this center offers various services, notably…
Kuhn, Gerard
More About Spurious Numerical Solutions Of DEs
NASA Technical Reports Server (NTRS)
Paper discusses reliability of time-dependent approach to numerical solution of nonlinear differential equations (DEs) that describe steady-state behaviors of physical systems. Time-dependent approach followed in related study described in "Spurious Numerical Solutions of Differential Equations" (ARC-13209).
Yee, H. C.; Sweby, P. K.
Zur Organisation des Zellkerns von Bacillus megaterium
Vergleichende Untersuchungen an Dünnschnitten durch Bacillus megaterium und den Dinoflagellaten Amphidinium elegans ließen folgende Aussagen über die Struktur des Kernmaterials der Bakterien zu:1.Bac. megaterium enthält zwischen zwei Kernteilungen in der vom Cytoplasma umgebenen Kerngrundsubstanz je ein einziges vollständig spiralisiertes Chromosom mit anscheinend zwei oder entsprechend mehr Chromatiden, wobei die Chromosomenschraubeselbstwiederum einen offenbar schraubigen Aufbau in makromolekularer Größenordnung aufweist.2.Bei der Teilung
P. Giesbrecht; G. Piekarski
La conduite du changement dans un environnement incertain est un thčme ŕ l'ordre du jour. Il amčne de nombreuses entreprises ŕ investir dans leur systčme de pilotage et la gestion des risques est une composante majeure de ce pilotage. Dans cette communication nous tenterons de montrer que, pour gérer les risques, il convient de travailler sur le systčme d'action de
René Demeestčre; Philippe Lorino
Chronique des tendances de la société française
[fre] La présente chronique porte sur trois groupes sociaux en transformation : les étudiants, les militaires et les retraités. Elle se termine sur l'évolution du moral des Français en 1993. • Les étudiants ont ŕ nouveau manifesté leur mécontentement en octobre 1993, une enquęte sur trois universités explique pourquoi ces manifestations n'ont pas été aussi massives et violentes qu'on aurait
Louis Chauvel; Henri Mendras; Pascal Vennesson
Pairwise agonist scanning-flow cytometry (PAS-FC) measures inside-out signaling and patient-specific response to combinatorial platelet agonists
Understanding the response of cells to multiple stimuli is vital for predicting donor specific responses and better understanding the signaling pathways involved. This is of particular importance in platelets because exposure of phosphatidylserine (PS) occurs upon costimulation but not with a single agonist. Here, we describe a multiplexed pairwise agonist scanning flow cytometry (PAS-FC) method of measuring platelet inside-out responses to all pairs of six platelet agonists (convulxin, SFLLRN, AYPGKF, ADP, U46619, and PGE2) used at their EC50 concentrations. These agonists allowed exploration of platelet signaling downstream of GPVI, PAR-1, PAR-4, P2Y1, P2Y12, TP, and IP receptors. The three-color flow cytometry method simultaneously measured integrin ?IIb?3 activation with PAC-1 antibody, P-selectin exposure (via ? granule release) with anti-P-selectin, and PS exposure with annexin V. These responses were consistent across a healthy male donor pool. In duplicate measurements with each donor, 4 of the 10 donors had a sufficiently unique 45-parameter (15 pairs × 3 colors) phenotype to self-cluster (P < 0.001). This method has the potential for efficiently scanning for patient specific responses across a broad agonist-receptor space.
Jaeger, Daniel T. L.; Diamond, Scott L.
Pairwise agonist scanning-flow cytometry (PAS-FC) measures inside-out signaling and patient-specific response to combinatorial platelet agonists.
Understanding the response of cells to multiple stimuli is vital for predicting donor specific responses and better understanding the signaling pathways involved. This is of particular importance in platelets because exposure of phosphatidylserine (PS) occurs upon costimulation but not with a single agonist. Here, we describe a multiplexed pairwise agonist scanning-flow cytometry (PAS-FC) method of measuring platelet inside-out responses to all pairs of six platelet agonists (convulxin, SFLLRN, AYPGKF, ADP, U46619, and PGE(2)) used at their EC(50) concentrations. These agonists allowed exploration of platelet signaling downstream of GPVI, PAR-1, PAR-4, P2Y(1), P2Y(12), TP, and IP receptors. The three-color flow cytometry method simultaneously measured integrin ?(IIb)?(3) activation with PAC-1 antibody, P-selectin exposure (via ? granule release) with anti-P-selectin, and PS exposure with annexin V. These responses were consistent across a healthy male donor pool. In duplicate measurements with each donor, 4 of the 10 donors had a sufficiently unique 45-parameter (15 pairs × 3 colors) phenotype to self-cluster (P < 0.001). This method has the potential for efficiently scanning for patient specific responses across a broad agonist-receptor space. PMID:23662898
Jaeger, Daniel T L; Diamond, Scott L
In utero beta 2 adrenergic agonist exposure and adverse neurophysiologic and behavioral outcomes.
