Sample records for antagonist cp-96345 blocks

  1. Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model. (United States)

    Evers, Andreas; Klebe, Gerhard


    The neurokinin-1 (NK1) receptor belongs to the family of G-protein-coupled receptors (GPCRs), which represents one of the most relevant target families in small-molecule drug design. In this paper, we describe a homology modeling of the NK1 receptor based on the high-resolution X-ray structure of rhodopsin and the successful virtual screening based on this protein model. The NK1 receptor model has been generated using our new MOBILE (modeling binding sites including ligand information explicitly) approach. Starting with preliminary homology models, it generates improved models of the protein binding pocket together with bound ligands. Ligand information is used as an integral part in the homology modeling process. For the construction of the NK1 receptor, antagonist CP-96345 was used to restrain the modeling. The quality of the obtained model was validated by probing its ability to accommodate additional known NK1 antagonists from structurally diverse classes. On the basis of the generated model and on the analysis of known NK1 antagonists, a pharmacophore model was deduced, which subsequently guided the 2D and 3D database search with UNITY. As a following step, the remaining hits were docked into the modeled binding pocket of the NK1 receptor. Finally, seven compounds were selected for biochemical testing, from which one showed affinity in the submicromolar range. Our results suggest that ligand-supported homology models of GPCRs may be used as effective platforms for structure-based drug design.

  2. 7-Chloroarctinone-b as a new selective PPARγ antagonist potently blocks adipocyte differentiation

    Institute of Scientific and Technical Information of China (English)

    Yong-tao LI; Li LI; Jing CHEN; Tian-cen HU; Jin HUANG; Yue-wei GUO; Hua-liang JIANG; Xu SHEN


    Aim: Peroxisome proliferator-activated receptor gamma (PPARy) is a therapeutic target for obesity, cancer and diabetes mellitus. In order to develop potent lead compounds for obesity treatment, we screened a natural product library for novel PPARy antagonists with inhibitory effects on adipocyte differentiation. Methods: Surface plasmon resonance (SPR) technology and cell-based transactivation assay were used to screen for PPARy antago-nists. To investigate the antagonistic mechanism of the active compound, we measured its effect on PPARy/RXRα heterodimerization and PPARy co-activator recruitment using yeast two-hybrid assay, Gal4/UAS cell-based assay and SPR based assay. The 3T3-L1 cell differentiation assay was used to evaluate the effect of the active compound on adipocyte differentiation. Results: A new thiophene-acetylene type of natural product, 7-chloroarctinone-b (CAB), isolated from the roots of Rhaponticum uniflo-rum, was discovered as a novel PPARγ antagonist capable of inhibiting rosiglitazone-induced PPARγ transcriptional activity. SPR analy-sis suggested that CAB bound tightly to PPARγ and considerably antagonized the potent PPARy agonist rosigtitazone-stimulated PPARγ-LBD/RXRα-LBD binding. Gal4/UAS and yeast two-hybrid assays were used to evaluate the antagonistic activity of CAB on rosiglitazone-induced recruitment of the coactivator for PPARy. CAB could efficiently antagonize both hormone and rosiglitazone-induced adipocyte differentiation in cell culture. Conclusion: CAB shows antagonistic activity to PPARγ and can block the adipocyte differentiation, indicating it may be of potential use as a lead therapeutic compound for obesity.

  3. The inability of CCK to block (or CCK antagonists to substitute for) the stimulus effects of chlordiazepoxide. (United States)

    Fox, M A; Levine, E S; Riley, A L


    To further examine the relationship between cholecystokinin (CCK) and GABA, the present study assessed the ability of the CCK-A antagonist devazepide and the CCK-B antagonist L-365,260 to substitute for the stimulus effects of chlordiazepoxide (CDP), as well as the ability of CCK-8s to block these effects, in female Long-Evans rats within the conditioned taste aversion baseline of drug discrimination learning. Both devazepide and L-365,260 failed to substitute for the discriminative stimulus properties of CDP, and CCK-8s failed to block its stimulus effects. The benzodiazepine diazepam did substitute for, and the benzodiazepine antagonist flumazenil did block, the stimulus effects of CDP. This suggests that the lack of substitution for, or antagonism of, CDP by the CCK antagonists and CCK-8s, respectively, was not due to the inability of the present design to assess such effects. Possible bases for the current findings, e.g., necessity of an anxiogenic baseline, drug and receptor specificity, as well as the dose-response nature of the interaction, were discussed. Given that a relationship between CCK and GABA has been reported in other designs, the present results suggest that such a relationship may be preparation specific.

  4. Block of the delayed rectifier current (IK) by the 5-HT3 antagonists ondansetron and granisetron in feline ventricular myocytes.


    de Lorenzi, F G; Bridal, T R; Spinelli, W


    1. We investigated the effects of two 5-HT3 antagonists, ondansetron and granisetron, on the action potential duration (APD) and the delayed rectifier current (IK) of feline isolated ventricular myocytes. Whole-cell current and action potential recordings were performed at 37 degrees C with the patch clamp technique. 2. Ondansetron and granisetron blocked IK with a KD of 1.7 +/- 1.0 and 4.3 +/- 1.7 microM, respectively. At a higher concentration (30 microM), both drugs blocked the inward rect...

  5. BF-1--a novel selective 5-HT2B receptor antagonist blocking neurogenic dural plasma protein extravasation in guinea pigs. (United States)

    Schmitz, Beate; Ullmer, Christoph; Segelcke, Daniel; Gwarek, Mirella; Zhu, Xin-Ran; Lübbert, Hermann


    Serotonin 5-HT2B receptor antagonists have been proposed as migraine prophylactic drugs, but previously available 5-HT2B receptor antagonists displayed multiple monoaminergic side effects and had to be withdrawn from the market. Here, we set out to identify a novel antagonist with high affinity and selectivity towards 5-HT2B receptors. To test the affinity of new compounds towards various receptors, we generated a broad series of cells functionally coupling human monoaminergic receptors to luciferase. Using the cell lines we revealed pimethixene (1-methyl-4-(9H-thioxanthen-9-ylidene)piperidine) as highly potent, albeit non-selective 5-HT2B receptor antagonist and optimized its chemical structure to create highly potent and selective 5-HT2B receptor antagonists. We selected the methoxythioxanthene BF-1 for further analysis. In comparison to pimethixene, it lacked high affinities to 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, dopamine D1 and D2 as well as muscarinic M1 and M2 receptors. BF-1 was tested as potential migraine prophylactic drug by blocking meta-chlorophenylpiperazine, (mCPP) or BW723C86 (5-((thiophen-2-yl)methoxy)-α-methyltryptamine) induced neurogenic dural plasma protein extravasation in a guinea pig model that may resemble a migraine attack. BF-1 was significantly more potent in this assay compared to the well know non-selective 5-HT2B antagonists, methysergide ((6aR,9R)-N-[(2S)-1-Hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide) or pizotifen (4-(1-methyl-4-piperidylidine)-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2]-thiophene). Therefore, we propose BF-1 as a new compound that may be developed for prophylactic migraine treatment without the typical monoaminergic side effects.

  6. Bicuculline, a GABAA-receptor antagonist, blocked HPA axis activation induced by ghrelin under an acute stress. (United States)

    Gastón, M S; Cid, M P; Salvatierra, N A


    Ghrelin is a peptide of 28 amino acids with a homology between species, which acts on the central nervous system to regulate different actions, including the control of growth hormone secretion and metabolic regulation. It has been suggested that central ghrelin is a mediator of behavior linked to stress responses and induces anxiety in rodents and birds. Previously, we observed that the anxiogenic-like behavior induced by ghrelin injected into the intermediate medial mesopallium (IMM) of the forebrain was blocked by bicuculline (a GABAA receptor competitive antagonist) but not by diazepam (a GABAA receptor allosteric agonist) in neonatal meat-type chicks (Cobb). Numerous studies have indicated that hypothalamic-pituitary-adrenal (HPA) axis activation mediates the response to stress in mammals and birds. However, it is still unclear whether this effect of ghrelin is associated with HPA activation. Therefore, we investigated whether anxiety behavior induced by intra-IMM ghrelin and mediated through GABAA receptors could be associated with HPA axis activation in the neonatal chick. In the present study, in an Open Field test, intraperitoneal bicuculline methiodide blocked anxiogenic-like behavior as well as the increase in plasma ACTH and corticosterone levels induced by ghrelin (30pmol) in neonatal chicks. Moreover, we showed for the first time that a competitive antagonist of GABAA receptor suppressed the HPA axis activation induced by an anxiogenic dose of ghrelin. These results show that the anxiogenic ghrelin action involves the activation of the HPA axis, with a complex functional interaction with the GABAA receptor.

  7. Perivagal antagonist treatment in rats selectively blocks the reflex and afferent responses of vagal lung C fibers to intravenous agonists. (United States)

    Lin, Yu-Jung; Lin, You Shuei; Lai, Ching Jung; Yuan, Zung Fan; Ruan, Ting; Kou, Yu Ru


    The terminals of vagal lung C fibers (VLCFs) express various types of pharmacological receptors that are important to the elicitation of airway reflexes and the development of airway hypersensitivity. We investigated the blockade of the reflex and afferent responses of VLCFs to intravenous injections of agonists using perivagal treatment with antagonists (PAT) targeting the transient receptor potential vanilloid 1, P2X, and 5-HT(3) receptors in anesthetized rats. Blockading these responses via perivagal capsaicin treatment (PCT), which blocks the neural conduction of C fibers, was also studied. We used capsaicin, α,β-methylene-ATP, and phenylbiguanide as the agonists, and capsazepine, iso-pyridoxalphosphate-6-azophenyl-2',5'-disulfonate, and tropisetron as the antagonists of transient receptor potential vanilloid 1, P2X, and 5-HT(3) receptors, respectively. We found that each of the PATs abolished the VLCF-mediated reflex apnea evoked by the corresponding agonist, while having no effect on the response to other agonists. Perivagal vehicle treatment failed to produce any such blockade. These blockades had partially recovered at 3 h after removal of the PATs. In contrast, PCT abolished the reflex apneic response to all three agonists. Both PATs and PCT did not affect the myelinated afferent-mediated apneic response to lung inflation. Consistently, our electrophysiological studies revealed that each of the PATs prevented the VLCF responses to the corresponding agonist, but not to any other agonist. PCT inevitably prevented the VLCF responses to all three agonists. Thus these PATs selectively blocked the stimulatory action of corresponding agonists on the VLCF terminals via mechanisms that are distinct from those of PCT. PAT may become a novel intervention for studying the pharmacological modulation of VLCFs.

  8. Differential blocking action of dihydropyridine Ca2+ antagonists on a T-type Ca2+ channel (alpha1G) expressed in Xenopus oocytes. (United States)

    Furukawa, Taiji; Nukada, Toshihide; Miura, Reiko; Ooga, Kyoji; Honda, Mituyoshi; Watanabe, Suguru; Koganesawa, Satoshi; Isshiki, Takaaki


    Recent reports show that efonidipine, a dihydropyridine Ca2+ antagonist, has blocking action on T-type Ca2+ channels, which may produce favorable actions on cardiovascular systems. However, the effects of other dihydropyridine Ca2+ antagonists on T-type Ca2+ channels have not been investigated yet. Therefore, in this study, we examined the effects of dihydropyridine compounds clinically used for treatment of hypertension on a T-type Ca2+ channel subtype, alpha1G, expressed in Xenopus oocytes. These effects were compared with those on T-type Ca2+ channel. Rabbit L-type (alpha1Calpha2/deltabeta1a) or rat T-type (alpha1G) Ca2+ channel was expressed in Xenopus oocytes by injection of cRNA for each subunit. The Ba currents through expressed channels were measured by conventional 2-microelectrode voltage-clamp methods. Twelve DHPs (amlodipine, barnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nitrendipine) and mibefradil were tested. Cilnidipine, felodipine, nifedipine, nilvadipine, minodipine, and nitrendipine had little effect on the T-type channel. The blocks by drugs at 10 microM were less than 10% at a holding potential of -100 mV. The remaining 6 drugs had blocking action on the T-type channel comparable to that on the L-type channel. The blocking actions were also comparable to that by mibefradil. These results show that many dihydropyridine Ca2+ antagonists have blocking action on the alpha1G channel subtype. The action of dihydropyridine Ca2+ antagonists in clinical treatment should be evaluated on the basis of subtype selectivity.

  9. Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology

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    Andrew D. Greenhalgh


    Subarachnoid haemorrhage (SAH is a major contributor to the burden of stroke on society. Treatment options are limited and animal models of SAH do not always mimic key pathophysiological hallmarks of the disease, thus hindering development of new therapeutics. Inflammation is strongly associated with brain injury after SAH in animals and patients, and inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1 represents a possible therapeutic target. Here we report that a rupture of the middle cerebral artery in the rat produces heterogeneous infarct patterns similar to those observed in human SAH. Administration of the IL-1 receptor antagonist (IL-1Ra reduced blood-brain barrier breakdown, and the extent of breakdown correlated with brain injury. After SAH, haem oxygenase-1 (HO-1 was strongly expressed around the bleed site and in the cortex and striatum, indicating the presence of free haem, a breakdown product of haemoglobin. HO-1 expression was also found in the same regions as microglial/macrophage expression of IL-1α. The direct effect of haem on IL-1α expression was confirmed in vitro using organotypic slice culture (OSC. Haem-induced cell death was dependent on IL-1 signalling, with IL-1Ra completely blocking cellular injury. Furthermore, stimulation of mouse primary mixed glial cells with haem induced the release of IL-1α, but not IL-1β. Thus, we suggest that haem, released from lysed red blood cells (RBCs in the subarachnoid space, acts as a danger-associated molecular pattern (DAMP driving IL-1-dependent inflammation. These data provide new insights into inflammation after SAH-induced brain injury and suggest IL-1Ra as a candidate therapeutic for the disease.

  10. Blocking S1P interaction with S1P{sub 1} receptor by a novel competitive S1P{sub 1}-selective antagonist inhibits angiogenesis

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    Fujii, Yasuyuki, E-mail: [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Ueda, Yasuji; Ohtake, Hidenori; Ono, Naoya; Takayama, Tetsuo; Nakazawa, Kiyoshi [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Igarashi, Yasuyuki [Laboratory of Biomembrane and Biofunctional Chemistry, Hokkaido University, Sapporo, Hokkaido 060-0812 (Japan); Goitsuka, Ryo [Division of Development and Aging, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba 278-0022 (Japan)


    Highlights: Black-Right-Pointing-Pointer The effect of a newly developed S1P{sub 1}-selective antagonist on angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1} is a critical component of VEGF-related angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vitro activity to inhibit angiogenesis. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vivo activity to inhibit angiogenesis. Black-Right-Pointing-Pointer The efficacy of S1P{sub 1}-selective antagonist for anti-cancer therapies. -- Abstract: Sphingosine 1-phosphate receptor type 1 (S1P{sub 1}) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P{sub 1} and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P{sub 1}-selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P{sub 1} antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P{sub 1} is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.

  11. Blocking of the PD-1/PD-L1 Interaction by a D-Peptide Antagonist for Cancer Immunotherapy. (United States)

    Chang, Hao-Nan; Liu, Bei-Yuan; Qi, Yun-Kun; Zhou, Yang; Chen, Yan-Ping; Pan, Kai-Mai; Li, Wen-Wen; Zhou, Xiu-Man; Ma, Wei-Wei; Fu, Cai-Yun; Qi, Yuan-Ming; Liu, Lei; Gao, Yan-Feng


    Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 has emerged as a promising immunotherapy for treating cancers. Using the technology of mirror-image phage display, we developed the first hydrolysis-resistant D-peptide antagonists to target the PD-1/PD-L1 pathway. The optimized compound (D) PPA-1 could bind PD-L1 at an affinity of 0.51 μM in vitro. A blockade assay at the cellular level and tumor-bearing mice experiments indicated that (D) PPA-1 could also effectively disrupt the PD-1/PD-L1 interaction in vivo. Thus D-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy.

  12. Medicinal chemistry of small molecule CCR5 antagonists for blocking HIV-1 entry: a review of structural evolution. (United States)

    Tian, Ye; Zhang, Dujuan; Zhan, Peng; Liu, Xinyong


    CCR5, a member of G protein-coupled receptors superfamily, plays an important role in the HIV-1 entry process. Antagonism of this receptor finally leads to the inhibition of R5 strains of HIV entry into the human cells. The identification of CCR5 antagonists as antiviral agents will provide more option for HAART. Now, more than a decade after the first small molecule CCR5 inhibitor was discovered, great achievements have been made. In this article, we will give a brief introduction of several series of small molecule CCR5 antagonists, focused on their appealing structure evolution, essential SAR information and thereof the enlightenment of strategies on CCR5 inhibitors design.

  13. The selective GABAB antagonist CGP-35348 blocks spike-wave bursts in the cholesterol synthesis rat absence epilepsy model. (United States)

    Smith, K A; Fisher, R S


    Slow IPSPs, which are believed to be involved in generation of the wave of spike-wave epileptiform discharges, are mediated by the GABAB receptor. We therefore examined the effect of the GABAB antagonist, Ciba Geigy Product, CGP-35348, in the cholesterol synthesis inhibitor model of absence epilepsy in rat. Rats received Ayerst-9944 (AY-9944), from 6-45 mg i.p. in the first few weeks of life. By 2 months after AY-9944 administration these rats exhibited recurrent spike-waves and behavioral arrests. In 10 such animals CGP-35348 was administered intraperitoneally in doses of 0 (vehicle), 10, 25 or 100 mg/kg. EEG recordings were obtained via previously implanted bone screws. Technologists blinded to treatment group counted spike-waves over a 4 h period post-injection. The average number of spike-wave burst seconds per 4 h of recording for all dosages and times was 52.4 +/- 81.4 (mean +/- S.D.) s. Mean burst times (seconds) were vehicle = 93.5 +/- 106.5; 10 mg/kg = 69.9 +/- 79.7; 25 mg/kg = 30.8 +/- 46.9; 100 mg/kg = 15.2 +/- 54, a mean 84% reduction at 100 mg/kg (ANOVA regression significant at 0.0001). Spike-waves were suppressed for at least 4 h after injection of CGP-35348. These findings supplement similar findings in other absence models, and support a potential role for GABAB antagonists in treatment of absence seizures.

  14. Modulatory effect of neurokinin- 1 and non- N- methyl- D- aspartate receptors on cardiosomatic reflex in rat spinal cord%脊髓NK1受体与非NMDA受体对大鼠心脏-躯体运动反射的调节作用

    Institute of Scientific and Technical Information of China (English)

    韩曼; 刘晓华; 杜剑青


    Objective To investigate the role of neurokinin-1 (NK1) receptor and non-N-methyl-D-aspartate (non-NMDA) receptor in modulating the cardiosomatic reflex in the spinal cord of rat. Methods The effects of intrathecal injection of NK1 receptor agonist Sar-SP and antagonist CP-96345 and non-NMDA receptor agonist NMDA and antagonist 6, 7-dinitro-1,4-dihydro-quinoxaline-2,3-dione (DNQX) on the cardiosomatic reflex were observed in rats. The changes of the cardiosomatic reflex were monitored by observing the electromyogram (EMG) responses of the dorsal spinotrapezius muscle to intrapericardial bradykinin (BK) injection. Results Intrathecal injection of Sar-SP significantly facilitated EMG responses to intrapericardial BK injection (P<0.05), which was completely blocked by intrathecal injection of NK1 antagonist CP-96345. Similarly, intrathecal injection of NMDA obviously facilitated the EMG responses (P<0.05), which was partially reversed by intrathecal injection of non-NMDA receptor antagonist DNQX. Intrathecal injection of Sar-SP along with NMDA significantly increased EMG as compared with single administration of Sar-SP or NMDA (P<0.05). Conclusion The spinal cord levels of NK1 receptor and non-NMDA receptor are involved in the modulation of the cardiosomatic reflex in rats.%目的:观察脊髓水平神经激肽-1(NK1)受体和非N-甲基-D-天门冬氨酸(NMDA)受体对大鼠心脏-躯体运动反射的调节作用。方法鞘内注射NK1受体激动剂Sar-SP及拮抗剂CP-96345与非NMDA受体激动剂NMDA及拮抗剂6,7-二硝基喹喔啉-2,3-二酮(DNQX),观察心包内注射缓激肽(BK)诱发大鼠心脏-躯体运动反射的变化,该反射以背斜方肌肌电(EMG)为观测指标。结果鞘内注射NK1受体激动剂Sar-SP后,对心包内BK诱发的背斜方肌EMG有明显的易化作用(P<0.05),这种易化作用被鞘内预先注射NK1拮抗剂CP-96345完全阻断;鞘内注射非NMDA受体激动剂NMDA后,对心包

  15. Vaginally administered PEGylated LIF antagonist blocked embryo implantation and eliminated non-target effects on bone in mice.

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    Ellen Menkhorst

    Full Text Available Female-controlled contraception/HIV prevention is critical to address health issues associated with gender inequality. Therefore, a contraceptive which can be administered in tandem with a microbicide to inhibit sexually transmitted infections, is desirable. Uterine leukemia inhibitory factor (LIF is obligatory for blastocyst implantation in mice and associated with infertility in women. We aimed to determine whether a PEGylated LIF inhibitor (PEGLA was an effective contraceptive following vaginal delivery and to identify non-uterine targets of PEGLA in mice.Vaginally-applied (125I-PEGLA accumulated in blood more slowly (30 min vs 10 min and showed reduced tissue and blood retention (24 h vs 96 h compared to intraperitoneal injection in mice. Vaginally-applied PEGLA blocked implantation. PEGLA administered by intraperitoneal injection inhibited bone remodelling whereas vaginally-applied PEGLA had no effect on bone. Further, PEGLA had no effect in an animal model of multiple sclerosis, experimental auto-immune encephalomyelitis, suggesting PEGLA cannot target the central nervous system.Vaginally-administered PEGLA is a promising non-hormonal contraceptive, one which could be delivered alone, or in tandem with a microbicide. Vaginal application reduced the total dose of PEGLA required to block implantation and eliminated the systemic effect on bone, showing the vagina is a promising site of administration for larger drugs which target organs within the reproductive tract.

  16. Bumetanide, an NKCC1 antagonist, does not prevent formation of epileptogenic focus but blocks epileptic focus seizures in immature rat hippocampus. (United States)

    Nardou, Romain; Ben-Ari, Yehezkel; Khalilov, Ilgam


    Excitatory GABA action induced by high [Cl(-)](i) is thought to contribute to seizure generation in neonatal neurons although the mechanism of this effect remains unclear. We report that bumetanide, a NKCC1 antagonist, reduces driving force of GABA-mediated currents (DF(GABA)) in neonatal hippocampal neurons and blocks the giant depolarizing potentials (GDPs), a spontaneous pattern of network activity. In the preparation composed of two intact interconnected hippocampi, bumetanide did not prevent generation of kainate-induced seizures, their propagation to the contralateral hippocampus, and formation of an epileptogenic mirror focus. However, in the isolated mirror focus, bumetanide effectively blocked spontaneous epileptiform activity transforming it to the GDP-like activity pattern. Bumetanide partially reduced DF(GABA) and therefore the excitatory action of GABA in epileptic neurons. Therefore bumetanide is a potent anticonvulsive agent although it cannot prevent formation of the epileptogenic mirror focus. We suggest that an additional mechanism other than NKCC1-mediated contributes to the persistent increase of DF(GABA) in epileptic neurons.

  17. Extinction of conditioned opiate withdrawal in rats is blocked by intracerebroventricular infusion of an NMDA receptor antagonist. (United States)

    Coleman, Brian R; Carlezon, William A; Myers, Karyn M


    Maladaptive conditioned responses (CRs) contribute to psychiatric disorders including anxiety disorders and addiction. Methods of reducing these CRs have been considered as possible therapeutic approaches. One such method is extinction, which involves exposure to CR-eliciting cues in the absence of the event they once predicted. In animal models, extinction reduces both fear and addiction-related CRs, and in humans, extinction-based cue exposure therapy (CET) reduces fear CRs. However, CET is less effective in drug addicts, for reasons that are not clear. Increased understanding of the neurobiology of extinction of drug-related CRs as compared to fear CRs may help illuminate this issue. Here, we examine the N-methyl-d-aspartate (NMDA) receptor-dependence of extinction of conditioned opiate withdrawal in rats. Using a place conditioning paradigm, we trained morphine-dependent rats to associate an environment with naloxone-precipitated withdrawal. We then extinguished that association by returning the rats repeatedly to the environment in the absence of acute withdrawal. In some rats we administered the NMDA receptor antagonist d,l-2-amino-5-phosphovaleric acid (AP5) intracerebroventricularly immediately prior to extinction training. In a subsequent test session, these rats avoided the formerly naloxone-paired environment, similar to rats that had not undergone extinction training. By contrast, rats that received vehicle prior to extinction training did not avoid the formerly naloxone-paired environment. This finding indicates that extinction of a drug-related CR (conditioned opiate withdrawal) is dependent on NMDA receptors, similar to extinction of conditioned fear. The locus of the critical NMDA receptors is unclear but may include basolateral amygdala and/or medial prefrontal cortex.

  18. Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. (United States)

    Silverman, Jill L; Tolu, Seda S; Barkan, Charlotte L; Crawley, Jacqueline N


    Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. BTBR T+tf/J (BTBR) is an inbred mouse strain that shows robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including well-replicated deficits in reciprocal social interactions and social approach, unusual patterns of ultrasonic vocalization, and high levels of repetitive self-grooming. These phenotypes offer straightforward behavioral assays for translational investigations of pharmacological compounds. Two suggested treatments for autism were evaluated in the BTBR mouse model. Methyl-6-phenylethynyl-pyridine (MPEP), an antagonist of the mGluR5 metabotropic glutamate receptor, blocks aberrant phenotypes in the Fmr1 mouse model of Fragile X, a comorbid neurodevelopmental disorder with autistic features. Risperidone has been approved by the United States Food and Drug Administration for the treatment of irritability, tantrums, and self-injurious behavior in autistic individuals. We evaluated the actions of MPEP and risperidone on two BTBR phenotypes, low sociability and high repetitive self-grooming. Open field activity served as an independent control for non-social exploratory activity and motor functions. C57BL/6J (B6), an inbred strain with high sociability and low self-grooming, served as the strain control. MPEP significantly reduced repetitive self-grooming in BTBR, at doses that had no sedating effects on open field activity. Risperidone reduced repetitive self-grooming in BTBR, but only at doses that induced sedation in both strains. No overall improvements in sociability were detected in BTBR after treatment with either MPEP or risperidone. Our findings suggest that antagonists of mGluR5 receptors may have selective therapeutic efficacy in treating repetitive behaviors in autism.

  19. The orexin-1 receptor antagonist SB-334867 blocks the effects of antipsychotics on the activity of A9 and A10 dopamine neurons: implications for antipsychotic therapy. (United States)

    Rasmussen, Kurt; Hsu, Mei-Ann; Yang, Yili


    Antipsychotic drugs alter the activity of dopamine neurons in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). As there is a dense projection of orexin neurons from the lateral hypothalamus to A10 dopaminergic neurons, and some antipsychotics have been shown to increase the expression of c-fos in orexin-containing cells in the hypothalamus, we hypothesized that stimulation of orexin receptors plays a role in the effects of antipsychotics on the activity of A9 and A10 dopamine cells. Single-unit recordings in anesthetized rats demonstrated the central effects of the selective orexin-1 receptor antagonist SB-334867 (2 mg/kg, intravenous), as it reversed the excitatory effects of orexin-A administration (6 microg, intracerebroventricular) on the activity of locus coeruleus (LC) cells. Recordings from midbrain dopamine neurons showed that acute administration of SB-334867 alone did not alter the number of spontaneously active A9 or A10 cells, but did reverse: (1) the increase in the number of spontaneously active A9 and/or A10 dopamine cells caused by the acute administration of haloperidol (1 mg/kg, subcutaneous) or olanzapine (10 mg/kg, s.c.) and (2) the decrease in the number of spontaneously active A9 and/or A10 dopamine cells caused by the chronic administration of haloperidol (1 mg/kg/day x 21 days, s.c.) or olanzapine (10 mg/kg/day x 21 days, s.c.). However, SB-334867 did not block a different electrophysiological effect of olanzapine, as it did not block the olanzapine-induced activation of LC cells. These results indicate that activation of orexin-1 receptors plays an important role on the effects of antipsychotic drugs on dopamine neuronal activity and may play an important role in the clinical effects of antipsychotic drugs.

  20. Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo.

    Directory of Open Access Journals (Sweden)

    Masami Suzuki

    Full Text Available The dormancy of tumor cells is a major problem in chemotherapy, since it limits the therapeutic efficacy of anti-tumor drugs that only target dividing cells. One potential way to overcome chemo-resistance is to "wake up" these dormant cells. Here we show that the opioid antagonist methylnaltrexone (MNTX enhances the effect of docetaxel (Doc by blocking a cell growth-suppressive pathway. We found that PENK, which encodes opioid growth factor (OGF and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs. The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc. In comparison with the use of Doc alone, the combined use of Doc and MNTX significantly prolongs survival, alleviates abdominal pain, and diminishes Doc-resistant spheroids on the peritoneal membrane in model mice. These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.

  1. Intracerebroventricular injection of mu- and delta-opiate receptor antagonists block 60 Hz magnetic field-induced decreases in cholinergic activity in the frontal cortex and hippocampus of the rat. (United States)

    Lai, H; Carino, M


    In previous research, we have found that acute exposure to a 60 Hz magnetic field decreased cholinergic activity in the frontal cortex and hippocampus of the rat as measured by sodium-dependent high-affinity choline uptake activity. We concluded that the effect was mediated by endogenous opioids inside the brain because it could be blocked by pretreatment of rats before magnetic field exposure with the opiate antagonist naltrexone, but not by the peripheral antagonist naloxone methiodide. In the present study, the involvement of opiate receptor subtypes was investigated. Rats were pretreated by intracerebroventricular injection of the mu-opiate receptor antagonist, beta-funaltrexamine, or the delta-opiate receptor antagonist, naltrindole, before exposure to a 60 Hz magnetic field (2 mT, 1 hour). It was found that the effects of magnetic field on high-affinity choline uptake in the frontal cortex and hippocampus were blocked by the drug treatments. These data indicate that both mu- and delta-opiate receptors in the brain are involved in the magnetic field-induced decreases in cholinergic activity in the frontal cortex and hippocampus of the rat.

  2. Systemic or intra-amygdala infusion of an endocannabinoid CB1 receptor antagonist AM251 blocked propofol-induced anterograde amnesia. (United States)

    Ren, Y; Wang, J; Xu, P B; Xu, Y J; Miao, C H


    Propofol is well-known for its anterograde amnesic actions. However, a recent experiment showed that propofol can also produce retrograde memory enhancement effects via an interaction with the endocannabinoid CB1 system. Therefore, the authors hypothesized that the regulating effect of propofol on the endocannabinoid CB1 system might also decrease the anterograde amnesic effect of propofol under some conditions, which might be a risk factor for intraoperative awareness. Since, the basolateral amygdala (BLA) has been confirmed to mediate propofol-induced anterograde amnesia and the BLA contains a high concentration of CB1 receptors, the authors investigated whether and how the endocannabinoid system, particularly the CB1 receptor within BLA, influences propofol-induced anterograde amnesia. Male Sprague-Dawley rats trained with inhibitory avoidance (IA) were systematically pre-trained using a memory-impairing dose of propofol (25 mg/kg). Before propofol administration, rats received an intraperitoneal injection of a CB1 receptor antagonist AM251 (1 mg/kg or 2 mg/kg) or a bilateral intra-BLA injection of AM251 (0.6 ng or 6 ng per 0.5 μl). Twenty-four hours after IA training, the IA retention latency was tested. It was found that systemic or intra-BLA injection of a non-regulating dose of AM251 (2 mg/kg or 6 ng per 0.5 μl, respectively) blocked the memory-impairing effect of propofol. These results indicate that the anterograde amnesic effect of propofol is mediated, in part, by activation of the CB1 cannabinoid receptors in the BLA.

  3. CXCR2 antagonists block the N-Ac-PGP-induced neutrophil influx in the airways of mice, but not the production of the chemokine CXCL1. (United States)

    Braber, Saskia; Overbeek, Saskia A; Koelink, Pim J; Henricks, Paul A J; Zaman, Guido J R; Garssen, Johan; Kraneveld, Aletta D; Folkerts, Gert


    Neutrophils are innate immune cells in chronic inflammatory diseases including chronic obstructive pulmonary disease (COPD) and can be attracted to the site of inflammation via the collagen breakdown product N-acetyl Proline-Glycine-Proline (N-Ac-PGP). To elucidate whether CXCR2 is involved in N-Ac-PGP-induced neutrophil migration and activation, studies using specific antagonists were performed in vivo. N-Ac-PGP and keratinocyte cell-derived chemokine (KC; CXCL1) were administered in C57Bl/6 mice via oropharyngeal aspiration. Intraperitoneal applications of CXCR2 antagonist SB225002 or SB332235 were administered 1h prior and 1h after oropharyngeal aspiration. Six hours after oropharyngeal aspiration mice were sacrificed. Neutrophil counts and CXCL1 levels were determined in bronchoalveolar lavage fluid, myleoperoxidase (MPO) levels were measured in lung tissue homogenates and an immunohistological staining for neutrophils was performed on lung tissue. N-Ac-PGP and CXCL1 induced a neutrophil influx in the bronchoalveolar lavage fluid and lung tissue, which was also reflected by increased MPO levels in lung tissue. The N-Ac-PGP- and CXCL1-induced neutrophil influx and the increased pulmonary tissue MPO levels were inhibited by the CXCR2 antagonists SB225002 and SB332235. Moreover, N-Ac-PGP administration enhanced the CXCL1 levels in bronchoalveolar lavage fluid, which could not be attenuated by both CXCR2 antagonists. In conclusion, neutrophil migration induced by N-Ac-PGP is mediated via direct CXCR2 interaction. The N-Ac-PGP-induced release of CXCL1 is independent of CXCR2. Related to the maximal effect of CXCL1, N-Ac-PGP is more potent at inducing neutrophil migration in the pulmonary tissue than into the bronchoalveolar lavage fluid, or N-ac-PGP may be more potent at inducing MPO levels in the lung tissue.

  4. Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid to the basolateral amygdala. (United States)

    Fanselow, M S; Kim, J J


    Rats, with chronic cannula placed bilaterally in the amygdala, received infusions of the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonovaleric acid (APV) before contextual Pavlovian fear conditioning. Administration of APV to the basolateral nucleus prevented acquisition of fear. Central nucleus infusions had no effect. It is concluded that an NMDA-mediated process near the basolateral region of the amygdala (e.g., lateral or basolateral nucleus) is essential for the learning of fear.

  5. Non-competitive metabotropic glutamate 1 receptor antagonists block activity of slowly adapting type I mechanoreceptor units in the rat sinus hair follicle. (United States)

    Cahusac, P M B; Mavulati, S C


    Previous studies suggested that Group I metabotropic glutamate (mGlu) receptors play a role in mechanotransduction processes of slowly adapting type I mechanoreceptors. Using an isolated rat sinus hair follicle preparation we tested a range of compounds. Surprisingly, only non-competitive mGlu1 receptor antagonists produced profound and long-lasting depression of mechanically evoked firing. 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (YM-298198) had an IC(50) of 8.7 muM (95% CI 5.7 to 13.2 microM), representing the most potent known blocker of type I mechanoreceptors. The derivative 6-amino-N-cyclohexyl-3-methylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (desmethyl YM-298198) had a comparable potency. Another compound 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) had a similar depressant effect, although it was less potent with an approximate IC(50) of 100 microM. Between three and seven times the concentration of CPCCOEt and YM-298198 respectively was required to produce similar depressions in slowly adapting type II units. No depression, and some weak excitatory effects, were observed using the following ligands: the competitive mGlu1 receptor antagonist alpha-amino-5-carboxy-3-methyl-2-thiopheneacetic acid (3-MATIDA) (300 microM), the phosphoserine phosphatase inhibitor dl-2-amino-3-phosphonopropionic acid (dl-AP3) (2 mM), non-competitive mGlu5 receptor antagonists 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; (S)-3,5-DHPG, (S)-3,5-dihydroxyphenylglycine (MTEP) (10 microM) and 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) (100 microM), the mGlu1 receptor agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) (500 microM), and the mGlu5 receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) (1 mM). The results suggest that the non-competitive mGlu1 receptor antagonists are not acting at conventional mGlu1 receptors but at other binding sites, possibly

  6. Bitopic Sphingosine 1-Phosphate Receptor 3 (S1P3) Antagonist Rescue from Complete Heart Block: Pharmacological and Genetic Evidence for Direct S1P3 Regulation of Mouse Cardiac Conduction (United States)

    Sanna, M. Germana; Vincent, Kevin P.; Repetto, Emanuela; Nguyen, Nhan; Brown, Steven J.; Abgaryan, Lusine; Riley, Sean W.; Leaf, Nora B.; Cahalan, Stuart M.; Kiosses, William B.; Kohno, Yasushi; Brown, Joan Heller; McCulloch, Andrew D.


    The molecular pharmacology of the G protein–coupled receptors for sphingosine 1-phosphate (S1P) provides important insight into established and new therapeutic targets. A new, potent bitopic S1P3 antagonist, SPM-354, with in vivo activity, has been used, together with S1P3-knockin and S1P3-knockout mice to define the spatial and functional properties of S1P3 in regulating cardiac conduction. We show that S1P3 is a key direct regulator of cardiac rhythm both in vivo and in isolated perfused hearts. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in vivo and S1P in isolated hearts induced a spectrum of cardiac effects, ranging from sinus bradycardia to complete heart block, as measured by a surface electrocardiogram in anesthetized mice and in volume-conducted Langendorff preparations. The agonist effects on complete heart block are absent in S1P3-knockout mice and are reversed in wild-type mice with SPM-354, as characterized and described here. Homologous knockin of S1P3-mCherry is fully functional pharmacologically and is strongly expressed by immunohistochemistry confocal microscopy in Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4)-positive atrioventricular node and His-Purkinje fibers, with relative less expression in the HCN4-positive sinoatrial node. In Langendorff studies, at constant pressure, SPM-354 restored sinus rhythm in S1P-induced complete heart block and fully reversed S1P-mediated bradycardia. S1P3 distribution and function in the mouse ventricular cardiac conduction system suggest a direct mechanism for heart block risk that should be further studied in humans. A richer understanding of receptor and ligand usage in the pacemaker cells of the cardiac system is likely to be useful in understanding ventricular conduction in health, disease, and pharmacology. PMID:26494861

  7. Beta-CCT, a selective BZ-omega1 receptor antagonist, blocks the anti-anxiety but not the amnesic action of chlordiazepoxide in mice. (United States)

    Belzung, C; Le Guisquet, A M; Griebel, G


    The aim of this study was to test further the hypothesis that different benzodiazepine (BZ-omega) receptor subtypes may mediate anxiolytic and amnesic effects of BZ agonists, using the selective BZ-omega1 receptor antagonist beta-CCT (beta-carboline-3-carboxylate t-butyl-ester). Experiments were performed in Swiss mice using the elevated plus-maze anxiety test and two learning tasks - passive avoidance and the radial arm maze. In the elevated plus-maze test, beta-CCT (30 mg/kg, i.p.) completely abolished the increase in open-arm entries induced by the BZ chlordiazepoxide (5mg/kg, i.p.). Chlordiazepoxide decreased retention latency in the passive avoidance step-through procedure, and increased the number of errors in the radial arm maze. These effects were not modified by beta-CCT. Except for a slight, albeit significant, amnesic effect in the passive avoidance test, beta-CCT was devoid of intrinsic activity when administered alone. These results are in agreement with previous studies using selective BZ-omega1 agonists, and thus provide further evidence that BZ-omega1 receptors may be involved in the anxiolytic but not in the amnesic effects of BZ agonists.

  8. GABAB antagonists

    DEFF Research Database (Denmark)

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


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

  9. Calcium-sensing receptor antagonist (calcilytic) NPS 2143 specifically blocks the increased secretion of endogenous Aβ42 prompted by exogenous fibrillary or soluble Aβ25-35 in human cortical astrocytes and neurons-therapeutic relevance to Alzheimer's disease. (United States)

    Armato, Ubaldo; Chiarini, Anna; Chakravarthy, Balu; Chioffi, Franco; Pacchiana, Raffaella; Colarusso, Enzo; Whitfield, James F; Dal Prà, Ilaria


    The "amyloid-β (Aβ) hypothesis" posits that accumulating Aβ peptides (Aβs) produced by neurons cause Alzheimer's disease (AD). However, the Aβs contribution by the more numerous astrocytes remains undetermined. Previously we showed that fibrillar (f)Aβ25-35, an Aβ42 proxy, evokes a surplus endogenous Aβ42 production/accumulation in cortical adult human astrocytes. Here, by using immunocytochemistry, immunoblotting, enzymatic assays, and highly sensitive sandwich ELISA kits, we investigated the effects of fAβ25-35 and soluble (s)Aβ25-35 on Aβ42 and Aβ40 accumulation/secretion by human cortical astrocytes and HCN-1A neurons and, since the calcium-sensing receptor (CaSR) binds Aβs, their modulation by NPS 2143, a CaSR allosteric antagonist (calcilytic). The fAβ25-35-exposed astrocytes and surviving neurons produced, accumulated, and secreted increased amounts of Aβ42, while Aβ40 also accrued but its secretion was unchanged. Accordingly, secreted Aβ42/Aβ40 ratio values rose for astrocytes and neurons. While slightly enhancing Aβ40 secretion by fAβ25-35-treated astrocytes, NPS 2143 specifically suppressed the fAβ25-35-elicited surges of endogenous Aβ42 secretion by astrocytes and neurons. Therefore, NPS 2143 addition always kept Aβ42/Aβ40 values to baseline or lower levels. Mechanistically, NPS 2143 decreased total CaSR protein complement, transiently raised proteasomal chymotrypsin activity, and blocked excess NO production without affecting the ongoing increases in BACE1/β-secretase and γ-secretase activity in fAβ25-35-treated astrocytes. Compared to fAβ25-35, sAβ25-35 also stimulated Aβ42 secretion by astrocytes and neurons and NPS 2143 specifically and wholly suppressed this effect. Therefore, since NPS 2143 thwarts any Aβ/CaSR-induced surplus secretion of endogenous Aβ42 and hence further vicious cycles of Aβ self-induction/secretion/spreading, calcilytics might effectively prevent/stop the progression to full-blown AD.

  10. Rock blocks


    Turner, W.


    Consider representation theory associated to symmetric groups, or to Hecke algebras in type A, or to q-Schur algebras, or to finite general linear groups in non-describing characteristic. Rock blocks are certain combinatorially defined blocks appearing in such a representation theory, first observed by R. Rouquier. Rock blocks are much more symmetric than general blocks, and every block is derived equivalent to a Rock block. Motivated by a theorem of J. Chuang and R. Kessar in the case of sym...

  11. Population Blocks. (United States)

    Smith, Martin H.


    Describes an educational game called "Population Blocks" that is designed to illustrate the concept of exponential growth of the human population and some potential effects of overpopulation. The game material consists of wooden blocks; 18 blocks are painted green (representing land), 7 are painted blue (representing water); and the remaining…

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

    NARCIS (Netherlands)

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


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

  13. Opioid Antagonist Impedes Exposure. (United States)

    Merluzzi, Thomas V.; And Others


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

  14. Zitongdong Block

    Institute of Scientific and Technical Information of China (English)


    @@ The Zitongdong Block (Eastern Zitong Block) is located in the northwest of the Sichuan Basin. Tectonically, it is situated in the east part of Zitong Depression, southeast of mid-Longmenshan folded and faulted belt( as shown on Fig. 8 ), covering an area of 1 730 km2. The traffic is very convenient, the No. 108 national highway passes through the north of the block. Topographically, the area belongs to low hilly land at the elevation of 500-700 m.

  15. Fine Tuning of a Type 1 Interferon Antagonist.

    Directory of Open Access Journals (Sweden)

    Victoria Urin

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

  16. Zitongxi Block

    Institute of Scientific and Technical Information of China (English)


    @@ Zitongxi Block (Western Zitong Block), is located in Zitong County, northwest of Sichuan Province (as shown on Fig. 8 ). Geologically. it is situated in the Zitong Depression, southwest of the middle Longmenshan faulted and folded belt, covering an area of 1 830 km2. Transportation is very convenient. A crisscross network of highways run through the block and the Baocheng railway is nearby. The climate is moderate. Most area belongs to hilly land with the elevation of 500-600 m.The Tongjiang River runs across the area.

  17. Chengzikou Block

    Institute of Scientific and Technical Information of China (English)


    @@ Chengzikou Block is located in the north of Hekou district, Dongying City, Shandong Province, adjacent to Bohai Bay. It can be geographically divided into three units: onshore, transitional zone and offshore ultrashallow zone, totally covering an area of 470 km2. The southern onshore area is low and gentle in topography;the northern shallow sea is at water depths of 2-8 m below sea level, and the transitional zone occupies more than 60% of the whole block. The climate belongs to temperate zone with seasonal wind. Highways are welldeveloped here, and the traffic is very convenient. The Chengzikou Block is about 80 km away from Dongying City and 290 km from Jinan City in the south. The northern offshore area of the block is 160 km away from Longkou port in the east and only 38 km away in the west from Zhuangxi port.

  18. Longmenshan Block

    Institute of Scientific and Technical Information of China (English)


    @@ Longmenshan Block is located in Jiange County of Jiangyou City in the northwest of Sichuan Basin. covering an area of 2 628 km2. Geologically, it is situated in the Mid-Longmenshan fault and fold belt, neighbouring Zitong Depression in its southeast. There are mountains surrounding its northwest , the rest area being hilly land,with the elevation of 500-700 m. The BaoCheng railway and the No. 108 highway run through the block, the traffic is very convenient.

  19. Tetrahydroindolizinone NK1 antagonists. (United States)

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


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

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

    Directory of Open Access Journals (Sweden)

    Marc P Maillard


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

  1. Chadong Block

    Institute of Scientific and Technical Information of China (English)


    @@ The Chadong Block, located in the east of Qaidam Basin, Qinghai Province, covers an area of 12 452 km2. It is bounded by Kunlum Mountains in the south and the northwest is closely adjacent to Aimunike Mountain.Rivers are widely distributed, which always run in NWSE direction, including the Sulunguole, Qaidam and Haluwusu Rivers. The traffic condition is good, the Qinghai-Tibet highway stretching through the whole area and the Lan-Qing railway, 20-50 km away from the block, passing from north to west. A lot of Mongolia minority people have settled there, of which herdsmen always live nearby the Qaidam River drainage area.

