Sample records for agonist tzp-101 accelerates

  1. Beta-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats. (United States)

    Frank, J A; Wang, Y; Osorio, O; Matthay, M A


    To determine whether beta-adrenergic agonist therapy increases alveolar liquid clearance during the resolution phase of hydrostatic pulmonary edema, we studied alveolar and lung liquid clearance in two animal models of hydrostatic pulmonary edema. Hydrostatic pulmonary edema was induced in sheep by acutely elevating left atrial pressure to 25 cmH(2)O and instilling 6 ml/kg body wt isotonic 5% albumin (prepared from bovine albumin) in normal saline into the distal air spaces of each lung. After 1 h, sheep were treated with a nebulized beta-agonist (salmeterol) or nebulized saline (controls), and left atrial pressure was then returned to normal. beta-Agonist therapy resulted in a 60% increase in alveolar liquid clearance over 3 h (P Ringer lactate). beta-Agonist therapy resulted in a significant decrease in excess lung water (P < 0.01) and significant improvement in arterial blood gases by 2 h (P < 0.03). These preclinical experimental studies support the need for controlled clinical trials to determine whether beta-adrenergic agonist therapy would be of value in accelerating the resolution of hydrostatic pulmonary edema in patients.

  2. Accelerated molecular dynamics simulations of the octopamine receptor using GPUs: discovery of an alternate agonist-binding position. (United States)

    Kastner, Kevin W; Izaguirre, Jesús A


    Octopamine receptors (OARs) perform key biological functions in invertebrates, making this class of G-protein coupled receptors (GPCRs) worth considering for insecticide development. However, no crystal structures and very little research exists for OARs. Furthermore, GPCRs are large proteins, are suspended in a lipid bilayer, and are activated on the millisecond timescale, all of which make conventional molecular dynamics (MD) simulations infeasible, even if run on large supercomputers. However, accelerated Molecular Dynamics (aMD) simulations can reduce this timescale to even hundreds of nanoseconds, while running the simulations on graphics processing units (GPUs) would enable even small clusters of GPUs to have processing power equivalent to hundreds of CPUs. Our results show that aMD simulations run on GPUs can successfully obtain the active and inactive state conformations of a GPCR on this reduced timescale. Furthermore, we discovered a potential alternate active-state agonist-binding position in the octopamine receptor which has yet to be observed and may be a novel GPCR agonist-binding position. These results demonstrate that a complex biological system with an activation process on the millisecond timescale can be successfully simulated on the nanosecond timescale using a simple computing system consisting of a small number of GPUs. Proteins 2016; 84:1480-1489. © 2016 Wiley Periodicals, Inc.

  3. Pharmacological profile of DA-6886, a novel 5-HT4 receptor agonist to accelerate colonic motor activity in mice. (United States)

    Lee, Min Jung; Cho, Kang Hun; Park, Hyun Min; Sung, Hyun Jung; Choi, Sunghak; Im, Weonbin


    DA-6886, the gastrointestinal prokinetic benzamide derivative is a novel 5-HT4 receptor agonist being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C). The purpose of this study was to characterize in vitro and in vivo pharmacological profile of DA-6886. We used various receptor binding assay, cAMP accumulation assay, organ bath experiment and colonic transit assay in normal and chemically constipated mice. DA-6886 exhibited high affinity and selectivity to human 5-HT4 receptor splice variants, with mean pKi of 7.1, 7.5, 7.9 for the human 5-HT4a, 5-HT4b and 5-HT4d, respectively. By contrast, DA-6886 did not show significant affinity for several receptors including dopamine D2 receptor, other 5-HT receptors except for 5-HT2B receptor (pKi value of 6.2). The affinity for 5-HT4 receptor was translated into functional agonist activity in Cos-7 cells expressing 5-HT4 receptor splice variants. Furthermore, DA-6886 induced relaxation of the rat oesophagus preparation (pEC50 value of 7.4) in a 5-HT4 receptor antagonist-sensitive manner. The evaluation of DA-6886 in CHO cells expressing hERG channels revealed that it inhibited hERG channel current with an pIC50 value of 4.3, indicating that the compound was 1000-fold more selective for the 5-HT4 receptor over hERG channels. In the normal ICR mice, oral administration of DA-6886 (0.4 and 2mg/kg) resulted in marked stimulation of colonic transit. Furthermore, in the loperamide-induced constipation mouse model, 2mg/kg of DA-6886 significantly improved the delay of colonic transit, similar to 10mg/kg of tegaserod. Taken together, DA-6886 is a highly potent and selective 5-HT4 receptor agonist to accelerate colonic transit in mice, which might be therapeutic agent having a favorable safety profile in the treatment of gastrointestinal motor disorders such as IBS-C and chronic constipation.

  4. Local release of pioglitazone (a peroxisome proliferator-activated receptor γ agonist) accelerates proliferation and remodeling phases of wound healing. (United States)

    Sakai, Shigeki; Sato, Keisuke; Tabata, Yasuhiko; Kishi, Kazuo


    Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily known for its anti-inflammatory and macrophage differentiation effects, as well as its ability to promote fat cell differentiation and reduce insulin resistance. Pioglitazone (Pio) is a PPARγ agonist used clinically as an anti-diabetic agent for improving insulin sensitivity in patients with diabetes. The objective of this study was to develop a drug delivery system (DDS) for the local release of Pio to promote wound healing. Pio of low aqueous solubility was water-solubilized by micelles formed from gelatin grafted with L-lactic acid oligomers, and incorporated into a biodegradable gelatin hydrogel. An 8-mm punch biopsy tool was used to prepare two skin wounds on either side of the midline of 8-week-old mice. Wounds were treated by the hydrogels with (Pio-hydrogel group) or without (control group) Pio, and the wound area were observed 1, 4, 7, and 14 days after treatment. In addition, a protein assay and immunohistological stain were performed to determine the effects of the Pio-hydrogel on inflammation and macrophage differentiation. The Pio-hydrogels promote wound healing. Moreover, Western blotting analysis demonstrated that treatment with Pio-hydrogels resulted in decreased levels of the cytokines MIP-2 and TGF-β, and increased levels of glucose-regulating adiponectin. It is concluded that Pio-incorporated hydrogels promote the proliferation and remodeling phases of wound healing, and may prove to be effective as wound dressings.

  5. GLP-1 Receptor Agonists (United States)

    ... in Balance › GLP-1 Receptor Agonists Fact Sheet GLP-1 Receptor Agonists May, 2012 Download PDFs English Espanol Editors Silvio ... are too high or too low. What are GLP-1 receptor agonist medicines? GLP-1 receptor agonist medicines, also called ...

  6. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart;


    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  7. [Melatonin receptor agonist]. (United States)

    Uchiyama, Makoto


    Melatonin is a hormone secreted by the pineal gland and is involved in the regulation of human sleep-wake cycle and circadian rhythms. The melatonin MT1 and MT2 receptors located in the suprachiasmatic nucleus in the hypothalamus play a pivotal role in the sleep-wake regulation. Based on the fact that MT1 receptors are involved in human sleep onset process, melatonin receptor agonists have been developed to treat insomnia. In this article, we first reviewed functions of melatonin receptors with special reference to MT1 and MT2, and properties and clinical application of melatonin receptor agonists as hypnotics.


    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

  9. Melatonin agonists and insomnia. (United States)

    Ferguson, Sally A; Rajaratnam, Shantha M W; Dawson, Drew


    The ability of melatonin to shift biological rhythms is well known. As a result, melatonin has been used in the treatment of various circadian rhythm sleep disorders, such as advanced and delayed sleep phase disorders, jet lag and shiftwork disorder. The current evidence for melatonin being efficacious in the treatment of primary insomnia is less compelling. The development of agents that are selective for melatonin receptors provides opportunity to further elucidate the actions of melatonin and its receptors and to develop novel treatments for specific types of sleep disorders. The agonists reviewed here - ramelteon, tasimelteon and agomelatine - all appear to be efficacious in the treatment of circadian rhythm sleep disorders and some types of insomnia. However, further studies are required to understand the mechanisms of action, particularly for insomnia. Clinical application of the agonists requires a good understanding of their phase-dependent properties. Long-term effects of melatonin should be evaluated in large-scale, independent randomized controlled trials.

  10. Pharmacogenetics of β2-Agonists


    Nobuyuki Hizawa


    Short-acting β2-agonists (SABAs) and long-acting β2-agonists (LABAs) are both important for treatment of asthma and chronic obstructive pulmonary disease (COPD) because of their bronchodilator and bronchoprotective effects. However, the use of these agonists, at least for asthma, has generated some controversy because of their association with increased mortality. Pharmacogenetics is the study of genetically determined variation in response to medications, which might prove useful for target ...

  11. EP4 agonist alleviates indomethacin-induced gastric lesions and promotes chronic gastric ulcer healing

    Institute of Scientific and Technical Information of China (English)

    Guang-Liang Jiang; Wha Bin Im; Yariv Donde; Larry A Wheeler


    AIM: To investigate EP4-selective agonist effect on indomethacin-induced gastric lesions and on the spontaneous healing of chronic gastric ulcers. METHODS: In a mouse model of gastric bleeding with high dose of indomethacin (20 mg/kg), an EP4-selective agonist was administered orally. Stomach lesions and gastric mucous regeneration were monitored. In a mouse model of chronic gastric ulcer induced by acetic acid, EP4 agonist effect on the healing of chronic gastric ulcer was evaluated in the presence or absence of low dose indomethacin (3 mg/kg). In cultured human gastric mucous cells, EP4 agonist effect on indomethacininduced apoptosis was assessed by flow cytometry. RESULTS: The EP4-selective agonist reduced high dose indomethacin-induced acute hemorrhagic damage and promoted mucous epithelial regeneration. Low-dose indomethacin aggravated ulcer bleeding and inflammation, and delayed the healing of the established chronic gastric ulcer. The EP4 agonist, when applied locally, not only offset indomethacin-induced gastric bleeding and inflammation, but also accelerated ulcer healing. In the absence of indomethacin, the EP4 agonist even accelerated chronic gastric ulcer healing and suppressed inflammatory cell infiltration in the granulation tissue. In vitro , the EP4 agonist protected human gastric mucous cells from indomethacin-induced apoptosis. CONCLUSION: EP4-selective agonist may prevent indomethacin-induced gastric lesions and promote healing of existing and indomethacin-aggravated gastric ulcers, via promoting proliferation and survival of mucous epithelial cells.

  12. A natural history of "agonist". (United States)

    Russo, Ruth


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

  13. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina


    Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists have become available for the treatment of type 2 diabetes. These agents exploit the physiological effects of GLP-1, which is able to address several of the pathophysiological features of type 2 diabetes. GLP-1R agonists...... presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide...

  14. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina


    Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists have become available for the treatment of type 2 diabetes. These agents exploit the physiological effects of GLP-1, which is able to address several of the pathophysiological features of type 2 diabetes. GLP-1R agonists...

  15. Pharmacogenetics of β2-Agonists

    Directory of Open Access Journals (Sweden)

    Nobuyuki Hizawa


    Full Text Available Short-acting β2-agonists (SABAs and long-acting β2-agonists (LABAs are both important for treatment of asthma and chronic obstructive pulmonary disease (COPD because of their bronchodilator and bronchoprotective effects. However, the use of these agonists, at least for asthma, has generated some controversy because of their association with increased mortality. Pharmacogenetics is the study of genetically determined variation in response to medications, which might prove useful for target therapies in highly responsive patients, especially for more expensive therapies or those with increased risk of side effects. Variation in response to both SABAs and LABAs has been observed in patients with polymorphisms in the β2 adrenoceptor gene (ADRB2. This review summarizes results from various studies on the possible relationship between ADRB2 polymorphisms and the bronchodilator or bronchoprotective effects of inhaled β2-agonists. By assessing the ADRB2 genotype, the hope is that it will be possible to predict the responsiveness to chronic administration of β2-agonists. Genetic testing, however, is of limited usefulness at this stage for ADRB2 because the common variants identified thus far account for only a small proportion of the variation observed for given responses. Carefully performed and adequately powered clinical trials continue to be important for achieving the goal of pharmacogenetic approaches to therapy.

  16. Future accelerators (?)

    Energy Technology Data Exchange (ETDEWEB)

    John Womersley


    I describe the future accelerator facilities that are currently foreseen for electroweak scale physics, neutrino physics, and nuclear structure. I will explore the physics justification for these machines, and suggest how the case for future accelerators can be made.

  17. Accelerating Value Creation with Accelerators

    DEFF Research Database (Denmark)

    Jonsson, Eythor Ivar


    accelerator programs. Microsoft runs accelerators in seven different countries. Accelerators have grown out of the infancy stage and are now an accepted approach to develop new ventures based on cutting-edge technology like the internet of things, mobile technology, big data and virtual reality. It is also...... with the traditional audit and legal universes and industries are examples of emerging potentials both from a research and business point of view to exploit and explore further. The accelerator approach may therefore be an Idea Watch to consider, no matter which industry you are in, because in essence accelerators...

  18. Accelerating Value Creation with Accelerators

    DEFF Research Database (Denmark)

    Jonsson, Eythor Ivar


    Accelerators can help to accelerate value creation. Accelerators are short-term programs that have the objective of creating innovative and fast growing ventures. They have gained attraction as larger corporations like Microsoft, Barclays bank and Nordea bank have initiated and sponsored accelera......Accelerators can help to accelerate value creation. Accelerators are short-term programs that have the objective of creating innovative and fast growing ventures. They have gained attraction as larger corporations like Microsoft, Barclays bank and Nordea bank have initiated and sponsored...... an approach to facilitate implementation and realization of business ideas and is a lucrative approach to transform research into ventures and to revitalize regions and industries in transition. Investors have noticed that the accelerator approach is a way to increase the possibility of success by funnelling...

  19. GnRH agonist triggering

    DEFF Research Database (Denmark)

    Kol, Shahar; Humaidan, Peter; Al Humaidan, Peter Samir Heskjær


    The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin (HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages...... triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients. Routinely, human chorionic gonadotrophin (HCG) is used to induce ovulation in fertility treatments. This approach deviates...... significantly from physiology and often results in insufficient hormonal support in early pregnancy and in ovarian hyperstimulation syndrome (OHSS). An alternative approach is to use a gonadotrophin-releasing hormone (GnRH) agonist which allows a more physiological trigger of ovulation and, most importantly...

  20. Impact of the AT(2) receptor agonist C21 on blood pressure and beyond

    DEFF Research Database (Denmark)

    Foulquier, Sébastien; Steckelings, Ulrike Muscha; Unger, Thomas


    It is now widely accepted that the angiotensin AT(2) receptor (AT(2)R) plays an important protective role during pathophysiologic conditions, acting as a repair system. The development of the first selective nonpeptide AT(2)R agonist C21 accelerated our understanding of AT(2)R-mediated protective...

  1. LIBO accelerates

    CERN Multimedia


    The prototype module of LIBO, a linear accelerator project designed for cancer therapy, has passed its first proton-beam acceleration test. In parallel a new version - LIBO-30 - is being developed, which promises to open up even more interesting avenues.


    Energy Technology Data Exchange (ETDEWEB)



    This paper compares various types of recirculating accelerators, outlining the advantages and disadvantages of various approaches. The accelerators are characterized according to the types of arcs they use: whether there is a single arc for the entire recirculator or there are multiple arcs, and whether the arc(s) are isochronous or non-isochronous.

  3. Regulation of membrane cholecystokinin-2 receptor by agonists enables classification of partial agonists as biased agonists. (United States)

    Magnan, Rémi; Masri, Bernard; Escrieut, Chantal; Foucaud, Magali; Cordelier, Pierre; Fourmy, Daniel


    Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at understanding the molecular mechanism by which pharmacological compounds regulate their presence at the cell surface is of paramount importance. In this context, using confocal microscopy and bioluminescence resonance energy transfer, we have investigated internalization and intracellular trafficking of the cholecystokinin-2 receptor (CCK2R) in response to both natural and synthetic ligands with different pharmacological features. We found that CCK and gastrin, which are full agonists on CCK2R-induced inositol phosphate production, rapidly and abundantly stimulate internalization. Internalized CCK2R did not rapidly recycle to plasma membrane but instead was directed to late endosomes/lysosomes. CCK2R endocytosis involves clathrin-coated pits and dynamin and high affinity and prolonged binding of β-arrestin1 or -2. Partial agonists and antagonists on CCK2R-induced inositol phosphate formation and ERK1/2 phosphorylation did not stimulate CCK2R internalization or β-arrestin recruitment to the CCK2R but blocked full agonist-induced internalization and β-arrestin recruitment. The extreme C-terminal region of the CCK2R (and more precisely phosphorylatable residues Ser(437)-Xaa(438)-Thr(439)-Thr(440)-Xaa(441)-Ser(442)-Thr(443)) were critical for β-arrestin recruitment. However, this region and β-arrestins were dispensable for CCK2R internalization. In conclusion, this study allowed us to classify the human CCK2R as a member of class B G-protein-coupled receptors with regard to its endocytosis features and identified biased agonists of the CCK2R. These new important insights will allow us to investigate the role of internalized CCK2R·β-arrestin complexes in cancers expressing this receptor and to develop new diagnosis and therapeutic strategies targeting this receptor.

  4. 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.

  5. Horizontal Accelerator (United States)

    Federal Laboratory Consortium — The Horizontal Accelerator (HA) Facility is a versatile research tool available for use on projects requiring simulation of the crash environment. The HA Facility is...


    Directory of Open Access Journals (Sweden)

    D. Cinghiţă


    Full Text Available In this work we study agonistic behavior of laboratory white mice when they are kept in captivity. For all this experimental work we used direct observation of mice, in small lists, because we need a reduced space to emphasize characteristics of agonistic behavior. Relations between members of the same species that live in organized groups are based in most cases on hierarchical structure. Relations between leader and subservient, decided by fighting, involve a thorough observation between individuals. Each member of a group has its own place on the ierarchical scale depending on resultes of fhights – it can be leader or it can be subsurvient, depending on if it wines or looses the fight. Once hierarchical scale made, every animal will adjust its behavior. After analyzing the obtained data we have enough reasons to believe that after fights the winner, usually, is the massive mouse, but it is also very important the sexual ripeness, so the immature male will be beaten. The leader male had a big exploring area and it checks up all territory.The females can be more aggressive, its fights are more brutal, than male fights are, when they fight for supremacy, but in this case fights are not as frequent as in the case of males. Always the superior female, on hierarchical scale, shows males its own statute, so the strongest genes will be perpetuated.

  7. Beta-agonists and animal welfare (United States)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  8. Accelerated Unification


    Arkani-Hamed, Nima; Cohen, Andrew; Georgi, Howard


    We construct four dimensional gauge theories in which the successful supersymmetric unification of gauge couplings is preserved but accelerated by N-fold replication of the MSSM gauge and Higgs structure. This results in a low unification scale of $10^{13/N}$ TeV.

  9. Particle Accelerators in China (United States)

    Zhang, Chuang; Fang, Shouxian

    As the special machines that can accelerate charged particle beams to high energy by using electromagnetic fields, particle accelerators have been widely applied in scientific research and various areas of society. The development of particle accelerators in China started in the early 1950s. After a brief review of the history of accelerators, this article describes in the following sections: particle colliders, heavy-ion accelerators, high-intensity proton accelerators, accelerator-based light sources, pulsed power accelerators, small scale accelerators, accelerators for applications, accelerator technology development and advanced accelerator concepts. The prospects of particle accelerators in China are also presented.


    Energy Technology Data Exchange (ETDEWEB)



    One of the major motivations driving recent interest in FFAGs is their use for the cost-effective acceleration of muons. This paper summarizes the progress in this area that was achieved leading up to and at the FFAG workshop at KEK from July 7-12, 2003. Much of the relevant background and references are also given here, to give a context to the progress we have made.

  11. Dopamine Agonists and Pathologic Behaviors

    Directory of Open Access Journals (Sweden)

    Brendan J. Kelley


    Full Text Available The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

  12. Endogenous Receptor Agonists: Resolving Inflammation

    Directory of Open Access Journals (Sweden)

    Gerhard Bannenberg


    Full Text Available Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A comprehensive understanding of the cellular and molecular events that control the termination of acute inflammation is needed in molecular terms given the widely held view that aberrant inflammation underlies many common diseases. This review focuses on recent advances in the understanding of the role of arachidonic acid and ω-3 polyunsaturated fatty acids (PUFA–derived lipid mediators in regulating the resolution of inflammation. Using a functional lipidomic approach employing LC-MS-MS–based informatics, recent studies, reviewed herein, uncovered new families of local-acting chemical mediators actively biosynthesized during the resolution phase from the essential fatty acids eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA. These new families of local chemical mediators are generated endogenously in exudates collected during the resolution phase, and were coined resolvins and protectins because specific members of these novel chemical families control both the duration and magnitude of inflammation in animal models of complex diseases. Recent advances on the biosynthesis, receptors, and actions of these novel anti-inflammatory and proresolving lipid mediators are reviewed with the aim to bring to attention the important role of specific lipid mediators as endogenous agonists in inflammation resolution.

  13. Laser acceleration (United States)

    Tajima, T.; Nakajima, K.; Mourou, G.


    The fundamental idea of Laser Wakefield Acceleration (LWFA) is reviewed. An ultrafast intense laser pulse drives coherent wakefield with a relativistic amplitude robustly supported by the plasma. While the large amplitude of wakefields involves collective resonant oscillations of the eigenmode of the entire plasma electrons, the wake phase velocity ˜ c and ultrafastness of the laser pulse introduce the wake stability and rigidity. A large number of worldwide experiments show a rapid progress of this concept realization toward both the high-energy accelerator prospect and broad applications. The strong interest in this has been spurring and stimulating novel laser technologies, including the Chirped Pulse Amplification, the Thin Film Compression, the Coherent Amplification Network, and the Relativistic Mirror Compression. These in turn have created a conglomerate of novel science and technology with LWFA to form a new genre of high field science with many parameters of merit in this field increasing exponentially lately. This science has triggered a number of worldwide research centers and initiatives. Associated physics of ion acceleration, X-ray generation, and astrophysical processes of ultrahigh energy cosmic rays are reviewed. Applications such as X-ray free electron laser, cancer therapy, and radioisotope production etc. are considered. A new avenue of LWFA using nanomaterials is also emerging.

  14. Metabotropic glutamate receptor agonists modify the pyloric output of the crustacean stomatogastric ganglion. (United States)

    Pérez-Acevedo, Nivia L; Krenz, Wulf D


    We have studied the effects of groups I, II, and III metabotropic glutamate receptor (mGluR) agonists and antagonists on pyloric activity in the stomatogastric ganglion (STG) of the Caribbean spiny lobster Panulirus argus. We have found that agonists for all three groups of mGluRs modify the pyloric output. The group I agonist, l-quisqualic acid (l-QA), activated the pyloric central pattern generator (CPG). When the pyloric rhythm was partially suppressed by sucrose-block of input fibers in the stomatogastric nerve (stn), l-QA accelerated the rhythmic activity. In addition, the number of spike discharges was increased in pyloric motoneurons: pyloric (PY), and lateral pyloric (LP). In completely blocked preparations, a slow pyloric rhythm was initiated by l-QA. Groups II and III agonists exerted an inhibitory effect on pyloric activity. The group II agonist, (2S,1'S,2'S)-2-(Carboxycyclopropyl)glycine (L-CCG-I), decreased both the frequency of the pyloric rhythm and the number of spike discharges in the motoneurons: ventricular dilator (VD), PY, and LP. The effects of L-CCG-I were dose-dependent. The group III agonist, l-(+)-2-Amino-4-phosphonobutyric acid (l-AP4), slightly decreased the frequency of the pyloric rhythm and suppressed spike discharges in the VD neuron. All effects of mGluR agonists were reversible. The effect of l-QA was blocked by the broad spectrum mGluR antagonist (S)-Methyl-4-carboxyphenylglycine (MCPG). The inhibitory effect of L-CCG-I was prevented by MCPG and by the group II/III mGluR antagonist (RS)-alpha-Methyl-4-phosphonophenylglycine (MPPG), and was partially blocked by the group II mGluR antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA). The inhibitory effect of l-AP4 was blocked by MPPG and partially blocked by APICA.

  15. The effects of the specific 5HT(4) receptor agonist, prucalopride, on colonic motility in healthy volunteers

    NARCIS (Netherlands)

    De Schryver, AMP; Andriesse, GI; Samsom, M; Smout, AJPM; Gooszen, HG; Akkermans, LMA


    Background: Prucalopride is a selective and specific 5-hydroxytryptamine(4) receptor agonist that is known to increase stool frequency and to accelerate colonic transit. Aim: To investigate the effect of prucalopride on high-amplitude propagated contractions and segmental pressure waves in healthy v

  16. Accelerators and the Accelerator Community

    Energy Technology Data Exchange (ETDEWEB)

    Malamud, Ernest; Sessler, Andrew


    In this paper, standing back--looking from afar--and adopting a historical perspective, the field of accelerator science is examined. How it grew, what are the forces that made it what it is, where it is now, and what it is likely to be in the future are the subjects explored. Clearly, a great deal of personal opinion is invoked in this process.

  17. PPAR Agonists and Cardiovascular Disease in Diabetes

    Directory of Open Access Journals (Sweden)

    Anna C. Calkin


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

  18. PPAR Agonists and Cardiovascular Disease in Diabetes (United States)

    Calkin, Anna C.; Thomas, Merlin C.


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

  19. PPAR Agonists and Cardiovascular Disease in Diabetes. (United States)

    Calkin, Anna C; Thomas, Merlin C


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

  20. Dihydrocodeine / Agonists for Alcohol Dependents

    Directory of Open Access Journals (Sweden)

    Albrecht eUlmer


    Full Text Available Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients.Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC to 102 heavily alcohol addict-ed patients, later, also Buprenorphine, Clomethiazole (>6 weeks, Baclofen and in one case Amphetamine, each on individual indication. This paper focuses on the data with DH, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC-treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-step scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details.Conclusions: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around ¼ of the patients already. Many further

  1. accelerating cavity

    CERN Multimedia

    On the inside of the cavitytThere is a layer of niobium. Operating at 4.2 degrees above absolute zero, the niobium is superconducting and carries an accelerating field of 6 million volts per metre with negligible losses. Each cavity has a surface of 6 m2. The niobium layer is only 1.2 microns thick, ten times thinner than a hair. Such a large area had never been coated to such a high accuracy. A speck of dust could ruin the performance of the whole cavity so the work had to be done in an extremely clean environment.

  2. Impact accelerations (United States)

    Vongierke, H. E.; Brinkley, J. W.


    The degree to which impact acceleration is an important factor in space flight environments depends primarily upon the technology of capsule landing deceleration and the weight permissible for the associated hardware: parachutes or deceleration rockets, inflatable air bags, or other impact attenuation systems. The problem most specific to space medicine is the potential change of impact tolerance due to reduced bone mass and muscle strength caused by prolonged weightlessness and physical inactivity. Impact hazards, tolerance limits, and human impact tolerance related to space missions are described.

  3. Muscimol as an ionotropic GABA receptor agonist. (United States)

    Johnston, Graham A R


    Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol(®)) and 4-PIOL.

  4. Identification of Selective ERRγ Inverse Agonists

    Directory of Open Access Journals (Sweden)

    Jina Kim


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

  5. Gonadotropin releasing hormone agonists: Expanding vistas

    Directory of Open Access Journals (Sweden)

    Navneet Magon


    Full Text Available Gonadotropin-releasing hormone (GnRH agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women′s healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

  6. Exploring prospects of β3-adrenoceptor agonists and inverse agonists for colon mobility control

    Directory of Open Access Journals (Sweden)

    Maria Grazia Perrone


    Full Text Available Inverse agonists are useful active ingredient of drugs clinically used to treat diseases mainly involving receptors endowed with non-endogenous agonist induced activity (constitutive or basal activity. SP-1e and SP-1g are the first two potent and highly selective β3-adrenoceptor inverse agonists [EC50=181 nM (IA=- 64% and 136 nM (IA=-73%, respectively], which their peculiar activity seems due to the absolute configurations of the two stereogenic centres present in each molecule. Rat proximal colon motility measurements allowed their further pharmacological characterization and pA2 values determination by Schild analysis (7.89 and 8.16, respectively. The purpose of our work is a further characterization of our novel β3-adrenoceptor agonists (SP-1a-d, SP-1f,1h and inverse agonists (SP-1e and SP-1g on rat proximal colon motility and a confirmation of their inverse agonist nature in a more complex system like the functional test on rat proximal colon. Male Wistar rats segment of the proximal colon were placed in organ baths containing Krebs solution. Muscle tension was recorded isotonically. Cumulative β3-AR agonists doses experiments were performed for each test compound: isoprenaline, BRL37344, SP-1a-d, SP-1f and SP-1h were dissolved in Krebs. The EC50 values of each agonists and pA2 of inverse agonists were determined. SP- 1a-d, SP-1f and SP-1h in rat colon have a muscle relaxing effect thus confirming their partial agonist activity found in CHO-K1 cell line. SP-1e and SP-1g behaved as antagonists with pA2 values of 7.89 and 8.16, respectively. In conclusion, experiments carried out by using isolated rat proximal colon allowed us to determine the pA2 values of the two β3-AR inverse agonists and add knowledge on the behavior of a novel set of compounds and their possible value as agents useful whenever is necessary to also control the colon motility.

  7. Recent advances in the discovery of alpha1-adrenoceptor agonists. (United States)

    Bishop, Michael J


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

  8. Subtype selective kainic acid receptor agonists

    DEFF Research Database (Denmark)

    Bunch, Lennart; Krogsgaard-Larsen, Povl


    (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (m......GluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists...

  9. Agonistic and reproductive interactions in Betta splendens. (United States)

    Bronstein, P M


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

  10. Signal Use by Octopuses in Agonistic Interactions. (United States)

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


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

  11. Agonist trigger: what is the best approach? Agonist trigger and low dose hCG

    DEFF Research Database (Denmark)

    Humaidan, Peter; Al Humaidan, Peter Samir Heskjær


    Low-dose hCG supplementation after GnRH agonist trigger may normalize reproductive outcome while minimizing the occurrence of OHSS in high risk IVF patients. (Fertil Steril (R) 2012;97:529-30. (C) 2012 by American Society for Reproductive Medicine.)......Low-dose hCG supplementation after GnRH agonist trigger may normalize reproductive outcome while minimizing the occurrence of OHSS in high risk IVF patients. (Fertil Steril (R) 2012;97:529-30. (C) 2012 by American Society for Reproductive Medicine.)...

  12. 2014 CERN Accelerator Schools: Plasma Wake Acceleration

    CERN Multimedia


    A specialised school on Plasma Wake Acceleration will be held at CERN, Switzerland from 23-29 November, 2014.   This course will be of interest to staff and students in accelerator laboratories, university departments and companies working in or having an interest in the field of new acceleration techniques. Following introductory lectures on plasma and laser physics, the course will cover the different components of a plasma wake accelerator and plasma beam systems. An overview of the experimental studies, diagnostic tools and state of the art wake acceleration facilities, both present and planned, will complement the theoretical part. Topical seminars and a visit of CERN will complete the programme. Further information can be found at:

  13. Dopamine agonist: pathological gambling and hypersexuality. (United States)


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

  14. Combining GLP-1 receptor agonists with insulin

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Vilsbøll, T


    physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase insulin release and suppress glucagon secretion in a glucose...... potential of GLP-1RA-insulin combination therapy, typically showing beneficial effects on glycaemic control and body weight, with a low incidence of hypoglycaemia and, in established insulin therapy, facilitating reductions in insulin dose. In this review, the physiological and pharmacological rationale...

  15. SNC 80 and related delta opioid agonists. (United States)

    Calderon, S N; Coop, A


    The discovery of the selective delta (delta) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, was a major advance in the field of delta-opioid ligands. Much research has been performed to uncover the structure-activity relationships (SAR) of this class of ligands and also to compare the diarylmethylpiperazines with the traditional morphinan-based delta opioids. This review focuses on the development of the SAR of this unique series of ligands, and discusses questions which remain unanswered.

  16. Sports doping: emerging designer and therapeutic β2-agonists. (United States)

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F


    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.

  17. Improved plasma accelerator (United States)

    Cheng, D. Y.


    Converging, coaxial accelerator electrode configuration operates in vacuum as plasma gun. Plasma forms by periodic injections of high pressure gas that is ionized by electrical discharges. Deflagration mode of discharge provides acceleration, and converging contours of plasma gun provide focusing.

  18. Accelerator Technology Division (United States)


    In fiscal year (FY) 1991, the Accelerator Technology (AT) division continued fulfilling its mission to pursue accelerator science and technology and to develop new accelerator concepts for application to research, defense, energy, industry, and other areas of national interest. This report discusses the following programs: The Ground Test Accelerator Program; APLE Free-Electron Laser Program; Accelerator Transmutation of Waste; JAERI, OMEGA Project, and Intense Neutron Source for Materials Testing; Advanced Free-Electron Laser Initiative; Superconducting Super Collider; The High-Power Microwave Program; (Phi) Factory Collaboration; Neutral Particle Beam Power System Highlights; Accelerator Physics and Special Projects; Magnetic Optics and Beam Diagnostics; Accelerator Design and Engineering; Radio-Frequency Technology; Free-Electron Laser Technology; Accelerator Controls and Automation; Very High-Power Microwave Sources and Effects; and GTA Installation, Commissioning, and Operations.

  19. High Energy Particle Accelerators

    CERN Multimedia

    Audio Productions, Inc, New York


    Film about the different particle accelerators in the US. Nuclear research in the US has developed into a broad and well-balanced program.Tour of accelerator installations, accelerator development work now in progress and a number of typical experiments with high energy particles. Brookhaven, Cosmotron. Univ. Calif. Berkeley, Bevatron. Anti-proton experiment. Negative k meson experiment. Bubble chambers. A section on an electron accelerator. Projection of new accelerators. Princeton/Penn. build proton synchrotron. Argonne National Lab. Brookhaven, PS construction. Cambridge Electron Accelerator; Harvard/MIT. SLAC studying a linear accelerator. Other research at Madison, Wisconsin, Fixed Field Alternate Gradient Focusing. (FFAG) Oakridge, Tenn., cyclotron. Two-beam machine. Comments : Interesting overview of high energy particle accelerators installations in the US in these early years. .

  20. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation


    Maharjan Anu S; Pilling Darrell; Gomer Richard H


    Abstract Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs) are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fi...

  1. Accelerators, Colliders, and Snakes (United States)

    Courant, Ernest D.


    The author traces his involvement in the evolution of particle accelerators over the past 50 years. He participated in building the first billion-volt accelerator, the Brookhaven Cosmotron, which led to the introduction of the "strong-focusing" method that has in turn led to the very large accelerators and colliders of the present day. The problems of acceleration of spin-polarized protons are also addressed, with discussions of depolarizing resonances and "Siberian snakes" as a technique for mitigating these resonances.