Beta 2 adrenergic receptor overstimulation during critical periods of prenatal development can induce a permanent shift in the balance of sympathetic-to-parasympathetic tone. This is a biologically plausible mechanism whereby beta 2 adrenergic agonists can induce functional and behavioral teratogenesis, which explains their association with increases in autism spectrum disorders, psychiatric disorders, poor cognitive, motor function and school performance, and changes in blood pressure in the offspring. The use of beta 2 adrenergic agonists should be limited to proven indications when alternate drugs are ineffective or unavailable; the risks of untreated disease to the mother and fetus are greater than the risk of the beta 2 adrenergic agonist. PMID:19961985
Witter, Frank R; Zimmerman, Andrew W; Reichmann, James P; Connors, Susan L
Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties.
The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species. PMID:23756062
McKinnell, R Murray; Armstrong, Scott R; Beattie, David T; Fatheree, Paul R; Long, Daniel D; Marquess, Daniel G; Shaw, Jeng-Pyng; Vickery, Ross G
3-Carboxamido-5-aryl-isoxazoles as new CB2 agonists for the treatment of colitis.
Recent investigations showed that anandamide, the main endogenous ligand of CB1 and CB2 cannabinoid receptors, possesses analgesic, antidepressant and anti-inflammatory effects. In the perspective to treat inflammatory bowel disease (IBD), our approach was to develop new selective CB2 receptor agonists without psychotropic side effects associated to CB1 receptors. In this purpose, a new series of 3-carboxamido-5-aryl-isoxazoles, never described previously as CB2 receptor agonists, was designed, synthesized and evaluated for their biological activity. The pharmacological results have identified great selective CB2 agonists with in vivo anti-inflammatory activity in a DSS-induced acute colitis mouse model. PMID:23849204
Tourteau, Aurélien; Andrzejak, Virginie; Body-Malapel, Mathilde; Lemaire, Lucas; Lemoine, Amélie; Mansouri, Roxane; Djouina, Madjid; Renault, Nicolas; El Bakali, Jamal; Desreumaux, Pierre; Muccioli, Giulio G; Lambert, Didier M; Chavatte, Philippe; Rigo, Benoît; Leleu-Chavain, Natascha; Millet, Régis
Induction of selective blood-tumor barrier permeability and macromolecular transport by a biostable kinin B1 receptor agonist in a glioma rat model.
Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg(9)BK (LDBK) and SarLys[dPhe(8)]desArg(9)BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T(1)-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites. PMID:22629405
Côté, Jérôme; Bovenzi, Veronica; Savard, Martin; Dubuc, Céléna; Fortier, Audrey; Neugebauer, Witold; Tremblay, Luc; Müller-Esterl, Werner; Tsanaclis, Ana-Maria; Lepage, Martin; Fortin, David; Gobeil, Fernand
Induction of Selective Blood-Tumor Barrier Permeability and Macromolecular Transport by a Biostable Kinin B1 Receptor Agonist in a Glioma Rat Model
Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[dPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites.
Cote, Jerome; Bovenzi, Veronica; Savard, Martin; Dubuc, Celena; Fortier, Audrey; Neugebauer, Witold; Tremblay, Luc; Muller-Esterl, Werner; Tsanaclis, Ana-Maria; Lepage, Martin; Fortin, David; Gobeil, Fernand
Endotoxin sensitization to kinin B1 receptor agonist in a non-human primate model: haemodynamic and pro-inflammatory effects
Although endotoxaemia induces kinin B1 receptors in several animal models, this condition is not documented in primates. This study examined the up-regulation of haemodynamic and pro-inflammatory responses to the B1 agonist des-Arg10-kallidin (dKD) in a non-human primate model. Green monkeys (Cercopithecus aethiops St Kitts) received lipopolysaccharide (LPS; 90??g?kg?1) or saline intravenously. After 4?h, anaesthetized monkeys were canulated via the carotid artery to monitor blood pressure changes following intra-arterial injections of dKD or the B2 agonist bradykinin (BK). Oedema induced by subcutaneous kinin administration was evaluated as the increase in ventral skin folds in anaesthetized monkeys injected with captopril at 4?h to 56 days post-LPS. LPS increased rectal temperature but did not affect blood pressure after 4?h. dKD reduced blood pressure (Emax: 27±4?mmHg; EC50: 130?pmol?kg?1) and increased heart rate (Emax: 33 b.p.m.) only after LPS. In contrast, the dose-dependent fall in blood pressure with BK was comparable in all groups. The selective B1 antagonist [Leu9]dKD (75?ng?kg?1?min?1, intravenously) abolished responses to dKD but not BK. dKD injection induced oedema dose-dependently (2.4±0.1?mm at 150?nmol) only following LPS (at 4?h to 12 days but not 56 days). In contrast, BK-induced oedema was present and stable in all monkeys. Co-administration of [Leu9]dKD (150?nmol) significantly reduced oedema induced by dKD (50?nmol). These results suggest LPS up-regulation of B1 receptor effects in green monkeys. This non-human primate model may be suitable for testing new, selective B1 antagonists with therapeutic potential as anti-inflammatory agents.