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

    LENUS (Irish Health Repository)

    Bates, John J


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

  3. Potent and orally efficacious benzothiazole amides as TRPV1 antagonists. (United States)

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


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

  4. Antagonists of IAP proteins as cancer therapeutics. (United States)

    Dynek, Jasmin N; Vucic, Domagoj


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

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

    Energy Technology Data Exchange (ETDEWEB)

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


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

  6. Synthesis of potential mescaline antagonists. (United States)

    DeSantis, F; Nieforth, K A


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

  7. Excitatory amino acid receptor antagonists

    DEFF Research Database (Denmark)

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


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


    Institute of Scientific and Technical Information of China (English)

    PENGDun-Ren; XIAOShao-Bo


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

  9. 海马NMDA受体经SP-NK1受体通路参与慢性应激诱发的抑郁样行为%Hippocampal NMDA Receptor is involved in Chronic Stress Induced Depressive-Like Behaviors via SP-NK1 Receptor Pathway

    Institute of Scientific and Technical Information of China (English)

    董素平; 徐畅; 原婷婷; 安书成


    theoretic mechanisms for depression, such as monoamine neurotransmitter imbalance theory, neural plasticity theory, but none of them can fully elucidate the formation of depression. Due to weakness of the antidepressant-like effect of monoamines, glutamate (Glu)and its receptors, especially N-methyl-D-aspartic acid (NMDA) receptor, and neuropeptides such as neuropeptide Y (NPY), substance P (SP), are drawing closer attention in recent years. Here, we are attempted to explore the interaction between Glu/NMDA receptor and SP/neurokinin 1 (NK1) receptor in chronic unpredictable mild stress (CUMS)-induced depression.CUMS-induced depression model was established in 250~300g weighted 90-day old Sprague-Dawley rats. Intrahippocampal microinjection of NK1 receptor antagonist CP-96345, NMDA receptor agonist NMDA or NMDA receptor antagonist MK-801 was performed under stereotaxic guide cannula. The body weight of rats was weighed on the 1st, 7th, 14th, and 21st days during the experiment. The behavioral conducts were observed by means of sucrose consumption test, open field test and tail suspension test. The substance P (SP) and glutamate (Glu) content in hippocampus were separately determined by High performance liquid chromatography (HPLC). One-way ANOVA, LSD and repeated measures in SPSS were used in datum analysis.Our data suggest that CUMS significantly induced the depressive-like behaviors in animals and the content of SP and Glu in hippocampus had increased significantly. Microinjection of NMDA into hippocampus resulted in similar animal depressive-like behaviors and an increased SP content compared to the CON/SAL group. Intrahippocampal injections of CP-96345 or MK-801 had effectively improved the depression-like behaviors induced by CUMS, and the elevation of SP level in hippocampus was attenuated in MK-801 injection, whereas Glu level remained unchanged in CP-96345 injection.Our results imply that hippocampal NMDA receptor may contribute to chronic stress induced depressive

  10. Ubiquitination profiling identifies sensitivity factors for IAP antagonist treatment. (United States)

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


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

  11. Ultrasound guided supraclavicular block.

    LENUS (Irish Health Repository)

    Hanumanthaiah, Deepak


    Ultrasound guided regional anaesthesia is becoming increasingly popular. The supraclavicular block has been transformed by ultrasound guidance into a potentially safe superficial block. We reviewed the techniques of performing supraclavicular block with special focus on ultrasound guidance.

  12. Glutamate antagonists limit tumor growth



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

  13. Block Cipher Analysis

    DEFF Research Database (Denmark)

    Miolane, Charlotte Vikkelsø

    Block ciphersarecryptographicprimitivesthatoperateon fixed sizetexts(blocks). Mostdesigns aim towards secure andfastencryption oflarge amounts ofdata. Block ciphers also serve as the building block of a number of hash functions and message authentication codes(MAC).Thetask of cryptanalysisisto en...... on small scale variants of AES. In the final part of the thesis we present a new block cipher proposal Present and examine its security against algebraic and differential cryptanalysis in particular.......Block ciphersarecryptographicprimitivesthatoperateon fixed sizetexts(blocks). Mostdesigns aim towards secure andfastencryption oflarge amounts ofdata. Block ciphers also serve as the building block of a number of hash functions and message authentication codes(MAC).Thetask of cryptanalysisisto...... ensurethat no attack violatesthe securitybounds specifiedbygeneric attack namely exhaustivekey search and table lookup attacks. This thesis contains a general introduction to cryptography with focus on block ciphers and important block cipher designs, in particular the Advanced Encryption Standard...

  14. Muscarinic Receptor Agonists and Antagonists

    Directory of Open Access Journals (Sweden)

    David R. Kelly


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

  15. New antagonist agents of neuropeptide y receptors

    Directory of Open Access Journals (Sweden)

    Ignacio Aldana


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

  16. The Effect of Sympathetic Antagonists on the Antidepressant Action of Alprazolam

    Directory of Open Access Journals (Sweden)

    Gorash ZM


    Full Text Available Alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam–induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a β1-selective adrenoceptor antagonist; propranolol, a non selective β-adrenoceptor antagonist; and prazocin, an α1-adrenoceptor antagonist. Results confirmed the antidepressant action of alprazolam and imipramine. Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. Atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. Propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments. In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates β2 receptors to produce an antidepressant action. Imipramine may act by activating β2 receptors by blocking or down-regulating β1 receptors.

  17. Total Spinal Block after Thoracic Paravertebral Block. (United States)

    Beyaz, Serbülent Gökhan; Özocak, Hande; Ergönenç, Tolga; Erdem, Ali Fuat; Palabıyık, Onur


    Thoracic paravertebral block (TPVB) can be performed with or without general anaesthesia for various surgical procedures. TPVB is a popular anaesthetic technique due to its low side effect profile and high analgesic potency. We used 20 mL of 0.5% levobupivacaine for a single injection of unilateral TPVB at the T7 level with neurostimulator in a 63 year old patient with co-morbid disease who underwent cholecystectomy. Following the application patient lost consciousness, and was intubated. Haemodynamic instability was normalised with rapid volume replacement and vasopressors. Anaesthetic drugs were stopped at the end of the surgery and muscle relaxant was antagonised. Return of mucle strenght was shown with neuromuscular block monitoring. Approximately three hours after TPVB, spontaneous breathing started and consciousness returned. A total spinal block is a rare and life-threatening complication. A total spinal block is a complication of spinal anaesthesia, and it can also occur after peripheral blocks. Clinical presentation is characterised by hypotension, bradicardia, apnea, and cardiac arrest. An early diagnosis and appropriate treatment is life saving. In this case report, we want to present total spinal block after TPVB.

  18. Serotonin receptor antagonists discriminate between PKA- and PKC-mediated plasticity in aplysia sensory neurons. (United States)

    Dumitriu, Bogdan; Cohen, Jonathan E; Wan, Qin; Negroiu, Andreea M; Abrams, Thomas W


    Highly selective serotonin (5-hydroxytryptamine, 5-HT) receptor antagonists developed for mammals are ineffective in Aplysia due to the evolutionary divergence of neurotransmitter receptors and because the higher ionic strength of physiological saline for marine invertebrates reduces antagonist affinity. It has therefore been difficult to identify antagonists that specifically block individual signaling cascades initiated by 5-HT. We studied two broad-spectrum 5-HT receptor antagonists that have been characterized biochemically in Aplysia CNS: methiothepin and spiperone. Methiothepin is highly effective in inhibiting adenylyl cyclase (AC)-coupled 5-HT receptors in Aplysia. Spiperone, which blocks phospholipase C (PLC)-coupled 5-HT receptors in mammals, does not block AC-coupled 5-HT receptors in Aplysia. In electrophysiological studies, we explored whether methiothepin and spiperone can be used in parallel to distinguish between the AC-cAMP and PLC-protein kinase C (PKC) modulatory cascades that are initiated by 5-HT. 5-HT-induced broadening of the sensory neuron action potential in the presence of tetraethylammonium/nifedipine, which is mediated by modulation of the S-K+ currents, was used an assay for the AC-cAMP cascade. Spike broadening initiated by 5 microM 5-HT was unaffected by 100 microM spiperone, whereas it was effectively blocked by 100 microM methiothepin. Facilitation of highly depressed sensory neuron-to-motor neuron synapses by 5-HT was used as an assay for the PLC-PKC cascade. Spiperone completely blocked facilitation of highly depressed synapses by 5 microM 5-HT. In contrast, methiothepin produced a modest, nonsignificant, reduction in the facilitation of depressed synapses. Interestingly, these experiments revealed that the PLC-PKC cascade undergoes desensitization during exposure to 5-HT.

  19. Generalized Block Failure

    DEFF Research Database (Denmark)

    Jönsson, Jeppe


    Block tearing is considered in several codes as a pure block tension or a pure block shear failure mechanism. However in many situations the load acts eccentrically and involves the transfer of a substantial moment in combination with the shear force and perhaps a normal force. A literature study...... yield lines around the block leads to simple interaction formulas similar to other interaction formulas in the codes.......Block tearing is considered in several codes as a pure block tension or a pure block shear failure mechanism. However in many situations the load acts eccentrically and involves the transfer of a substantial moment in combination with the shear force and perhaps a normal force. A literature study...

  20. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists

    DEFF Research Database (Denmark)

    Ebert, B; Thorkildsen, C; Andersen, S;


    Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However......, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA...... receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence...


    Institute of Scientific and Technical Information of China (English)

    黄廷祝; 黎稳


    The block H-matrices are studied by the concept of G-functions, several concepts of block matrices are introduced. Equivalent characters of block H-matrices are obtained. Spectrum localizations claracterized by Gfunctions for block matrices are got.

  2. Block TERM factorization of block matrices

    Institute of Scientific and Technical Information of China (English)

    SHE Yiyuan; HAO Pengwei


    Reversible integer mapping (or integer transform) is a useful way to realize Iossless coding, and this technique has been used for multi-component image compression in the new international image compression standard JPEG 2000. For any nonsingular linear transform of finite dimension, its integer transform can be implemented by factorizing the transform matrix into 3 triangular elementary reversible matrices (TERMs) or a series of single-row elementary reversible matrices (SERMs). To speed up and parallelize integer transforms, we study block TERM and SERM factorizations in this paper. First, to guarantee flexible scaling manners, the classical determinant (det) is generalized to a matrix function, DET, which is shown to have many important properties analogous to those of det. Then based on DET, a generic block TERM factorization,BLUS, is presented for any nonsingular block matrix. Our conclusions can cover the early optimal point factorizations and provide an efficient way to implement integer transforms for large matrices.

  3. Antagonism of apomorphine-enhanced startle by alpha 1-adrenergic antagonists. (United States)

    Davis, M; Kehne, J H; Commissaris, R L


    The present study investigated the possible involvement of central noradrenergic neurons in mediating the excitatory effect of the dopamine agonist apomorphine on the acoustic startle response in rats. Experiment 1 assessed the effects of intraperitoneal (i.p.) administration of adrenergic antagonists on apomorphine-enhanced startle. The excitation of startle produced by apomorphine (1.0-3.0 mg/kg i.p.) was blocked by the alpha 1-adrenergic antagonists prazosin (0.03-1.0 mg/kg) and WB-4101 (1.0 mg/kg). Prazosin was very potent in this regard, having an ED50 of 0.03 mg/kg. Blockade of beta-adrenergic receptors with propranolol (20 mg/kg) or blockade of peripheral alpha-adrenergic receptors with phentolamine (10 mg/kg) failed to alter the effect of apomorphine. Prazosin did not block the enhancement of startle produced by other drugs (5-methoxy-N,N-dimethyltryptamine, strychnine), nor did it alter the entry of apomorphine into the brain. The alpha 1-adrenergic antagonists piperoxane (0.03 mg/kg), yohimbine (0.03 mg/kg) or RX781094 (0.07 mg/kg) markedly potentiated apomorphine excitation. These data indicated that specific blockade of central alpha 1-adrenergic receptors prevents apomorphine-enhanced startle. In contrast to the effects of alpha 1-adrenergic antagonists, Experiment 2 found that other drugs that produce an acute (clonidine, 0.040 mg/kg) or chronic (intraventricular 6-hydroxydopamine, 2 X 200 micrograms; DSP4, 50 mg/kg i.p.) disruption of noradrenergic transmission failed to affect apomorphine excitation. Thus, the ability of alpha 1-adrenergic antagonists to block apomorphine's excitation of startle cannot be explained by a simple dopamine-norepinephrine interaction. Alternative hypothesis are discussed.

  4. Antagonists of the kappa opioid receptor. (United States)

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


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

  5. Antagonistic formation motion of cooperative agents

    Institute of Scientific and Technical Information of China (English)

    卢婉婷; 代明香; 薛方正


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

  6. Lesson Thirteen Trifascicular Block

    Institute of Scientific and Technical Information of China (English)

    鲁端; 王劲


    @@ A complete trifascicular block would result in complete AV block. The idio ventricular rhythm has a slower rate and a wide QRS complex because the pacemaker is located at the peripheral part of the conduction system distal to the sites of the block1. Such a rhythm may be difficult to differentiate from bifascicular or bundle branch block combined with complete block at a higher level such as the AV node or His bundle2. Besides a slower ventricular rate, a change in the morphology of the QRS complex from a previous known bifascicular pattern would be strongly suggestive of a trifascicular origin of the complete AV block3. A His bundle recording is required for a definitive diagnosis, however.

  7. Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD. (United States)

    Moulton, Bart C; Fryer, Allison D


    In the lungs, parasympathetic nerves provide the dominant control of airway smooth muscle with release of acetylcholine onto M3 muscarinic receptors. Treatment of airway disease with anticholinergic drugs that block muscarinic receptors began over 2000 years ago. Pharmacologic data all indicated that antimuscarinic drugs should be highly effective in asthma but clinical results were mixed. Thus, with the discovery of effective β-adrenergic receptor agonists the use of muscarinic antagonists declined. Lack of effectiveness of muscarinic antagonists is due to a variety of factors including unwanted side effects (ranging from dry mouth to coma) and the discovery of additional muscarinic receptor subtypes in the lungs with sometimes competing effects. Perhaps the most important problem is ineffective dosing due to poorly understood differences between routes of administration and no effective way of testing whether antagonists block receptors stimulated physiologically by acetylcholine. Newer muscarinic receptor antagonists are being developed that address the problems of side effects and receptor selectivity that appear to be quite promising in the treatment of asthma and chronic obstructive pulmonary disease.

  8. Blockade of the stimulus properties of mescaline by a serotonin antagonist. (United States)

    Winter, J C


    It is known that the effects of mescaline (3, 4, 5-trimethoxyphenylethylamine), a hallucinogen, can function as a discriminative stimulus. The present investigation examined the ability of cinanserin, a serotinin antagonist, to block the stimulus properties of mescaline in the rat. After a reliable discrimination was established between the effects following the injection of mescaline (10 mg/kg) and those following administration of saline, subjects were pretreated with cinanserin HC1 (3 mg/kg) and then treated with mescaline. Such pretreatment was found to block discrimination, i.e., the response rate following the administration of mescaline plus cinanserin was appropriate for the saline condition. The present data suggest that antagonists of serotonin may be useful in furthering our understanding of phenethylamine hallucinogens.

  9. The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients

    NARCIS (Netherlands)

    vanMegen, HJGM; Westenberg, HGM; denBoer, JA; Slaap, B; vanEsRadhakishun, F; Pande, AC


    The effects of the cholecystokinin-B (CCK-B) receptor antagonist CI-988 on symptoms elicited by the cholecystokinin tetrapeptide (CCK4) were studied in DSM-IIIR patients with panic disorder. The study employed a double-blind, two-period incomplete block design. Patients (n = 14) received two differe

  10. Vaninolol: a new selective beta 1-adrenoceptor antagonist derived from vanillin. (United States)

    Wu, B N; Hwang, T L; Liao, C F; Chen, I J


    The beta-adrenoceptor blocking properties of vaninolol ((+/-)4-[4'-(2-hydroxy-3-tert-butyl-aminopropoxy)-3'-methoxyphenyl]- 3-buten-2-one), derived from vanillin, were first investigated under in vivo and in vitro conditions. Vaninolol (0.1, 0.5, 1.0 mg/kg, i.v.), as well as propranolol, produced a dose-dependent bradycardia response and a sustained pressor action in urethane-anesthetized normotensive rats. Vaninolol inhibited the tachycardia effects induced by (-)isoproterenol, but had no blocking effect on the arterial pressor responses induced by phenylephrine. These findings suggested that vaninolol possessed beta-adrenergic blocking activity, but was without alpha-adrenergic blocking activity. In isolated guinea-pig tissues, vaninolol antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that vaninolol was a beta-adrenoceptor competitive antagonist. The effect of vaninolol was more potent on the atria than on tracheal tissues, indicating it had some beta 1-adrenoceptor selectivity. On the other hand, the order of the hydrophilicity was atenolol > vaninolol > propranolol. In addition, vaninolol had a mild direct cardiac depression at high concentrations and was without intrinsic sympathomimetic activity (ISA). Furthermore, binding characteristics of vaninolol and other beta-adrenoceptor antagonists were evaluated in [3H]dihydroalprenolol binding to guinea-pig ventricular membranes. The order of potency of beta-adrenoceptor antagonists in competing for the binding sites was (-)propranolol > vaninolol > or = atenolol. In conclusion, vaninolol was found to be a selective beta 1-adrenoceptor antagonist with relatively low lipophilicity in comparison with propranolol, devoid of ISA, and had a mild myocardial depressant effect.

  11. Benzodiazepine receptor antagonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

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


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

  12. Blocked Urethral Valves (United States)

    ... Blocked Urethral Valves Health Issues Listen Español Text Size Email Print Share Blocked Urethral Valves Page Content Article Body Urine leaves the bladder through a tube called the urethra, which in boys passes through the penis. Rarely, small membranes form across the urethra in ...

  13. Types of Heart Block (United States)

    ... P wave as it normally would. If an electrical signal is blocked before it reaches the ventricles, they won't contract and pump blood to the lungs and the rest of the body. Second-degree heart block is divided into two ...

  14. Related Drupal Nodes Block

    NARCIS (Netherlands)

    Van der Vegt, Wim


    Related Drupal Nodes Block This module exposes a block that uses Latent Semantic Analysis (Lsa) internally to suggest three nodes that are relevant to the node a user is viewing. This module performs three tasks. 1) It periodically indexes a Drupal site and generates a Lsa Term Document Matrix. Inde

  15. The Block Neighborhood

    CERN Document Server

    Arrighi, Pablo


    We define the block neighborhood of a reversible CA, which is related both to its decomposition into a product of block permutations and to quantum computing. We give a purely combinatorial characterization of the block neighborhood, which helps in two ways. First, it makes the computation of the block neighborhood of a given CA relatively easy. Second, it allows us to derive upper bounds on the block neighborhood: for a single CA as function of the classical and inverse neighborhoods, and for the composition of several CAs. One consequence of that is a characterization of a class of "elementary" CAs that cannot be written as the composition of two simpler parts whose neighborhoods and inverse neighborhoods would be reduced by one half.

  16. QSAR and pharmacophore analysis of a series of piperidinyl urea derivatives as HERG blockers and H3 antagonists. (United States)

    Moorthy, N S Hari Narayana; Ramos, Maria J; Fernandes, Pedro A


    In the present study, a computational based pharmacophore and structural analysis were performed on a series of piperidinyl urea derivatives, a limited number of compounds which have variation in structures and activities that exhibit hERG blocking and H3 antagonistic activities. The conducted QSAR studies demonstrated that the developed models are statistically significant, which have been confirmed through validation. The Q2 values for the models developed with hERG blocking activity are > 0.8 and with the H3 antagonistic activity are > 0.6. The descriptors contributed in the models show that the distributed polar properties on the vdW surface of the molecules are important for the hERG blocking activity. The vsurf_ descriptors (surface area, volume and shape) such as vsurf_DD13 and vsurf_Wp4 correlate with the H3 antagonistic activity of these compounds. The distances between the pharmacophore sites were measured in order to confirm their significance to the activities. The results reveal that the acceptor (acc), donor (don), hydrophobic (hyd) and aromatic/hydrophobic (aro/hyd) pharmacophore properties are favorable contours sites for both the activities. Also, our study reveals that the distance between the polar contours (acc, don, etc) has to be small for better hERG blocking activity. The distances between the aro/hyd to the polar groups should be higher for better hERG blocking activity. However, the H3 antagonistic activity for these series depends upon hydrophobic property of the molecules, particularly the hyd and the hyd/aro contours of the molecules. Hence, these results reveal the requirements on the structural properties and the distances between the pharmacophore contour sites of the molecules responsible for their hERG and H3 antagonistic activities.

  17. Clinical experience in Europe with uroselective alpha1-antagonists. (United States)

    Debruyne, F M; Van der Poel, H G


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

  18. Characterization of mechanisms involved in presynaptic inhibition of sympathetic pressor effects induced by some 5-HT1 receptor antagonists. (United States)

    Fernández, M M; Calama, E; Morán, A; Martín, M L; San Román, L


    1. In a previous study, we showed that the presynaptic inhibitory action of 5-hydroxytryptamine receptor agonists on sympathetic pressor effects obtained in the pithed rats were mainly mediated by activation of 5-HT1A and 5-HT1D receptor subtypes. At the time, we observed that some 5-HT1 receptors antagonists - WAY 100,635 and NAN-190 (both 5-HT1A receptor antagonists), methiothepin (a 5-HT1,2,5,6,7 receptor antagonist) and spiperone (a 5-HT1,2 receptor antagonist) - reduced per se the pressor effects obtained by electrical stimulation. The aim of the present work was to investigate the mechanism participating in this inhibitory effect. 2. The inhibition induced by WAY 100,635 (1000 microg kg-1, i.v.) was blocked after i.v. treatment with idazoxan, an alpha2-adrenoceptor antagonist (300 and 1000 microg kg-1) and was not modified after i.v. treatment with propranolol, a beta-adrenoceptor antagonist (1000 microg kg-1) and sulpiride, a D2 receptor antagonist (1000 microg kg-1). The inhibition induced by spiperone (500 microg kg-1 i.v.) was significantly blocked by sulpiride (1000 microg kg-1) and was not modified by idazoxan or propranolol. 3. Sulpiride (1000 microg kg-1) partially blocked the inhibition induced by methiothepin (50 microg kg-1 i.v.). Only pretreatment with idazoxan (300 microg kg-1) modified the inhibition induced by NAN-190 (100 microg kg-1 i.v.), such inhibition increasing after intravenous administration of idazoxan. 4. All the antagonists used in our experiments failed to inhibit the pressor responses elicited by i.v. noradrenaline administration. 5. The above results suggest that the inhibitory effects of these 5-HT1 receptor antagonists are presynaptic in nature, but not related to the blockade of 5-HT1 receptors subtypes. The simultaneous activation or inhibition of other receptor systems could explain the inhibition produced by each 5-HT1 receptor antagonist studied.

  19. Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure. (United States)

    Sica, Domenic A


    Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered.

  20. Block copolymer battery separator (United States)

    Wong, David; Balsara, Nitash Pervez


    The invention herein described is the use of a block copolymer/homopolymer blend for creating nanoporous materials for transport applications. Specifically, this is demonstrated by using the block copolymer poly(styrene-block-ethylene-block-styrene) (SES) and blending it with homopolymer polystyrene (PS). After blending the polymers, a film is cast, and the film is submerged in tetrahydrofuran, which removes the PS. This creates a nanoporous polymer film, whereby the holes are lined with PS. Control of morphology of the system is achieved by manipulating the amount of PS added and the relative size of the PS added. The porous nature of these films was demonstrated by measuring the ionic conductivity in a traditional battery electrolyte, 1M LiPF.sub.6 in EC/DEC (1:1 v/v) using AC impedance spectroscopy and comparing these results to commercially available battery separators.

  1. Hawaii Census 2000 Blocks (United States)

    U.S. Environmental Protection Agency — This data layer represents Census 2000 demographic data derived from the PL94-171 redistricting files and SF3. Census geographic entities include blocks, blockgroups...

  2. Steroidal neuromuscular blocking agents

    NARCIS (Netherlands)

    Wierda, JMKH; Mori, K; Ohmura, A; Toyooka, H; Hatano, Y; Shingu, K; Fukuda, K


    Since 1964 approximately 20 steroidal neuromuscular blocking agents have been evaluated clinically. Pancuronium, a bisquaternary compound designed on the drawingboard, was the first steroidal relaxant introduced into clinical practice worldwide in the 1970's. Although a major improvement, pancuroniu

  3. Superalloy Lattice Block Structures (United States)

    Nathal, M. V.; Whittenberger, J. D.; Hebsur, M. G.; Kantzos, P. T.; Krause, D. L.


    Initial investigations of investment cast superalloy lattice block suggest that this technology will yield a low cost approach to utilize the high temperature strength and environmental resistance of superalloys in lightweight, damage tolerant structural configurations. Work to date has demonstrated that relatively large superalloy lattice block panels can be successfully investment cast from both IN-718 and Mar-M247. These castings exhibited mechanical properties consistent with the strength of the same superalloys measured from more conventional castings. The lattice block structure also accommodates significant deformation without failure, and is defect tolerant in fatigue. The potential of lattice block structures opens new opportunities for the use of superalloys in future generations of aircraft applications that demand strength and environmental resistance at elevated temperatures along with low weight.

  4. Auxin-Oxylipin Crosstalk: Relationship of Antagonists

    Institute of Scientific and Technical Information of China (English)

    Maik Hoffmann; Mathias Hentrich; Stephan Pollmann


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

  5. TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis. (United States)

    Schwartz, Erica S; La, Jun-Ho; Scheff, Nicole N; Davis, Brian M; Albers, Kathryn M; Gebhart, G F


    Visceral afferents expressing transient receptor potential (TRP) channels TRPV1 and TRPA1 are thought to be required for neurogenic inflammation and development of inflammatory hyperalgesia. Using a mouse model of chronic pancreatitis (CP) produced by repeated episodes (twice weekly) of caerulein-induced AP (AP), we studied the involvement of these TRP channels in pancreatic inflammation and pain-related behaviors. Antagonists of the two TRP channels were administered at different times to block the neurogenic component of AP. Six bouts of AP (over 3 wks) increased pancreatic inflammation and pain-related behaviors, produced fibrosis and sprouting of pancreatic nerve fibers, and increased TRPV1 and TRPA1 gene transcripts and a nociceptive marker, pERK, in pancreas afferent somata. Treatment with TRP antagonists, when initiated before week 3, decreased pancreatic inflammation and pain-related behaviors and also blocked the development of histopathological changes in the pancreas and upregulation of TRPV1, TRPA1, and pERK in pancreatic afferents. Continued treatment with TRP antagonists blocked the development of CP and pain behaviors even when mice were challenged with seven more weeks of twice weekly caerulein. When started after week 3, however, treatment with TRP antagonists was ineffective in blocking the transition from AP to CP and the emergence of pain behaviors. These results suggest: (1) an important role for neurogenic inflammation in pancreatitis and pain-related behaviors, (2) that there is a transition from AP to CP, after which TRP channel antagonism is ineffective, and thus (3) that early intervention with TRP channel antagonists may attenuate the transition to and development of CP effectively.

  6. Pharmacological characterization of a dopamine transporter ligand that functions as a cocaine antagonist. (United States)

    Desai, Rajeev I; Grandy, David K; Lupica, Carl R; Katz, Jonathan L


    An N-butyl analog of benztropine, JHW007 [N-(n-butyl)-3α-[bis(4'-fluorophenyl)methoxy]-tropane], binds to dopamine transporters (DAT) but has reduced cocaine-like behavioral effects and antagonizes various effects of cocaine. The present study further examined mechanisms underlying these effects. Cocaine dose-dependently increased locomotion, whereas JHW007 was minimally effective but increased activity 24 hours after injection. JHW007 (3-10 mg/kg) dose-dependently and fully antagonized the locomotor-stimulant effects of cocaine (5-60 mg/kg), whereas N-methyl and N-allyl analogs and the dopamine (DA) uptake inhibitor GBR12909 [1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride] stimulated activity and failed to antagonize effects of cocaine. JHW007 also blocked the locomotor-stimulant effects of the DAT inhibitor GBR12909 but not stimulation produced by the δ-opioid agonist SNC 80 [4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide], which increases activity through nondopaminergic mechanisms. JHW007 blocked locomotor-stimulant effects of cocaine in both DA D2- and CB1-receptor knockout and wild-type mice, indicating a lack of involvement of these targets. Furthermore, JHW007 blocked effects of cocaine on stereotyped rearing but enhanced stereotyped sniffing, suggesting that interference with locomotion by enhanced stereotypies is not responsible for the cocaine-antagonist effects of JHW007. Time-course data indicate that administration of JHW007 antagonized the locomotor-stimulant effects of cocaine within 10 minutes of injection, whereas occupancy at the DAT, as determined in vivo, did not reach a maximum until 4.5 hours after injection. The σ1-receptor antagonist BD 1008 [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide] blocked the locomotor-stimulant effects of cocaine. Overall, these findings suggest that JHW007 has cocaine-antagonist effects

  7. Therapeutic efficacy and immunological response of CCL5 antagonists in models of contact skin reaction.

    Directory of Open Access Journals (Sweden)

    Miriam Canavese

    Full Text Available Skin-infiltrating T-cells play a predominant role in allergic and inflammatory skin diseases such as atopic dermatitis, psoriasis and allergic contact dermatitis. These T-cells are attracted by several chemotactic factors including the chemokine CCL5/RANTES, a CC chemokine inducing both the migration and activation of specific leukocyte subsets. CCL5 has been found to be associated with various cell-mediated hypersensitive disorders such as psoriasis, atopic dermatitis and irritant contact dermatitis. We have used two antagonists, the first, Met-CCL5, a dual CCR1/CCR5 antagonist and the second, a variant in which GAG binding is abrogated, (44AANA(47-CCL5, which acts as a dominant negative inhibitor of CCL5. The antagonists were tested in two models of contact skin reaction. The first, irritant contact dermatitis (ICD is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals. The second, contact hypersensitivity (CHS is a T-cell dependent model, mimicking in part the T-cell-mediated skin diseases such as psoriasis. In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears. These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.

  8. Infusions of alpha-2 noradrenergic agonists and antagonists into the amygdala: effects on kindling. (United States)

    Pelletier, M R; Corcoran, M E


    We reported previously that activation of alpha-2 adrenoceptors with infusions of clonidine into the amygdala/pyriform region is sufficient to retard kindling. To characterize further the involvement in kindling of alpha-2 receptors in the amygdala/pyriform, we exposed rats to unilateral intraamygdaloid infusions of a variety of noradrenergic drugs followed by either low-frequency stimulation of the amygdala, to induce rapid kindling, or conventional high-frequency stimulation. Infusions and electrical stimulation were administered once every 48 h. The prophylactic effects of clonidine were blocked by simultaneous infusion of idazoxan, an alpha-2 adrenergic antagonist, which suggests strongly that these effects were produced at an alpha-2 receptor. Intraamygdaloid infusions of xylazine, another alpha-2 agonist, also significantly retarded low-frequency kindling. Unexpectedly, intraamygdaloid infusions of the alpha-2 antagonists idazoxan, yohimbine, and SK&F 104856 failed to accelerate kindling. Infusion of the alpha-1 antagonist corynanthine also failed to affect kindling. We propose that the alpha-2 adrenoceptors in the amygdala/pyriform region contribute to the prophylactic effects of systemically administered clonidine and that the facilitation of kindling observed after systemic administration of alpha-2 antagonists may be due to blockade of alpha-2 adrenoceptors outside of the amygdala/pyriform region.

  9. Genetic factors influencing pyrimidine-antagonist chemotherapy

    NARCIS (Netherlands)

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


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

  10. Why are mineralocorticoid receptor antagonists cardioprotective?

    NARCIS (Netherlands)

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


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

  11. Right bundle branch block

    DEFF Research Database (Denmark)

    Bussink, Barbara E; Holst, Anders Gaarsdal; Jespersen, Lasse;


    AimsTo determine the prevalence, predictors of newly acquired, and the prognostic value of right bundle branch block (RBBB) and incomplete RBBB (IRBBB) on a resting 12-lead electrocardiogram in men and women from the general population.Methods and resultsWe followed 18 441 participants included.......5%/2.3% in women, P Right bundle branch block was associated with significantly.......60-1.62). The presence of IRBBB was not associated with any adverse outcome.ConclusionIn this cohort study, RBBB and IRBBB were two to three times more common among men than women. Right bundle branch block was associated with increased cardiovascular risk and all-cause mortality, whereas IRBBB was not. Contrary...

  12. The GHS-R Blocker D-[Lys3] GHRP-6 Serves as CCR5 Chemokine Receptor Antagonist

    Directory of Open Access Journals (Sweden)

    Kalpesh Patel, Vishwa Deep Dixit, Jun Ho Lee, Jie Wan Kim, Eric M. Schaffer, Dzung Nguyen, Dennis D. Taub


    Full Text Available [D-Lys3]-Growth Hormone Releasing Peptide-6 (DLS is widely utilized in vivo and in vitro as a selective ghrelin receptor (GHS-R antagonist. This antagonist is one of the most common antagonists utilized in vivo to block GHS-R function and activity. Here, we found that DLS also has the ability to modestly block chemokine function and ligand binding to the chemokine receptor CCR5. The DLS effects on RANTES binding and Erk signaling as well as calcium mobilization appears to be much stronger than its effects on MIP-1α and MIP-1β. CCR5 have been shown to act as major co-receptor for HIV-1 entry into the CD4 positive host cells. To this end, we also found that DLS blocks M-tropic HIV-1 propagation in activated human PBMCs. These data demonstrate that DLS may not be a highly selective GHS-R1a inhibitor and may also effects on other G-protein coupled receptor (GPCR family members. Moreover, DLS may have some potential clinical applications in blocking HIV infectivity and CCR5-mediated migration and function in various inflammatory disease states.


    Johnston, Colin


    Aldosterone's deleterious pathophysiological effects on the cardiovascular system if blocked by mineralcorticord antagonists (MRAs) logically should lead to improvement in heart function and outcomes in heart failure (HF). The first trial to test this hypothesis was tthe RALES trial in 1999 which treated patients with class III-IV HF with spironolactone. It showed significant reduction in mortality and cardiovascular hospitalzation rates. This was confirmed & extended in EMHASIS-HF RCT with classs II-III being treated with ACEIs & BB who received placebo or elperinone (a MRA) with again a statistically significant fall in mortality & hospitalization.The possible cardioprotective effects of MRA post acute myocardial infarct (MI) is less clear. The EPHESUS RCT in 2003 demostrated that elperinone given 3-14 days AMI in patients with early signs of HF reduced mortality & morbidity. However in the ALBTROSS trial using spironolactone 2 days after AMI showed no benfit in patients without HF but in a subgroup with ST elevation there was a 80% reduction in mortality after 6 months. However a recent meta-analysis from 25 RCT with data invovling 19,333 patients with either HF or post MI assigned aldosterone antagonists (AA)or placebo showed a 18% reduction in mortality including a 20% fall in CV mortality and a 19% reduction in SCD.The role of AA in HFPEF is even even more contraversial. The TOPCAT RCT of 3445 patients with symptomatc HFPEF randomised to spironolactone failed to meet the primary composite end point of death, aborted cardiac arrest or hospitalization although there was a reduction in hospitalization for HF (HR 0.83 P = 0.04).The differences between selective or non-selective MRAs, their ADRs & off target effects will also be discussed.

  14. Postcountershock myocardial damage after pretreatment with adrenergic and calcium channel antagonists in halothane-anesthetized dogs

    Energy Technology Data Exchange (ETDEWEB)

    Gaba, D.M.; Metz, S.; Maze, M.


    Transthoracic electric countershock can cause necrotic myocardial lesions in humans as well as experimental animals. The authors investigated the effect on postcountershock myocardial damage of pretreatment with prazosin, an alpha-1 antagonist; L-metoprolol, a beta-1 antagonist, and verapamil, a calcium channel-blocking agent. Twenty dogs were anesthetized with halothane and given two transthoracic countershocks of 295 delivered joules each after drug or vehicle treatment. Myocardial injury was quantitated 24 h following countershock by measuring the uptake of technetium-99m pyrophosphate in the myocardium. Elevated technetium-99m pyrophosphate uptake occurred in visible lesions in most dogs regardless of drug treatment. For each of four parameters of myocardial damage there was no statistically significant difference between control animals and those treated with prazosin, metoprolol, or verapamil. These data suggest that adrenergic or calcium channel-mediated mechanisms are not involved in the pathogenesis of postcountershock myocardial damage.

  15. Neurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomiting. (United States)

    Aziz, Fahad


    Chemotherapy can be a life-prolonging treatment for many cancer patients, but it is often associated with profound nausea and vomiting that is so distressing that patients may delay or decline treatment to avoid these side effects. The discovery of several NK1 receptor antagonists is a big revolution to dealt this problem. NK1 receptor antagonists prevent both acute and delayed chemotherapy-induced nausea and vomiting (CINV). These agents act centrally at NK-1 receptors in vomiting centers within the central nervous system to block their activation by substance P released as an unwanted consequence of chemotherapy. By controlling nausea and vomiting, these agents help improve patients' daily living and their ability to complete multiple cycles of chemotherapy. They are effective for both moderately and highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rates; however, additional appraisal of specific data from RCTs is needed.

  16. Therapeutic Opportunities for Caffeine and A2A Receptor Antagonists in Retinal Diseases. (United States)

    Boia, Raquel; Ambrósio, António Francisco; Santiago, Ana Raquel


    Caffeine, the major component of coffee, is the most consumed psychostimulant in the world. Caffeine is an adenosine analog and acts as a nonselective adenosine receptor antagonist. The majority of the effects of caffeine are mainly mediated by the blockade of adenosine receptors, and the proved neuroprotective effects of caffeine in brain disorders have been mimicked by the blockade of adenosine A2A receptor (A2AR). A growing body of evidence demonstrates that microglia-mediated neuroinflammation plays a key role in the pathophysiology of brain and retinal diseases. Moreover, the control of microglia reactivity by blocking A2AR has been proposed to be the mechanism underlying the observed protective effects of caffeine. Hence, it is conceivable that caffeine and A2AR antagonists offer therapeutic value for the treatment of retinal diseases, mainly those involving microglia-mediated neuroinflammation.

  17. Contaminated soil concrete blocks

    NARCIS (Netherlands)

    Korte, de A.C.J.; Brouwers, H.J.H.; Limbachiya, Mukesh C.; Kew, Hsein Y.


    According to Dutch law the contaminated soil needs to be remediated or immobilised. The main focus in this article is the design of concrete blocks, containing contaminated soil, that are suitable for large production, financial feasible and meets all technical and environmental requirements. In ord

  18. Effects of Block Scheduling

    Directory of Open Access Journals (Sweden)

    William R. Veal


    Full Text Available This study examined the effects of a tri-schedule on the academic achievement of students in a high school. The tri-schedule consists of traditional, 4x4 block, and hybrid schedules running at the same time in the same high school. Effectiveness of the schedules was determined from the state mandated test of basic skills in reading, language, and mathematics. Students who were in a particular schedule their freshman year were tested at the beginning of their sophomore year. A statistical ANCOVA test was performed using the schedule types as independent variables and cognitive skill index and GPA as covariates. For reading and language, there was no statistically significant difference in test results. There was a statistical difference mathematics-computation. Block mathematics is an ideal format for obtaining more credits in mathematics, but the block format does little for mathematics achievement and conceptual understanding. The results have content specific implications for schools, administrations, and school boards who are considering block scheduling adoption.

  19. Concrete Block Pavements (United States)


    1967, Cedergren 1974, Federal Highway .’,U .. V,47 -’":: 37 Administration 1980). Block pavements have essentially the same prob- lems with moisture...Vicksburg, Miss. Cedergren , H. R. 1974. Drainage of Highway and Airfield Pavements, John Wiley and Sons, New VOk. I Cement and Concrete Association

  20. Block That Pain! (United States)

    ... along with the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of General Medical Sciences (NIGMS). This finding shows that a specific combination of two molecules can block only pain-related neurons. It holds the promise of major ...


    Institute of Scientific and Technical Information of China (English)


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

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

    NARCIS (Netherlands)

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


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

  3. High affinity retinoic acid receptor antagonists: analogs of AGN 193109. (United States)

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


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

  4. Novel benzimidazole-based MCH R1 antagonists. (United States)

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


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

  5. Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships. (United States)

    Robertson, D W; Lacefield, W B; Bloomquist, W; Pfeifer, W; Simon, R L; Cohen, M L


    Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.

  6. Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists.

    Directory of Open Access Journals (Sweden)

    Ji Ho Suh

    Full Text Available The androgen receptor (AR surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC cells. These effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared MJC13 and classic AR antagonists such as flutamide and bicalutamide. Microarray analysis and confirmatory qRT-PCR reveals that MJC13 and flutamide inhibit dihydrotestosterone (DHT-dependent genes in LNCaP PC cells. Both compounds are equally effective on a genome wide basis and as effective as second generation AR antagonists (MDV3100, ARN-509 at selected genes. MJC13 inhibits AR binding to the prostate specific antigen (PSA promoter more strongly than flutamide, consistent with different mechanisms of action. Examination of efficacy of MJC13 in conditions that reflect aspects castrate resistant prostate cancer (CRPC reveals that it inhibits flutamide activation of an AR mutant (ART877A that emerges during flutamide withdrawal syndrome, but displays greatly restricted gene-specific activity in 22Rv1 cells that express a constitutively active truncated AR and is inactive against glucocorticoid receptor (GR, which can co-opt androgen-dependent signaling networks in CRPC. Importantly, MJC13 inhibits AR interactions with SRC2 and β-catenin in the nucleus and, unlike flutamide, strongly inhibits amplification of AR activity obtained with transfected SRC2 and β-catenin. MJC13 also inhibits DHT and β-catenin-enhanced cell division in LNCaP cells. Thus, a surface-directed antagonist can block AR activity in some conditions in which a classic antagonist fails and may display utility in particular forms of CRPC.

  7. Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists. (United States)

    Suh, Ji Ho; Chattopadhyay, Arundhati; Sieglaff, Douglas H; Storer Samaniego, Cheryl; Cox, Marc B; Webb, Paul


    The androgen receptor (AR) surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC) cells. These effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared MJC13 and classic AR antagonists such as flutamide and bicalutamide. Microarray analysis and confirmatory qRT-PCR reveals that MJC13 and flutamide inhibit dihydrotestosterone (DHT)-dependent genes in LNCaP PC cells. Both compounds are equally effective on a genome wide basis and as effective as second generation AR antagonists (MDV3100, ARN-509) at selected genes. MJC13 inhibits AR binding to the prostate specific antigen (PSA) promoter more strongly than flutamide, consistent with different mechanisms of action. Examination of efficacy of MJC13 in conditions that reflect aspects castrate resistant prostate cancer (CRPC) reveals that it inhibits flutamide activation of an AR mutant (ART877A) that emerges during flutamide withdrawal syndrome, but displays greatly restricted gene-specific activity in 22Rv1 cells that express a constitutively active truncated AR and is inactive against glucocorticoid receptor (GR), which can co-opt androgen-dependent signaling networks in CRPC. Importantly, MJC13 inhibits AR interactions with SRC2 and β-catenin in the nucleus and, unlike flutamide, strongly inhibits amplification of AR activity obtained with transfected SRC2 and β-catenin. MJC13 also inhibits DHT and β-catenin-enhanced cell division in LNCaP cells. Thus, a surface-directed antagonist can block AR activity in some conditions in which a classic antagonist fails and may display utility in particular forms of CRPC.

  8. [Cutaneous adverse effects of TNFalpha antagonists]. (United States)

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


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

  9. Aminopyrimidine derivatives as adenosine antagonists / Janke Kleynhans


    Kleynhans, Janke


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

  10. The Justification of Antagonistic Response to Wrongdoing


    Goldman, David Michael


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

  11. Antagonistic parent-offspring co-adaptation.

    Directory of Open Access Journals (Sweden)

    Mathias Kölliker

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

  12. Recovery from blocking between outcomes. (United States)

    Wheeler, Daniel S; Miller, Ralph R


    Contemporary associative learning research largely focuses on cue competition phenomena that occur when 2 cues are paired with a common outcome. Little research has been conducted to investigate similar phenomena occurring when a single cue is trained with 2 outcomes. Three conditioned lick suppression experiments with rats assessed whether treatments known to alleviate blocking between cues would also attenuate blocking between outcomes. In Experiment 1, conditioned responding recovered from blocking between outcomes when a long retention interval was interposed between training and testing. Experiment 2 obtained recovery from blocking between outcomes when the blocking outcome was extinguished after the blocking treatment. In Experiment 3, a recovery from blocking between outcomes occurred when a reminder stimulus was presented in a novel context prior to testing. Collectively, these studies demonstrate that blocking of outcomes, like blocking of cues, appears to be caused by a deficit in the expression of an acquired association.

  13. Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant Glucagon-like Peptide-1 Receptor (GLP-1R) Noncompetitive Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione Core. (United States)

    Nance, Kellie D; Days, Emily L; Weaver, C David; Coldren, Anastasia; Farmer, Tiffany D; Cho, Hyekyung P; Niswender, Colleen M; Blobaum, Anna L; Niswender, Kevin D; Lindsley, Craig W


    A duplexed, functional multiaddition high throughput screen and subsequent optimization effort identified the first orally bioavailable and CNS penetrant glucagon-like peptide-1 receptor (GLP-1R) noncompetitive antagonist. Antagonist 5d not only blocked exendin-4-stimulated insulin release in islets but also lowered insulin levels while increasing blood glucose in vivo.


    Directory of Open Access Journals (Sweden)

    Komang Mega Puspadisari


    Full Text Available Superficial cervical plexus block is one of the regional anesthesia in  neck were limited to thesuperficial fascia. Anesthesia is used to relieve pain caused either during or after the surgery iscompleted. This technique can be done by landmark or with ultrasound guiding. The midpointof posterior border of the Sternocleidomastoid was identified and the prosedure done on thatplace or on the level of cartilage cricoid.

  15. Managing access block. (United States)

    Cameron, Peter; Scown, Paul; Campbell, Donald


    There is pessimism regarding the ability of the Acute Health Sector to manage access block for emergency and elective patients. Melbourne Health suffered an acute bed crisis in 2001 resulting in record ambulance diversions and emergency department (ED) delays. We conducted an observational study to reduce access block for emergency patients whilst maintaining elective throughput at Melbourne Health. This involved a clinician-led taskforce using previously proven principles for organisational change to implement 51 actions to improve patient access over a three-month period. The primary outcome measures were ambulance diversion, emergency patients waiting more than 12 hours for an inpatient bed, elective throughput and theatre cancellations. Despite a reduction in multi-day bed numbers all primary objectives were met, ambulance diversion decreased to minimal levels, 12-hour waits decreased by 40% and elective throughput was maintained. Theatre cancellations were also minimised. We conclude that access block can be improved by clinician-led implementation of proven process improvements over a short time frame. The ability to sustain change over the longer term requires further study.

  16. Dopamine transporter-dependent and -independent striatal binding of the benztropine analog JHW 007, a cocaine antagonist with low abuse liability (United States)

    The benztropine analog JHW 007 displays high affinity for the dopamine transporter (DAT), but unlike typical DAT ligands, has relatively low abuse liability and blocks effects of cocaine,including its self-administration. To determine sites responsible for the cocaine-antagonist effects of JHW 007, ...

  17. The Antiinflammatory Cytokine Interleukin-1 Receptor Antagonist Protects from High-Fat Diet-Induced Hyperglycemia


    Sauter, Nadine S; Fabienne T Schulthess; Galasso, Ryan; Castellani, Lawrence W.; Maedler, Kathrin


    Subclinical inflammation is a recently discovered phenomenon in type 2 diabetes. Elevated cytokines impair β-cell function and survival. A recent clinical trial shows that blocking IL-1β signaling by IL-1 receptor antagonist (IL-1Ra) improves β-cell secretory function in patients with type 2 diabetes. In the present study, we provide further mechanisms of the protective role of IL-1Ra on the β-cell. IL-1Ra prevented diabetes in vivo in C57BL/6J mice fed a high-fat/high-sucrose diet (HFD) for ...

  18. Blood flow distribution with adrenergic and histaminergic antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Baker, C.H.; Davis, D.L.; Sutton, E.T.


    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects.

  19. From the Cover: Glutamate antagonists limit tumor growth (United States)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy


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

  20. Block Transfer Handbook: Constructing and Negotiating Block Transfer Agreements. (United States)

    Finlay, Finola

    The purpose of this handbook is to provide resources for institutions or articulation committees who are engaged in the task of investigating the feasibility of block transfer agreements. Block transfer is the process whereby a block of credits is granted to students who have successfully completed a certificate, diploma, or cluster of courses…

  1. Demographic Data - MDC_Block (United States)

    NSGIC GIS Inventory (aka Ramona) — A polygon feature class of Miami-Dade Census 2000 Blocks. Census blocks are areas bounded on all sides by visible and/or invisible features shown on a map prepared...

  2. Habitat Blocks and Wildlife Corridors (United States)

    Vermont Center for Geographic Information — Habitat blocks are areas of contiguous forest and other natural habitats that are unfragmented by roads, development, or agriculture. Vermonts habitat blocks are...


    Institute of Scientific and Technical Information of China (English)

    张建梅; 陈永红; 王晓红; 唐朝枢


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

  4. Porous block nanofiber composite filters

    Energy Technology Data Exchange (ETDEWEB)

    Ginley, David S.; Curtis, Calvin J.; Miedaner, Alexander; Weiss, Alan J.; Paddock, Arnold


    Porous block nano-fiber composite (110), a filtration system (10) and methods of using the same are disclosed. An exemplary porous block nano-fiber composite (110) includes a porous block (100) having one or more pores (200). The porous block nano-fiber composite (110) also includes a plurality of inorganic nano-fibers (211) formed within at least one of the pores (200).