  2. Far field acceleration

    Energy Technology Data Exchange (ETDEWEB)

    Fernow, R.C.


    Far fields are propagating electromagnetic waves far from their source, boundary surfaces, and free charges. The general principles governing the acceleration of charged particles by far fields are reviewed. A survey of proposed field configurations is given. The two most important schemes, Inverse Cerenkov acceleration and Inverse free electron laser acceleration, are discussed in detail.

  3. Accelerators and Dinosaurs

    CERN Document Server

    Turner, Michael Stanley


    Using naturally occuring particles on which to research might have made accelerators become extinct. But in fact, results from astrophysics have made accelerator physics even more important. Not only are accelerators used in hospitals but they are also being used to understand nature's inner workings by searching for Higgs bosons, CP violation, neutrino mass and dark matter (2 pages)

  4. The CERN Accelerator School

    CERN Multimedia


    Introduction to accelerator physics The CERN Accelerator School: Introduction to Accelerator Physics, which should have taken place in Istanbul, Turkey, later this year has now been relocated to Budapest, Hungary.  Further details regarding the new hotel and dates will be made available as soon as possible on a new Indico site at the end of May.

  5. Acceleration: It's Elementary (United States)

    Willis, Mariam


    Acceleration is one tool for providing high-ability students the opportunity to learn something new every day. Some people talk about acceleration as taking a student out of step. In actuality, what one is doing is putting a student in step with the right curriculum. Whole-grade acceleration, also called grade-skipping, usually happens between…

  6. The Accelerator Reliability Forum

    CERN Document Server

    Lüdeke, Andreas; Giachino, R


    A high reliability is a very important goal for most particle accelerators. The biennial Accelerator Reliability Workshop covers topics related to the design and operation of particle accelerators with a high reliability. In order to optimize the over-all reliability of an accelerator one needs to gather information on the reliability of many different subsystems. While a biennial workshop can serve as a platform for the exchange of such information, the authors aimed to provide a further channel to allow for a more timely communication: the Particle Accelerator Reliability Forum [1]. This contribution will describe the forum and advertise it’s usage in the community.

  7. Industrial Application of Accelerators

    CERN Document Server

    CERN. Geneva


    At CERN, we are very familiar with large, high energy particle accelerators. However, in the world outside CERN, there are more than 35000 accelerators which are used for applications ranging from treating cancer, through making better electronics to removing harmful micro-organisms from food and water. These are responsible for around $0.5T of commerce each year. Almost all are less than 20 MeV and most use accelerator types that are somewhat different from what is at CERN. These lectures will describe some of the most common applications, some of the newer applications in development and the accelerator technology used for them. It will also show examples of where technology developed for particle physics is now being studied for these applications. Rob Edgecock is a Professor of Accelerator Science, with a particular interest in the medical applications of accelerators. He works jointly for the STFC Rutherford Appleton Laboratory and the International Institute for Accelerator Applications at the Univer...

  8. Industrial Application of Accelerators

    CERN Document Server

    CERN. Geneva


    At CERN, we are very familiar with large, high energy particle accelerators. However, in the world outside CERN, there are more than 35000 accelerators which are used for applications ranging from treating cancer, through making better electronics to removing harmful micro-organisms from food and water. These are responsible for around $0.5T of commerce each year. Almost all are less than 20 MeV and most use accelerator types that are somewhat different from what is at CERN. These lectures will describe some of the most common applications, some of the newer applications in development and the accelerator technology used for them. It will also show examples of where technology developed for particle physics is now being studied for these applications. Rob Edgecock is a Professor of Accelerator Science, with a particular interest in the medical applications of accelerators. He works jointly for the STFC Rutherford Appleton Laboratory and the International Institute for Accelerator Applications at the Uni...

  9. The importance of β2-agonists in myocardial infarction

    DEFF Research Database (Denmark)

    Rørth, Rasmus; Fosbøl, Emil L; Mogensen, Ulrik M;


    PURPOSE: β2-Agonists are widely used for relief of respiratory symptoms. Studies so far have reported conflicting results regarding use of β2-agonists and risk of myocardial infarction (MI). Yet, coronary angiographical data and longitudinal outcomes data are sparse and could help explain...

  10. Estrogen receptor beta agonists in neurobehavioral investigations. (United States)

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


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

  11. Particle-accelerator decommissioning

    Energy Technology Data Exchange (ETDEWEB)

    Opelka, J.H.; Mundis, R.L.; Marmer, G.J.; Peterson, J.M.; Siskind, B.; Kikta, M.J.


    Generic considerations involved in decommissioning particle accelerators are examined. There are presently several hundred accelerators operating in the United States that can produce material containing nonnegligible residual radioactivity. Residual radioactivity after final shutdown is generally short-lived induced activity and is localized in hot spots around the beam line. The decommissioning options addressed are mothballing, entombment, dismantlement with interim storage, and dismantlement with disposal. The recycle of components or entire accelerators following dismantlement is a definite possibility and has occurred in the past. Accelerator components can be recycled either immediately at accelerator shutdown or following a period of storage, depending on the nature of induced activation. Considerations of cost, radioactive waste, and radiological health are presented for four prototypic accelerators. Prototypes considered range from small accelerators having minimal amounts of radioactive mmaterial to a very large accelerator having massive components containing nonnegligible amounts of induced activation. Archival information on past decommissionings is presented, and recommendations concerning regulations and accelerator design that will aid in the decommissioning of an accelerator are given.

  12. Accelerator and radiation physics

    CERN Document Server

    Basu, Samita; Nandy, Maitreyee


    "Accelerator and radiation physics" encompasses radiation shielding design and strategies for hadron therapy accelerators, neutron facilities and laser based accelerators. A fascinating article describes detailed transport theory and its application to radiation transport. Detailed information on planning and design of a very high energy proton accelerator can be obtained from the article on radiological safety of J-PARC. Besides safety for proton accelerators, the book provides information on radiological safety issues for electron synchrotron and prevention and preparedness for radiological emergencies. Different methods for neutron dosimetry including LET based monitoring, time of flight spectrometry, track detectors are documented alongwith newly measured experimental data on radiation interaction with dyes, polymers, bones and other materials. Design of deuteron accelerator, shielding in beam line hutches in synchrotron and 14 MeV neutron generator, various radiation detection methods, their characteriza...

  13. Leaky Fermi accelerators

    CERN Document Server

    Shah, Kushal; Rom-Kedar, Vered; Turaev, Dmitry


    A Fermi accelerator is a billiard with oscillating walls. A leaky accelerator interacts with an environment of an ideal gas at equilibrium by exchange of particles through a small hole on its boundary. Such interaction may heat the gas: we estimate the net energy flow through the hole under the assumption that the particles inside the billiard do not collide with each other and remain in the accelerator for sufficiently long time. The heat production is found to depend strongly on the type of the Fermi accelerator. An ergodic accelerator, i.e. one which has a single ergodic component, produces a weaker energy flow than a multi-component accelerator. Specifically, in the ergodic case the energy gain is independent of the hole size, whereas in the multi-component case the energy flow may be significantly increased by shrinking the hole size.

  14. Accelerator reliability workshop

    Energy Technology Data Exchange (ETDEWEB)

    Hardy, L.; Duru, Ph.; Koch, J.M.; Revol, J.L.; Van Vaerenbergh, P.; Volpe, A.M.; Clugnet, K.; Dely, A.; Goodhew, D


    About 80 experts attended this workshop, which brought together all accelerator communities: accelerator driven systems, X-ray sources, medical and industrial accelerators, spallation sources projects (American and European), nuclear physics, etc. With newly proposed accelerator applications such as nuclear waste transmutation, replacement of nuclear power plants and others. Reliability has now become a number one priority for accelerator designers. Every part of an accelerator facility from cryogenic systems to data storage via RF systems are concerned by reliability. This aspect is now taken into account in the design/budget phase, especially for projects whose goal is to reach no more than 10 interruptions per year. This document gathers the slides but not the proceedings of the workshop.

  15. Power Converters for Accelerators

    CERN Document Server

    Visintini, R


    Particle accelerators use a great variety of power converters for energizing their sub-systems; while the total number of power converters usually depends on the size of the accelerator or combination of accelerators (including the experimental setup), the characteristics of power converters depend on their loads and on the particle physics requirements: this paper aims to provide an overview of the magnet power converters in use in several facilities worldwide.


    Energy Technology Data Exchange (ETDEWEB)



    Due to their finite lifetime, muons must be accelerated very rapidly. It is challenging to make the magnets ramp fast enough to accelerate in a synchrotron, and accelerating in a linac is very expensive. One can use a recirculating accelerator (like CEBAF), but one needs a different arc for each turn, and this limits the number of turns one can use to accelerate, and therefore requires significant amounts of RF to achieve the desired energy gain. An alternative method for muon acceleration is using a fixed field alternating gradient (FFAG) accelerator. Such an accelerator has a very large energy acceptance (a factor of two or three), allowing one to use the same arc with a magnetic field that is constant over time. Thus, one can in principle make as many turns as one can tolerate due to muon decay, therefore reducing the RF cost without increasing the arc cost. This paper reviews the current status of research into the design of FFAGs for muon acceleration. Several current designs are described and compared. General design considerations are also discussed.

  17. High Gradient Accelerator Research

    Energy Technology Data Exchange (ETDEWEB)

    Temkin, Richard [Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Dept. of Physics. Plasma Science and Fusion Center


    The goal of the MIT program of research on high gradient acceleration is the development of advanced acceleration concepts that lead to a practical and affordable next generation linear collider at the TeV energy level. Other applications, which are more near-term, include accelerators for materials processing; medicine; defense; mining; security; and inspection. The specific goals of the MIT program are: • Pioneering theoretical research on advanced structures for high gradient acceleration, including photonic structures and metamaterial structures; evaluation of the wakefields in these advanced structures • Experimental research to demonstrate the properties of advanced structures both in low-power microwave cold test and high-power, high-gradient test at megawatt power levels • Experimental research on microwave breakdown at high gradient including studies of breakdown phenomena induced by RF electric fields and RF magnetic fields; development of new diagnostics of the breakdown process • Theoretical research on the physics and engineering features of RF vacuum breakdown • Maintaining and improving the Haimson / MIT 17 GHz accelerator, the highest frequency operational accelerator in the world, a unique facility for accelerator research • Providing the Haimson / MIT 17 GHz accelerator facility as a facility for outside users • Active participation in the US DOE program of High Gradient Collaboration, including joint work with SLAC and with Los Alamos National Laboratory; participation of MIT students in research at the national laboratories • Training the next generation of Ph. D. students in the field of accelerator physics.

  18. FFAGS for rapid acceleration

    Energy Technology Data Exchange (ETDEWEB)

    Carol J. Johnstone and Shane Koscielniak


    When large transverse and longitudinal emittances are to be transported through a circular machine, extremely rapid acceleration holds the advantage that the beam becomes immune to nonlinear resonances because there is insufficient time for amplitudes to build up. Uncooled muon beams exhibit large emittances and require fast acceleration to avoid decay losses and would benefit from this style of acceleration. The approach here employs a fixed-field alternating gradient or FFAG magnet structure and a fixed frequency acceleration system. Acceptance is enhanced by the use only of linear lattice elements, and fixed-frequency rf enables the use of cavities with large shunt resistance and quality factor.

  19. The cardiovascular effects of peroxisome proliferator-activated receptor agonists. (United States)

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


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

  20. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation

    Directory of Open Access Journals (Sweden)

    Maharjan Anu S


    Full Text Available Abstract Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF-α accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN-α, IFN-γ, interleukin (IL-12, aggregated immunoglobulin G (IgG or serum amyloid P (SAP, factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-α, IFN-γ, granulocyte colony-stimulating factor and tumor growth factor β1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes. Conclusions Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure.

  1. KEK digital accelerator (United States)

    Iwashita, T.; Adachi, T.; Takayama, K.; Leo, K. W.; Arai, T.; Arakida, Y.; Hashimoto, M.; Kadokura, E.; Kawai, M.; Kawakubo, T.; Kubo, Tomio; Koyama, K.; Nakanishi, H.; Okazaki, K.; Okamura, K.; Someya, H.; Takagi, A.; Tokuchi, A.; Wake, M.


    The High Energy Accelerator Research Organization KEK digital accelerator (KEK-DA) is a renovation of the KEK 500 MeV booster proton synchrotron, which was shut down in 2006. The existing 40 MeV drift tube linac and rf cavities have been replaced by an electron cyclotron resonance (ECR) ion source embedded in a 200 kV high-voltage terminal and induction acceleration cells, respectively. A DA is, in principle, capable of accelerating any species of ion in all possible charge states. The KEK-DA is characterized by specific accelerator components such as a permanent magnet X-band ECR ion source, a low-energy transport line, an electrostatic injection kicker, an extraction septum magnet operated in air, combined-function main magnets, and an induction acceleration system. The induction acceleration method, integrating modern pulse power technology and state-of-art digital control, is crucial for the rapid-cycle KEK-DA. The key issues of beam dynamics associated with low-energy injection of heavy ions are beam loss caused by electron capture and stripping as results of the interaction with residual gas molecules and the closed orbit distortion resulting from relatively high remanent fields in the bending magnets. Attractive applications of this accelerator in materials and biological sciences are discussed.

  2. Accelerators Beyond The Tevatron?

    Energy Technology Data Exchange (ETDEWEB)

    Lach, Joseph; /Fermilab


    Following the successful operation of the Fermilab superconducting accelerator three new higher energy accelerators were planned. They were the UNK in the Soviet Union, the LHC in Europe, and the SSC in the United States. All were expected to start producing physics about 1995. They did not. Why?


    Energy Technology Data Exchange (ETDEWEB)

    Sessler, Andrew M.


    Diverse methods proposed for the acceleration of particles by means of collective fields are reviewed. A survey is made of the various currently active experimental programs devoted to investigating collective acceleration, and the present status of the research is briefly noted.

  4. Asia honours accelerator physicists

    CERN Multimedia


    "Steve Meyers of Cern and Jie Wei of Beijing's Tsinghua University are the first recipients of a new prize for particle physics. The pair were honoured for their contributions to numerous particle-accelerator projects - including Cern's Large Hadron Collider - by the Asian Committee for Future Accelerators (ACFA)..." (1 paragraph)

  5. Unique interaction pattern for a functionally biased ghrelin receptor agonist

    DEFF Research Database (Denmark)

    Sivertsen, Bjørn Behrens; Lang, Manja; Frimurer, Thomas M.


    /13) pathway. The recognition pattern of wFw-Isn-NH(2) with the ghrelin receptor also differed significantly from that of all previously characterized unbiased agonists. Most importantly, wFw-Isn-NH(2) was not dependent on GluIII:09 (Glu3.33), which otherwise is an obligatory TM III anchor point residue...... orientation as compared with, for example, the wFw peptide agonists. It is concluded that the novel peptide-mimetic ligand wFw-Isn-NH(2) is a biased ghrelin receptor agonist and that the selective signaling pattern presumably is due to its unique receptor recognition pattern lacking interaction with key...

  6. Accelerators, Beams And Physical Review Special Topics - Accelerators And Beams

    Energy Technology Data Exchange (ETDEWEB)

    Siemann, R.H.; /SLAC


    Accelerator science and technology have evolved as accelerators became larger and important to a broad range of science. Physical Review Special Topics - Accelerators and Beams was established to serve the accelerator community as a timely, widely circulated, international journal covering the full breadth of accelerators and beams. The history of the journal and the innovations associated with it are reviewed.

  7. The Accelerated Kepler Problem

    CERN Document Server

    Namouni, Fathi


    The accelerated Kepler problem is obtained by adding a constant acceleration to the classical two-body Kepler problem. This setting models the dynamics of a jet-sustaining accretion disk and its content of forming planets as the disk loses linear momentum through the asymmetric jet-counterjet system it powers. The dynamics of the accelerated Kepler problem is analyzed using physical as well as parabolic coordinates. The latter naturally separate the problem's Hamiltonian into two unidimensional Hamiltonians. In particular, we identify the origin of the secular resonance in the accelerated Kepler problem and determine analytically the radius of stability boundary of initially circular orbits that are of particular interest to the problem of radial migration in binary systems as well as to the truncation of accretion disks through stellar jet acceleration.

  8. On Accelerated Black Holes

    CERN Document Server

    Letelier, P S; Letelier, Patricio S.; Oliveira, Samuel R.


    The C-metric is revisited and global interpretation of some associated spacetimes are studied in some detail. Specially those with two event horizons, one for the black hole and another for the acceleration. We found that the spacetime fo an accelerated Schwarzschild black hole is plagued by either conical singularities or lack of smoothness and compactness of the black hole horizon. By using standard black hole thermodynamics we show that accelerated black holes have higher Hawking temperature than Unruh temperature. We also show that the usual upper bound on the product of the mass and acceleration parameters (<1/sqrt(27)) is just a coordinate artifact. The main results are extended to accelerated Kerr black holes. We found that they are not changed by the black hole rotation.

  9. Nicotine receptor partial agonists for smoking cessation

    Directory of Open Access Journals (Sweden)

    Kate Cahill

    Full Text Available BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist and reducing smoking satisfaction (acting as an antagonist. OBJECTIVES: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including cytisine, dianicline and varenicline for smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist' in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, PsycINFO and Web of Science using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialized register was in December 2011. We also searched online clinical trials registers. SELECTION CRITERIA: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow-up. The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs, using the Mantel-Haenszel fixed-effect model. MAIN RESULTS: Two recent cytisine trials (937 people


    Directory of Open Access Journals (Sweden)

    Ni Luh Putu Ayu Maha Iswari


    Full Text Available Melatonin is a hormone that has an important role in the mechanism of sleep. Hypnotic effects of melatonin and melatonin receptor agonist are mediated via MT1 and MT2 receptors, especially in circadian rhythm pacemaker, suprachiasmatic nucleus, which is worked on the hypothalamic sleep switch. This mechanism is quite different with the GABAergic drugs such as benzodiazepine. Agonist melatonin triggers the initiation of sleep and normalize circadian rhythms so that makes it easier to maintain sleep. The main disadvantage of melatonin in helping sleep maintenance on primary insomnia is that the half life is very short. The solution to this problem is the use of prolonged-release melatonin and melatonin receptor agonist agents such as ramelteon. Melatoninergic agonist does not cause withdrawal effects, dependence, as well as cognitive and psychomotor disorders as often happens on the use of benzodiazepine.  

  11. Cosmic particle acceleration

    Energy Technology Data Exchange (ETDEWEB)

    Zimbardo, Gaetano; Perri, Silvia [Universita della Calabria, Dipartimento di Fisica, 87036 Rende (Italy)


    The most popular mechanism for the acceleration of cosmic rays, which is thought to operate in supernova remnant shocks as well as at heliospheric shocks, is the diffusive shock acceleration, which is a Fermi mechanism based on normal diffusion. On the other hand, in the last few years it has been shown that the transport of plasma particles in the presence of electric and magnetic turbulence can be superdiffusive rather than normal diffusive. The term 'superdiffusive' refers to the mean square displacement of particle positions growing superlinearly with time, as compared to the normal linear growth. In particular, superdiffusion is characterized by a non Gaussian statistical process called Levy random walk. We show how diffusive shock acceleration is modified by superdiffusion, and how this yields new predictions for the cosmic ray spectral index, for the acceleration time, and for the spatial profile of energetic particles. A comparison with observations of particle acceleration at heliospheric shocks and at supernova remnant shocks is done. We discuss how superdiffusive shock acceleration allows to explain the observations of hard ion spectra at the solar wind termination shock detected by Voyager 2, of hard radio spectra due to synchrotron emission of electrons accelerated at supernova remnant shocks, and how it can help to explain the observations of 'thin rims' in the X-ray synchrotron emission.

  12. The miniature accelerator

    CERN Multimedia

    Antonella Del Rosso


    The image that most people have of CERN is of its enormous accelerators and their capacity to accelerate particles to extremely high energies. But thanks to some cutting-edge studies on beam dynamics and radiofrequency technology, along with innovative construction techniques, teams at CERN have now created the first module of a brand-new accelerator, which will be just 2 metres long. The potential uses of this miniature accelerator will include deployment in hospitals for the production of medical isotopes and the treatment of cancer. It’s a real David-and-Goliath story.   Serge Mathot, in charge of the construction of the "mini-RFQ", pictured with the first of the four modules that will make up the miniature accelerator. The miniature accelerator consists of a radiofrequency quadrupole (RFQ), a component found at the start of all proton accelerator chains around the world, from the smallest to the largest. The LHC is designed to produce very high-intensity beams ...

  13. Application of Accelerators and Storage Rings: Accelerators in Medicine

    CERN Document Server

    Amaldi, U


    This document is part of Subvolume C 'Accelerators and Colliders' of Volume 21 'Elementary Particles' of Landolt-Börnstein - Group I 'Elementary Particles, Nuclei and Atoms'. It contains the the Section '11.3 Accelerators in Medicine' of the Chapter '11 Application of Accelerators and Storage Rings' with the content: 11.3 Accelerators in Medicine 11.3.1 Accelerators and Radiopharmaceuticals 11.3.2 Accelerators and Cancer Therapy

  14. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control]. (United States)

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


    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

  15. Toll-like receptor agonists in cancer therapy


    Adams, Sylvia


    Toll-like receptors (TLRs) are pattern-recognition receptors related to the Drosophila Toll protein. TLR activation alerts the immune system to microbial products and initiates innate and adaptive immune responses. The naturally powerful immunostimulatory property of TLR agonists can be exploited for active immunotherapy against cancer. Antitumor activity has been demonstrated in several cancers, and TLR agonists are now undergoing extensive clinical investigation. This review discusses recen...

  16. Confronting Twin Paradox Acceleration (United States)

    Murphy, Thomas W.


    The resolution to the classic twin paradox in special relativity rests on the asymmetry of acceleration. Yet most students are not exposed to a satisfactory analysis of what exactly happens during the acceleration phase that results in the nonaccelerated observer's more rapid aging. The simple treatment presented here offers both graphical and quantitative solutions to the problem, leading to the correct result that the acceleration-induced age gap is 2Lβ years when the one-way distance L is expressed in light-years and velocity β ≡v/c .

  17. Short-Acting Beta-Agonist Research: A Perspective

    Directory of Open Access Journals (Sweden)

    Malcolm R Sears


    Full Text Available Asthma mortality increased sharply in New Zealand in 1977, prompting a national investigation into circumstances of asthma deaths. Subsequent observations of improved asthma control in subjects withdrawn from regular beta2-agonist treatment raised the question of whether asthma severity and, therefore, mortality could relate to frequent beta-agonist use. A randomized controlled trial of regular inhaled fenoterol versus as-needed bronchodilator use showed worsened asthma control during regular treatment despite concomitant use of inhaled corticosteroids. Assessment of these findings led to delay in the publishing of the American Asthma Guidelines, which were modified to suggest caution in using beta2-agonist treatments. Simultaneously, case control studies in New Zealand suggested that prescription of fenoterol was a substantial risk factor for asthma mortality. The causal association was hotly debated, but increasing evidence pointed to an adverse effect of fenoterol on asthma severity and, hence, mortality. This was supported by dramatic decreases in both morbidity and mortality when fenoterol was effectively withdrawn from use in New Zealand. The link between worsening asthma morbidity and mortality, and the use of potent short-acting beta2-agonists fulfills the Bradford Hill criteria for attributing causality. Application of evidence from randomized, controlled trials of short-acting beta-agonist use has led to a major shift in therapy in asthma to the recommendation of as-needed use only of short-acting beta-agonists and decreased patient reliance on regular bronchodilator therapy.

  18. Histamine H3-receptor inverse agonists as novel antipsychotics. (United States)

    Ito, Chihiro


    Schizophrenia (SZ) that is resistant to treatment with dopamine (DA) D2 antagonists may involve changes other than those in the dopaminergic system. Recently, histamine (HA), which regulates arousal and cognitive functions, has been suggested to act as a neurotransmitter in the central nervous system. Four HA receptors-H1, H2, H3, and H4-have been identified. Our recent basic and clinical studies revealed that brain HA improved the symptoms of SZ. The H3 receptor is primarily localized in the central nervous system, and it acts not only as a presynaptic autoreceptor that modulates the HA release but also as a presynaptic heteroreceptor that regulates the release of other neurotransmitters such as monoamines and amino acids. H3-receptor inverse agonists have been considered to improve cognitive functions. Many atypical antipsychotics are H3-receptor antagonists. Imidazole-containing H3-receptor inverse agonists inhibit not only cytochrome P450 but also hERG potassium channels (encoded by the human ether-a-go-go-related gene). Several imidazole H3-receptor inverse agonists also have high affinity for H4 receptors, which are expressed at high levels in mast cells and leukocytes. Clozapine is an H4-receptor agonist; this agonist activity may be related to the serious side effect of agranulocytosis caused by clozapine. Therefore, selective non-imidazole H3-receptor inverse agonists can be considered as novel antipsychotics that may improve refractory SZ.

  19. Acceleration of cutaneous wound healing by brassinosteroids. (United States)

    Esposito, Debora; Rathinasabapathy, Thirumurugan; Schmidt, Barbara; Shakarjian, Michael P; Komarnytsky, Slavko; Raskin, Ilya


    Brassinosteroids are plant growth hormones involved in cell growth, division, and differentiation. Their effects in animals are largely unknown, although recent studies showed that the anabolic properties of brassinosteroids are possibly mediated through the phosphoinositide 3-kinase/protein kinase B signaling pathway. Here, we examined biological activity of homobrassinolide (HB) and its synthetic analogues in in vitro proliferation and migration assays in murine fibroblast and primary keratinocyte cell culture. HB stimulated fibroblast proliferation and migration and weakly induced keratinocyte proliferation in vitro. The effects of topical HB administration on progression of wound closure were further tested in the mouse model of cutaneous wound healing. C57BL/6J mice were given a full-thickness dermal wound, and the rate of wound closure was assessed daily for 10 days, with adenosine receptor agonist CGS-21680 as a positive control. Topical application of brassinosteroid significantly reduced wound size and accelerated wound healing in treated animals. mRNA levels of transforming growth factor beta and intercellular adhesion molecule 1 were significantly lower, while tumor necrosis factor alpha was nearly suppressed in the wounds from treated mice. Our data suggest that topical application of brassinosteroids accelerates wound healing by positively modulating inflammatory and reepithelialization phases of the wound repair process, in part by enhancing Akt signaling in the skin at the edges of the wound and enhancing migration of fibroblasts in the wounded area. Targeting this signaling pathway with brassinosteroids may represent a promising approach to the therapy of delayed wound healing.

  20. Vibration control in accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Montag, C.


    In the vast majority of accelerator applications, ground vibration amplitudes are well below tolerable magnet jitter amplitudes. In these cases, it is necessary and sufficient to design a rigid magnet support structure that does not amplify ground vibration. Since accelerator beam lines are typically installed at an elevation of 1-2m above ground level, special care has to be taken in order to avoid designing a support structure that acts like an inverted pendulum with a low resonance frequency, resulting in untolerable lateral vibration amplitudes of the accelerator components when excited by either ambient ground motion or vibration sources within the accelerator itself, such as cooling water pumps or helium flow in superconducting magnets. In cases where ground motion amplitudes already exceed the required jiter tolerances, for instance in future linear colliders, passive vibration damping or active stabilization may be considered.

  1. Joint International Accelerator School

    CERN Multimedia

    CERN Accelerator School


    The CERN and US Particle Accelerator Schools recently organised a Joint International Accelerator School on Beam Loss and Accelerator Protection, held at the Hyatt Regency Hotel, Newport Beach, California, USA from 5-14 November 2014. This Joint School was the 13th in a series of such schools, which started in 1985 and also involves the accelerator communities in Japan and Russia.   Photo courtesy of Alfonse Pham, Michigan State University.   The school attracted 58 participants representing 22 different nationalities, with around half from Europe and the other half from Asia and the Americas. The programme comprised 26 lectures, each of 90 minutes, and 13 hours of case study. The students were given homework each day and had an opportunity to sit a final exam, which counted towards university credit. Feedback from the participants was extremely positive, praising the expertise and enthusiasm of the lecturers, as well as the high standard and quality of their lectures. Initial dis...

  2. Rejuvenating CERN's Accelerators

    CERN Multimedia


    In the coming years and especially in 2005, CERN's accelerators are going to receive an extensive renovation programme to ensure they will perform reliably and effectively when the LHC comes into service.

  3. Dielectric assist accelerating structure (United States)

    Satoh, D.; Yoshida, M.; Hayashizaki, N.


    A higher-order TM02 n mode accelerating structure is proposed based on a novel concept of dielectric loaded rf cavities. This accelerating structure consists of ultralow-loss dielectric cylinders and disks with irises which are periodically arranged in a metallic enclosure. Unlike conventional dielectric loaded accelerating structures, most of the rf power is stored in the vacuum space near the beam axis, leading to a significant reduction of the wall loss, much lower than that of conventional normal-conducting linac structures. This allows us to realize an extremely high quality factor and a very high shunt impedance at room temperature. A simulation of a 5 cell prototype design with an existing alumina ceramic indicates an unloaded quality factor of the accelerating mode over 120 000 and a shunt impedance exceeding 650 M Ω /m at room temperature.

  4. Accelerating Cosmologies from Compactification

    CERN Document Server

    Townsend, P K; Townsend, Paul K.; Wohlfarth, Mattias N.R.


    A solution of the (4+n)-dimensional vacuum Einstein equations is found for which spacetime is compactified on a compact hyperbolic manifold of time-varying volume to a flat four-dimensional FLRW cosmology undergoing accelerated expansion in Einstein conformal frame. This shows that the `no-go' theorem forbidding acceleration in `standard' (time-independent) compactifications of string/M-theory does not apply to `cosmological' (time-dependent) hyperbolic compactifications.

  5. Accelerating News Issue 2

    CERN Document Server

    Kahle, K; Wildner, E


    In this summer issue we look at how developments in collimator materials could have applications in aerospace and beyond, and how Polish researchers are harnessing accelerators for medical and industrial uses. We see how the LHC luminosity upgrade is linking with European industry and US researchers, and how the neutrino oscillation community is progressing. We find out the mid-term status of TIARA-PP and how it is mapping European accelerator education resources.

  6. Biomedical accelerator mass spectrometry (United States)

    Freeman, Stewart P. H. T.; Vogel, John S.


    Ultrasensitive SIMS with accelerator based spectrometers has recently begun to be applied to biomedical problems. Certain very long-lived radioisotopes of very low natural abundances can be used to trace metabolism at environmental dose levels ( [greater-or-equal, slanted] z mol in mg samples). 14C in particular can be employed to label a myriad of compounds. Competing technologies typically require super environmental doses that can perturb the system under investigation, followed by uncertain extrapolation to the low dose regime. 41Ca and 26Al are also used as elemental tracers. Given the sensitivity of the accelerator method, care must be taken to avoid contamination of the mass spectrometer and the apparatus employed in prior sample handling including chemical separation. This infant field comprises the efforts of a dozen accelerator laboratories. The Center for Accelerator Mass Spectrometry has been particularly active. In addition to collaborating with groups further afield, we are researching the kinematics and binding of genotoxins in-house, and we support innovative uses of our capability in the disciplines of chemistry, pharmacology, nutrition and physiology within the University of California. The field can be expected to grow further given the numerous potential applications and the efforts of several groups and companies to integrate more the accelerator technology into biomedical research programs; the development of miniaturized accelerator systems and ion sources capable of interfacing to conventional HPLC and GMC, etc. apparatus for complementary chemical analysis is anticipated for biomedical laboratories.

  7. Accelerators for America's Future (United States)

    Bai, Mei


    Particle accelerator, a powerful tool to energize beams of charged particles to a desired speed and energy, has been the working horse for investigating the fundamental structure of matter and fundermental laws of nature. Most known examples are the 2-mile long Stanford Linear Accelerator at SLAC, the high energy proton and anti-proton collider Tevatron at FermiLab, and Large Hadron Collider that is currently under operation at CERN. During the less than a century development of accelerator science and technology that led to a dazzling list of discoveries, particle accelerators have also found various applications beyond particle and nuclear physics research, and become an indispensible part of the economy. Today, one can find a particle accelerator at almost every corner of our lives, ranging from the x-ray machine at the airport security to radiation diagnostic and therapy in hospitals. This presentation will give a brief introduction of the applications of this powerful tool in fundermental research as well as in industry. Challenges in accelerator science and technology will also be briefly presented

  8. Diffusive Shock Acceleration and Reconnection Acceleration Processes (United States)

    Zank, G. P.; Hunana, P.; Mostafavi, P.; Le Roux, J. A.; Li, Gang; Webb, G. M.; Khabarova, O.; Cummings, A.; Stone, E.; Decker, R.


    Shock waves, as shown by simulations and observations, can generate high levels of downstream vortical turbulence, including magnetic islands. We consider a combination of diffusive shock acceleration (DSA) and downstream magnetic-island-reconnection-related processes as an energization mechanism for charged particles. Observations of electron and ion distributions downstream of interplanetary shocks and the heliospheric termination shock (HTS) are frequently inconsistent with the predictions of classical DSA. We utilize a recently developed transport theory for charged particles propagating diffusively in a turbulent region filled with contracting and reconnecting plasmoids and small-scale current sheets. Particle energization associated with the anti-reconnection electric field, a consequence of magnetic island merging, and magnetic island contraction, are considered. For the former only, we find that (i) the spectrum is a hard power law in particle speed, and (ii) the downstream solution is constant. For downstream plasmoid contraction only, (i) the accelerated spectrum is a hard power law in particle speed; (ii) the particle intensity for a given energy peaks downstream of the shock, and the distance to the peak location increases with increasing particle energy, and (iii) the particle intensity amplification for a particular particle energy, f(x,c/{c}0)/f(0,c/{c}0), is not 1, as predicted by DSA, but increases with increasing particle energy. The general solution combines both the reconnection-induced electric field and plasmoid contraction. The observed energetic particle intensity profile observed by Voyager 2 downstream of the HTS appears to support a particle acceleration mechanism that combines both DSA and magnetic-island-reconnection-related processes.

  9. Cytisine-based nicotinic partial agonists as novel antidepressant compounds. (United States)

    Mineur, Yann S; Eibl, Christoph; Young, Grace; Kochevar, Christopher; Papke, Roger L; Gündisch, Daniela; Picciotto, Marina R


    Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the beta2 subunit (beta2(*)), results in antidepressant-like effects. Previous studies have shown that cytisine, a partial agonist at alpha4/beta2(*) nAChRs, and a full agonist at alpha3/beta4(*) and alpha7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models. We tested cytisine and two derivatives, 5-bromo-cytisine (5-Br-Cyt) and 3-(pyridin-3'-yl)-cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at alpha4/beta2(*) nAChRS but had no agonist effects at other nAChRs normally targeted by cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly. These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.