deBlois, Denis; Horlick, Robert A
Modes d'élevage alternatifs des porcs : (1) Effets sur les performances de croissance, les qualités des carcasses et des viandes et l'aptitude ŕ la transformation en jambons cuits et secs
des viandes, la composition chimique des muscles et l'aptitude ŕ la transformation en jambons cuits et secs. En été, les performances de croissance (vitesse de croissance, indice de consommation) sont similaires. En hiver, la vites- se de croissance des animaux plein air et courette est réduite, et l'indice de consommation augmenté dans les trois sys- tčmes alternatifs. La composition des
Patrick CHEVILLON; Antoine VAUTIER; Anne-Sophie GUILLARD; Edwige GILBERT; Bénédicte LEBRET; Claudia TERLOUW
Late DES thrombosis: a lot of smoke, very little fire?
Recent studies and editorials have stirred controversy and generated tremendous publicity in the lay press related to the safety of drug-eluting stents (DES) for the treatment of coronary artery disease. Questions have been raised regarding the risks of late, or very late stent thrombosis with DES. The purpose of this editorial and review of stent thrombosis is to illuminate some counterpoints to some of the attention surrounding the issues of late DES thrombosis. The risks of DES stent thrombosis versus BMS may have been overstated by flawed studies. Late stent thrombosis does occur with both BMS and DES, and may or may not be modestly higher with DES. The time course of very late "DES thrombosis," suggests that persistent plaque ruptures and disease progression in the target vessel may cause some, or many of these events. There is still much to be learned about the biology of DES. Although there is a small risk of late thrombosis with DES, there is little question that this technology provides benefit to the vast majority of patients compared with prior revascularization strategies, using balloon angioplasty, BMS, or bypass surgery. Substantial resources should be devoted to creating more biocompatible DES systems, and to minimizing the risks of both early and late stent thrombosis. PMID:17323356
Fischell, Tim A; Holmes, David R
Matériaux pour la dépollution des gaz d'échappement automobile
NASA Astrophysics Data System (ADS)
Les premičres législations antipollution ont été mises en place suite ŕ la détection, aux Etats Unis plus particuličrement en Californie, du smog photochimique et des pluies acides, néfastes pour la faune et la flore. Les estimations de la contribution de l'automobile aux émissions de composés, considérés comme précurseurs de ces phénomčnes, ont été suffisantes pour provoquer la mise en place de normes draconiennes en matičre d'émissions automobiles. Les matériaux catalytiques ont été évalués en tant que solution possible pour réduire les émissions ŕ l'échappement. En Europe, l'utilisation des catalyseurs trois voies a été généralisée sur les véhicules essence fonctionnant ŕ richesse stoechiométrique ŕ partir de 1993. Une nouvelle génération de catalyseurs appelée pičge ŕ oxydes d'azote (NOx) est maintenant nécessaire pour le post-traitement des gaz d'échappement des motorisations ŕ essence fonctionnant en mélange pauvre (combustion en présence d'un excčs d'oxygčne) pour diminuer la consommation et par conséquent réduire les émissions du CO2 connu pour son impact sur l'effet de serre. La dépollution des moteurs diesel via un catalyseur d'oxydation a été généralisée en Europe depuis 1996. La sévérisation des normes européennes impose pour les moteurs diesel le recours ŕ des matériaux spécifiques pour le traitement des oxydes d'azotes et des particules par l'intermédiaire de filtres ŕ particules dont l'efficacité de filtration est supérieure ŕ 95%, mais doivent subir des régénérations périodiques.
Mouaddib-Moral, N.; Gauthier, C.