  5. Properties of blocked linear systems. (United States)

    Chen, Weitian; Anderson, Brian D O; Deistler, Manfred; Filler, Alexander


    This paper presents a systematic study on the properties of blocked linear systems that have resulted from blocking discrete-time linear time invariant systems. The main idea is to explore the relationship between the blocked and the unblocked systems. Existing results are reviewed and a number of important new results are derived. Focus is given particularly on the zero properties of the blocked system as no such study has been found in the literature.

  6. Appropriate schemata and building blocks

    Institute of Scientific and Technical Information of China (English)

    Yang Haijun; Li Minqiang


    Appropriate schemata as a novel concept to characterize building blocks are introduced, and then, the traits of appropriate schemata are presented. The effects of building blocks by search operators are analyzed. Hence, the experiments on RR-8X8 are employed to verify that appropriate schemata construct the building blocks. The validity of appropriate schemata and building blocks from the views of theory and practice is presented.

  7. Blocking the Hawking radiation

    DEFF Research Database (Denmark)

    Autzen, M.; Kouvaris, C.


    grows after its formation (and eventually destroys the star) instead of evaporating. The fate of the black hole is dictated by the two opposite mechanics, i.e., accretion of nuclear matter from the center of the star and Hawking radiation that tends to decrease the mass of the black hole. We study how...... the assumptions for the accretion rate can in fact affect the critical mass beyond which a black hole always grows. We also study to what extent degenerate nuclear matter can impede Hawking radiation due to the fact that emitted particles can be Pauli blocked at the core of the star....

  8. Property Blocks: Games and Activities. (United States)

    Humphreys, Alan, Ed.; Dailey, Jean, Ed.

    This pamphlet describes the property blocks produced by MINNEMAST, and discusses their use in the development of thinking processes. Classification systems, including block diagrams and tree diagrams, are discussed. Sixteen classroom activities and eleven games which use the blocks are described. Suggestions to the teacher for further reading are…

  9. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

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


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

  10. The discovery of novel human androgen receptor antagonist chemotypes using a combined pharmacophore screening procedure. (United States)

    Voet, Arnout; Helsen, Christine; Zhang, Kam Y J; Claessens, Frank


    Unraveling the mechanisms involved in castration- and therapy-resistant prostate cancer has led to a renewed interest in androgen receptor (AR)-targeted therapeutics. Anti-androgens that block the activity of the AR therefore remain a valid therapeutic option. However, they must be more effective than, or display a distinct mechanism of action or binding mode from those of bicalutamide and hydroxyflutamide, which are currently in clinical use. For that reason, the second-generation anti-androgen MDV3100 was developed. MDV3100, however, shares its 4-cyano-3-(trifluoromethyl)phenyl group with bicalutamide and hydroxyflutamide required for binding to the AR. In this work, we used a combined strategy to find new antagonist structures distinct from the 4-cyano-3-(trifluoromethyl)phenyl group to avoid cross-resistance for these compounds and to find structures without agonist activity on mutant ARs (AR W741C and AR T877A). We found two novel chemotypes with AR-antagonistic activity (IC(50): 3-6 μM) by virtual screening and confirmed their biological activity in an androgen-responsive reporter assay. The design of our computational approach was validated by the observation of strongly decreased or absence of agonistic activity on the two mutant ARs. Further structural derivatization to optimize the potency of these compounds can render these chemotypes into very promising, alternative AR antagonists for prostate cancer therapy.

  11. Retinoid antagonists inhibit normal patterning during limb regeneration in the axolotl, Ambystoma mexicanum. (United States)

    Del Rincón, Sonia V; Scadding, Steven R


    Retinoic acid (RA) has been detected in the regenerating limb of the axolotl, and exogenous RA can proximalize, posteriorize, and ventralize blastemal cells. Thus, RA may be an endogenous regulatory factor during limb regeneration. We have investigated whether endogenous retinoids are essential for patterning during axolotl (Ambystoma mexicanum) limb regeneration by using retinoid antagonists that bind to specific RAR (retinoic acid receptor) or RXR (retinoid X receptor) retinoid receptor subtypes. Retinoid antagonists (Ro41-5253, Ro61-8431, LE135, and LE540) were administered to regenerating limbs using implanted silastin blocks loaded with each antagonist. The skeletal pattern of regenerated limbs treated with Ro41-5253 or Ro61-8431 differed only slightly from control limbs. Treatment with LE135 inhibited limb regeneration, while treatment with LE540 allowed relatively normal limb regeneration. When LE135 and LE540 were implanted together, regeneration was not completely inhibited and a hand-like process regenerated. These results demonstrate that interfering with retinoid receptors can modify pattern in the regenerating limb indicating that endogenous retinoids are important during patterning of the regenerating limb.

  12. TRPA1 and TRPV1 Antagonists Do Not Inhibit Human Acidosis-Induced Pain. (United States)

    Schwarz, Matthias G; Namer, Barbara; Reeh, Peter W; Fischer, Michael J M


    Acidosis occurs in a variety of pathophysiological and painful conditions where it is thought to excite or contribute to excitation of nociceptive neurons. Despite potential clinical relevance the principal receptor for sensing acidosis is unclear, but several receptors have been proposed. We investigated the contribution of the acid-sensing ion channels, transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin type 1 (TRPA1) to peripheral pain signaling. We first established a human pain model using intraepidermal injection of the TRPA1 agonist carvacrol. This resulted in concentration-dependent pain sensations, which were reduced by experimental TRPA1 antagonist A-967079. Capsaicin-induced pain was reduced by the TRPV1 inhibitor BCTC. Amiloride was used to block acid-sensing ion channels. Testing these antagonists in a double-blind and randomized experiment, we probed the contribution of the respective channels to experimental acidosis-induced pain in 15 healthy human subjects. A continuous intraepidermal injection of pH 4.3 was used to counter the buffering capacity of tissue and generate a prolonged painful stimulation. In this model, addition of A-967079, BCTC or amiloride did not reduce the reported pain. In conclusion, target-validated antagonists, applied locally in human skin, have excluded the main hypothesized targets and the mechanism of the human acidosis-induced pain remains unclear.

  13. Quantitative kinetics analysis of BMP2 uptake into cells and its modulation by BMP antagonists. (United States)

    Alborzinia, Hamed; Schmidt-Glenewinkel, Hannah; Ilkavets, Iryna; Breitkopf-Heinlein, Katja; Cheng, Xinlai; Hortschansky, Peter; Dooley, Steven; Wölfl, Stefan


    Bone morphogenetic proteins (BMPs) are members of the TGFβ family of signaling proteins and play an important role during development and in tissue formation. BMP signaling is a well-studied process, which is initiated through binding of cognate receptors and processed through activation of Smad downstream mediators. A hallmark of BMP signaling is its modulation at the extracellular level through specific antagonists. Although it had been shown that BMP and TGFβ receptors are internalized following activation, little is known about the fate of BMP ligands. We prepared biologically active fluorescently labeled BMP2 and quantitatively analyzed its binding and uptake in cells using flow cytometry and confocal microscopy. Exogenous BMP2 was rapidly bound to the cell surface and subsequently internalized in a time-dependent manner and accumulated in the cell center. Although binding to the cell surface was limited by binding sites at the beginning, internalization continously increased with time, after a short delay. Using different inhibitors we found that internalization of BMP2 through endosomal particles occurred in a clathrin-dependent pathway. Furthermore, uptake of BMP2 was modulated in strikingly different ways by BMP2 antagonists. Although Noggin and Gremlin increased BMP2 uptake, Chordin blocked BMP2 uptake, which was concentration dependent in both cases. In conclusion, our findings present interesting mechanisms for the modulation of BMP signaling by concentration gradients of BMP ligands and antagonists in a dose- and time-dependent manner, which can provide an explanation of some properties of the BMP regulatory network.

  14. Humanoid by ROBO-BLOCK (United States)

    Niimi, Hirofumi; Koike, Minoru; Takeuchi, Seiichi; Douhara, Noriyoshi


    Humanoid by ROBO-BLOCK (robot block system) and the rational formula of robots were proposed. ROBO-BLOCK is composed of servo motors, the parts for servomotor rotor, the brackets for servomotor fixation, the board parts and the controllers. A robot can be assembled easily by ROBO-BLOCK. Meanwhile, it is convenient when the structure of the robot can be described easily as a character. The whole structure of the robot is expressed as rational formula of the robot to show molecule structure in chemistry. ROBO-BLOCK can be useful for not only the research but also the education. Creative student experiment was done in the college of industrial technology.

  15. Antioxidant effects of calcium antagonists in rat brain homogenates. (United States)

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


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

  16. Sexually antagonistic selection in human male homosexuality.

    Directory of Open Access Journals (Sweden)

    Andrea Camperio Ciani

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

  17. Sexually antagonistic selection in human male homosexuality. (United States)

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


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

  18. Activins and activin antagonists in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

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


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

  19. ETA-receptor antagonists or allosteric modulators?

    DEFF Research Database (Denmark)

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


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

  20. Zebrafish phenotypic screen identifies novel Notch antagonists. (United States)

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


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

  1. The α1 Antagonist Doxazosin Alters the Behavioral Effects of Cocaine in Rats

    Directory of Open Access Journals (Sweden)

    Colin N. Haile


    Full Text Available Medications that target norepinephrine (NE neurotransmission alter the behavioral effects of cocaine and may be beneficial for stimulant-use disorders. We showed previously that the short-acting, α1-adrenergic antagonist, prazosin, blocked drug-induced reinstatement of cocaine-seeking in rats and doxazosin (DOX, a longer-acting α1 antagonist blocked cocaine’s subjective effects in cocaine-dependent volunteers. To further characterize DOX as a possible pharmacotherapy for cocaine dependence, we assessed its impact on the development and expression of cocaine-induced locomotor sensitization in rats. Rats (n = 6–8 were administered saline, cocaine (COC, 10 mg/kg or DOX (0.3 or 1.0 mg/kg alone or in combination for 5 consecutive days (development. Following 10-days of drug withdrawal, all rats were administered COC and locomotor activity was again assessed (expression. COC increased locomotor activity across days indicative of sensitization. The high dose (1.0 mg/kg, but not the low dose (0.3 mg/kg of DOX significantly decreased the development and expression of COC sensitization. DOX alone did not differ from saline. These results are consistent with studies showing that α1 receptors are essential for the development and expression of cocaine’s behavioral effects. Results also suggest that blockade of both the development and expression of locomotor sensitization may be important characteristics of possible pharmacotherapies for cocaine dependence in humans.

  2. Spintronics: Conceptual Building Blocks (United States)

    Ansermet, J.-Ph.

    The purpose of this introduction to spintronics is to provide some elementary description of its conceptual building blocks. Thus, it is intended for a newcomer to the field. After recalling rudimentary descriptions of spin precession and spin relaxation, spin-dependent transport is treated within the Boltzmann formalism. This suffices to introduce key notions such as the spin asymmetry of the conductivities in the two-current model, the spin diffusion length, and spin accumulation. Two basic mechanisms of spin relaxation are then presented, one arising from spin-orbit scattering and the other from electron-magnon collisions. Finally, the action of a spin-polarized current on magnetization is presented in a thermodynamics framework. This introduces the notion of spin torque and the characteristic length scale over which the transverse spin polarization of conduction electron decays as it is injected into a magnet.

  3. Photovoltaic building blocks

    DEFF Research Database (Denmark)

    Hanberg, Peter Jesper; Jørgensen, Anders Michael


    it directcompetitive with fossil energy sources a further reduction is needed. By increasing the efficiency of the solar cells one gain an advantage through the whole chain of cost. So that per produced Watt of power less material is spent, installation costs are lower, less area is used etc. With an average...... efficiency of about 15% for commercial Silicon solar cells there is still much to gain. DTU Danchip provides research facilities, equipment and expertise for the building blocks that comprises fabricating the efficient solar cell. In order to get more of the sun light into the device we provide thin film......Photovoltaics (PV), better known as solar cells, are now a common day sight on many rooftops in Denmark.The installed capacity of PV systems worldwide is growing exponentially1 and is the third most importantrenewable energy source today. The cost of PV is decreasing fast with ~10%/year but to make...

  4. Celiac ganglia block

    Energy Technology Data Exchange (ETDEWEB)

    Akinci, Devrim [Department of Radiology, Hacettepe University School of Medicine, Sihhiye, 06100 Ankara (Turkey); Akhan, Okan [Department of Radiology, Hacettepe University School of Medicine, Sihhiye, 06100 Ankara (Turkey)]. E-mail:


    Pain occurs frequently in patients with advanced cancers. Tumors originating from upper abdominal viscera such as pancreas, stomach, duodenum, proximal small bowel, liver and biliary tract and from compressing enlarged lymph nodes can cause severe abdominal pain, which do not respond satisfactorily to medical treatment or radiotherapy. Percutaneous celiac ganglia block (CGB) can be performed with high success and low complication rates under imaging guidance to obtain pain relief in patients with upper abdominal malignancies. A significant relationship between pain relief and degree of tumoral celiac ganglia invasion according to CT features was described in the literature. Performing the procedure in the early grades of celiac ganglia invasion on CT can increase the effectiveness of the CGB, which is contrary to World Health Organization criteria stating that CGB must be performed in patients with advanced stage cancer. CGB may also be effectively performed in patients with chronic pancreatitis for pain palliation.

  5. Atomic Basic Blocks (United States)

    Scheler, Fabian; Mitzlaff, Martin; Schröder-Preikschat, Wolfgang

    Die Entscheidung, einen zeit- bzw. ereignisgesteuerten Ansatz für ein Echtzeitsystem zu verwenden, ist schwierig und sehr weitreichend. Weitreichend vor allem deshalb, weil diese beiden Ansätze mit äußerst unterschiedlichen Kontrollflussabstraktionen verknüpft sind, die eine spätere Migration zum anderen Paradigma sehr schwer oder gar unmöglich machen. Wir schlagen daher die Verwendung einer Zwischendarstellung vor, die unabhängig von der jeweils verwendeten Kontrollflussabstraktion ist. Für diesen Zweck verwenden wir auf Basisblöcken basierende Atomic Basic Blocks (ABB) und bauen darauf ein Werkzeug, den Real-Time Systems Compiler (RTSC) auf, der die Migration zwischen zeit- und ereignisgesteuerten Systemen unterstützt.

  6. Evaluation of H2 receptor antagonists in chronic idiopathic urticaria

    Directory of Open Access Journals (Sweden)

    Minocha Y


    Full Text Available H1-antagonist (hydroxyzine hydrochloride in dosage of 10 mg-25 mg thrice a day failed to elicit satisfactory response in 60 out of 170 patients of chronic idiopathic urticaria. Additional administration of H2-antagonist (cimetidine in dosage of 200 mg four times a day, in patients not responding earlier to H1-antagonist alones exhibited moderate to good improvement of various parameters of urticaria in approximately 85% patients

  7. Dihydromorphine-peptide hybrids with delta receptor agonistic and mu receptor antagonistic actions

    Energy Technology Data Exchange (ETDEWEB)

    Smith, C.B.; Medzihradsky, F.; Woods, J.H.


    The actions of two morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated mouse vas deferens and upon displacement of /sup 3/H-etorphine from rat brain membranes. NIH-9833 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-phenylalanyl-L-leucine ethyl ester HCl) was a potent agonist upon the vas deferens. Its EC50 for inhibition of the twitch was 1.2 +/- 0.1 nM. Both naltrexone (10/sup -7/ M) a relatively nonselective opioid antagonist, and ICI-174864 (10/sup -/' M) a highly selective delta receptor antagonist, blocked the actions of NIH-9833 which indicates that this drug is a delta receptor agonist. In contrast, NIH-9835 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl), which differs from NIH-9835 by the presence of a single amino acid residue, was devoid of opioid agonistic activity but was a potent antagonist of the inhibitory actions on the vas deferens of morphine and sufentanil. NIH-9833 and NIH-9835 were potent displacers of /sup 3/H-etorphine from rat cerebral membranes with EC50's of 0.58 nM and 1.7 nM, respectively. The observation that addition of a single glycyl group changes a dihydromorphine-peptide analog from a potent delta receptor agonist to an equally potent mu receptor antagonist suggests that the two receptor sites might be structurally quite similar.

  8. Large Block Test Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Lin, W


    This report documents the Large-Block Test (LBT) conducted at Fran Ridge near Yucca Mountain, Nevada. The LBT was a thermal test conducted on an exposed block of middle non-lithophysal Topopah Spring tuff (Tptpmn) and was designed to assist in understanding the thermal-hydrological-mechanical-chemical (THMC) processes associated with heating and then cooling a partially saturated fractured rock mass. The LBT was unique in that it was a large (3 x 3 x 4.5 m) block with top and sides exposed. Because the block was exposed at the surface, boundary conditions on five of the six sides of the block were relatively well known and controlled, making this test both easier to model and easier to monitor. This report presents a detailed description of the test as well as analyses of the data and conclusions drawn from the test. The rock block that was tested during the LBT was exposed by excavation and removal of the surrounding rock. The block was characterized and instrumented, and the sides were sealed and insulated to inhibit moisture and heat loss. Temperature on the top of the block was also controlled. The block was heated for 13 months, during which time temperature, moisture distribution, and deformation were monitored. After the test was completed and the block cooled down, a series of boreholes were drilled, and one of the heater holes was over-cored to collect samples for post-test characterization of mineralogy and mechanical properties. Section 2 provides background on the test. Section 3 lists the test objectives and describes the block site, the site configuration, and measurements made during the test. Section 3 also presents a chronology of events associated with the LBT, characterization of the block, and the pre-heat analyses of the test. Section 4 describes the fracture network contained in the block. Section 5 describes the heating/cooling system used to control the temperature in the block and presents the thermal history of the block during the test

  9. Antagonism of non-depolarising neuromuscular block: current practice. (United States)

    Kopman, A F; Eikermann, M


    There is now mounting evidence that even small degrees of postoperative residual neuromuscular block increases the incidence of adverse respiratory events in the Post Anaesthesia Care Unit and may increase longer-term morbidity as well. In the absence of quantitative neuromuscular monitoring, residual block is easily missed. A very strong case can be made for the routine administration of a non-depolarising antagonist unless it can be objectively demonstrated that complete recovery has occurred spontaneously. However, the use of acetylcholinesterase inhibitors is associated with the potential for cardiovascular and respiratory side-effects, so there are cogent reasons for using low doses when the level of neuromuscular block is not intense. As little as 0.015-0.025 of neostigmine is required at a train-of-four count of four with minimal fade, whereas 0.04-0.05 is needed at a train-of-four count of two or three. If only a single twitch or none at all can be evoked, neostigmine should not be expected to promptly reverse neuromuscular block, and antagonism is best delayed till a train-of-four-count of two is achieved.

  10. Dimensional Reduction for Conformal Blocks

    CERN Document Server

    Hogervorst, Matthijs


    We consider the dimensional reduction of a CFT, breaking multiplets of the d-dimensional conformal group SO(d+1,1) up into multiplets of SO(d,1). This leads to an expansion of d-dimensional conformal blocks in terms of blocks in d-1 dimensions. In particular, we obtain a formula for 3d conformal blocks as an infinite sum over 2F1 hypergeometric functions with closed-form coefficients.

  11. Hepcidin antagonists for potential treatments of disorders with hepcidin excess

    Directory of Open Access Journals (Sweden)

    Poli eMaura


    Full Text Available The discovery of hepcidin clarified the basic mechanism of the control of systemic iron homeostasis. Hepcidin is mainly produced by the liver as a propeptide and processed by furin into the mature active peptide. Hepcidin binds ferroportin, the only cellular iron exporter, causing the internalization and degradation of both. Thus hepcidin blocks iron export from the key cells for dietary iron absorption (enterocytes, recycling of haemoglobin iron (the macrophages and the release of storage iron from hepatocytes, resulting in the reduction of systemic iron availability. The BMP/HJV/SMAD pathway is the major regulator of hepcidin expression that responds to iron status. Also inflammation stimulates hepcidin via the IL6/STAT3 pathway with a support of an active BMP/HJV/SMAD pathway. In some pathological conditions hepcidin level is inadequately elevated and reduces iron availability in the body, resulting in anemia. These conditions occur in the genetic Iron Refractory Iron Deficiency Anemia (IRIDA and the common Anemia of Chronic Disease (ACD or Anemia of Inflammation. Currently, there is no definite treatment for ACD. Erythropoiesis stimulating agents and intravenous iron have been proposed in some cases but they are scarcely effective and may have adverse effects. Alternative approaches aimed to a pharmacological control of hepcidin expression have been attempted, targeting different regulatory steps. They include hepcidin sequestering agents (antibodies, anticalins and aptamers, inhibitors of BMP/SMAD or of IL6/STAT3 pathway or of hepcidin transduction (siRNA/shRNA or ferroportin stabilizers. In this review we summarized the biochemical interactions of the proteins involved in the BMP/HJV/SMAD pathway and its natural inhibitors, the murine and rat models with high hepcidin levels currently available and finally the progresses in the development of hepcidin antagonists, with particular attention to the role of heparins and heparin sulphate

  12. Mutually-Antagonistic Interactions in Baseball Networks

    CERN Document Server

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


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

  13. Mutually-antagonistic interactions in baseball networks (United States)

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


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

  14. The Attractiveness of Opposites: Agonists and Antagonists.

    LENUS (Irish Health Repository)

    O'Brien, Tony


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

  15. Perspectives in Drug Development and Clinical Pharmacology: The Discovery of Histamine H1 and H2 Antagonists. (United States)

    Jones, Alan Wayne


    Knowledge about the history and development of therapeutic agents holds a central position in the education and training of pharmacists and pharmacologists. Students enjoy learning about the discovery of drugs, including details about the pioneer workers involved (apothecaries, organic chemists, pharmacologists, and physiologists) and the role played by serendipity. The treatment of people suffering from allergies and the development of drugs that block the actions of histamine at H1 and H2 receptors are the subject of this review. Pharmaceutical products that block H1 receptors are widely used as prophylactic treatment for seasonal allergies that plague millions of people worldwide. The development of H2 receptor antagonists revolutionized treatment of gastric hyperacidity, the principal cause of peptic ulcers. Antihistamine research has changed focus toward the development of drugs that block the action of histamine at H3 and H4 receptors and the therapeutic potential is gradually being appreciated.

  16. Common blocks for ASQS(12

    Directory of Open Access Journals (Sweden)

    Lorenzo Milazzo


    Full Text Available An ASQS(v is a particular Steiner system featuring a set of v vertices and two separate families of blocks, B and G, whose elements have a respective cardinality of 4 and 6. It has the property that any three vertices of X belong either to a B-block or to a G-block. The parameter cb is the number of common blocks in two separate ASQSs, both defined on the same set of vertices X . In this paper it is shown that cb ≤ 29 for any pair of ASQSs(12.

  17. Antagonistic activity of marine sponges associated Actinobacteria

    Institute of Scientific and Technical Information of China (English)

    Selvakumar Dharmaraj; Dhevendaran Kandasamy


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

  18. Eikonalization of Conformal Blocks

    CERN Document Server

    Fitzpatrick, A Liam; Walters, Matthew T; Wang, Junpu


    Classical field configurations such as the Coulomb potential and Schwarzschild solution are built from the $t$-channel exchange of many light degrees of freedom. We study the CFT analog of this phenomenon, which we term the `eikonalization' of conformal blocks. We show that when an operator $T$ appears in the OPE $\\mathcal{O}(x) \\mathcal{O}(0)$, then the large spin $\\ell$ Fock space states $[TT \\cdots T]_{\\ell}$ also appear in this OPE with a computable coefficient. The sum over the exchange of these Fock space states in an $\\langle \\mathcal{O} \\mathcal{O} \\mathcal{O} \\mathcal{O} \\rangle$ correlator build the classical `$T$ field' in the dual AdS description. In some limits the sum of all Fock space exchanges can be represented as the exponential of a single $T$ exchange in the 4-pt correlator of $\\mathcal{O}$. Our results should be useful for systematizing $1/\\ell$ perturbation theory in general CFTs and simplifying the computation of large spin OPE coefficients. As examples we obtain the leading $\\log \\ell$...

  19. [Effects of the histamine H2 receptor antagonist roxatidine acetate on stomach and liver alcohol dehydrogenase and serum alcohol level]. (United States)

    Beil, W; Sewing, K F


    Some histamine-H2-receptor antagonists block gastric first-pass metabolism of ethanol and lead to increased blood alcohol concentrations after ingestion of a low dose (0.15 and 0.3 g/kg) of alcohol. To investigate whether the histamine-H2-receptor antagonist roxatidine acetate has a similar effect, we administered a low dose (0.3 g/kg) of ethanol to eleven volunteers before and after seven days treatment with roxatidine acetate (150 mg once daily). No effect of the drug on mean peak serum alcohol concentrations or on areas under the serum alcohol curves was found. In vitro, roxatidine acetate and its active metabolite roxatidine had almost no effect on guinea-pig gastric alcohol dehydrogenase activity. We conclude that roxatidine acetate does not block gastric first-pass metabolism of ethanol and can be considered as a safe histamine-H2-receptor antagonist in individuals who do not refrain from alcohol consumption under treatment for gastric or duodenal ulcer disease.

  20. Adductor Canal Block versus Femoral Nerve Block and Quadriceps Strength

    DEFF Research Database (Denmark)

    Jæger, Pia Therese; Nielsen, Zbigniew Jerzy Koscielniak; Henningsen, Lene Marianne;


    : The authors hypothesized that the adductor canal block (ACB), a predominant sensory blockade, reduces quadriceps strength compared with placebo (primary endpoint, area under the curve, 0.5-6 h), but less than the femoral nerve block (FNB; secondary endpoint). Other secondary endpoints were...


    NARCIS (Netherlands)



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

  2. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology

    NARCIS (Netherlands)

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


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

  3. Antagonistic and Bargaining Games in Optimal Marketing Decisions (United States)

    Lipovetsky, S.


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

  4. Optimisation of GnRH antagonist use in ART

    NARCIS (Netherlands)

    Hamdine, O.


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

  5. Cyclic nucleotide-gated channel block by hydrolysis-resistant tetracaine derivatives. (United States)

    Andrade, Adriana L; Melich, Kenneth; Whatley, G Gregory; Kirk, Sarah R; Karpen, Jeffrey W


    To meet a pressing need for better cyclic nucleotide-gated (CNG) channel antagonists, we have increased the biological stability of tetracaine-based blockers by synthesizing amide and thioamide linkage substitutions of tetracaine (1) and a higher affinity octyl tail derivative (5). We report the apparent K(D) values, the mechanism of block, and the in vitro hydrolysis rates for these compounds. The ester linkage substitutions did not adversely affect CNG channel block; unexpectedly, thioamide substitution in 1 (compound 8) improved block significantly. Furthermore, the ester linkage substitutions did not appear to affect the mechanism of block in terms of the strong state preference for closed channels. All ester substituted compounds, especially the thioamide substitutions, were more resistant to hydrolysis by serum cholinesterase than their ester counterparts. These findings have implications for dissecting the physiological roles of CNG channels, treating certain forms of retinal degeneration, and possibly the current clinical uses of compound 1.

  6. Block Transfer Agreement Evaluation Project (United States)

    Bastedo, Helena


    The objective of this project is to evaluate for the British Columbia Council on Admissions and Transfer (BCCAT) the effectiveness of block transfer agreements (BTAs) in the BC Transfer System and recommend steps to be taken to improve their effectiveness. Findings of this study revealed that institutions want to expand block credit transfer;…

  7. Four-block beam collimator

    CERN Multimedia


    The photo shows a four-block collimator installed on a control table for positioning the alignment reference marks. Designed for use with the secondary beams, the collimators operated in vacuum conditions. The blocks were made of steel and had a standard length of 1 m. The maximum aperture had a square coss-section of 144 cm2. (See Annual Report 1976.)

  8. OPAL Various Lead Glass Blocks

    CERN Multimedia

    These lead glass blocks were part of a CERN detector called OPAL (one of the four experiments at the LEP particle detector). OPAL uses some 12 000 blocks of glass like this to measure particle energies in the electromagnetic calorimeter. This detector measured the energy deposited when electrons and photons were slowed down and stopped.

  9. Block storage subsystem performance analysis

    CERN Document Server

    CERN. Geneva


    You feel that your service is slow because of the storage subsystem? But there are too many abstraction layers between your software and the raw block device for you to debug all this pile... Let's dive on the platters and check out how the block storage sees your I/Os! We can even figure out what those patterns are meaning.

  10. Evaluation of selective NK(1) receptor antagonist CI-1021 in animal models of inflammatory and neuropathic pain. (United States)

    Gonzalez, M I; Field, M J; Hughes, J; Singh, L


    CI-1021 ([(2-benzofuran)-CH(2)OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH (3))Ph) is a selective and competitive neurokinin-1 (NK(1)) receptor antagonist. This study examines its activity in animal models of inflammatory and neuropathic pain. In mice, CI-1021 (1-30 mg/kg, s.c.) dose dependently blocked the development of the late phase of the formalin response with a minimum effective dose (MED) of 3 mg/kg. Two chemically unrelated NK(1) receptor antagonists, CP-99,994 (3-30 mg/kg) and SR 140333 (1-100 mg/kg), also dose dependently blocked the late phase, with respective MEDs of 3 and 10 mg/kg. PD 156982, a NK(1) receptor antagonist with poor central nervous system penetration, failed to have any effect. However, when administered i. c.v., it selectively blocked the late phase of the formalin response. Chronic constrictive injury (CCI) to a sciatic nerve in the rat induced spontaneous pain, thermal and mechanical hyperalgesia, and cold, dynamic, and static allodynia. CI-1021 (10-100 mg/kg) and morphine (3 mg/kg) blocked all the responses except dynamic allodynia. Carbamazepine (100 mg/kg) was weakly effective against all the responses. Once daily administration of morphine (3 mg/kg, s. c.) in CCI rats led to the development of tolerance within 6 days. Similar administration of CI-1021 (100 mg/kg, s.c.) for up to 10 days did not induce tolerance. Moreover, the morphine tolerance failed to cross-generalize to CI-1021. CI-1021 blocked the CCI-induced hypersensitivity in the guinea pig, with a MED of 0.1 mg/kg, p.o. CI-1021 (10-100 mg/kg, s.c.) did not show sedative/ataxic action in the rat rota-rod test. It is suggested that NK(1) receptor antagonists possess a superior side effect profile to carbamazepine and morphine and may have a therapeutic use for the treatment of inflammatory and neuropathic pain.

  11. Design and Synthesis of a Series of Pyrido[2,3-d]pyrimidine Derivatives as CCR4 Antagonists

    Directory of Open Access Journals (Sweden)

    Ying Wang


    Full Text Available A series of pyrido[2,3-d]pyrimidine derivatives were designed and synthesized based on known CC chemokine receptor 4 (CCR4 antagonists. The activities of all the newly synthesized compounds were evaluated using a chemotaxis inhibition assay. Compound 6b was proven to be a potent CCR4 antagonist that can block cell chemotaxis induced by macrophage-derived chemokine (MDC, thymus and activation regulated chemokine (TARC, and CKLF1, the natural ligands of CCR4. In addition, compound 6b is more effective than budesonide in the murine rhinitis model. The intravenous injection LD50 of compound 6b is 175 mg/kg and the oral LD50 is greater than 2,000 mg/kg.

  12. Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xuejuan; Fani, Melpomeni [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); Schulz, Stefan [Jena University Hospital - Friedrich Schiller University Jena, Department of Pharmacology and Toxicology, Jena (Germany); Rivier, Jean [The Salk Institute for Biological Studies, The Clayton Foundation Laboratories for Peptide Biology, La Jolla, CA (United States); Reubi, Jean Claude [University of Bern, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, Bern (Switzerland); Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); University Hospital Freiburg, Department of Nuclear Medicine, Freiburg (Germany)


    Targeting of tumours positive for somatostatin receptors (sst) with radiolabelled peptides is of interest for tumour localization, staging, therapy follow-up and targeted radionuclide therapy. The peptides used clinically are exclusively agonists, but recently we have shown that the radiolabelled somatostatin-based antagonist {sup 111}In-DOTA-sst2-ANT may be preferable to agonists. However, a comprehensive study of this radiolabelled antagonist to determine its significance was lacking. The present report describes the evaluation of this novel antagonist labelled with {sup 111}In and {sup 177}Lu in three different tumour models. Radiopeptide binding, internalization and dissociation studies were performed using cells expressing HEK293-rsst{sub 2}. Biodistribution studies were performed in HEK293-rsst{sub 2}, HEK293-hsst{sub 2} and HEK293-rsst{sub 3} xenografted mice. Saturation binding analysis confirmed earlier IC{sub 50} data for {sup 111/nat}In-DOTA-sst2-ANT and showed similar affinity of {sup 177/nat}Lu-DOTA-sst2-ANT for the sst{sub 2}. Only low internalization was found in cell culture (6.68 {+-} 0.06 % at 4 h), which was not unexpected for an antagonist, and this could be further reduced by the addition of sucrose. No internalization was observed in HEK293 cells not expressing sst. Both results indicate that the internalization was specific. {sup 111}In-DOTA-sst2-ANT and {sup 177}Lu-DOTA-sst2-ANT were shown to target tumour xenografts expressing the rat and the human sst{sub 2} receptor with no differences in their uptake or pharmacokinetics. The uptake in rsst{sub 2} and hsst{sub 2} was high (about 30 %IA/g 4 h after injection) and surprisingly long-lasting (about 20-23 %IA/g 24 h after injection). Kidney uptake was blocked by approximately 50 % by lysine or Gelofusine. These results indicate that radiolabelled somatostatin-based antagonists may be superior to corresponding agonists. The long tumour retention time of {sup 177}Lu-DOTA-sst2-ANT indicates that

  13. The NK-1 Receptor Antagonist L-732,138 Induces Apoptosis and Counteracts Substance P-Related Mitogenesis in Human Melanoma Cell Lines

    Energy Technology Data Exchange (ETDEWEB)

    Muñoz, Miguel, E-mail:; Rosso, Marisa; González-Ortega, Ana [Research Laboratory on Neuropeptides, Virgen del Rocío University Hospital, Sevilla (Spain); Coveñas, Rafael [Institute of Neurosciences of Castilla y León (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems (Laboratory 14), Salamanca (Spain)


    It has been recently demonstrated that substance P (SP) and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition in human melanoma cells, respectively. However, the antitumor action of the NK-1 receptor antagonist L-732,138 on such cells is unknown. The aim of this study was to demonstrate an antitumor action of L-732,138 against three human melanoma cell lines (COLO 858, MEL HO, COLO 679). We found that L-732,138 elicits cell growth inhibition in a concentration dependent manner in the melanoma cells studied. Moreover, L-732,138 blocks SP mitogen stimulation. The specific antitumor action of L-732,138 occurred through the NK-1 receptor and melanoma cell death was by apoptosis. These findings indicate that the NK-1 receptor antagonist L-732,138 could be a new antitumor agent in the treatment of human melanoma.

  14. Nalmefene: radioimmunoassay for a new opioid antagonist. (United States)

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


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

  15. Antagonistic Neural Networks Underlying Differentiated Leadership Roles

    Directory of Open Access Journals (Sweden)

    Richard Eleftherios Boyatzis


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

  16. Conformal Nets II: Conformal Blocks (United States)

    Bartels, Arthur; Douglas, Christopher L.; Henriques, André


    Conformal nets provide a mathematical formalism for conformal field theory. Associated to a conformal net with finite index, we give a construction of the `bundle of conformal blocks', a representation of the mapping class groupoid of closed topological surfaces into the category of finite-dimensional projective Hilbert spaces. We also construct infinite-dimensional spaces of conformal blocks for topological surfaces with smooth boundary. We prove that the conformal blocks satisfy a factorization formula for gluing surfaces along circles, and an analogous formula for gluing surfaces along intervals. We use this interval factorization property to give a new proof of the modularity of the category of representations of a conformal net.

  17. Pharmacophore-based virtual screening, biological evaluation and binding mode analysis of a novel protease-activated receptor 2 antagonist (United States)

    Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon Hee; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun Kyung; No, Kyoung Tai; Pae, Ae Nim


    Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe2435.39 is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na+ allosteric site in contrast to PAR2 agonist that showed Na+ relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.

  18. Pharmacophore-based virtual screening, biological evaluation and binding mode analysis of a novel protease-activated receptor 2 antagonist. (United States)

    Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon Hee; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun Kyung; No, Kyoung Tai; Pae, Ae Nim


    Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe243(5.39) is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na(+) allosteric site in contrast to PAR2 agonist that showed Na(+) relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.

  19. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists. (United States)

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


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

  20. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Mohammad eKhanfar


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

  1. Identification of a novel conformationally constrained glucagon receptor antagonist. (United States)

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


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

  2. New potential uroselective NO-donor alpha1-antagonists. (United States)

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


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

  3. Effects of dopamine antagonists on methamphetamine-induced dopamine release in high and low alcohol preference rats. (United States)

    Nishiguchi, Minori; Kinoshita, Hiroshi; Kasuda, Shogo; Takahashi, Montonori; Yamamura, Takehiko; Matsui, Kiyoshi; Ouchi, Harumi; Minami, Takako; Hishida, Shigeru; Nishio, Hajime


    The authors have previously shown that high alcohol preference rats (HAP) have a significantly higher sensitivity than low alcohol preference rats (LAP) for methamphetamine (MAP). In this study, changes in dopamine and serotonin release induced by MAP (1 mg/kg, intraperitoneally) after pre-treatment with D1 and D2 receptor antagonists were examined in the striatum of rats with different alcohol preferences to elucidate differences in receptor levels between the two rat strains. D1 receptor antagonist SCH23390 or D2 receptor antagonist haloperidol were administrated intracerebroventricularly 10 min before MAP stimulation. This study investigated the effect of methamphetamine-induced dopamine and serotonin release in striatum using microdialysis of freely moving rats coupled to ECD-HPLC. With haloperidol treatment both strains of rats showed a significantly greater maximum increase on MAP-induced dopamine release compared with respective control rats. However, after SCH23390 treatment only HAP rats showed a significantly greater increase in dopamine release compared with controls. SCH23390 blocks mainly D1 receptors only in the post-synaptic membrane, whereas haloperidol blocks D2 receptors in both the pre-synaptic and post-synaptic membranes. The MAP-induced increase in dopamine release following haloperidol pre-treatment was greater than SCH23390 pre-treatment in both strains. This result indicates that D2 receptors (autoreceptors) in the pre-synaptic membrane were blocked, leading to the elimination of the feedback function that regulates dopamine release. These data suggested that alcohol preference is associated with the action of MAP, and the dopaminergic mechanism, specifically the D1 system in the striatum, might have a different pathway dependent on alcohol preference.

  4. Gabapentin and the neurokinin(1) receptor antagonist CI-1021 act synergistically in two rat models of neuropathic pain. (United States)

    Field, Mark J; Gonzalez, M Isabel; Tallarida, Ronald J; Singh, Lakhbir


    The present study examines the effect of combinations of gabapentin (Neurontin) and a selective neurokinin (NK)(1) receptor antagonist, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-2-benzofuranylmethyl ester (CI-1021), in two models of neuropathic pain. Dose responses to both gabapentin and CI-1021 were performed against static allodynia induced in the streptozocin and chronic constriction injury (CCI) models. Theoretical additive lines were calculated from these data. Dose responses to various fixed dose ratios of a gabapentin/CI-1021 combination were then examined in both models. In the streptozocin model, administration of gabapentin/CI-1021 combinations at fixed dose ratios of 1:1 and 60:1 resulted in an additive effect with dose response similar to the theoretical additive line. However, a synergistic interaction was seen after fixed dose ratios of 10:1, 20:1, and 40:1 with static allodynia completely blocked and the dose responses shifted approximately 8-, 30-, and 10-fold leftward, respectively, from the theoretical additive values. In the CCI model, after fixed dose ratios of 5:1 and 20:1, combinations of gabapentin and CI-1021 produced an additive response. At the fixed dose ratio of 10:1 static allodynia was completely blocked with an approximate 10-fold leftward shift of the dose response from the theoretical additive value, indicating synergy. The combination of gabapentin with a structurally unrelated NK(1) receptor antagonist, (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), also produced synergy, at a fixed dose ratio of 20:1. This ratio completely blocked streptozocin-induced static allodynia and was approximately shifted leftward 5-fold from the theoretical additive value. These data suggest a synergistic interaction between gabapentin and NK(1) receptor antagonists in animal models of neuropathic pain.

  5. A selective adenosine A2A receptor antagonist ameliorated hyperlocomotion in an animal model of lateral fluid percussion brain injury. (United States)

    Mullah, Saad Habib-E-Rasul; Inaji, Motoki; Nariai, Tadashi; Ishibashi, Satoru; Ohno, Kikuo


    Increased concentration of extracellular adenosine after brain injury is supposed to be one of the causes of secondary brain damage. The purpose of the present study is to examine whether or not administration of adenosine A2A receptor antagonist may be efficacious in ameliorating neurological symptoms by blocking secondary brain damage through cascades initiated by adenosine A2a receptor.Mongolian gerbils were divided into four groups: the trauma-medication (T-M), trauma-saline (T-S), sham-medication (S-M), and sham-saline (S-S) groups. Trauma groups received lateral fluid percussion injury. Medication groups received i.p. injection of SCH58261 (selective adenosine A2A receptor antagonist) until the fifth post-injury day. Open-field locomotion test and grabbing test were conducted before and 1, 3, 5, 7, and 9 days after injury.The total distance of movement in the T-S group was significantly greater than in the other three groups at all time points. In the T-M group, administration of SCH58261 significantly blocked hyperlocomotion, which was observed in the T-S group. There was no significant difference in the total distance among the T-M, S-M, and S-S groups. In the grabbing test, grabbing time was significantly increased in the T-S group 3, 5, 7, and 9 days after the operation. SCH58261 also improved grabbing time in the T-M group.Adenosine A2A antagonist successfully suppressed the trauma-induced hyperlocomotion, presumably by blocking secondary brain damage.

  6. MarineMineralsProgramBlocks (United States)

    Bureau of Ocean Energy Management, Department of the Interior — This data set contains OCS block outlines and delineated polygons in ESRI ArcGIS shape file format for the BOEM Gulf of Mexico Region that contain sediment resources...

  7. Hawaii Census 2000 Block Groups (United States)

    U.S. Environmental Protection Agency — This data layer represents Census 2000 demographic data derived from the PL94-171 redistricting files and SF3. Census geographic entities include blocks, blockgroups...

  8. Left bundle-branch block

    DEFF Research Database (Denmark)

    Risum, Niels; Strauss, David; Sogaard, Peter;


    The relationship between myocardial electrical activation by electrocardiogram (ECG) and mechanical contraction by echocardiography in left bundle-branch block (LBBB) has never been clearly demonstrated. New strict criteria for LBBB based on a fundamental understanding of physiology have recently...

  9. Multi-block and path modelling procedures

    DEFF Research Database (Denmark)

    Høskuldsson, Agnar


    The author has developed a unified theory of path and multi-block modelling of data. The data blocks are arranged in a directional path. Each data block can lead to one or more data blocks. It is assumed that there is given a collection of input data blocks. Each of them is supposed to describe one...

  10. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia - critical appraisal of suvorexant. (United States)

    Norman, Jessica L; Anderson, Sarah L


    Insomnia, a highly prevalent disorder, can be detrimental to patients' overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra) is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of patients with chronic insomnia.

  11. Tetrazolyl isoxazole amino acids as ionotropic glutamate receptor antagonists: synthesis, modelling and molecular pharmacology. (United States)

    Frølund, Bente; Greenwood, Jeremy R; Holm, Mai M; Egebjerg, Jan; Madsen, Ulf; Nielsen, Birgitte; Bräuner-Osborne, Hans; Stensbøl, Tine B; Krogsgaard-Larsen, Povl


    Two 3-(5-tetrazolylmethoxy) analogues, 1a and 1b, of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), a selective AMPA receptor agonist, and (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), a GluR5-preferring agonist, were synthesized. Compounds 1a and 1b were pharmacologically characterized in receptor binding assays, and electrophysiologically on homomeric AMPA receptors (GluR1-4), homomeric (GluR5 and GluR6) and heteromeric (GluR6/KA2) kainic acid receptors, using two-electrode voltage-clamped Xenopus laevis oocytes expressing these receptors. Both analogues proved to be antagonists at all AMPA receptor subtypes, showing potencies (Kb=38-161 microM) similar to that of the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA) (Kb=43-76 microM). Furthermore, the AMOA analogue, 1a, blocked two kainic acid receptor subtypes (GluR5 and GluR6/KA2), showing sevenfold preference for GluR6/KA2 (Kb=19 microM). Unlike the iGluR antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid [(S)-ATPO], the corresponding tetrazolyl analogue, 1b, lacks kainic acid receptor effects. On the basis of docking to a crystal structure of the isolated extracellular ligand-binding core of the AMPA receptor subunit GluR2 and a homology model of the kainic acid receptor subunit GluR5, we were able to rationalize the observed structure-activity relationships.

  12. CRF receptor antagonist astressin-B reverses and prevents alopecia in CRF over-expressing mice.

    Directory of Open Access Journals (Sweden)

    Lixin Wang

    Full Text Available Corticotropin-releasing factor (CRF signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, astressin-B (5 µg/mouse injected peripherally once a day for 5 days in 4-9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that astressin-B revived the hair follicle from the telogen to anagen phase. However, astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF₂ receptor antagonist, astressin₂-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress.

  13. Cardiovascular effects of selective agonists and antagonists of histamine H3 receptors in the anaesthetized rat. (United States)

    Coruzzi, G; Gambarelli, E; Bertaccini, G; Timmerman, H


    The cardiovascular responses to a series of selective histamine H3 receptor agonists, (R) alpha-methylhistamine, imetit and immepip and selective antagonists, thioperamide, clobenpropit and clophenpropit, were studied in anaesthetized rats. At 0.003-1 mumol/kg i.v. doses, H3 agonists failed to produce any significant change in the basal blood pressure and heart rate. Larger doses of (R) alpha-methylhistamine increased the blood pressure and heart rate and higher doses of imetit caused vasodepressor responses and reduced heart rate, whereas immepip proved virtually inactive. While (R) alpha-methylhistamine-induced effects were not blocked by histamine H1-, H2- and H3-receptor antagonists, they were however reduced by idazoxan and propranolol, which indicates that the mechanisms involved are adrenergic. The effects induced by imetit are not related to histamine H3 receptors but are mediated by indirect (via 5HT3 receptors) cholinergic mechanisms, since these effects were prevented by 1 mg/kg i.v. atropine and by 0.1 mg/kg i.v. ondansetron. Similarly, the H3 antagonists per se failed to change basal cardiovascular function up to 10 mumol/kg i.v. and only at 30 mumol/kg i.v. were marked decreases observed in the blood pressure and heart rate with a significant reduction in the effects of noradrenaline. These data indicate that in anaesthetized rats, histamine H3 receptor activation or blockade has no effect on basal cardiovascular function. The effects recorded after the administration of large doses of (R) alpha-methylhistamine and imetit are clearly unrelated to histamine H3 receptors and should be taken into account when using these compounds as H3 ligands for "in vivo" experiments.