  10. Are Dopamine Agonists Neuroprotective in Parkinson‘s disease?

    Institute of Scientific and Technical Information of China (English)

    乐卫东; Jank.J


    Dopamine(DA) agonists are playing increasingly important role in the treatment of not only advanced Parkinson's disease(PD) and in PD patient with levodopa(L-DO-PA)-induced motor fluctuations,but also in early treatment of the disease.This shift has been largely due to the demonstrated L-DOPA-sparing effect of DA agonists and their putative neuroprotective effect,based largely on experimental in vitro and in vivo studies.In this article we review the evidence of neuroprotection by DA agonists pramipexole,ropinirole,pergolide,bromocriptine and apomorphine in cell cultures and animal models of nigral injury.Most of the studies suggest that DA agonists exert their neuroprotection via directly scavenging free radicals or increasing the activities of radical-scavenging enzymes,and enhancing neurotrophic activity.The finding that pramipexole can normalize mitochondrial membrane potential and inhibit activity of caspase-3 in cytoylasmic hybrid cells made from mitochondrial DNA of nonfamilial Alzheimer's disease patients,however,suggests even a broader implication for the neuroprotective role of DA agonists.Although the clinical evidence for neuroprotection by DA agonists is still limited,the preliminary results from several on-going clinal trials are promising.Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progresion of PD using various surrogate markers of neuronal degeneration such as18F-L-DOPA PET and123I β-CIT SPECT.The results of these experimental and clinical studies will improve our understanding of the action of DA agonists and provide critical information needed for planning future therapeutic strategies in PD and related neurodegenerative disorders.

  11. Are Dopamine Agonists Neuroprotective in Parkinson′s Disease?

    Institute of Scientific and Technical Information of China (English)


    Dopamine (DA) agonists are playing increasingly important role in the treatment of not only advanced Parkinson′s disease (PD) and in PD patient with levodopa (L-DOPA)-induced motor fluctuations,but also in early treatment of the disease.This shift has been largely due to the demonstrated L-DOPA-sparing effect of DA agonists and their putative neuroprotective effect,based largely on experimental in vitro and in vivo studies.In this article we review the evidence of neuroprotection by DA agonists pramipexole,ropinirole,pergolide,bromocriptine and apomorphine in cell cultures and animal models of nigral injury.Most of the studies suggest that DA agonists exert their neuroprotection via directly scavenging free radicals or increasing the activities of radical-scavenging enzymes,and enhancing neurotrophic activity.The finding that pramipexole can normalize mitochondrial membrane potential and inhibit activity of caspase-3 in cytoplasmic hybrid cells made from mitochondrial DNA of nonfamilial Alzheimer′s disease patients,however,suggests even a broader implication for the neuroprotective role of DA agonists.Although the clinical evidence for neuroprotection by DA agonists is still limited,the preliminary results from several on-going clinical trials are promising.Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progresion of PD using various surrogate markers of neuronal degeneration such as 18 F-L-DOPA PET and 123 I β-CIT SPECT.The results of these experimental and clinical studies will improve our understanding of the action of DA agonists and provide critical information needed for planning future therapeutic strategies in PD and related neurodegenerative disorders.``

  12. Romiplostim: a second-generation thrombopoietin agonist. (United States)

    Cohn, Claudia S; Bussel, James B


    in bone marrow reticulin have been reported. Other TPO nonpeptide mimetics have been created by using a similar strategy with libraries of nonpeptide molecules that can stimulate TPO-dependent cell lines. Eltrombopag and AKR-501 are two drugs of this type that have shown positive results in clinical trials. In addition, antibodies that can stimulate the c-Mpl receptor are being engineered to act as potent TPO agonists. These and other drugs in preclinical development represent a new line of therapy for thrombocytopenic patients.

  13. The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain - A detailed case report. (United States)

    Zeman, Adam; Hoefeijzers, Serge; Milton, Fraser; Dewar, Michaela; Carr, Melanie; Streatfield, Claire


    We describe a patient in whom long-term, therapeutic infusion of the selective gamma-amino-butyric acid type B (GABAB) receptor agonist, baclofen, into the cerebrospinal fluid (CSF) gave rise to three distinct varieties of memory impairment: i) repeated, short periods of severe global amnesia, ii) accelerated long-term forgetting (ALF), evident over intervals of days and iii) a loss of established autobiographical memories. This pattern of impairment has been reported in patients with temporal lobe epilepsy (TLE), in particular the subtype of Transient Epileptic Amnesia (TEA). The amnesic episodes and accelerated forgetting remitted on withdrawal of baclofen, while the autobiographical amnesia (AbA) persisted. This exceptional case highlights the occurrence of 'non-standard' forms of human amnesia, reflecting the biological complexity of memory processes. It suggests a role for GABAB signalling in the modulation of human memory over multiple time-scales and hints at its involvement in 'epileptic amnesia'.

  14. Small type accelerator. Try for accelerator driven system

    CERN Document Server

    Mori, Y


    FFAG (Fixed-field alternating gradient) accelerator for accelerator driven subcritical reactor, which aims to change from long-lived radioactive waste to short-lived radioactivity, is introduced. It is ring accelerator. The performance needed is proton as accelerator particle, 10MW (total) beam power, about 1GeV beam energy, >30% power efficiency and continuous beam. The feature of FFAG accelerator is constant magnetic field. PoP (Proof-of-principle)-FFAG accelerator, radial type, was run at first in Japan in 2000. The excursion is about some ten cm. In principle, beam can be injected and extracted at any place of ring. The 'multi-fish' acceleration can accelerate beams to 100% duty by repeating acceleration. 150MeV-FFAG accelerator has been started since 2001. It tried to practical use, for example, treatment of cancer. (S.Y.)

  15. Dielectric laser accelerators (United States)

    England, R. Joel; Noble, Robert J.; Bane, Karl; Dowell, David H.; Ng, Cho-Kuen; Spencer, James E.; Tantawi, Sami; Wu, Ziran; Byer, Robert L.; Peralta, Edgar; Soong, Ken; Chang, Chia-Ming; Montazeri, Behnam; Wolf, Stephen J.; Cowan, Benjamin; Dawson, Jay; Gai, Wei; Hommelhoff, Peter; Huang, Yen-Chieh; Jing, Chunguang; McGuinness, Christopher; Palmer, Robert B.; Naranjo, Brian; Rosenzweig, James; Travish, Gil; Mizrahi, Amit; Schachter, Levi; Sears, Christopher; Werner, Gregory R.; Yoder, Rodney B.


    The use of infrared lasers to power optical-scale lithographically fabricated particle accelerators is a developing area of research that has garnered increasing interest in recent years. The physics and technology of this approach is reviewed, which is referred to as dielectric laser acceleration (DLA). In the DLA scheme operating at typical laser pulse lengths of 0.1 to 1 ps, the laser damage fluences for robust dielectric materials correspond to peak surface electric fields in the GV /m regime. The corresponding accelerating field enhancement represents a potential reduction in active length of the accelerator between 1 and 2 orders of magnitude. Power sources for DLA-based accelerators (lasers) are less costly than microwave sources (klystrons) for equivalent average power levels due to wider availability and private sector investment. Because of the high laser-to-particle coupling efficiency, required pulse energies are consistent with tabletop microJoule class lasers. Combined with the very high (MHz) repetition rates these lasers can provide, the DLA approach appears promising for a variety of applications, including future high-energy physics colliders, compact light sources, and portable medical scanners and radiative therapy machines.

  16. Role of dopamine agonists in Parkinson's disease: an update. (United States)

    Bonuccelli, Ubaldo; Pavese, Nicola


    At present, dopamine agonists play an important role in antiparkinsonian therapy since they were proved effective in the management of both advanced- and early-stage Parkinson's disease. In the latter, they are often regarded as first-choice medication to delay the introduction of levodopa therapy. Despite sharing the capacity to directly stimulate dopamine receptors, dopamine agonists show different pharmacological properties as they act on different subsets of dopamine receptors. This, in theory, provides the advantage of obtaining a different antiparkinsonian activity or safety profile with each agent. However, there is very little evidence that any of the marketed dopamine agonists should be consistently preferred in the management of patients with Parkinson's disease. Pergolide and cabergoline are now considered a second-line choice after the proven association with valvular fibrosis. Transdermal administration (rotigotine) and subcutaneous infusion (apomorphine) of dopamine receptor agonists are now available alternatives to oral administration and provide continuous dopaminergic stimulation. Continuous subcutaneous apomorphine infusion during waking hours leads to a large reduction in daily 'off' time, dyskinesias and levodopa daily dose. Almost all currently used dopamine agonists are able to provide neuroprotective effects towards dopaminergic neurons during in vitro and in vivo experiments. This neuroprotection may be the result of different mechanisms including antioxidation, scavenging of free radicals, suppression of lipid peroxidation and inhibition of apoptosis. However, the disease-modifying effect of these agents in Parkinson's disease remains to be ascertained.

  17. Intracerebroventricular administration of kappa-agonists induces convulsions in mice. (United States)

    Bansinath, M; Ramabadran, K; Turndorf, H; Shukla, V K


    Intracerebroventricular (ICV) administration of kappa-agonists (PD 117302, U-50488H and U-69593) induced convulsions in a dose-related manner in mice. The dose at which 50% of animals convulsed (CD50) was in nmol ranges for all opioids. Among the opioids used, PD 117302 was the most potent convulsant. ICV administration of either vehicle alone or U-53445E, a non-kappa-opioid (+) enantiomer of U-50488H did not induce convulsions. The convulsive response of kappa-agonists was differentially susceptible for antagonism by naloxone and/or MR 2266. Collectively, these findings support the view that convulsions induced by kappa-agonists in mice involve stereospecific opioid receptor mechanisms. Furthermore, the convulsant effect of kappa-agonists could not be modified by pretreatment with MK-801, ketamine, muscimol or baclofen. It is concluded that kappa-opioid but not NMDA or GABA receptor mechanisms are involved in convulsions induced by kappa-agonists. These results are the first experimental evidence implicating stereospecific kappa-receptor mechanisms in opioid-induced convulsions in mice.

  18. Plasma-based accelerator structures

    Energy Technology Data Exchange (ETDEWEB)

    Schroeder, Carl B. [Univ. of California, Berkeley, CA (United States)


    Plasma-based accelerators have the ability to sustain extremely large accelerating gradients, with possible high-energy physics applications. This dissertation further develops the theory of plasma-based accelerators by addressing three topics: the performance of a hollow plasma channel as an accelerating structure, the generation of ultrashort electron bunches, and the propagation of laser pulses is underdense plasmas.

  19. Chronic administration of EP4-selective agonist exacerbates albuminuria and fibrosis of the kidney in streptozotocin-induced diabetic mice through IL-6. (United States)

    Mohamed, Riyaz; Jayakumar, Calpurnia; Ramesh, Ganesan


    Diabetic nephropathy is currently the most common cause of end-stage renal disease in the western world. Exacerbated inflammation of the kidney is known to contribute acceleration of nephropathy. Despite increased COX-2-mediated production of prostanoid metabolite PGE2, knowledge on its involvement in the progression of diabetic kidney disease is not complete. Here, we show the cross talk of the PGE2-EP4 pathways and IL-6 in inducing albuminuria and fibrosis in an animal model of type 1 diabetes. Hyperglycemia causes enhanced COX-2 expression and PGE2 production. Administration of PGE2 receptor EP4-selective agonist ONO-AE1-329 for 12 weeks exacerbated fibrosis and albuminuria. Diabetes-induced expression of inflammatory cytokines TNFα and TGFβ1 was enhanced in EP4 agonist-treated mice kidney. In addition, urinary excretion of cytokines (TNFα and IL-6) and chemokines (MCP-1 and IP-10) were significantly more in EP4-treated mice than vehicle-treated diabetes. Diabetes-induced collagen I and CTGF expression were also significantly higher in EP4-treated mice. However, EP4 agonist did not alter macrophage infiltration but increased cytokine and chemokine production in RAW264.7 cells. Interestingly, EP4-induced IL-6 expression in the kidney was localized in proximal and distal tubular epithelial cells. To confirm further whether EP4 agonist increases fibrosis and albuminuria through an increase in IL-6 expression, IL-6-knockout mice were administered with EP4 agonist. IL-6-knockout mice were resistant to EP4-induced exacerbation of albuminuria and diabetes and EP4-induced fibrosis. Our data suggest that EP4 agonist through IL-6 induces glomerulosclerosis and interstitial fibrosis, and IL-6 represents a new factor in the EP4 pathway.

  20. Superconducting Accelerator Magnets

    CERN Document Server

    Mess, K H; Wolff, S


    The main topic of the book are the superconducting dipole and quadrupole magnets needed in high-energy accelerators and storage rings for protons, antiprotons or heavy ions. The basic principles of low-temperature superconductivity are outlined with special emphasis on the effects which are relevant for accelerator magnets. Properties and fabrication methods of practical superconductors are described. Analytical methods for field calculation and multipole expansion are presented for coils without and with iron yoke. The effect of yoke saturation and geometric distortions on field quality is studied. Persistent magnetization currents in the superconductor and eddy currents the copper part of the cable are analyzed in detail and their influence on field quality and magnet performance is investigated. Superconductor stability, quench origins and propagation and magnet protection are addressed. Some important concepts of accelerator physics are introduced which are needed to appreciate the demanding requirements ...

  1. Particle accelerator physics

    CERN Document Server

    Wiedemann, Helmut


    Particle Accelerator Physics is an in-depth and comprehensive introduction to the field of high-energy particle acceleration and beam dynamics. Part I gathers the basic tools, recalling the essentials of electrostatics and electrodynamics as well as of particle dynamics in electromagnetic fields. Part II is an extensive primer in beam dynamics, followed in Part III by the introduction and description of the main beam parameters. Part IV is devoted to the treatment of perturbations in beam dynamics. Part V discusses the details of charged particle accleration. Part VI and Part VII introduce the more advanced topics of coupled beam dynamics and the description of very intense beams. Part VIII is an exhaustive treatment of radiation from accelerated charges and introduces important sources of coherent radiation such as synchrotrons and free-electron lasers. Part IX collects the appendices gathering useful mathematical and physical formulae, parameters and units. Solutions to many end-of-chapter problems are give...

  2. Uniform Acceleration in General Relativity

    CERN Document Server

    Friedman, Yaakov


    We extend de la Fuente and Romero's defining equation for uniform acceleration in a general curved spacetime from linear acceleration to the full Lorentz covariant uniform acceleration. In a flat spacetime background, we have explicit solutions. We use generalized Fermi-Walker transport to parallel transport the Frenet basis along the trajectory. In flat spacetime, we obtain velocity and acceleration transformations from a uniformly accelerated system to an inertial system. We obtain the time dilation between accelerated clocks. We apply our acceleration transformations to the motion of a charged particle in a constant electromagnetic field and recover the Lorentz-Abraham-Dirac equation.

  3. Microelectromechanical acceleration-sensing apparatus

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Robb M. (Albuquerque, NM); Shul, Randy J. (Albuquerque, NM); Polosky, Marc A. (Albuquerque, NM); Hoke, Darren A. (Albuquerque, NM); Vernon, George E. (Rio Rancho, NM)


    An acceleration-sensing apparatus is disclosed which includes a moveable shuttle (i.e. a suspended mass) and a latch for capturing and holding the shuttle when an acceleration event is sensed above a predetermined threshold level. The acceleration-sensing apparatus provides a switch closure upon sensing the acceleration event and remains latched in place thereafter. Examples of the acceleration-sensing apparatus are provided which are responsive to an acceleration component in a single direction (i.e. a single-sided device) or to two oppositely-directed acceleration components (i.e. a dual-sided device). A two-stage acceleration-sensing apparatus is also disclosed which can sense two acceleration events separated in time. The acceleration-sensing apparatus of the present invention has applications, for example, in an automotive airbag deployment system.

  4. Studies of accelerated compact toruses

    Energy Technology Data Exchange (ETDEWEB)

    Hartman, C.W.; Eddleman, J.; Hammer, J.H.


    In an earlier publication we considered acceleration of plasma rings (Compact Torus). Several possible accelerator configurations were suggested and the possibility of focusing the accelerated rings was discussed. In this paper we consider one scheme, acceleration of a ring between coaxial electrodes by a B/sub theta/ field as in a coaxial rail-gun. If the electrodes are conical, a ring accelerated towards the apex of the cone undergoes self-similar compression (focusing) during acceleration. Because the allowable acceleration force, F/sub a/ = kappaU/sub m//R where (kappa < 1), increases as R/sup -2/, the accelerating distance for conical electrodes is considerably shortened over that required for coaxial electrodes. In either case, however, since the accelerating flux can expand as the ring moves, most of the accelerating field energy can be converted into kinetic energy of the ring leading to high efficiency.

  5. Marked increases in mucociliary clearance produced by synergistic secretory agonists or inhibition of the epithelial sodium channel (United States)

    Joo, Nam Soo; Jeong, Jin Hyeok; Cho, Hyung-Ju; Wine, Jeffrey J.


    Mucociliary clearance (MCC) is a critical host innate defense mechanism in airways, and it is impaired in cystic fibrosis (CF) and other obstructive lung diseases. Epithelial fluid secretion and absorption modify MCC velocity (MCCV). We tested the hypotheses that inhibiting fluid absorption accelerates MCCV, whereas inhibiting fluid secretion decelerates it. In airways, ENaC is mainly responsible for fluid absorption, while anion channels, including CFTR and Ca2+-activated chloride channels mediate anion/fluid secretion. MCCV was increased by the cAMP-elevating agonists, forskolin or isoproterenol (10 μM) and by the Ca2+-elevating agonist, carbachol (0.3 μM). The CFTR-selective inhibitor, CFTRinh-172, modestly reduced MCCV-increases induced by forskolin or isoproterenol but not increases induced by carbachol. The ENaC inhibitor benzamil increased basal MCCV as well as MCCV increases produced by forskolin or carbachol. MCC velocity was most dramatically accelerated by the synergistic combination of forskolin and carbachol, which produced near-maximal clearance rates regardless of prior treatment with CFTR or ENaC inhibitors. In CF airways, where CFTR-mediated secretion (and possibly synergistic MCC) is lost, ENaC inhibition via exogenous agents may provide therapeutic benefit, as has long been proposed. PMID:27830759

  6. Accelerating News Issue 4

    CERN Document Server

    Szeberenyi, A; Wildner, E


    In this winter issue, we are very pleased to announce the approval of EuCARD-2 by the European Commission. We look at the conclusions of EUROnu in proposing future neutrino facilities at CERN, a new milestone reached by CLIC and progress on the SPARC upgrade using C-band technology. We also report on recent events: second Joint HiLumi LHC-LARP Annual Meeting and workshop on Superconducting technologies for the Next Generation of Accelerators aiming at closer collaboration with industry. The launch of the Accelerators for Society brochure is also highlighted.

  7. Shielding high energy accelerators

    CERN Document Server

    Stevenson, Graham Roger


    After introducing the subject of shielding high energy accelerators, point source, line-of-sight models, and in particular the Moyer model. are discussed. Their use in the shielding of proton and electron accelerators is demonstrated and their limitations noted. especially in relation to shielding in the forward direction provided by large, flat walls. The limitations of reducing problems to those using it cylindrical geometry description are stressed. Finally the use of different estimators for predicting dose is discussed. It is suggested that dose calculated from track-length estimators will generally give the most satisfactory estimate. (9 refs).

  8. In silico discovery of novel Retinoic Acid Receptor agonist structures

    Directory of Open Access Journals (Sweden)

    Samuels Herbert H


    Full Text Available Abstract Background Several Retinoic Acid Receptors (RAR agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia. Results We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually to the structure of the receptor with the Internal Coordinates Mechanics (ICM program. Thirty ligand candidates were tested in vitro. Conclusions Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.

  9. Compulsive eating and weight gain related to dopamine agonist use. (United States)

    Nirenberg, Melissa J; Waters, Cheryl


    Dopamine agonists have been implicated in causing compulsive behaviors in patients with Parkinson's disease (PD). These have included gambling, hypersexuality, hobbyism, and other repetitive, purposeless behaviors ("punding"). In this report, we describe 7 patients in whom compulsive eating developed in the context of pramipexole use. All of the affected patients had significant, undesired weight gain; 4 had other comorbid compulsive behaviors. In the 5 patients who lowered the dose of pramipexole or discontinued dopamine agonist treatment, the behavior remitted and no further weight gain occurred. Physicians should be aware that compulsive eating resulting in significant weight gain may occur in PD as a side-effect of dopamine agonist medications such as pramipexole. Given the known risks of the associated weight gain and obesity, further investigation is warranted.

  10. Principles of agonist recognition in Cys-loop receptors

    Directory of Open Access Journals (Sweden)

    Timothy eLynagh


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

  11. Glucagon-like peptide 1 receptor agonist (GLP-1 RA)

    DEFF Research Database (Denmark)

    von Scholten, Bernt Johan; Hansen, Tine Willum; Goetze, Jens Peter;


    AIMS: In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim was to inve......AIMS: In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim...

  12. Partial agonistic action of endomorphins in the mouse spinal cord. (United States)

    Mizoguchi, H; Wu, H E; Narita, M


    The partial agonistic properties of endogenous mu-opioid peptides endomorphin-1 and endomorphin-2 for G-protein activation were determined in the mouse spinal cord, monitoring the increases in guanosine-5'-o-(3-[35S]thio)triphosphate binding. The G-protein activation induced by endogenous opioid peptide beta-endorphin in the spinal cord was significantly, but partially, attenuated by co-incubation with endomorphin-1 or endomorphin-2. The data indicates that endomorphin-1 and endomorphin-2 are endogenous partial agonists for mu-opioid receptor in the mouse spinal cord.

  13. SPS accelerating cavity

    CERN Multimedia


    One of the SPS acceleration cavities (200 MHz, travelling wave structure). On the ceiling one sees the coaxial transmission line which feeds the power from the amplifier, located in a surface building above, to the upstream end of the cavity. See 7603195 for more details, 7411032 for the travelling wave structure, and also 8104138, 8302397.

  14. Prospects for Accelerator Technology (United States)

    Todd, Alan


    Accelerator technology today is a greater than US$5 billion per annum business. Development of higher-performance technology with improved reliability that delivers reduced system size and life cycle cost is expected to significantly increase the total accelerator technology market and open up new application sales. Potential future directions are identified and pitfalls in new market penetration are considered. Both of the present big market segments, medical radiation therapy units and semiconductor ion implanters, are approaching the "maturity" phase of their product cycles, where incremental development rather than paradigm shifts is the norm, but they should continue to dominate commercial sales for some time. It is anticipated that large discovery-science accelerators will continue to provide a specialty market beset by the unpredictable cycles resulting from the scale of the projects themselves, coupled with external political and economic drivers. Although fraught with differing market entry difficulties, the security and environmental markets, together with new, as yet unrealized, industrial material processing applications, are expected to provide the bulk of future commercial accelerator technology growth.

  15. The CERN accelerator complex

    CERN Multimedia

    De Melis, Cinzia


    The LHC is the last ring (dark blue line) in a complex chain of particle accelerators. The smaller machines are used in a chain to help boost the particles to their final energies and provide beams to a whole set of smaller experiments, which also aim to uncover the mysteries of the Universe.

  16. Atmospheric and accelerator neutrinos

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Yoichiro [Kamioka Observatory, Institute for Cosmic Ray Research, University of Tokyo Higashi-Mozumi, Kamioka, Hida-City, Gifu 506-1205 (Japan)


    Results from the atmospheric neutrino measurements are presented. Evidence for the {nu}{sub {tau}} appearance in the atmospheric neutrino events was shown by statistical methods. The long baseline oscillation experiment using man-made neutrinos has confirmed the atmospheric neutrino oscillation. The future accelerator experiments are briefly discussed.

  17. Acceleration and Special Relativity

    CERN Document Server

    Yahalomi, E M


    The integration of acceleration over time before reaching the uniformvelocity turns out to be the source of all the special relativity effects. Itexplains physical phenomena like clocks comparisons. The equations forspace-time, mass and energy are presented. This phenomenon complements theexplanation for the twins paradox. A Universal reference frame is obtained.

  18. The CERN Accelerator School

    CERN Multimedia


      Introduction to accelerator physics This course will take place in Istanbul, Turkey, from 18 to 30 September 2016. It is now open for registration, and further information can be found here:

  19. The CERN Accelerator School

    CERN Multimedia


    Introduction to accelerator physics This course will take place in Budapest, Hungary, from 2 to 14 October 2016. It is now open for registration and further information can be found at: and

  20. The CERN accelerator complex

    CERN Multimedia

    Haffner, Julie


    The LHC is the last ring (dark grey line) in a complex chain of particle accelerators. The smaller machines are used in a chain to help boost the particles to their final energies and provide beams to a whole set of smaller experiments, which also aim to uncover the mysteries of the Universe.

  1. The CERN accelerator complex

    CERN Multimedia

    Christiane Lefèvre


    The LHC is the last ring (dark grey line) in a complex chain of particle accelerators. The smaller machines are used in a chain to help boost the particles to their final energies and provide beams to a whole set of smaller experiments, which also aim to uncover the mysteries of the Universe.

  2. SPS accelerating cavity

    CERN Multimedia

    CERN PhotoLab


    One of the SPS accelerating cavities (200 MHz, travelling wave structure). The power that is fed into the upstream end of the cavity is extracted at the downstream end and sent into a dump load. See 7603195 for more details, 7411032 for the travelling wave structure, and also 8011289, 8302397.

  3. Combined generating-accelerating buncher for compact linear accelerators (United States)

    Savin, E. A.; Matsievskiy, S. V.; Sobenin, N. P.; Sokolov, I. D.; Zavadtsev, A. A.


    Described in the previous article [1] method of the power extraction from the modulated electron beam has been applied to the compact standing wave electron linear accelerator feeding system, which doesnt require any connection waveguides between the power source and the accelerator itself [2]. Generating and accelerating bunches meet in the hybrid accelerating cell operating at TM020 mode, thus the accelerating module is placed on the axis of the generating module, which consists from the pulsed high voltage electron sources and electrons dumps. This combination makes the accelerator very compact in size which is very valuable for the modern applications such as portable inspection sources. Simulations and geometry cold tests are presented.

  4. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists. (United States)

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


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

  5. Neurodegeneration in accelerated aging. (United States)

    Scheibye-Knudsen, Moren


    The growing proportion of elderly people represents an increasing economic burden, not least because of age-associated diseases that pose a significant cost to the health service. Finding possible interventions to age-associated disorders therefore have wide ranging implications. A number of genetically defined accelerated aging diseases have been characterized that can aid in our understanding of aging. Interestingly, all these diseases are associated with defects in the maintenance of our genome. A subset of these disorders, Cockayne syndrome, Xeroderma pigmentosum group A and ataxia-telangiectasia, show neurological involvement reminiscent of what is seen in primary human mitochondrial diseases. Mitochondria are the power plants of the cells converting energy stored in oxygen, sugar, fat, and protein into ATP, the energetic currency of our body. Emerging evidence has linked this organelle to aging and finding mitochondrial dysfunction in accelerated aging disorders thereby strengthens the mitochondrial theory of aging. This theory states that an accumulation of damage to the mitochondria may underlie the process of aging. Indeed, it appears that some accelerated aging disorders that show neurodegeneration also have mitochondrial dysfunction. The mitochondrial alterations may be secondary to defects in nuclear DNA repair. Indeed, nuclear DNA damage may lead to increased energy consumption, alterations in mitochondrial ATP production and defects in mitochondrial recycling, a term called mitophagy. These changes may be caused by activation of poly-ADP-ribose-polymerase 1 (PARP1), an enzyme that responds to DNA damage. Upon activation PARP1 utilizes key metabolites that attenuate pathways that are normally protective for the cell. Notably, pharmacological inhibition of PARP1 or reconstitution of the metabolites rescues the changes caused by PARP1 hyperactivation and in many cases reverse the phenotypes associated with accelerated aging. This implies that modulation

  6. Nonlinear dynamics in particle accelerators

    CERN Document Server

    Dilão, Rui


    This book is an introductory course to accelerator physics at the level of graduate students. It has been written for a large audience which includes users of accelerator facilities, accelerator physicists and engineers, and undergraduates aiming to learn the basic principles of construction, operation and applications of accelerators.The new concepts of dynamical systems developed in the last twenty years give the theoretical setting to analyse the stability of particle beams in accelerator. In this book a common language to both accelerator physics and dynamical systems is integrated and dev

  7. Mass spectrometry with accelerators. (United States)

    Litherland, A E; Zhao, X-L; Kieser, W E


    As one in a series of articles on Canadian contributions to mass spectrometry, this review begins with an outline of the history of accelerator mass spectrometry (AMS), noting roles played by researchers at three Canadian AMS laboratories. After a description of the unique features of AMS, three examples, (14)C, (10)Be, and (129)I are given to illustrate the methods. The capabilities of mass spectrometry have been extended by the addition of atomic isobar selection, molecular isobar attenuation, further ion acceleration, followed by ion detection and ion identification at essentially zero dark current or ion flux. This has been accomplished by exploiting the techniques and accelerators of atomic and nuclear physics. In 1939, the first principles of AMS were established using a cyclotron. In 1977 the selection of isobars in the ion source was established when it was shown that the (14)N(-) ion was very unstable, or extremely difficult to create, making a tandem electrostatic accelerator highly suitable for assisting the mass spectrometric measurement of the rare long-lived radioactive isotope (14)C in the environment. This observation, together with the large attenuation of the molecular isobars (13)CH(-) and (12)CH 2(-) during tandem acceleration and the observed very low background contamination from the ion source, was found to facilitate the mass spectrometry of (14)C to at least a level of (14)C/C ~ 6 × 10(-16), the equivalent of a radiocarbon age of 60,000 years. Tandem Accelerator Mass Spectrometry, or AMS, has now made possible the accurate radiocarbon dating of milligram-sized carbon samples by ion counting as well as dating and tracing with many other long-lived radioactive isotopes such as (10)Be, (26)Al, (36)Cl, and (129)I. The difficulty of obtaining large anion currents with low electron affinities and the difficulties of isobar separation, especially for the heavier mass ions, has prompted the use of molecular anions and the search for alternative

  8. Melatonin agonists for treatment of sleep and depressive disorders

    Directory of Open Access Journals (Sweden)

    Seithikurippu R. Pandi-Perumal


    Full Text Available Melatonin the hormone secreted by the pineal gland has been effective in improving sleep both in normal sleepers and insomniacs and has been used successfully in treating sleep and circadian rhythm sleep disorders. The lack of consistency in the reports published by the authors is attributed to the differential bioavailabilty and short half-life of melatonin. Sleep disturbances are also prominent features of depressive disorders. To overcome this problem, melatonergic agonists with sleep promoting properties have been introduced in clinical practice. Ramelteon, the MT1/ MT2 melatonergic agonist, has been used in a large number of clinical trials involving chronic insomniacs and has been found effective in improving the total sleep time and sleep efficiency of insomniacs and has not manifested serious adverse effects. The development of another MT1/MT2 melatonergic agonist agomelatine with antagonsim to 5-HT2c serotonin receptors has been found useful not only in treating sleep problems of patients but also as a first line antidepressant with earlier onset of actions in patients with major depressive disorder. An agonist for MT3 melatonin receptor has also been found effective in animal models of depression. [J Exp Integr Med 2011; 1(3.000: 149-158

  9. [Alpha 2-adrenoceptor agonists for the treatment of chronic pain]. (United States)

    Kulka, P J


    The antinociceptive effect of alpha(2)-adrenoceptor agonists is mediated by activation of descending inhibiting noradrenergic systems, which modulates 'wide-dynamic-range' neurones. Furthermore, they inhibit the liberation of substance P and endorphines and activate serotoninergic neurones. Despite this variety of antinociceptive actions, there is still little experience with alpha(2)-adrenoceptor agonists as therapeutic agents for use in chronic pain syndromes. Studies in animals and patients have shown that the transdermal, epidural and intravenous administration of the alpha(2)-adrenoceptor agonist clonidine reduces pain intensity in neuropathic pain syndromes for periods varying from some hours up to 1 month. Patients suffering from lancinating or sharp pain respond best to this therapy. Topically applied clonidine (200-300 microg) relieves hyperalgesia in sympathetically maintained pain. Epidural administration of 300 microg clonidine dissolved in 5 ml NaCl 0.9 % has also been shown to be effective. In patients suffering from cancer pain tolerant to opioids, pain control has proved possible again with combinations of opioids and clonidine. In isolated cases clonidine has been administered epidurally at a dose of 1500 microg/day for almost 5 months without evidence for any histotoxic property of clonidine. Side effects often observed during administration of alpha(2)-adrenoceptor agonists are dry mouth, sedation, hypotension and bradycardia. Therapeutic interventions are usually not required.

  10. Pharmacophore-driven identification of PPARγ agonists from natural sources

    DEFF Research Database (Denmark)

    Petersen, R. K.; Christensen, Kathrine Bisgaard; Assimopoulou, A. N.;


    In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk...

  11. Use of ß-adrenergic agonists in hybrid catfish (United States)

    Ractopamine hydrochloride (RH) is a potent ß-adrenergic agonist that has been used in some species of fish to improve growth performance and dress out characteristics. While this metabolic modifier has been shown to have positive effects on growth of fish, little research has focused on the mechani...

  12. Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonists

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Due-Hansen, Maria E; Urban, Christian;


    FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metaboli...

  13. Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Bruning, J.B.; Chalmers, M.J.; Prasad, S.; Bushby, S.A.; Kamenecka, T.A.; He, Y.; Nettles, K.W.; Griffin, P.R.


    Binding to helix 12 of the ligand-binding domain of PPAR{gamma} is required for full agonist activity. Previously, the degree of stabilization of the activation function 2 (AF-2) surface was thought to correlate with the degree of agonism and transactivation. To examine this mechanism, we probed structural dynamics of PPAR{gamma} with agonists that induced graded transcriptional responses. Here we present crystal structures and amide H/D exchange (HDX) kinetics for six of these complexes. Amide HDX revealed each ligand induced unique changes to the dynamics of the ligand-binding domain (LBD). Full agonists stabilized helix 12, whereas intermediate and partial agonists did not at all, and rather differentially stabilized other regions of the binding pocket. The gradient of PPAR{gamma} transactivation cannot be accounted for solely through changes to the dynamics of AF-2. Thus, our understanding of allosteric signaling must be extended beyond the idea of a dynamic helix 12 acting as a molecular switch.

  14. Principles of agonist recognition in Cys-loop receptors

    DEFF Research Database (Denmark)

    Lynagh, Timothy Peter; Pless, Stephan Alexander


    diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework...