Etude theorique et experimentale des evaporateurs de dioxyde de carbone operant dans des conditions de givrage
NASA Astrophysics Data System (ADS)
Les evaporateurs de refrigeration sont surtout du type tube a ailettes, appeles serpentins, et fonctionnent dans l'une des conditions suivantes: seche, humide ou avec formation de givre. Il a ete demontre que la formation du givre sur la paroi exterieure de l'echangeur engendre une surconsommation energetique a cause des operations de degivrage puisque 15 a 20% seulement de la chaleur produite sert au degivrage tandis que le reste est dissipee dans l'environnement [1]. Avec l'avenement des nouveaux refrigerants, moins nocifs envers l'environnement, l'industrie du froid se trouve penalisee du fait que peu ou pas de composantes mecaniques (compresseur, pompe, echangeur...etc.) adaptees sont disponibles [3]. Il s'agit pour la communaute des frigoristes de combler ce retard technologique en redeveloppant ces composantes mecaniques afin qu'elles soient adaptees aux nouveaux refrigerants. Dans cette optique, et afin de mieux comprendre le comportement thermique des evaporateurs au CO2 fonctionnant dans des conditions seches, qu'un groupe de chercheurs du CanmetENERGIE avaient lance, en 2000, un programme de R & D. Dans le cadre de programme un outil de simulation des evaporateurs au CO2 a ete developpe et un banc d'essai contenant une boucle secondaire de refrigeration utilisant le CO2 comme refrigerant a ete construit. Comme continuite de ce travail de recherche, en 2006 ce meme groupe de recherche a lance un nouveau projet qui consiste a faire une etude theorique et experimentale des evaporateurs au CO2 operants dans des conditions de givrage. Et, c'est exactement dans le cadre de ce projet que se positionne ce travail de these. Ce travail de recherche a ete entrepris pour mieux comprendre le comportement thermique et hydrodynamique des serpentins fonctionnant dans des conditions de givrage, l'effet des circuits de refrigerant ainsi que celui des parametres geometriques et d'operation. Pour cela, un travail theorique supporte par une etude experimentale a ete effectue. Dans la partie theorique, un modele traitant les aspects thermique, hydrodynamique et massique a ete elabore. Sur la base de ce modele a ete ecrit un programme informatique en langage FORTRAN 6.6. Il est base sur la discretisation du serpentin en volumes de controle, est entierement automatise et peut traiter des echangeurs de chaleur avec des circuits de refrigerant complexes pouvant avoir des entrees et sorties multiples ainsi que des bifurcations. La presence simultanee des trois phases thermodynamiques du refrigerant (liquide sous refroidi, fluide sature, vapeur surchauffee) dans le serpentin est aussi prise en charge. Le modele a ete valide pour un fonctionnement avec et sans formation de givre en utilisant des donnees experimentales disponibles dans la litterature et celles obtenues sur le banc d'essai de CanmetENERGIE. Celui-ci a ete mis a jour pour les besoins de la presente recherche et pour cela, un systeme de surchauffe et d'injection de la vapeur d'eau dans une enceinte a tres basse temperature a ete dimensionne, fabrique et installe. Un dispositif de visualisation de la formation de givre, ainsi qu'un equipement de mesure de la temperature, de la pression et de l'humidite relative de l'air ont aussi ete ajoutes. Une fois le modele valide, des simulations numeriques sur le serpentin avec et sans formation de givre ont ete effectuees. Un premier cas de base a servi comme reference pour d'autres cas pour lesquels une etude parametrique sur la geometrie et le fonctionnement a ete menee. Il a ete montre par rapport au cas de base que : 1. la diminution de la densite des ailettes sur des rangees specifiques du serpentin donne une surface minimale (Amin) plus grande, retardant ainsi l'obstruction totale du serpentin par le givre et permet donc un temps de fonctionnement plus grand et une frequence de degivrage plus faible. 2. une bonne configuration de circuit de refrigerant augmente le temps de fonctionnement du serpentin de 200 % et delivre une puissance frigorifique moyenne superieures de 20 % par rapport a celle du cas de base. 3. la diminution d
Bendaoud, Adlane Larbi
Determination des Parametres Atmospheriques des Etoiles Naines Blanches de Type DB
NASA Astrophysics Data System (ADS)