  14. Effect of dopamine and serotonin receptor antagonists on fencamfamine-induced abolition of latent inhibition. (United States)

    de Aguiar, Cilene Rejane Ramos Alves; de Aguiar, Marlison José Lima; DeLucia, Roberto; Silva, Maria Teresa Araujo


    The purpose of this investigation was to verify the role of dopamine and serotonin receptors in the effect of fencamfamine (FCF) on latent inhibition. FCF is a psychomotor stimulant with an indirect dopaminergic action. Latent inhibition is a model of attention. Latent inhibition is blocked by dopaminergic agents and facilitated by dopamine receptor agonists. FCF has been shown to abolish latent inhibition. The serotonergic system may also participate in the neurochemical mediation of latent inhibition. The selective dopamine D(1) receptor antagonist SCH 23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), D(2) receptor antagonists pimozide (PIM) and methoclopramide (METH), and serotonin 5-HT(2A/C) receptor antagonist ritanserin (RIT) were used in the present study. Latent inhibition was evaluated using a conditioned emotional response procedure. Male Wistar rats that were water-restricted were subjected to a three-phase procedure: preexposure to a tone, tone-shock conditioning, and a test of the effect of the tone on licking frequency. All of the drugs were administered before the preexposure and conditioning phases. The results showed that FCF abolished latent inhibition, and this effect was clearly antagonized by PIM and METH and moderately attenuated by SCH 23390. At the doses used in the present study, RIT pretreatment did not affect latent inhibition and did not eliminate the effect of FCF, suggesting that the FCF-induced abolition of latent inhibition is not mediated by serotonin 5-HT(2A/C) receptors. These results suggest that the effect of FCF on latent inhibition is predominantly related to dopamine D(2) receptors and that dopamine D(2) receptors participate in attention processes.


    Institute of Scientific and Technical Information of China (English)

    Guojun Liu


    Nanostructure fabrication from block copolymers in my group normally involves polymer design, synthesis, selfassembly, selective domain crosslinking, and sometimes selective domain removal. Preparation of thin films with nanochannels was used to illustrate the strategy we took. In this particular case, a linear triblock copolymer polyisopreneblock-poly(2-cinnamoylethyl methacrylate)-block-poly(t-butyl acrylate), PI-b-PCEMA-b-PtBA, was used. Films, 25 to50μm thick, were prepared from casting on glass slides a toluene solution of PI-b-PCEMA-b-PtBA and PtBA homopolymer,hPtBA, where hPtBA is shorter than the PtBA block. At the hPtBA mass fraction of 20% relative to the triblock or the total PtBA (hPtBA and PtBA block) volume fraction of 0.44, hPtBA and PtBA formed a seemingly continuous phase in the matrix of PCEMA and PI. Such a block segregation pattern was locked in by photocrosslinking the PCEMA domain. Nanochannels were formed by extracting out hPtBA with solvent. Alternatively, larger channels were obtained from extracting out hPtBA and hydrolyzing the t-butyl groups of the PtBA block. Such membranes were not liquid permeable but had gas permeability constants ~6 orders of magnitude higher than that of low-density polyethylene films.

  16. The pharmacological properties of lipophilic calcium antagonists. (United States)

    van Zwieten, P A


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

  17. Development of a peptidomimetic antagonist of neuropeptide FF receptors for the prevention of opioid-induced hyperalgesia. (United States)

    Bihel, Frédéric; Humbert, Jean-Paul; Schneider, Séverine; Bertin, Isabelle; Wagner, Patrick; Schmitt, Martine; Laboureyras, Emilie; Petit-Demoulière, Benoît; Schneider, Elodie; Mollereau, Catherine; Simonnet, Guy; Simonin, Frédéric; Bourguignon, Jean-Jacques


    Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-effects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain.

  18. A novel BLyS antagonist peptide designed based on the 3-D complex structure of BCMA and BLyS. (United States)

    Sun, Jian; Feng, Jiannan; Li, Yan; Shen, Beifen


    B lymphocyte stimulator (BLyS) is a member of tumor necrosis factor (TNF) family. Because of its roles in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren syndrome (SS), BLyS antagonists have been tested to treat SLE- and RA-like symptoms in mice and obtained optimistic results. So far, reported BLyS antagonists were mostly decoyed BLyS receptors or anti-BLyS antibodies. In this study, a novel BLyS antagonist peptide, PT, was designed based on the modeling 3-D complex structure of BCMA and BLyS. The interaction mode of PT with BLyS was analyzed theoretically. The results of competitive ELISA demonstrated that PT could inhibit the binding of BCMA-Fc and anti-BLyS antibody to BLyS in vitro. In addition, PT could partly block the proliferating activity of BLyS on mice splenocytes. The BLyS antagonizing activity of PT was significant (p<0.05). This study highlights the possibility of using BLyS antagonist peptide to neutralize BLyS activity. Further optimization of PT with computer-guided molecular design method to enhance its biopotency may be useful in developing new BLyS antagonists to treat BLyS-related autoimmune diseases.

  19. Blockade of catecholamine-induced growth by adrenergic and dopaminergic receptor antagonists in Escherichia coli O157:H7, Salmonella enterica and Yersinia enterocolitica

    Directory of Open Access Journals (Sweden)

    Lyte Mark


    Full Text Available Abstract Background The ability of catecholamines to stimulate bacterial growth was first demonstrated just over a decade ago. Little is still known however, concerning the nature of the putative bacterial adrenergic and/or dopaminergic receptor(s to which catecholamines (norepinephrine, epinephrine and dopamine may bind and exert their effects, or even whether the binding properties of such a receptor are similar between different species. Results Use of specific catecholamine receptor antagonists revealed that only α, and not β, adrenergic antagonists were capable of blocking norepinephrine and epinephrine-induced growth, while antagonism of dopamine-mediated growth was achieved with the use of a dopaminergic antagonist. Both adrenergic and dopaminergic antagonists were highly specific in their mechanism of action, which did not involve blockade of catecholamine-facilitated iron-acquisition. Use of radiolabeled norepinephrine suggested that the adrenergic antagonists could be acting by inhibiting catecholamine uptake. Conclusion The present data demonstrates that the ability of a specific pathogen to respond to a particular hormone is dependent upon the host anatomical region in which the pathogen causes disease as well as the neuroanatomical specificity to which production of the particular hormone is restricted; and that both are anatomically coincidental to each other. As such, the present report suggests that pathogens with a high degree of exclusivity to the gastrointestinal tract have evolved response systems to neuroendocrine hormones such as norepinephrine and dopamine, but not epinephrine, which are found with the enteric nervous system.

  20. Effects of GABA receptor antagonists on thresholds of P23H rat retinal ganglion cells to electrical stimulation of the retina (United States)

    Jensen, Ralph J.; Rizzo, Joseph F., III


    An electronic retinal prosthesis may provide useful vision for patients suffering from retinitis pigmentosa (RP). In animal models of RP, the amount of current needed to activate retinal ganglion cells (RGCs) is higher than in normal, healthy retinas. In this study, we sought to reduce the stimulation thresholds of RGCs in a degenerate rat model (P23H-line 1) by blocking GABA receptor mediated inhibition in the retina. We examined the effects of TPMPA, a GABAC receptor antagonist, and SR95531, a GABAA receptor antagonist, on the electrically evoked responses of RGCs to biphasic current pulses delivered to the subretinal surface through a 400 µm diameter electrode. Both TPMPA and SR95531 reduced the stimulation thresholds of ON-center RGCs on average by 15% and 20% respectively. Co-application of the two GABA receptor antagonists had the greatest effect, on average reducing stimulation thresholds by 32%. In addition, co-application of the two GABA receptor antagonists increased the magnitude of the electrically evoked responses on average three-fold. Neither TPMPA nor SR95531, applied alone or in combination, had consistent effects on the stimulation thresholds of OFF-center RGCs. We suggest that the effects of the GABA receptor antagonists on ON-center RGCs may be attributable to blockage of GABA receptors on the axon terminals of ON bipolar cells.

  1. Preclinical anticonvulsant and neuroprotective profile of 8319, a non-competitive NMDA antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Fielding, S.; Wilker, J.C.; Chernack, J.; Ramirez, V.; Wilmot, C.A.; Martin, L.L.; Payack, J.F.; Cornfeldt, M.L.; Rudolphi, K.A.; Rush, D.K. (Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ (USA))


    8319, ((+-)-2-Amino-N-ethyl-alpha- (3-methyl-2-thienyl) benzeneethanamine 2HCl), is a novel compound with the profile of a non-competitive NMDA antagonist. The compound displaced (3H) TCP with high affinity (IC50 = 43 nM), but was inactive at the NMDA, benzodiazepine and GABA sites; in vivo, 8319 showed good efficacy as an anticonvulsant and potential neuroprotective agent. It blocked seizures induced by NMDLA, supramaximal electroshock, pentylenetetrazol (PTZ), picrotoxin, and thiosemicarbazide with ED50's of 1-20 mg/kg ip. As a neuroprotective agent, 8319 (30-100 mg/kg sc) prevented the death of dorsal hippocampal pyramidal cells induced by direct injection of 20 nmol NMDA. At 15 mg/kg ip, the compound was also effective against hippocampal neuronal necrosis induced via bilateral occlusion of the carotid arteries in gerbils. In summary, 8319 is a noncompetitive NMDA antagonist with good anticonvulsant activity and may possess neuroprotective properties useful in the treatment of brain ischemia.

  2. Disruption of insect diapause using agonists and an antagonist of diapause hormone. (United States)

    Zhang, Qirui; Nachman, Ronald J; Kaczmarek, Krzysztof; Zabrocki, Janusz; Denlinger, David L


    The dormant state known as diapause is widely exploited by insects to circumvent winter and other adverse seasons. For an insect to survive, feed, and reproduce at the appropriate time of year requires fine coordination of the timing of entry into and exit from diapause. One of the hormones that regulates diapause in moths is the 24-aa neuropeptide, diapause hormone (DH). Among members of the Helicoverpa/Heliothis complex of agricultural pests, DH prompts the termination of pupal diapause. Based on the structure of DH, we designed several agonists that are much more active than DH in breaking diapause. One such agonist that we describe also prevents the entry into pupal diapause when administered to larvae that are environmentally programmed for diapause. In addition, we used the unique antagonist development strategy of incorporating a dihydroimidazole ("Jones") trans-Proline mimetic motif into one of our DH agonists, thereby converting the agonist into a DH antagonist that blocks the termination of diapause. These results suggest potential for using such agents or next-generation derivatives for derailing the success of overwintering in pest species.

  3. Molecular structure of two gastrokinetic compounds, cisapride and R53757: comparison with dopaminergic D 2 antagonists (United States)

    Collin, S.; Vercauteren, D. P.; Evrard, G.; Durant, F.; Tollenaere, J. P.; Moereels, H.


    The crystal structures of the title compounds have been solved by direct methods from single crystal X-ray diffraction. Cisapride: monoclinic, space group P2 1/ n with a=34.210(4), b=7.642(2), c=9.435(1) Å, β=90.93(1)°, Z=4, final R factor=0.044 for 1178 observed reflections. R53757: monoclinic, space group P2 1/ n with a=28.896(3), b=8.054(2), c=10.957(2) Å, β=91.79(1)°, Z=4, final R factor=0.032 for 933 observed reflections. Cisapride, a non-dopamine blocking gastrokinetic, and its closely related analog, R53757, are compared to two very potent D 2 antagonists, tropapride and R48788. The analysis of the X-ray determined structures completed by theoretical conformational studies suggests that the structural requirements for all compounds studied seem to be very similar. As shown by PCILO calculations, the presence of a methoxy group on the cisapride piperidine ring does not prevent an optimal orientation of the three putative pharmacophoric elements described for the D 2 receptor. Only the nature of the nitrogen lateral chain differs between the D 2 antagonists and cisapride.

  4. Selective Glucocorticoid Receptor (GR-II Antagonist Reduces Body Weight Gain in Mice

    Directory of Open Access Journals (Sweden)

    Tomoko Asagami


    Full Text Available Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (=8 received one of the following: CORT 108297 (80 mg/kg QD, CORT 108297 (40 mg/kg BID, mifepristone (30 mg/kg BID, rosiglitazone (10 mg/kg QD, or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain.

  5. Alpha 2-adrenoceptor antagonist potencies of two hydroxylated metabolites of yohimbine. (United States)

    Berlan, M.; Le Verge, R.; Galitzky, J.; Le Corre, P.


    1. The alpha 2-adrenoceptor antagonist capacities of two hydroxylated metabolites of yohimbine in man (10-OH-yohimbine and 11-OH-yohimbine) were investigated on the alpha 2-adrenoceptors of human platelets and adipocytes and compared to those of yohimbine. 2. Yohimbine and 11-OH-yohimbine exhibited similar alpha 2-adrenoceptor affinity in biological studies i.e. inhibition of adrenaline-induced platelet aggregation and inhibition of UK14304-induced antilipolysis in adipocytes. 3. Yohimbine and the two metabolites displaced [3H]-RX 821002 binding with equivalent affinities in platelet and adipocyte membranes with the following order of potency: yohimbine > 11-OH-yohimbine > 10-OH-yohimbine. However, when binding studies were carried out in binding buffer supplemented with 5% albumin, the apparent affinity of yohimbine was reduced about 10 fold and was similar to that of 11-OH-yohimbine. 4. Yohimbine and its metabolites were bound to different extents to plasma proteins, the bound fraction being 82%, 43% and 32% respectively for yohimbine, 11-OH-yohimbine and 10-OH-yohimbine. 5. These results show that the main hydroxylated metabolite of yohimbine in man (11-OH-yohimbine) possesses alpha 2-adrenoceptor antagonist properties. The discrepancies found in binding studies (i.e. 10 fold lower affinity of 11-OH-yohimbine than yohimbine for alpha 2-adrenoceptors but similar capacities in blocking biological alpha 2-adrenoceptor effects in cells) are attributable to the higher degree of binding of yohimbine to plasma protein. PMID:8097957

  6. Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension. (United States)

    de Raaf, Michiel Alexander; Beekhuijzen, Manon; Guignabert, Christophe; Vonk Noordegraaf, Anton; Bogaard, Harm Jan


    The Pregnancy Prevention Program (PPP) is in place to prevent drug-induced developmental malformations. Remarkably, among the ten PPP-enlisted drugs are three endothelin-1 (ET-1) receptor antagonists (ERA's: ambrisentan, bosentan and macitentan), which are approved for the treatment of Pulmonary Arterial Hypertension (PAH). This review describes the effects of ERA's in PAH pathobiology and cardiopulmonary fetal development. While ERA's hamper pathological remodeling of the pulmonary vasculature and as such exert beneficial effects in PAH, they disturb fetal development of cardiopulmonary tissues. By blocking ET-1-mediated positive inotropic effects and myocardial fetal gene induction, ERA's may affect right ventricular adaptation to the increased pulmonary vascular resistance in both the fetus and the adult PAH patient.

  7. EO-199, a specific antagonist of antiarrhythmic drugs: Assessment by binding experiments and in vivo studies

    Energy Technology Data Exchange (ETDEWEB)

    Oppenheimer, E.; Harel, G.; Lipinsky, D.; Sarne, Y. (Tel-Aviv Univ. (Israel))


    EO-199, a demethylated analog of the novel class I antiarrhythmic drug EO-122 was found to antagonize the antiarrhythmic activity of EO-122 and that of procainamide (Class I{sub A}). EO-199 did not block significantly the activity of a class I{sub B} antiarrhythmic agent, lidocaine. EO-199 also displaced the specific binding of ({sup 3}H)EO-122 to rate heart membranes similarly to procainamide whereas lidocaine did not. The correlation between binding experiments and pharmacological effects points to a possible subclassification of these drugs; the two chemical analogs EO-199 and EO-122, as well as procainamide (I{sub A}) but not lidocaine (I{sub B}), compete at the same site or the same state of the sodium channel. The availability of a specific antagonist might be useful for studying the mechanism of action of antiarrhythmic drugs as well as an antidote in cases of antiarrhythmics overdose intoxication.

  8. Screening and identification of receptor antagonist for shiga toxin from random peptides displayed on filamentous bacteriophages

    Institute of Scientific and Technical Information of China (English)

    韩照中; 苏国富; 黄翠芬


    The bacteriophage clones which can bind with shiga toxin B subunit (StxB) and inhibit cytotoxicity of shiga toxin were obtained by using antibody capturing method from a 15-mer random peptide library displayed on the surface of bacteriophage fd. Among them, one peptide encoded by the random DNA region of a selected bacteriophage (A12) was synthesized and tested in vitro and in vivo, where the peptide competed with the receptor of shiga toxin to bind StxB, and inhibited the cytotoxicity and enterotoxicity of shiga toxin. The peptide can also block other apparently unrelated StxB binding bacteriophage (A3), which suggests that there are overlapping StxB interaction sites for those ligands with different sequences. The results provide a demonstration of bacteriophage display to screen peptide ligands for a small and/or unable biotinylated molecule by antibodies-capturing strategy, and take the lead for the development of receptor antagonists for shiga toxin.

  9. 5-HT3 and 5-HT4 antagonists inhibit peristaltic contractions in guinea-pig distal colon by mechanisms independent of endogenous 5-HT

    Directory of Open Access Journals (Sweden)

    Tiong Cheng Sia


    Full Text Available Recent studies have shown that endogenous serotonin is not required for colonic peristalsis in vitro, nor gastrointestinal (GI transit in vivo. However, antagonists of 5-Hydroxytryptamine (5-HT receptors can inhibit peristalsis and GI-transit in mammals, including humans. This raises the question of how these antagonists inhibit GI-motility and transit, if depletion of endogenous 5-HT does not cause any significant inhibitory changes to either GI-motility or transit ? We investigated the mechanism by which 5-HT3 and 5-HT4 antagonists inhibit distension-evoked peristaltic contractions in guinea-pig distal colon. In control animals, repetitive peristaltic contractions of the circular muscle were evoked in response to fixed fecal pellet distension. Distension-evoked peristaltic contractions were unaffected in animals with mucosa and submucosal plexus removed, that were also treated with reserpine (to deplete neuronal 5-HT. In control animals, peristaltic contractions were blocked temporarily by ondansetron (1-10µM and SDZ-205-557 (1-10µM in many animals. Interestingly, after this temporary blockade, and whilst in the continued presence of these antagonists, peristaltic contractions recovered, with characteristics no different from controls. Surprisingly, similar effects were seen in mucosa-free preparations, which had no detectable 5-HT, as detected by mass spectrometry. In summary, distension-evoked peristaltic reflex contractions of the circular muscle layer of the guinea-pig colon can be inhibited temporarily, or permanently, in the same preparation by selective 5-HT3 and 5-HT4 antagonists, depending on the concentration of the antagonists applied. These effects also occur in preparations that lack any detectable 5-HT. We suggest caution should be exercised when interpreting the effects of 5-HT3 and 5-HT4 antagonists; and the role of endogenous 5-HT, in the generation of distension-evoked colonic peristalsis.


    Directory of Open Access Journals (Sweden)

    B. B. Gegenava


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

  11. Structure-based drug design identifies novel LPA3 antagonists. (United States)

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


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

  12. Secondary prevention with calcium antagonists after acute myocardial infarction

    DEFF Research Database (Denmark)

    Hansen, J F


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

  13. Perampanel: A Selective AMPA Antagonist for Treating Seizures


    Krauss, Gregory L.


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

  14. Complications of TNF-α antagonists and iron homeostasis (United States)

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

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

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen


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

  16. Structure-activity relationships of benzothiazole GPR35 antagonists. (United States)

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


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

  17. Deficiency of interleukin-1 receptor antagonist responsive to anakinra. (United States)

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


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

  18. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists


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


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

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

    DEFF Research Database (Denmark)

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


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

  20. Skin delivery by block copolymer nanoparticles (block copolymer micelles). (United States)

    Laredj-Bourezg, Faiza; Bolzinger, Marie-Alexandrine; Pelletier, Jocelyne; Valour, Jean-Pierre; Rovère, Marie-Rose; Smatti, Batoule; Chevalier, Yves


    Block copolymer nanoparticles often referred to as "block copolymer micelles" have been assessed as carriers for skin delivery of hydrophobic drugs. Such carriers are based on organic biocompatible and biodegradable materials loaded with hydrophobic drugs: poly(lactide)-block-poly(ethylene glycol) copolymer (PLA-b-PEG) nanoparticles that have a solid hydrophobic core made of glassy poly(d,l-lactide), and poly(caprolactone)-block-poly(ethylene glycol) copolymer (PCL-b-PEG) nanoparticles having a liquid core of polycaprolactone. In vitro skin absorption of all-trans retinol showed a large accumulation of retinol in stratum corneum from both block copolymer nanoparticles, higher by a factor 20 than Polysorbate 80 surfactant micelles and by a factor 80 than oil solution. Additionally, skin absorption from PLA-b-PEG nanoparticles was higher by one order of magnitude than PCL-b-PEG, although their sizes (65nm) and external surface (water-swollen PEG layer) were identical as revealed by detailed structural characterizations. Fluorescence microscopy of histological skin sections provided a non-destructive picture of the storage of Nile Red inside stratum corneum, epidermis and dermis. Though particle cores had a different physical states (solid or liquid as measured by (1)H NMR), the ability of nanoparticles for solubilization of the drug assessed from their Hildebrand solubility parameters appeared the parameter of best relevance regarding skin absorption.

  1. Rational design of an auxin antagonist of the SCF(TIR1) auxin receptor complex. (United States)

    Hayashi, Ken-ichiro; Neve, Joshua; Hirose, Masakazu; Kuboki, Atsuhito; Shimada, Yukihisa; Kepinski, Stefan; Nozaki, Hiroshi


    The plant hormone auxin is a master regulator of plant growth and development. By regulating rates of cell division and elongation and triggering specific patterning events, indole 3-acetic acid (IAA) regulates almost every aspect of plant development. The perception of auxin involves the formation of a ternary complex consisting of an F-box protein of the TIR1/AFB family of auxin receptors, the auxin molecule, and a member the Aux/IAA family of co-repressor proteins. In this study, we identified a potent auxin antagonist, α-(phenylethyl-2-oxo)-IAA, as a lead compound for TIR1/AFB receptors by in silico virtual screening. This molecule was used as the basis for the development of a more potent TIR1 antagonist, auxinole (α-[2,4-dimethylphenylethyl-2-oxo]-IAA), using a structure-based drug design approach. Auxinole binds TIR1 to block the formation of the TIR1-IAA-Aux/IAA complex and so inhibits auxin-responsive gene expression. Molecular docking analysis indicates that the phenyl ring in auxinole would strongly interact with Phe82 of TIR1, a residue that is crucial for Aux/IAA recognition. Consistent with this predicted mode of action, auxinole competitively inhibits various auxin responses in planta. Additionally, auxinole blocks auxin responses of the moss Physcomitrella patens, suggesting activity over a broad range of species. Our works not only substantiates the utility of chemical tools for plant biology but also demonstrates a new class of small molecule inhibitor of protein-protein interactions common to mechanisms of perception of other plant hormones, such as jasmonate, gibberellin, and abscisic acid.

  2. Optimal Backward Perturbation Analysis for the Block Skew Circulant Linear Systems with Skew Circulant Blocks

    Directory of Open Access Journals (Sweden)

    Zhaolin Jiang


    Full Text Available We first give the block style spectral decomposition of arbitrary block skew circulant matrix with skew circulant blocks. Secondly, we obtain the singular value of block skew circulant matrix with skew circulant blocks as well. Finally, based on the block style spectral decomposition, we deal with the optimal backward perturbation analysis for the block skew circulant linear system with skew circulant blocks.

  3. MC148 encoded by human molluscum contagiosum poxvirus is an antagonist for human but not murine CCR8

    DEFF Research Database (Denmark)

    Lüttichau, H R; Gerstoft, J; Schwartz, T W


    The viral CC chemokines MC148, encoded by the poxvirus molluscum contagiosum, and viral macrophage inflammatory protein (vMIP)-I and vMIP-II, encoded by human herpesvirus 8, were probed on the murine CC receptor (CCR) 8 in parallel with human CCR8. In calcium mobilization assays, vMIP-I acted...... as a high-affinity agonist, whereas vMIP-II acted as a low-affinity antagonist on the murine CCR8 as well as the human CCR8. MC148 was found to bind and block responses through the human CCR8 with high affinity, but surprisingly MC148 was unable to bind and block responses through the murine CCR8. Because...

  4. Contrasting reduced overshadowing and blocking. (United States)

    Wheeler, Daniel S; Miller, Ralph R


    Preexposure of a cue without an outcome (X-) prior to compound pairings with the outcome (XZ-->O) can reduce overshadowing of a target cue (Z). Moreover, pairing a cue with an outcome (X-->O) before compound training can enhance its ability to compete with another cue (i.e., blocking). Four experiments were conducted in a conditioned bar-press suppression preparation with rats to determine whether spacing of the X- or X-->O trials would differentially affect reduced overshadowing and blocking. Experiment 1a showed that reduced overshadowing was larger with massed trials than with spaced trials. Experiment 1b found that blocking was larger with spaced trials than with massed trials. Experiments 2a and 2b indicated that these effects of trial spacing were both mediated by the associative status of the context at test. The results are interpreted in the framework of contemporary learning theories.

  5. Diversity Gain through Antenna Blocking

    Directory of Open Access Journals (Sweden)

    V. Dehghanian


    Full Text Available As part of the typical usage mode, interaction between a handheld receiver antenna and the operator's RF absorbing body and nearby objects is known to generate variability in antenna radiation characteristics through blocking and pattern changes. It is counterintuitive that random variations in blocking can result in diversity gain of practical applicability. This diversity gain is quantified from a theoretical and experimental perspective. Measurements carried out at 1947.5 MHz verify the theoretical predictions, and a diversity gain of 3.1 dB was measured through antenna blocking and based on the utilized measurement setup. The diversity gain can be exploited to enhance signal detectability of handheld receivers based on a single antenna in indoor multipath environments.

  6. Block ground interaction of rockfalls (United States)

    Volkwein, Axel; Gerber, Werner; Kummer, Peter


    During a rockfall the interaction of the falling block with the ground is one of the most important factors that define the evolution of a rockfall trajectory. It steers the rebound, the rotational movement, possibly brake effects, friction losses and damping effects. Therefore, if most reliable rockfall /trajectory simulation software is sought a good understanding of the block ground interaction is necessary. Today's rockfall codes enable the simulation of a fully 3D modelled block within a full 3D surface . However, the details during the contact, i.e. the contact duration, the penetration depth or the dimension of the marks in the ground are usually not part of the simulation. Recent field tests with rocks between 20 and 80 kg have been conducted on a grassy slope in 2014 [1]. A special rockfall sensor [2] within the blocks measured the rotational velocity and the acting accelerations during the tests. External video records and a so-called LocalPositioningSystem deliver information on the travel velocity. With these data not only the flight phases of the trajectories but also the contacts with the ground can be analysed. During the single jumps of a block the flight time, jump length, the velocity, and the rotation are known. During the single impacts their duration and the acting accelerations are visible. Further, the changes of rotational and translational velocity influence the next jump of the block. The change of the rotational velocity over the whole trajectory nicely visualizes the different phases of a rockfall regarding general acceleration and deceleration in respect to the inclination and the topography of the field. References: [1] Volkwein A, Krummenacher B, Gerber W, Lardon J, Gees F, Brügger L, Ott T (2015) Repeated controlled rockfall trajectory testing. [Abstract] Geophys. Res. Abstr. 17: EGU2015-9779. [2] Volkwein A, Klette J (2014) Semi-Automatic Determination of Rockfall Trajectories. Sensors 14: 18187-18210.

  7. Calcium antagonistic effects of Bambusa Rigida investigated by 45Ca and its protection on myocardial ischemia of rats

    Institute of Scientific and Technical Information of China (English)

    LIN Rushan; YE Ling; YANG Yuanyou; LIAO Jiali; MO Shangwu; LIU Ning


    An investigation was conducted using 45Ca as a radioactive tracer to evaluate calcium antagonistic effects of several extracts from Bambusa Rigida in living rats. The relationship between the flavonoid and saccharide contents of Bambusa Rigida and calcium antagonistic effects were also analyzed. The protective effects of the alkali extracts ofBambusa Rigida on myocardial ischemia were investigated in living rats. The results indicated that the alkali extracts of Bambusa Rigida had a prominent influence on Ca2+ influx and efflux in the isolated rat aorta and heart, as they could obviously block 45Ca entering into cells and stimulate efflux of intracellular Ca2+. Moreover, the alkali extracts of Bambusa Rigida had favorable protective effects on myocardial ischemia induced either by isoproterenol injection (ISO) or by the ligation of coronary artery. These results implied that the Bambusa Rigida had attractive potential for the treatment of heart, cerebrovascular and other diseases. However, the conclusion that whether the flavonoid or saccharide in Bambusa Rigida affected the calcium antagonistic effects and Ca2+ channels or not was hard to make within the results of the investigation.

  8. Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening. (United States)

    Wang, Xing; Zhang, Yuxin; Liu, Qing; Ai, Zhixin; Zhang, Yanling; Xiang, Yuhong; Qiao, Yanjiang


    Endothelin-1 receptors (ETAR and ETBR) act as a pivotal regulator in the biological effects of ET-1 and represent a potential drug target for the treatment of multiple cardiovascular diseases. The purpose of the study is to discover dual ETA/ETB receptor antagonists from traditional Chinese herbs. Ligand- and structure-based virtual screening was performed to screen an in-house database of traditional Chinese herbs, followed by a series of in vitro bioassay evaluation. Aristolochic acid A (AAA) was first confirmed to be a dual ETA/ETB receptor antagonist based intracellular calcium influx assay and impedance-based assay. Dose-response curves showed that AAA can block both ETAR and ETBR with IC50 of 7.91 and 7.40 μM, respectively. Target specificity and cytotoxicity bioassay proved that AAA is a selective dual ETA/ETB receptor antagonist and has no significant cytotoxicity on HEK293/ETAR and HEK293/ETBR cells within 24 h. It is a feasible and effective approach to discover bioactive compounds from traditional Chinese herbs using in silico screening combined with in vitro bioassay evaluation. The structural characteristic of AAA for its activity was especially interpreted, which could provide valuable reference for the further structural modification of AAA.

  9. Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening

    Directory of Open Access Journals (Sweden)

    Xing Wang


    Full Text Available Endothelin-1 receptors (ETAR and ETBR act as a pivotal regulator in the biological effects of ET-1 and represent a potential drug target for the treatment of multiple cardiovascular diseases. The purpose of the study is to discover dual ETA/ETB receptor antagonists from traditional Chinese herbs. Ligand- and structure-based virtual screening was performed to screen an in-house database of traditional Chinese herbs, followed by a series of in vitro bioassay evaluation. Aristolochic acid A (AAA was first confirmed to be a dual ETA/ETB receptor antagonist based intracellular calcium influx assay and impedance-based assay. Dose-response curves showed that AAA can block both ETAR and ETBR with IC50 of 7.91 and 7.40 μM, respectively. Target specificity and cytotoxicity bioassay proved that AAA is a selective dual ETA/ETB receptor antagonist and has no significant cytotoxicity on HEK293/ETAR and HEK293/ETBR cells within 24 h. It is a feasible and effective approach to discover bioactive compounds from traditional Chinese herbs using in silico screening combined with in vitro bioassay evaluation. The structural characteristic of AAA for its activity was especially interpreted, which could provide valuable reference for the further structural modification of AAA.

  10. OPAL 96 Blocks Lead Glass

    CERN Multimedia

    This array of 96 lead glass bricks formed part of the OPAL electromagnetic calorimeter. One half of the complete calorimeter is shown in the picture above. There were 9440 lead glass counters in the OPAL electromagnetic calorimeter. These are made of Schott type SF57 glass and each block weighs about 25 kg and consists of 76% PbO by weight. Each block has a Hamamatsu R2238 photomultiplier glued on to it. The complete detector was in the form of a cylinder 7m long and 6m in diameter. It was used to measure the energy of electrons and photons produced in LEP interactions.

  11. AHR-11797: a novel benzodiazepine antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, D.N.; Kilpatrick, B.F.; Hannaman, P.K.


    AHR-11797(5,6-dihydro-6-methyl-1-phenyl-/sup 3/H-pyrrolo(3,2,1-ij)quinazolin-3-one) displaced /sup 3/H-flunitrazepam (IC/sub 50/ = 82 nM) and /sup 3/H-Ro 15-1877 (IC/sub 50/ = 104 nM) from rat brain synaptosomes. AHR-11797 did not protect mice from seizures induced by maximal electroshock or subcutaneous Metrazol (scMET), nor did it induce seizures in doses up to the lethal dose. However, at 31.6 mg/kg, IP, it significantly increased the anticonvulsant ED/sub 50/ of chlordiazepoxide (CDPX) from 1.9 to 31.6 mg/kg, IP. With 56.7 mg/kg, IP, of AHR-11797, CDPX was inactive in doses up to 100 mg/kg, IP. AHR-11797 did not significantly increase punished responding in the Geller and Seifter conflict procedure, but it did attenuate the effects of diazepam. Although the compound is without anticonvulsant or anxiolytic activity, it did have muscle relaxant properties. AHR-11797 blocked morphine-induced Straub tail in mice (ED/sub 50/ = 31 mg/kg, IP) and it selectively suppressed the polysnaptic linguomandibular reflex in barbiturate-anesthetized cats. The apparent muscle relaxant activity of AHR-11797 suggests that different receptor sites are involved for muscle relaxant vs. anxiolytic/anticonvulsant activities of the benzodiazepines.

  12. Metabotropic glutamate 2/3 receptor antagonists improve behavioral and prefrontal dopaminergic alterations in the chronic corticosterone-induced depression model in mice. (United States)

    Ago, Yukio; Yano, Koji; Araki, Ryota; Hiramatsu, Naoki; Kita, Yuki; Kawasaki, Toshiyuki; Onoe, Hirotaka; Chaki, Shigeyuki; Nakazato, Atsuro; Hashimoto, Hitoshi; Baba, Akemichi; Takuma, Kazuhiro; Matsuda, Toshio


    Metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists have an antidepressant-like effect, but the exact mechanism still remains unclear. This study examined the effects of mGlu2/3 receptor antagonists in chronic corticosterone-treated mice which could be used as an animal model of depression. In the forced swim test, the mGlu2/3 receptor antagonists MGS0039 (1.0 mg/kg, i.p.) and LY341495 (0.3 mg/kg, i.p) significantly reduced the increased immobility time of mice pretreated with corticosterone (20 mg/kg, s.c.) for 21 days, while desipramine (30 mg/kg, i.p.) and fluoxetine (30 mg/kg, i.p.) did not. The antidepressant-like effect of LY341495 was not blocked by the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist NBQX (10 mg/kg, i.p.). Systemic administration of LY341495 did not affect basal release of glutamate, dopamine or serotonin in the prefrontal cortex of the control or chronic corticosterone-treated mice. Chronic corticosterone markedly enhanced high K(+)-induced release of dopamine, but not serotonin or glutamate, in the prefrontal cortex. This neurochemical change was blocked by systemic administration of MGS0039 and LY341495, but not desipramine or fluoxetine. These results suggest that chronic corticosterone-treated mice could be used as an animal model of treatment-resistant depression. This study also suggests that the prefrontal dopaminergic system is involved in the antidepressant-like effect of mGlu2/3 receptor antagonists in the chronic corticosterone-induced depression model.

  13. Sympathetic blocks for visceral cancer pain management

    DEFF Research Database (Denmark)

    Mercadante, Sebastiano; Klepstad, Pal; Kurita, Geana Paula


    The neurolytic blocks of sympathetic pathways, including celiac plexus block (CPB) and superior hypogastric plexus block (SHPB) , have been used for years. The aim of this review was to assess the evidence to support the performance of sympathetic blocks in cancer patients with abdominal visceral...

  14. A pharmacophore model for dopamine D4 receptor antagonists (United States)

    Boström, Jonas; Gundertofte, Klaus; Liljefors, Tommy


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

  15. Preventing the stress-induced shift from goal-directed to habit action with a β-adrenergic antagonist. (United States)

    Schwabe, Lars; Höffken, Oliver; Tegenthoff, Martin; Wolf, Oliver T


    Stress modulates instrumental action in favor of habit processes that encode the association between a response and preceding stimuli and at the expense of goal-directed processes that learn the association between an action and the motivational value of the outcome. Here, we asked whether this stress-induced shift from goal-directed to habit action is dependent on noradrenergic activation and may therefore be blocked by a β-adrenoceptor antagonist. To this end, healthy men and women were administered a placebo or the β-adrenoceptor antagonist propranolol before they underwent a stress or a control procedure. Shortly after the stress or control procedure, participants were trained in two instrumental actions that led to two distinct food outcomes. After training, one of the food outcomes was selectively devalued by feeding participants to satiety with that food. A subsequent extinction test indicated whether instrumental behavior was goal-directed or habitual. As expected, stress after placebo rendered participants' behavior insensitive to the change in the value of the outcome and thus habitual. After propranolol intake, however, stressed participants behaved, same as controls, goal-directed, suggesting that propranolol blocked the stress-induced bias toward habit behavior. Our findings show that the shift from goal-directed to habitual control of instrumental action under stress necessitates noradrenergic activation and could have important clinical implications, particularly for addictive disorders.

  16. Effects of oral cetirizine, a selective H1 antagonist, on allergen- and exercise-induced bronchoconstriction in subjects with asthma.

    LENUS (Irish Health Repository)

    Gong, H


    The protective efficacy of oral cetirizine, a selective and potent H1-receptor antagonist, against the immediate bronchoconstrictive response to allergen inhalation and exercise challenge was evaluated in 16 subjects with stable, predominantly mild asthma. The subjects underwent double-blind, crossover pretreatments in randomized order in two separate protocols with (1) three daily oral doses of 20 mg of cetirizine and placebo, followed by allergen inhalation, and (2) single oral doses of cetirizine (5, 10, and 20 mg), albuterol (4 mg), and placebo, followed by exercise with cold-air inhalation. Cetirizine failed to decrease bronchial sensitivity to inhaled allergen in eight of 10 subjects. Neither cetirizine nor albuterol uniformly inhibited exercise-induced bronchoconstriction. Serum concentrations of cetirizine were consistent with systemic H1-blocking activity. Modest bronchodilation occurred after administration of cetirizine and albuterol before exercise but not after the third dose of cetirizine in the allergen protocol. One subject developed moderate drowsiness during multiple dosing with cetirizine. Thus, cetirizine, in the doses studied, is not uniformly effective in preventing allergen- or exercise-induced bronchoconstriction. Histamine is one of many mediators participating in immediate asthmatic responses, and selective H1 antagonists do not completely block these airway events. However, cetirizine may still clinically benefit some patients with asthma, such as patients with allergic rhinitis or urticaria.

  17. Blockade of murine T cell activation by antagonists of P2Y6 and P2X7 receptors. (United States)

    Tsukimoto, Mitsutoshi; Tokunaga, Akihiro; Harada, Hitoshi; Kojima, Shuji


    Extracellular nucleotides and their metabolites activate ionotropic P2X and metabotropic P2Y receptors on the surface of various types of cells. Here, we investigated the involvement of P2X and P2Y receptor-mediated signaling in TCR-dependent T cell activation. Murine T cells were activated by stimulation of TCR, and both CD25 expression and interleukin (IL)-2 production were observed in activated T cells. Ecto-nucleotidase apyrase and P2Y6 antagonist MRS2578 significantly blocked the increases of both CD25 expression and IL-2 production, and P2X7 antagonists A438079 and oxidized ATP inhibited IL-2 production rather than CD25 expression, suggesting the involvement of P2Y6 and P2X7 receptors in different processes of T cell activation. MRS2578 also blocked TCR-dependent elevation of cytosolic Ca2+ in T cells. The P2X7 and P2Y6 receptors were expressed in murine CD4 T cells. In conclusion, our results indicate that activation of P2Y6 and P2X7 receptors contributes to T cell activation via TCR.

  18. Scattering matrices with block symmetries


    Życzkowski, Karol


    Scattering matrices with block symmetry, which corresponds to scattering process on cavities with geometrical symmetry, are analyzed. The distribution of transmission coefficient is computed for different number of channels in the case of a system with or without the time reversal invariance. An interpolating formula for the case of gradual time reversal symmetry breaking is proposed.

  19. Architectures for block Toeplitz systems

    NARCIS (Netherlands)

    Bouras, Ilias; Glentis, George-Othon; Kalouptsidis, Nicholas


    In this paper efficient VLSI architectures of highly concurrent algorithms for the solution of block linear systems with Toeplitz or near-to-Toeplitz entries are presented. The main features of the proposed scheme are the use of scalar only operations, multiplications/divisions and additions, and th

  20. Building Blocks for Personal Brands (United States)

    Thomas, Lisa Carlucci


    In this article, the author discusses the four essential building blocks for personal brands: (1) name; (2) message; (3) channels; and (4) bridges. However, outstanding building materials can only take a person so far. The author emphasizes that vision, determination, faith, a sense of humor, and humility are also required.

  1. First Degree Pacemaker Exit Block

    Directory of Open Access Journals (Sweden)

    Johnson Francis


    Full Text Available Usually atrial and ventricular depolarizations follow soon after the pacemaker stimulus (spike on the ECG. But there can be an exit block due to fibrosis at the electrode - tissue interface at the lead tip. This can increase the delay between the spike and atrial or ventricular depolarization.

  2. Interleukin-1 Antagonist Anakinra in Amyotrophic Lateral Sclerosis--A Pilot Study.

    Directory of Open Access Journals (Sweden)

    André Maier

    Full Text Available Preclinical studies show that blocking Interleukin-1 (IL-1 retards the progression of Amyotrophic Lateral Sclerosis (ALS. We assessed the safety of Anakinra (ANA, an IL-1 receptor antagonist, in ALS patients. In a single arm pilot study we treated 17 ALS patients with ANA (100 mg daily for one year. We selected patients with dominant or exclusive lower motor neuron degeneration (LMND presentation, as peripheral nerves may be more accessible to the drug. Our primary endpoint was safety and tolerability. Secondary endpoints included measuring disease progression with the revised ALS functional rating scale (ALSFRSr. We also quantified serum inflammatory markers. For comparison, we generated a historical cohort of 47 patients that fit the criteria for enrollment, disease characteristics and rate of progression of the study group. Only mild adverse events occurred in ALS patients treated with ANA. Notably, we observed lower levels of cytokines and the inflammatory marker fibrinogen during the first 24 weeks of treatment. Despite of this, we could not detect a significant reduction in disease progression during the same period in patients treated with ANA compared to controls as measured by the ALSFRSr. In the second part of the treatment period we observed an increase in serum inflammatory markers. Sixteen out of the 17 patients (94% developed antibodies against ANA. This study showed that blocking IL-1 is safe in patients with ALS. Further trials should test whether targeting IL-1 more efficiently can help treating this devastating NCT01277315.

  3. Novel Fluorine-Containing NMDA Antagonists for Brain Imaging: In Vitro Evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Alvarado, M.; Biegon, A.


    The NMDA receptor has been implicated in neuronal death following stroke, brain injury and neurodegenerative disorders (e.g. Alzheimer's, Parkinson's and Huntington's disease) and in physiological functions (e.g. memory and cognition). Non-competitive antagonists, such as MK- 801 and CNS-1102, that block the action of glutamate at the NMDA receptor have been shown to be neuroprotective by blocking the influx of calcium into the cells. As a result, they are being considered as therapeutic agents for the above mentioned diseases. Several Fluorine-containing novel analogs of NMDA channel blockers have been synthesized and evaluated in search of a compound suitable for 18F labeling and Positron Emission Tomography (PET). Based on in vitro binding assay studies on rat brain membranes, the novel compounds examined displayed a range of affinities. Preliminary analyses indicated that chlorine is the best halogen on the ring, and that ethyl fluoro derivatives are more potent than methyl-fluoro compounds. Further analysis based on autoradiography will be needed to examine the regional binding characteristics of the novel compounds examined in this study. Labeling with 18F will allow the use of these compounds in humans, generating new insights into mechanisms and treatment of diseases involving malfunction of the glutamatergic system in the brain.

  4. A cannabinoid CB(1) receptor antagonist ameliorates impairment of recognition memory on withdrawal from MDMA (Ecstasy). (United States)

    Nawata, Yoko; Hiranita, Takato; Yamamoto, Tsuneyuki


    (+/-)-3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') abusers have persistent neuropsychiatric deficits including memory impairments after the cessation of abuse. On the other hand, cannabinoid CB(1) receptors have been implicated in learning/memory, and are highly expressed in the hippocampus, a region of the brain believed to have an important function in certain forms of learning and memory. In this study, we clarified the mechanism underlying the cognitive impairment that develops during MDMA withdrawal from the standpoint of the cannabinoid CB(1) receptors. Mice were administered MDMA (10 mg/kg, i.p.) once a day for 7 days. On the 7th day of withdrawal, a novel object recognition task was performed and the amount of cannabinoid CB(1) receptor protein was measured with western blotting. Recognition performance was impaired on the 7th day of withdrawal. This impairment was blocked by AM251, a cannabinoid CB(1) receptor antagonist, administered 30 min before the training trial or co-administered with MDMA. At this time, the level of cannabinoid CB(1) receptor protein increased significantly in the hippocampus but not the prefrontal cortex or striatum. This increase of CB(1) receptor protein in the hippocampus was also blocked by the co-administration of AM251. Furthermore, CB(1) receptor knockout mice showed no impairment of recognition performance on the withdrawal from MDMA. The impairment of recognition memory during withdrawal from MDMA may result from the activation of cannabinoid CB(1) receptors in the hippocampus.

  5. Histamine H3 receptor antagonist OUP-186 attenuates the proliferation of cultured human breast cancer cell lines. (United States)

    Tanaka, Satoshi; Sakaguchi, Minoru; Yoneyama, Hiroki; Usami, Yoshihide; Harusawa, Shinya


    Histamine is involved in various physiological functions, including its neurotransmitter actions in the central nervous system and its action as a causative agent of inflammation, allergic reactions, and gastric acid secretions. Histamine expression and biosynthesis have been detected in breast cancer cells. It was recently suggested that the histamine H3 receptor (H3R) plays a role in the proliferation of breast cancer cells. We recently developed the non-imidazole H3R antagonist OUP-186 which exhibited a potent and selective human H3R antagonistic activity as well as no activity against the human histamine H4 receptor (H4R). In this study, we compared the effects of OUP-186 on the proliferation of estrogen receptor negative (ER-) breast cancer cells (MDA-MB-231) and ER+ breast cancer cells (MCF7) to the effects of clobenpropit (potent imidazole-containing H3R antagonist). OUP-186 and clobenpropit suppressed the proliferation of breast cancer cells. The IC50 values at 48 h for OUP-186 and clobenpropit were approximately 10 μM and 50 μM, respectively. Furthermore, OUP-186 potently induced cell death by activating caspase-3/7, whereas cell death was only slightly induced by clobenpropit. In addition, OUP-186 treatment blocked the proliferation increase triggered by 100 μM (R)-(-)-α-methylhistamine (H3R agonist). The use of 4-methylhistamine (H4R agonist) and JNJ10191584 (selective H4R antagonist) did not affect breast cancer proliferation. These results indicate that OUP-186 potently suppresses proliferation and induces caspase-dependent apoptotic death in both ER+ and ER-breast cancer cells.

  6. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia – critical appraisal of suvorexant

    Directory of Open Access Journals (Sweden)

    Norman JL


    Full Text Available Jessica L Norman, Sarah L Anderson Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA Abstract: Insomnia, a highly prevalent disorder, can be detrimental to patients’ overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of

  7. Pourfour Du Petit syndrome after interscalene block. (United States)

    Santhosh, Mysore Chandramouli Basappji; Pai, Rohini B; Rao, Raghavendra P


    Interscalene block is commonly associated with reversible ipsilateral phrenic nerve block, recurrent laryngeal nerve block, and cervical sympathetic plexus block, presenting as Horner's syndrome. We report a very rare Pourfour Du Petit syndrome which has a clinical presentation opposite to that of Horner's syndrome in a 24-year-old male who was given interscalene block for open reduction and internal fixation of fracture upper third shaft of left humerus.

  8. Endoscopic sphenopalatine ganglion block for pain relief


    Murty, P. S. N.; Prasanna, Atma


    The anaesthetic effect of the sphenopalatine (SPG) block has been well utilized for intranasal topical anaesthesia but the analgesic efficacy of (SPG) block, though well documented in literature, has not been put into practice. The methods available for SPG block till date were blind as they do not visualize the foramen. Nasal endoscopies have been used to visualize the foramen for an effective block. The authors present their experience with the endoscopic sphenopalatine ganglion block for p...

  9. Pourfour Du Petit syndrome after interscalene block

    Directory of Open Access Journals (Sweden)

    Mysore Chandramouli Basappji Santhosh


    Full Text Available Interscalene block is commonly associated with reversible ipsilateral phrenic nerve block, recurrent laryngeal nerve block, and cervical sympathetic plexus block, presenting as Horner′s syndrome. We report a very rare Pourfour Du Petit syndrome which has a clinical presentation opposite to that of Horner′s syndrome in a 24-year-old male who was given interscalene block for open reduction and internal fixation of fracture upper third shaft of left humerus.