  15. Acceleration of microparticle

    CERN Document Server

    Shibata, H


    A microparticle (dust) ion source has been installed at the high voltage terminal of the 3.75 MV single ended Van de Graaff electrostatic accelerator and a beam line for microparticle experiments has been build at High Fluence Irradiation Facility (HIT) of Research Center for Nuclear Science and Technology, the University of Tokyo. Microparticle acceleration has been successful in obtaining expected velocities of 1-20 km/s or more for micron or submicron sized particles. Development of in situ dust detectors and analyzers on board satellites and spacecraft in the expected mass and velocity range of micrometeoroids and investigation of hypervelocity impact phenomena by using time of flight mass spectrometry, impact flash or luminescence measurement and scanning electron or laser microscope observation for metals, ceramics, polymers and semiconductors bombarded by micron-sized particles were started three years ago. (author)

  16. Particle accelerator physics

    CERN Document Server

    Wiedemann, Helmut


    This book by Helmut Wiedemann is a well-established, classic text, providing an in-depth and comprehensive introduction to the field of high-energy particle acceleration and beam dynamics. The present 4th edition has been significantly revised, updated and expanded. The newly conceived Part I is an elementary introduction to the subject matter for undergraduate students. Part II gathers the basic tools in preparation of a more advanced treatment, summarizing the essentials of electrostatics and electrodynamics as well as of particle dynamics in electromagnetic fields. Part III is an extensive primer in beam dynamics, followed, in Part IV, by an introduction and description of the main beam parameters and including a new chapter on beam emittance and lattice design. Part V is devoted to the treatment of perturbations in beam dynamics. Part VI then discusses the details of charged particle acceleration. Parts VII and VIII introduce the more advanced topics of coupled beam dynamics and describe very intense bea...


    Energy Technology Data Exchange (ETDEWEB)

    Perri, S.; Zimbardo, G. [Dipartimento di Fisica, Universita della Calabria, Ponte P. Bucci Cubo 31C, I-87036 Rende (Italy)


    The theory of diffusive shock acceleration is extended to the case of superdiffusive transport, i.e., when the mean square deviation grows proportionally to t{sup {alpha}}, with {alpha} > 1. Superdiffusion can be described by a statistical process called Levy random walk, in which the propagator is not a Gaussian but it exhibits power-law tails. By using the propagator appropriate for Levy random walk, it is found that the indices of energy spectra of particles are harder than those obtained where a normal diffusion is envisaged, with the spectral index decreasing with the increase of {alpha}. A new scaling for the acceleration time is also found, allowing substantially shorter times than in the case of normal diffusion. Within this framework we can explain a number of observations of flat spectra in various astrophysical and heliospheric contexts, for instance, for the Crab Nebula and the termination shock of the solar wind.

  18. Accelerating QDP++ using GPUs

    CERN Document Server

    Winter, Frank


    Graphic Processing Units (GPUs) are getting increasingly important as target architectures in scientific High Performance Computing (HPC). NVIDIA established CUDA as a parallel computing architecture controlling and making use of the compute power of GPUs. CUDA provides sufficient support for C++ language elements to enable the Expression Template (ET) technique in the device memory domain. QDP++ is a C++ vector class library suited for quantum field theory which provides vector data types and expressions and forms the basis of the lattice QCD software suite Chroma. In this work accelerating QDP++ expression evaluation to a GPU was successfully implemented leveraging the ET technique and using Just-In-Time (JIT) compilation. The Portable Expression Template Engine (PETE) and the C API for CUDA kernel arguments were used to build the bridge between host and device memory domains. This provides the possibility to accelerate Chroma routines to a GPU which are typically not subject to special optimisation. As an ...

  19. accelerating cavity from LEP

    CERN Multimedia

    This is an accelerating cavity from LEP, with a layer of niobium on the inside. Operating at 4.2 degrees above absolute zero, the niobium is superconducting and carries an accelerating field of 6 million volts per metre with negligible losses. Each cavity has a surface of 6 m2. The niobium layer is only 1.2 microns thick, ten times thinner than a hair. Such a large area had never been coated to such a high accuracy. A speck of dust could ruin the performance of the whole cavity so the work had to be done in an extremely clean environment. These challenging requirements pushed European industry to new achievements. 256 of these cavities are now used in LEP to double the energy of the particle beams.

  20. Hardware Accelerated Simulated Radiography

    Energy Technology Data Exchange (ETDEWEB)

    Laney, D; Callahan, S; Max, N; Silva, C; Langer, S; Frank, R


    We present the application of hardware accelerated volume rendering algorithms to the simulation of radiographs as an aid to scientists designing experiments, validating simulation codes, and understanding experimental data. The techniques presented take advantage of 32 bit floating point texture capabilities to obtain validated solutions to the radiative transport equation for X-rays. An unsorted hexahedron projection algorithm is presented for curvilinear hexahedra that produces simulated radiographs in the absorption-only regime. A sorted tetrahedral projection algorithm is presented that simulates radiographs of emissive materials. We apply the tetrahedral projection algorithm to the simulation of experimental diagnostics for inertial confinement fusion experiments on a laser at the University of Rochester. We show that the hardware accelerated solution is faster than the current technique used by scientists.

  1. Accelerators for Cancer Therapy (United States)

    Lennox, Arlene J.


    The vast majority of radiation treatments for cancerous tumors are given using electron linacs that provide both electrons and photons at several energies. Design and construction of these linacs are based on mature technology that is rapidly becoming more and more standardized and sophisticated. The use of hadrons such as neutrons, protons, alphas, or carbon, oxygen and neon ions is relatively new. Accelerators for hadron therapy are far from standardized, but the use of hadron therapy as an alternative to conventional radiation has led to significant improvements and refinements in conventional treatment techniques. This paper presents the rationale for radiation therapy, describes the accelerators used in conventional and hadron therapy, and outlines the issues that must still be resolved in the emerging field of hadron therapy.

  2. Accelerated Parallel Texture Optimization

    Institute of Scientific and Technical Information of China (English)

    Hao-Da Huang; Xin Tong; Wen-Cheng Wang


    Texture optimization is a texture synthesis method that can efficiently reproduce various features of exemplar textures. However, its slow synthesis speed limits its usage in many interactive or real time applications. In this paper, we propose a parallel texture optimization algorithm to run on GPUs. In our algorithm, k-coherence search and principle component analysis (PCA) are used for hardware acceleration, and two acceleration techniques are further developed to speed up our GPU-based texture optimization. With a reasonable precomputation cost, the online synthesis speed of our algorithm is 4000+ times faster than that of the original texture optimization algorithm and thus our algorithm is capable of interactive applications. The advantages of the new scheme are demonstrated by applying it to interactive editing of flow-guided synthesis.


    Energy Technology Data Exchange (ETDEWEB)

    Sessler, A.M.


    But a glance at the Livingston chart, Fig. 1, of accelerator particle energy as a function of time shows that the energy has steadily, exponentially, increased. Equally significant is the fact that this increase is the envelope of diverse technologies. If one is to stay on, or even near, the Livingston curve in future years then new acceleration techniques need to be developed. What are the new acceleration methods? In these two lectures I would like to sketch some of these new ideas. I am well aware that they will probably not result in high energy accelerators within this or the next decade, but conversely, it is likely that these ideas will form the basis for the accelerators of the next century. Anyway, the ideas are stimulating and suffice to show that accelerator physicists are not just 'engineers', but genuine scientists deserving to be welcomed into the company of high energy physicists. I believe that outsiders will find this field surprisingly fertile and, certainly fun. To put it more personally, I very much enjoy working in this field and lecturing on it. There are a number of review articles which should be consulted for references to the original literature. In addition there are three books on the subject. Given this material, I feel free to not completely reference the material in the remainder of this article; consultation of the review articles and books will be adequate as an introduction to the literature for references abound (hundreds are given). At last, by way of introduction, I should like to quote from the end of Ref. 2 for I think the remarks made there are most germane. Remember that the talk was addressed to accelerator physicists: 'Finally, it is often said, I think by physicists who are not well-informed, that accelerator builders have used up their capital and now are bereft of ideas, and as a result, high energy physics will eventually--rather soon, in fact--come to a halt. After all, one can't build too many

  4. Quantum dot-based screening system for discovery of g protein-coupled receptor agonists. (United States)

    Lee, Junghan; Kwon, Yong-Jun; Choi, Youngseon; Kim, Hi Chul; Kim, Keumhyun; Kim, JinYeop; Park, Sun; Song, Rita


    Cellular imaging has emerged as an important tool to unravel biological complexity and to accelerate the drug-discovery process, including cell-based screening, target identification, and mechanism of action studies. Recently, semiconductor nanoparticles known as quantum dots (QDs) have attracted great interest in cellular imaging applications due to their unique photophysical properties such as size, tunable optical property, multiplexing capability, and photostability. Herein, we show that QDs can also be applied to assay development and eventually to high-throughput/content screening (HTS/HCS) for drug discovery. We have synthesized QDs modified with PEG and primary antibodies to be used as fluorescent probes for a cell-based HTS system. The G protein-coupled receptor (GPCR) family is known to be involved in most major diseases. We therefore constructed human osteosarcoma (U2OS) cells that specifically overexpress two types of differently tagged GPCRs: influenza hemagglutinin (HA) peptide-tagged κ-opioid receptors (κ-ORs) and GFP-tagged A3 adenosine receptors (A3AR). In this study, we have demonstrated that 1) anti-HA antibody-conjugated QDs could specifically label HA-tagged κ-ORs, 2) subsequent treatment of QD-tagged GPCR agonists allowed agonist-induced translocation to be monitored in real time, 3) excellent emission spectral properties of QD permitted the simultaneous detection of two GPCRs in one cell, and 4) the robust imaging capabilities of the QD-antibody conjugates could lead to reproducible quantitative data from high-content cellular images. These results suggest that the present QD-based GPCR inhibitor screening system can be a promising platform for further drug screening applications.

  5. Accelerated plate tectonics. (United States)

    Anderson, D L


    The concept of a stressed elastic lithospheric plate riding on a viscous asthenosphere is used to calculate the recurrence interval of great earthquakes at convergent plate boundaries, the separation of decoupling and lithospheric earthquakes, and the migration pattern of large earthquakes along an arc. It is proposed that plate motions accelerate after great decoupling earthquakes and that most of the observed plate motions occur during short periods of time, separated by periods of relative quiescence.

  6. Future Accelerator Magnet Needs

    CERN Document Server

    Devred, Arnaud; Yamamoto, A


    Superconducting magnet technology is continually evolving in order to meet the demanding needs of new accelerators and to provide necessary upgrades for existing machines. A variety of designs are now under development, including high fields and gradients, rapid cycling and novel coil configurations. This paper presents a summary of R&D programs in the EU, Japan and the USA. A performance comparison between NbTi and Nb3Sn along with fabrication and cost issues are also discussed.

  7. LEP copper accelerating cavities

    CERN Multimedia

    Laurent Guiraud


    These copper cavities were used to generate the radio frequency electric field that was used to accelerate electrons and positrons around the 27-km Large Electron-Positron (LEP) collider at CERN, which ran from 1989 to 2000. The copper cavities were gradually replaced from 1996 with new superconducting cavities allowing the collision energy to rise from 90 GeV to 200 GeV by mid-1999.

  8. Melatonin receptor agonists: new options for insomnia and depression treatment. (United States)

    Spadoni, Gilberto; Bedini, Annalida; Rivara, Silvia; Mor, Marco


    The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT₁ or MT₂ subtype-selective compounds are available up to now. Administration of the MT₂-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT₂ receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT₁ or MT₂ receptors are expected in coming years.

  9. Accelerator mass spectrometry. (United States)

    Hellborg, Ragnar; Skog, Göran


    In this overview the technique of accelerator mass spectrometry (AMS) and its use are described. AMS is a highly sensitive method of counting atoms. It is used to detect very low concentrations of natural isotopic abundances (typically in the range between 10(-12) and 10(-16)) of both radionuclides and stable nuclides. The main advantages of AMS compared to conventional radiometric methods are the use of smaller samples (mg and even sub-mg size) and shorter measuring times (less than 1 hr). The equipment used for AMS is almost exclusively based on the electrostatic tandem accelerator, although some of the newest systems are based on a slightly different principle. Dedicated accelerators as well as older "nuclear physics machines" can be found in the 80 or so AMS laboratories in existence today. The most widely used isotope studied with AMS is 14C. Besides radiocarbon dating this isotope is used in climate studies, biomedicine applications and many other fields. More than 100,000 14C samples are measured per year. Other isotopes studied include 10Be, 26Al, 36Cl, 41Ca, 59Ni, 129I, U, and Pu. Although these measurements are important, the number of samples of these other isotopes measured each year is estimated to be less than 10% of the number of 14C samples.

  10. Accelerated Profile HMM Searches.

    Directory of Open Access Journals (Sweden)

    Sean R Eddy


    Full Text Available Profile hidden Markov models (profile HMMs and probabilistic inference methods have made important contributions to the theory of sequence database homology search. However, practical use of profile HMM methods has been hindered by the computational expense of existing software implementations. Here I describe an acceleration heuristic for profile HMMs, the "multiple segment Viterbi" (MSV algorithm. The MSV algorithm computes an optimal sum of multiple ungapped local alignment segments using a striped vector-parallel approach previously described for fast Smith/Waterman alignment. MSV scores follow the same statistical distribution as gapped optimal local alignment scores, allowing rapid evaluation of significance of an MSV score and thus facilitating its use as a heuristic filter. I also describe a 20-fold acceleration of the standard profile HMM Forward/Backward algorithms using a method I call "sparse rescaling". These methods are assembled in a pipeline in which high-scoring MSV hits are passed on for reanalysis with the full HMM Forward/Backward algorithm. This accelerated pipeline is implemented in the freely available HMMER3 software package. Performance benchmarks show that the use of the heuristic MSV filter sacrifices negligible sensitivity compared to unaccelerated profile HMM searches. HMMER3 is substantially more sensitive and 100- to 1000-fold faster than HMMER2. HMMER3 is now about as fast as BLAST for protein searches.

  11. Optimizing accelerator technology

    CERN Multimedia

    Katarina Anthony


    A new EU-funded research and training network, oPAC, is bringing together 22 universities, research centres and industry partners to optimize particle accelerator technology. CERN is one of the network’s main partners and will host 5 early-stage researchers in the BE department.   A diamond detector that will be used for novel beam diagnostics applications in the oPAC project based at CIVIDEC. (Image courtesy of CIVIDEC.) As one of the largest Marie Curie Initial Training Networks ever funded by the EU – to the tune of €6 million – oPAC extends well beyond the particle physics community. “Accelerator physics has become integral to research in almost every scientific discipline – be it biology and life science, medicine, geology and material science, or fundamental physics,” explains Carsten P. Welsch, oPAC co-ordinator based at the University of Liverpool. “By optimizing the operation of accelerators, all of these...

  12. Berkeley Proton Linear Accelerator (United States)

    Alvarez, L. W.; Bradner, H.; Franck, J.; Gordon, H.; Gow, J. D.; Marshall, L. C.; Oppenheimer, F. F.; Panofsky, W. K. H.; Richman, C.; Woodyard, J. R.


    A linear accelerator, which increases the energy of protons from a 4 Mev Van de Graaff injector, to a final energy of 31.5 Mev, has been constructed. The accelerator consists of a cavity 40 feet long and 39 inches in diameter, excited at resonance in a longitudinal electric mode with a radio-frequency power of about 2.2 x 10{sup 6} watts peak at 202.5 mc. Acceleration is made possible by the introduction of 46 axial "drift tubes" into the cavity, which is designed such that the particles traverse the distance between the centers of successive tubes in one cycle of the r.f. power. The protons are longitudinally stable as in the synchrotron, and are stabilized transversely by the action of converging fields produced by focusing grids. The electrical cavity is constructed like an inverted airplane fuselage and is supported in a vacuum tank. Power is supplied by 9 high powered oscillators fed from a pulse generator of the artificial transmission line type.

  13. French nuclear physics accelerator opens (United States)

    Dumé, Belle


    A new €140m particle accelerator for nuclear physics located at the French Large Heavy Ion National Accelerator (GANIL) in Caen was inaugurated last month in a ceremony attended by French president François Hollande.

  14. Plasma accelerator experiments in Yugoslavia (United States)

    Purić, J.; Astashynski, V. M.; Kuraica, M. M.; Dojčinovié, I. P.


    An overview is given of the results obtained in the Plasma Accelerator Experiments in Belgrade, using quasi-stationary high current plasma accelerators constructed within the framework of the Yugoslavia-Belarus Joint Project. So far, the following plasma accelerators have been realized: Magnetoplasma Compressor type (MPC); MPC Yu type; one stage Erosive Plasma Dynamic System (EPDS) and, in final stage of construction two stage Quasi-Stationary High Current Plasma Accelerator (QHPA).

  15. Accelerating in de Sitter spacetimes

    CERN Document Server

    Cotaescu, Ion I


    We propose a definition of uniform accelerated frames in de Sitter spacetimes exploiting the Nachtmann group theoretical method of introducing coordinates on these manifolds. Requiring the transformation between the static frame and the accelerated one to depend continuously on acceleration in order to recover the well-known Rindler approach in the flat limit, we obtain a result with a reasonable physical meaning.

  16. Structural determinants of agonist-specific kinetics at the ionotropic glutamate receptor 2

    DEFF Research Database (Denmark)

    Holm, Mai Marie; Lunn, Marie-Louise; Traynelis, Stephen F;


    Glutamate receptors (GluRs) are the most abundant mediators of the fast excitatory neurotransmission in the human brain. Agonists will, after activation of the receptors, induce different degrees of desensitization. The efficacy of agonists strongly correlates with the agonist-induced closure of ...

  17. Agonist signalling properties of radiotracers used for imaging of dopamine D-2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, Jan-Peter; Michel, Martin C.; Janssen, Henk M.; Janssen, Anton G.; Elsinga, Philip H.; Booij, Jan


    Background: Dopamine D-2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists ar

  18. PPAR Agonist-Induced Reduction of Mcp1 in Atherosclerotic Plaques of Obese, Insulin-Resistant Mice Depends on Adiponectin-Induced Irak3 Expression (United States)

    Arnould, Thierry; Tsatsanis, Christos; Holvoet, Paul


    Synthetic peroxisome proliferator-activated receptor (PPAR) agonists are used to treat dyslipidemia and insulin resistance. In this study, we examined molecular mechanisms that explain differential effects of a PPARα agonist (fenofibrate) and a PPARγ agonist (rosiglitazone) on macrophages during obesity-induced atherogenesis. Twelve-week-old mice with combined leptin and LDL-receptor deficiency (DKO) were treated with fenofibrate, rosiglitazone or placebo for 12 weeks. Only rosiglitazone improved adipocyte function, restored insulin sensitivity, and inhibited atherosclerosis by decreasing lipid-loaded macrophages. In addition, it increased interleukin-1 receptor-associated kinase-3 (Irak3) and decreased monocyte chemoattractant protein-1 (Mcp1) expressions, indicative of a switch from M1 to M2 macrophages. The differences between fenofibrate and rosiglitazone were independent of Pparγ expression. In bone marrow-derived macrophages (BMDM), we identified the rosiglitazone-associated increase in adiponectin as cause of the increase in Irak3. Interestingly, the deletion of Irak3 in BMDM (IRAK3−/− BMDM) resulted in activation of the canonical NFκB signaling pathway and increased Mcp1 protein secretion. Rosiglitazone could not decrease the elevated Mcp1 secretion in IRAK3−/− BMDM directly and fenofibrate even increased the secretion, possibly due to increased mitochondrial reactive oxygen species production. Furthermore, aortic extracts of high-fat insulin-resistant LDL-receptor deficient mice, with lower adiponectin and Irak3 and higher Mcp1, showed accelerated atherosclerosis. In aggregate, our results emphasize an interaction between PPAR agonist-mediated increase in adiponectin and macrophage-associated Irak3 in the protection against atherosclerosis by PPAR agonists. PMID:23620818

  19. PPAR agonist-induced reduction of Mcp1 in atherosclerotic plaques of obese, insulin-resistant mice depends on adiponectin-induced Irak3 expression.

    Directory of Open Access Journals (Sweden)

    Maarten Hulsmans

    Full Text Available Synthetic peroxisome proliferator-activated receptor (PPAR agonists are used to treat dyslipidemia and insulin resistance. In this study, we examined molecular mechanisms that explain differential effects of a PPARα agonist (fenofibrate and a PPARγ agonist (rosiglitazone on macrophages during obesity-induced atherogenesis. Twelve-week-old mice with combined leptin and LDL-receptor deficiency (DKO were treated with fenofibrate, rosiglitazone or placebo for 12 weeks. Only rosiglitazone improved adipocyte function, restored insulin sensitivity, and inhibited atherosclerosis by decreasing lipid-loaded macrophages. In addition, it increased interleukin-1 receptor-associated kinase-3 (Irak3 and decreased monocyte chemoattractant protein-1 (Mcp1 expressions, indicative of a switch from M1 to M2 macrophages. The differences between fenofibrate and rosiglitazone were independent of Pparγ expression. In bone marrow-derived macrophages (BMDM, we identified the rosiglitazone-associated increase in adiponectin as cause of the increase in Irak3. Interestingly, the deletion of Irak3 in BMDM (IRAK3(-/- BMDM resulted in activation of the canonical NFκB signaling pathway and increased Mcp1 protein secretion. Rosiglitazone could not decrease the elevated Mcp1 secretion in IRAK3(-/- BMDM directly and fenofibrate even increased the secretion, possibly due to increased mitochondrial reactive oxygen species production. Furthermore, aortic extracts of high-fat insulin-resistant LDL-receptor deficient mice, with lower adiponectin and Irak3 and higher Mcp1, showed accelerated atherosclerosis. In aggregate, our results emphasize an interaction between PPAR agonist-mediated increase in adiponectin and macrophage-associated Irak3 in the protection against atherosclerosis by PPAR agonists.

  20. APT accelerator. Topical report

    Energy Technology Data Exchange (ETDEWEB)

    Lawrence, G.; Rusthoi, D. [comp.] [ed.


    The Accelerator Production of Tritium (APT) project, sponsored by Department of Energy Defense Programs (DOE/DP), involves the preconceptual design of an accelerator system to produce tritium for the nation`s stockpile of nuclear weapons. Tritium is an isotope of hydrogen used in nuclear weapons, and must be replenished because of radioactive decay (its half-life is approximately 12 years). Because the annual production requirements for tritium has greatly decreased since the end of the Cold War, an alternative approach to reactors for tritium production, based on a linear accelerator, is now being seriously considered. The annual tritium requirement at the time this study was undertaken (1992-1993) was 3/8 that of the 1988 goal, usually stated as 3/8-Goal. Continued reduction in the number of weapons in the stockpile has led to a revised (lower) production requirement today (March, 1995). The production requirement needed to maintain the reduced stockpile, as stated in the recent Nuclear Posture Review (summer 1994) is approximately 3/16-Goal, half the previous level. The Nuclear Posture Review also requires that the production plant be designed to accomodate a production increase (surge) to 3/8-Goal capability within five years, to allow recovery from a possible extended outage of the tritium plant. A multi-laboratory team, collaborating with several industrial partners, has developed a preconceptual APT design for the 3/8-Goal, operating at 75% capacity. The team has presented APT as a promising alternative to the reactor concepts proposed for Complex-21. Given the requirements of a reduced weapons stockpile, APT offers both significant safety, environmental, and production-fexibility advantages in comparison with reactor systems, and the prospect of successful development in time to meet the US defense requirements of the 21st Century.

  1. Muon Acceleration - RLA and FFAG

    Energy Technology Data Exchange (ETDEWEB)

    Bogacz, Alex


    Various acceleration schemes for muons are presented. The overall goal of the acceleration systems: large acceptance acceleration to 25 GeV and 'beam shaping' can be accomplished by various fixed field accelerators at different stages. They involve three superconducting linacs: a single pass linear Pre-accelerator followed by a pair of multi-pass Recirculating Linear Accelerators (RLA) and finally a non-scaling FFAG ring. The present baseline acceleration scenario has been optimized to take maximum advantage of appropriate acceleration scheme at a given stage. The solenoid based Pre-accelerator offers very large acceptance and facilitates correction of energy gain across the bunch and significant longitudinal compression trough induced synchrotron motion. However, far off-crest acceleration reduces the effective acceleration gradient and adds complexity through the requirement of individual RF phase control for each cavity. The RLAs offer very efficient usage of high gradient superconducting RF and ability to adjust path-length after each linac pass through individual return arcs with uniformly periodic FODO optics suitable for chromatic compensation of emittance dilution with sextupoles. However, they require spreaders/recombiners switchyards at both linac ends and significant total length of the arcs. The non-scaling Fixed Field Alternating Gradient (FFAG) ring combines compactness with very large chromatic acceptance (twice the injection energy) and it allows for large number of passes through the RF (at least eight, possibly as high as 15).

  2. Hardware Accelerated Power Estimation

    CERN Document Server

    Coburn, Joel; Raghunathan, Anand


    In this paper, we present power emulation, a novel design paradigm that utilizes hardware acceleration for the purpose of fast power estimation. Power emulation is based on the observation that the functions necessary for power estimation (power model evaluation, aggregation, etc.) can be implemented as hardware circuits. Therefore, we can enhance any given design with "power estimation hardware", map it to a prototyping platform, and exercise it with any given test stimuli to obtain power consumption estimates. Our empirical studies with industrial designs reveal that power emulation can achieve significant speedups (10X to 500X) over state-of-the-art commercial register-transfer level (RTL) power estimation tools.

  3. 2014 CERN Accelerator Schools

    CERN Multimedia


    A specialised school on Power Converters will be held in Baden, Switzerland, from 7 to 14 May 2014. Please note that the deadline for applications is 7 FEBRUARY 2014. A course on Introduction to Accelerator Physics will be held in Prague, Czech Republic, from 31 August to 12 September 2014. Applications are now open for this school; the application deadline is 25 APRIL 2014. Further information on these schools and other CAS events can be found on the CAS website and on the Indico page. For further information please contact

  4. Accelerated Innovation Pilot (United States)

    Davis, Jeffrey


    Opportunities: I. Engage NASA team (examples) a) Research and technology calls . provide suggestions to AES, HRP, OCT. b) Use NASA@Work to solicit other ideas; (possibly before R+D calls). II. Stimulate collaboration (examples) a) NHHPC. b) Wharton Mack Center for Technological Innovation (Feb 2013). c) International ] DLR ] :envihab (July 2013). d) Accelerated research models . NSF, Myelin Repair Foundation. III. Engage public Prizes (open platform: InnoCentive,, NTL; Rice Business Plan, etc.) IV. Use same methods to engage STEM.

  5. Medical applications of accelerators

    CERN Document Server

    Rossi, Sandro


    At Present, about five thousands accelerators are devoted to biomedical applications. They are mainly used in radiotherapy, research and medical radioisotopes production. In this framework oncological hadron-therapy deserves particular attention since it represents a field in rapid evolution thanks to the joint efforts of laboratories with long experiences in particle physics. It is the case of CERN where the design of an optimised synchrotron for medical applications has been pursued. These lectures present these activities with particular attention to the new developments which are scientifically interesting and/or economically promising.

  6. Accelerating abelian gauge dynamics

    CERN Document Server

    Adler, Stephen Louis


    In this paper, we suggest a new acceleration method for Abelian gauge theories based on linear transformations to variables which weight all length scales equally. We measure the autocorrelation time for the Polyakov loop and the plaquette at β=1.0 in the U(1) gauge theory in four dimensions, for the new method and for standard Metropolis updates. We find a dramatic improvement for the new method over the Metropolis method. Computing the critical exponent z for the new method remains an important open issue.


    DEFF Research Database (Denmark)

    Jensen, Jens Stissing; Koch, Christian


    By viewing the construction industry as a technological innovation system (TIS) this paper discusses possible initiatives to accelerate nanotechnological innovations. The point of departure is a recent report on the application of nano-technology in the Danish construction industry, which concludes...... of the system are furthermore poorly equipped at identifying potentials within high-tech areas. In order to exploit the potentials of nano-technology it is thus argued that an alternative TIS needs to be established. Initiatives should identify and support “incubation rooms” or marked niches in order...


    Directory of Open Access Journals (Sweden)

    Divya G.S


    Full Text Available PPAR-γ regulates cellular differentiation, development and metabolism. They play these essential roles by functioning as transcription factors regulating the expression of genes. The PPARs mainly are of three types α, β and γ. The PPAR-γ expressed in three forms γ1, γ2 and γ3 present in different tissues. When PPAR binds its ligand, transcription of target gene is increased or decreased. Tzds were able to induce cell differentiation and apoptosis or inhibit cell proliferation both in vitro and in vivo. However, widespread use of thiazolidinediones (TZDs, the clinically used synthetic PPAR gamma agonists, has been limited by adverse effects. So in this review we are suggesting some new molecules other than thiazolidine diones which can act as potential anticancer agents, after explaining the mechanism of action of PPAR-γ agonists as anticancer agents especially thiazolidinediones.

  9. Grooming, rank, and agonistic support in tufted capuchin monkeys. (United States)

    Schino, Gabriele; Di Giuseppe, Francesca; Visalberghi, Elisabetta


    Studies investigating the relation between allogrooming and social rank in capuchin monkeys (genus Cebus) have yielded inconsistent results. In this study, we investigated the relation between grooming, agonistic support, aggression and social rank in a captive group of tufted capuchin monkeys (C. apella). Differently from most previous studies, we based our analyses on a relatively large database and studied a group with known genealogical relationships. Tufted capuchin females did not exchange grooming for rank-related benefits such as agonistic support or reduced aggression. Coherently with this picture, they did not groom up the hierarchy and did not compete for accessing high-ranking grooming partners. It is suggested that a small group size, coupled with a strong kin bias, may make the exchange of grooming for rank-related benefits impossible or unprofitable, thus eliminating the advantages of grooming up the hierarchy. We provide several possible explanations for the heterogeneity of results across capuchin studies that have addressed similar questions.

  10. Particle acceleration mechanisms

    CERN Document Server

    Petrosyan, V


    We review the possible mechanisms for production of non-thermal electrons which are responsible for non-thermal radiation in clusters of galaxies. Our primary focus is on non-thermal Bremsstrahlung and inverse Compton scattering, that produce hard X-ray emission. We briefly review acceleration mechanisms and point out that in most astrophysical situations, and in particular for the intracluster medium, shocks, turbulence and plasma waves play a crucial role. We consider two scenarios for production of non-thermal radiation. The first is hard X-ray emission due to non-thermal Bremsstrahlung by nonrelativistic particles. Non-thermal tails are produced by accelerating electrons from the background plasma with an initial Maxwellian distribution. However, these tails are accompanied by significant heating and they are present for a short time of <10^6 yr, which is also the time that the tail will be thermalised. Such non-thermal tails, even if possible, can only explain the hard X-ray but not the radio emission...

  11. Accelerator School Success

    CERN Multimedia


    Accelerator specialists don't grow on trees: training them is the job of the CERN Accelerator School (CAS). Group photo during visit to the Daresbury Laboratory. CAS and the CCLRC Daresbury Laboratory jointly organised a specialised school on Power Converters in Warrington, England from 12-18 May 2004. The last CAS Power Converter course was in 1990, so there was plenty of ground to cover. The challenging programme proposed a review of the state of the art and the latest developments in the field, including 30 hours of tuition. The school also included a visit to the CCLRC Daresbury laboratory, a one-day excursion to Liverpool and Chester and a themed (Welsh medieval) dinner at the school's closure. A record attendance of 91 students of more than 20 different nationalities included not only participants from Europe and North America but also from Armenia, Taiwan, India, Turkey, Iran and for the first time, fee-paying students from China and Australia. European industry showed a welcome and solid interest in...

  12. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    Energy Technology Data Exchange (ETDEWEB)

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K. (GSKPA)


    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  13. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond. (United States)

    Xia, Yang; Kellems, Rodney E


    Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT₁) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT₁ agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT₁ agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT₁ agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT₁ agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT₁. These

  14. Agonistic Vocalisations in Domestic Cats : A Case Study


    Schötz, Susanne


    Introducing a new cat to a home with resident cats may lead to stress, aggression and even fights. In this case study 468 agonistic cat vocalisations were recorded as one cat was introduced to three resident cats in her new home. Six vocalisation types were identified: growl, howl, howl-growl, hiss, spit and snarl. Numerous other intermediate and complex vocalisations were also observed. An acoustic analysis showed differences within and between all types. Future studies include further acous...

  15. CRM 1-mediated degradation and agonist-induced down-regulation of beta-adrenergic receptor mRNAs. (United States)

    Bai, Ying; Lu, Huafei; Machida, Curtis A


    The beta1-adrenergic receptor (beta1-AR) mRNAs are post-transcriptionally regulated at the level of mRNA stability and undergo accelerated agonist-mediated degradation via interaction of its 3' untranslated region (UTR) with RNA binding proteins, including the HuR nuclear protein. In a previous report [Kirigiti et al. (2001). Mol. Pharmacol. 60:1308-1324], we examined the agonist-mediated down-regulation of the rat beta1-AR mRNAs, endogenously expressed in the rat C6 cell line and ectopically expressed in transfectant hamster DDT1MF2 and rat L6 cells. In this report, we determined that isoproterenol treatment of neonatal rat cortical neurons, an important cell type expressing beta1-ARs in the brain, results in significant decreases in beta1-AR mRNA stability, while treatment with leptomycin B, an inhibitor of the nuclear export receptor CRM 1, results in significant increases in beta1-AR mRNA stability and nuclear retention. UV-crosslinking/immunoprecipitation and glycerol gradient fractionation analyses indicate that the beta1-AR 3' UTR recognize complexes composed of HuR and multiple proteins, including CRM 1. Cell-permeable peptides containing the leucine-rich nuclear export signal (NES) were used as inhibitors of CRM 1-mediated nuclear export. When DDT1MF2 transfectants were treated with isoproterenol and peptide inhibitors, only the co-addition of the NES inhibitor reversed the isoproterenol-induced reduction of beta1-AR mRNA levels. Our results suggest that CRM 1-dependent NES-mediated mechanisms influence the degradation and agonist-mediated down-regulation of the beta1-AR mRNAs.