Les etoiles naines blanches dont les spectres visibles sont domines par des raies fortes d'helium neutre sont subdivisees en trois classes, DB (raies d'helium neutre seulement), DBA (raies d'helium neutre et d'hydrogene) et DBZ (raies d'helium neutre et d'elements lourds). Nous analysons trois echantillons de spectres observes de ces types de naines blanches. Les echantillons consistent, respectivement, de 48 spectres dans le domaine du visible (3700-5100 A). 24 dans l'ultraviolet (1200-3100 A) et quatre dans la partie rouge du visible (5100-6900) A). Parmi les objets de l'echantillon visible, nous identifions quatre nouvelles DBA, ainsi que deux nouvelles DBZ, auparavant classees DB. L'analyse nous permet de determiner spectroscopiquement les parametres atmospheriques, soit la temperature effective, la gravite de surface, ainsi que l'abondance relative de l'hydrogene, N(H)/N(He), dans le cas des DBA. Pour les objets plus chauds que ~15,000 K, la gravite de surface determinee est fiable, et nous obtenons les masses stellaires avec une relation masse -rayon theorique. Les exigences propres a l'analyse de ces objets ont requis d'importantes ameliorations dans la modelisation de leurs atmospheres et distributions de flux de radiation emis par ces derniers. Nous avons inclus dans les modeles d'atmospheres, pour la premiere fois a notre connaissance, les effets dus a la molecule He_sp{2 }{+}, ainsi que l'equation d'etat de Hummer et Mihalas (1988), qui tient compte des perturbations entre particules dans le calcul des populations des differents niveaux atomiques. Nous traitons la convection dans le cadre de la theorie de la longueur de melange. Trois grilles de modeles d'atmospheres a l'ETL (equilibre thermodynamique local) ont ete produites, pour un ensemble de temperatures effectives, gravites de surface et abondances d'hydrogene couvrant les proprietes des etoiles de nos echantillons; elles sont caracterisees par differentes parametrisations appelees, respectivement, ML1, ML2 et ML3, de la theorie de longueur de melange. Nous avons calcule une grille de spectres synthetiques avec les memes parametrisations que la grille de modeles d'atmospheres. Notre traitement de l'elargissement des raies de l'helium neutre a ete ameliore de facon significative par rapport aux etudes precedentes. D'une part, nous tenons compte de l'elargissement des raies produit par les interactions entre l'emetteur et les particules neutres (elargissements par resonance et de van der Waals) en plus de celui par les particules chargees (elargissement Stark). D'autre part, nous avons calcule nous-memes les profils Stark avec les meilleures theories d'elargissement disponibles pour la majorite des raies observees; ces profils depassent en qualite ce qui a ete publie jusqu'a ce jour. Nous avons calcule la distribution de masse des etoiles DB plus chaudes que 15,000 K. La distribution de masse des DB est tres etroite, avec environ les trois quarts des etoiles incluses dans l'intervalle 0.55-0.65 Modot. La masse moyenne des etoiles DB est de 0.58 M_? avec sigma = 0.07. La difference principale entre les distributions de masse des DB et DA est la faible proportion de DB dans les ailes de la distribution, ce qui implique que les DA moins massives que ~0.4 M odot et plus massives que ~0.8 M_? ne se convertissent pas en DB. Les objets les plus massifs de notre echantillon sont de type DBA, ce qui suggere que la masse elevee favorise la visibilite de l'hydrogene. (Abstract shortened by UMI.).
Beauchamp, Alain
Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin-1 receptor in the grey squirrel (Sciurus carolinensis).
The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1R?24) variant. We demonstrate that the MC1R?24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1R?24. We conclude that the deletion in the MC1R?24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R. PMID:24879893
McRobie, Helen R; King, Linda M; Fanutti, Cristina; Symmons, Martyn F; Coussons, Peter J
Les effets des interfaces sur les proprietes magnetiques et de transport des multicouches nickel/iron et cobalt/silver
NASA Astrophysics Data System (ADS)
Cette these est consacree a l'etude de l'evolution structurale des proprietes magnetiques et de transport des multicouches Ni/Fe et nanostructures a base de Co et de l'Ag. Dans une premiere partie, essentiellement bibliographique, nous introduisons quelques concepts de base relies aux proprietes magnetiques et de transport des multicouches metalliques. Ensuite, nous presentons une breve description des methodes d'analyse des resultats. La deuxieme partie est consacree a l'etude des proprietes magnetiques et de transport des multicouches ferromagnetiques/ferromagnetiques Ni/Fe. Nous montrerons qu'une interpretation coherente de ces proprietes necessite la prise en consideration des effets des interfaces. Nous nous attacherons a mettre en evidence, a evaluer et a etudier les effets de ces interfaces ainsi que leur evolution, et ce, suite a des traitements thermiques tel que le depot a temperature elevee et l'irradiation ionique. Les analyses correlees de la structure et de la magnetoresistance nous permettront d'emettre des conclusions sur l'influence des couches tampons entre l'interface et le substrat ainsi qu'entre les couches elles-memes sur le comportement magnetique des couches F/F. La troisieme partie est consacree aux systeme