  10. Metabolic forearm vasodilation is enhanced following Bier block with phentolamine. (United States)

    Moradkhan, Raman; McQuillan, Patrick; Hogeman, Cynthia; Leuenberger, Andrea; Linton-Frazier, Latoya; Leuenberger, Urs A


    The extent to which sympathetic nerve activity restrains metabolic vasodilation in skeletal muscle remains unclear. We determined forearm blood flow (FBF; ultrasound/Doppler) and vascular conductance (FVC) responses to 10 min of ischemia [reactive hyperemic blood flow (RHBF)] and 10 min of systemic hypoxia (inspired O(2) fraction = 0.1) before and after regional sympathetic blockade with the alpha-receptor antagonist phentolamine via Bier block in healthy humans. In a control group, we performed sham Bier block with saline. Consistent with alpha- receptor inhibition, post-phentolamine, basal FVC (FBF/mean arterial pressure) increased (pre vs. post: 0.42 +/- 0.05 vs. 1.03 +/- 0.21 units; P phentolamine, total RHBF (over 3 min) increased substantially (pre vs. post: 628 +/- 75 vs. 826 +/- 92 ml/min; P phentolamine (pre vs. post: 0.43 +/- 0.06 vs. 1.16 +/- 0.17 units; P < 0.01; n = 8) but not post-saline (pre vs. post: 0.93 +/- 0.16 vs. 0.87 +/- 0.19 ml/min; P = not significant; n = 5), the FVC response to hypoxia (arterial O(2) saturation = 77 +/- 1%) was markedly enhanced. These data suggest that sympathetic vasoconstrictor nerve activity markedly restrains skeletal muscle vasodilation induced by local (forearm ischemia) and systemic (hypoxia) vasodilator stimuli.

  11. Limiting Spectral Distribution of Block Matrices with Toeplitz Block Structure

    CERN Document Server

    Basu, Riddhipratim; Ganguly, Shirshendu; Hazra, Rajat Subhra


    We study two specific symmetric random block Toeplitz (of dimension $k \\times k$) matrices: where the blocks (of size $n \\times n$) are (i) matrices with i.i.d. entries, and (ii) asymmetric Toeplitz matrices. Under suitable assumptions on the entries, their limiting spectral distributions (LSDs) exist (after scaling by $\\sqrt{nk}$) when (a) $k$ is fixed and $n \\to\\infty$ (b) $n$ is fixed and $k\\rightarrow \\infty$ (c) $n$ and $k$ go to $\\infty$ simultaneously. Further the LSD's obtained in (a) and (b) coincide with those in (c) when $n$ or respectively $k$ tends to infinity. This limit in (c) is the semicircle law in case (i). In Case (ii) the limit is related to the limit of the random symmetric Toepiltz matrix as obtained by Bryc et al.(2006) and Hammond and Miller(2005).

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

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Tuminello


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

  13. Discovery of the improved antagonistic prolactin variants by library screening. (United States)

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


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


    Directory of Open Access Journals (Sweden)



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

  15. Neuroprotective Effects of Glutamate Antagonists and Extracellular Acidity (United States)

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


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

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

    LENUS (Irish Health Repository)

    Mocanu, E V


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

  17. Development and characterization of high affinity leptins and leptin antagonists. (United States)

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


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

  18. Development and Characterization of High Affinity Leptins and Leptin Antagonists* (United States)

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


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

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

    DEFF Research Database (Denmark)

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


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

  20. Barnidipine, a long-acting slow onset calcium antagonist. (United States)

    Korstanje, C


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

  1. Hyperglycemia of Diabetic Rats Decreased by a Glucagon Receptor Antagonist (United States)

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


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

  2. On the Eigenvalues and Eigenvectors of Block Triangular Preconditioned Block Matrices

    KAUST Repository

    Pestana, Jennifer


    Block lower triangular matrices and block upper triangular matrices are popular preconditioners for 2×2 block matrices. In this note we show that a block lower triangular preconditioner gives the same spectrum as a block upper triangular preconditioner and that the eigenvectors of the two preconditioned matrices are related. © 2014 Society for Industrial and Applied Mathematics.

  3. Antagonists of Calcium Fluxes and Calmodulin Block Activation of the p21-Activated Protein Kinases in Neutrophils

    NARCIS (Netherlands)

    Lian, J.P. (Jian); Crossley, L. (Lisa); Zhan, Q. (Qian); Huang, R. (Riyun); Coffer, P.J.; Toker, A. (Alex); Robinson, D. (Dwight); Badwey, J.A. (John)


    Neutrophils stimulated with fMLP or a variety of other chemoattractants that bind to serpentine receptors coupled to heterotrimeric G proteins exhibit rapid activation of two p21-activated protein kinases (Paks) with molecular masses of ~63 and 69 kDa (y- and a-Pak). Previous studies have shown that

  4. The Vasopressin 1b Receptor Antagonist A-988315 Blocks Stress Effects on the Retrieval of Object-Recognition Memory

    NARCIS (Netherlands)

    Barsegyan, A.; Atsak, P.; Hornberger, W.B.; Jacobson, P.B.; Gaalen, M.M. van; Roozendaal, B.


    Stress-induced activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and high circulating glucocorticoid levels are well known to impair the retrieval of memory. Vasopressin can activate the HPA axis by stimulating vasopressin 1b (V1b) receptors located on the pituitary. In the present s

  5. Graphs obtained from collections of blocks

    Directory of Open Access Journals (Sweden)

    Colton Magnant


    Full Text Available Given a collection of $d$-dimensional rectangular solids called blocks, no two of which sharing interior points, construct a block graph by adding a vertex for each block and an edge if the faces of the two corresponding blocks intersect nontrivially.  It is known that if $d \\geq 3$, such block graphs can have arbitrarily large chromatic number.  We prove that the chromatic number can be bounded with only a mild restriction on the sizes of the blocks.  We also show that block graphs of block configurations arising from partitions of $d$-dimensional hypercubes into sub-hypercubes are at least $d$-connected.  Bounds on the diameter and the hamiltonicity of such block graphs are also discussed.

  6. A conformal block Farey tail

    CERN Document Server

    Maloney, Alexander; Ng, Gim Seng


    We investigate the constraints of crossing symmetry on CFT correlation functions. Four point conformal blocks are naturally viewed as functions on the upper-half plane, on which crossing symmetry acts by PSL(2,Z) modular transformations. This allows us to construct a unique, crossing symmetric function out of a given conformal block by averaging over PSL(2,Z). In some two dimensional CFTs the correlation functions are precisely equal to the modular average of the contributions of a finite number of light states. For example, in the two dimensional Ising and tri-critical Ising model CFTs, the correlation functions of identical operators are equal to the PSL(2,Z) average of the Virasoro vacuum block; this determines the 3 point function coefficients uniquely in terms of the central charge. The sum over PSL(2,Z) in CFT2 has a natural AdS3 interpretation as a sum over semi-classical saddle points, which describe particles propagating along rational tangles in the bulk. We demonstrate this explicitly for the corre...

  7. Study into a possible mechanism responsible for the antidepressant-like activity of the selective 5-HT6 receptor antagonist SB-399885 in rats. (United States)

    Wesołowska, Anna


    The mechanism of the antidepressant-like activity of the selective 5-hydroxytryptamine(6) (5-HT(6) receptor antagonist N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885) was studied in the forced swim test in rats. SB-399885 administered intraperitoneally at a single dose of 10 mg/kg potently shortened the immobility time in rats. That potential antidepressant-like effect of SB-399885 was not modified in animals with a lesion of the 5-HT system produced by p-chloroamphetamine (p-CA, 2 x 10 mg/kg). The anti-immobility effect of SB-399885 was blocked by the dopamine D(1)- and D(2)-like receptor antagonists SCH 23390 (0.063 mg/kg) and sulpiride (10 mg/kg), respectively, as well as by the alpha(2)-adrenoceptor antagonist idazoxan (4 mg/kg), but it was not changed by the alpha(1)-adrenoceptor antagonist prazosin (1 mg/kg). Neither sulpiride (10 mg/kg) or idazoxan (4 mg/kg) nor SCH-23390 (0.063 mg/kg) administered jointly with SB-399885 (10 mg/kg) noticeably changed the exploratory locomotor activity of rats evaluated by the open field test. The results described in the present paper indicate that the anti-immobility activity of SB-399885 is not connected with 5-HT innervation, and that D(1)- and D(2)-like receptors and alpha(2)-adrenoceptors are involved in this action.

  8. Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension. (United States)

    Li, Wencheng; Sullivan, Michelle N; Zhang, Sheng; Worker, Caleb J; Xiong, Zhenggang; Speth, Robert C; Feng, Yumei


    We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension.

  9. 5-Hydroxytryptamine3 receptor antagonists and cardiac side effects

    DEFF Research Database (Denmark)

    Brygger, Louise; Herrstedt, Jørn


    INTRODUCTION: 5-Hydroxytryptamine3-receptor antagonists (5-HT3-RA) are the most widely used antiemetics in oncology, and although tolerability is high, QTC prolongation has been observed in some patients. AREAS COVERED: The purpose of this article is to outline the risk of cardiac adverse events...

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

    Directory of Open Access Journals (Sweden)

    Tanya Onushko

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

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

    Directory of Open Access Journals (Sweden)

    Bruce Lyeth


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

  12. How Hybrid Organizations Turn Antagonistic Assets into Complementarities

    DEFF Research Database (Denmark)

    Hockerts, Kai


    This article focuses on people excluded from traditional markets as employees, producers, or consumers on the grounds that they lack the appropriate skills. It describes the processes through which these perceived liabilities can be overcome by so-called hybrid organizations. Hybrids pursue expli...... for complementarities, and by creating demands for antagonistic assets, or by using partnerships....

  13. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

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


    Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered: Preclin......Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered...... receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...... antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT2A receptor...

  14. Facilitative and antagonistic interactions between plant viruses in mixed infections. (United States)

    Syller, Jerzy


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

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

    NARCIS (Netherlands)

    Kooistra, Hilde Afra Margaretha


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

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

    NARCIS (Netherlands)

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


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

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

    NARCIS (Netherlands)

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


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

  18. Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists. (United States)

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


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

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

    DEFF Research Database (Denmark)

    Bisgaard, H; Nielsen, K G


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

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

    NARCIS (Netherlands)

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


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

  1. Komplikationer til langtidsbehandling med vitamin K-antagonister

    DEFF Research Database (Denmark)

    May, O; Garne, E; Mickley, H


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

  2. Influence of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rat. (United States)

    Farzin, D; Attarzadeh, M


    The effects of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rats were investigated. Subcutaneous (s.c.) injection of various doses of apomorphine (0. 125-1.25 mg/kg) induced licking. The licking response was counted by direct observation and recorded for a 75-min period. Intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection of the histamine H(1) or H(2) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 and 100 microg per rat), or dimaprit (10 and 15 mg/kg, i.p.), respectively, potentiated apomorphine-induced licking, while the histamine H(3) receptor agonist, imetit (5 and 10 mg/kg, i.p.), reduced the licking response induced by apomorphine. Pretreatment with various histamine receptor antagonists, dexchlorpheniramine (30 and 40 mg/kg, i.p.), diphenhydramine (20, 30 and 40 mg/kg, i.p.), famotidine (30 and 40 mg/kg, s.c.) and ranitidine (20, 30 and 40 mg/kg), reduced apomorphine-induced licking, while thioperamide (5 and 10 mg/kg, i.p.) potentiated the apomorphine effect. The effects of HTMT and dimaprit were blocked by dexchlorpheniramine (20 mg/kg, i.p.) and famotidine (20 mg/kg, s.c.), respectively. The inhibitory effect elicited by imetit on apomorphine-induced licking behavior was also abolished in animals treated with thioperamide (2.5 mg/kg, i.p.). The results suggest that histaminergic mechanisms may be involved in the modulation of apomorphine-induced licking behavior.

  3. The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder. (United States)

    Taylor, Fletcher; Raskind, Murray A


    Heightened noradrenergic reactivity may be a contributing factor in the pathophysiology of posttraumatic stress disorder (PTSD). Prazosin is an alpha1-adrenoceptor antagonist commonly used as an antihypertensive agent. Because alpha1-adrenergic activity has been associated with fear and startle responses, a drug that blocks central alpha1-adrenergic activity may be useful in the treatment of PTSD symptoms. An outpatient who had been exposed to civilian trauma and had subsequent chronic refractory PTSD was thus prescribed prazosin. The marked reduction in PTSD symptoms, particularly sleep and nightmares, prompted the following open-label feasibility trial. Five outpatients with non-combat-related PTSD were consecutively identified and received prazosin in a 6-week open-label trial. In each case, the prazosin doses were slowly increased until optimal benefit was achieved. Change was assessed with the Clinician-Administered PTSD Scale for DSM-IV, One Week Symptom Version (CAPS-SX), the Clinical Global Impression of Change Scale (CGIC), and the Clinical Impression of Change-Nightmares (CIC-Nightmares) score. All five patients experienced moderate to marked improvement on the CGIC. The CAPS-SX PTSD nightmare and sleep PTSD categories showed at least a four-point reduction of those symptoms. All patients reported at least moderate improvement on the CIC-Nightmare score. Optimal doses of prazosin ranged from 1 to 4 mg/day. The drug was reasonably tolerated, and there were no drug discontinuations. These preliminary findings provide a rationale for blind placebo-controlled efficacy trials of the alpha 1 antagonist prazosin for PTSD.

  4. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Yi; Qin, Ling; Ortiz Zacarías, Natalia V.; de Vries, Henk; Han, Gye Won; Gustavsson, Martin; Dabros, Marta; Zhao, Chunxia; Cherney, Robert J.; Carter, Percy; Stamos, Dean; Abagyan, Ruben; Cherezov, Vadim; Stevens, Raymond C.; IJzerman, Adriaan P.; Heitman, Laura H.; Tebben, Andrew; Kufareva, Irina; Handel , Tracy M. (Vertex Pharm); (Leiden-MC); (USC); (BMS); (UCSD)


    CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases2 including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer3. These disease associations have motivated numerous preclinical studies and clinical trials4 (see in search of therapies that target the CCR2–chemokine axis. To aid drug discovery efforts5, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]7) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein–protein interactions, receptor–chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.

  5. Myofascial force transmission via extramuscular pathways occurs between antagonistic muscles. (United States)

    Huijing, Peter A; Baan, Guus C


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

  6. Accumulation of Deleterious Mutations Near Sexually Antagonistic Genes

    Directory of Open Access Journals (Sweden)

    Tim Connallon


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

  7. Striatal pre- and postsynaptic profile of adenosine A(2A receptor antagonists.

    Directory of Open Access Journals (Sweden)

    Marco Orru

    Full Text Available Striatal adenosine A(2A receptors (A(2ARs are highly expressed in medium spiny neurons (MSNs of the indirect efferent pathway, where they heteromerize with dopamine D(2 receptors (D(2Rs. A(2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A(1 receptors (A(1Rs. It has been hypothesized that postsynaptic A(2AR antagonists should be useful in Parkinson's disease, while presynaptic A(2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A(2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261 showed no clear preference. Radioligand-binding experiments were performed in cells expressing A(2AR-D(2R and A(1R-A(2AR heteromers to determine possible differences in the affinity of these compounds for different A(2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A(2AR when co-expressed with D(2R than with A(1R. KW-6002 showed the best relative affinity for A(2AR co-expressed with D(2R than co-expressed with A(1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile

  8. Acute-phase responses in transgenic mice with CNS overexpression of IL-1 receptor antagonist. (United States)

    Lundkvist, J; Sundgren-Andersson, A K; Tingsborg, S; Ostlund, P; Engfors, C; Alheim, K; Bartfai, T; Iverfeldt, K; Schultzberg, M


    The interleukin-1 (IL-1) receptor antagonist (IL-1ra) is an endogenous antagonist that blocks the effects of the proinflammatory cytokines IL-1alpha and IL-1beta by occupying the type I IL-1 receptor. Here we describe transgenic mice with astrocyte-directed overexpression of the human secreted IL-1ra (hsIL-1ra) under the control of the murine glial fibrillary acidic protein (GFAP) promoter. Two GFAP-hsIL-1ra strains have been generated and characterized further: GILRA2 and GILRA4. These strains show a brain-specific expression of the hsIL-1ra at the mRNA and protein levels. The hsIL-1ra protein was approximated to approximately 50 ng/brain in cytosolic fractions of whole brain homogenates, with no differences between male and female mice or between the two strains. Furthermore, the protein is secreted, inasmuch as the concentration of hsIL-1ra in the cerebrospinal fluid was 13 (GILRA2) to 28 (GILRA4) times higher in the transgenic mice than in the control animals. To characterize the transgenic phenotype, GILRA mice and nontransgenic controls were injected with recombinant human IL-1beta (central injection) or lipopolysaccharide (LPS, peripheral injection). The febrile response elicited by IL-1beta (50 ng/mouse icv) was abolished in hsIL-1ra-overexpressing animals, suggesting that the central IL-1 receptors were occupied by antagonist. The peripheral LPS injection (25 micrograms/kg ip) triggered a fever in overexpressing and control animals. Moreover, no differences were found in LPS-induced (100 and 1,000 micrograms/kg ip; 1 and 6 h after injection) IL-1beta and IL-6 serum levels between GILRA and wild-type mice. On the basis of these results, we suggest that binding of central IL-1 to central IL-1 receptors is not important in LPS-induced fever or LPS-induced IL-1beta and IL-6 plasma levels.

  9. Effects of the nonpeptide V(1) vasopressin receptor antagonist SR49059 in hypertensive patients. (United States)

    Thibonnier, M; Kilani, A; Rahman, M; DiBlasi, T P; Warner, K; Smith, M C; Leenhardt, A F; Brouard, R


    We assessed the clinical and pharmacological profile of the orally active V(1) vascular vasopressin (AVP) receptor nonpeptide antagonist SR49059 (SR) during the osmotic stimulation of AVP release in hypertensive patients. In a double-blind crossover-versus-placebo study, 24 untreated stage I or II essential hypertensive patients (12 whites and 12 blacks) received a single 300 mg oral dose of SR 2 hours before the stimulation of AVP secretion with a 5% hypertonic saline infusion. Hemodynamic, humoral, and hormonal parameters were monitored for up to 28 hours after drug administration. SR did not alter blood pressure or heart rate before the saline infusion and did not reduce the blood pressure increment induced by the hypertonic saline infusion. However, the blood pressure peak at the end of the hypertonic saline infusion was slightly lower in the presence of SR (P=0.04). Heart rate was significantly faster between 4 and 6 hours after SR administration (P=0.02). The rise in plasma sodium and osmolality triggered by the saline infusion was not modified by SR, but AVP release was slightly greater in the presence of SR (P<0.0003). AVP-induced aggregation of blood platelets in vitro was significantly reduced by SR, with a peak effect 2 hours after drug administration that coincided with the SR peak plasma concentration. Plasma renin activity and aldosterone before and after the saline infusion were not modified by SR. Urine volume and osmolality were not altered by SR administration. SR effects were similar in the 2 ethnic groups as well as in salt-sensitive versus salt-resistant patients. In a situation of AVP osmotic release and volume expansion in hypertensive patients, a single oral dose of the V(1) vascular AVP receptor nonpeptide antagonist SR49059, which is able to block AVP-induced platelet aggregation, exerts a transient vasodilation effect that is not associated with a sustained blood pressure reduction. SR49059 is a pure V(1) vascular receptor antagonist that

  10. Hillslope-derived blocks retard river incision (United States)

    Shobe, Charles M.; Tucker, Gregory E.; Anderson, Robert S.


    The most common detachment-limited river incision models ignore the effects of sediment on fluvial erosion, yet steep reaches of mountain rivers often host clusters of large (>1 m) blocks. We argue that this distribution of blocks is a manifestation of an autogenic negative feedback in which fast vertical river incision steepens adjacent hillslopes, which deliver blocks to the channel. Blocks inhibit incision by shielding the bed and enhancing form drag. We explore this feedback with a 1-D channel-reach model in which block delivery by hillslopes depends on the river incision rate. Results indicate that incision-dependent block delivery can explain the block distribution in Boulder Creek, Colorado. The proposed negative feedback may significantly slow knickpoint retreat, channel adjustment, and landscape response compared to rates predicted by current theory. The influence of hillslope-derived blocks may complicate efforts to extract base level histories from river profiles.

  11. Demographic Data - MDC_BlockGroup (United States)

    NSGIC GIS Inventory (aka Ramona) — A polygon feature class of Miami-Dade County Census 2000 Block Groups. A census Block Group is a statistical subdivision of a census Tract consisting of a cluster...

  12. Pretreatment with aldosterone or corticosterone blocks the memory-enhancing effects of nimodipine, captopril, CGP 37,849, and strychnine in mice. (United States)

    Mondadori, C; Gentsch, C; Hengerer, B; Ducret, T; Borkowski, J; Racine, A; Lederer, R; Haeusler, A


    Oral pretreatment with aldosterone or corticosterone blocked the memory-enhancing effects of the calcium antagonist nimodipine, the ACE inhibitor captopril, the NMDA blocker CGP 37,849, and the glycine antagonist strychnine in a passive-avoidance test in mice. The memory-disturbing effects of phenobarbitone, diazepam, CGP 37,849 and scopolamine were not influenced by the hormonal pretreatment. These findings could indicate the involvement of a steroid-sensitive mechanism in drug-induced improvement of memory. In the light of clinical observations showing elevated cortisol levels in Alzheimer patients, the results might also explain why only a limited number of these patients respond to therapy with memory enhancers.

  13. Slickenside developed in chert block (United States)

    Ando, J.; Hayasaka, Y.; Nishiwaki, T.


    We observe the microstructures of slickenside developed in chert block mainly with a TEM, in order to clarify generation mechanism of the slickenside. This chert block occurs in the Jurassic accretionary complex in eastern Yamaguchi Prefecture, Japan. The complex, chaotic sediment, is composed of allochthonous blocks, mainly of chert, limestone, sandstone and mudstone in the argillaceous matrix. The color of the undeformed chert is pale blue to white, while the surface of slickenside is black. The stereo microscopy indicates the top surface of slickenside is covered with a transparent material, whose composition is mainly Si, measured by EPMA. The striation is well developed on the transparent-Si-material. We made thin sections, parallel and perpendicular to striation and slickenside, respectively. On the thin sections, the elongated quartz grains are oriented obliquely to the slickenside with 20-30 degree. Many fluid inclusions, which represent healed microcracks, are observed within the quartz grains. These quartz grains show strong undulose extinction and bulging-recrystallization. Apatite grains are also observed as a main constituent mineral. We made TEM foils from the above thin section by FIB. TEM observation indicates the amorphous layer with several ten nanometers in width distributes along the slickenside. (We speculate the most part of the amorphous layer are taken away during polishing of the thin section, because the strength of the amorphous layer is weak. Therefore we now make thin section again with care.) The tangled dislocations are developed within the quartz grains. They make subgrains with ca. 1 micrometer in size. These results suggest the slickenside was generated by the frictional melting of quartz grains on slip plane under very high stress condition, same as pseudotachylyte.

  14. Practical Binary Adaptive Block Coder

    CERN Document Server

    Reznik, Yuriy A


    This paper describes design of a low-complexity algorithm for adaptive encoding/ decoding of binary sequences produced by memoryless sources. The algorithm implements universal block codes constructed for a set of contexts identified by the numbers of non-zero bits in previous bits in a sequence. We derive a precise formula for asymptotic redundancy of such codes, which refines previous well-known estimate by Krichevsky and Trofimov, and provide experimental verification of this result. In our experimental study we also compare our implementation with existing binary adaptive encoders, such as JBIG's Q-coder, and MPEG AVC (ITU-T H.264)'s CABAC algorithms.

  15. Design, synthesis, and structure-activity relationship of novel CCR2 antagonists. (United States)

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


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

  16. New Considerations of Turbo Block Codes

    Institute of Scientific and Technical Information of China (English)

    YUEDianwu; EdSHWEDYK


    It is shown that (1) a general linear systematic block code can be expressed as a turbo block code and therefore can be decoded using any turbo decoding algorithm; (2) a turbo block code can be also encoded and decoded without any interleaver with the same performance as when an interleaver is present.

  17. Writer's block in a Chinese sample. (United States)

    Lee, Sy-Ying; Krashen, Stephen


    To assess whether writer's block occurs in languages other than English, a Chinese language translation of Rose's Writer's Block questionnaire was administered to 98 university students in Taiwan. Analysis suggests that writer's block occurs for Chinese students, and, as in English, it is related to premature editing and to a lack of strategies for dealing with complex writing tasks.

  18. Micellization and Dynamics of a Block Copolymer

    DEFF Research Database (Denmark)

    Hvidt, Søren


    Triblock copolymers of the type EPE, where E and P denote ethylene oxide and propylene oxide blocks, respectively, are industrially important copolymers often called Pluronics or Poloxamers. EPE copolymers form micelles with a core of P blocks and different micellar shapes depending on block leng...

  19. Cutaneous Sensory Block Area, Muscle-Relaxing Effect, and Block Duration of the Transversus Abdominis Plane Block

    DEFF Research Database (Denmark)

    Støving, Kion; Rothe, Christian; Rosenstock, Charlotte V


    into a medial and lateral part by a vertical line through the anterior superior iliac spine. We measured muscle thickness of the 3 lateral abdominal muscle layers with ultrasound in the relaxed state and during maximal voluntary muscle contraction. The volunteers reported the duration of the sensory block...... and the abdominal muscle-relaxing effect. RESULTS: The lateral part of the cutaneous sensory block area was a median of 266 cm2 (interquartile range, 191-310 cm2) and the medial part 76 cm 2(interquartile range, 54-127 cm2). In all the volunteers, lateral wall muscle thickness decreased significantly by 9.2 mm (6......BACKGROUND AND OBJECTIVES: The transversus abdominis plane (TAP) block is a widely used nerve block. However, basic block characteristics are poorly described. The purpose of this study was to assess the cutaneous sensory block area, muscle-relaxing effect, and block duration. METHODS: Sixteen...

  20. Seismicity of the Jalisco Block (United States)

    Nunez-Cornu, F. J.; Rutz, M.; Camarena-Garcia, M.; Trejo-Gomez, E.; Reyes-Davila, G.; Suarez-Plascencia, C.


    In April 2002 began to transmit the stations of the first phase of Jalisco Telemetric Network located at the northwest of Jalisco Block and at the area of Volcan de Fuego (Colima Volcano), in June were deployed four additional MarsLite portable stations in the Bahia de Banderas area, and by the end of August one more portable station at Ceboruco Volcano. The data of these stations jointly with the data from RESCO (Colima Telemetric Network) give us the minimum seismic stations coverage to initiate in a systematic and permanent way the study of the seismicity in this very complex tectonic region. A preliminary analysis of seismicity based on the events registered by the networks using a shutter algorithm, confirms several important features proposed by microseismicity studies carried out between 1996 and 1998. A high level of seismicity inside and below of Rivera plate is observed, this fact suggest a very complex stress pattern acting on this plate. Shallow seismicity at south and east of Bahia de Banderas also suggest a complex stress pattern in this region of the Jalisco Block, events at more than 30 km depth are located under the mouth of the bay and in face of it, a feature denominated Banderas Boundary mark the change of the seismic regime at north of this latitude (20.75°N), however some shallow events were located at the region of Nayarit.

  1. Isostatic compression of buffer blocks. Middle scale

    Energy Technology Data Exchange (ETDEWEB)

    Ritola, J.; Pyy, E. [VTT Technical Research Centre of Finland, Espoo (Finland)


    Manufacturing of buffer components using isostatic compression method has been studied in small scale in 2008 (Laaksonen 2010). These tests included manufacturing of buffer blocks using different bentonite materials and different compression pressures. Isostatic mould technology was also tested, along with different methods to fill the mould, such as vibration and partial vacuum, as well as a stepwise compression of the blocks. The development of manufacturing techniques has continued with small-scale (30 %) blocks (diameter 600 mm) in 2009. This was done in a separate project: Isostatic compression, manufacturing and testing of small scale (D = 600 mm) buffer blocks. The research on the isostatic compression method continued in 2010 in a project aimed to test and examine the isostatic manufacturing process of buffer blocks at 70 % scale (block diameter 1200 to 1300 mm), and the aim was to continue in 2011 with full-scale blocks (diameter 1700 mm). A total of nine bentonite blocks were manufactured at 70 % scale, of which four were ring-shaped and the rest were cylindrical. It is currently not possible to manufacture full-scale blocks, because there is no sufficiently large isostatic press available. However, such a compression unit is expected to be possible to use in the near future. The test results of bentonite blocks, produced with an isostatic pressing method at different presses and at different sizes, suggest that the technical characteristics, for example bulk density and strength values, are somewhat independent of the size of the block, and that the blocks have fairly homogenous characteristics. Water content and compression pressure are the two most important properties determining the characteristics of the compressed blocks. By adjusting these two properties it is fairly easy to produce blocks at a desired density. The commonly used compression pressure in the manufacturing of bentonite blocks is 100 MPa, which compresses bentonite to approximately

  2. 5alpha-Reduced androgens block estradiol-BSA-stimulated release of oxytocin. (United States)

    Caldwell, Jack D; Song, Yan; Englöf, Ila; Höfle, Simone; Key, Mary; Morris, Mariana


    In this study we test the postulate that estradiol conjugated to bovine serum albumin (E-BSA) acts via receptors for the steroid-binding protein sex hormone binding globulin (SHBG) by attempting to block E-BSA-stimulated release of oxytocin with two antagonists of SHBG receptor actions: the 5alpha-reduced androgens dihydrotestosterone (DHT) and 3alpha-diol. Simultaneous superfusion with either DHT or 3alpha-diol significantly blocked E-BSA-stimulated release of oxytocin. We also found that a wide range of free 17beta-estradiol was unable to stimulate oxytocin release, suggesting that E-BSA stimulates receptors other than those for free estradiol to release oxytocin, perhaps SHBG receptors.

  3. Blocking of periodontal afferents with anesthesia and its influence on elevator EMG activity. (United States)

    Manns, A E; Garcia, C; Miralles, R; Bull, R; Rocabado, M


    The effect of anesthetic blocking of the periodontal afferents of the canine teeth was studied in order to determine its influence on any changes in the jaw elevation activity. Unilateral integrated EMG recordings were made of the masseter and anterior temporal muscles during maximal voluntary clenching in centric occlusion and laterotrusive position with canine contact. After anesthetic blocking of the periodontal afferents of one or both ipsilateral canines, a significant increase was observed of the EMG activity of both jaw elevator muscles studied, in centric occlusion as well as with canine contact. The elevator activity increase was of a greater magnitude when antagonistic canines were anesthetized. These findings thus support the hypothesis that high threshold periodontal receptors exert an inhibitory effect on jaw elevator muscular activity.

  4. Design and discovery of 1,3-benzodiazepines as novel dopamine antagonists. (United States)

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


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

  5. Dopamine D2 antagonist-induced striatal Nur77 expression requires activation of mGlu5 receptors by cortical afferents

    Directory of Open Access Journals (Sweden)

    Jérôme eMaheux


    Full Text Available Dopamine D2 receptor antagonists modulate gene transcription in the striatum. However, the molecular mechanism underlying this effect remains elusive. Here we used the expression of Nur77, a transcription factor of the orphan nuclear receptor family, as readout to explore the role of dopamine, glutamate and adenosine receptors in the effect of a dopamine D2 antagonist in the striatum. First, we investigated D2 antagonist-induced Nur77 mRNA in D2L receptor knockout mice. Surprisingly, deletion of the D2L receptor isoform did not reduce eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Next, we tested if an ibotenic acid-induced cortical lesion could block the effect of eticlopride on Nur77 expression. Cortical lesions strongly reduced eticlopride-induced striatal upregulation of Nur77 mRNA. Then, we investigated if glutamatergic neurotransmission could modulate eticlopride-induced Nur77 expression. A combination of a metabotropic glutamate type 5 (mGlu5 and adenosine A2A receptor antagonists abolished eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Direct modulation of Nur77 expression by striatal glutamate and adenosine receptors was confirmed using corticostriatal organotypic cultures. Taken together, these results indicate that blockade of postsynaptic D2 receptors is not sufficient to trigger striatal transcriptional activity and that interaction with corticostriatal presynaptic D2 receptors and subsequent activation of postsynaptic glutamate and adenosine receptors in the striatum is required. Thus, these results uncover an unappreciated role of presynaptic D2 heteroreceptors and support a prominent role of glutamate in the effect of D2 antagonists.

  6. A novel muscarinic antagonist R2HBJJ inhibits non-small cell lung cancer cell growth and arrests the cell cycle in G0/G1.

    Directory of Open Access Journals (Sweden)

    Nan Hua

    Full Text Available Lung cancers express the cholinergic autocrine loop, which facilitates the progression of cancer cells. The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers (SCLCs. In this study we intended to investigate the growth inhibitory effect of R2HBJJ, a novel muscarinic antagonist, on non-small cell lung cancer (NSCLC cells and the possible mechanisms. The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs. R2HBJJ presented a strong anticholinergic activity on carbachol-induced contraction of guinea-pig trachea. R2HBJJ markedly suppressed the growth of NSCLC cells, such as H1299, H460 and H157. In H1299 cells, both R2HBJJ and its leading compound R2-PHC displayed significant anti-proliferative activity as M3 receptor antagonist darifenacin. Exogenous replenish of ACh could attenuate R2HBJJ-induced growth inhibition. Silencing M3 receptor or ChAT by specific-siRNAs resulted in a growth inhibition of 55.5% and 37.9% on H1299 cells 96 h post transfection, respectively. Further studies revealed that treatment with R2HBJJ arrested the cell cycle in G0/G1 by down-regulation of cyclin D1-CDK4/6-Rb. Therefore, the current study reveals that NSCLC cells express an autocrine and paracrine cholinergic system which stimulates the growth of NSCLC cells. R2HBJJ, as a novel mAChRs antagonist, can block the local cholinergic loop by antagonizing predominantly M3 receptors and inhibit NSCLC cell growth, which suggest that M3 receptor antagonist might be a potential chemotherapeutic regimen for NSCLC.

  7. System Synthesis for Networks of Programmable Blocks

    CERN Document Server

    Mannion, Ryan; Cotterell, Susan; Vahid, Frank


    The advent of sensor networks presents untapped opportunities for synthesis. We examine the problem of synthesis of behavioral specifications into networks of programmable sensor blocks. The particular behavioral specification we consider is an intuitive user-created network diagram of sensor blocks, each block having a pre-defined combinational or sequential behavior. We synthesize this specification to a new network that utilizes a minimum number of programmable blocks in place of the pre-defined blocks, thus reducing network size and hence network cost and power. We focus on the main task of this synthesis problem, namely partitioning pre-defined blocks onto a minimum number of programmable blocks, introducing the efficient but effective PareDown decomposition algorithm for the task. We describe the synthesis and simulation tools we developed. We provide results showing excellent network size reductions through such synthesis, and significant speedups of our algorithm over exhaustive search while obtaining...

  8. Anti-calmodulins and tricyclic adjuvants in pain therapy block the TRPV1 channel. (United States)

    Oláh, Zoltán; Jósvay, Katalin; Pecze, László; Letoha, Tamás; Babai, Norbert; Budai, Dénes; Otvös, Ferenc; Szalma, Sándor; Vizler, Csaba


    Ca(2+)-loaded calmodulin normally inhibits multiple Ca(2+)-channels upon dangerous elevation of intracellular Ca(2+) and protects cells from Ca(2+)-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca(2+). Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca(2+)-uptake via the vanilloid inducible Ca(2+)-channel/inflamatory pain receptor 1 (TRPV1), which suggests that calmodulin inhibitors may block pore formation and Ca(2+) entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced (45)Ca(2+)-uptake at microM concentrations: calmidazolium (broad range) > or = trifluoperazine (narrow range) chlorpromazine/amitriptyline>fluphenazine>W-7 and W-13 (only partially). Most likely a short acidic domain at the pore loop of the channel orifice functions as binding site either for Ca(2+) or anti-calmodulin drugs. Camstatin, a selective peptide blocker of calmodulin, inhibits vanilloid-induced Ca(2+)-uptake in intact TRPV1(+) cells, and suggests an extracellular site of inhibition. TRPV1(+), inflammatory pain-conferring nociceptive neurons from sensory ganglia, were blocked by various anti-psychotic and anti-calmodulin drugs. Among them, calmidazolium, the most effective calmodulin agonist, blocked Ca(2+)-entry by a non-competitive kinetics, affecting the TRPV1 at a different site than the vanilloid binding pocket. Data suggest that various calmodulin antagonists dock to an extracellular site, not found in other Ca(2+)-channels. Calmodulin antagonist-evoked inhibition of TRPV1 and NMDA receptors/Ca(2+)-channels was validated by microiontophoresis of calmidazolium to laminectomised rat monitored with extracellular single unit recordings in vivo. These unexpected findings may explain empirically noted efficacy of clinical pain adjuvant therapy that justify efforts to develop hits into painkillers, selective to sensory Ca(2

  9. Anti-calmodulins and tricyclic adjuvants in pain therapy block the TRPV1 channel.

    Directory of Open Access Journals (Sweden)

    Zoltán Oláh

    Full Text Available Ca(2+-loaded calmodulin normally inhibits multiple Ca(2+-channels upon dangerous elevation of intracellular Ca(2+ and protects cells from Ca(2+-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca(2+. Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca(2+-uptake via the vanilloid inducible Ca(2+-channel/inflamatory pain receptor 1 (TRPV1, which suggests that calmodulin inhibitors may block pore formation and Ca(2+ entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced (45Ca(2+-uptake at microM concentrations: calmidazolium (broad range > or = trifluoperazine (narrow range chlorpromazine/amitriptyline>fluphenazine>>W-7 and W-13 (only partially. Most likely a short acidic domain at the pore loop of the channel orifice functions as binding site either for Ca(2+ or anti-calmodulin drugs. Camstatin, a selective peptide blocker of calmodulin, inhibits vanilloid-induced Ca(2+-uptake in intact TRPV1(+ cells, and suggests an extracellular site of inhibition. TRPV1(+, inflammatory pain-conferring nociceptive neurons from sensory ganglia, were blocked by various anti-psychotic and anti-calmodulin drugs. Among them, calmidazolium, the most effective calmodulin agonist, blocked Ca(2+-entry by a non-competitive kinetics, affecting the TRPV1 at a different site than the vanilloid binding pocket. Data suggest that various calmodulin antagonists dock to an extracellular site, not found in other Ca(2+-channels. Calmodulin antagonist-evoked inhibition of TRPV1 and NMDA receptors/Ca(2+-channels was validated by microiontophoresis of calmidazolium to laminectomised rat monitored with extracellular single unit recordings in vivo. These unexpected findings may explain empirically noted efficacy of clinical pain adjuvant therapy that justify efforts to develop hits into painkillers, selective to sensory Ca(2

  10. Lead optimization studies of cinnamic amide EP2 antagonists. (United States)

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


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

  11. Anti-antimicrobial peptides: folding-mediated host defense antagonists. (United States)

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


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

  12. Churg-Strauss syndrome associated with leukotriene receptor antagonists (LTRA). (United States)

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


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

  13. Potential Clinical Implications of the Urotensin II Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Emilie Kane


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

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

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen


    Considerable evidence has emerged to suggest that histamine participates in the regulation of the inflammatory response, immune reaction, coagulation cascade, and cardiovascular function. Furthermore, histamine may play a major role in the growth of normal and malignant tissue as a regulator...... of proliferation and angiogenesis. Specific histamine receptors have been identified on the surface of bone marrow cells, immune competent cells, endothelial cells, fibroblasts, and also on malignant cells. This has prompted research in regulation by specific histamine receptor agonists and antagonists. Results...... from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor...

  15. Non-imidazole histamine NO-donor H3-antagonists. (United States)

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


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

  16. General Floorplans with L/T-Shaped Blocks Using Corner Block List

    Institute of Scientific and Technical Information of China (English)

    Yu-Chun Ma; Xian-Long Hong; She-Qin Dong; C.K.Cheng; Jun Gu


    With the recent advent of deep submicron technology and new packing schemes, the components in the integrated circuit are often not rectangular. On the basis of the representation of Corner Block List (CBL), we propose a new method of handling rectilinear blocks. In this paper, the handling of the rectilinear blocks is simplified by transforming the L/T-shaped block problem into the align-abutment constraint problem. We devise the block rejoining process and block alignment operation for forming the L/T-shaped blocks into their original configurations. The shape flexibility of the soft blocks, and the rotation and reflection of L/T-shaped blocks are exploited to obtain a tight packing. The empty rooms are introduced to the process of block rejoining. The efficiency and effectiveness of the proposed method are demonstrated by the experimental results on a set of some benchmark examples.

  17. Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists (United States)


    Center for Substance Abuse Research Lewis Katz School of Medicine at Temple University 3500 N, Broad Street Philadelphia, PA 19140 AND ADDRESS(ES) 8...processes), affect the ability of opioid drugs to counteract pain. We predicted that one way of increasing the effectiveness of the pain-relieving... drugs would be to eliminate or reduce the activity of the chemokines by administering chemokine receptor antagonists (CRAs). The blockade of one or

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

    DEFF Research Database (Denmark)

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


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

  19. Exploration of a new series of PAR1 antagonists. (United States)

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


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

  20. Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine


    Funder JW


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

  1. N-methyl-D-aspartate antagonist activity of alpha- and beta-sulfallorphans. (United States)

    Shukla, V K; Lemaire, S


    Resolved equatorial (alpha) and axial (beta) forms of S-allylmorphinans, alpha-sulfallorphan and beta-sulfallorphan, were tested for their ability to compete with the binding of phencyclidine and sigma receptor ligands to mouse brain membranes and to antagonize N-methyl-D-aspartate (NMDA)-induced convulsions in mice. alpha- and beta-sulfallorphans displayed distinct binding affinities for phencyclidine and sigma sites, inhibiting the binding of [3H]-(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten++ +-5, 10-imine ([3H]MK-801) with Ki values of 2.32 and 0.13 microM and that of [3H](+)-pentazocine with Ki values of 1.97 and 1.61 microM, respectively. Intracerebroventricular administration of these compounds in mice caused dose-dependent inhibitions of NMDA-induced convulsions, but did not affect convulsions induced by (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainic acid and bicuculline. alpha- and beta-sulfallorphans blocked the convulsive activity of NMDA (1 nmol/mouse; intracerebroventricular) with ED50 values of 0.48 and 0.015 nmol/mouse, as compared with 0.55, 0.039 and 0.013 nmol/mouse for dextrorphan, MK-801 and (+/-)3-(2-carboxypiperazine-4yl)propyl-1-proprionic acid, respectively. The structurally related compound, dextrallorphan, significantly but less potently blocked NMDA-induced convulsions (ED60, 2.68 nmol/mouse). At the protective doses, alpha- and beta-sulfallorphans markedly reduced NMDA- and AMPA-induced mortality without inducing locomotion and falling behavior. These results indicate that alpha- and beta-sulfallorphans are potent and selective NMDA antagonists devoid of motor side effects at protective doses.

  2. Effects of the N-methyl-D-Aspartate receptor antagonist dextromethorphan on vibrotactile adaptation

    Directory of Open Access Journals (Sweden)

    Folger Stephen E


    Full Text Available Abstract Background Previous reports have demonstrated that short durations of vibrotactile stimuli (less than or equal to 2 sec effectively and consistently modify both the perceptual response in humans as well as the neurophysiological response in somatosensory cortex. The change in cortical response with adaptation has been well established by a number of studies, and other reports have extended those findings in determining that both GABA- and NMDAR-mediated neurotransmission play a significant role in the dynamic response of somatosensory cortical neurons. In this study, we evaluated the impact that dextromethorphan (DXM, an NMDAR antagonist, had on two distinct vibrotactile adaptation tasks. Results All subjects, both those that ingested 60 mg DXM and those that ingested placebo, were evaluated for their amplitude discriminative capacity between two simultaneously delivered vibrotactile stimuli both with and without 3 conditions of pre-exposure to adapting stimulation. The results demonstrated that the perceptual metrics of subjects who ingested 60 mg DXM were significantly altered from that of controls when the amplitude discrimination task followed one of the conditions of adapting stimulation. Without the condition of pre-exposure to an adapting stimulus (or stimuli, there was little difference between the observations obtained from the subjects that ingested DXM and controls. Peak impact on subject response occurred at 60 min post-ingestion, whereas the scores of controls who ingested placebo were not impacted. Conclusion The results – that DXM blocks vibrotactile adaptation – is consistent with the suggestion that NMDAR-mediated neurotransmission plays a significant role in the perceptual adaptive response. This finding is also consistent with neurophysiological findings that report observations of the effects of NMDAR block on the SI cortical response to repetitive vibrotactile stimulation.

  3. Effects of the N-methyl-D-Aspartate receptor antagonist dextromethorphan on vibrotactile adaptation (United States)

    Folger, Stephen E; Tannan, Vinay; Zhang, Zheng; Holden, Jameson K; Tommerdahl, Mark


    Background Previous reports have demonstrated that short durations of vibrotactile stimuli (less than or equal to 2 sec) effectively and consistently modify both the perceptual response in humans as well as the neurophysiological response in somatosensory cortex. The change in cortical response with adaptation has been well established by a number of studies, and other reports have extended those findings in determining that both GABA- and NMDAR-mediated neurotransmission play a significant role in the dynamic response of somatosensory cortical neurons. In this study, we evaluated the impact that dextromethorphan (DXM), an NMDAR antagonist, had on two distinct vibrotactile adaptation tasks. Results All subjects, both those that ingested 60 mg DXM and those that ingested placebo, were evaluated for their amplitude discriminative capacity between two simultaneously delivered vibrotactile stimuli both with and without 3 conditions of pre-exposure to adapting stimulation. The results demonstrated that the perceptual metrics of subjects who ingested 60 mg DXM were significantly altered from that of controls when the amplitude discrimination task followed one of the conditions of adapting stimulation. Without the condition of pre-exposure to an adapting stimulus (or stimuli), there was little difference between the observations obtained from the subjects that ingested DXM and controls. Peak impact on subject response occurred at 60 min post-ingestion, whereas the scores of controls who ingested placebo were not impacted. Conclusion The results – that DXM blocks vibrotactile adaptation – is consistent with the suggestion that NMDAR-mediated neurotransmission plays a significant role in the perceptual adaptive response. This finding is also consistent with neurophysiological findings that report observations of the effects of NMDAR block on the SI cortical response to repetitive vibrotactile stimulation. PMID:18796147

  4. Cryptanalysis of Selected Block Ciphers

    DEFF Research Database (Denmark)

    Alkhzaimi, Hoda A.

    thoroughly, no security assessment is given. We present a series of observations on the presented construction that, in some cases, yield attacks, while in other cases may provide basis of further analysis by the cryptographic community. Specifically, The attacks obtained are using classical- as well...... ciphers initiatives, and the Competition for Authenticated Encryption: Security, Applicability, and Robustness (CAESAR). In this thesis, we first present cryptanalytic results on different ciphers. We propose attack named the Invariant Subspace Attack. It is utilized to break the full block cipher...... PRINTcipher for a significant fraction of its keys. This new attack also gives us new insights into other, more well-established attacks. In addition, we also show that for weak keys, strongly biased linear approximations exists for any number of rounds. Furthermore, we provide variety of attacks...