  16. Exenatide (a GLP-1 agonist) improves the antioxidative potential of in vitro cultured human monocytes/macrophages. (United States)

    Bułdak, Łukasz; Łabuzek, Krzysztof; Bułdak, Rafał Jakub; Machnik, Grzegorz; Bołdys, Aleksandra; Okopień, Bogusław


    Macrophages are dominant cells in the pathogenesis of atherosclerosis. They are also a major source of reactive oxygen species (ROS). Oxidative stress, which is particularly high in subjects with diabetes, is responsible for accelerated atherosclerosis. Novel antidiabetic drugs (e.g., glucagon-like peptide-1 (GLP-1) agonists) were shown to reduce ROS level. Therefore, we conceived a study to evaluate the influence of exenatide, a GLP-1 agonist, on redox status in human monocytes/macrophages cultured in vitro, which may explain the beneficial effects of incretin-based antidiabetic treatment. Human macrophages obtained from 10 healthy volunteers were in vitro subjected to the treatment with GLP-1 agonist (exenatide) in the presence of lipopolysaccharide (LPS), antagonist of GLP-1 receptors (exendin 9-39), or protein kinase A inhibitor (H89). Afterwards, reactive oxygen species, malondialdehyde level, NADPH oxidase, and antioxidative enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase] expression was evaluated. Finally, we estimated the activity of the abovementioned enzymes in the presence of H89. According to our findings, exenatide reduced ROS and malondialdyhyde (MDA) level by decreasing the expression of ROS-generating NADPH oxidase and by increasing the expression and activities of SOD and GSH-Px. We also showed that this effect was significantly inhibited by exendin 9-39 (a GLP-1 antagonist) and blocked by H89. Exenatide improved the antioxidative potential and reduced oxidative stress in cultured human monocytes/macrophages, and this finding may be responsible for the pleiotropic effects of incretin-based therapies. This effect relied on the stimulation of GLP-1 receptor.

  17. Acceleration in Linear and Circular Motion (United States)

    Kellington, S. H.; Docherty, W.


    Describes the construction of a simple accelerometer and explains its use in demonstrating acceleration, deceleration, constant speed, measurement of acceleration, acceleration and the inclined plane and angular and radial acceleration. (GS)

  18. 2014 Joint International Accelerator School: Beam Loss and Accelerator Protection

    CERN Document Server

    JAS - Joint US-CERN-Japan-Russia Accelerator School


    Many particle accelerators operate with very high beam power and very high energy stored in particle beams as well as in magnet systems. In the future, the beam power in high intensity accelerators will further increase. The protection of the accelerator equipment from the consequences of uncontrolled release of the energy is essential. This was the motivation for organizing a first school on beam losses and accelerator protection (in general referred to as machine protection). During the school the methods and technologies to identify, mitigate, monitor and manage the technical risks associated with the operation of accelerators with high-power beams or subsystems with large stored energy were presented. At the completion of the school the participants should have been able to understand the physical phenomena that can damage machine subsystems or interrupt operations and to analyze an accelerator facility to produce a register of technical risks and the corresponding risk mitigation and management strategie...

  19. Biological Rationale for the Use of PPARγ Agonists in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Hayley Patricia Ellis


    Full Text Available Glioblastoma Multiforme (GBM is the most common primary intrinsic CNS tumour and has an extremely poor overall survival, despite advances in neurosurgery, chemotherapy and radiation therapy. There has been interesting preliminary evidence suggesting that patients receiving the group of anti-diabetic drugs known as PPARγ (Peroxisome proliferator-activated receptor gamma agonists have a lower incidence of glioma. The nuclear hormone receptor PPARγ has been found to be expressed in high grade gliomas, and its activation has been shown to have several antineoplastic effects on human and rat glioma cell lines, and in some instances an additional protective increase in antioxidant enzymes has been observed in normal astrocytes. At present, no clinical trials are underway with regards to treating glioma patients using PPARγ agonists, as Pioglitazone and Rosiglitazone are only FDA-approved for use in treatment of type-2 diabetes. This review presents the case for evaluating the potential of PPARγ agonists as novel adjuvants in the treatment of high grade glioma. We introduce the PPARγ pathway, PPARγ gene and its products and examine recent research in glioblastoma.

  20. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    Directory of Open Access Journals (Sweden)

    Fergus Keane


    Full Text Available Pituitary apoplexy represents an uncommon endocrine emergency with potentially life-threatening consequences. Drug-induced pituitary apoplexy is a rare but important consideration when evaluating patients with this presentation. We describe an unusual case of a patient with a known pituitary macroadenoma presenting with acute-onset third nerve palsy and headache secondary to tumour enlargement and apoplexy. This followed gonadotropin-releasing hormone (GNRH agonist therapy used to treat metastatic prostate carcinoma. Following acute management, the patient underwent transphenoidal debulking of his pituitary gland with resolution of his third nerve palsy. Subsequent retrospective data interpretation revealed that this had been a secretory gonadotropinoma and GNRH agonist therapy resulted in raised gonadotropins and testosterone. Hence, further management of his prostate carcinoma required GNRH antagonist therapy and external beam radiotherapy. This case demonstrates an uncommon complication of GNRH agonist therapy in the setting of a pituitary macroadenoma. It also highlights the importance of careful, serial data interpretation in patients with pituitary adenomas. Finally, this case presents a unique insight into the challenges of managing a hormonal-dependent prostate cancer in a patient with a secretory pituitary tumour.

  1. Suppression of atherosclerosis by synthetic REV-ERB agonist

    Energy Technology Data Exchange (ETDEWEB)

    Sitaula, Sadichha [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Billon, Cyrielle [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States); Kamenecka, Theodore M.; Solt, Laura A. [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Burris, Thomas P., E-mail: [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States)


    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.

  2. LHRH Agonists for the Treatment of Prostate Cancer: 2012. (United States)

    Lepor, Herbert; Shore, Neal D


    The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge ("clinical flare") and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT.

  3. Pharmacophore-driven identification of PPARγ agonists from natural sources (United States)

    Petersen, Rasmus K.; Christensen, Kathrine B.; Assimopoulou, Andreana N.; Fretté, Xavier; Papageorgiou, Vassilios P.; Kristiansen, Karsten; Kouskoumvekaki, Irene


    In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPARγ agonist through bioassay-guided chromatographic fractionations of Chios mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPARγ. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPARγ agonists; while at the same time it manifests that natural products are highly relevant for use in virtual screening-based drug discovery.

  4. Investigation on laser accelerators. Plasma beat wave accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Miura, Akihiko; Miyamoto, Yasuaki; Hagiwara, Masayoshi; Suzuki, Mitsutoshi; Sudo, Osamu [Power Reactor and Nuclear Fuel Development Corp., Tokai, Ibaraki (Japan). Tokai Works


    Laser accelerator technology has characteristics of high energy, compact, short pulse and high luminescence{center_dot}low emittance. This means potential many applications in wide ranges of fields as well as high energy and nuclear physics. High power short laser pulses are injected to a plasma in the typical example of laser accelerators. Large electric fields are induced in the plasma. Electrons in the plasma are accelerated with the ponderomotive force of the electric field. The principles of interaction on beat wave, wakefield accelerators, inverse free electron laser and inverse Cherenkov radiation are briefly introduced. The overview of plasma beat wave accelerator study is briefly described on the programs at Chalk River Laboratories(Canada), UCLA(USA), Osaka Univ. (Japan) and Ecole Polytechnique (France). Issues of the plasma beat wave accelerator are discussed from the viewpoint of application. Existing laser technologies of CO{sub 2}, YAG and YFL are available for the present day accelerator technology. An acceleration length of beat wave interaction is limited due to its phase condition. Ideas on multi-staged acceleration using the phasing plasma fiber are introduced. (Y. Tanaka)

  5. CERN Accelerator School: Registration open for Advanced Accelerator Physics course

    CERN Multimedia


    Registration is now open for the CERN Accelerator School’s Advanced Accelerator Physics course to be held in Warsaw, Poland from 27 September to 9 October 2015.   The course will be of interest to physicists and engineers who wish to extend their knowledge of Accelerator Physics. The programme offers core lectures on accelerator physics in the mornings and a practical course with hands-on tuition in the afternoons.  Further information can be found at:

  6. CERN Accelerator School: Registration open for Advanced Accelerator Physics course

    CERN Multimedia


    Registration is now open for the CERN Accelerator School’s Advanced Accelerator Physics course to be held in Warsaw, Poland from 27 September to 9 October 2015.   The course will be of interest to physicists and engineers who wish to extend their knowledge of accelerator physics. The programme offers core lectures on accelerator physics in the mornings and a practical course with hands-on tuition in the afternoons.  Further information can be found at:

  7. Agonists and inverse agonists for the herpesvirus 8-encoded constitutively active seven-transmembrane oncogene product, ORF-74

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Kledal, T N; Bräuner-Osborne, Hans


    A number of CXC chemokines competed with similar, nanomolar affinity against 125I-interleukin-8 (IL-8) binding to ORF-74, a constitutively active seven-transmembrane receptor encoded by human herpesvirus 8. However, in competition against 125I-labeled growth-related oncogene (GRO)-alpha, the ORF-74...... receptor was highly selective for GRO peptides, with IL-8 being 10,000-fold less potent. The constitutive stimulating activity of ORF-74 on phosphatidylinositol turnover was not influenced by, for example, IL-8 binding. In contrast, GRO peptides acted as potent agonists in stimulating ORF-74 signaling......, whereas IP-10 and stromal cell-derived factor-1alpha surprisingly acted as inverse agonists. These peptides had similar pharmacological properties with regard to enhancing or inhibiting, respectively, the stimulatory effect of ORF-74 on NIH-3T3 cell proliferation. Construction of a high affinity zinc...

  8. Electrostatic accelerators fundamentals and applications

    CERN Document Server


    Electrostatic accelerators are an important and widespread subgroup within the broad spectrum of modern, large particle acceleration devices. They are specifically designed for applications that require high-quality ion beams in terms of energy stability and emittance at comparatively low energies (a few MeV). Their ability to accelerate virtually any kind of ion over a continuously tunable range of energies make them a highly versatile tool for investigations in many research fields including, but not limited to, atomic and nuclear spectroscopy, heavy ion reactions, accelerator mass spectroscopy as well as ion-beam analysis and modification. The book is divided into three parts. The first part concisely introduces the field of accelerator technology and techniques that emphasize their major modern applications. The second part treats the electrostatic accelerator per se: its construction and operational principles as well as its maintenance. The third part covers all relevant applications in which electrosta...


    Courant, E.D.; Livingston, M.S.; Snyder, H.S.


    An improved apparatus is presented for focusing charged particles in an accelerator. In essence, the invention includes means for establishing a magnetic field in discrete sectors along the path of moving charged particles, the magnetic field varying in each sector in accordance with the relation. B = B/ sub 0/ STAln (r-r/sub 0/)/r/sub 0/!, where B/sub 0/ is the value of the magnetic field at the equilibrium orbit of radius r/sub 0/ of the path of the particles, B equals the magnetic field at the radius r of the chamber and n equals the magnetic field gradient index, the polarity of n being abruptly reversed a plurality of times as the particles travel along their arcuate path. With this arrangement, the particles are alternately converged towards the axis of their equillbrium orbit and diverged therefrom in successive sectors with a resultant focusing effect.

  10. Hadron accelerators for radiotherapy (United States)

    Owen, Hywel; MacKay, Ranald; Peach, Ken; Smith, Susan


    Over the last twenty years the treatment of cancer with protons and light nuclei such as carbon ions has moved from being the preserve of research laboratories into widespread clinical use. A number of choices now exist for the creation and delivery of these particles, key amongst these being the adoption of pencil beam scanning using a rotating gantry; attention is now being given to what technologies will enable cheaper and more effective treatment in the future. In this article the physics and engineering used in these hadron therapy facilities is presented, and the research areas likely to lead to substantive improvements. The wider use of superconducting magnets is an emerging trend, whilst further ahead novel high-gradient acceleration techniques may enable much smaller treatment systems. Imaging techniques to improve the accuracy of treatment plans must also be developed hand-in-hand with future sources of particles, a notable example of which is proton computed tomography.

  11. Dynamics of pyroelectric accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Ghaderi, R.; Davani, F. Abbasi, E-mail: [Radiation Application Department, Shahid Beheshti University, Tehran (Iran, Islamic Republic of)


    Pyroelectric crystals are used to produce high energy electron beams. We have derived a method to model electric potential generation on LiTaO{sub 3} crystal during heating cycle. In this method, effect of heat transfer on the potential generation is investigated by some experiments. In addition, electron emission from the crystal surface is modeled by measurements and analysis. These spectral data are used to present a dynamic equation of electric potential with respect to thickness of the crystal and variation of its temperature. The dynamic equation's results for different thicknesses are compared with measured data. As a result, to attain more energetic electrons, best thickness of the crystals could be extracted from the equation. This allows for better understanding of pyroelectric crystals and help to study about current and energy of accelerated electrons.

  12. Testing Gravity on Accelerators

    CERN Document Server

    Kalaydzhyan, Tigran


    Weak equivalence principle (WEP) is one of the cornerstones of the modern theories of gravity, stating that the trajectory of a freely falling test body is independent of its internal structure and composition. Even though WEP is known to be valid for the normal matter with a high precision, it has never been experimentally confirmed for relativistic matter and antimatter. We make an attempt to constrain possible deviations from WEP utilizing the modern accelerator technologies. We analyze the (absence of) vacuum Cherenkov radiation, photon decay, anomalous synchrotron losses and the Compton spectra to put limits on the isotropic Lorentz violation and further convert them to the constraints on the difference between the gravitational and inertial masses of the relativistic electrons/positrons. Our main result is the 0.1% limit on the mentioned difference.

  13. Acceleration of cosmic rays

    Energy Technology Data Exchange (ETDEWEB)

    Berezhko, E [Yu.G. Shafer Institute of Cosmophysical Research and Aeronomy, 31 Lenin Ave., 677980 Yakutsk (Russian Federation)], E-mail:


    Cosmic ray (CR) origin problem is briefly discussed. It is argued that CRs with energies up to 10{sup 17} eV are produced in galactic supernova remnants, whereas ultra high energy CRs are extragalactic. CR composition strongly changes within the transition from galactic to extragalactic CR component, therefore precise measurements of CR composition at energies 10{sup 17} - 10{sup 19} eV are needed for the reliable determination of this transition. The possible sources of extragalactic CRs are briefly discussed. It is argued that CR acceleration at the shock created by the expanding cocoons around active galactic nuclei has to be considered as a prime candidate for the sources of extragalactic CRs.

  14. SPS accelerating cavity

    CERN Multimedia


    The SPS started up with 2 accelerating cavities (each consisting of 5 tank sections) in LSS3. They have a 200 MHz travelling wave structure (see 7411032 and 7802190) and 750 kW of power is fed to each of the cavities from a 1 MW tetrode power amplifier, located in a surface building above, via a coaxial transmission line. Clemens Zettler, builder of the SPS RF system, is standing at the side of one of the cavities. In 1978 and 1979 another 2 cavities were added and entered service in 1980. These were part of the intensity improvement programme and served well for the new role of the SPS as proton-antiproton collider. See also 7411032, 8011289, 8104138, 8302397.

  15. The treatment of Parkinson's disease with dopamine agonists

    Directory of Open Access Journals (Sweden)

    Frank, Wilhelm


    Full Text Available Parkinson’s disease is a chronic degenerative organic disease with unknown causes. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body. The questions of this report are concerned the efficiency and safety of a treatment with dopamine agonists. Furthermore the cost-effectiveness is investigated as well as ethic questions. The goal is to give recommendation for the use of dopamine agonists to the German health system. A systematic literature search was done. The identified studies have different methodological quality and investigate different hypothesis and different outcome criteria. Therefore a qualitative method of information synthesis was chosen. Since the introduction of L-Dopa in the 1960´s it is considered as the most effective substance to reduce all the cardinal symptoms of Parkinson disease. This substance was improved in the course of time. Firstly some additional substances were given (decarbonxylase inhibitors, catechol-o-transferase inhibitors (COMT-inhibitors, monoaminoxydase-inhibitors (MAO-inhibitors and NMDA-antagonists (N-Methyl-d-aspartat-antagonists. In the practical therapy of Parkinson dopamine agonists play an important role, because they directly use the dopamine receptors. The monotherapy of Parkinson disease is basically possible and is used in early stages of the disease. Clinical practise has shown, that an add on therapy with dopamine agonists can led to a reduction of the dose of L-dopa and a reduction of following dyskinesia. The studies for effectiveness include studies for the initial therapy, monotherapy and add-on-therapy. Basically there is a good effectiveness of dopamine

  16. NOD2 Agonist Promotes the Production of Inflammatory Cytokines in VSMC in Synergy with TLR2 and TLR4 Agonists

    Directory of Open Access Journals (Sweden)

    Jinghua Sun


    Full Text Available Objective. To investigate the expression of NOD2 in human VSMCs, its role in the production of inflammatory cytokines in VSMC and the possible interaction of NOD2-mediated signaling pathway with those mediated by TLR2 and TLR4. Methods. Human coronary artery smooth muscle cells were stimulated with NOD2 agonist MDP alone or in combination with either TLR2 agonist PAM3 or TLR4 agonist LPSs. The mRNA expression of NOD2 and FGF-2 were measured by RT-PCR. The concentration of IL-8 and TNF-α in the culture supernatants was determined by ELISA. VSMC proliferation ability was analyzed by MTT assay. Results. MDP up regulated the expression of NOD2 mRNA in VSMC in a time-dependent manner, up regulated the expression of FGF-2 mRNA in VSMC, induced the production of IL-8 and TNF-α, and promoted the proliferation of VSMC. Additionally, MDP synergied with LPS and PAM3 to promote the proliferation of VSMC and induce the production of IL-8 and TNF-α. Conclusion. The activation of NOD2-mediated innate immune signaling pathway can increase the proliferation ability of VSMC and induce the production of inflammatory cytokines in VSMC. It is also shown a synergistic effect with TLR2- and TLR4-mediated signaling pathways in this process.

  17. 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.

  18. Project X: Accelerator Reference Design

    CERN Document Server

    Holmes, S D; Chase, B; Gollwitzer, K; Johnson, D; Kaducak, M; Klebaner, A; Kourbanis, I; Lebedev, V; Leveling, A; Li, D; Nagaitsev, S; Ostroumov, P; Pasquinelli, R; Patrick, J; Prost, L; Scarpine, V; Shemyakin, A; Solyak, N; Steimel, J; Yakovlev, V; Zwaska, R


    Part 1 of "Project X: Accelerator Reference Design, Physics Opportunities, Broader Impacts". Part 1 contains the volume Preface and a description of the conceptual design for a high-intensity proton accelerator facility being developed to support a world-leading program of Intensity Frontier physics over the next two decades at Fermilab. Subjects covered include performance goals, the accelerator physics design, and the technological basis for such a facility.

  19. NIIEFA accelerators for applied purposes (United States)

    Vorogushin, M. F.; Strokach, A. P.; Filatov, O. G.


    Since the foundation of the institute, we have designed and delivered more than three hundred different accelerators to Russia and abroad: cyclotrons, linear accelerators, and neutron generators. The technical characteristics of our equipment makes it competitive on the international market. Here we present the application, main parameters, and status of accelerators manufactured by NIIEFA, as well as prospects for the development of electrophysical systems for applied purposes.

  20. Landing the uniformly accelerating observers


    Rothenstein, Bernhard; Popescu, Stefan; Gruber, Ronald P.


    Observers of the uniformly accelerating observers or the observers who make up the system of uniformly accelerating observers reach the same velocity V at different times ti which depends on V and on theirs acceleration gi. Considering a platform that moves with constant velocity V, the observers can land smoothly on it. Their ages and locations in the inertial reference frame attached to the platform are reckoned and compared.

  1. Collective accelerator for electron colliders

    Energy Technology Data Exchange (ETDEWEB)

    Briggs, R.J.


    A recent concept for collective acceleration and focusing of a high energy electron bunch is discussed, in the context of its possible applicability to large linear colliders in the TeV range. The scheme can be considered to be a member of the general class of two-beam accelerators, where a high current, low voltage beam produces the acceleration fields for a trailing high energy bunch.

  2. Thomas Precession by Uniform Acceleration

    CERN Document Server

    Pardy, Miroslav


    We determine the nonlinear transformations between coordinate systems which are mutually in a constant symmetrical accelerated motion. The maximal acceleration limit follows from the kinematical origin and it is an analogue of the maximal velocity in special relativity. We derive the dependence of mass, length, time, Doppler effect, Cherenkov effect and transition radiation angle on acceleration as an analogue phenomena in special theory of relativity. The last application of our method is the Thomas precession by uniform acceleration with the possible role in the modern physics and cosmology. The comparison of derived results with other relativistic methods is necessary.

  3. Superconducting Radiofrequency (SRF) Acceleration Technology (United States)

    Federal Laboratory Consortium — SRF cavities enable accelerators to increase particle beam energy levels while minimizing the use of electrical power by all but eliminating electrical resistance....


    Energy Technology Data Exchange (ETDEWEB)

    Perri, S.; Zimbardo, G., E-mail: [Dipartimento di Fisica, Università della Calabria, Ponte P. Bucci, I-87036 Rende (Italy)


    The analysis of time profiles of particles accelerated at interplanetary shocks allows particle transport properties to be inferred. The frequently observed power-law decay upstream, indeed, implies a superdiffusive particle transport when the level of magnetic field variance does not change as the time interval from the shock front increases. In this context, a superdiffusive shock acceleration (SSA) theory has been developed, allowing us to make predictions of the acceleration times. In this work we estimate for a number of interplanetary shocks, including the solar wind termination shock, the acceleration times for energetic protons in the framework of SSA and we compare the results with the acceleration times predicted by standard diffusive shock acceleration. The acceleration times due to SSA are found to be much shorter than in the classical model, and also shorter than the interplanetary shock lifetimes. This decrease of the acceleration times is due to the scale-free nature of the particle displacements in the framework of superdiffusion. Indeed, very long displacements are possible, increasing the probability for particles far from the front of the shock to return, and short displacements have a high probability of occurrence, increasing the chances for particles close to the front to cross the shock many times.

  5. Thomas Edison Accelerated Elementary School. (United States)

    Levin, Henry M.; Chasin, Gene

    This paper describes early outcomes of a Sacramento, California, elementary school that participated in the Accelerated Schools Project. The school, which serves many minority and poor students, began training for the project in 1992. Accelerated Schools were designed to advance the learning rate of students through a gifted and talented approach,…

  6. COMPASS Accelerator Design Technical Overview

    Energy Technology Data Exchange (ETDEWEB)

    Nanni, Emilio; Dolgashev, Valery; Tantawi, Sami; Neilson, Jeff; /SLAC


    This report is a survey of technical options for generating a MeV-class accelerator for space based science applications. The survey was performed focusing on the primary technical requirements of the accelerator in the context of a satellite environment with its unique challenges of limited electrical power (PE), thermal isolation, dimensions, payload requirement and electrical isolation.

  7. Identification of human dopamine receptors agonists from Chinese herbs

    Institute of Scientific and Technical Information of China (English)

    Yi-lin ZHANG; Hai-qing ZHANG; Xiao-yu LIU; Shi-neng HUA; Lu-bing ZHOU; Jun YU; Xue-hai TAN


    Aim: To find human dopamine receptors, especially D1-like receptor specific ago-nists from Chinese herbs as potential antihypertension drug leads. Methods: Two D1-like receptor cell lines carrying a β-lactamase reporter gene, and a D2 receptor cell line coexpressing a promiscuous G protein G15 were constructed using HEK293 cells. A natural compound library made from fractionated samples of herbal ex-tracts was used for high-throughput screening (HTS) against one of the cell lines,HEK/D5R/CRE-blax. The interested hits were evaluated for their activities against various dopamine receptors. Results: Fourteen hits were identified from primary screening, of which 2 of the better hit samples, HD0522 and HD0059, were selected for further material and activity analysis, and to obtain 2 compounds that ap-peared as 2 single peaks in HPLC, HD0522H01 and HD0059H01. HD0059H01 could activate D1, D2, and D5 receptors, with EC50 values of 2.28 μg/mL, 0.85 μg/mL, and 1.41 μg/mL, respectively. HD0522H01 could only activate D1R and D5R with EC50 values of 2.95 μg/mL and 8.38 μg/mL. Conclusion: We established cell-based assays for 3 different human dopamine receptors and identified specific agonists HD0522H01 and HD0059H01 through HTS. The specific agonist to D1-like receptors, HD0522H01, may become a new natural product-based drug lead for antihypertension treatment.

  8. Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders. (United States)

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


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

  9. Comparative endpoint sensitivity of in vitro estrogen agonist assays. (United States)

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


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

  10. Biased signaling by peptide agonists of protease activated receptor 2. (United States)

    Jiang, Yuhong; Yau, Mei-Kwan; Kok, W Mei; Lim, Junxian; Wu, Kai-Chen; Liu, Ligong; Hill, Timothy A; Suen, Jacky Y; Fairlie, David P


    Protease activated receptor 2 (PAR2) is associated with metabolism, obesity, inflammatory, respiratory and gastrointestinal disorders, pain, cancer and other diseases. The extracellular N-terminus of PAR2 is a common target for multiple proteases, which cleave it at different sites to generate different N-termini that activate different PAR2-mediated intracellular signaling pathways. There are no synthetic PAR2 ligands that reproduce the same signaling profiles and potencies as proteases. Structure-activity relationships here for 26 compounds spanned a signaling bias over 3 log units, culminating in three small ligands as biased agonist tools for interrogating PAR2 functions. DF253 (2f-LAAAAI-NH2) triggered PAR2-mediated calcium release (EC50 2 μM) but not ERK1/2 phosphorylation (EC50 > 100 μM) in CHO cells transfected with hPAR2. AY77 (Isox-Cha-Chg-NH2) was a more potent calcium-biased agonist (EC50 40 nM, Ca2+; EC50 2 μM, ERK1/2), while its analogue AY254 (Isox-Cha-Chg-A-R-NH2) was an ERK-biased agonist (EC50 2 nM, ERK1/2; EC50 80 nM, Ca2+). Signaling bias led to different functional responses in human colorectal carcinoma cells (HT29). AY254, but not AY77 or DF253, attenuated cytokine-induced caspase 3/8 activation, promoted scratch-wound healing and induced IL-8 secretion, all via PAR2-ERK1/2 signaling. Different ligand components were responsible for different PAR2 signaling and functions, clues that can potentially lead to drugs that modulate different pathway-selective cellular and physiological responses.

  11. SPS RF Accelerating Cavity

    CERN Multimedia


    This picture shows one of the 2 new cavities installed in 1978-1979. The main RF-system of the SPS comprises four cavities: two of 20 m length and two of 16.5 m length. They are all installed in one long straight section (LSS 3). These cavities are of the travelling-wave type operating at a centre frequency of 200.2 MHz. They are wideband, filling time about 700 ns and untuned. The power amplifiers, using tetrodes are installed in a surface building 200 m from the cavities. Initially only two cavities were installed, a third cavity was installed in 1978 and a forth one in 1979. The number of power amplifiers was also increased: to the first 2 MW plant a second 2 MW plant was added and by end 1979 there were 8 500 kW units combined in pairs to feed each of the 4 cavities with up to about 1 MW RF power, resulting in a total accelerating voltage of about 8 MV. See also 7412016X, 7412017X, 7411048X

  12. LHC Dipoles Accelerate

    CERN Multimedia


    Andrezej Siemko (left), Peter Sievers (centre), and Lucio Rossi (right), have the exciting challenge of preparing and testing 2000 magnets for the LHC. The LHC is going to require a lot of powerful magnets by the time it begins operation in 2006. More specifically, it is going to need 130 special magnets, 400 quadrupoles, and a whopping 1250 dipoles! Preparing and testing these magnets for the conditions they will encounter in the LHC is not an easy task. But evaluation of the most recently received magnet, from the German company Noell, is showing that while the monumental task of receiving and testing nearly 2000 magnets is going to be exhausting, the goals are definitely attainable. At the moment and over the next year, pre-series magnets (the magnets that CERN uses to fine tune performance) are arriving slowly (90 in total will arrive), but by 2003 the rate of series magnet arrival will accelerate to 9 per week, that's over 450 in a single year! And working with these magnets when they arrive is tough. ...

  13. The entangled accelerating universe

    Energy Technology Data Exchange (ETDEWEB)

    Gonzalez-Diaz, Pedro F. [Colina de los Chopos, Instituto de Fisica Fundamental, Consejo Superior de Investigaciones Cientificas, Serrano 121, 28006 Madrid (Spain); Estacion Ecologica de Biocosmologia, Pedro de Alvarado, 14, 06411-Medellin (Spain)], E-mail:; Robles-Perez, Salvador [Colina de los Chopos, Instituto de Fisica Fundamental, Consejo Superior de Investigaciones Cientificas, Serrano 121, 28006 Madrid (Spain); Estacion Ecologica de Biocosmologia, Pedro de Alvarado, 14, 06411-Medellin (Spain)


    Using the known result that the nucleation of baby universes in correlated pairs is equivalent to spacetime squeezing, we show in this Letter that there exists a T-duality symmetry between two-dimensional warp drives, which are physically expressible as localized de Sitter little universes, and two-dimensional Tolman-Hawking and Gidding-Strominger baby universes respectively correlated in pairs, so that the creation of warp drives is also equivalent to spacetime squeezing. Perhaps more importantly, it has been also seen that the nucleation of warp drives entails a violation of the Bell's inequalities, and hence the phenomena of quantum entanglement, complementarity and wave function collapse. These results are generalized to the case of any dynamically accelerating universe filled with dark or phantom energy whose creation is also physically equivalent to spacetime squeezing and to the violation of the Bell's inequalities, so that the universe we are living in should be governed by essential sharp quantum theory laws and must be a quantum entangled system.

  14. EXHIBITION: Accelerated Particles

    CERN Multimedia


    An exhibition of plastic arts and two evenings of performances by sound and visual artists as part of CERN's 50th anniversary celebrations. Fifty candles for CERN, an international laboratory renowned for fundamental research, is a cause for celebration. Since March this year, Geneva and neighbouring parts of France have been the venues for a wealth of small and large-scale events, which will continue until November. Given CERN's location in the commune of Meyrin, the ForuMeyrin is hosting exhibitions of plastic arts and performances entitled: Accelerated Particles. Several works will be exhibited and performed in two 'salons'. Salon des matières: An exhibition of plastic arts From Tues 12 October to Wed 3 November 2004 Tuesdays to Fridays: 16:00 to 19:00 Saturdays: 14:00 to 18:00 Exhibition open late on performance nights, entrance free Salon des particules: Musical and visual performances Tues 12 and Mon 25 October from 20:00 to 23:00 Preview evening for both events: Tues 12 October from 18:...

  15. EXHIBITION: Accelerated Particles

    CERN Multimedia

    2004-01-01 An exhibition of plastic arts and two evenings of performances by sound and visual artists as part of CERN's fiftieth anniversary celebrations. The fiftieth anniversary of a world famous organization like CERN, an international laboratory specializing in fundamental research, is a cause for celebration. Since March this year, Geneva and neighbouring parts of France have been the venues for a wealth of small and large-scale events, which will continue until November. Given CERN's location in the commune of Meyrin, the ForuMeyrin is hosting two "salons" consisting of an exhibition of plastic arts and evenings of music and visual arts performances with the collective title of "Accelerated Particles". Several works will be exhibited and performed. Salon des matières: An exhibition of plastic arts Until Wednesday 3 November 2004. Tuesdays to Fridays: 4.00 p.m. to 7.00 p.m. Saturdays: 2.00 p.m. to 6.00 p.m. Doors open late on the evening of the performances. Salon des ...

  16. Accelerated shallow water modeling (United States)

    Gandham, Rajesh; Medina, David; Warburton, Timothy


    ln this talk we will describe our ongoing developments in accelerated numerical methods for modeling tsunamis, and oceanic fluid flows using two dimensional shallow water model and/or three dimensional incompressible Navier Stokes model discretized with high order discontinuous Galerkin methods. High order discontinuous Galerkin methods can be computationally demanding, requiring extensive computational time to simulate real time events on traditional CPU architectures. However, recent advances in computing architectures and hardware aware algorithms make it possible to reduce simulation time and provide accurate predictions in a timely manner. Hence we tailor these algorithms to take advantage of single instruction multiple data (SIMD) architecture that is seen in modern many core compute devices such as GPUs. We will discuss our unified and extensive many-core programming library OCCA that alleviates the need to completely re-design the solvers to keep up with constantly evolving parallel programming models and hardware architectures. We will present performance results for the flow simulations demonstrating performance leveraging multiple different multi-threading APIs on GPU and CPU targets.

  17. Actinides, accelerators and erosion (United States)

    Tims, S. G.; Fifield, L. K.


    Fallout isotopes can be used as artificial tracers of soil erosion and sediment accumulation. The most commonly used isotope to date has been 137Cs. Concentrations of 137Cs are, however, significantly lower in the Southern Hemisphere, and furthermore have now declined to 35% of original values due to radioactive decay. As a consequence the future utility of 137Cs is limited in Australia, with many erosion applications becoming untenable within the next 20 years, and there is a need to replace it with another tracer. Plutonium could fill this role, and has the advantages that there were six times as many atoms of Pu as of 137Cs in fallout, and any loss to decay has been negligible due to the long half-lives of the plutonium isotopes. Uranium-236 is another long-lived fallout isotope with significant potential for exploitation as a tracer of soil and sediment movement. Uranium is expected to be more mobile in soils than plutonium (or caesium), and hence the 236U/Pu ratio will vary with soil depth, and so could provide an independent measure of the amount of soil loss. In this paper we discuss accelerator based ultra-sensitive measurements of plutonium and 236U isotopes and their advantages over 137Cs as tracers of soil erosion and sediment movement.

  18. Actinides, accelerators and erosion

    Directory of Open Access Journals (Sweden)

    Fifield L.K.


    Full Text Available Fallout isotopes can be used as artificial tracers of soil erosion and sediment accumulation. The most commonly used isotope to date has been 137Cs. Concentrations of 137Cs are, however, significantly lower in the Southern Hemisphere, and furthermore have now declined to 35% of original values due to radioactive decay. As a consequence the future utility of 137Cs is limited in Australia, with many erosion applications becoming untenable within the next 20 years, and there is a need to replace it with another tracer. Plutonium could fill this role, and has the advantages that there were six times as many atoms of Pu as of 137Cs in fallout, and any loss to decay has been negligible due to the long half-lives of the plutonium isotopes. Uranium-236 is another long-lived fallout isotope with significant potential for exploitation as a tracer of soil and sediment movement. Uranium is expected to be more mobile in soils than plutonium (or caesium, and hence the 236U/Pu ratio will vary with soil depth, and so could provide an independent measure of the amount of soil loss. In this paper we discuss accelerator based ultra-sensitive measurements of plutonium and 236U isotopes and their advantages over 137Cs as tracers of soil erosion and sediment movement.

  19. Energy Innovation Acceleration Program

    Energy Technology Data Exchange (ETDEWEB)

    Wolfson, Johanna [Fraunhofer USA Inc., Center for Sustainable Energy Systems, Boston, MA (United States)


    The Energy Innovation Acceleration Program (IAP) – also called U-Launch – has had a significant impact on early stage clean energy companies in the Northeast and on the clean energy economy in the Northeast, not only during program execution (2010-2014), but continuing into the future. Key results include: Leverage ratio of 105:1; $105M in follow-on funding (upon $1M investment by EERE); At least 19 commercial products launched; At least 17 new industry partnerships formed; At least $6.5M in revenue generated; >140 jobs created; 60% of assisted companies received follow-on funding within 1 year of program completion; In addition to the direct measurable program results summarized above, two primary lessons emerged from our work executing Energy IAP:; Validation and demonstration awards have an outsized, ‘tipping-point’ effect for startups looking to secure investments and strategic partnerships. An ecosystem approach is valuable, but an approach that evaluates the needs of individual companies and then draws from diverse ecosystem resources to fill them, is most valuable of all.


    Energy Technology Data Exchange (ETDEWEB)



    Over the last few years, several novel magnet designs have been introduced to meet the requirements of new, high performance accelerators and beam lines. For example, the FAIR project at GSI requires superconducting magnets ramped at high rates ({approx} 4 T/s) in order to achieve the design intensity. Magnets for the RIA and FAIR projects and for the next generation of LHC interaction regions will need to withstand high doses of radiation. Helical magnets are required to maintain and control the polarization of high energy protons at RHIC. In other cases, novel magnets have been designed in response to limited budgets and space. For example, it is planned to use combined function superconducting magnets for the 50 GeV proton transport line at J-PARC to satisfy both budget and performance requirements. Novel coil winding methods have been developed for short, large aperture magnets such as those used in the insertion region upgrade at BEPC. This paper will highlight the novel features of these exotic magnets.

  1. Ramelteon: A melatonin receptor agonist for the treatment of insomnia

    Directory of Open Access Journals (Sweden)

    Devi V


    Full Text Available Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for the treatment of insomnia characterized by difficulty in sleep onset. It is a nonscheduled drug since it lacks the potential for abuse and does not interact with neurotransmitter receptors most associated with these phenomena. Although the effects of ramelteon use> 5 weeks are unknown, the available data confirms its safety and efficacy for short-term use. Clinical use and future research should uncover more information about ramelteon′s properties.

  2. Discovery of a potent and selective GPR120 agonist. (United States)

    Shimpukade, Bharat; Hudson, Brian D; Hovgaard, Christine Kiel; Milligan, Graeme; Ulven, Trond


    GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist.

  3. Induction of depersonalization by the serotonin agonist meta-chlorophenylpiperazine. (United States)

    Simeon, D; Hollander, E; Stein, D J; DeCaria, C; Cohen, L J; Saoud, J B; Islam, N; Hwang, M


    Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization. There was a significant correlation between the induction of depersonalization and increase in panic, but not nervousness, anxiety, sadness, depression, or drowsiness. This report suggests that serotonergic dysregulation may in part underlie depersonalization.

  4. 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.

  5. Particle Acceleration in Astrophysical Sources

    CERN Document Server

    Amato, Elena


    Astrophysical sources are extremely efficient accelerators. Some sources emit photons up to multi-TeV energies, a signature of the presence, within them, of particles with energies much higher than those achievable with the largest accelerators on Earth. Even more compelling evidence comes from the study of Cosmic Rays, charged relativistic particles that reach the Earth with incredibly high energies: at the highest energy end of their spectrum, these subatomic particles are carrying a macroscopic energy, up to a few Joules. Here I will address the best candidate sources and mechanisms as cosmic particle accelerators. I will mainly focus on Galactic sources such as Supernova Remnants and Pulsar Wind Nebulae, which being close and bright, are the best studied among astrophysical accelerators. These sources are held responsible for most of the energy that is put in relativistic particles in the Universe, but they are not thought to accelerate particles up to the highest individual energies, $\\approx 10^{20}$ eV...

  6. Shear Acceleration in Expanding Flows

    CERN Document Server

    Rieger, F M


    Shear flows are naturally expected to occur in astrophysical environments and potential sites of continuous non-thermal Fermi-type particle acceleration. Here we investigate the efficiency of expanding relativistic outflows to facilitate the acceleration of energetic charged particles to higher energies. To this end, the gradual shear acceleration coefficient is derived based on an analytical treatment. The results are applied to the context of the relativistic jets of active galactic nuclei. The inferred acceleration timescale is investigated for a variety of conical flow profiles (i.e., power law, Gaussian, Fermi-Dirac) and compared to the relevant radiative and non-radiative loss timescales. The results exemplify that relativistic shear flows are capable of boosting cosmic-rays to extreme energies. Efficient electron acceleration, on the other hand, requires weak magnetic fields and may thus be accompanied by a delayed onset of particle energization and affect the overall jet appearance (e.g., core, ridge ...

  7. The ISAC post-accelerator (United States)

    Laxdal, R. E.; Marchetto, M.


    The acceleration chain of the ISAC facility boosts the energy of both radioactive and stable light and heavy ions for beam delivery to both a medium energy area in ISAC-I and a high energy area in ISAC-II. The post-accelerator comprises a 35.4 MHz RFQ to accelerate beams of A/q ≤ 30 from 2 keV/u to 150 keV/u and a post stripper, 106.1 MHz variable energy drift tube linac (DTL) to accelerate ions of A/q ≤ 6 to a final energy between 0.15 MeV/u to 1.5 MeV/u. A 40 MV superconducting linac further accelerates beam from 1.5 MeV/u to energies above the Coulomb barrier. All linacs operate cw to preserve beam intensity.

  8. Industrial accelerators and their applications

    CERN Document Server

    Hamm, Marianne E


    This unique new book is a comprehensive review of the many current industrial applications of particle accelerators, written by experts in each of these fields. Readers will gain a broad understanding of the principles of these applications, the extent to which they are employed, and the accelerator technology utilized. The book also serves as a thorough introduction to these fields for non-experts and laymen. Due to the increased interest in industrial applications, there is a growing interest among accelerator physicists and many other scientists worldwide in understanding how accelerators are used in various applications. The government agencies that fund scientific research with accelerators are also seeking more information on the many commercial applications that have been or can be developed with the technology developments they are funding. Many industries are also doing more research on how they can improve their products or processes using particle beams.

  9. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment. (United States)

    Yang, Li; Islam, Mohammad R; Karamyan, Vardan T; Abbruscato, Thomas J


    To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype.

  10. Beam acceleration through proton radio frequency quadrupole accelerator in BARC (United States)

    Bhagwat, P. V.; Krishnagopal, S.; Mathew, J. V.; Singh, S. K.; Jain, P.; Rao, S. V. L. S.; Pande, M.; Kumar, R.; Roychowdhury, P.; Kelwani, H.; Rama Rao, B. V.; Gupta, S. K.; Agarwal, A.; Kukreti, B. M.; Singh, P.


    A 3 MeV proton Radio Frequency Quadrupole (RFQ) accelerator has been designed at the Bhabha Atomic Research Centre, Mumbai, India, for the Low Energy High Intensity Proton Accelerator (LEHIPA) programme. The 352 MHz RFQ is built in 4 segments and in the first phase two segments of the LEHIPA RFQ were commissioned, accelerating a 50 keV, 1 mA pulsed proton beam from the ion source, to an energy of 1.24 MeV. The successful operation of the RFQ gave confidence in the physics understanding and technology development that have been achieved, and indicate that the road forward can now be traversed rather more quickly.

  11. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson's disease and multiple system atrophy. (United States)

    Klos, Kevin J; Bower, James H; Josephs, Keith A; Matsumoto, Joseph Y; Ahlskog, J Eric


    Pathological hypersexuality developed in 13 patients with PD and two patients ultimately diagnosed clinically with MSA. Hypersexuality began within 8 months after starting dopamine agonist therapy in 14 of 15 cases, including four on agonist monotherapy. It resolved in the four cases where the agonist was stopped, despite continued levodopa therapy. This was not an isolated behavioral problem in most, with additional compulsive or addictive behaviors coinciding in nine patients (60%). A systematic literature review of pathological hypersexuality in PD revealed similar medication histories; combining these cases with our series, 26 of 29 patients (90%) were on adjuvant dopamine agonists.

  12. Long-acting beta(2)-agonists in management of childhood asthma

    DEFF Research Database (Denmark)

    Bisgaard, H


    This review assesses the evidence regarding the use of long-acting beta(2)-agonists in the management of pediatric asthma. Thirty double-blind, randomized, controlled trials on the effects of formoterol and salmeterol on lung function in asthmatic children were identified. Single doses of inhaled......, long-acting beta(2)-agonists provide effective bronchodilatation and bronchoprotection when used as intermittent, single-dose treatment of asthma in children, but not when used as regular treatment. Future studies should examine the positioning of long-acting beta(2)-agonists as an "as needed" rescue...... medication instead of short-acting beta(2)-agonists for pediatric asthma management....

  13. Accelerated cleanup risk reduction

    Energy Technology Data Exchange (ETDEWEB)

    Knapp, R.B.; Aines, R.M.; Blake, R.G.; Copeland, A.B.; Newmark, R.L.; Tompson, A.F.B.


    There is no proven technology for remediating contaminant plume source regions in a heterogeneous subsurface. This project is an interdisciplinary effort to develop the requisite new technologies so that will be rapidly accepted by the remediation community. Our technology focus is hydrous pyrolysis/oxidation (HPO) which is a novel in situ thermal technique. We have expanded this core technology to leverage the action of steam injection and place an in situ microbial filter downstream to intercept and destroy the accelerated movement of contaminated groundwater. Most contaminant plume source regions, including the chlorinated solvent plume at LLNL, are in subsurface media characterized by a wide range in hydraulic conductivity. At LLNL, the main conduits for contaminant transport are buried stream channels composed of gravels and sands; these have a hydraulic conductivity in the range of 10{sup -1} to 10{sup -2} cm/s. Clay and silt units with a hydraulic conductivity of 10{sup -1} to 10{sup -6} cm/s bound these buried channels; these are barriers to groundwater movement and contain the highest contaminant concentrations in the source region. New remediation technologies are required because the current ones preferentially access the high conductivity units. HPO is an innovative process for the in situ destruction of contaminants in the entire subsurface. It operates by the injection of steam. We have demonstrated in laboratory experiments that many contaminants rapidly oxidize to harmless compounds at temperatures easily achieved by injecting steam, provided sufficient dissolved oxygen is present. One important challenge in a heterogeneous source region is getting heat, contaminants, and an oxidizing agent in the same place at the same time. We have used the NUFT computer program to simulate the cyclic injection of steam into a contaminated aquifer for design of a field demonstration. We used an 8 hour, steam/oxygen injection cycle followed by a 56 hour relaxation

  14. Accelerating DSMC data extraction.

    Energy Technology Data Exchange (ETDEWEB)

    Gallis, Michail A.; Piekos, Edward Stanley


    In many direct simulation Monte Carlo (DSMC) simulations, the majority of computation time is consumed after the flowfield reaches a steady state. This situation occurs when the desired output quantities are small compared to the background fluctuations. For example, gas flows in many microelectromechanical systems (MEMS) have mean speeds more than two orders of magnitude smaller than the thermal speeds of the molecules themselves. The current solution to this problem is to collect sufficient samples to achieve the desired resolution. This can be an arduous process because the error is inversely proportional to the square root of the number of samples so we must, for example, quadruple the samples to cut the error in half. This work is intended to improve this situation by employing more advanced techniques, from fields other than solely statistics, for determining the output quantities. Our strategy centers on exploiting information neglected by current techniques, which collect moments in each cell without regard to one another, values in neighboring cells, nor their evolution in time. Unlike many previous acceleration techniques that modify the method itself, the techniques examined in this work strictly post-process so they may be applied to any DSMC code without affecting its fidelity or generality. Many potential methods are drawn from successful applications in a diverse range of areas, from ultrasound imaging to financial market analysis. The most promising methods exploit relationships between variables in space, which always exist in DSMC due to the absence of shocks. Disparate techniques were shown to produce similar error reductions, suggesting that the results shown in this report may be typical of what is possible using these methods. Sample count reduction factors of approximately three to five were found to be typical, although factors exceeding ten were shown on some variables under some techniques.

  15. Accelerated coffee pulp composting. (United States)

    Sánchez, G; Olguín, E J; Mercado, G


    The effect of two abundant, easily available and very low-cost agro-industrial organic residues, i.e., filter cake from the sugar industry and poultry litter, on the composting stabilization time of coffee pulp and on the quality of the produced compost, was evaluated. Piles of one cubic meter were built and monitored within the facilities of a coffee processing plant in the Coatepec region of the State of Veracruz, Mexico. Manual aeration was carried out once a week. A longer thermophilic period (28 days) and a much lower C/N ratio (in the range of 6.9-9.1) were observed in the piles containing the amendments, as compared to the control pile containing only coffee pulp (14 days and a C/N ratio of 14.4, respectively). The maximum assimilation rate of the reducing sugars was 1.6 g kg-1 d-1 (from 7.5 to 5.3%) during the first two weeks when accelerators were present in the proportion of 20% filter cake plus 20% poultry litter, while they accumulated at a rate of 1.2 g kg-1 d-1 (from 7.4 to 9.13%) during the same period in the control pile. The best combination of amendments was 30% filter cake with 20% poultry litter, resulting in a final nitrogen content as high as 4.81%. The second best combination was 20% filter cake with 10% poultry litter, resulting in a compost which also contained a high level of total nitrogen (4.54%). It was concluded that the use of these two residues enhanced the composting process of coffee pulp, promoting a shorter stabilization period and yielding a higher quality of compost.

  16. Operation of the accelerator

    Energy Technology Data Exchange (ETDEWEB)

    Pardo, R.C.; Batzka, B.; Billquist, P.J. [and others


    Fiscal Year 1994 was the first year of seven-day operation since ATLAS became a national user facility in 1985. ATLAS made the most of the opportunity this year by providing 5200 hours of beam on-target to the research program. A record number of 60 experiments were completed and the {open_quotes}facility reliability{close_quotes} remained near the 90% level. Seven-day operation was made possible with the addition to the staff of two operator positions providing single-operator coverage during the weekend period. The normally scheduled coverage was augmented by an on-call list of system experts who respond to emergencies with phone-in advice and return to the Laboratory when necessary. This staffing approach continues but we rearranged our staffing patterns so that we now have one cryogenics engineer working a shift pattern which includes 8-hour daily coverage during the weekend. ATLAS provided a beam mix to users consisting of 26 different isotopic species, 23% of which were for A>100 in FY 1994. Approximately 60% of the beam time was provided by the Positive Ion Injector, slightly less than the usage rate of FY 1993. Experiments using uranium or lead beams accounted for 16.4% of the total beam time. The ECR ion source and high-voltage platform functioned well throughout the year. A new technique for solid material production in the source was developed which uses a sputtering process wherein the sample of material placed near the plasma chamber wall is biased negatively. Plasma ions are accelerated into the sample and material is sputtered from the surface into the plasma. This technique is now used routinely for many elements. Runs of calcium, germanium, nickel, lead, tellurium, and uranium were carried out with this technique.

  17. Pregnane X receptor agonists enhance intestinal epithelial wound healing and repair of the intestinal barrier following the induction of experimental colitis. (United States)

    Terc, Joshua; Hansen, Ashleigh; Alston, Laurie; Hirota, Simon A


    The intestinal epithelial barrier plays a key role in the maintenance of homeostasis within the gastrointestinal tract. Barrier dysfunction leading to increased epithelial permeability is associated with a number of gastrointestinal disorders including the inflammatory bowel diseases (IBD) - Crohn's disease and ulcerative colitis. It is thought that the increased permeability in patients with IBD may be driven by alterations in the epithelial wound healing response. To this end considerable study has been undertaken to identify signaling pathways that may accelerate intestinal epithelial wound healing and normalize the barrier dysfunction observed in IBD. In the current study we examined the role of the pregnane X receptor (PXR) in modulating the intestinal epithelial wound healing response. Mutations and reduced mucosal expression of the PXR are associated with IBD, and others have reported that PXR agonists can dampen intestinal inflammation. Furthermore, stimulation of the PXR has been associated with increased cell migration and proliferation, two of the key processes involved in wound healing. We hypothesized that PXR agonists would enhance intestinal epithelial repair. Stimulation of Caco-2 intestinal epithelial cells with rifaximin, rifampicin and SR12813, all potent agonists of the PXR, significantly increased wound closure. This effect was driven by p38 MAP kinase-dependent cell migration, and occurred in the absence of cell proliferation. Treating mice with a rodent specific PXR agonist, pregnenolone 16α-carbonitrile (PCN), attenuated the intestinal barrier dysfunction observed in the dextran sulphate sodium (DSS) model of experimental colitis, an effect that occurred independent of the known anti-inflammatory effects of PCN. Taken together our data indicate that the activation of the PXR can enhance intestinal epithelial repair and suggest that targeting the PXR may help to normalize intestinal barrier dysfunction observed in patients with IBD

  18. "small ACCELERATORS" 24 May - 2 June 2005

    CERN Multimedia


    CERN Accelerator School and Kernfysisch Versneller Instituut (KVI) Groningen, the Netherlands announce a course on "Small Accelerators", Hotel Golden Tulip Drenthe, Zeegse, the Netherlands, 24 May - 2 June 2005. This specialised course is dedicated to the physics and the main applications of small accelerators. The course will review the different accelerator types as well as their specificities in terms of accelerator physics.

  19. Structural complexes of the agonist, inverse agonist and antagonist bound C5a receptor: insights into pharmacology and signaling. (United States)

    Rana, Soumendra; Sahoo, Amita Rani; Majhi, Bharat Kumar


    The C5a receptor (C5aR) is a pharmacologically important G-protein coupled receptor (GPCR) that interacts with (h)C5a, by recruiting both the "orthosteric" sites (site1 at the N-terminus and site2 at the ECS, extra cellular surface) on C5aR in a two site-binding model. However, the complex pharmacological landscape and the distinguishing chemistry operating either at the "orthosteric" site1 or at the functionally important "orthosteric" site2 of C5aR are still not clear, which greatly limits the understanding of C5aR pharmacology. One of the major bottlenecks is the lack of an experimental structure or a refined model structure of C5aR with appropriately defined active sites. The study attempts to understand the pharmacology at the "orthosteric" site2 of C5aR rationally by generating a highly refined full-blown model structure of C5aR through advanced molecular modeling techniques, and further subjecting it to automated docking and molecular dynamics (MD) studies in the POPC bilayer. The first series of structural complexes of C5aR respectively bound to a linear native peptide agonist ((h)C5a-CT), a small molecule inverse agonist (NDT) and a cyclic peptide antagonist (PMX53) are reported, apparently establishing the unique pharmacological landscape of the "orthosteric" site2, which also illustrates an energetically distinct but coherent competitive chemistry ("cation-π" vs. "π-π" interactions) involved in distinguishing the established ligands known for targeting the "orthosteric" site2 of C5aR. Over a total of 1 μs molecular dynamics (MD) simulation in the POPC bilayer, it is evidenced that while the agonist prefers a "cation-π" interaction, the inverse agonist prefers a "cogwheel/L-shaped" interaction in contrast to the "edge-to-face/T-shaped" type π-π interactions demonstrated by the antagonist by engaging the F275(7.28) of the C5aR. In the absence of a NMR or crystallographically guided model structure of C5aR, the computational model complexes not only

  20. How does agonistic behaviour differ in albino and pigmented fish?

    Directory of Open Access Journals (Sweden)

    Ondřej Slavík


    Full Text Available In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics.

  1. 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.

  2. How does agonistic behaviour differ in albino and pigmented fish? (United States)

    Slavík, Ondřej; Horký, Pavel; Wackermannová, Marie


    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics.

  3. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity (United States)

    Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel; Sankaranarayanan, Ishwarya; Aron, Jennifer L.; Maazi, Hadi; Chen, Lin; Akbari, Omid


    Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma. PMID:27752043

  4. 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.

  5. Identification of agonists for a group of human odorant receptors

    Directory of Open Access Journals (Sweden)

    Daniela eGonzalez-Kristeller


    Full Text Available Olfaction plays a critical role in several aspects of the human life. Odorants are detected by hundreds of odorant receptors (ORs which belong to the superfamily of G protein-coupled receptors. These receptors are expressed in the olfactory sensory neurons of the nose. The information provided by the activation of different combinations of ORs in the nose is transmitted to the brain, leading to odorant perception and emotional and behavioral responses. There are ~400 intact human ORs, and to date only a small percentage of these receptors (~10% have known agonists. The determination of the specificity of the human ORs will contribute to a better understanding of how odorants are discriminated by the olfactory system. In this work, we aimed to identify human specific ORs, that is, ORs that are present in humans but absent from other species, and their corresponding agonists. To do this, we first selected 22 OR gene sequences from the human genome with no counterparts in the mouse, rat or dog genomes. Then we used a heterologous expression system to screen a subset of these human ORs against a panel of odorants of biological relevance, including foodborne aroma volatiles. We found that different types of odorants are able to activate some of these previously uncharacterized human ORs.

  6. Toll-Like Receptor 9 Agonists for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Davide Melisi


    Full Text Available The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

  7. AMP is an adenosine A1 receptor agonist. (United States)

    Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A; Jin, Jian; Janzen, William P; Frye, Stephen V; Zylka, Mark J


    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.

  8. GLP-1 receptor agonist-induced polyarthritis: a case report. (United States)

    Ambrosio, Maria Luisa; Monami, Matteo; Sati, Lavinia; Marchionni, Niccolò; Di Bari, Mauro; Mannucci, Edoardo


    Occasional cases of bilateral, symmetrical, seronegative polyarthritis have been reported in patients treated with dipeptidyl peptidase-4 inhibitors (Crickx et al. in Rheumatol Int, 2013). We report here a similar case observed during treatment with a GLP-1 receptor agonist. A 42-year-old man with type 2 diabetes treated with metformin 1,500 mg/day and liraglutide 1.8 mg/day. After 6 months from the beginning of treatment, the patient complained of bilateral arthralgia (hands, feet, ankles, knees, and hips). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and leukocytes were increased. Rheumatoid factor, anticyclic citrullinated protein antibody, antinuclear antibodies, anti-Borrelia, and burgdorferi antibodies were all negative, and myoglobin and calcitonin were normal. Liraglutide was withdrawn, and the symptoms completely disappeared within 1 week, with normalization of ESR, CRP, fibrinogen, and leukocytes. Previously described cases of polyarthritis associated with DPP4 inhibitors had been attributed to a direct effect of the drugs on inflammatory cells expressing the enzyme. The present case, occurred during treatment with a GLP-1 receptor agonists, suggests a possibly different mechanism, mediated by GLP-1 receptor stimulation, which deserved further investigation.

  9. Melatonin and melatonin agonist for delirium in the elderly patients. (United States)

    Chakraborti, Dwaipayan; Tampi, Deena J; Tampi, Rajesh R


    The objective of this review is to summarize the available data on the use of melatonin and melatonin agonist for the prevention and management of delirium in the elderly patients from randomized controlled trials (RCTs). A systematic search of 5 major databases PubMed, MEDLINE, PsychINFO, Embase, and Cochrane Library was conducted. This search yielded a total of 2 RCTs for melatonin. One study compared melatonin to midazolam, clonidine, and control groups for the prevention and management of delirium in individuals who were pre- and posthip post-hip arthroplasty. The other study compared melatonin to placebo for the prevention of delirium in older adults admitted to an inpatient internal medicine service. Data from these 2 studies indicate that melatonin may have some benefit in the prevention and management of delirium in older adults. However, there is no evidence that melatonin reduces the severity of delirium or has any effect on behaviors or functions in these individuals. Melatonin was well tolerated in these 2 studies. The search for a melatonin agonist for delirium in the elderly patients yielded 1 study of ramelteon. In this study, ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo. Ramelteon was well tolerated in this study.

  10. Cold suppresses agonist-induced activation of TRPV1. (United States)

    Chung, M-K; Wang, S


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

  11. Proton Acceleration at Oblique Shocks (United States)

    Galinsky, V. L.; Shevchenko, V. I.


    Acceleration at the shock waves propagating oblique to the magnetic field is studied using a recently developed theoretical/numerical model. The model assumes that resonant hydromagnetic wave-particle interaction is the most important physical mechanism relevant to motion and acceleration of particles as well as to excitation and damping of waves. The treatment of plasma and waves is self-consistent and time dependent. The model uses conservation laws and resonance conditions to find where waves will be generated or damped, and hence particles will be pitch-angle-scattered. The total distribution is included in the model and neither introduction of separate population of seed particles nor some ad hoc escape rate of accelerated particles is needed. Results of the study show agreement with diffusive shock acceleration models in the prediction of power spectra for accelerated particles in the upstream region. However, they also reveal the presence of spectral break in the high-energy part of the spectra. The role of the second-order Fermi-like acceleration at the initial stage of the acceleration is discussed. The test case used in the paper is based on ISEE-3 data collected for the shock of 1978 November 12.

  12. Application of electron accelerator worldwide

    Energy Technology Data Exchange (ETDEWEB)

    Machi, Sueo [Japan Atomic Industrial Forum, Inc., Tokyo (Japan)


    Electron accelerator is an important radiation source for radiation technology, which covers broad fields such as industry, health care, food and environmental protection. There are about 1,000 electron accelerators for radiation processing worldwide. Electron accelerator has advantage over Co-60 irradiator in term of high dose rate and power, assurance of safety, and higher economic performance at larger volume of irradiation. Accelerator generating higher energy in the range of 10 MeV and high power electron beam is now commercially available. There is a trend to use high-energy electron accelerator replacing Co-60 in case of large through-put of medical products. Irradiated foods, in particular species, are on the commercial market in 35 countries. Electron accelerator is used efficiently and economically for production of new or modified polymeric materials through radiation-induced cross-linking, grafting and polymerization reaction. Another important application of electron beam is the curing of surface coatings in the manufacture of products. Electron accelerators of large capacity are used for cleaning exhaust gases in industrial scale. Economic feasibility studies of this electron beam process have shown that this technology is more cost effective than the conventional process. It should be noted that the conventional limestone process produce gypsum as a by-product, which cannot be used in some countries. By contrast, the by-product of the electron beam process is a valuable fertilizer. (Y. Tanaka)

  13. 2014 CERN Accelerator Schools: Beam Loss and Accelerator Protection

    CERN Multimedia


    The US-CERN-JAPAN-RUSSIA Joint International Accelerator School is organising a course on Beam Loss and Accelerator Protection to be held in Newport Beach, California, USA from 5-14 November, 2014.    This school is intended for physicists and engineers who are or may be engaged in the design, construction, and/or operation of accelerators with high power photon or particle beams and/or accelerator sub-systems with large stored energy. Application deadlines are 15 August and 4 September. Further information on this Joint School can be found at:

  14. Electromagnetic acceleration of permanent magnets

    CERN Document Server

    Dolya, S N


    We consider the acceleration of the permanent magnets, consisting of neodymium iron boron by means of the running magnetic field gradient. It is shown that the specific magnetic moment per nucleon in neodymium iron boron is determined by the remained magnetization of the substance. The maximum accessable gradient of the magnetic field accelerating the permanent magnets is determined by the coercive force thirty kilogauss. For the neodymium iron boron magnets this gradient is equal to twenty kilogauss divided by one centimeter. The finite velocity of the magnets six kilometers per second, the length of acceleration is six hundred thirty-seven meters.

  15. SNEAP 80: symposium of Northeastern Accelerator personnel

    Energy Technology Data Exchange (ETDEWEB)

    Billen, J.H. (ed.)


    Reports of operations are presented for twenty-seven facilities, along with reports on accelerators in progress, ion sources, insulating gases, charging systems, stripping foils, accelerating tubes, and upgraded accelerator systems. (GHT)

  16. Terahertz-driven linear electron acceleration

    CERN Document Server

    Nanni, Emilio Alessandro; Ravi, Koustuban; Fallahi, Arya; Moriena, Gustavo; Miller, R J Dwayne; Kärtner, Franz X


    The cost, size and availability of electron accelerators is dominated by the achievable accelerating gradient. Conventional high-brightness radio-frequency (RF) accelerating structures operate with 30-50 MeV/m gradients. Electron accelerators driven with optical or infrared sources have demonstrated accelerating gradients orders of magnitude above that achievable with conventional RF structures. However, laser-driven electron accelerators require intense sources and suffer from low bunch charge, sub-micron tolerances and sub-femtosecond timing requirements due to the short wavelength of operation. Here, we demonstrate the first linear acceleration of electrons with keV energy gain using optically-generated terahertz (THz) pulses. THz-driven accelerating structures enable high-gradient electron accelerators with simple accelerating structures, high repetition rates and significant charge per bunch. Increasing the operational frequency of accelerators into the THz band allows for greatly increased accelerating ...

  17. Particle accelerator; the Universe machine

    CERN Multimedia

    Yurkewicz, Katie


    "In summer 2008, scientists will switch on one of the largest machines in the world to search for the smallest of particle. CERN's Large Hadron Collider particle accelerator has the potential to chagne our understanding of the Universe."

  18. IGBT accelerated aging data set. (United States)

    National Aeronautics and Space Administration — Preliminary data from thermal overstress accelerated aging using the aging and characterization system. The data set contains aging data from 6 devices, one device...

  19. Accelerator structure work for NLC

    Energy Technology Data Exchange (ETDEWEB)

    Miller, R.H.; Adolphsen, C.; Bane, K.L.F.; Deruyter, H.; Farkas, Z.D.; Hoag, H.A.; Holtkamp, N.; Lavine, T.; Loew, G.A.; Nelson, E.M.; Palmer, R.B.; Paterson, J.M.; Ruth, R.D.; Thompson, K.A.; Vlieks, A.; Wang, J.W.; Wilson, P.B. [Stanford Linear Accelerator Center, Menlo Park, CA (United States); Gluckstern, R. [Maryland Univ., College Park, MD (United States); Ko, K.; Kroll, N. [Stanford Linear Accelerator Center, Menlo Park, CA (United States)]|[California Univ., San Diego, La Jolla, CA (United States). Dept. of Physics


    The NLC design achieves high luminosity with multiple bunches in each RF pulse. Acceleration of a train of bunches without emittance growth requires control of long range dipole wakefields. SLAC is pursuing a structure design which suppresses the effect of wakefields by varying the physical dimensions of successive cells of the disk-loaded traveling wave structure in a manner which spreads the frequencies of the higher mode while retaining the synchronism between the electrons and the accelerating mode. The wakefields of structures incorporating higher mode detuning have been measured at the Accelerator Test Facility at Argonne. Mechanical design and brazing techniques which avoid getting brazing alloy into the interior of the accelerator are being studied. A test facility for high-power testing of these structures is complete and high power testing has begun.

  20. Advanced Superconducting Test Accelerator (ASTA) (United States)

    Federal Laboratory Consortium — The Advanced Superconducting Test Accelerator (ASTA) facility will be based on upgrades to the existing NML pulsed SRF facility. ASTA is envisioned to contain 3 to...

  1. Advanced Superconducting Test Accelerator (ASTA) (United States)

    Federal Laboratory Consortium — The Advanced Superconducting Test Accelerator (ASTA) facility will be based on upgrades to the existing NML pulsed SRF facility. ASTA is envisioned to contain 3 to 6...

  2. Particle acceleration around SNR shocks

    Energy Technology Data Exchange (ETDEWEB)

    Morlino, G., E-mail: [INAF-Osservatorio Astrofisico di Arcetri, Largo E. Fermi, 5, 50125 Firenze (Italy)


    We review the basic features of particle acceleration theory around collisionless shocks in supernova remnants (SNRs). We show how non-linear effects induced by the back reaction of accelerated particles onto the shock dynamics are of paramount importance to support the hipotesys that SNRs are the factories of Galactic cosmic rays. Recent developments in the modeling of the mechanism of diffusive shock acceleration are discussed, with emphasis on the role of magnetic field amplification and the presence of neutrals in the circumstellar environment. Special attention will be devoted to observational consequences of non-linear effects on the multi-wavelength spectrum of SNRs, with emphasis on X-ray and gamma-ray emission. Finally we also discuss how Balmer lines, detected from several young SNRs, can be used to estimate the shock dynamical properties and the efficiency of CR acceleration.

  3. Particle acceleration around SNR shocks

    CERN Document Server

    Morlino, Giovanni


    We review the basic features of particle acceleration theory around collisionless shocks in supernova remnants (SNRs). We show how non linear effects induced by the back reaction of accelerated particles onto the shock dynamics are of paramount importance to support the hipotesys that SNRs are the factories of Galactic cosmic rays. Recent developments in the modeling of the mechanism of diffusive shock acceleration are discussed, with emphasis on the role of magnetic field amplification and the presence of neutrals in the circumstellar environment. Special attention will be devoted to observational consequences of non linear effects on the multi-wavelength spectrum of SNRs, with emphasis on X-ray and gamma-ray emission. Finally we also discuss how Balmer lines, detected from several young SNRs, can be used to estimate the shock dynamical properties and the efficiency of CR acceleration.

  4. Accelerating advanced-materials commercialization (United States)

    Maine, Elicia; Seegopaul, Purnesh


    Long commercialization times, high capital costs and sustained uncertainty deter investment in innovation for advanced materials. With appropriate strategies, technology and market uncertainties can be reduced, and the commercialization of advanced materials accelerated.

  5. The KEK Digital Accelerator and Its Brothers (United States)

    Takayama, Ken

    Circular induction accelerators developed in the last 10 years are discussed. They are characterized by induction acceleration of a charged beam bunch trapped in the barrier bucket. This property enables acceleration of any ion species from an extremely low energy to relativistic energy in a single accelerator ring. In the future, a racetrack-shaped fixed field induction accelerator (induction microtron) could be realized as a unique accelerator for cluster ions such as C-60 and Si-100.

  6. Technology of superconducting accelerator dipoles

    Energy Technology Data Exchange (ETDEWEB)

    Hassenzahl, W.V.; Meuser, R.B.; Taylor, C.


    We discuss accelerator dipoles and their characteristics. Other types of magnets, in particular bubble chamber magnets have been quite successful. Their performance is based on cryogenic stability which is addressed only briefly in this chapter. This type of stability is not available to the accelerator designer because of the large quantities of copper or other stabilizer that would reduce the current density in the windings to an unacceptably low value.

  7. Bucharest heavy ion accelerator facility

    Energy Technology Data Exchange (ETDEWEB)

    Ceausescu, V.; Dobrescu, S.; Duma, M.; Indreas, G.; Ivascu, M.; Papureanu, S.; Pascovici, G.; Semenescu, G.


    The heavy ion accelerator facility of the Heavy Ion Physics Department at the Institute of Physics and Nuclear Engineering in Bucharest is described. The Tandem accelerator development and the operation of the first stage of the heavy ion postaccelerating system are discussed. Details are given concerning the resonance cavities, the pulsing system matching the dc beam to the RF cavities and the computer control system.

  8. Sequentially pulsed traveling wave accelerator (United States)

    Caporaso, George J.; Nelson, Scott D.; Poole, Brian R.