  5. Approaches to the rational design of selective melanocortin receptor antagonists (United States)

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


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

  6. Synergistic and antagonistic drug combinations depend on network topology. (United States)

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


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

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

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    Sachiko Yamada

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

  8. IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα (United States)

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


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

  9. Histamine H1 antagonists and clinical characteristics of febrile seizures

    Directory of Open Access Journals (Sweden)

    Zolaly MA


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

  10. Receptor discrimination and control of agonist-antagonist binding. (United States)

    Tallarida, R J


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

  11. μ Opioid receptor: novel antagonists and structural modeling (United States)

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


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

  12. Newer calcium channel antagonists and the treatment of hypertension. (United States)

    Cummins, D F


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

  13. [Ultrasound for peripheral neural block]. (United States)

    Kefalianakis, F


    Ultrasound is well established in medicine. Unfortunately, ultrasound is still rarely used in the area of anesthesia. The purpose of the article is to illustrate the possibilities and limitations of ultrasound in regional anesthesia. The basic principles of ultrasound are the piezoelectric effect and the behaviour of acoustic waveforms in human tissue. Ultrasound imaging in medicine uses high frequency pulses of sound waves (2.5-10 MHz). The following images are built up from the reflected sounds. The ultrasound devices used in regional anesthesia (commonly by 10 MHz) deliver a two-dimensional view. The main step for a successful regional anaesthesia is to identify the exact position of the nerve. In addition, specific surface landmarks and the use of peripheral nerve stimulator help to detect the correct position of the needle. Nerves are demonstrated as an composition of hyperechogenic (white) and hypoechogenic (black) areas. The surrounding hyperechogenic parts are epi- and perineurium, the dark hypoechogenic part is the neural tissue. The composition of peripheral nerves are always similar, but the quantities of each part, of surrounding perineurium and nerval structures, differ. Further the imaging of nerves is significantly influenced by the angle of beam to the nerve and the surrounding anatomic structures. Only experience and correct interpretation make the ultrasound a valid method in clinical practice. Correct interpretation has to be learned by standardized education. Three examples of peripheral nerve blocks are described. The detection of nerves and the visualization of the correct spread of local anesthetics to the nerves are the main principles of effective ultrasound-guided regional anesthesia, whereas closest proximity of the needle to the target nerve is not necessary. The described examples of ultrasound guidance for nerval block illustrates the specific procedures with reduced probability of nerval irritation, high success and low rate of

  14. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia – critical appraisal of suvorexant (United States)

    Norman, Jessica L; Anderson, Sarah L


    Insomnia, a highly prevalent disorder, can be detrimental to patients’ overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra) is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of patients with chronic insomnia. PMID:27471419

  15. Anxiogenic and Stressor Effects of the Hypothalamic Neuropeptide RFRP-3 Are Overcome by the NPFFR Antagonist GJ14. (United States)

    Kim, Joon S; Brownjohn, Phil W; Dyer, Blake S; Beltramo, Massimiliano; Walker, Christopher S; Hay, Debbie L; Painter, Gavin F; Tyndall, Joel D A; Anderson, Greg M


    RFamide-related peptide-3 (RFRP-3) is a recently discovered neuropeptide that has been proposed to play a role in the stress response. We aimed to elucidate the role of RFRP-3 and its receptor, neuropeptide FF (NPFF1R), in modulation of stress and anxiety responses. To achieve this, we characterized a new NPFF1R antagonist because our results showed that the only commercially available putative antagonist, RF9, is in fact an agonist at both NPFF1R and the kisspeptin receptor (KISS1R). We report here the identification and pharmacological characterization of GJ14, a true NPFFR antagonist. In in vivo tests of hypothalamic-pituitary-adrenal (HPA) axis function, GJ14 completely blocked RFRP-3-induced corticosterone release and neuronal activation in CRH neurons. Furthermore, chronic infusion of GJ14 led to anxiolytic-like behavior, whereas RFRP-3 infusion had anxiogenic effects. Mice receiving chronic RFRP-3 infusion also had higher basal circulating corticosterone levels. These results indicate a stimulatory action of RFRP-3 on the HPA axis, consistent with the dense expression of NPFF1R in the vicinity of CRH neurons. Importantly, coinfusion of RFRP-3 and GJ14 completely reversed the anxiogenic and HPA axis-stimulatory effects of RFRP-3. Here we have established the role of RFRP-3 as a regulator of stress and anxiety. We also show that GJ14 can reverse the effects of RFRP-3 both in vitro and in vivo. Infusion of GJ14 causes anxiolysis, revealing a novel potential target for treating anxiety disorders.

  16. Antiproliferative effect of growth hormone-releasing hormone (GHRH antagonist on ovarian cancer cells through the EGFR-Akt pathway

    Directory of Open Access Journals (Sweden)

    Varga Jozsef


    Full Text Available Abstract Background Antagonists of growth hormone-releasing hormone (GHRH are being developed for the treatment of various human cancers. Methods MTT assay was used to test the proliferation of SKOV3 and CaOV3. The splice variant expression of GHRH receptors was examined by RT-PCR. The expression of protein in signal pathway was examined by Western blotting. siRNA was used to block the effect of EGFR. Results In this study, we investigated the effects of a new GHRH antagonist JMR-132, in ovarian cancer cell lines SKOV3 and CaOV3 expressing splice variant (SV1 of GHRH receptors. MTT assay showed that JMR-132 had strong antiproliferative effects on SKOV3 and CaOV3 cells in both a time-dependent and dose-dependent fashion. JMR-132 also induced the activation and increased cleaved caspase3 in a time- and dose-dependent manner in both cell lines. In addition, JMR-132 treatments decreased significantly the epidermal growth factor receptor (EGFR level and the phosphorylation of Akt (p-Akt, suggesting that JMR-132 inhibits the EGFR-Akt pathway in ovarian cancer cells. More importantly, treatment of SKOV3 and CaOV3 cells with 100 nM JMR-132 attenuated proliferation and the antiapoptotic effect induced by EGF in both cell lines. After the knockdown of the expression of EGFR by siRNA, the antiproliferative effect of JMR-132 was abolished in SKOV3 and CaOV3 cells. Conclusions The present study demonstrates that the inhibitory effect of the GHRH antagonist JMR-132 on proliferation is due, in part, to an interference with the EGFR-Akt pathway in ovarian cancer cells.

  17. Interactions between an alpha2-adrenergic antagonist and a beta3-adrenergic agonist on the expression of UCP2 and UCP3 in rats.



    This experimental trial was devised to assess whether selective β3-adrenergic receptor (AR) stimulation and simultaneous blockade of α2-AR would affect thermoregulation. With this purpose, the individual and combined administration of a β3-AR agonist, trecadrine, and an α2-AR antagonist, yohimbine, were evaluated. Yohimbine produced a marked decrease (p < 0.001) in body temperature one hour after administration (5 mg kg−1, i.p.) and blocked the thermogenic effect of trecadrine (1 mg kg−1, i.p...

  18. Kinetic modeling of 11C-LY2795050, a novel antagonist radiotracer for PET imaging of the kappa opioid receptor in humans


    Naganawa, Mika; Zheng, Ming-Qiang; Nabulsi, Nabeel; Tomasi, Giampaolo; Henry, Shannan; Lin, Shu-Fei; Ropchan, Jim; Labaree, David; Tauscher, Johannes; Neumeister, Alexander; Carson, Richard E.; Huang, Yiyun


    11C-LY2795050 is a novel kappa opioid receptor (KOR) antagonist tracer for positron emission tomography (PET) imaging. The purpose of this first-in-human study was to determine the optimal kinetic model for analysis of 11C-LY2795050 imaging data. Sixteen subjects underwent baseline scans and blocking scans after oral naltrexone. Compartmental modeling and multilinear analysis-1 (MA1) were applied using the arterial input functions. Two-tissue compartment model and MA1 were found to be the bes...

  19. Concise and enantioselective synthesis of Fmoc-Pmp(But)2-OH and design of potent Pmp-containing Grb2-SH2 domain antagonists. (United States)

    Li, Peng; Zhang, Manchao; Peach, Megan L; Liu, Hongpeng; Yang, Dajun; Roller, Peter P


    [reaction: see text] L-Phosphonomethylphenylalanine (L-Pmp) is an important phosphatase-resistant pTyr analogue. A most concise and stereoselective approach to the synthesis of the suitably protected Fmoc-Pmp(Bu(t))(2)-OH was developed in order to incorporate the functionally significant L-Pmp residue into peptides and peptidomimetics efficiently using standard Fmoc protocol. With this key building block, we are able to efficiently synthesize a series of potent Pmp-containing Grb2-SH2 domain antagonists, which can be used as chemotherapeutic leads for the treatment of erbB2-overexpressed breast cancer.

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

    Institute of Scientific and Technical Information of China (English)

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


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

  1. Effects of excitatory amino acid antagonists on evoked and spontaneous excitatory potentials in guinea-pig hippocampus. (United States)

    Cotman, C W; Flatman, J A; Ganong, A H; Perkins, M N


    Evoked and spontaneous excitatory post-synaptic potentials (e.p.s.p.s) at the mossy fibre input to CA3 pyramidal neurones were recorded intracellularly in slices from the guinea-pig hippocampus. The effects of several amino acid antagonists on these responses were examined. L-2-amino-4-phosphonobutyrate (L-AP4), L-serine-O-phosphate (L-SOP), kynurenate, and N-(p-bromobenzoyl)piperazine-2,3-dicarboxylate (pBB-PzDA) reduced the amplitude of evoked mossy fibre e.p.s.p.s without affecting membrane potential or input resistance. Antagonism of mossy fibre spontaneous miniature e.p.s.p.s (m.e.p.s.p.s) by these compounds fell into two groups. L-AP4 and L-SOP applied at concentrations that blocked evoked e.p.s.p.s did not affect amplitude distributions of spontaneous m.e.p.s.p.s. Kynurenate and pBB-PzDA significantly affected the amplitude distributions and reduced the mean amplitude of spontaneous m.e.p.s.p.s. These results are consistent with a presynaptic site of action for L-AP4 and L-SOP and a post-synaptic site of action for kynurenate and pBB-PzDA as antagonists of e.p.s.p.s at the guinea-pig mossy fibre-CA3 pyramidal neurone synapse.

  2. Apoptosis and the FLIP and NF-kappa B proteins as pharmacodynamic criteria for biosimilar TNF-alpha antagonists

    Directory of Open Access Journals (Sweden)

    Urbano PCM


    Full Text Available Paulo César Martins Urbano,1 Vanete Thomaz Soccol,1 Valderilio Feijó Azevedo2 1Biotechnology and Bioprocess Engineering Program, Federal University of Parana, Curitiba, Parana, Brazil; 2Hospital de Clínicas, Federal University of Parana, Curitiba, Parana, Brazil Abstract: Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale. The imminent expiration of the patents on reference biological products which block the cytokine TNF-α (tumor necrosis factor-α raises the possibility of bringing so-called biosimilars to the market (similar to the biologicals of reference products. This occurrence is inevitable, but criteria to adequately evaluate these medications are now needed. Even among controversy, there is a demand from publications correlating the pro-apoptotic mechanism of the original TNF-α antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol in the treatment of rheumatoid arthritis and other diseases. In this article, the authors discuss the possibility of utilizing the pro-apoptotic effect correlated with the regulation of the anti-apoptotic proteins FLIP and NF-κB as new criteria for analyzing the pharmacodynamics of possible biosimilar TNF-α antagonists which should be submitted to regulatory agencies for evaluation. Keywords: anti-TNF drugs, rheumatoid arthritis, apoptosis, NF-κB, FLIP

  3. Apoptosis and the FLIP and NF-kappa B proteins as pharmacodynamic criteria for biosimilar TNF-alpha antagonists. (United States)

    Urbano, Paulo César Martins; Soccol, Vanete Thomaz; Azevedo, Valderilio Feijó


    Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale. The imminent expiration of the patents on reference biological products which block the cytokine TNF-α (tumor necrosis factor-α) raises the possibility of bringing so-called biosimilars to the market (similar to the biologicals of reference products). This occurrence is inevitable, but criteria to adequately evaluate these medications are now needed. Even among controversy, there is a demand from publications correlating the pro-apoptotic mechanism of the original TNF-α antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) in the treatment of rheumatoid arthritis and other diseases. In this article, the authors discuss the possibility of utilizing the pro-apoptotic effect correlated with the regulation of the anti-apoptotic proteins FLIP and NF-κB as new criteria for analyzing the pharmacodynamics of possible biosimilar TNF-α antagonists which should be submitted to regulatory agencies for evaluation.

  4. Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.

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    Fouad Brahimi

    Full Text Available A library of peptidomimetics was assembled combinatorially into dimers on a triazine-based core. The pharmacophore corresponds to β-turns of the neurotrophin polypeptides neurotrophin-3 (NT-3, nerve growth factor (NGF, or brain-derived neurotrophic factor (BDNF. These are the natural ligands for TrkC, TrkA, and TrkB receptors, respectively. The linker length and the side-chain orientation of each monomer within the bivalent mimics were systematically altered, and the impact of these changes on the function of each ligand was evaluated. While the monovalent peptidomimetics had no detectable binding or bioactivity, four bivalent peptidomimetics (2c, 2d, 2e, 3f are selective TrkC ligands with antagonistic activity, and two bivalent peptidomimetics (1a, 1b are TrkC and TrkA ligands with antagonistic activity. All these bivalent compounds block ligand-dependent receptor activation and cell survival, without affecting neuritogenic differentiation. This work adds to our understanding of how the neurotrophins function through Trk receptors, and demonstrates that peptidomimetics can be designed to selectively disturb specific biological signals, and may be used as pharmacological probes or as therapeutic leads. The concept of altering side-chain, linker length, and sequence orientation of a subunit within a pharmacophore provides an easy modular approach to generate larger libraries with diversified bioactivity.

  5. Combined drug therapy in porcine endotoxemia. Hemodynamic and proteolytic effects of antagonists against histamine, serotonin and endorphin. (United States)

    Naess, F; Roeise, O; Stadaas, J O; Aasen, A O


    In order to investigate the importance of potential mediators of pathophysiologic derangements in endotoxemia, we have examined the effects of the combined administration of antagonists against histamine, serotonin and endorphins in a porcine model of endotoxemia. The treatment regimen significantly reduced the increase in pulmonary artery pressure, pulmonary vascular resistance and systemic arterial pressure seen in the early stages of endotoxemia. Also, cardiac output was better maintained. However, the hemodynamic performance after an observation period of 5 h was not statistically different from untreated animals. The treatment regimen did not hinder the activation of the kallikreinkinin and fibrinolytic systems of plasma, which was evident in both treated and untreated animals, and could not counteract the increase in hematocrit or leukopenia seen in this model. This study shows that the combined blocking of histamine, serotonin and endorphines is not enough to abrogate the detrimental effects of endotoxin in a porcine model.

  6. Effects of the NMDA receptor antagonists on deltamethrin-induced striatal dopamine release in conscious unrestrained rats. (United States)

    Morikawa, Takuya; Furuhama, Kazuhisa


    To better understand the neurotoxicity caused by the pyrethroid pesticide, we examined the effects of the N-methyl-D-aspartate (NMDA) receptor antagonists MK-801, a non-competitive cation channel blocker, and 2-amino-5-phosphonovaleric acid (APV), a competitive Na(+) channel blocker, on extracellular dopamine levels in male Sprague-Dawley rats receiving the type II pyrethroid deltamethrin using an in vivo microdialysis system. Deltamethrin (60 mg/kg, i.p.) evidently increased striatal dopamine levels with a peak time of 120 min, and the local infusion (i.c.) of either MK-801(650 muM) or APV (500 muM) completely blocked these actions. The fluctuation in the dopamine metabolite 3-MT also resembled that in dopamine. Our results suggest that dopamine-releasing neurons would be modulated via the NMDA receptor by the excitatory glutamatergic neurons after deltamethrin treatment.

  7. Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. (United States)

    Hargreaves, Richard; Ferreira, Juan Camilo Arjona; Hughes, David; Brands, Jos; Hale, Jeff; Mattson, Britta; Mills, Sandy


    Chemotherapy can be a life-prolonging treatment for many cancer patients, but it is often associated with profound nausea and vomiting that is so distressing that patients may delay or decline treatment to avoid these side effects. EMEND (aprepitant) is the first and only neurokinin-1 (NK-1) receptor antagonist available on the market for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Aprepitant acts centrally at NK-1 receptors in vomiting centers within the central nervous system to block their activation by substance P released as an unwanted consequence of chemotherapy. By controlling nausea and vomiting, EMEND helps improve patients' daily living and their ability to complete multiple cycles of chemotherapy. The development of aprepitant included a novel nanoparticle formulation to optimize oral absorption and innovative chemistry to discover a prodrug form suitable for intravenous administration to improve compliance and convenience for healthcare professionals and cancer patients.

  8. LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury. (United States)

    Ji, Benxiu; Li, Mingwei; Wu, Wu-Tian; Yick, Leung-Wah; Lee, Xinhua; Shao, Zhaohui; Wang, Joy; So, Kwok-Fai; McCoy, John M; Pepinsky, R Blake; Mi, Sha; Relton, Jane K


    LINGO-1 is a CNS-specific protein and a functional component of the NgR1/p75/LINGO-1 and NgR1/TAJ(TROY)/LINGO-1 signaling complexes that mediate inhibition of axonal outgrowth. These receptor complexes mediate the axonal growth inhibitory effects of Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp) via RhoA activation. Soluble LINGO-1 (LINGO-1-Fc), which acts as an antagonist of these pathways by blocking LINGO-1 binding to NgR1, was administered to rats after dorsal or lateral hemisection of the spinal cord. LINGO-1-Fc treatment significantly improved functional recovery, promoted axonal sprouting and decreased RhoA activation and increased oligodendrocyte and neuronal survival after either rubrospinal or corticospinal tract transection. These experiments demonstrate an important role for LINGO-1 in modulating axonal outgrowth in vivo and that treatment with LINGO-1-Fc can significantly enhance recovery after spinal cord injury.

  9. Interleukin-1 receptor antagonist suppresses neurotrophin response in injured rat brain. (United States)

    DeKosky, S T; Styren, S D; O'Malley, M E; Goss, J R; Kochanek, P; Marion, D; Evans, C H; Robbins, P D


    Traumatic brain injury (TBI) induces astrocytic and microglial activation and proliferation and augmented production of the cytokine interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF). The increase in NGF temporally follows the increase in IL-1 beta, suggesting that the IL-1 beta up-regulation after trauma directly induces the increase in NGF. We examined the effect of IL-1 receptor antagonist protein (IL-1ra) on microglial proliferation and NGF production in rat cortex, following two different models of TBI. Rabbit fibroblasts infected with a retroviral vector containing the human IL-1ra gene were implanted into the wound cavity immediately following a cortical stab wound or 6 hours after a weight drop-induced trauma. Both microglial proliferation and NGF up-regulation were decreased significantly in animals receiving IL-1ra-expressing cells compared with animals receiving naive (untransfected) fibroblasts. These data demonstrate that the increase in NGF after central nervous system trauma is directly mediated through IL-1 beta and that blocking IL-1 beta following brain injury leads to suppression of an NGF-mediated reparative response. Such blockade of inflammation, however, may prove to be of significant therapeutic benefit in human brain injury and other inflammatory states.

  10. Therapy for acute pancreatitis with platelet-activating factor receptor antagonists

    Institute of Scientific and Technical Information of China (English)

    Chong Chen; Shi-Hai Xia; Hong Chen; Xiao-Hong Li


    Acute pancreatitis (AP) causes release of plateletactivating factor (PAF),which induces systemic effects that contribute to circulatory disturbances and multiple organ failure.PAF is a cell surface secretion of bioactive lipid,which could produce physiological and pathological effects by binding to its cell surface receptor called platelet-activating factor receptor (PAF-R).Studies showed that PAF participates in the occurrence and development of AP and administration of platelet-activating factor receptor antagonists (PAF-RAs) could significantly reduce local and systemic events after AP.PAF has also been implicated as a key mediator in the progression of severe AP,which can lead to complications and unacceptably high mortality rates.Several classes of PAF-RA show PAFRAs significant local and systemic effects on reducing inflammatory changes.As a preventive treatment,PAF-RA could block a series of PAF-mediatedinflammatory injury and thus improve the prognosis of AR This review introduces the important role of PAF-RA in the treatment of AP.

  11. The Antiinflammatory Cytokine Interleukin-1 Receptor Antagonist Protects from High-Fat Diet-Induced Hyperglycemia (United States)

    Sauter, Nadine S.; Schulthess, Fabienne T.; Galasso, Ryan; Castellani, Lawrence W.; Maedler, Kathrin


    Subclinical inflammation is a recently discovered phenomenon in type 2 diabetes. Elevated cytokines impair β-cell function and survival. A recent clinical trial shows that blocking IL-1β signaling by IL-1 receptor antagonist (IL-1Ra) improves β-cell secretory function in patients with type 2 diabetes. In the present study, we provide further mechanisms of the protective role of IL-1Ra on the β-cell. IL-1Ra prevented diabetes in vivo in C57BL/6J mice fed a high-fat/high-sucrose diet (HFD) for 12 wk; it improved glucose tolerance and insulin secretion. High-fat diet treatment increased serum levels of free fatty acids and of the adipokines resistin and leptin, which were reduced by IL-1Ra treatment. In addition, IL-1Ra counteracted adiponectin levels, which were decreased by high-fat feeding. Studies on isolated islets revealed that IL-1Ra specifically acted on the β-cell. IL-1Ra protected islets from HFD treated animals from β-cell apoptosis, induced β-cell proliferation, and improved glucose-stimulated insulin secretion. Insulin mRNA was reduced in islets from mice fed a HFD but normalized in the IL-1Ra group. Our results show that IL-1Ra improves β-cell survival and function, and support the potential role for IL-1Ra in the treatment of diabetes. PMID:18239070

  12. Chemokine receptor CCR5 antagonist maraviroc: medicinal chemistry and clinical applications. (United States)

    Xu, Guoyan G; Guo, Jia; Wu, Yuntao


    The human immunodeficiency virus (HIV) causes acquired immumodeficiency syndrome (AIDS), one of the worst global pandemic. The virus infects human CD4 T cells and macrophages, and causes CD4 depletion. HIV enters target cells through the binding of the viral envelope glycoprotein to CD4 and the chemokine coreceptor, CXCR4 or CCR5. In particular, the CCR5-utilizing viruses predominate in the blood during the disease course. CCR5 is expressed on the surface of various immune cells including macrophages, monocytes, microglia, dendric cells, and active memory CD4 T cells. In the human population, the CCR5 genomic mutation, CCR5Δ32, is associated with relative resistance to HIV. These findings paved the way for the discovery and development of CCR5 inhibitors to block HIV transmission and replication. Maraviroc, discovered as a CCR5 antagonist, is the only CCR5 inhibitor that has been approved by both US FDA and the European Medicines Agency (EMA) for treating HIV/AIDS patients. In this review, we summarize the medicinal chemistry and clinical studies of Maraviroc.

  13. [Calcium antagonists in anesthesia. Additive analgesia using nimodipine in heart surgery]. (United States)

    von Bormann, B; Boldt, J; Sturm, G; Kling, D; Weidler, B; Lohmann, E; Hempelmann, G


    Stress and pain induced by surgical trauma seem to be attenuated when calcium antagonists have been applied. In order to ascertain the effect of nimodipine, a new strong acting calcium channel blocker on plasma levels of various stress hormones twenty patients undergoing cardiovascular surgery where investigated in two groups. Ten patients received high-dose fentanyl anaesthesia (mean: 2,45 mg fentanyl/patient), whereas another ten patients were treated with 0,1 mg fentanyl/patient in addition to nimodipine 1,0 micrograms/kgbw X min (from onset of anaesthesia until start of extracorporeal circulation). Between the two groups were no significant differences with respect to perioperative course and postoperative demand for analgetics. Plasma levels of ACTH, somatotropin, glucose and free glycerol were markedly elevated in all patients (n = 20) intra- and postoperatively, whereas cortisol and prolactin remained unchanged. The present data suggest an additive analgesic effect of nimodipine during surgery. This phenomenon is possibly due to a blocking effect of calcium channel blockers on nociceptive nerves. The present model assumes that calcium is essential in pain perception and that decreased calcium would result in analgesia.

  14. Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

    Directory of Open Access Journals (Sweden)

    John D. Chan


    Full Text Available 5-hydroxytryptamine (5-HT is a key regulator of muscle contraction in parasitic flatworms. In Schistosoma mansoni, the myoexcitatory action of 5-HT is effected through activation of a serotonergic GPCR (Sm.5HTRL, prioritizing pharmacological characterization of this target for anthelmintic drug discovery. Here, we have examined the effects of several aporphine alkaloids on the signaling activity of a heterologously expressed Sm.5HTRL construct using a cAMP biosensor assay. Four structurally related natural products – nuciferine, D-glaucine, boldine and bulbocapnine – were demonstrated to block Sm.5HTRL evoked cAMP generation with the potency of GPCR blockade correlating well with the ability of each drug to inhibit contractility of schistosomule larvae. Nuciferine was also effective at inhibiting both basal and 5-HT evoked motility of adult schistosomes. These data advance our understanding of structure-affinity relationships at Sm.5HTRL, and demonstrate the effectiveness of Sm.5HTRL antagonists as hypomotility-evoking drugs across different parasite life cycle stages.

  15. Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination. (United States)

    Qiao, Huanyu; Prasada Rao, H B D; Yang, Ye; Fong, Jared H; Cloutier, Jeffrey M; Deacon, Dekker C; Nagel, Kathryn E; Swartz, Rebecca K; Strong, Edward; Holloway, J Kim; Cohen, Paula E; Schimenti, John; Ward, Jeremy; Hunter, Neil


    Crossover recombination facilitates the accurate segregation of homologous chromosomes during meiosis. In mammals, poorly characterized regulatory processes ensure that every pair of chromosomes obtains at least one crossover, even though most recombination sites yield non-crossovers. Designation of crossovers involves selective localization of the SUMO ligase RNF212 to a minority of recombination sites, where it stabilizes pertinent factors such as MutSγ (ref. 4). Here we show that the ubiquitin ligase HEI10 (also called CCNB1IP1) is essential for this crossover/non-crossover differentiation process. In HEI10-deficient mice, RNF212 localizes to most recombination sites, and dissociation of both RNF212 and MutSγ from chromosomes is blocked. Consequently, recombination is impeded, and crossing over fails. In wild-type mice, HEI10 accumulates at designated crossover sites, suggesting that it also has a late role in implementing crossing over. As with RNF212, dosage sensitivity for HEI10 indicates that it is a limiting factor for crossing over. We suggest that SUMO and ubiquitin have antagonistic roles during meiotic recombination that are balanced to effect differential stabilization of recombination factors at crossover and non-crossover sites.

  16. Recombinant interleukin-1 receptor antagonist attenuates the severity of chronic pancreatitis induced by TNBS in rats. (United States)

    Xu, Chunfang; Shen, Jiaqing; Zhang, Jing; Jia, Zhenyu; He, Zhilong; Zhuang, Xiaohui; Xu, Ting; Shi, Yuqi; Zhu, Shunying; Wu, Mingyuan; Han, Wei


    Chronic pancreatitis (CP) is a common disease in the department of gastroenterology, with the main symptoms of exocrine and/or endocrine insufficiency and abdominal pain. The pathogenic mechanism of CP is still not fully clarified and the aims of treatment now are to relieve symptoms. In this study, we attempted to find a connection between interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1Ra) in trinitrobenzene sulfonic acid (TNBS)-induced chronic pancreatitis, and then the therapeutic effect of recombinant IL-1Ra was also detected in the CP model. Chronic pancreatitis was induced by intraductal infusion of TNBS in SD rats followed by a consecutive administration of rIL-1Ra, and the histological changes and collagen content in the pancreas were measured, as well as the abdominal hypersensitivity. We found that rhIL-1Ra could attenuate the severity of chronic pancreatic injury, modulate the extracellular matrix secretion, focal proliferation and apoptosis, and cellular immunity in TNBS-induced CP. Interestingly, rIL-1Ra could also block the pancreatitis-induced referred abdominal hypersensitivity. In conclusion, IL-1Ra may play a protective role in CP and rIL-1Ra would be a potential therapeutic target for the treatment of CP, while its possible mechanisms and clinical usage still need further investigation.

  17. Anti free radical action of calcium antagonists and H1 and H2 receptors antagonists in neoplastic disease. (United States)

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


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

  18. Conformational studies of 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists leading to new spirocyclic antagonists. (United States)

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


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

  19. Interactions between permeant and blocking anions inside the CFTR chloride channel pore. (United States)

    Linsdell, Paul


    Binding of cytoplasmic anionic open channel blockers within the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is antagonized by extracellular Cl(-). In the present work, patch clamp recording was used to investigate the interaction between extracellular Cl(-) (and other anions) and cytoplasmic Pt(NO2)4(2-) ions inside the CFTR channel pore. In constitutively open (E1371Q-CFTR) channels, these different anions bind to two separate sites, located in the outer and inner vestibules of the pore respectively, in a mutually antagonistic fashion. A mutation in the inner vestibule (I344K) that greatly increased Pt(NO2)4(2-) binding affinity also greatly strengthened antagonistic Cl(-):blocker interactions as well as the voltage-dependence of block. Quantitative analysis of ion binding affinity suggested that the I344K mutation strengthened interactions not only with intracellular Pt(NO2)4(2-) ions but also with extracellular Cl(-), and that altered blocker Cl(-)- and voltage-dependence were due to the introduction of a novel type of antagonistic ion:ion interaction inside the pore that was independent of Cl(-) binding in the outer vestibule. It is proposed that this mutation alters the arrangement of anion binding sites inside the pore, allowing both Cl(-) and Pt(NO2)4(2-) to bind concurrently within the inner vestibule in a strongly mutually antagonistic fashion. However, the I344K mutation does not increase single channel conductance following disruption of Cl(-) binding in the outer vestibule in R334Q channels. Implications for the arrangement of ion binding sites in the pore, and their functional consequences for blocker binding and for rapid Cl(-) permeation, are discussed.

  20. Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like activity. (United States)

    Galici, Ruggero; Boggs, Jamin D; Miller, Kirsten L; Bonaventure, Pascal; Atack, John R


    5-HT7 receptors have been linked to a number of psychiatric disorders including anxiety and depression. The localization of 5-HT7 receptors in the thalamus, a key sensory processing center, and the high affinity of many atypical antipsychotic compounds for these receptors have led to the speculation of the utility of 5-HT7 antagonists in schizophrenia. The goal of these studies was to examine the effects of pharmacologic blockade and genetic ablation of 5-HT7 receptors in animal models predictive of antipsychotic-like activity. We evaluated the effects of SB-269970, a selective 5-HT7 receptor antagonist, on amphetamine and ketamine-induced hyperactivity and prepulse inhibition (PPI) deficits. In addition, sensorimotor gating function and locomotor activity were evaluated in 5-HT7 knockout mice. Locomotor activity was measured for up to 180 min using an automated infrared photobeam system, and PPI was evaluated in startle chambers. SB-269970 (3, 10 and 30 mg/kg, intraperitoneally) significantly blocked amphetamine [3 mg/kg, subcutaneously (s.c.)] and ketamine (30 mg/kg, s.c.)-induced hyperactivity and reversed amphetamine (10 mg/kg, s.c.)-induced but not ketamine (30 mg/kg, s.c.)-induced PPI deficits, without changing spontaneous locomotor activity and startle amplitude. The largest dose of SB-269970 did not block the effects of amphetamine in 5-HT7 knockout mice. Collectively, these results indicate that blockade of 5-HT7 receptors partially modulates glutamatergic and dopaminergic function and could be clinically useful for the treatment of positive symptoms of schizophrenia.

  1. The nucleocapsid protein of measles virus blocks host interferon response

    Energy Technology Data Exchange (ETDEWEB)

    Takayama, Ikuyo; Sato, Hiroki; Watanabe, Akira; Omi-Furutani, Mio; Sugai, Akihiro; Kanki, Keita; Yoneda, Misako; Kai, Chieko, E-mail:


    Measles virus (MV) belongs to the genus Morbillivirus of the family Paramyxoviridae. A number of paramyxoviruses inhibit host interferon (IFN) signaling pathways in host immune systems by various mechanisms. Inhibition mechanisms have been described for many paramyxoviruses. Although there are inconsistencies among previous reports concerning MV, it appears that P/V/C proteins interfere with the pathways. In this study, we confirmed the effects of MV P gene products of a wild MV strain on IFN pathways and examined that of other viral proteins on it. Interestingly, we found that N protein acts as an IFN-{alpha}/{beta} and {gamma}-antagonist as strong as P gene products. We further investigated the mechanisms of MV-N inhibition, and revealed that MV-N blocks the nuclear import of activated STAT without preventing STAT and Jak activation or STAT degradation, and that the nuclear translocation of MV-N is important for the inhibition. The inhibitory effect of the N protein was observed as a common feature of other morbilliviruses. The results presented in this report suggest that N protein of MV as well as P/V/C proteins is involved in the inhibition of host IFN signaling pathways.

  2. Efficient Distribution of Triggered Synchronous Block Diagrams (United States)


    called a trigger. At a given synchronous step, if the trigger is true , the block fires normally; otherwise, the block stutters , that is, keeps its...outputs have the same value as in the previous step, but they are still transmitted to downstream blocks. In this paper we present an implementation...optimizations that apply to general Triggered SBDs, we also present further optimizations for the case of Timed SBDs. 1.1 Motivating Examples Fig. 1

  3. Advanced heart block in acute rheumatic fever. (United States)

    Hubail, Zakariya; Ebrahim, Ishaq M


    First degree heart block is considered a minor criterion for the diagnosis of this condition. The cases presented here demonstrate that higher degrees of heart block do occur in rheumatic fever. Children presenting with acquired heart block should be worked-up for rheumatic fever. Likewise, it is imperative to serially follow the electrocardiogram in patients already diagnosed with acute rheumatic fever, as the conduction abnormalities can change during the course of the disease.

  4. Advanced heart block in acute rheumatic fever



    First degree heart block is considered a minor criterion for the diagnosis of this condition. The cases presented here demonstrate that higher degrees of heart block do occur in rheumatic fever. Children presenting with acquired heart block should be worked-up for rheumatic fever. Likewise, it is imperative to serially follow the electrocardiogram in patients already diagnosed with acute rheumatic fever, as the conduction abnormalities can change during the course of the disease.

  5. Selective blockade of drug-induced place preference conditioning by ACPC, a functional NDMA-receptor antagonist. (United States)

    Papp, Marius; Gruca, Piotr; Willner, Paul


    ACPC (1-aminocyclopropanecarboxylic acid) is a partial agonist at the strychnine-insensitive glycine receptor site on the NMDA receptor complex, and a functional NMDA antagonist. A series of experiments was conducted to assess the effects of ACPC in a biased place conditioning paradigm. As previously reported, ACPC itself did not support either appetitive or aversive place conditioning. However, co-administration of ACPC (200 mg/kg) blocked the acquisition of place preferences conditioned using a variety of psychoactive drugs (amphetamine, cocaine, nomifensine, diazepam, morphine, nicotine). No tolerance was seen to this effect following two weeks of chronic ACPC administration. Overall, ACPC did not affect the expression of place conditioning when administered immediately before the post-conditioning test. However, these effects appeared somewhat variable between drugs, and further analysis showed that ACPC did block the expression of preferences conditioned with some drugs (diazepam, morphine, nicotine), but not others (amphetamine, cocaine, nomifensine). The effects of ACPC could not be accounted for by state dependence, as ACPC blocked morphine and cocaine place preferences when administered during both the acquisition and the expression phase of conditioning. In contrast to the blockade by ACPC of drug-induced place preferences, ACPC had no effect on the acquisition of place preferences conditioned using a variety of natural non-drug reinforcers (food, sucrose, social interaction, novelty). ACPC also had no effect on the acquisition of drug-induced place aversions (naloxone, picrotoxin). Thus, ACPC selectively blocked appetitive conditioning by drug reinforcers, without affecting either appetitive conditioning by natural reinforcers or drug-induced aversions. As place preference conditioning has been demonstrated to have high predictive validity for detecting compounds with an abuse potential in humans, this selective action suggests that ACPC might have some

  6. Using Interference to Block RFID Tags

    DEFF Research Database (Denmark)

    Krigslund, Rasmus; Popovski, Petar; Pedersen, Gert Frølund

    We propose a novel method to block RFID tags from responding, using intentional interference. We focus on the experimental evaluation, where we impose interference on the download and uplink, respectively. The results are positive, where modulated CCI shows most effective to block a tag.......We propose a novel method to block RFID tags from responding, using intentional interference. We focus on the experimental evaluation, where we impose interference on the download and uplink, respectively. The results are positive, where modulated CCI shows most effective to block a tag....

  7. Modelling of multi-block data

    DEFF Research Database (Denmark)

    Høskuldsson, Agnar; Svinning, K.


    Here is presented a unified approach to modelling multi-block regression data. The starting point is a partition of the data X into L data blocks, X = (X-1, X-2,...X-L), and the data Y into M data-blocks, Y = (Y-1, Y-2,...,Y-M). The methods of linear regression, X -> Y, are extended to the case...... these methods can be extended to a network of data blocks. Examples of the optimisation procedures in a network are shown. The examples chosen are the ones that are useful to work within industrial production environments. The methods are illustrated by simulated data and data from cement production....

  8. A New Relationship between Block Designs

    Directory of Open Access Journals (Sweden)

    Alexander Shramchenko


    Full Text Available We propose a procedure of constructing new block designs starting from a given one by looking at the intersections of its blocks with various sets and grouping those sets according to the structure of the intersections. We introduce a symmetric relationship of friendship between block designs built on a set V and consider families of block designs where all designs are friends of each other, the so-called friendly families. We show that a friendly family admits a partial ordering. Furthermore, we exhibit a map from the power set of V, partially ordered by inclusion, to a friendly family of a particular type which preserves the partial order.

  9. Recent developments in paediatric neuraxial blocks

    Directory of Open Access Journals (Sweden)

    Vrushali Chandrashekhar Ponde


    Full Text Available Paediatric anaesthesia and paediatric regional anaesthesia are intertwined. Almost all surgeries unless contradicted could be and should be supplemented with a regional block. The main objective of this review is to elaborate on the recent advances of the central neuraxial blocks, such as application of ultrasound guidance and electrical stimulation in the pursuit of safety and an objective end point. This review also takes account of the traditional technique and understand the benefits as well the risk of each as compared with the recent technique. The recent trends in choosing the most appropriate peripheral block for a given surgery thereby sparing the central neuroaxis is considered. A penile block for circumcision or a sciatic block for unilateral foot surgery, rather than caudal epidural would have a better risk benefit equation. Readers will find a special mention on the recent thoughts on continuous epidural analgesia in paediatrics, especially its rise and fall, yet its unique importance. Lastly, the issue of block placements under sedation or general anaesthesia with its implication in this special population is dealt with. We conducted searches in MEDLINE (PubMed and assessed the relevance of the abstracts of citations identified from literature searches. The search was carried out in English, for last 10 years, with the following key words: Recent advances in paediatric regional anaesthesia; ultrasound guidance for central neuraxial blocks in children; role of electrical stimulation in neuraxial blocks in children; complications in neuraxial block. Full-text articles of potentially relevant abstracts were retrieved for further review.

  10. PACS photometer calibration block analysis

    CERN Document Server

    Moór, A; Kiss, Cs; Balog, Z; Billot, N; Marton, G


    The absolute stability of the PACS bolometer response over the entire mission lifetime without applying any corrections is about 0.5% (standard deviation) or about 8% peak-to-peak. This fantastic stability allows us to calibrate all scientific measurements by a fixed and time-independent response file, without using any information from the PACS internal calibration sources. However, the analysis of calibration block observations revealed clear correlations of the internal source signals with the evaporator temperature and a signal drift during the first half hour after the cooler recycling. These effects are small, but can be seen in repeated measurements of standard stars. From our analysis we established corrections for both effects which push the stability of the PACS bolometer response to about 0.2% (stdev) or 2% in the blue, 3% in the green and 5% in the red channel (peak-to-peak). After both corrections we still see a correlation of the signals with PACS FPU temperatures, possibly caused by parasitic h...

  11. Comparative study between ultrasound guided tap block and paravertebral block in upper abdominal surgeries. Randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Ruqaya M. Elsayed


    Conclusion: We concluded that ultrasound guided transversus abdominis plane block and thoracic paravertebral block were safe and effective anesthetic technique for upper abdominal surgery with longer and potent postoperative analgesia in thoracic paravertebral block than transversus abdominis block.

  12. Classification and virtual screening of androgen receptor antagonists. (United States)

    Li, Jiazhong; Gramatica, Paola


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

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

    Directory of Open Access Journals (Sweden)

    William R Rice


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

  14. Discovery of dopamine D₄ receptor antagonists with planar chirality. (United States)

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


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

  15. Lymphocyte homing antagonists in the treatment of inflammatory bowel diseases. (United States)

    Saruta, Masayuki; Papadakis, Konstantinos A


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

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

    DEFF Research Database (Denmark)

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


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

  17. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay. (United States)

    Wang, Si; Bovee, Toine F H


    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter.

  18. Antagonistic action of pitrazepin on human and rat GABAA receptors (United States)

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


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

  19. Phenotypic Identification of the Redox Dye Methylene Blue as an Antagonist of Heat Shock Response Gene Expression in Metastatic Melanoma Cells

    Directory of Open Access Journals (Sweden)

    Georg T. Wondrak


    Full Text Available Repurposing approved and abandoned non-oncological drugs is an alternative developmental strategy for the identification of anticancer therapeutics that has recently attracted considerable attention. Due to the essential role of the cellular heat shock response in cytoprotection through the maintenance of proteostasis and suppression of apoptosis, small molecule heat shock response antagonists can be harnessed for targeted induction of cytotoxic effects in cancer cells. Guided by gene expression array analysis and a phenotypic screen interrogating a collection of 3,7-diamino-phenothiazinium derivatives, we have identified the redox-drug methylene blue (MB, used clinically for the infusional treatment of methemoglobinemia, as a negative modulator of heat shock response gene expression in human metastatic melanoma cells. MB-treatment blocked thermal (43 °C and pharmacological (celastrol, geldanamycin induction of heat shock response gene expression, suppressing Hsp70 (HSPA1A and Hsp27 (HSPB1 upregulation at the mRNA and protein level. MB sensitized melanoma cells to the apoptogenic activity of geldanamycin, an Hsp90 antagonist known to induce the counter-regulatory upregulation of Hsp70 expression underlying cancer cell resistance to geldanamycin chemotherapy. Similarly, MB-cotreatment sensitized melanoma cells to other chemotherapeutics (etoposide, doxorubicin. Taken together, these data suggest feasibility of repurposing the non-oncological redox drug MB as a therapeutic heat shock response antagonist for cancer cell chemosensitization.

  20. Toward an Alternative Therapeutic Approach for Skin Infections: Antagonistic Activity of Lactobacilli Against Antibiotic-Resistant Staphylococcus aureus and Pseudomonas aeruginosa. (United States)

    Hafez, Mohamed M; Maghrabi, Ibrahim A; Zaki, Noha M


    The wide spread of antimicrobial resistance has urged the need of alternative therapeutic approach. In this context, probiotic lactobacilli have been reported for the prevention and treatment of many gastrointestinal and urogenital infections. However, very little is known about their antagonistic activity against skin pathogens. Accordingly, the present study aimed to investigate the potential of lactobacilli to interfere with pathogenesis features of two antibiotic-resistant skin pathogens, namely methicillin-resistant Staphylococcus aureus and multiple-resistant Pseudomonas aeruginosa. A total of 49 lactobacilli were recovered, identified and tested for their antagonistic activities against the aforementioned pathogens. Of these, eight isolates were capable of blocking the adherence of pathogens to mammalian cells independent of the skin pathogen tested or model adopted. Moreover, three Lactobacillus isolates (LRA4, LC2 and LR5) effectively prevented the pathogen internalization into epithelial cells in addition to potentiating phagocyte-mediated pathogen killing. Interestingly, the lactobacilli LC2, LF9 and LRA4 markedly inhibited the growth of P. aeruginosa and S. aureus isolates in coculture experiments. Besides, the lactobacilli LRA4, LC2, LR5 and LF9 have counteracted pathogen cytotoxicity. Taken together, the present study revealed some inhibitory activities of lactobacilli against two antibiotic-resistant skin pathogens. Moreover, it revealed two lactobacilli, namely LC2 and LRA4, with antagonistic capacity against different virulence determinants of skin pathogens. These lactobacilli are considered promising probiotic candidates that may represent an alternative therapeutic approach for skin infections.

  1. Erosion patterns on dissolving blocks (United States)

    Courrech du Pont, Sylvain; Cohen, Caroline; Derr, Julien; Berhanu, Michael


    Patterns in nature are shaped under water flows and wind action, and the understanding of their morphodynamics goes through the identification of the physical mechanisms at play. When a dissoluble body is exposed to a water flow, typical patterns with scallop-like shapes may appear [1,2]. These shapes are observed on the walls of underground rivers or icebergs. We experimentally study the erosion of dissolving bodies made of salt, caramel or ice into water solutions without external flow. The dissolving mixture, which is created at the solid/liquid interface, undergoes a buoyancy-driven instability comparable to a Rayleigh-Bénard instability so that the dissolving front destabilizes into filaments. This mechanism yields to spatial variations of solute concentration and to differential dissolution of the dissolving block. We first observe longitudinal stripes with a well defined wavelength, which evolve towards chevrons and scallops that interact and move again the dissolving current. Thanks to a careful analysis of the competing physical mechanisms, we propose scaling laws, which account for the characteristic lengths and times of the early regime in experiments. The long-term evolution of patterns is understood qualitatively. A close related mechanism has been proposed to explain structures observed on the basal boundary of ice cover on brakish lakes [3] and we suggest that our experiments are analogous and explain the scallop-like patterns on iceberg walls. [1] P. Meakin and B. Jamtveit, Geological pattern formation by growth and dissolution in aqueous systems, Proc. R. Soc. A 466, 659-694 (2010). [2] P.N. Blumberg and R.L. Curl, Experimental and theoretical studies of dissolution roughness, J. Fluid Mech. 65, 735-751 (1974). [3] L. Solari and G. Parker, Morphodynamic modelling of the basal boundary of ice cover on brakish lakes, J.G.R. 118, 1432-1442 (2013).

  2. New routes to the synthesis of amylose-block-polystyrene rod-coil block copolymers

    NARCIS (Netherlands)

    Loos, Katja; Müller, Axel H.E.


    Hybrid block copolymers amylose-block-polystyrene were synthesized by covalent attachment of maltoheptaose derivatives to end-functionalized polystyrene and subsequent enzymatic grafting from polymerization. The maltoheptaose derivatives were attached by reductive amination or hydrosilation to amino

  3. Block-based image hashing with restricted blocking strategy for rotational robustness (United States)

    Xiang, Shijun; Yang, Jianquan


    Image hashing is a potential solution for image content authentication (a desired image hashing algorithm should be robust to common image processing operations and various geometric distortions). In the literature, researchers pay more attention to block-based image hashing algorithms due to their robustness to common image processing operations (such as lossy compression, low-pass filtering, and additive noise). However, the block-based hashing strategies are sensitive to rotation processing operations. This indicates that the robustness of the block-based hashing methods against rotation operations is an important issue. Towards this direction, in this article we propose a restricted blocking strategy by investigating effect of two rotation operations on an image and its blocks in both theoretical and experimental ways. Furthermore, we apply the proposed blocking strategy for the recently reported non-negative matrix factorization (NMF) hashing. Experimental results have demonstrated the validity of the block-based hashing algorithms with restricted blocking strategy for rotation operations.

  4. Block Gas Sol Unit in Haderslev

    DEFF Research Database (Denmark)

    Vejen, Niels Kristian


    Investigation of a SDHW system based on a Block Gas Sol Unit from Baxi A/S installed by a consumer i Haderslev, Denmark.......Investigation of a SDHW system based on a Block Gas Sol Unit from Baxi A/S installed by a consumer i Haderslev, Denmark....

  5. Light extraction block with curved surface (United States)

    Levermore, Peter; Krall, Emory; Silvernail, Jeffrey; Rajan, Kamala; Brown, Julia J.


    Light extraction blocks, and OLED lighting panels using light extraction blocks, are described, in which the light extraction blocks include various curved shapes that provide improved light extraction properties compared to parallel emissive surface, and a thinner form factor and better light extraction than a hemisphere. Lighting systems described herein may include a light source with an OLED panel. A light extraction block with a three-dimensional light emitting surface may be optically coupled to the light source. The three-dimensional light emitting surface of the block may includes a substantially curved surface, with further characteristics related to the curvature of the surface at given points. A first radius of curvature corresponding to a maximum principal curvature k.sub.1 at a point p on the substantially curved surface may be greater than a maximum height of the light extraction block. A maximum height of the light extraction block may be less than 50% of a maximum width of the light extraction block. Surfaces with cross sections made up of line segments and inflection points may also be fit to approximated curves for calculating the radius of curvature.