    A sequentially pulsed traveling wave compact accelerator having two or more pulse forming lines each with a switch for producing a short acceleration pulse along a short length of a beam tube, and a trigger mechanism for sequentially triggering the switches so that a traveling axial electric field is produced along the beam tube in synchronism with an axially traversing pulsed beam of charged particles to serially impart energy to the particle beam.


    Energy Technology Data Exchange (ETDEWEB)



    Colleagues of mine have asked me few times why we have today so much interest in Fixed-Field Alternating-Gradient (FFAG) accelerators when these were invented a long time ago, and have always been ignored since then. I try here to give a reply with a short history of FFAG accelerators, at least as I know it. I take also the opportunity to clarify few definitions.

  10. Hamiltonian mechanics of stochastic acceleration. (United States)

    Burby, J W; Zhmoginov, A I; Qin, H


    We show how to find the physical Langevin equation describing the trajectories of particles undergoing collisionless stochastic acceleration. These stochastic differential equations retain not only one-, but two-particle statistics, and inherit the Hamiltonian nature of the underlying microscopic equations. This opens the door to using stochastic variational integrators to perform simulations of stochastic interactions such as Fermi acceleration. We illustrate the theory by applying it to two example problems.

  11. Dark Energy or local acceleration?

    CERN Document Server

    Feoli, Antonio


    We find that an observer with a suitable acceleration relative to the frame comoving whit the cosmic fluid, in the context of the FRW decelerating universe, measures the same cosmological redshift as the LambdaCDM model. The estimated value of this acceleration is beta = 1.4x10^-9m/s^2. The problem of a too high peculiar velocity can be solved assuming, for the observer, a sort of helical motion.

  12. PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

    Directory of Open Access Journals (Sweden)

    Monica Puligheddu

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα, nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p. or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2% for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.. Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key

  13. Impact of efficacy at the μ-opioid receptor on antinociceptive effects of combinations of μ-opioid receptor agonists and cannabinoid receptor agonists. (United States)

    Maguire, David R; France, Charles P


    Cannabinoid receptor agonists, such as Δ(9)-tetrahydrocannabinol (Δ(9)-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ(9)-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ(9)-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ(9)-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ(9)-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain.

  14. Vacuum Brazing of Accelerator Components (United States)

    Singh, Rajvir; Pant, K. K.; Lal, Shankar; Yadav, D. P.; Garg, S. R.; Raghuvanshi, V. K.; Mundra, G.


    Commonly used materials for accelerator components are those which are vacuum compatible and thermally conductive. Stainless steel, aluminum and copper are common among them. Stainless steel is a poor heat conductor and not very common in use where good thermal conductivity is required. Aluminum and copper and their alloys meet the above requirements and are frequently used for the above purpose. The accelerator components made of aluminum and its alloys using welding process have become a common practice now a days. It is mandatory to use copper and its other grades in RF devices required for accelerators. Beam line and Front End components of the accelerators are fabricated from stainless steel and OFHC copper. Fabrication of components made of copper using welding process is very difficult and in most of the cases it is impossible. Fabrication and joining in such cases is possible using brazing process especially under vacuum and inert gas atmosphere. Several accelerator components have been vacuum brazed for Indus projects at Raja Ramanna Centre for Advanced Technology (RRCAT), Indore using vacuum brazing facility available at RRCAT, Indore. This paper presents details regarding development of the above mentioned high value and strategic components/assemblies. It will include basics required for vacuum brazing, details of vacuum brazing facility, joint design, fixturing of the jobs, selection of filler alloys, optimization of brazing parameters so as to obtain high quality brazed joints, brief description of vacuum brazed accelerator components etc.

  15. Ponderomotive Acceleration by Relativistic Waves

    CERN Document Server

    Lau, Calvin; Yeh, Po-Chun; Luk, Onnie; McClenaghan, Joseph; Ebisuzaki, Toshikazu; Tajima, Toshiki


    In the extreme high intensity regime of electromagnetic (EM) waves in plasma, the acceleration process is found to be dominated by the ponderomotive acceleration (PA). While the wakefields driven by the ponderomotive force of the relativistic intensity EM waves are important, they may be overtaken by the PA itself in the extreme high intensity regime when the dimensionless vector potential $a_0$ of the EM waves far exceeds unity. The energy gain by this regime (in 1D) is shown to be (approximately) proportional to $a_0^2$. Before reaching this extreme regime, the coexistence of the PA and the wakefield acceleration (WA) is observed where the wave structures driven by the wakefields show the phenomenon of multiple and folded wave-breakings. Investigated are various signatures of the acceleration processes such as the dependence on the mass ratio for the energy gain as well as the energy spectral features. The relevance to high energy cosmic ray acceleration and to the relativistic laser acceleration is conside...

  16. High-Intensity Proton Accelerator

    Energy Technology Data Exchange (ETDEWEB)

    Jay L. Hirshfield


    Analysis is presented for an eight-cavity proton cyclotron accelerator that could have advantages as compared with other accelerators because of its potentially high acceleration gradient. The high gradient is possible since protons orbit in a sequence of TE111 rotating mode cavities of equally diminishing frequencies with path lengths during acceleration that greatly exceed the cavity lengths. As the cavities operate at sequential harmonics of a basic repetition frequency, phase synchronism can be maintained over a relatively wide injection phase window without undue beam emittance growth. It is shown that use of radial vanes can allow cavity designs with significantly smaller radii, as compared with simple cylindrical cavities. Preliminary beam transport studies show that acceptable extraction and focusing of a proton beam after cyclic motion in this accelerator should be possible. Progress is also reported on design and tests of a four-cavity electron counterpart accelerator for experiments to study effects on beam quality arising from variations injection phase window width. This device is powered by four 500-MW pulsed amplifiers at 1500, 1800, 2100, and 2400 MHz that provide phase synchronous outputs, since they are driven from a with harmonics derived from a phase-locked 300 MHz source.

  17. Antinociceptive interactions between Mu-opioid receptor agonists and the serotonin uptake inhibitor clomipramine in rhesus monkeys: role of Mu agonist efficacy. (United States)

    Banks, Matthew L; Rice, Kenner C; Negus, S Stevens


    Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine.

  18. Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice (United States)

    Sharma, Pawan; Yi, Roslyn; Nayak, Ajay P.; Wang, Nadan; Tang, Francesca; Knight, Morgan J.; Pan, Shi; Oliver, Brian; Deshpande, Deepak A.


    Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.

  19. Trialkyltin rexinoid-X receptor agonists selectively potentiate thyroid hormone induced programs of xenopus laevis metamorphosis

    NARCIS (Netherlands)

    Mengeling, Brenda J.; Murk, Albertinka J.; Furlow, J.D.


    The trialkyltins tributyltin (TBT) and triphenyltin (TPT) can function as rexinoid-X receptor (RXR) agonists. We recently showed that RXR agonists can alter thyroid hormone (TH) signaling in a mammalian pituitary TH-responsive reporter cell line, GH3.TRE-Luc. The prevalence of TBT and TPT in the

  20. 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.

  1. Synthesis of urea acetates as potential PPARα/γ,dual agonists

    Institute of Scientific and Technical Information of China (English)

    Chang Yan Zhao; Chang Qing Shi; Yuan Wei Chen


    In the quest for novel PPARα/γ dual agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia,we designed and synthesized a series of urea acetates as potential PPARα/γ dual agonists.The structure of the target compounds,intermediates were characterized by 1H NMR,HRMS.

  2. 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.

  3. Sumatriptan (5-HT1D receptor agonist) does not exacerbate symptoms in obsessive compulsive disorder

    NARCIS (Netherlands)

    Pian, KLH; Westerberg, HGM; van Megen, HJGM; den Boer, JA


    The non-selective serotonin (5-HT) receptor agonist meta-chlorophenylpiperazine (mCPP) has been reported to elicit symptoms in patients with obsessive compulsive disorder (OCD). MK-212, another nonselective 5-HT receptor agonist, does not seem to induce obsessive compulsive symptoms in OCD patients.

  4. Recurrence of hyperprolactinemia after withdrawal of dopamine agonists: systematic review and meta-analysis.

    NARCIS (Netherlands)

    Dekkers, O.M.; Lagro, J.; Burman, P.; Jorgensen, J.O.; Romijn, J.A.; Pereira, A.M.


    CONTEXT: Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear in all details. OBJECTIVE: The aim of the study was to assess the effect of dopamine agonist withdrawal

  5. The 5-HT(1F) receptor agonist lasmiditan as a potential treatment of migraine attacks

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer C; Olesen, Jes


    Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo...

  6. Efficacy and safety of the PPARγ partial agonist balaglitazone compared with pioglitazone and placebo

    DEFF Research Database (Denmark)

    Henriksen, Kim; Byrjalsen, Inger; Qvist, Per;


    Treatment of patients with perioxisome proliferator-activated receptor-¿ full agonists are associated with weight gain, heart failure, peripheral oedema, and bone loss. However, the safety of partial perioxisome proliferator-activated receptor-¿ agonists has not been established in a clinical tri...

  7. Drug-induced Hypothermia by 5HT1A Agonists Provide Neuroprotection in Experimental Stroke

    DEFF Research Database (Denmark)

    Johansen, Flemming Fryd; Hasseldam, Henrik; Nybro Smith, Matthias;


    with .55°C ranging between .1-1.4°C. CONCLUSIONS: 5-hydroxytryptamine receptor 1A (5HT1A) agonists significantly reduce infarct volumes in MCAO rats primarily because of the hypothermic drug effect. 5HT1A agonists may be introduced to reduce body temperatures rapidly and prepare patients for further...

  8. Metabolic effects of beta2-agonists in relation to exercise performance

    DEFF Research Database (Denmark)

    Kalsen, Anders


    Beta2-agonists are frequently used in the treatment of asthma and exercise-induced bronchoconstriction in elite athletes. However, aside from a bronchodilatory effect, beta2-agonists have also been shown to improve exercise performance, which makes these substances subjected to misuse by elite...

  9. Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120). (United States)

    Sparks, Steven M; Chen, Grace; Collins, Jon L; Danger, Dana; Dock, Steven T; Jayawickreme, Channa; Jenkinson, Stephen; Laudeman, Christopher; Leesnitzer, M Anthony; Liang, Xi; Maloney, Patrick; McCoy, David C; Moncol, David; Rash, Vincent; Rimele, Thomas; Vulimiri, Padmaja; Way, James M; Ross, Sean


    The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein.

  10. A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites

    DEFF Research Database (Denmark)

    Kongsbak, Kristine Grønning; Bergmann, Rikke; Sørensen, Pernille Louise


    We present a full-length a1b2c2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate...

  11. Major drawbacks and additional benefits of agonist trigger--not ovarian hyperstimulation syndrome related

    DEFF Research Database (Denmark)

    Shapiro, Bruce S; Andersen, Claus Yding


    . The agonist trigger might alter other paradigms as well, such as making oocyte donation more efficient per stimulation by virtually eliminating follicular-phase cycle cancellation, coasting, and premature triggering. There are both corresponding potential benefits and drawbacks of using the agonist trigger...

  12. Locomotion induced by ventral tegmental microinjections of a nicotinic agonist. (United States)

    Museo, E; Wise, R A


    Bilateral microinjections of the nicotinic agonist cytisine (0.1, 1 or 10 nanomoles per side) into the ventral tegmental area increased locomotor activity. This increase in locomotion was antagonized by mecamylamine (2 mg/kg, IP), a nicotinic antagonist that readily crosses the blood-brain barrier, and by pimozide (0.3 mg/kg, IP), a central dopaminergic antagonist. Hexamethonium (2 mg/kg, IP), a nicotinic antagonist that, unlike mecamylamine, does not cross the blood-brain barrier, had no effect; this suggests that mecamylamine's attenuation of cytisine-induced locomotor activity resulted from a blockade of central and not peripheral nicotinic receptors. The data support the notion that nicotinic and dopaminergic substrates interact at the level of the VTA to produce increases in locomotor activity.

  13. Use of thrombopoietin receptor agonists in childhood immune thrombocytopenia

    Directory of Open Access Journals (Sweden)

    Angelica Maria Garzon


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

  14. N-methyl-D-aspartic acid receptor agonists

    DEFF Research Database (Denmark)

    Madsen, U; Frydenvang, Karla Andrea; Ebert, B


    (R,S)-2-Amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid [(R,S)-AMAA, 4] is a potent and selective agonist at the N-methyl-D-aspartic acid (NMDA) subtype of excitatory amino acid receptors. Using the Ugi "four-component condensation" method, the two diastereomers (2R)- and (2S)-2-[3-(benzyloxy......) showed peak affinity for [3H]AMPA receptor sites (IC50 = 72 +/- 13 microM) and was shown to be a more potent inhibitor of [3H]CPP binding (IC50 = 3.7 +/- 1.5 microM) than (S)-AMAA (9) (IC50 = 61 +/- 6.4 microM). Neither enantiomer of AMAA affected [3H]kainic acid receptor binding significantly...

  15. Prokinetic effects of a ghrelin receptor agonist GHRP-6 in diabetic mice

    Institute of Scientific and Technical Information of China (English)

    Qi Zheng; Wen-Cai Qiu; Jun Yan; Wei-Gang Wang; Song Yu; Zhi-Gang Wang; Kai-Xing Ai


    AIM: To investigate the effects of a ghrelin receptor agonist GHRP-6 on delayed gastrointestinal transit in alloxan-induced diabetic mice.METHODS: A diabetic mouse model was established by intraperitoneal injection with alloxan.Mice were randomized into two main groups: normal mice and diabetic mice treated with GHRP-6 at doses of 0,20,50,100 and 200 μg/kg ip.Gastric emptying (GE),intestinal tTansit (IT),and colonic transit (CT) were studied in mice after they had a phenol red meal following injection of GHRP-6.Based on the most effective GHRP-6 dosage,atropine was given at 1 mg/kg for 15 min before the GHRP-6 injection for each measurement.The mice in each group were sacrificed 20 min later and the percentages of GE,IT,and CT were calculated.RESULTS: Percentages of GE,IT,and CT were significantly decreased in diabetic mice as compared to control mice.In the diabetic mice,GHRP-6 improved both GE and IT,but not CT.The most effective dose of GHRP-6 was 200 μg/kg and atropine blocked the prokinetic effects of GHRP-6 on GE and IT.CONCLUSION: GHRP-6 accelerates delayed GE and IT,but has no effect on CT in diabetic mice.GHRP-6 may exert its prokinetic effects via the cholinergic pathway in the enteric nervous system,and therefore,has therapeutic potential for diabetic patients with delayed upper gastrointestinal transit.

  16. 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.

  17. Agonist and antagonist effects of cytisine in vivo. (United States)

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


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

  18. Could dopamine agonists aid in drug development for anorexia nervosa? (United States)

    Frank, Guido K W


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

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

    Directory of Open Access Journals (Sweden)

    Guido eFrank


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

  20. Accelerator and electrodynamics capability review

    Energy Technology Data Exchange (ETDEWEB)

    Jones, Kevin W [Los Alamos National Laboratory


    Los Alamos National Laboratory (LANL) uses capability reviews to assess the science, technology and engineering (STE) quality and institutional integration and to advise Laboratory Management on the current and future health of the STE. Capability reviews address the STE integration that LANL uses to meet mission requirements. The Capability Review Committees serve a dual role of providing assessment of the Laboratory's technical contributions and integration towards its missions and providing advice to Laboratory Management. The assessments and advice are documented in reports prepared by the Capability Review Committees that are delivered to the Director and to the Principal Associate Director for Science, Technology and Engineering (PADSTE). Laboratory Management will use this report for STE assessment and planning. LANL has defined fifteen STE capabilities. Electrodynamics and Accelerators is one of the seven STE capabilities that LANL Management (Director, PADSTE, technical Associate Directors) has identified for review in Fiscal Year (FY) 2010. Accelerators and electrodynamics at LANL comprise a blend of large-scale facilities and innovative small-scale research with a growing focus on national security applications. This review is organized into five topical areas: (1) Free Electron Lasers; (2) Linear Accelerator Science and Technology; (3) Advanced Electromagnetics; (4) Next Generation Accelerator Concepts; and (5) National Security Accelerator Applications. The focus is on innovative technology with an emphasis on applications relevant to Laboratory mission. The role of Laboratory Directed Research and Development (LDRD) in support of accelerators/electrodynamics will be discussed. The review provides an opportunity for interaction with early career staff. Program sponsors and customers will provide their input on the value of the accelerator and electrodynamics capability to the Laboratory mission.

  1. Combining a GLP-1 receptor agonist and basal insulin: study evidence and practical considerations. (United States)

    Carris, Nicholas W; Taylor, James R; Gums, John G


    Most patients with diabetes mellitus require multiple medications to achieve glycemic goals. Considering this and the increasing incidence of type 2 diabetes worldwide, the need for effective combination therapy is pressing. Basal insulin and glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes. Though both classes of medication are exclusively injectable, which may cause initial hesitation from providers, evidence for their combined use is substantial. This review summarizes the theoretical benefit, supporting evidence, and implementation of a combined basal insulin-GLP-1 receptor agonist regimen. Basal insulin added to a GLP-1 receptor agonist reduces hemoglobin A1c (HbA1c) without weight gain or significantly increased hypoglycemia. A GLP-1 receptor agonist added to basal insulin reduces HbA1c and body weight. Compared with the addition of meal-time insulin to basal insulin, a GLP-1 receptor agonist produces similar or greater reduction in HbA1c, weight loss instead of weight gain, and less hypoglycemia. Gastrointestinal adverse events are common with GLP-1 receptor agonists, especially during initiation and titration. However, combination with basal insulin is not expected to augment expected adverse events that come with using a GLP-1 receptor agonist. Basal insulin can be added to a GLP-1 receptor agonist with a slow titration to target goal fasting plasma glucose. In patients starting a GLP-1 receptor agonist, the dose of basal insulin should be decreased by 20 % in patients with an HbA1c ≤8 %. The evidence from 15 randomized prospective studies supports the combined use of a GLP-1 receptor agonist with basal insulin in a broad range of patients with uncontrolled type 2 diabetes.

  2. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. (United States)

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


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

  3. CAS Accelerator Physics (RF for Accelerators) in Denmark

    CERN Multimedia

    Barbara Strasser


    The CERN Accelerator School (CAS) and Aarhus University jointly organised a specialised course on RF for Accelerators, at the Ebeltoft Strand Hotel, Denmark from 8 to 17 June 2010.   Caption The challenging programme focused on the introduction of the underlying theory, the study and the performance of the different components involved in RF systems, the RF gymnastics and RF measurements and diagnostics. This academic part was supplemented with three afternoons dedicated to practical hands-on exercises. The school was very successful, with 100 participants representing 25 nationalities. Feedback from the participants was extremely positive, praising the expertise and enthusiasm of the lecturers, as well as the high standard and excellent quality of their lectures. In addition to the academic programme, the participants were able to visit a small industrial exhibition organised by Aarhus University and take part in a one-day excursion consisting of a visit of the accelerators operated ...

  4. Acceleration schedules for a recirculating heavy-ion accelerator

    Energy Technology Data Exchange (ETDEWEB)

    Sharp, W.M.; Grote, D.P.


    Recent advances in solid-state switches have made it feasible to design programmable, high-repetition-rate pulsers for induction accelerators. These switches could lower the cost of recirculating induction accelerators, such as the ''small recirculator'' at Lawrence Livermore National Laboratory (LLNL), by substantially reducing the number of induction modules. Numerical work is reported here to determine what effects the use of fewer pulsers at higher voltage would have on the beam quality of the LLNL small recirculator. Lattices with different numbers of pulsers are examined using the fluid/envelope code CIRCE, and several schedules for acceleration and compression are compared for each configuration. For selected schedules, the phase-space dynamics is also studied using the particle-in-cell code WARP3d.

  5. Acceleration of injected electrons by the plasma beat wave accelerator (United States)

    Joshi, C.; Clayton, C. E.; Marsh, K. A.; Dyson, A.; Everett, M.; Lal, A.; Leemans, W. P.; Williams, R.; Katsouleas, T.; Mori, W. B.


    In this paper we describe the recent work at UCLA on the acceleration of externally injected electrons by a relativistic plasma wave. A two frequency laser was used to excite a plasma wave over a narrow range of static gas pressures close to resonance. Electrons with energies up to our detection limit of 9.1 MeV were observed when 2.1 MeV electrons were injected in the plasma wave. No accelerated electrons above the detection threshold were observed when the laser was operated on a single frequency or when no electrons were injected. Experimental results are compared with theoretical predictions, and future prospects for the plasma beat wave accelerator are discussed.

  6. The Accelerator Markup Language and the Universal Accelerator Parser

    Energy Technology Data Exchange (ETDEWEB)

    Sagan, D.; Forster, M.; /Cornell U., LNS; Bates, D.A.; /LBL, Berkeley; Wolski, A.; /Liverpool U. /Cockcroft Inst. Accel. Sci. Tech.; Schmidt, F.; /CERN; Walker, N.J.; /DESY; Larrieu, T.; Roblin, Y.; /Jefferson Lab; Pelaia, T.; /Oak Ridge; Tenenbaum, P.; Woodley, M.; /SLAC; Reiche, S.; /UCLA


    A major obstacle to collaboration on accelerator projects has been the sharing of lattice description files between modeling codes. To address this problem, a lattice description format called Accelerator Markup Language (AML) has been created. AML is based upon the standard eXtensible Markup Language (XML) format; this provides the flexibility for AML to be easily extended to satisfy changing requirements. In conjunction with AML, a software library, called the Universal Accelerator Parser (UAP), is being developed to speed the integration of AML into any program. The UAP is structured to make it relatively straightforward (by giving appropriate specifications) to read and write lattice files in any format. This will allow programs that use the UAP code to read a variety of different file formats. Additionally, this will greatly simplify conversion of files from one format to another. Currently, besides AML, the UAP supports the MAD lattice format.

  7. Derivation of Hamiltonians for accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Symon, K.R.


    In this report various forms of the Hamiltonian for particle motion in an accelerator will be derived. Except where noted, the treatment will apply generally to linear and circular accelerators, storage rings, and beamlines. The generic term accelerator will be used to refer to any of these devices. The author will use the usual accelerator coordinate system, which will be introduced first, along with a list of handy formulas. He then starts from the general Hamiltonian for a particle in an electromagnetic field, using the accelerator coordinate system, with time t as independent variable. He switches to a form more convenient for most purposes using the distance s along the reference orbit as independent variable. In section 2, formulas will be derived for the vector potentials that describe the various lattice components. In sections 3, 4, and 5, special forms of the Hamiltonian will be derived for transverse horizontal and vertical motion, for longitudinal motion, and for synchrobetatron coupling of horizontal and longitudinal motions. Hamiltonians will be expanded to fourth order in the variables.

  8. Industrial Electron Accelerators Type ILU

    CERN Document Server

    Auslender, Vadim; Cheskidov, Vladimir; Faktorovich, Boris; Gorbunov, Vladimir; Gornakov, Igor; Nekhaev, V E; Panfilov, Alexander; Sidorov, Alexander; Tkachenko, Vadim; Tuvik, Alfred; Voronin, Leonid


    The report describes the electron accelerators of ILU series covering the energy range from 0.5 to 5 MeV with beam power up to 50 kW. The pulse linear accelerators type ILU are developed since 1970 in Budker institute of Nuclear Physics and are supplied to the industry. The ILU machines are purposed for wide application in various technological processes and designed for long continuous and round-the-clock work in industrial conditions. A principle of acceleration of electrons in the gap of HF resonator is used in the ILU machines. The HF resonator has toroidal form. The electron gun is placed in one of the protruding electrodes forming the accelerating gap of the resonator. The resonator is fed from HF autogenerator realized on the industrial triode, the feedback signal is given from the resonator. The absence of outer beam injection and usage of self-excited HF generator simplify the design of accelerator and ensure its reliable operation.

  9. Accelerator Technology Division annual report, FY 1989

    Energy Technology Data Exchange (ETDEWEB)


    This paper discusses: accelerator physics and special projects; experiments and injectors; magnetic optics and beam diagnostics; accelerator design and engineering; radio-frequency technology; accelerator theory and simulation; free-electron laser technology; accelerator controls and automation; and high power microwave sources and effects.

  10. 38 CFR 9.14 - Accelerated Benefits. (United States)


    ...' GROUP LIFE INSURANCE AND VETERANS' GROUP LIFE INSURANCE § 9.14 Accelerated Benefits. (a) What is an Accelerated Benefit? An Accelerated Benefit is a payment of a portion of your Servicemembers' Group Life...? ____ Yes__ No__ The patient applied for an accelerated benefit under his/her government life...

  11. Risk factors for accelerated atherosclerosis in young women with hyperprolactinemia. (United States)

    Medic-Stojanoska, Milica; Icin, Tijana; Pletikosic, Ivana; Bajkin, Ivana; Novakovic-Paro, Jovanka; Stokic, Edita; Spasic, Dragan T; Kovacev-Zavisic, Branka; Abenavoli, Ludovico


    Prolactin is a metabolic hormone. The hypothesis is that hyperprolactinemia can cause metabolic and inflammatory changes which are associated with accelerated atherosclerotic process, but the treatment of hyperprolactinemia with dopamine agonists, leads to reversibility of these processes. The first aim of this study was to determine whether hyperprolactinemia in premenopausal women is accompanied with the increase in body mass index (BMI), changes in body composition, lipid disturbances, the presence of inflammation and changes in systolic and diastolic blood pressure as risk factors for the development of early atherosclerosis. The second aim was to know whether the therapy of hyperprolactinemia and prolactin normalization lead to improvement of the observed parameters. Twenty female patients with prolactinomas, before and during treatment with dopamine agonists and 16 healthy controls were evaluated. Prolactin, BMI, total body fat, free fat mass, total body water, total cholesterol, triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL) and fibrinogen as well as systolic and diastolic blood pressure were measured at baseline and during the therapy. Hyperprolactinemic patients had pathologic and significantly higher levels of prolactin (PRL) than the controls (p=0.000). The BMI, body fat, total body water (TBW), total cholesterol, triglycerides, LDL were in normal range and higher in the patients than in the controls. HDL was lower in hyperprolactinemic females than controls. The difference was significant only for body fat (fat % p=0.006; fat kg p=0.009). Fibrinogen was slightly increased in patients compared with the controls. Hyperprolactinemic patients had normal, but increased levels of systolic and diastolic blood pressure compared with the controls. The difference with border significance was found in diastolic blood pressure (p=0.065). The correlation of PRL with all the observed parameters was positive apart from HDL, but relatively

  12. In pursuit of alpha4beta2 nicotinic receptor partial agonists for smoking cessation: carbon analogs of (-)-cytisine. (United States)

    Coe, Jotham W; Vetelino, Michael G; Bashore, Crystal G; Wirtz, Michael C; Brooks, Paige R; Arnold, Eric P; Lebel, Lorraine A; Fox, Carol B; Sands, Steven B; Davis, Thomas I; Schulz, David W; Rollema, Hans; Tingley, F David; O'Neill, Brian T


    The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.

  13. Linear accelerator for radioisotope production

    Energy Technology Data Exchange (ETDEWEB)

    Hansborough, L.D.; Hamm, R.W.; Stovall, J.E.


    A 200- to source of 70- to 90-MeV protons would be a valuable asset to the nuclear medicine program. A linear accelerator (linac) can achieve this performance, and it can be extended to even higher energies and currents. Variable energy and current options are available. A 70-MeV linac is described, based on recent innovations in linear accelerator technology; it would be 27.3 m long and cost approx. $6 million. By operating the radio-frequency (rf) power system at a level necessary to produce a beam current, the cost of power deposited in the radioisotope-production target is comparable with existing cyclotrons. If the rf-power system is operated at full power, the same accelerator is capable of producing an beam, and the cost per beam watt on the target is less than half that of comparable cyclotrons.

  14. Virtual gap dielectric wall accelerator (United States)

    Caporaso, George James; Chen, Yu-Jiuan; Nelson, Scott; Sullivan, Jim; Hawkins, Steven A


    A virtual, moving accelerating gap is formed along an insulating tube in a dielectric wall accelerator (DWA) by locally controlling the conductivity of the tube. Localized voltage concentration is thus achieved by sequential activation of a variable resistive tube or stalk down the axis of an inductive voltage adder, producing a "virtual" traveling wave along the tube. The tube conductivity can be controlled at a desired location, which can be moved at a desired rate, by light illumination, or by photoconductive switches, or by other means. As a result, an impressed voltage along the tube appears predominantly over a local region, the virtual gap. By making the length of the tube large in comparison to the virtual gap length, the effective gain of the accelerator can be made very large.

  15. Symposium on accelerator mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)



    The area of accelerator mass spectrometry has expanded considerably over the past few years and established itself as an independent and interdisciplinary research field. Three years have passed since the first meeting was held at Rochester. A Symposium on Accelerator Mass Spectrometry was held at Argonne on May 11-13, 1981. In attendance were 96 scientists of whom 26 were from outside the United States. The present proceedings document the program and excitement of the field. Papers are arranged according to the original program. A few papers not presented at the meeting have been added to complete the information on the status of accelerator mass spectrometry. Individual papers were prepared separately for the data base.

  16. A Multibunch Plasma Wakefield Accelerator

    CERN Document Server

    Kallos, Efthymios; Ben-Zvi, Ilan; Katsouleas, Thomas C; Kimura, Wayne D; Kusche, Karl; Muggli, Patric; Pavlishin, Igor; Pogorelsky, Igor; Yakimenko, Vitaly; Zhou, Feng


    We investigate a plasma wakefield acceleration scheme where a train of electron microbunches feeds into a high density plasma. When the microbunch train enters such a plasma that has a corresponding plasma wavelength equal to the microbunch separation distance, a strong wakefield is expected to be resonantly driven to an amplitude that is at least one order of magnitude higher than that using an unbunched beam. PIC simulations have been performed using the beamline parameters of the Brookhaven National Laboratory Accelerator Test Facility operating in the configuration of the STELLA inverse free electron laser (IFEL) experiment. A 65 MeV electron beam is modulated by a 10.6 um CO2 laser beam via an IFEL interaction. This produces a train of ~90 microbunches separated by the laser wavelength. In this paper, we present both a simple theoretical treatment and simulation results that demonstrate promising results for the multibunch technique as a plasma-based accelerator.

  17. Niobium LEP 2 accelerating cavities

    CERN Multimedia

    An accelerating cavity from LEP. This could be cut open to show the layer of niobium on the inside. Operating at 4.2 degrees above absolute zero, the niobium is superconducting and carries an accelerating field of 6 million volts per metre with negligible losses. Each cavity has a surface of 6 m2. The niobium layer is only 1.2 microns thick, ten times thinner than a hair. Such a large area had never been coated to such a high accuracy. A speck of dust could ruin the performance of the whole cavity so the work had to be done in an extremely clean environment. These challenging requirements pushed European industry to new achievements. 256 of these cavities were used in an upgrade of the LEP accelerator to double the energy of the particle beams.

  18. Superconducting Magnets for Particle Accelerators

    CERN Document Server

    Rossi, L


    Superconductivity has been the most influential technology in the field of accelerators in the last 30 years. Since the commissioning of the Tevatron, which demonstrated the use and operability of superconductivity on a large scale, superconducting magnets and rf cavities have been at the heart of all new large accelerators. Superconducting magnets have been the invariable choice for large colliders, as well as cyclotrons and large synchrotrons. In spite of the long history of success, superconductivity remains a difficult technology, requires adequate R&D and suitable preparation, and has a relatively high cost. Hence, it is not surprising that the development has also been marked by a few setbacks. This article is a review of the main superconducting accelerator magnet projects; it highlights the main characteristics and main achievements, and gives a perspective on the development of superconducting magnets for the future generation of very high energy colliders.

  19. Harmonic ratcheting for fast acceleration (United States)

    Cook, N.; Brennan, J. M.; Peggs, S.


    A major challenge in the design of rf cavities for the acceleration of medium-energy charged ions is the need to rapidly sweep the radio frequency over a large range. From low-power medical synchrotrons to high-power accelerator driven subcritical reactor systems, and from fixed focus alternating gradient accelerators to rapid cycling synchrotrons, there is a strong need for more efficient, and faster, acceleration of protons and light ions in the semirelativistic range of hundreds of MeV/u. A conventional way to achieve a large, rapid frequency sweep (perhaps over a range of a factor of 6) is to use custom-designed ferrite-loaded cavities. Ferrite rings enable the precise tuning of the resonant frequency of a cavity, through the control of the incremental permeability that is possible by introducing a pseudoconstant azimuthal magnetic field. However, rapid changes over large permeability ranges incur anomalous behavior such as the "Q-loss" and "f-dot" loss phenomena that limit performance while requiring high bias currents. Notwithstanding the incomplete understanding of these phenomena, they can be ameliorated by introducing a "harmonic ratcheting" acceleration scheme in which two or more rf cavities take turns accelerating the beam—one turns on when the other turns off, at different harmonics—so that the radio frequency can be constrained to remain in a smaller range. Harmonic ratcheting also has straightforward performance advantages, depending on the particular parameter set at hand. In some typical cases it is possible to halve the length of the cavities, or to double the effective gap voltage, or to double the repetition rate. This paper discusses and quantifies the advantages of harmonic ratcheting in general. Simulation results for the particular case of a rapid cycling medical synchrotron ratcheting from harmonic number 9 to 2 show that stability and performance criteria are met even when realistic engineering details are taken into consideration.

  20. The Toledo heavy ion accelerator

    Energy Technology Data Exchange (ETDEWEB)

    Haar, R.R. (Dept. of Physics and Astronomy, Univ. of Toledo, OH (United States)); Beideck, D.J. (Dept. of Physics and Astronomy, Univ. of Toledo, OH (United States)); Curtis, L.J. (Dept. of Physics and Astronomy, Univ. of Toledo, OH (United States)); Kvale, T.J. (Dept. of Physics and Astronomy, Univ. of Toledo, OH (United States)); Sen, A. (Dept. of Physics and Astronomy, Univ. of Toledo, OH (United States)); Schectman, R.M. (Dept. of Physics and Astronomy, Univ. of Toledo, OH (United States)); Stevens, H.W. (Dept. of Physics and Astronomy, Univ. of Toledo, OH (United States))


    The recently installed 330 kV electrostatic positive ion accelerator at the University of Toledo is described. Experiments have been performed using ions ranging from H[sup +] to Hg[sup 2+] and exotic molecules such as HeH[sup +]. Most of these experiments involve the beam-foil studies of the lifetimes of excited atomic states and the apparatus used for these experiments is also described. Another beamline is available for ion-implantation. The Toledo heavy ion accelerator facility welcomes outside users. (orig.)