  6. Benchmarking Block Ciphers for Wireless Sensor Networks

    NARCIS (Netherlands)

    Law, Y.W.; Doumen, J.M.; Hartel, P.H.


    Choosing the most storage- and energy-efficient block cipher specifically for wireless sensor networks (WSNs) is not as straightforward as it seems. To our knowledge so far, there is no systematic evaluation framework for the purpose. We have identified the candidates of block ciphers suitable for W

  7. The Block Grant Record: Lessons from Experience. (United States)

    Hastings, Anne H.


    Evaluates the performance of federal block grants in health, law enforcement, peoplepower training, community development, and Social Security programs, to help forecast the effects of such grants in education. Finds that block grants did not improve local control, accountability, citizen participation, efficiency, targeting of funds, or program…


    NARCIS (Netherlands)

    Hilberer, A; Gill, R.E; Herrema, J.K; Malliaras, G.G; Wildeman, J.; Hadziioannou, G


    In this article we review results obtained in our laboratory on the design and study of new light-emitting polymers. We are interested in the synthesis and characterisation of block copolymers with regularly alternating conjugated and non conjugated sequences. The blocks giving rise to luminescence

  9. PEO-related block copolymer surfactants

    DEFF Research Database (Denmark)

    Mortensen, K.


    Non-ionic block copolymer systems based on hydrophilic poly(ethylene oxide) and more hydrophobic co-polymer blocks are used intensively in a variety of industrial and personal applications. A brief description on the applications is presented. The physical properties of more simple model systems ...

  10. Earthquake Resistant Submarine Drydock Block System Design (United States)


    acceleration time history. It Is observed that the block on block surfaces for this system had been painted. According to Rabinowicz (1987) [13J, a...Maryland, 1982, p. 272. 166 13. Rabinowicz , Ernest, Lecture, "Tribology", M.I.T., Course 2.800, Fall 1987. 14. Telephone conversation between Tingley

  11. Micellization and Characterization of Block Copolymer Detergents

    DEFF Research Database (Denmark)

    Hvidt, Søren

    Triblock copolymers of the type EPE, where E and P denote ethylene oxide and propylene oxide blocks, respectively, are used widely in industry as emulsifiers, anti-foaming agents, and in delayed drug release. EPE copolymers form micelles with a core of P blocks and different micellar shapes depen...

  12. Haplotype block structure is conserved across mammals

    NARCIS (Netherlands)

    Guryev, Victor; Smits, Bart M G; van de Belt, Jose; Verheul, Mark; Hubner, Norbert; Cuppen, Edwin


    Genetic variation in genomes is organized in haplotype blocks, and species-specific block structure is defined by differential contribution of population history effects in combination with mutation and recombination events. Haplotype maps characterize the common patterns of linkage disequilibrium i

  13. C++ application development with Code::Blocks

    CERN Document Server

    Modak, Biplab Kumar


    This is a comprehensive tutorial with step-by-step instructions on how to develop applications with Code::Blocks.This book is for C++ developers who wish to use Code::Blocks to create applications with a consistent look and feel across multiple platforms. This book assumes that you are familiar with the basics of the C++ programming language.

  14. Exercise-induced bronchoconstriction: The effects of montelukast, a leukotriene receptor antagonist

    Directory of Open Access Journals (Sweden)

    James P Kemp


    Full Text Available James P KempClinical Professor of Pediatrics, Division of Immunology and Allergy, University of California School of Medicine, San Diego, CA, USAAbstract: Exercise-induced bronchoconstriction (EIB is very common in both patients with asthma and those who are otherwise thought to be normal. The intensity of exercise as well as the type of exercise is important in producing symptoms. This may make some types of exercise such as swimming more suitable and extended running more difficult for patients with this condition. A better understanding of EIB will allow the physician to direct the patient towards a type of exercise and medications that can result in a more active lifestyle without the same concern for resulting symptoms. This is especially important for schoolchildren who are usually enrolled in physical education classes and elite athletes who may desire to participate in competitive sports. Fortunately several medications (short- and long-acting β2-agonists, cromolyn, nedocromil, inhaled corticosteroids, and more recently leukotriene modifiers have been shown to be effective in preventing or attenuating the effects of exercise in many patients. In addition, inhaled β2-agonists have been shown to quickly reverse the airway obstruction that develops in patients and continue to be the reliever medications of choice. Inhaled corticosteroids are increasingly being recommended as regular therapy now that the role of inflammation and airway injury has been identified in EIB. With the discovery that there is a release of mediators such as histamine and leukotrienes from cells in the airway following exercise with resulting airway obstruction in susceptible individuals, interest has turned to attenuating their effects with mediator antagonists especially those that block the effects of leukotrienes. Studies with an oral leukotriene antagonist, montelukast, have shown beneficial effects in adults and children aged as young as 6 years with EIB

  15. Kinin B1 receptor antagonists inhibit diabetes-induced hyperalgesia in mice. (United States)

    Gabra, Bichoy H; Sirois, Pierre


    Insulin-dependent diabetes mellitus (type 1 diabetes) is an inflammatory autoimmune disease associated with vascular permeability changes leading to many complications including nephropathy, retinopathy, neuropathy, hypertension and hyperalgesia. The bradykinin B(1) receptors (BKB(1)-R) were recently found to be upregulated alongside the development of type 1 diabetes and to be involved in its complications. Kinins are important mediators of a variety of biological effects including cardiovascular homeostasis, inflammation and nociception. In the present study, we studied the effect of a selective BKB(1)-R agonist desArg(9)-BK (DBK) and two selective receptor antagonists, the R-715 (Ac-Lys-[D-beta Nal(7), Ile(8)] desArg(9)-BK) and the R-954 (Ac-Orn-[Oic(2), alphaMe Phe(5), D-beta Nal(7), Ile(8)] desArg(9)-BK) on diabetic hyperalgesia. Type 1 diabetes was induced in male CD-1 mice via a single injection of streptozotocin (STZ, 200mg/kg, i.p.), one week before the test. Nociception, a measure of hyperalgesia, was assessed using the plantar stimulation (Hargreaves) and the tail-immersion tests. The induction of type 1 diabetes provoked a significant hyperalgesic activity in diabetic mice, causing an 11% decrease in plantar stimulation reaction time and 13% decrease in tail-immersion reaction time, compared to normal mice. Following acute administration of R-715 (100-600 microg/kg, i.p.), or R-954 (50-400 microg/kg, i.p.), the STZ-induced hyperalgesic activity was blocked in a dose-dependent manner and the hot plate and tail-immersion latencies of diabetic mice returned to normal values observed in control healthy mice. In addition, the acute administration of DBK (400 microg/kg, i.p.) significantly potentiated diabetes-induced hyperalgesia, an effect that was totally reversed by R-715 (1.6-2.4 mg/kg, i.p.) and R-954 (0.8-1.2mg/kg, i.p.). These results provide further evidence for the implication of the BKB(1)-R in type 1 diabetic hyperalgesia and suggest a novel

  16. Ultrasonographic evaluation of neck hematoma and block salvage after failed neurostimulation-guided interscalene block. (United States)

    Howell, Stephen M; Unger, M W Todd; Colson, James D; Serafini, Mario


    Ultrasound-guided regional anesthetic techniques have shown some advantages over conventional paresthesia and neurostimulation techniques. We report the case of a neurostimulation-guided continuous interscalene block that would have ended in complication were it not for experience with ultrasound-guided regional anesthesia. Familiarity with ultrasound-guided block techniques permitted assessment of a neck hematoma during interscalene block and ultimately allowed successful peripheral nerve block.

  17. Blending of styrene-block-butadiene-block-styrene copolymer with sulfonated vinyl aromatic polymers


    Ruggeri, Giacomo; Passaglia, Elisa; Giorgi, Ivan; Picchioni, Francesco; Aglietto, Mauro


    Different polymers containing sulfonic groups attached to the phenyl rings were prepared by sulfonation of polystyrene (PS) and styrene-block-(ethylene-co-1-butene)-block-styrene (SEBS). The sulfonation degree (SD) was varied between 1 and 20 mol% of the styrene units. Polyphase materials containing sulfonated units were prepared by blending styrene-block-butadiene-block-styrene (SBS), with both sulfonated PS and sulfonated SEBS in a Brabender mixer. Such a procedure was performed as an alter...

  18. A Nonlinear Multi-Scale Interaction Model for Atmospheric Blocking: The Eddy-Blocking Matching Mechanism (United States)

    Luo, Dehai; Cha, Jing; Zhong, Linhao; Dai, Aiguo


    In this paper, a nonlinear multi-scale interaction (NMI) model is used to propose an eddy-blocking matching (EBM) mechanism to account for how synoptic eddies reinforce or suppress a blocking flow. It is shown that the spatial structure of the eddy vorticity forcing (EVF) arising from upstream synoptic eddies determines whether an incipient block can grow into a meandering blocking flow through its interaction with the transient synoptic eddies from the west. Under certain conditions, the EVF exhibits a low-frequency oscillation on timescales of 2-3 weeks. During the EVF phase with a negative-over- positive dipole structure, a blocking event can be resonantly excited through the transport of eddy energy into the incipient block by the EVF. As the EVF changes into an opposite phase, the blocking decays. The NMI model produces life cycles of blocking events that resemble observations. Moreover, it is shown that the eddy north-south straining is a response of the eddies to a dipole- or Ω-type block. In our model, as in observations, two synoptic anticyclones (cyclones) can attract and merge with one another as the blocking intensifies, but only when the feedback of the blocking on the eddies is included. Thus, we attribute the eddy straining and associated vortex interaction to the feedback of the intensified blocking on synoptic eddies. The results illustrate the concomitant nature of the eddy deformation, whose role as a PV source for the blocking flow becomes important only during the mature stage of a block. Our EBM mechanism suggests that an incipient block flow is amplified (or suppressed) under certain conditions by the EVF coming from the upstream of the blocking region.

  19. The undesirable effects of neuromuscular blocking drugs

    DEFF Research Database (Denmark)

    Claudius, C; Garvey, L H; Viby-Mogensen, J


    Neuromuscular blocking drugs are designed to bind to the nicotinic receptor at the neuromuscular junction. However, they also interact with other acetylcholine receptors in the body. Binding to these receptors causes adverse effects that vary with the specificity for the cholinergic receptor...... in question. Moreover, all neuromuscular blocking drugs may cause hypersensitivity reactions. Often the symptoms are mild and self-limiting but massive histamine release can cause systematic reactions with circulatory and respiratory symptoms and signs. At the end of anaesthesia, no residual effect...... of a neuromuscular blocking drug should be present. However, the huge variability in response to neuromuscular blocking drugs makes it impossible to predict which patient will suffer postoperative residual curarization. This article discusses the undesirable effects of the currently available neuromuscular blocking...

  20. Fermion RG blocking transformations and IR structure

    CERN Document Server

    Cheng, X


    We explore fermion RG block-spinning transformations on the lattice with the aim of studying the IR structure of gauge theories and, in particular, the existence of IR fixed points for varying fermion content. In the case of light fermions the main concern and difficulty is ensuring locality of any adopted blocking scheme. We discuss the problem of constructing a local blocked fermion action in the background of arbitrary gauge fields. We then discuss the carrying out of accompanying gauge field blocking. In the presence of the blocked fermions implementation of MCRG is not straightforward. By adopting judicious approximations we arrive at an easily implementable approximate RG recursion scheme that allows quick, inexpensive estimates of the location of conformal windows for various groups and fermion representations. We apply this scheme to locate the conformal windows in the case of SU(2) and SU(3) gauge groups. Some of the reasons for the apparent efficacy of this and similar decimation schemes are discuss...


    Institute of Scientific and Technical Information of China (English)

    DING Youjun; QI Daquan


    Synthesis and characterization of a series of Polysulfone (PSF)-Polyester (PEs) block copolymers were studied.The degree of randomness (B) of these block copolymers was calculated from the intensities of their proton signals in 1H NMR spectra and lies in the region of 0 < B < 1. It was shown that the degree of randomness (B) and the average sequence length (L) in block copolymers were relatively dependent on the reaction conditions, various feed ratios and structure of diols.The phenomenon was observed, when the PSF-PEs block copolymers dissolved in different solvents they had different viscosities and molecular conformations.The PSF-PEs block copolymers had better solvent resistance than homo-polysulfone.

  2. The newly developed CRF1-receptor antagonists, NGD 98-2 and NGD 9002, suppress acute stress-induced stimulation of colonic motor function and visceral hypersensitivity in rats.

    Directory of Open Access Journals (Sweden)

    Mulugeta Million

    Full Text Available Corticotropin releasing factor receptor 1 (CRF1 is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD in conscious rats. CRF1 antagonists or vehicle were administered orogastrically (og or subcutaneously (sc before either intracerebroventricular (icv or intraperitoneal (ip injection of CRF (10 µg/kg, exposure to water avoidance stress (WAS, 60 min or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval. Fecal pellet output (FPO, diarrhea and visceromotor responses were monitored. In vehicle (og-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og reduced the CRF-induced FPO response with an inhibitory IC50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67-87% and decreased WAS-induced-FPO by 23-53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD.

  3. [3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine) is a novel, potent, and selective antagonist radioligand for P2X7 receptors. (United States)

    Donnelly-Roberts, Diana L; Namovic, Marian T; Surber, Bruce; Vaidyanathan, Srirajan X; Perez-Medrano, Arturo; Wang, Ying; Carroll, William A; Jarvis, Michael F


    ATP-sensitive P2X7 receptors are localized on cells of immunological origin including peripheral macrophages and glial cells in the CNS. Activation of P2X7 receptors leads to rapid changes in intracellular calcium concentrations, release of the pro-inflammatory cytokine IL-1beta, and following prolonged agonist exposure, the formation of cytolytic pores in plasma membranes. Data from gene knockout studies and recently described selective antagonists indicate a role for P2X7 receptor activation in inflammation and pain. While several species selective P2X7 antagonists exist, A-804598 represents a structurally novel, competitive, and selective antagonist that has equivalent high affinity at rat (IC50 = 10 nM), mouse (IC50 = 9 nM) and human (IC50 = 11 nM) P2X7 receptors. A-804598 also potently blocked agonist stimulated release of IL-1beta and Yo-Pro uptake from differentiated THP-1 cells that natively express human P2X7 receptors. A-804598 was tritiated ([3H]A-804598; 8.1Ci/mmol) and utilized to study recombinant rat P2X7 receptors expressed in 1321N1 cells. [3H]A-804598 labeled a single class of high affinity binding sites (Kd=2.4 nM and apparent Bmax=0.56 pmol/mg). No specific binding was observed in untransfected 1321N1 cells. The pharmacological profile for P2X antagonists to inhibit [3H]A-804598 binding correlated with their ability to block functional activation of P2X7 receptors (r=0.95, PP2X7 receptors described to date and [3H]A-804598 is a high affinity antagonist radioligand that specifically labels rat P2X7 receptors.

  4. A note on "Block H-matrices and spectrum of block matrices"

    Institute of Scientific and Technical Information of China (English)

    LIU Jian-zhou; HUANG Ze-jun


    In this paper, we make further discussions and improvements on the results presented in the previously published work "Block H-matrices and spectrum of block matrices". Furthermore, a new bound for eigenvalues of block matrices is given with examples to show advantages of the new result.

  5. The evolution of histamine H₃ antagonists/inverse agonists. (United States)

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


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

  6. Evodiamine as a novel antagonist of aryl hydrocarbon receptor

    Energy Technology Data Exchange (ETDEWEB)

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


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

  7. CCR9 Antagonists in the Treatment of Ulcerative Colitis

    Directory of Open Access Journals (Sweden)

    Pirow Bekker


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

  8. Suppression of Aldosterone Synthesis and Secretion by Channel Antagonists

    Directory of Open Access Journals (Sweden)

    Keiichi Ikeda


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

  9. CGRP antagonists and antibodies for the treatment of migraine. (United States)

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


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

  10. Implications of hedgehog signaling antagonists for cancer therapy

    Institute of Scientific and Technical Information of China (English)

    Jingwu Xie


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

  11. Rogue sperm indicate sexually antagonistic coevolution in nematodes.

    Directory of Open Access Journals (Sweden)

    Ronald E Ellis


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

  12. Human homosexuality: a paradigmatic arena for sexually antagonistic selection? (United States)

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


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

  13. Comparative proteome analysis of two antagonist Bacillus subtilis strains. (United States)

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


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

  14. Anti-diabetic efficacy and impact on amino acid metabolism of GRA1, a novel small-molecule glucagon receptor antagonist.

    Directory of Open Access Journals (Sweden)

    James Mu

    Full Text Available Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism.

  15. Polyvalent integrin antagonist-decorated superparamagnetic iron oxide nanoparticles for triggering apoptosis in human leukemia cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Say, R Latin-Small-Letter-Dotless-I dvan, E-mail: [Anadolu Universitesi, Kimya Boeluemue, Fen Fakueltesi (Turkey); Yazar, Suzan [Sanovel Pharmaceutical Company (Turkey); Ugur, Alper; Huer, Deniz [Anadolu Universitesi, Kimya Boeluemue, Fen Fakueltesi (Turkey); Denizli, Adil [Hacettepe University, Department of Chemistry (Turkey); Ersoez, Arzu [Anadolu Universitesi, Kimya Boeluemue, Fen Fakueltesi (Turkey)


    Integrin family members are the main mediators of cell adhesion to the extracellular matrix and active as intra- and extracellular signaling molecules in a variety of processes. They bind to their ligands by interacting with short amino acid sequences, that is, RGD (arginine-glycine-aspartic acid) sequence. RGD sequences have been used to enhance cell binding to artificial surfaces, so RGD mimics have been used to block integrin binding to its ligand. Integrin-ligand interactions are dependent on divalent cations, and Mg{sup 2+} provide higher-affinity binding to ligand for many integrins. In this study, we have designed new integrin antagonists using methacryloyl amidoaspartic acid (MAASP) monomer-conjugated silanized super paramagnetic iron oxide nanoparticles (SPIONs, the size of the nanoparticles was verified with an average size of 32.6 nm) and poly(MAASP-co-EDMA) shell-decorated silanized SPIONs. Several mechanisms have been proposed to describe uptake of modified SPIONs into the cells, including receptor-mediated endocytosis. Our aim is to bind these modified SPIONs to the integrin-mediated aspartic acid ends of MAASP monomers and block integrin binding to their ligand.

  16. Cardamonin, a Novel Antagonist of hTRPA1 Cation Channel, Reveals Therapeutic Mechanism of Pathological Pain

    Directory of Open Access Journals (Sweden)

    Shifeng Wang


    Full Text Available The increasing demand for safe and effective treatments of chronic pain has promoted the investigation of novel analgesic drugs. Some herbals have been known to be able to relieve pain, while the chemical basis and target involved in this process remained to be clarified. The current study aimed to find anti-nociceptive candidates targeting transient receptor potential ankyrin 1 (TRPA1, a receptor that implicates in hyperalgesia and neurogenic inflammation. In the current study, 156 chemicals were tested for blocking HEK293/TRPA1 ion channel by calcium-influx assay. Docking study was conducted to predict the binding modes of hit compound with TRPA1 using Discovery Studio. Cytotoxicity in HEK293 was conducted by Cell Titer-Glo assay. Additionally, cardiotoxicity was assessed via xCELLigence RTCA system. We uncovered that cardamonin selectively blocked TRPA1 activation while did not interact with TRPV1 nor TRPV4 channel. A concentration-dependent inhibitory effect was observed with IC50 of 454 nM. Docking analysis of cardamonin demonstrated a compatible interaction with A-967079-binding site of TRPA1. Meanwhile, cardamonin did not significantly reduce HEK293 cell viability, nor did it impair cardiomyocyte constriction. Our data suggest that cardamonin is a selective TRPA1 antagonist, providing novel insight into the target of its anti-nociceptive activity.

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


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


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

  18. A new pyrrolyl-quinoxalinedione series of non-NMDA glutamate receptor antagonists: pharmacological characterization and comparison with NBQX and valproate in the kindling model of epilepsy. (United States)

    Löscher, W; Lehmann, H; Behl, B; Seemann, D; Teschendorf, H J; Hofmann, H P; Lubisch, W; Höger, T; Lemaire, H G; Gross, G


    Antagonists at the ionotropic non-NMDA [AMPA (amino-methyl proprionic acid)/kainate] type of glutamate receptors have been suggested to possess several advantages compared to NMDA (N-methyl-D-aspartate) receptor antagonists, particularly in terms of risk/benefit ratio, but the non-NMDA receptor antagonists available so far have not fulfilled this promise. From a large series of pyrrolyl-quinoxalinedione derivatives, we selected six new competitive non-NMDA receptor antagonists. The basis of selection was high potency and selectivity for AMPA and/or kainate receptors, high in vivo potency after systemic administration, and an acceptable ratio between neuroprotective or anticonvulsant effects and adverse effects. Pharmacological characteristics of these novel compounds are described in this study with special emphasis on their effects in the kindling model of temporal lobe epilepsy, the most common type of epilepsy in humans. In most experiments, NBQX and the major antiepileptic drug valproate were used for comparison with the novel compounds. The novel non-NMDA receptor antagonists markedly differed in their AMPA and kainate receptor affinities from NBQX. Thus, while NBQX essentially did not bind to kainate receptors at relevant concentrations, several of the novel compounds exhibited affinity to rat brain kainate receptors or recombinant kainate receptor subtypes in addition to AMPA receptors. One compound, LU 97175, bound to native high affinity kainate receptors and rat GluR5-GluR7 subunits, i.e. low affinity kainate binding sites, with much higher affinities than to AMPA receptors. All compounds potently blocked AMPA-induced cell death in vitro and, except LU 97175, AMPA-induced convulsions in vivo. In the kindling model, compounds with a high affinity for GluR7 (LU 97175) or compounds (LU 115455, LU 136541) which potently bind to AMPA receptors and low affinity kainate receptor subunits were potent anticonvulsants in the kindling model, whereas the AMPA

  19. Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. (United States)

    Porter, Richard H P; Jaeschke, Georg; Spooren, Will; Ballard, Theresa M; Büttelmann, Bernd; Kolczewski, Sabine; Peters, Jens-Uwe; Prinssen, Eric; Wichmann, Jürgen; Vieira, Eric; Mühlemann, Andreas; Gatti, Silvia; Mutel, Vincent; Malherbe, Pari


    Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] is an atypical anxiolytic agent with unknown molecular target that has previously been demonstrated both in rodents and human to exert anxiolytic activity. Here, we report that fenobam is a selective and potent metabotropic glutamate (mGlu)5 receptor antagonist acting at an allosteric modulatory site shared with 2-methyl-6-phenylethynyl-pyridine (MPEP), the protypical selective mGlu5 receptor antagonist. Fenobam inhibited quisqualate-evoked intracellular calcium response mediated by human mGlu5 receptor with IC(50) = 58 +/- 2 nM. It acted in a noncompetitive manner, similar to MPEP and demonstrated inverse agonist properties, blocking 66% of the mGlu5 receptor basal activity (in an over expressed cell line) with an IC(50) = 84 +/- 13 nM. [(3)H]Fenobam bound to rat and human recombinant receptors with K(d) values of 54 +/- 6 and 31 +/- 4 nM, respectively. MPEP inhibited [(3)H]fenobam binding to human mGlu5 receptors with a K(i) value of 6.7 +/- 0.7 nM, indicating a common binding site shared by both allosteric antagonists. Fenobam exhibits anxiolytic activity in the stress-induced hyperthermia model, Vogel conflict test, Geller-Seifter conflict test, and conditioned emotional response with a minimum effective dose of 10 to 30 mg/kg p.o. Furthermore, fenobam is devoid of GABAergic activity, confirming previous reports that fenobam acts by a mechanism distinct from benzodiazepines. The non-GABAergic activity of fenobam, coupled with its robust anxiolytic activity and reported efficacy in human in a double blind placebo-controlled trial, supports the potential of developing mGlu5 receptor antagonists with an improved therapeutic window over benzodiazepines as novel anxiolytic agents.

  20. Chronic escitalopram treatment caused dissociative adaptation in serotonin (5-HT) 2C receptor antagonist-induced effects in REM sleep, wake and theta wave activity. (United States)

    Kostyalik, Diána; Kátai, Zita; Vas, Szilvia; Pap, Dorottya; Petschner, Péter; Molnár, Eszter; Gyertyán, István; Kalmár, Lajos; Tóthfalusi, László; Bagdy, Gyorgy


    Several multi-target drugs used in treating psychiatric disorders, such as antidepressants (e.g. agomelatine, trazodone, nefazodone, amitriptyline, mirtazapine, mianserin, fluoxetine) or most atypical antipsychotics, have 5-hydroxytryptamine 2C (5-HT2C) receptor-blocking property. Adaptive changes in 5-HT2C receptor-mediated functions are suggested to contribute to therapeutic effects of selective serotonin reuptake inhibitor (SSRI) antidepressants after weeks of treatment, at least in part. Beyond the mediation of anxiety and other functions, 5-HT2C receptors are involved in sleep regulation. Anxiety-related adaptive changes caused by antidepressants have been studied extensively, although sleep- and electroencephalography (EEG)-related functional studies are still lacking. The aim of this study was to investigate the effects of chronic SSRI treatment on 5-HT2C receptor antagonist-induced functions in different vigilance stages and on quantitative EEG (Q-EEG) spectra. Rats were treated with a single dose of the selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg, i.p.) or vehicle at the beginning of passive phase following a 20-day-long SSRI (escitalopram; 10 mg/kg/day, osmotic minipump) or VEHICLE pretreatment. Fronto-parietal electroencephalogram, electromyogram and motility were recorded during the first 3 h of passive phase. We found that the chronic escitalopram pretreatment attenuated the SB-242084-caused suppression in rapid eye movement sleep (REMS). On the contrary, the 5-HT2C receptor antagonist-induced elevations in passive wake and theta (5-9 Hz) power density during active wake and REMS were not affected by the SSRI. In conclusion, attenuation in certain, but not all vigilance- and Q-EEG-related functions induced by the 5-HT2C receptor antagonist, suggests dissociation in 5-HT2C receptor adaptation.

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


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


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

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



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


    Directory of Open Access Journals (Sweden)

    K. Sridharan


    Full Text Available The Tyre tread pattern is the arrangement of blocks, grooves and voids, sipes and channels designed into the tread to enhance its grip on the road. Tread is the uppermost part of any tyre which contact into the road and it has its own performance towards mileage, traction, low noise and heat built up properties. It would be meaningful to conduct an extended analysis on the tyre tread blocks for its performance in static and dynamic condition to predict its behavior and wear of tread block in on-road condition. The Finite Element software Abaqus is used for the present analysis of the tread block and its behavior was studied on two different contact surfaces. The tread block is modeled in six different shapes and analyzed for is performance. The deformation stress strain characteristic of different blocks is studied which will be useful in deciding the contact behavior, friction and road grip. The regular shape/geometry has common behavior and the mixed type geometry shows a distinguished variation in the analysis. The dynamic stiffness and deformed shape was analyzed in this study and it has its own effect in tyre design. The tread block dynamics study by geometric shape would be vital in tread pattern optimization to enhance the traction, better hydroplaning and rolling resistance under all operating conditions.

  4. Development of Alkali Activated Geopolymer Masonry Blocks (United States)

    Venugopal, K.; Radhakrishna; Sasalatti, Vinod


    Cement masonry units are not considered as sustainable since their production involves consumption of fuel, cement and natural resources and therefore it is essential to find alternatives. This paper reports on making of geopolymer solid & hollow blocks and masonry prisms using non conventional materials like fly ash, ground granulated blast furnace slag (GGBFS) and manufactured sand and curing at ambient temperature. They were tested for water absorption, initial rate of water absorption, dry density, dimensionality, compressive, flexural and bond-strength which were tested for bond strength with and without lateral confinement, modulus of elasticity, alternative drying & wetting and masonry efficiency. The properties of geopolymer blocks were found superior to traditional masonry blocks and the masonry efficiency was found to increase with decrease in thickness of cement mortar joints. There was marginal difference in strength between rendered and unrendered geopolymer masonry blocks. The percentage weight gain after 7 cycles was less than 6% and the percentage reduction in strength of geopolymer solid blocks and hollow blocks were 26% and 28% respectively. Since the properties of geopolymer blocks are comparatively better than the traditional masonry they can be strongly recommended for structural masonry.

  5. Circular block matching based video stabilization (United States)

    Xu, Lidong; Fu, Fangwen; Lin, Xinggang


    Video sequences captured by handheld digital camera need to be stabilized to eliminate the tiresome effects caused by camera"s undesirable shake or jiggle. The key issue of video stabilization is to estimate the global motion parameters between two successive frames. In this paper, a novel circular block matching algorithm is proposed to estimate the global motion parameters. This algorithm can deal with not only translational motion but even large rotational motion. For an appointed circular block in current frame, a four-dimensional rotation invariant feature vector is firstly extracted from it and used to judge if it is an effective block. Then the rotation invariant features based circular block matching process is performed to find the best matching blocks in reference frame for those effective blocks. With the matching results of any two effective blocks, a two-dimensional motion model is constructed to produce one group of frame motion parameters. A statistical method is proposed to calculate the estimated global motion parameters with all groups of global motion parameters. Finally, using the estimated motion parameters as the initial values, an iteration algorithm is introduced to obtain the refined global motion parameters. The experimental results show that the proposed algorithm is excellent in stabilizing frames with even burst global translational and rotational motions.

  6. Gaussian curvature analysis allows for automatic block placement in multi-block hexahedral meshing. (United States)

    Ramme, Austin J; Shivanna, Kiran H; Magnotta, Vincent A; Grosland, Nicole M


    Musculoskeletal finite element analysis (FEA) has been essential to research in orthopaedic biomechanics. The generation of a volumetric mesh is often the most challenging step in a FEA. Hexahedral meshing tools that are based on a multi-block approach rely on the manual placement of building blocks for their mesh generation scheme. We hypothesise that Gaussian curvature analysis could be used to automatically develop a building block structure for multi-block hexahedral mesh generation. The Automated Building Block Algorithm incorporates principles from differential geometry, combinatorics, statistical analysis and computer science to automatically generate a building block structure to represent a given surface without prior information. We have applied this algorithm to 29 bones of varying geometries and successfully generated a usable mesh in all cases. This work represents a significant advancement in automating the definition of building blocks.

  7. Measurement of soil moisture using gypsum blocks

    DEFF Research Database (Denmark)

    Friis Dela, B.

    the building. Consequently, measuring the moisture of the surrounding soil is of great importance for detecting the source of moisture in a building. Up till now, information has been needed to carry out individual calibrations for the different types of gypsum blocks available on the market and to account......For the past 50 years, gypsum blocks have been used to determine soil moisture content. This report describes a method for calibrating gypsum blocks for soil moisture measurements. Moisture conditions inside a building are strongly influenced by the moisture conditions in the soil surrounding...

  8. Theory of circuit block switch-off

    Directory of Open Access Journals (Sweden)

    S. Henzler


    Full Text Available Switching-off unused circuit blocks is a promising approach to supress static leakage currents in ultra deep sub-micron CMOS digital systems. Basic performance parameters of Circuit Block Switch-Off (CBSO schemes are defined and their dependence on basic circuit parameters is estimated. Therefore the design trade-off between strong leakage suppression in idle mode and adequate dynamic performance in active mode can be supported by simple analytic investigations. Additionally, a guideline for the estimation of the minimum time for which a block deactivation is useful is derived.

  9. Lidocaine block of cardiac sodium channels


    Bean, BP; Cohen, CJ; Tsien, RW


    Lidocaine block of cardiac sodium channels was studied in voltage-clamped rabbit purkinje fibers at drug concentrations ranging from 1 mM down to effective antiarrhythmic doses (5-20 μM). Dose-response curves indicated that lidocaine blocks the channel by binding one-to-one, with a voltage-dependent K(d). The half-blocking concentration varied from more than 300 μM, at a negative holding potential where inactivation was completely removed, to approximately 10 μM, at a depolarized holding pote...

  10. Comparative Analysis of Sandcrete Hollow Blocks and Laterite Interlocking Blocks as Walling Elements

    Directory of Open Access Journals (Sweden)

    Akeem Ayinde Raheem


    Full Text Available This study considered the production and testing of sandcrete hollow blocks and laterite interlocking blocks with a view to comparing their physical characteristics and production cost. Some units of sandcrete hollow blocks and laterite interlocking blocks were made using machine vibrated sandcrete block mould and hydraulic interlocking block making machine respectively. The blocks were tested to determine their density and compressive strength. The results obtained from the tests were compared with the specifications of Nigerian Building and Road Research Institute (2006, Nigerian Building Code (2006, and Nigerian Industrial Standards (2000. The results indicated that the compressive strength of 225mm and 150mm sandcrete hollow blocks varies from 1.59 N/mm2 to 4.25 N/mm2 and 1.48N/mm2 to 3.35N/mm2 respectively, as the curing age increases from 7 to 28 days. For laterite interlocking blocks, the strength varies from 1.70N/mm2 at 7 days to 5.03N/mm2 at 28 days. All the blocks produced satisfied the minimum requirements in terms of compressive strength, by all available codes. The cost per square metre of 225mm and 150mm sandcrete hollow blocks are ₦2,808:00 and ₦2,340:00 respectively, while that of laterite interlocking blocks is ₦2,121:20.It was concluded that laterite interlocking blocks have better strength and are cheaper than sandcrete hollow blocks.

  11. Blocking NMDA receptors delays death in rats with acute liver failure by dual protective mechanisms in kidney and brain. (United States)

    Cauli, Omar; González-Usano, Alba; Cabrera-Pastor, Andrea; Gimenez-Garzó, Carla; López-Larrubia, Pilar; Ruiz-Sauri, Amparo; Hernández-Rabaza, Vicente; Duszczyk, Malgorzata; Malek, Michal; Lazarewicz, Jerzy W; Carratalá, Arturo; Urios, Amparo; Miguel, Alfonso; Torregrosa, Isidro; Carda, Carmen; Montoliu, Carmina; Felipo, Vicente


    Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration.

  12. 1α,25-Dihydroxyvitamin D3-26,23-lactam analogues function as vitamin D receptor antagonists in human and rodent cells (United States)

    Ishizuka, Seiichi; Kurihara, Noriyoshi; Hiruma, Yuko; Miura, Daishiro; Namekawa, Jun-ichi; Tamura, Azusa; Kato-Nakamura, Yuko; Nakano, Yusuke; Takenouchi, Kazuya; Hashimoto, Yuichi; Nagasawa, Kazuo; Roodman, G. David


    (23S,25S)-N-Benzyl-1α,25-dihydroxyvitamin D3-26,23-lactam ((23S,25S)-N-benzyl- 1α,25-(OH)2D3-26,23-lactam, (23S,25S)-DLAM-1P) antagonizes nuclear vitamin D receptor (VDR)-mediated differentiation of human promyelocytic leukemia (HL-60) cells [Bioorg. Med. Chem. Lett. 14, 2579–2583(2004)]. To enhance its VDR antagonistic actions, we synthesized multiple analogues of 1α,25-(OH)2D3-26,23-lactam. Among these analogues, (23S,25S)-N-phenetyl-1α,25-(OH)2D3-26,23-lactam, ((23S,25S)- DLAM-2P) had the strongest VDR binding affinity, which was 3 times higher than that of (23S,25S)-DLAM-1P. The 1α,25-(OH)2D3-26,23-lactam analogues never induced HL-60 cell differentiation even at 10−6M, but (23S,25S)-DLAM-1P and (23S,25S)-DLAM-2P significantly and dose-dependently inhibited HL-60 differentiation induced by 10−8M 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3). These compounds also inhibited human and mouse cultures of osteoclast formation by marrow cells treated with 1α,25-(OH)2D3. Moreover, the 1α,25-(OH)2D3-26,23-lactam analogues minimally induced 25-hydroxy- vitamin D3-24-hydroxylase gene expression in HL-60 cells and human and mouse osteoblastic cells, but 10−6M (23S,25S)-DLAM-1P or (23S,25S)-DLAM-2P significantly blocked 24-hydroxylase gene expression induced by 10−8M 1α,25-(OH)2D3. (23S,25S)- DLAM-2P was 5 to 12 times more potent as a Vitamin D antagonist than (23S,25S)-DLAM-1P in HL-60 cells, human and mouse bone marrow cultures. These results demonstrate that (23S,25S)-DLAM-1P and (23S,25S)-DLAM-2P antagonize HL-60 cell differentiation and osteoclast formation by human and mouse osteoclast precursors induced by 1α,25-(OH)2D3 through blocking VDR-mediated gene transcription. In contrast, (23S)-25-deoxy-1α-hydroxyvitamin D3-26,23-lactone, which only blocks human VDR, these vitamin D antagonists can block VDR in human cells and rodent cells. PMID:18501591

  13. Effects of antagonists of growth hormone-releasing hormone (GHRH) on GH and insulin-like growth factor I levels in transgenic mice overexpressing the human GHRH gene, an animal model of acromegaly. (United States)

    Kovacs, M; Kineman, R D; Schally, A V; Zarandi, M; Groot, K; Frohman, L A


    Transgenic mice overexpressing the human GH-releasing hormone (hGHRH) gene, an animal model of acromegaly, were used to investigate the effects of potent GHRH antagonists MZ-4-71 and MZ-5-156 on the excessive GH and insulin-like growth factor I (IGF-I) secretion caused by overproduction of hGHRH. Because metallothionein (MT)-GHRH mice express the hGHRH transgene in various tissues, including the pituitary and hypothalamus, initial experiments focused on the effectiveness of the GHRH antagonists in blocking basal and stimulated GH secretion from pituitary cells in vitro. Both MZ-4-71 and MZ-5-156 suppressed basal release of GH from superfused MT-GHRH pituitary cells, apparently by blocking the action of endogenously produced hGHRH. In addition, these antagonists effectively eliminated the response to stimulatory action of exogenous hGHRH(1-29)NH2 (30 and 100 nM). To ascertain whether MZ-4-71 and MZ-5-156 could antagonize the effect of hGHRH hyperstimulation in vivo, each antagonist was administered to MT-GHRH transgenic mice in a single iv dose of 10-200 microg. Both compounds decreased serum GH levels in transgenic mice by 39-72% at 1 h after injection. The inhibitory effect of 50 microg MZ-5-156 was maintained for 5 h. Twice daily ip administration of 100 microg MZ-5-156 for 3 days suppressed the highly elevated serum GH and IGF-I concentrations in transgenic mice by 56.8% and 39.0%, respectively. This treatment also reduced IGF-I messenger RNA levels in the liver by 21.8% but did not affect the level of GH messenger RNA in the pituitary. Our results demonstrate that GHRH antagonists MZ-4-71 and MZ-5-156 can inhibit elevated GH levels caused by overproduction of hGHRH. The suppression of circulating GH concentrations induced by the antagonists seems to be physiologically relevant, because both IGF-I secretion and synthesis also were reduced. Our findings, showing the suppression of GH and IGF-I secretion with GHRH antagonists, suggest that this class of analogs

  14. Conessine, an H3 receptor antagonist, alters behavioral and neurochemical effects of ethanol in mice. (United States)

    Morais-Silva, Gessynger; Ferreira-Santos, Mariane; Marin, Marcelo T


    Ethanol abuse potential is mainly due to its reinforcing properties, crucial in the transition from the recreational to pathological use. These properties are mediated by mesocorticolimbic and nigrostriatal dopaminergic pathways and neuroadaptations in these pathways seem to be responsible for addiction. Both pathways are modulated by other neurotransmitters systems, including neuronal histaminergic system. Among the histamine receptors, H3 receptor stands out due to its role in modulation of histamine and other neurotransmitters release. Thus, histaminergic system, through H3 receptors, may have an important role in ethanol addiction development. Aiming to understand these interactions, conessine, an H3 receptor antagonist, was given to mice subjected to the evaluation of ethanol-induced psychostimulation, ethanol CPP and quantification of norepinephrine, dopamine, serotonin and their metabolites in mesocorticolimbic and nigrostriatal pathways following acute ethanol treatment. Systemic conessine administration exacerbated ethanol effects on locomotor activity. Despite of conessine reinforcing effect on CPP, this drug did not alter acquisition of ethanol CPP. Ethanol treatment affects the serotoninergic neurotransmission in the ventral tegmental area, the dopaminergic neurotransmission in the pre-frontal cortex (PFC) and caudate-putamen nucleus (CPu) and the noradrenergic neurotransmission in the CPu. In the PFC, conessine blocked ethanol effects on dopaminergic and noradrenergic neurotransmission. The blockade of H3 receptors and ethanol seem to interact in the modulation of dopaminergic neurotransmission of nigrostriatal pathway, decreasing dopamine metabolites in substantia nigra. In conclusion, conessine was able to change psychostimulant effect of ethanol, without altering its reinforcing properties. This exacerbation of ethanol-induced psychostimulation would be related to alterations in dopaminergic neurotransmission in the nigrostriatal pathway.

  15. Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm. (United States)

    Clemmons, David R; Chihara, Kazuo; Freda, Pamela U; Ho, Ken K Y; Klibanski, Anne; Melmed, Shlomo; Shalet, Stephen M; Strasburger, Christian J; Trainer, Peter J; Thorner, Michael O


    Acromegaly is associated with significant morbidities and a 2- to 3-fold increase in mortality because of the excessive metabolic action of GH and IGF-I, a marker of GH output. Reductions in morbidity correspond with decreases in IGF-I, and mortality is lowered following normalization of IGF-I or GH levels. Therefore, this has become an important end point. Current guidelines for the treatment of acromegaly have not considered recent advances in medical therapy, in particular, the place of pegvisomant, a GH receptor antagonist. Treatment goals include normalizing biochemical markers, controlling tumor mass, preserving pituitary function, and relieving signs and symptoms. Surgery reduces tumor volume and is considered first-line therapy. Radiation reduces tumor volume and GH and IGF-I levels, but the onset of action is slow and hypopituitarism typically develops. Therefore, pharmacotherapy is often used following surgery or as first-line therapy for nonresectable tumors. Dopamine agonists can be considered in patients exhibiting minimal disease or those with GH-prolactin-cosecreting tumors but will not achieve hormone normalization in most patients. Somatostatin analogs effectively suppress GH and IGF-I in most patients, but intolerance (e.g. diarrhea, cramping, gallstones) can occur. Pegvisomant, the newest therapeutic option, blocks GH action at peripheral receptors, normalizes IGF-I levels, reduces signs and symptoms, and corrects metabolic defects. Pegvisomant does not appear to affect tumor size and has few adverse effects. Pegvisomant is the most effective drug treatment for acromegaly in normalizing IGF-I and producing a clinical response; it is the preferred agent in patients resistant to or intolerant of somatostatin analogs.

  16. Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody. (United States)

    Stewart, Ross; Morrow, Michelle; Hammond, Scott A; Mulgrew, Kathy; Marcus, Danielle; Poon, Edmund; Watkins, Amanda; Mullins, Stefanie; Chodorge, Matthieu; Andrews, John; Bannister, David; Dick, Emily; Crawford, Nicola; Parmentier, Julie; Alimzhanov, Marat; Babcook, John S; Foltz, Ian N; Buchanan, Andrew; Bedian, Vahe; Wilkinson, Robert W; McCourt, Matthew


    Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR.

  17. Cannabinoid CB1 receptor antagonist rimonabant disrupts nicotine reward-associated memory in rats. (United States)

    Fang, Qin; Li, Fang-Qiong; Li, Yan-Qin; Xue, Yan-Xue; He, Ying-Ying; Liu, Jian-Feng; Lu, Lin; Wang, Ji-Shi


    Exposure to cues previously associated with drug intake leads to relapse by activating previously acquired memories. Based on previous findings, in which cannabinoid CB(1) receptors were found to be critically involved in specific aspects of learning and memory, we investigated the role of CB(1) receptors in nicotine reward memory using a rat conditioned place preference (CPP) model. In Experiment 1, rats were trained for CPP with alternating injections of nicotine (0.5mg/kg, s.c.) and saline to acquire the nicotine-conditioned memory. To examine the effects of rimonabant on the reconsolidation of nicotine reward memory, rats were administered rimonabant (0, 0.3, and 3.0mg/kg, i.p.) immediately after reexposure to the drug-paired context. In Experiment 2, rats were trained for CPP similarly to Experiment 1. To examine the effects of rimonabant on the reinstatement of nicotine reward memory, rimonabant (0, 0.3, and 3.0mg/kg, i.p.) was administered before the test of nicotine-induced CPP reinstatement. In Experiment 3, to evaluate whether rimonabant itself produces a reward memory, rats were trained for CPP with alternating injections of different doses of rimonabant (0, 0.3, and 3.0mg/kg) and saline. Rimonabant at a dose of 3.0mg/kg significantly disrupted the reconsolidation of nicotine memory and significantly blocked the reinstatement of nicotine-induced CPP. However, rimonabant itself did not produce CPP. These findings provide clear evidence that CB(1) receptors play a role in nicotine reward memory, suggesting that CB(1) receptor antagonists may be a potential target for managing nicotine addiction.

  18. Interleukin-1 receptor antagonist protects against lipopolysaccharide induced diaphragm weakness in preterm lambs.

    Directory of Open Access Journals (Sweden)

    Kanakeswary Karisnan

    Full Text Available Chorioamnionitis (inflammation of the fetal membranes is strongly associated with preterm birth and in utero exposure to inflammation significantly impairs contractile function in the preterm lamb diaphragm. The fetal inflammatory response to intra-amniotic (IA lipopolysaccharide (LPS is orchestrated via interleukin 1 (IL-1. We aimed to determine if LPS induced contractile dysfunction in the preterm diaphragm is mediated via the IL-1 pathway. Pregnant ewes received IA injections of recombinant human IL-1 receptor antagonist (rhIL-1ra (Anakinra; 100 mg or saline (Sal 3 h prior to second IA injections of LPS (4 mg or Sal at 119d gestational age (GA. Preterm lambs were killed after delivery at 121d GA (term = 150 d. Muscle fibres dissected from the right hemi-diaphragm were mounted in an in vitro muscle test system for assessment of contractile function. The left hemi-diaphragm was snap frozen for molecular and biochemical analyses. Maximum specific force in lambs exposed to IA LPS (Sal/LPS group was 25% lower than in control lambs (Sal/Sal group; p=0.025. LPS-induced diaphragm weakness was associated with higher plasma IL-6 protein, diaphragm IL-1β mRNA and oxidised glutathione levels. Pre-treatment with rhIL-1ra (rhIL-1ra/LPS ameliorated the LPS-induced diaphragm weakness and blocked systemic and local inflammatory responses, but did not prevent the rise in oxidised glutathione. These findings indicate that LPS induced diaphragm dysfunction is mediated via IL-1 and occurs independently of oxidative stress. Therefore, the IL-1 pathway represents a potential therapeutic target in the management of impaired diaphragm function in preterm infants.

  19. Exploring Energy Efficiency of Lightweight Block Ciphers

    DEFF Research Database (Denmark)

    Banik, Subhadeep; Bogdanov, Andrey; Regazzoni, Francesco


    lightweight block ciphers, and thereby try to predict the optimal value of r at which an r-round unrolled architecture for a cipher is likely to be most energy efficient. We also try to relate our results to some physical design parameters like the signal delay across a round and algorithmic parameters like......In the last few years, the field of lightweight cryptography has seen an influx in the number of block ciphers and hash functions being proposed. One of the metrics that define a good lightweight design is the energy consumed per unit operation of the algorithm. For block ciphers, this operation...... is the encryption of one plaintext. By studying the energy consumption model of a CMOS gate, we arrive at the conclusion that the energy consumed per cycle during the encryption operation of an r-round unrolled architecture of any block cipher is a quadratic function in r. We then apply our model to 9 well known...

  20. Formation of Anisotropic Block Copolymer Gels (United States)

    Liaw, Chya Yan; Shull, Kenneth; Henderson, Kevin; Joester, Derk


    Anisotropic, fibrillar gels are important in a variety of processes. Biomineralization is one example, where the mineralization process often occurs within a matrix of collagen or chitin fibers that trap the mineral precursors and direct the mineralization process. We wish to replicate this type of behavior within block copolymer gels. Particularly, we are interested in employing gels composed of cylindrical micelles, which are anisotropic and closely mimic biological fibers. Micelle geometry is controlled in our system by manipulating the ratio of molecular weights of the two blocks and by controlling the detailed thermal processing history of the copolymer solutions. Small-Angle X-ray Scattering and Dynamic Light Scattering are used to determine the temperature dependence of the gel formation process. Initial experiments are based on a thermally-reversible alcohol-soluble system, that can be subsequently converted to a water soluble system by hydrolysis of a poly(t-butyl methacrylate) block to a poly (methacrylic acid) block. MRSEC.

  1. EnviroAtlas - Milwaukee, WI - Block Groups (United States)

    U.S. Environmental Protection Agency — This EnviroAtlas dataset is the base layer for the Milwaukee, WI EnviroAtlas area. The block groups are from the US Census Bureau and are included/excluded based on...

  2. Extrinsic germanium Blocked Impurity Bank (BIB) detectors (United States)

    Krabach, Timothy N.; Huffman, James E.; Watson, Dan M.


    Ge:Ga blocked-impurity-band (BIB) detectors with long wavelength thresholds greater than 190 microns and peak quantum efficiencies of 4 percent, at an operating temperature of 1.8 K, have been fabricated. These proof of concept devices consist of a high purity germanium blocking layer epitaxially grown on a Ga-doped Ge substrate. This demonstration of BIB behavior in germanium enables the development of far infrared detector arrays similar to the current silicon-based devices. Present efforts are focussed on improving the chemical vapor deposition process used to create the blocking layer and on the lithographic processing required to produce monolithic detector arrays in germanium. Approaches to test the impurity levels in both the blocking and active layers are considered.

  3. EnviroAtlas - Fresno, CA - Block Groups (United States)

    U.S. Environmental Protection Agency — This EnviroAtlas dataset is the base layer for the Fresno, CA EnviroAtlas area. The block groups are from the US Census Bureau and are included/excluded based on...

  4. Functionalization of Block Copolymer Vesicle Surfaces

    Directory of Open Access Journals (Sweden)

    Wolfgang Meier


    Full Text Available In dilute aqueous solutions certain amphiphilic block copolymers self-assemble into vesicles that enclose a small pool of water with a membrane. Such polymersomes have promising applications ranging from targeted drug-delivery devices, to biosensors, and nanoreactors. Interactions between block copolymer membranes and their surroundings are important factors that determine their potential biomedical applications. Such interactions are influenced predominantly by the membrane surface. We review methods to functionalize block copolymer vesicle surfaces by chemical means with ligands such as antibodies, adhesion moieties, enzymes, carbohydrates and fluorophores. Furthermore, surface-functionalization can be achieved by self-assembly of polymers that carry ligands at their chain ends or in their hydrophilic blocks. While this review focuses on the strategies to functionalize vesicle surfaces, the applications realized by, and envisioned for, such functional polymersomes are also highlighted.

  5. EnviroAtlas - Portland, OR - Block Groups (United States)

    U.S. Environmental Protection Agency — This EnviroAtlas dataset is the base layer for the Portland, OR EnviroAtlas area. The block groups are from the US Census Bureau and are included/excluded based on...

  6. EnviroAtlas - Cleveland, OH - Block Groups (United States)

    U.S. Environmental Protection Agency — This EnviroAtlas dataset is the base layer for the Cleveland, OH EnviroAtlas community. The block groups are from the US Census Bureau and are included/excluded...

  7. EnviroAtlas - Paterson, NJ - Block Groups (United States)

    U.S. Environmental Protection Agency — This EnviroAtlas dataset is the base layer for the Paterson, NJ EnviroAtlas area. The block groups are from the US Census Bureau and are included/excluded based on...

  8. EnviroAtlas - Memphis, TN - Block Groups (United States)

    U.S. Environmental Protection Agency — This EnviroAtlas dataset is the base layer for the Memphis, TN EnviroAtlas community. The block groups are from the US Census Bureau and are included/excluded based...

  9. EnviroAtlas - Phoenix, AZ - Block Groups (United States)

    U.S. Environmental Protection Agency — This EnviroAtlas dataset is the base layer for the Phoenix, AZ EnviroAtlas area. The block groups are from the US Census Bureau and are included/excluded based on...

  10. 1/f scaling in heart rate requires antagonistic autonomic control (United States)

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


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

  11. Pathological gambling induced by dopamine antagonists: a case report. (United States)

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


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

  12. Pharmacoepidemiological assessment of drug interactions with vitamin K antagonists

    DEFF Research Database (Denmark)

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


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

  13. Discovery and characterization of carbamothioylacrylamides as EP2 selective antagonists. (United States)

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


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

  14. [Antifibrillatory activity of dipeptide antagonist of nerve growth factor]. (United States)

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


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

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

    Directory of Open Access Journals (Sweden)

    Ashok K Dubey


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

  16. Algorithms for Finding the Inverses of Factor Block Circulant Matrices

    Institute of Scientific and Technical Information of China (English)


    In this paper, algorithms for finding the inverse of a factor block circulant matrix,a factor block retrocirculant matrix and partitioned matrix with factor block circulant blocks over the complex field are presented respectively. In addition, two algorithms for the inverse of a factor block circulant matrix over the quaternion division algebra are proposed.

  17. Adaptive cosine transform image coding with variable block size and constant block distortion (United States)

    Daut, David G.; Wu, Jia-Chyi


    An adaptive discrete cosine transform (DCT) image coding system is implemented with the same average distortion designated for each variable size image block. The variable block size segmentation is performed using a quadtree data structure by dividing the perceptually more important regions of an image into smaller size blocks compared to the size of blocks containing lesser amounts of spatial activity. Due to the nonstationarity of real-world images, each image block is described by a space-varying nonstationary Gauss-Markov random field. The space-varying autoregressive parameters are estimated using an on-line modified least- squares estimator. For each assumed space-varying nonstationary image block, a constant average distortion is assigned and the code rate for each image block is allowed to vary in order to meet the fixed distortion criterion. Simulation results show that reconstructed images coded at low average distortion, based on an assumed space-varying nonstationary image model, using variable size blocks and with variable bit rate per block possess high-quality subjective (visual) and objective (measured) quality at low average bit rates. Performance gains are achieved due to the distortion being distributed more uniformly among the blocks as compared with fixed-rate, stationary image transform coding schemes.

  18. Agonistic and antagonistic estrogens in licorice root (Glycyrrhiza glabra). (United States)

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


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

  19. Anticonvulsive effect of nonimidazole histamine H3 receptor antagonists. (United States)

    Sadek, Bassem; Kuder, Kamil; Subramanian, Dhanasekaran; Shafiullah, Mohamed; Stark, Holger; Lażewska, Dorota; Adem, Abdu; Kieć-Kononowicz, Katarzyna


    To determine the potential of histamine H3 receptor (H3R) ligands as new antiepileptic drugs (AEDs), aromatic ether, and diether derivatives (1-12) belonging to the nonimidazole class of ligands, with high in-vitro binding affinity at human H3R, were tested for their in-vivo anticonvulsive activity in the maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in rats. The anticonvulsive effects of a systemic injection of 1-12 on MES-induced and PTZ-kindled seizures were evaluated against the reference AED phenytoin (PHT) and the structurally related H3R antagonist/inverse agonist pitolisant (PIT). Among the most promising ligands 2, 4, 5, and 11, there was a significant and dose-dependent reduction in the duration of tonic hind limb extension (THLE) in MES-induced seizure subsequent to administration of 4 and 5 [(5, 10, and 15 mg/kg, intraperitoneally (i.p.)]. The protective effects observed for the 1-(3-(3-(4-chlorophenyl)propoxy)propyl)-3-methylpiperidine derivative 11 at 10 mg/kg, i.p. were significantly greater than those of PIT, and were reversed by pretreatment with the central nervous system penetrant H1R antagonist pyrilamine (PYR) (10 mg/kg). Moreover, the protective action of the reference AED PHT, at a dose of 5 mg/kg (without considerable protection in the MES model), was significantly augmented when coadministered with derivative 11 (5 mg/kg, i.p.). Surprisingly, pretreatment with derivative 7 (10 mg/kg, i.p.), an ethylphenoxyhexyl-piperidine derivative without considerable protection in the MES model, potently altered PTZ-kindled seizure, significantly prolonged myoclonic latency time, and clearly shortened the total seizure time when compared with control, PHT, and PIT. These interesting results highlight the potential of H3R ligands as new AEDs or as adjuvants to available AED therapeutics.

  20. Alpha antagonists and intraoperative floppy iris syndrome: A spectrum

    Directory of Open Access Journals (Sweden)

    Sharif A Issa


    Full Text Available Sharif A Issa, Omar H Hadid, Oliver Baylis, Margaret DayanDepartment of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UKBackground: To determine occurrence of features of intraoperative floppy iris syndrome (IFIS during cataract surgery in patients taking systemic alpha-antagonists (AA.Methods: We prospectively studied patients on AA and who underwent phacoemulsification. The following were recorded: pupil diameter preoperatively, iris flaccidity, iris prolapse and peroperative miosis.Results: We studied 40 eyes of 31 subjects. Mean age was 78 years. Overall, 14 eyes (13 patients showed signs of IFIS: 9/13 (69% eyes of patients on tamsulosin, 1/18 (6% eyes in the doxazosin group, 2/2 prazosin patients, 1/4 eyes in the indoramin group, and 1/2 eyes in two patients on a combination of doxazosin and tamsulosin. Most cases (92% had only one or two signs of IFIS. Bilateral cataract surgery was undertaken in 9 patients but only one patient (on tamsulosin had features of IFIS in both eyes, while 4 patients (2 on tamsulosin and 2 on other AA showed signs of IFIS in one eye only, and 4 patients did not show IFIS in either eye.Conclusion: Most AA were associated with IFIS, but it tends to present as a spectrum of signs rather than full triad originally described. Tamsulosin was most likely to be associated with IFIS; however, its intake does not necessarily mean that IFIS will occur. For patients on AA, the behavior of the iris intraoperatively in one eye is a poor predictor of the other eye. Surgeons should anticipate the occurrence of IFIS in any patient on AA.Keywords: alpha blocker, alpha antagonist, cataract surgery, intraoperative floppy iris syndrome, tamsulosin.

  1. Building-block selectivity of polyketide synthases. (United States)

    Liou, Grace F; Khosla, Chaitan


    For the past decade, polyketide synthases have presented an exciting paradigm for the controlled manipulation of complex natural product structure. These multifunctional enzymes catalyze the biosynthesis of polyketide natural products by stepwise condensation and modification of metabolically derived building blocks. In particular, regioselective modification of polyketide structure is possible by alterations in either intracellular acyl-CoA pools or, more commonly, by manipulation of acyl transferases that act as the primary gatekeepers for building blocks.

  2. Permutations with Ascending and Descending Blocks

    CERN Document Server

    Steinhardt, Jacob


    We investigate permutations in terms of their cycle structure and descent set. To do this, we generalize the classical bijection of Gessel and Reutenauer to deal with permutations that have some ascending and some descending blocks. We then provide the first bijective proofs of some known results. We also solve some problems posed in [3] by Eriksen, Freij, and Wastlund, who study derangements that descend in blocks of prescribed lengths.

  3. Dietary cholesterol modulates pathogen blocking by Wolbachia.

    Directory of Open Access Journals (Sweden)

    Eric P Caragata

    Full Text Available The bacterial endosymbiont Wolbachia pipientis protects its hosts from a range of pathogens by limiting their ability to form infections inside the insect. This "pathogen blocking" could be explained by innate immune priming by the symbiont, competition for host-derived resources between pathogens and Wolbachia, or the direct modification of the cell or cellular environment by Wolbachia. Recent comparative work in Drosophila and the mosquito Aedes aegypti has shown that an immune response is not required for pathogen blocking, implying that there must be an additional component to the mechanism. Here we have examined the involvement of cholesterol in pathogen blocking using a system of dietary manipulation in Drosophila melanogaster in combination with challenge by Drosophila C virus (DCV, a common fly pathogen. We observed that flies reared on cholesterol-enriched diets infected with the Wolbachia strains wMelPop and wMelCS exhibited reduced pathogen blocking, with viral-induced mortality occurring 2-5 days earlier than flies reared on Standard diet. This shift toward greater virulence in the presence of cholesterol also corresponded to higher viral copy numbers in the host. Interestingly, an increase in dietary cholesterol did not have an effect on Wolbachia density except in one case, but this did not directly affect the strength of pathogen blocking. Our results indicate that host cholesterol levels are involved with the ability of Wolbachia-infected flies to resist DCV infections, suggesting that cholesterol contributes to the underlying mechanism of pathogen blocking.

  4. Tunable Morphologies from Charged Block Copolymers

    Energy Technology Data Exchange (ETDEWEB)

    Goswami, Monojoy [ORNL; Sumpter, Bobby G [ORNL; Mays, Jimmy [ORNL; Messman, Jamie M [ORNL


    The bulk morphologies formed by a new class of charged block copolymers, 75 vol % fluorinated polyisoprene (FPI) 25 vol% sulfonated polystyrene (PSS) with 50% sulfonation, are characterized, and the fundamental underlying forces that promote the self-assembly processes are elucidated. The results show how the bulk morphologies are substantially different from their uncharged diblock counterparts (PS-PI) and also how morphology can be tuned with volume fraction of the charged block and the casting solvent. A physical understanding based on the underlying strong electrostatic interactions between the charged block and counterions is obtained using Monte Carlo (MC) and Molecular Dynamics (MD) simulations. The 75/25 FPI-PSS shows hexagonal morphologies with the minority blocks (PSS) forming the continuous phase due to charge percolation and the FPI blocks arranged in hexagonal cylinders. Some long-range order can be sustained even if lipophobicity is increased (addition of water), albeit with lower dimensional structures. However, thermal annealing provides sufficient energy to disrupt the percolated charges and promotes aggregation of ionic sites which leads to a disordered system. Diverse and atypical morphologies are readily accessible by simply changing the number distribution of the charges on PSS block.

  5. Helical Ordering in Chiral Block Copolymers (United States)

    Zhao, Wei; Hong, Sung Woo; Chen, Dian; Grason, Gregory; Russell, Thomas


    Introducing molecular chirality into the segments of block copolymers can influence the nature of the resultant morphology. Such an effect was found for poly(styrene-b-L-lactide) (PS-b-PLLA) diblock copolymers where hexagonally packed PLLA helical microdomains (H* phase) form in a PS matrix. However, molecular ordering of PLLA within the helical microdomains and the transfer of chirality from the segmental level to the mesoscale is still not well understood. We developed a field theoretic model to describe the interactions between segments of chiral blocks, which have the tendency to form a ``cholesteric'' texture. Based on the model, we calculated the bulk morphologies of chiral AB diblock copolymers using self-consistent field theory (SCFT). Experiments show that the H* phase only forms when microphase separation between PS and PLLA block happens first and crystallization of PLLA block is suppressed or happens within confined microdomain. Hence, crystalline ordering is not necessary for H* phase formation. The SCFT offers the chance to explore the range of thermodynamic stability of helical structures in the phase diagram of chiral block copolymer melts, by tuning parameters not only like the block segregation strength and composition, but also new parameters such as the ratio between preferred helical pitch to the radius of gyration and the Frank elastic constant for inter-segment distortions.

  6. Block copolymer membranes for aqueous solution applications

    KAUST Repository

    Nunes, Suzana Pereira


    Block copolymers are known for their intricate morphology. We review the state of the art of block copolymer membranes and discuss perspectives in this field. The main focus is on pore morphology tuning with a short introduction on non-porous membranes. The two main strategies for pore formation in block copolymer membranes are (i) film casting and selective block sacrifice and (ii) self-assembly and non-solvent induced phase separation (SNIPS). Different fundamental aspects involved in the manufacture of block copolymer membranes are considered, including factors affecting the equilibrium morphology in solid films, self-assembly of copolymer in solutions and macrophase separation by solvent-non-solvent exchange. Different mechanisms are proposed for different depths of the SNIPS membrane. Block copolymer membranes can be prepared with much narrower pore size distribution than homopolymer membranes. Open questions and indications of what we consider the next development steps are finally discussed. They include the synthesis and application of new copolymers and specific functionalization, adding characteristics to respond to stimuli and chemical environment, polymerization-induced phase separation, and the manufacture of organic-inorganic hybrids.

  7. Adaptive overlapped sub-blocks contrast enhancement (United States)

    Chen, Anqiu; Yuan, Fei; Liu, Jing; Liu, Siqi; Li, An; Zheng, Zhenrong


    In this paper, an overlapped sub-block gray-level average method for contrast enhancement is presented. The digital image correction of uneven illumination under microscope transmittance is a problem in image processing, also sometimes the image in the dark place need to correct the uneven problem. A new correction method was proposed based on the mask method and sub-blocks gray-level average method because Traditional mask method and background fitting method are restricted due to application scenarios, and the corrected image brightness is low by using background fitting method, so it has some limitations of the application. In this paper, we introduce a new method called AOSCE for image contrast enhancement. The image is divided into many sub-blocks which are overlapped, calculate the average gray-level of the whole image as M and the calculate the average gray-level of each one as mi, next for each block it can get d = mi - m, each block minus d to get a new image, and then get the minimum gray-level of each block into a matrix DD to get the background, and use bilinearity to get the same scale of the image. over fitting the image in matlab in order to get smoother image, then minus the background to get the contrast enhancement image.

  8. Comparison of GnRH Agonist, GnRH Antagonist, and GnRH Antagonist Mild Protocol of Controlled Ovarian Hyperstimulation in Good Prognosis Patients

    Directory of Open Access Journals (Sweden)

    Martin Stimpfel


    Full Text Available The reports on how to stimulate the ovaries for oocyte retrieval in good prognosis patients are contradictory and often favor one type of controlled ovarian hyperstimulation (COH. For this reason, we retrospectively analyzed data from IVF/ICSI cycles carried out at our IVF Unit in good prognosis patients (aged <38 years, first and second attempts of IVF/ICSI, more than 3 oocytes retrieved to elucidate which type of COH is optimal at our condition. The included patients were undergoing COH using GnRH agonist, GnRH antagonist or GnRH antagonist mild protocol in combination with gonadotrophins. We found significant differences in the average number of retrieved oocytes, immature oocytes, fertilized oocytes, embryos, transferred embryos, embryos frozen per cycle, and cycles with embryo freezing between studied COH protocols. Although there were no differences in live birth rate (LBR, miscarriages, and ectopic pregnancies between compared protocols, pregnancy rate was significantly higher in GnRH antagonist mild protocol in comparison with both GnRH antagonist and GnRH agonist protocols and cumulative LBR per cycle was significantly higher in GnRH antagonist mild protocol in comparison to GnRH agonist protocol. Our data show that GnRH antagonist mild protocol of COH could be the best method of choice in good prognosis patients.

  9. Synthesis of segmented (pb(ps-block-pb)(n)) and (pb(san-block- pb)(n)) block-copolymers via polymeric thermal iniferters

    NARCIS (Netherlands)

    Kroeze, E; ten Brinke, G.; Hadziioannou, G


    A technique is described for the synthesis of segmented poly(butadiene-block-styrene) block copolymers and segmented poly(butadiene-block-(styrene-co-acrylonitrile)) block copolymers through polybutadiene-based thermal iniferters. Dihydroxy- and dicarboxy-terminated polybutadienes were transformed i

  10. Agar composition affects in vitro screening of biocontrol activity of antagonistic microorganisms. (United States)

    Bosmans, L; De Bruijn, I; De Mot, R; Rediers, H; Lievens, B


    Agar-based screening assays are the method of choice when evaluating antagonistic potential of bacterial biocontrol-candidates against pathogens. We showed that when using the same medium, but different agar compositions, the activity of a bacterial antagonist against Agrobacterium was strongly affected. Consequently, results from in vitro screenings should be interpreted cautiously.

  11. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview. (United States)

    Soltani, Hoda; Pardakhty, Abbas


    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of "new drug delivery systems" is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  12. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview


    Soltani, Hoda; Pardakhty, Abbas


    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of “new drug delivery systems” is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  13. Screening of Fungus Antagonists against Six Main Disease Pathogens in Crops

    Institute of Scientific and Technical Information of China (English)


    28 soil samples were collected from the rhizosphere of 16 plant species in six different districts in Hunan. As a result of isolation and purification, 122 fungus strains were obtained of which the antagonistic activity was tested against six fungus pathogens in tomato, cotton, cucumber, chilli, rice and rape, and 17 strains were found antagonistic to one or more pathogenic fungi.

  14. Agar composition affects in vitro screening of biocontrol activity of antagonistic microorganisms

    NARCIS (Netherlands)

    Bosmans, Lien; De Bruijn, I.; de Mot, Rene; Readers, Hans; Lievens, Bart


    Agar-based screening assays are the method of choice when evaluating antagonistic potential of bacterial biocontrol-candidates against pathogens.Weshowed thatwhen using the samemedium, but different agar compositions, the activity of a bacterial antagonist against Agrobacteriumwas strongly affected.

  15. Anti-inflammatory properties of a novel peptide interleukin 1 receptor antagonist

    DEFF Research Database (Denmark)

    Klementiev, Boris; Li, Shizhong; Korshunova, Irina


    Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide.......Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide....

  16. Discovery of the CCR1 antagonist, BMS-817399, for the treatment of rheumatoid arthritis. (United States)

    Santella, Joseph B; Gardner, Daniel S; Duncia, John V; Wu, Hong; Dhar, Murali; Cavallaro, Cullen; Tebben, Andrew J; Carter, Percy H; Barrish, Joel C; Yarde, Melissa; Briceno, Stephanie W; Cvijic, Mary Ellen; Grafstrom, R Robert; Liu, Richard; Patel, Sima R; Watson, Andrew J; Yang, Guchen; Rose, Anne V; Vickery, Rodney D; Caceres-Cortes, Janet; Caporuscio, Christian; Camac, Daniel M; Khan, Javed A; An, Yongmi; Foster, William R; Davies, Paul; Hynes, John


    High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.

  17. Inhibition of tryptase release from human colon mast cells by histamine receptor antagonists. (United States)

    He, Shao-Heng; Xie, Hua; Fu, Yi-Ling


    The main objective of this study was to investigate the ability of histamine receptor antagonists to modulate tryptase release from human colon mast cells induced by histamine. Enzymatically dispersed cells from human colon were challenged with histamine in the absence or presence of the histamine receptor antagonists, and the tryptase release was determined. It was found that histamine induced tryptase release from colon mast cells was inhibited by up to approximately 61.5% and 24% by the H1 histamine receptor antagonist terfenadine and the H2 histamine receptor antagonist cimetidine, respectively, when histamine and its antagonists were added to cells at the same time. The H3 histamine receptor antagonist clobenpropit had no effect on histamine induced tryptase release from colon mast cells at all concentrations tested. Preincubation of terfenadine, cimetidine or clobenpropit with cells for 20 minutes before challenging with histamine did not enhance the ability of these antihistamines to inhibit histamine induced tryptase release. Apart from terfenadine at 100 microg/ml, the antagonists themselves did not stimulate tryptase release from colon mast cells following both 15 minutes and 35 minutes incubation periods. It was concluded that H1 and H2 histamine receptor antagonists were able to inhibit histamine induced tryptase release from colon mast cells. This not only added some new data to our hypothesis of self-amplification mechanisms of mast cell degranulation, but also suggested that combining these two types of antihistamine drugs could be useful for the treatment of inflammatory bowel disease (IBD).

  18. Survivin mRNA antagonists using locked nucleic acid, potential for molecular cancer therapy

    DEFF Research Database (Denmark)

    Fisker, Niels; Westergaard, Majken; Hansen, Henrik Frydenlund;


    synergistic effect when combining the mRNA antagonists against Survivin with the chemotherapeutic Taxol. This effect was demonstrated at concentrations of antagonists far lower than any previously demonstrated, indicating the high potential of locked nucleic acid for therapeutic use. Further characterisations...

  19. Transitions between male and female heterogamety caused by sex-antagonistic selection

    NARCIS (Netherlands)

    van Doorn, G. Sander; Kirkpatrick, Mark


    Many animal taxa show frequent and rapid transitions between male heterogamety (XY) and female heterogamety (ZW). We develop a model showing how these transitions can be driven by sex-antagonistic selection. Sex-antagonistic selection acting on loci linked to a new sex-determination mutation can cau

  20. Draft genome sequence of the antagonistic rhizosphere bacterium Serratia plymuthica strain PRI-2C. (United States)

    Garbeva, P; van Elsas, J D; de Boer, W


    Serratia plymuthica strain PRI-2C is a rhizosphere bacterial strain with antagonistic activity against different plant pathogens. Here we present the 5.39-Mb (G+C content, 55.67%) draft genome sequence of S. plymuthica strain PRI-2C with the aim of providing insight into the genomic basis of its antagonistic activity.

  1. The Early Paleozoic paleogeography of the North China block and the other major blocks of China

    Institute of Scientific and Technical Information of China (English)


    With the summarization of the Early Paleozoic paleomagnetic data recently obtained from the three major blocks of China, the Early Paleozoic (I.e. Cambrian and Ordovician) paleogeographic positions of the North China, South China and Tarim blocks were discussed in detail. The North China, South China and Tarim blocks were inferred to be located adjacent to East Gondwana in low latitudes of the Southern Hemisphere during the Early Cambrian. During the Early-Middle Ordovician, the South China and Tarim blocks were also located in low latitudes of the Southern Hemisphere with some affinities of the Gondwanaland, whereas the North China block may have episodically separated from the Gondwanaland, and might be sited close to the North America and Siberia. The reestablished paleogeographic configurations are in agreement with the studies on the biogeography, paleoclimate and sedimental facies of the North China and South China blocks.

  2. Effects of dopamine receptor agonist and antagonists on cholestasis-induced anxiolytic-like behaviors in rats. (United States)

    Reza Zarrindast, Mohammad; Eslimi Esfahani, Delaram; Oryan, Shahrbano; Nasehi, Mohammad; Torabi Nami, Mohammad


    Dysfunctions in the dopamine transmission system have been suggested to contribute to the pathogenesis of hepatic encephalopathy. In an experimental animal model, cholestasis induction through bile duct ligation may present several main pathological features of hepatic encephalopathy. Dopaminergic systems are shown to play pivotal roles in regulation of anxiety-like behaviors. The main bile duct in male Wistar rats, weighing 220-240 g, was ligated using two ligatures plus duct transection in between. Anxiety-like behaviors were measured using the elevated plus maze task. Cholestasis increased the open arm time percentage (%OAT), 13 but not 10 days after bile duct ligation, indicating an anxiolytic-like effect. Sole intraperitoneal injection of apomorphine (dopamine D1/D2 receptor agonist, 0.25 mg/kg), SCH23390 (dopamine D1 receptor antagonist, 0.005, 0.01 and 0.02 mg/kg) or sulpiride (dopamine D2 receptor antagonist, 0.125, 0.25 and 0.5 mg/kg) did not alter %OAT, open arm entries percentage (%OAE) and locomotor activity in the sham-operated rats. Meanwhile, the higher dose apomorphine (0.5 mg/kg) induced anxiolytic-like behaviors in this group. The subthreshold dose injection of SCH23390 or sulpiride, partially reversed the anxiolytic-like behaviors induced by cholestasis (13 days after bile duct ligation). On the other hand, subthreshold dose of apomorphine in cholestatic rats (10 days post bile duct ligation) induced anxiolytic-like effects which could be blocked by SCH23390 or sulpiride. The effective doses of above drugs did not alter locomotor activity, number of rearings, groomings and defections. These findings suggested that the dopaminergic system may potentially be involved in the modulation of cholestasis-induced anxiolytic-like behaviors in rats.

  3. An electrophysiological analysis of the effects of noradrenaline and alpha-receptor antagonists on neuromuscular transmission in mammalian muscular arteries. (United States)

    Holman, M E; Surprenant, A


    1 The effects of exogenously applied noradrenaline (NA) and alpha-adrenoceptor antagonists on the mechanical and intracellularly recorded responses to perivascular nerve stimulation were examined in the rabbit ear artery, rabbit saphenous artery and rat tail artery. 2 Excitatory junction potentials ( and action potentials recorded from these smooth muscles were not blocked or depressed by phentolamine, phenoxybenzamine, prazosin, or labetolol in concentrations as high as 10 microgram/ml. Phentolamine (1 to 10 microgram/ml) depressed neurally-evoked contractions of the ear and saphenous, but not the tail artery, and also depressed the contractions produced by direct muscle stimulation in the ear and saphenous arteries. Prazosin and labetolol (0.1 to 10 microgram/ml) had no effect on the neurally evoked contractile response in any of the arteries examined. 3 The amplitude of the steady-state e.j.p. during repetitive stimulation at 0.45 to 2 Hz was increased by phentolamine or phenoxybenzamine but not by prazosin or labetolol. Phentolamine and phenoxybenzamine also increased the amplitude of the e.j.p. evoked by a single stimulus in the majority of the preparations. 4 Concentrations of NA greater than or equal to 1 microgram/ml depolarized the smooth muscle while concentrations greater than or equal to 0.5 microgram/ml depressed the amplitude of the recorded from these arteries. alpha-Antagonists did not suppress either the NA-induced membrane depolarization or depression of 5 These observations call into question the physiological relevance of both pre- and postsynaptic alpha-receptors in regard to adrenergic neuromuscular transmission in muscular arteries.

  4. Antagonistic activity of autosimbionts А. viridans, B. subtilis and their probiotic association to conditionally microflora

    Directory of Open Access Journals (Sweden)

    Stepansky D.A.


    Full Text Available In this research the data on examination of antagonist qualities of bioassotiantes A. viridans and strain B. subtilis 3 towards pathogenic and opportunistic pathogenic microflora isolated from oropharynx and nasopharynx of children who were in contact with patients with pulmonary tuberculosis (MBT + are submitted. The expressed antagonist activity of autosimbionts A. viridans towards pathogenic and opportunistic pathogenic microflora was shown. Common antagonist activity of A. viridans (k N 1 and B. subtilis 3 towards diverse strains of test-cultures is 1,5-2 times higher, than separate antagonist activity of A. viridans (k №1 and B. subtilis 3. Received research data showed the possibility of continuing work on development of probiotic associations, that contain representatives of normal microflora - bioassociants A. viridans and probiotic strains B. subtilis 3 with broadspectrum of antagonistic activity in relation to the various groups of bacterium.

  5. Screening of antagonistic bacteria for biological control of nursery wilt of black pepper (Piper nigrum). (United States)

    Anith, K N; Radhakrishnan, N V; Manomohandas, T P


    Bacterial antagonists of Phytophthora capsici were isolated from underground shoot portions of rooted cuttings of black pepper. Initially isolates were screened by dual culture on potato dextrose agar and carrot agar. Further, a screening was done on black pepper shoots for supression of lesion caused by the pathogen. Most of the antagonists showed varying levels of antagonism in the dual culture and the shoot assay. Isolate PN-026, showing the highest suppression of lesion development in the shoot assay was found to be the most efficient antagonist in reducing Phytophthora capsici induced nursery wilt of black pepper. This screening involving the host, pathogen, and the antagonist, performed on black pepper shoot (the planting material for this vegetatively propagated crop), could be used as a rapid and reliable method for the isolation of efficient bacterial antagonists of P. capsici.

  6. Adductor canal block versus femoral nerve block for analgesia after total knee arthroplasty

    DEFF Research Database (Denmark)

    Jaeger, Pia; Zaric, Dusanka; Fomsgaard, Jonna Storm;


    Femoral nerve block (FNB), a commonly used postoperative pain treatment after total knee arthroplasty (TKA), reduces quadriceps muscle strength essential for mobilization. In contrast, adductor canal block (ACB) is predominately a sensory nerve block. We hypothesized that ACB preserves quadriceps...... muscle strength as compared with FNB (primary end point) in patients after TKA. Secondary end points were effects on morphine consumption, pain, adductor muscle strength, morphine-related complications, and mobilization ability....

  7. Synthesis of polyacrylonitrile-block-polydimethylsiloxane-block-polyacrylonitrile triblock copolymers via RAFT polymerization

    Institute of Scientific and Technical Information of China (English)

    Zheng Yue; Deng Xu Wang; Jing Quan Liu; Jie Zhang; Sheng Yu Feng


    A new A-B-A type of block copolymers,polyacrylonitrile-block-polydimethylsiloxane-block-polyacrylonitrile (PAN-b-PDMS-b-PAN),which comprises two polymer blocks of different polarities and compatibilities,were synthesized for the first time via reversible addition-fragmentation chain transfer polymerization.Reaction kinetics was investigated.PAN-b-PDMS-b-PAN films were prepared by spin-coating on glass chips.Significant order on the film surface morphologies was observed.(C) 2012 Jie Zhang.Published by Elsevier B.V.on behalf of Chinese Chemical Society.All rights reserved.

  8. [Effectiveness of sympathetic block using various technics]. (United States)

    Weissenberg, W


    Blocking of sympathetic conduction aims at permanent or temporary elimination of those pain pathways conducted by the sympathetic nervous system. In order to provide an objective evaluation of sufficient blocking effect, earlier inquiries referred to parameters such as: (1) observation of clinical signs such as Horner's syndrome, Guttman's sign, anhidrosis, extended venous filling; (2) difference in skin temperature of at least 1.5 degrees C between blocked and unblocked side; (3) increase in amplitude of the pulse wave; and (4) depression of the psychogalvanic reflex (PGR) on the blocked side (Fig. 1). In clinical practice, these control parameters are effective because they are time-saving, technically simple, and highly evidential. Further parameters for evaluating sympathetic blockade are examination of hydrosis by means of color indicators such as bromocresol and ninhydrin, oscillometry, and plethysmography. The effectiveness of sympathetic blockade after stellate ganglion and sympathetic trunk blocks has been verified by various authors. In a clinical study, 16 patients were divided into four groups in order to test the effectiveness of sympathetic blockade after spinal anesthesia with 3 ml 0.75% bupivacaine (group I) and 4 ml 0.75% bupivacaine (group II) and after peridural anesthesia with 15 ml 0.75% bupivacaine (group III) and 20 ml 0.75% bupivacaine (group IV) by means of temperature difference, response of pulse wave amplitude and PGR between blocked lower and unblocked upper extremity, and sensory levels of block. The patients were classified as ASA I and II; their ages varied from 20 to 63 years.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. A potential vorticity perspective on atmospheric blocking? (United States)

    Croci Maspoli, M.; Schwierz, C.


    A persistent large-scale anomaly of the west to east flow in the midlatitudes with a weakening and meridional splitting of the jet can be specified as atmospheric blocking. Lifetimes last from several days up to weeks so that blocking can therefore significantly determine monthly circulation index values. The vertical range affected by this phenomenon covers the entire troposphere as mirrored in increased surface pressure as well as an elevated tropopause and is also felt in the lower-stratosphere. Here we seek to shed more light on the physical mechanisms related to blocking by adopting the PV (potential vorticity) perspective with a focus on tropopause-level dynamics. Processes such as Rossby-wave breaking and diabatic heating can modify the conservative behaviour of the PV and are therefore important features for the formation and maintenance of atmospheric blocking. This motivates the definition of a novel blocking index based upon the three-dimensional structure of the phenomenon. A vertically integrated measure (PV within the 500 - 150 hPa layer, VIPV) is calculated, underlining the quasi-barotropic nature of blocked atmospheric state. Benefits of the new index include: representation of the two-dimensional structure of the phenomenon, its lifecycle and geographical distribution. The investigation is conducted over the period 1979 to 2001 using ECMWF reanalysis data. Characteristics of the VIPV field are presented. The new VIPV index is compared to a standard blocking index (e.g. Tibaldi and Molteni (1989)) on a case study basis and also with respect to seasonal variability. Relations to climate modes/indices (NAO, AO) are also discussed.

  10. Decomposition of Data Mining Algorithms into Unified Functional Blocks

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    Ivan Kholod


    Full Text Available The present paper describes the method of creating data mining algorithms from unified functional blocks. This method splits algorithms into independently functioning blocks. These blocks must have unified interfaces and implement pure functions. The method allows us to create new data mining algorithms from existing blocks and improves the existing algorithms by optimizing single blocks or the whole structure of the algorithms. This becomes possible due to a number of important properties inherent in pure functions and hence functional blocks.

  11. Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease. (United States)

    Yang, Xingxing; Chen, Xiaojuan; Bian, Guangxing; Tu, Jian; Xing, Yaling; Wang, Yayun; Chen, Zhongbin


    The emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe pulmonary disease in humans and represents the second example of a highly pathogenic coronavirus (CoV) following severe acute respiratory syndrome coronavirus (SARS-CoV). Genomic studies revealed that two viral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), process the polyproteins encoded by the MERS-CoV genomic RNA. We previously reported that SARS-CoV PLpro acts as both deubiquitinase (DUB) and IFN antagonist, but the function of the MERS-CoV PLpro was poorly understood. In this study, we characterized MERS-CoV PLpro, which is a protease and can recognize and process the cleavage sites (CS) of nsp1-2, nsp2-3 and nsp3-4. The LXGG consensus cleavage sites in the N terminus of pp1a/1ab, which is generally essential for CoV PLpro-mediated processing, were also characterized in MERS-CoV. MERS-CoV PLpro, like human SARS-CoV PLpro and NL63-CoV PLP2, is a viral deubiquitinating enzyme. It acts on both K48- and K63-linked ubiquitination and ISG15-linked ISGylation. We confirmed that MERS-CoV PLpro acts as an IFN antagonist through blocking the phosphorylation and nuclear translocation of IFN regulatory factor 3 (IRF3). These findings indicate that MERS-CoV PLpro acts as a viral DUB and suppresses production of IFN-β by an interfering IRF3-mediated signalling pathway, in addition to recognizing and processing the CS at the N terminus of replicase polyprotein to release the non-structural proteins. The characterization of proteolytic processing, DUB and IFN antagonist activities of MERS-CoV PLpro would reveal the interactions between MERS-CoV and its host, and be applicable to develop strategies targeting PLpro for the effective control of MERS-CoV infection.

  12. AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies. (United States)

    Seely, Kathryn A; Brents, Lisa K; Franks, Lirit N; Rajasekaran, Maheswari; Zimmerman, Sarah M; Fantegrossi, William E; Prather, Paul L


    Mu-opioid and CB1-cannabinoid agonists produce analgesia; however, adverse effects limit use of drugs in both classes. Additive or synergistic effects resulting from concurrent administration of low doses of mu- and CB1-agonists may produce analgesia with fewer side effects. Synergism potentially results from interaction between mu-opioid receptors (MORs) and CB1 receptors (CB1Rs). AM-251 and rimonabant are CB1R antagonist/inverse agonists employed to validate opioid-cannabinoid interactions, presumed to act selectively at CB1Rs. Therefore, the potential for direct action of these antagonists at MORs is rarely considered. This study determined if AM-251 and/or rimonabant directly bind and modulate the function of MORs. Surprisingly, AM-251 and rimonabant, but not a third CB1R inverse agonist AM-281, bind with mid-nanomolar affinity to human MORs with a rank order of affinity (K(i)) of AM-251 (251 nM) > rimonabant (652 nM) > AM281 (2135 nM). AM-251 and rimonabant, but not AM-281, also competitively antagonize morphine induced G-protein activation in CHO-hMOR cell homogenates (K(b) = 719 or 1310 nM, respectively). AM-251 and rimonabant block morphine inhibition of cAMP production, while only AM-251 elicits cAMP rebound in CHO-hMOR cells chronically exposed to morphine. AM-251 and rimonabant (10 mg/kg) attenuate morphine analgesia, whereas the same dose of AM-281 produces little effect. Therefore, in addition to high CB1R affinity, AM-251 and rimonabant bind to MORs with mid-nanomolar affinity and at higher doses may affect morphine analgesia via direct antagonism at MORs. Such CB1-independent of these antagonists effects may contribute to reported inconsistencies when CB1/MOR interactions are examined via pharmacological methods in CB1-knockout versus wild-type mice.

  13. Ultrasound guided TAP block versus ultrasound guided caudal block for pain relief in children undergoing lower abdominal surgeries

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    Wafaa Mohamed Alsadek


    Conclusion: TAP block and caudal block under ultrasound guidance proved to be safe with no recorded complications either intra or postoperatively. Patient and parent satisfaction was markedly observed in case of TAP block.

  14. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

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    Sadek B


    , in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-ylpropoxyphenylmethanol, and its (S-enantiomer (4 significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R-enantiomer (3 in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H3R agonist R-(α-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1–6 revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1–6 showed stereoselectivity in different convulsion models in male adult rats. Keywords: histamine, H3 receptor, isomeric antagonists, anticonvulsant activity, stereo­selectivity

  15. Mineral resources estimation based on block modeling (United States)

    Bargawa, Waterman Sulistyana; Amri, Nur Ali


    The estimation in this paper uses three kinds of block models of nearest neighbor polygon, inverse distance squared and ordinary kriging. The techniques are weighting scheme which is based on the principle that block content is a linear combination of the grade data or the sample around the block being estimated. The case study in Pongkor area, here is gold-silver resource modeling that allegedly shaped of quartz vein as a hydrothermal process of epithermal type. Resources modeling includes of data entry, statistical and variography analysis of topography and geological model, the block model construction, estimation parameter, presentation model and tabulation of mineral resources. Skewed distribution, here isolated by robust semivariogram. The mineral resources classification generated in this model based on an analysis of the kriging standard deviation and number of samples which are used in the estimation of each block. Research results are used to evaluate the performance of OK and IDS estimator. Based on the visual and statistical analysis, concluded that the model of OK gives the estimation closer to the data used for modeling.

  16. Chain exchange in block copolymer micelles (United States)

    Lu, Jie; Bates, Frank; Lodge, Timothy


    Block copolymer micelles are aggregates formed by self-assembly of amphiphilic copolymers dispersed in a selective solvent, driven by unfavorable interactions between the solvent and the core-forming block. Due to the relatively long chains being subject to additional thermodynamic and dynamic constraints (e.g., entanglements, crystallinity, vitrification), block copolymer micelles exhibit significantly slower equilibration kinetics than small molecule surfactants. As a result, details of the mechanism(s) of equilibration in block copolymer micelles remain unclear. This present works focuses on the chain exchange kinetics of poly(styrene-b-ethylenepropylene) block copolymers in squalane (C30H62) using time-resolved small angle neutron scattering (TR-SANS). A mixture of h-squalane and d-squalane is chosen so that it contrast matches a mixed 50/50 h/d polystyrene micelle core. When the temperature is appropriate and isotopically labeled chains undergo mixing, the mean core contrast with respect to the solvent decreases, and the scattering intensity is therefore reduced. This strategy allows direct probing of chain exchange rate from the time dependent scattering intensity I(q, t).

  17. Natural convection through enclosed disconnected solid blocks

    Energy Technology Data Exchange (ETDEWEB)

    Lao, Fernando Cesar De; Junqueira, Silvio L.M.; Franco, Admilson T. [Universidade Tecnologica Federal do Parana (UTFPR), Curitiba, PR (Brazil)]. E-mails:;;; Lage, Jose L. [Southern Methodist University (SMU), Dallas, TX (United States)]. E-mail:


    In this study, the natural convection inside a fluid filled, enclosure containing several solid obstructions and being heated from the side is modeled and numerically simulated. The solid obstructions are equally spaced, conducting, and disconnected square blocks. The mathematical model is based on the balance equations of mass, momentum and energy, which are then solved numerically via the finite-volume method with the SIMPLEST algorithm and the HYBRID scheme. The effects of varying the solid-fluid thermal conductivity ratio (K), the fluid volume-fraction or porosity ({phi}), the number of solid blocks (N) and the heating strength (represented by the Rayleigh number, Ra) of the enclosure on the Nusselt number based on the surface-averaged heat transfer coefficient along the heated wall of the enclosure are studied. The results indicate a competing effect caused by the proximity of the solid blocks to the heated and cooled walls, vis-a-vis hindering the boundary layer growth, hence reducing the heat transfer effectiveness, and at the same time enhancing the heat transfer when the blocks' thermal conductivity is larger than that of the fluid. An analytical estimate of the minimum number of blocks beyond which the convection hindrance becomes predominant is presented and validated by the numerical results. (author)

  18. Haplotype block structure is conserved across mammals.

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    Victor Guryev


    Full Text Available Genetic variation in genomes is organized in haplotype blocks, and species-specific block structure is defined by differential contribution of population history effects in combination with mutation and recombination events. Haplotype maps characterize the common patterns of linkage disequilibrium in populations and have important applications in the design and interpretation of genetic experiments. Although evolutionary processes are known to drive the selection of individual polymorphisms, their effect on haplotype block structure dynamics has not been shown. Here, we present a high-resolution haplotype map for a 5-megabase genomic region in the rat and compare it with the orthologous human and mouse segments. Although the size and fine structure of haplotype blocks are species dependent, there is a significant interspecies overlap in structure and a tendency for blocks to encompass complete genes. Extending these findings to the complete human genome using haplotype map phase I data reveals that linkage disequilibrium values are significantly higher for equally spaced positions in genic regions, including promoters, as compared to intergenic regions, indicating that a selective mechanism exists to maintain combinations of alleles within potentially interacting coding and regulatory regions. Although this characteristic may complicate the identification of causal polymorphisms underlying phenotypic traits, conservation of haplotype structure may be employed for the identification and characterization of functionally important genomic regions.

  19. Site-directed mutagenesis at the human B2 receptor and molecular modelling to define the pharmacophore of non-peptide bradykinin receptor antagonists. (United States)

    Meini, Stefania; Cucchi, Paola; Bellucci, Francesca; Catalani, Claudio; Faiella, Angela; Rotondaro, Luigi; Quartara, Laura; Giolitti, Alessandro; Maggi, Carlo Alberto


    Combining site-directed mutagenesis with information obtained from molecular modelling of the bradykinin (BK) human B2 receptor (hB2R) as derived from the bovine rhodopsin crystal structure [Science 289 (2000) 739], we previously defined a putative binding mode for the non-peptide B2 receptor antagonists, FR173657 and LF16-0687 [Can J Physiol Pharmacol 80 (2002) 303]. The present work is aimed to define the specific role of the quinoline moiety in the pharmacophore of these non-peptide antagonists. The effect of the mutations I110A, L114A (TM, transmembrane 3), W256A (TM6), F292A, Y295A and Y295F (TM7) was evaluated. None of the mutations affected the binding interaction of peptide ligands: the agonist BK and the peptide antagonist MEN 11270. The affinities in competing for [3H]-BK binding and in blocking the BK-induced IP production by the non-peptide antagonists LF16-0687 and FR173657 at the wild type and mutant receptors were analysed. While the affinities of LF16-0687 and FR173657 were crucially decreased at the I110A, Y295A, and Y295F mutants, the W256A mutation affected the affinity of the LF16-0687 only. The important contribution of the quinoline moiety was shown by the inability of an analogue of LF16-0687, lacking this moiety, to affect BK binding at the wild type receptor. On the other hand, the benzamidine group did not interact with mutated residues, since LF16-0687 analogues without this group or with an oxidated benzamidine displayed pairwise loss of affinity on wild type and mutated receptors. Further differences between FR173657 and LF16-0687 were highlighted at the I110 and Y295 mutants when comparing binding (pK(i)) and functional antagonist (pKB) affinity. First, the I110A mutation similarly impaired their binding affinity (250-fold), but at a less extent the antagonist potency of FR173657 only. Second, both the hydroxyl and the phenyl moieties of the Y295 residue had a specific role in the LF16-0687 interaction with the receptor, as

  20. Dopamine D(3) receptor antagonists: The quest for a potentially selective PET ligand. Part two: Lead optimization. (United States)

    Micheli, Fabrizio; Holmes, Ian; Arista, Luca; Bonanomi, Giorgio; Braggio, Simone; Cardullo, Francesca; Di Fabio, Romano; Donati, Daniele; Gentile, Gabriella; Hamprecht, Dieter; Terreni, Silvia; Heidbreder, Christian; Savoia, Chiara; Griffante, Cristiana; Worby, Angela


    The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.