  1. Geometric integration for particle accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Forest, Etienne [High Energy Accelerator Research Organization (KEK), 1-1 Oho, Tsukuba, Ibaraki 305-0801 (Japan)


    This paper is a very personal view of the field of geometric integration in accelerator physics-a field where often work of the highest quality is buried in lost technical notes or even not published; one has only to think of Simon van der Meer Nobel prize work on stochastic cooling-unpublished in any refereed journal. So I reconstructed the relevant history of geometrical integration in accelerator physics as much as I could by talking to collaborators and using my own understanding of the field. The reader should not be too surprised if this account is somewhere between history, science and perhaps even fiction.

  2. Thermodynamics of Accelerating Black Holes. (United States)

    Appels, Michael; Gregory, Ruth; Kubizňák, David


    We address a long-standing problem of describing the thermodynamics of an accelerating black hole. We derive a standard first law of black hole thermodynamics, with the usual identification of entropy proportional to the area of the event horizon-even though the event horizon contains a conical singularity. This result not only extends the applicability of black hole thermodynamics to realms previously not anticipated, it also opens a possibility for studying novel properties of an important class of exact radiative solutions of Einstein equations describing accelerated objects. We discuss the thermodynamic volume, stability, and phase structure of these black holes.

  3. Electron Cloud Effects in Accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Furman, M.A.


    Abstract We present a brief summary of various aspects of the electron-cloud effect (ECE) in accelerators. For further details, the reader is encouraged to refer to the proceedings of many prior workshops, either dedicated to EC or with significant EC contents, including the entire ?ECLOUD? series [1?22]. In addition, the proceedings of the various flavors of Particle Accelerator Conferences [23] contain a large number of EC-related publications. The ICFA Beam Dynamics Newsletter series [24] contains one dedicated issue, and several occasional articles, on EC. An extensive reference database is the LHC website on EC [25].

  4. Electron Cloud Effects in Accelerators

    CERN Document Server

    Furman, M A


    We present a brief summary of various aspects of the electron-cloud effect (ECE) in accelerators. For further details, the reader is encouraged to refer to the proceedings of many prior workshops, either dedicated to EC or with significant EC contents, including the entire "ECLOUD" series [122]. In addition, the proceedings of the various flavors of Particle Accelerator Conferences [23] contain a large number of EC-related publications. The ICFA Beam Dynamics Newsletter series [24] contains one dedicated issue, and several occasional articles, on EC. An extensive reference database is the LHC website on EC [25].

  5. Calorimetry at industrial electron accelerators

    DEFF Research Database (Denmark)

    Miller, Arne; Kovacs, A.


    Calorimetry is a convenient way to measure doses at industrial electron accelerators, where high absorbed doses (1-100 kGy) are delivered at dose rates of 102-105 Gy s-1 or even higher. Water calorimeters have been used for this purpose for several years, but recently other materials such as grap......Calorimetry is a convenient way to measure doses at industrial electron accelerators, where high absorbed doses (1-100 kGy) are delivered at dose rates of 102-105 Gy s-1 or even higher. Water calorimeters have been used for this purpose for several years, but recently other materials...

  6. OpenMP for Accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Beyer, J C; Stotzer, E J; Hart, A; de Supinski, B R


    OpenMP [13] is the dominant programming model for shared-memory parallelism in C, C++ and Fortran due to its easy-to-use directive-based style, portability and broad support by compiler vendors. Similar characteristics are needed for a programming model for devices such as GPUs and DSPs that are gaining popularity to accelerate compute-intensive application regions. This paper presents extensions to OpenMP that provide that programming model. Our results demonstrate that a high-level programming model can provide accelerated performance comparable to hand-coded implementations in CUDA.

  7. Superconducting linear accelerator system for NSC

    Indian Academy of Sciences (India)

    P N Prakash; T S Datta; B P Ajith Kumar; J Antony; P Barua; J Chacko; A Choudhury; G K Chadhari; S Ghosh; S Kar; S A Krishnan; Manoj Kumar; Rajesh Kumar; A Mandal; D S Mathuria; R S Meena; R Mehta; K K Mistri; A Pandey; M V Suresh Babu; B K Sahu; A Sarkar; S S K Sonti; A Rai; S Venkatramanan; J Zacharias; R K Bhowmik; A Roy


    This paper reports the construction of a superconducting linear accelerator as a booster to the 15 UD Pelletron accelerator at Nuclear Science Centre, New Delhi. The LINAC will use superconducting niobium quarter wave resonators as the accelerating element. Construction of the linear accelerator has progressed sufficiently. Details of the entire accelerator system including the cryogenics facility, RF electronics development, facilities for fabricating niobium resonators indigenously, and present status of the project are presented.

  8. Usefulness of HeLa cells to evaluate inverse agonistic activity of antihistamines. (United States)

    Mizuguchi, Hiroyuki; Ono, Shohei; Hattori, Masashi; Sasaki, Yohei; Fukui, Hiroyuki


    Antihistamines are thought to antagonize histamine and prevent it from binding to the histamine H1 receptor (H1R). However, recent studies indicate that antihistamines are classified into two groups, i.e., inverse agonists and neutral antagonists on the basis of their ability to down-regulate the constitutive activity of H1R. As H1R is an allergy-sensitive gene whose expression influences the severity of allergic symptoms, inverse agonists should more potently alleviate allergic symptoms than neutral antagonists by inhibiting H1R constitutive activity. Therefore, it is important to assess inverse agonistic activity of antihistamines. Here we report a novel assay method using HeLa cells expressing H1R endogenously for evaluation of inverse agonistic activity of antihistamines. Pretreatment with inverse agonists down-regulated H1R gene expression below to its basal level. On the other hand, basal H1R mRNA expression was unchanged by neutral antagonist pretreatment. Both inverse agonists and neutral antagonists suppressed histamine-induced H1R mRNA elevation. Classification of antihistamines on the basis of their suppressive activity of basal H1R gene expression was consistent with that of inositol phosphate accumulation in H1R-overexpressed cells. Our data suggest that the assay method using HeLa cells is more convenient and useful than the existing methods and may contribute to develop new antihistamines with inverse agonistic activity.

  9. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    Energy Technology Data Exchange (ETDEWEB)

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi, E-mail:


    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  10. Potency and characterization of estrogen-receptor agonists in United Kingdom estuarine sediments. (United States)

    Thomas, Kevin V; Balaam, Jan; Hurst, Mark; Nedyalkova, Zoya; Mekenyan, Ovanes


    The activity of estrogen-receptor (ER) agonists in sediments collected from the United Kingdom (UK) estuaries was assessed using the in vitro recombinant yeast estrogen screen (YES assay). The YES assay was successfully used to determine the in vitro ER agonist potency of pore waters and solvent extracts of sediments collected from UK estuaries. Estrogen-receptor agonists were detected in 66% of the pore water samples and in 91% of the sediment solvent extracts tested. The pore waters tested had ER agonist potencies from less than 2 to 68 ng 17beta-estradiol (E2) L(-1), whereas sediment extracts had potencies from less than 0.2 to 13 microg E2 kg(-1). A toxicity identification evaluation approach using bioassay-directed fractionation was used in an attempt to identify the ER agonists in extracts of sediments collected from the Tyne and Tees estuaries (UK). Gas chromatography-mass spectrometry was used to provide lists of compounds in the fractions obtained that were evaluated for known ER agonist activity using published data and an ER quantitative structure-activity relationship model. Toxicity identification evaluation characterization failed to identify any ER agonists in pore water extracts; however, three compounds in sediment solvent extracts were identified as ER agonists. Nonylphenol, cinnarizine, and cholesta-4,6-dien-3-one were identified in the sample collected from the Tyne estuary. Important ER agonist substances that contaminate marine sediments remain unidentified. The present study as well as previous work on effluents point toward the involvement of natural products in the estrogenic burdens of marine sediments. Further work is required to establish the relative contribution of natural products and anthropogenic chemicals to current environmental impacts in the context of the Oslo and Paris Commission strategy to eliminate hazardous substances by 2020.

  11. Binding Mode of Insulin Receptor and Agonist Peptide

    Institute of Scientific and Technical Information of China (English)


    Insulin is a protein hormone secreted by pancreatic β cells. One of its main functions is to keep the balance of glucose inside the body by regulating the absorption and metabolism of glucose in the periphery tissue, as well as the production and storage of hepatic glycogen. The insulin receptor is a transmembrane glycoprotein in which two α subunits with a molecular weight of 135 kD and twoβ subunits with a molecular weight of 95 kD are joined by a disulfide bond to form a β-α-α-β structure. The extracellular α subunit, especially, its three domains near the N-terminal are partially responsible for signal transduction or ligand-binding, as indicated by the experiments. The extracellular α subunits are involved in binding the ligands. The experimental results indicate that the three domains of the N-terminal of the α subunits are the main determinative parts of the insulin receptor to bind the insulin or mimetic peptide.We employed the extracellular domain (PDBID: 1IGR) of the insulin-like growth factor-1 receptor (IGF-1 R ) as the template to simulate and optimize the spatial structures of the three domains in the extracellular domain of the insulin receptor, which includes 468 residues. The work was accomplished by making use of the homology program in the Insight Ⅱ package on an Origin3800 server. The docking calculations of the insulin receptor obtained by homology with hexapeptides were carried out by means of the program Affinity. The analysis indicated that there were hydrogen bonding, and electrostatic and hydrophobic effects in the docking complex of the insulin receptor with hexapeptides.Moreover, we described the spatial orientation of a mimetic peptide with agonist activity in the docking complex. We obtained a rough model of binding of DLAPSQ or STIVYS with the insulin receptor, which provides the powerful theoretical support for designing the minimal insulin mimetic peptide with agonist activity, making it possible to develop oral small

  12. Receptors and Channels Targeted by Synthetic Cannabinoid Receptor Agonists and Antagonists


    Pertwee, R. G.


    It is widely accepted that non-endogenous compounds that target CB1 and/or CB2 receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Δ9-tetrahydrocannabinol or nabilone, both CB1/CB2 receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB2-selective agonists, peripherally restricted CB1/CB2 receptor ago...

  13. Quantitative phosphoproteomics dissection of seven-transmembrane receptor signaling using full and biased agonists

    DEFF Research Database (Denmark)

    Christensen, Gitte L; Kelstrup, Christian D; Lyngsø, Christina;


    , we performed a global quantitative phosphoproteomics analysis of the AT(1)R signaling network. We analyzed ligand-stimulated SILAC (stable isotope labeling by amino acids in cell culture) cells by high resolution (LTQ-Orbitrap) MS and compared the phosphoproteomes of the AT(1)R agonist angiotensin II......(q)-dependent and -independent AT(1)R signaling. This study provides substantial novel insight into angiotensin II signal transduction and is the first study dissecting the differences between a full agonist and a biased agonist from a 7TMR on a systems-wide scale. Importantly, it reveals a previously unappreciated diversity...

  14. Behavioural effects of the benzodiazepine receptor partial agonist RO 16-6028 in mice. (United States)

    Belzung, C; Misslin, R; Vogel, E


    The imidazo-diazepinone RO 16-6028 is a benzodiazepine receptor partial agonist which exhibits some anti-conflict effects in the two-chambered light/dark test without significantly affecting the behaviour of mice confronted with the staircase test. In addition, this drug slightly reduced locomotion and more markedly rearing in a free exploration procedure. These results indicate that RO 16-6028 appears to produce some anxiolytic and sedative properties like full agonists, but with weaker magnitude. This could be related to the benzodiazepine partial agonistic profile of the compound.

  15. Ponderomotive Acceleration in Coronal Loops (United States)

    Dahlburg, R. B.; Laming, J. M.; Taylor, B. D.; Obenschain, K.


    Ponderomotive acceleration has been asserted to be a cause of the first ionization potential (FIP) effect, the well-known enhancement in abundance by a factor of 3-4 over photospheric values of elements in the solar corona with FIP less than about 10 eV. It is shown here by means of numerical simulations that ponderomotive acceleration occurs in solar coronal loops, with the appropriate magnitude and direction, as a “by-product” of coronal heating. The numerical simulations are performed with the HYPERION code, which solves the fully compressible three-dimensional magnetohydrodynamic equations including nonlinear thermal conduction and optically thin radiation. Numerical simulations of coronal loops with an axial magnetic field from 0.005 to 0.02 T and lengths from 25,000 to 75,000 km are presented. In the simulations the footpoints of the axial loop magnetic field are convected by random, large-scale motions. There is a continuous formation and dissipation of field-aligned current sheets, which act to heat the loop. As a consequence of coronal magnetic reconnection, small-scale, high-speed jets form. The familiar vortex quadrupoles form at reconnection sites. Between the magnetic footpoints and the corona the reconnection flow merges with the boundary flow. It is in this region that the ponderomotive acceleration occurs. Mirroring the character of the coronal reconnection, the ponderomotive acceleration is also found to be intermittent.

  16. CERNois wins prestigious accelerator award

    CERN Multimedia

    Katarina Anthony


    During the 2nd International Particle Accelerator Conference, CERN’s Rogelio Tomás García became the first Spaniard to receive the Frank Sacherer Prize for his work in particle beam optics.   Rogelio Tomás García at the 2nd International Particle Accelerator Conference. The Frank Sacherer Prize is awarded to physicists who have made a “significant, original contribution to the accelerator field" early on in their career. This year the prize was given to Rogelio Tomás García who, at only 35 years of age, has made important contributions to the optics design, optics measurement, and correction techniques applied at both the LHC and Brookhaven’s RHIC. “Tomás has had a vital impact on CERN’s beam optics studies and has made very impressive achievements in the field of beam optics,” says Oliver Brüning, Head of the Accelerators and Beam Physics...

  17. Thomas Jefferson National Accelerator Facility

    Energy Technology Data Exchange (ETDEWEB)

    Grames, Joseph; Higinbotham, Douglas; Montgomery, Hugh


    The Thomas Jefferson National Accelerator Facility (Jefferson Lab) in Newport News, Virginia, USA, is one of ten national laboratories under the aegis of the Office of Science of the U.S. Department of Energy (DOE). It is managed and operated by Jefferson Science Associates, LLC. The primary facility at Jefferson Lab is the Continuous Electron Beam Accelerator Facility (CEBAF) as shown in an aerial photograph in Figure 1. Jefferson Lab was created in 1984 as CEBAF and started operations for physics in 1995. The accelerator uses superconducting radio-frequency (srf) techniques to generate high-quality beams of electrons with high-intensity, well-controlled polarization. The technology has enabled ancillary facilities to be created. The CEBAF facility is used by an international user community of more than 1200 physicists for a program of exploration and study of nuclear, hadronic matter, the strong interaction and quantum chromodynamics. Additionally, the exceptional quality of the beams facilitates studies of the fundamental symmetries of nature, which complement those of atomic physics on the one hand and of high-energy particle physics on the other. The facility is in the midst of a project to double the energy of the facility and to enhance and expand its experimental facilities. Studies are also pursued with a Free-Electron Laser produced by an energy-recovering linear accelerator.

  18. Program Evaluation: Accelerating Retained Students (United States)

    Juneau, Lisa


    The purpose of this program evaluation was to evaluate the first year of an acceleration program that allowed students who were retained a grade level for not performing on academic level in early elementary school an opportunity to rejoin their age appropriate class. The primary focus of the evaluation was to evaluate the effectiveness of an…

  19. Cosmological Acceleration from Gravitational Waves

    CERN Document Server

    Marochnik, Leonid


    It is shown that the classical gravitational waves of super-horizon wavelengths are able to form the de Sitter accelerated expansion of the empty (with no matter fields) Universe. The contemporary Universe is about 70% empty and asymptotically is going to become completely empty, so the effect caused by emptiness should be already very noticeable. It could manifest itself as the dark energy.

  20. Observations of Collective Ion Acceleration. (United States)


    possible benefit can be listed. In cancer therapy, radiation produced by ion beams may be more selectively directed into tumors. Ion beams in spallation...34Autoresonant Accelerator Concept," Phys. Rev. Lett. 31, 1234 (1973). 50. S. Humphries, J. J. Lee, and R. N. Sudan, "Generation of Incense Pulsed Ion Beams

  1. CLIC Drive Beam Accelerating Structures

    CERN Document Server

    Wegner, Rolf


    Travelling structures for accelerating the high-current (4.2 A) CLIC Drive Beam to an energy of 2.37 GeV are presented. The structures are optimised for efficiency (full beam loading operation) and a desired filling time. Higher order modes are studied and are reduced by detuning along the structure and by damping with silicon carbide loads.

  2. Physics Needs for Future Accelerators

    CERN Document Server

    Lykken, J D


    Contents: 1. Prologomena to any meta future physics 1.1 Physics needs for building future accelerators 1.2 Physics needs for funding future accelerators 2. Physics questions for future accelerators 2.1 Crimes and misapprehensions 2.1.1 Organized religion 2.1.2 Feudalism 2.1.3 Trotsky was right 2.2 The Standard Model as an effective field theory 2.3 What is the scale of new physics? 2.4 What could be out there? 2.5 Model-independent conclusions 3. Future accelerators 3.1 What is the physics driving the LHC? 3.2 What is the physics driving the LC? 3.2.1 Higgs physics is golden 3.2.2 LHC won't be sufficient to unravel the new physics as the TeV scale 3.2.3 LC precision measurements can pin down new physics scales 3.3 Why a Neutrino Factory? 3.4 Pushing the energy frontier

  3. Post-LHC accelerator magnets

    Energy Technology Data Exchange (ETDEWEB)

    Gourlay, Stephen A.


    The design and practicality of future accelerators, such as hadron colliders and neutrino factories being considered to supercede the LHC, will depend greatly on the choice of superconducting magnets. Various possibilities will be reviewed and discussed, taking into account recent progress and projected improvements in magnet design and conductor development along with the recommendations from the 2001 Snowmass workshop.

  4. Repair of overheating linear accelerator

    Energy Technology Data Exchange (ETDEWEB)

    Barkley, Walter; Baldwin, William; Bennett, Gloria; Bitteker, Leo; Borden, Michael; Casados, Jeff; Fitzgerald, Daniel; Gorman, Fred; Johnson, Kenneth; Kurennoy, Sergey; Martinez, Alberto; O’Hara, James; Perez, Edward; Roller, Brandon; Rybarcyk, Lawrence; Stark, Peter; Stockton, Jerry


    Los Alamos Neutron Science Center (LANSCE) is a proton accelerator that produces high energy particle beams for experiments. These beams include neutrons and protons for diverse uses including radiography, isotope production, small feature study, lattice vibrations and material science. The Drift Tube Linear Accelerator (DTL) is the first portion of a half mile long linear section of accelerator that raises the beam energy from 750 keV to 100 MeV. In its 31st year of operation (2003), the DTL experienced serious issues. The first problem was the inability to maintain resonant frequency at full power. The second problem was increased occurrences of over-temperature failure of cooling hoses. These shortcomings led to an investigation during the 2003 yearly preventative maintenance shutdown that showed evidence of excessive heating: discolored interior tank walls and coper oxide deposition in the cooling circuits. Since overheating was suspected to be caused by compromised heat transfer, improving that was the focus of the repair effort. Investigations revealed copper oxide flow inhibition and iron oxide scale build up. Acid cleaning was implemented with careful attention to protection of the base metal, selection of components to clean and minimization of exposure times. The effort has been very successful in bringing the accelerator through a complete eight month run cycle allowing an incredible array of scientific experiments to be completed this year (2003-2004). This paper will describe the systems, investigation analysis, repair, return to production and conclusion.

  5. Agonists and Antagonists of TGF-β Family Ligands. (United States)

    Chang, Chenbei


    The discovery of the transforming growth factor β (TGF-β) family ligands and the realization that their bioactivities need to be tightly controlled temporally and spatially led to intensive research that has identified a multitude of extracellular modulators of TGF-β family ligands, uncovered their functions in developmental and pathophysiological processes, defined the mechanisms of their activities, and explored potential modulator-based therapeutic applications in treating human diseases. These studies revealed a diverse repertoire of extracellular and membrane-associated molecules that are capable of modulating TGF-β family signals via control of ligand availability, processing, ligand-receptor interaction, and receptor activation. These molecules include not only soluble ligand-binding proteins that were conventionally considered as agonists and antagonists of TGF-β family of growth factors, but also extracellular matrix (ECM) proteins and proteoglycans that can serve as "sink" and control storage and release of both the TGF-β family ligands and their regulators. This extensive network of soluble and ECM modulators helps to ensure dynamic and cell-specific control of TGF-β family signals. This article reviews our knowledge of extracellular modulation of TGF-β growth factors by diverse proteins and their molecular mechanisms to regulate TGF-β family signaling.

  6. Ontogenesis of agonistic vocalizations in the cichlid fish Metriaclima zebra. (United States)

    Bertucci, Frédéric; Scaion, Delphine; Beauchaud, Marilyn; Attia, Joël; Mathevon, Nicolas


    While acoustic communication has been described in adults of various fish species, our knowledge about the ontogeny of fish sound production is limited. In adults, sound signals are known to be involved during aggressive interactions. However, aggressive behaviour may appear early in the life of fishes due to the possible competition for food and space. If acoustic signals are used to send information to competitors, sounds are likely to play a role during interactions between juvenile fish as well. The apparition and evolution of sound production were monitored in a group of juveniles of the cichlid fish Metriaclima zebra from hatching to 4 months of age. In addition, the link between vocalizations and agonistic behaviour was studied during dyadic interactions at three different ages. Sounds production appeared to be present early in the development of this fish and increased along with the number of aggressive behaviours. Recorded sounds consisted, in juveniles, in isolated pulses showing a decrease in frequency and duration as the fish grew. In adults, sounds became bursts of pulses but the transition from isolated to repetitive pulses was not observed. These results are compared to the existing literature on sound production ontogeny in fishes.

  7. Basic understanding of gonadotropin-releasing hormone-agonist triggering. (United States)

    Casper, Robert F


    A single bolus of human chorionic gonadotropin (hCG) at midcycle has been the gold standard for triggering final oocyte maturation and ovulation in assisted reproductive technology cycles. More recently, gonadotropin-releasing hormone (GnRH)-agonist (GnRH-a) triggering has been introduced. The GnRH-a trigger may allow a more physiologic surge of both luteinizing hormone (LH) and follicle-stimulating hormone, although whether the combined surge will result in improved oocyte and embryo quality remains to be seen. However, the short duration of the LH surge with the GnRH-a trigger (approximately 34 hours) has been shown to be beneficial for preventing ovarian hyperstimulation syndrome in GnRH antagonist in vitro fertilization (IVF) cycles when compared with the prolonged elevation of hCG (≥6 days) after exposure to an hCG bolus. This review discusses the physiologic basis for the use of a GnRH-a trigger in IVF cycles.

  8. Accelerator applications in energy and security

    CERN Document Server

    Chou, Weiren


    As accelerator science and technology progressed over the past several decades, the accelerators themselves have undergone major improvements in multiple performance factors: beam energy, beam power, and beam brightness. As a consequence, accelerators have found applications in a wide range of fields in our life and in our society. The current volume is dedicated to applications in energy and security, two of the most important and urgent topics in today's world. This volume makes an effort to provide a review as complete and up to date as possible of this broad and challenging subject. It contains overviews on each of the two topics and a series of articles for in-depth discussions including heavy ion accelerator driven inertial fusion, linear accelerator-based ADS systems, circular accelerator-based ADS systems, accelerator-reactor interface, accelerators for fusion material testing, cargo inspection, proton radiography, compact neutron generators and detectors. It also has a review article on accelerator ...

  9. Technology and applications of advanced accelerator concepts

    CERN Document Server

    Chou, Weiren


    Since its invention in the 1920s, particle accelerators have made tremendous progress in accelerator science, technology and applications. However, the fundamental acceleration principle, namely, to apply an external radiofrequency (RF) electric field to accelerate charged particles, remains unchanged. As this method (either room temperature RF or superconducting RF) is approaching its intrinsic limitation in acceleration gradient (measured in MeV/m), it becomes apparent that new methods with much higher acceleration gradient (measured in GeV/m) must be found for future very high energy accelerators as well as future compact (table-top or room-size) accelerators. This volume introduces a number of advanced accelerator concepts (AAC) — their principles, technologies and potential applications. For the time being, none of them stands out as a definitive direction in which to go. But these novel ideas are in hot pursuit and look promising. Furthermore, some AAC requires a high power laser system. This has the ...

  10. Acute and Chronic Effects of ß2-Adrenoceptor Agonists in Relation to Exercise Performance and Doping with Emphasis on Terbutaline

    DEFF Research Database (Denmark)

    Hostrup, Morten

    , the underlying mechanisms by which β2-agonists affect performance in humans are inadequately explored. The purpose of this PhD was to investigate acute and chronic effects of high dose administration of terbutaline and to examine underlying mechanisms by which terbutaline affects performance.......This thesis addresses the performance enhancing effects of β2-agonists (asthma medication) with emphasis on terbutaline in the context of doping. Given the high prevalence of asthma in the athletic population, β2-agonists are among the most used drugs in competitive sport. While there is consensus...... that therapeutic inhalation of β2-agonists is without performance enhancing effects, oral β2-agonists are considered performance-enhancing. Since the systemic uptake of inhaled β2-agonists is higher than after oral intake, it may be that high dose inhalation of β2-agonists is performance enhancing. Moreover...

  11. Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?

    DEFF Research Database (Denmark)

    Schwartz, Thue W; Holst, Birgitte


    Many small-molecule agonists also display allosteric properties. Such ago-allosteric modulators act as co-agonists, providing additive efficacy--instead of partial antagonism--and they can affect--and often improve--the potency of the endogenous agonist. Surprisingly, the apparent binding sites...... different binding modes. In another, dimeric, receptor scenario, the endogenous agonist binds to one protomer while the ago-allosteric modulator binds to the other, 'allosteric' protomer. It is suggested that testing for ago-allosteric properties should be an integral part of the agonist drug discovery...... process because a compound that acts with--rather than against--the endogenous agonist could be an optimal agonist drug....

  12. CAS - CERN Accelerator School: Advanced Accelerator Physics Course

    CERN Document Server

    Herr, W


    This report presents the proceedings of the Course on Advanced Accelerator Physics organized by the CERN Accelerator School. The course was held in Trondheim, Norway from 18 to 29 August 2013, in collaboration with the Norwegian University of Science and Technology. Its syllabus was based on previous courses and in particular on the course held in Berlin 2003 whose proceedings were published as CERN Yellow Report CERN- 2006-002. The field has seen significant advances in recent years and some topics were presented in a new way and other topics were added. The lectures were supplemented with tutorials on key topics and 14 hours of hands on courses on Optics Design and Corrections, RF Measurement Techniques and Beam Instrumentation and Diagnostics. These courses are a key element of the Advanced Level Course.

  13. The Effects of Inhaled β-Adrenergic Agonists in Transient Tachypnea of the Newborn

    Directory of Open Access Journals (Sweden)

    Esengul Keleş MD


    Full Text Available Aim. To investigate the efficacy of an inhaled β-adrenergic agonists in transient tachypnea of the newborn (TTN. Method. We retrospectively analyzed a cohort of 51 term infants (Group 1 and 37 term infants (Group 2 monitored in the newborn intensive care unit diagnosed with TTN. Infants in Group 1 received humidified oxygen alone, and infants in Group 2 were administered the inhaled β-2 agonist plus humidified oxygen. Results. TTN clinical respiratory assessment, respiratory rate, oxygen saturation values, need for supplemental oxygen therapy, blood gas PH, PO2, and duration of hospitalization were significantly improved in infants in Group 2 as compared with infants in Group 1 (P .05. Conclusion. Inhaled β-adrenergic agonist added to humidified oxygen was found to improve clinical and laboratory parameters. We believe that further studies should be conducted with larger groups to demonstrate the efficacy of β-2 agonists in TTN patients.

  14. [Pramipexol: a new dopaminergic agonist for the treatment of Parkinson disease]. (United States)

    Grandas, F; Galiano, M L


    Pramipexol is a novel nonergot dopamine agonist which has high selectivity for intereacting with dopamine D2 receptors (especially with D3 receptor subtype). It has been effective in early Parkinson's disease as monotherapy and as adjunctive therapy with L-dopa in advanced stages of the disease. Clinical improvement can be observed after 3 or 4 weeks of treatment. The adverse events profile of pramipexol is similar, in general, to that of other dopamine receptor agonists, although it can be foreseen that pramipexol should not induce side effects related to the ergot chemical structure such as eritromelalgia, distal vasospasm, retroperitoneal fibrosis or pleural effusions. Nevertheless, the potential advantages of this promising dopamine agonist should be tested in well-designed prospective comparative studies with other available ergot and nonergot dopamine agonists.

  15. Two cases of takotsubo cardiomyopathy in patients treated with high doses of inhaled beta-2-agonists

    DEFF Research Database (Denmark)

    Thomsen, Camilla Fjord; Jeppesen, Jørgen Lykke; Stride, Nis Ottesen


    Takotsubo cardiomyopathy (TCM) is characterised by reversible left ventricular dysfunction in patients presenting with acute coronary syndrome (ACS). TCM is considered multifactorial, and the repetitive exposure to inhaled beta-2-agonists has been suspected to induce TCM in predisposed individuals...

  16. Inhibition of AMPA Receptors by Polyamine Toxins is Regulated by Agonist Efficacy and Stargazin

    DEFF Research Database (Denmark)

    Poulsen, Mette H; Lucas, Simon; Strømgaard, Kristian;


    The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are glutamate-gated cation channels mediating the majority of fast excitatory synaptic transmission in the central nervous system (CNS). Polyamine toxins derived from spiders and wasps are use- and voltage-dependent...... explored the effect of the TARP γ-2 (also known as stargazin) on the inhibitory potency of three structurally different polyamine toxins at Ca(2+)-permeable homomeric GluA1 AMPARs expressed in oocytes. We find that polyamine toxin IC50 is differentially affected by presence of stargazin depending...... on the efficacy of the agonists used to activate GluA1. Co-assembly of GluA1 receptors with stargazin increases the potency of the polyamine toxins when activated by the weak partial agonist kainate, but has no effect in presence of full-agonist L-glutamate (Glu) and partial agonist (RS)-willardiine....

  17. Dopamine Agonist in Treatment of ADHD with Restless Legs Syndrome and ODD

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap


    Full Text Available A 6-year-old male with attention deficit hyperactivity disorder who responded poorly to methylphenidate (MPH was benefited following treatment with the dopamine agonist ropinirole, in a report from the Hopital Robert Debre, Paris, France.

  18. Ingestion of TRP channel agonists attenuates exercise-induced muscle cramps. (United States)

    Craighead, Daniel H; Shank, Sean W; Gottschall, Jinger S; Passe, Dennis H; Murray, Bob; Alexander, Lacy M; Kenney, W Larry


    Exercise associated muscle cramping (EAMC) is a poorly understood problem that is neuromuscular in origin. Ingestion of transient receptor potential (TRP) channel agonists has been efficacious in attenuating electrically-induced muscle cramps.

  19. Synthesis of 2-(Benzodioxol-2-yl)acetic Acids as PPARδ Agonists

    Institute of Scientific and Technical Information of China (English)

    Jian Lei KANG; Zhi Bing ZHENG; Dan QIN; Li Li WANG; Song LI


    A new series of compounds, 2-(benzodioxol-2-yl)acetic acids, have been synthesized. Their structures were confirmed by MS and 1H-NMR. The preliminary pharmacological screening showed that these compounds exhibited potent human PPARδ agonist activities.

  20. Non-linear eye movements during visual-vestibular interaction under body oscillation with step-mode lateral linear acceleration. (United States)

    Mori, Shigeo; Katayama, Naomi


    We investigated visual-vestibular interactions in normal humans, where a constant speed of optokinetic stimulation was combined with whole body oscillation of lateral linear acceleration (10 m stroke). The acceleration mode was not sinusoidal, but rectangular (step). The pure optokinetic reflex (reference OKR) and the OKR under combined stimulation (combined OKR) were induced by a random-dot pattern projected onto a hemispherical dome-screen affixed to a chair on a linear accelerator. The translational vestibulo-ocular reflex (tVOR) was determined separately in the dark during acceleration-step oscillation. Since the tVOR was masked by the OKR under combined stimulation, the interaction was assessed as changes in combined-OKR velocity at two segments of opposing acceleration; in other words, tVOR directions identical to (agonistic) and opposite to (antagonistic) the OKR direction. When a moderate optokinetic stimulus-speed of 40 deg/s was combined with a moderate acceleration of 0.3 G (3.0 m/s2) as in Experiment 1 (N=10), the combined-OKR velocity always increased during the agonistic condition, and the motion of the visual pattern was perceived as slow and clear in this segment. On the other hand, during the antagonistic condition, the combined-OKR velocity either remained unchanged or increased moderately, and the motion of the visual pattern was sensed as fast and unclear. Notably, in most subjects, the velocity difference in combined-OKR between the agonistic and antagonistic conditions was around the value of the tVOR velocity. In five of the ten subjects who completed an additional test session with the acceleration level increased from 0.3 to 0.5 G (4.9 m/s2), similar findings were maintained individually, suggesting independent behavior of tVOR. Therefore, we hypothesized that the interaction could be direction-selective; in other words, both tVOR and OKR are additive during the agonistic condition, but tVOR is suppressed during the antagonistic condition

  1. An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists

    Directory of Open Access Journals (Sweden)

    Xia Chen


    Full Text Available Various 2,3 subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are expected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines. Several 2,3 subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery addressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2 mg was the comparator in three studies. Three 2,3-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498, one 1-selective GABAA agonists (zolpidem, and another full agonist (alprazolam were examined. Pharmacological selectivity was assessed by determination of regression lines for the change from baseline of saccadic-peak-velocity- (ΔSPV- relative effect, relative to changes in different pharmacodynamic endpoints (ΔPD. SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes of the ΔSPV-ΔPD relations were consistently lower with the 2,3 selective GABA-A agonists than with lorazepam, indicating that their PD effects are less than their SPV-effects. The ΔSPV-ΔPD relations of lorazepam were comparable to alprazolam. Zolpidem showed relatively higher impairments in ΔPD relative to ΔSPV, but did not significantly differ from lorazepam. These PD results support the pharmacological selectivity of the 2,3-selective GABA-A agonists, implying an improved therapeutic window.

  2. Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, Scott K.; Washburn, David G.; Frazee, James S.; Madauss, Kevin P.; Hoang, Tram H.; Lapinski, Leahann; Grygielko, Eugene T.; Glace, Lindsay E.; Trizna, Walter; Williams, Shawn P.; Duraiswami, Chaya; Bray, Jeffrey D.; Laping, Nicholas J.; (GSKNC); (GSKPA)


    Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

  3. Discovery of a novel series of potent S1P1 agonists. (United States)

    Crosignani, Stefano; Bombrun, Agnes; Covini, David; Maio, Maurizio; Marin, Delphine; Quattropani, Anna; Swinnen, Dominique; Simpson, Don; Sauer, Wolfgang; Françon, Bernard; Martin, Thierry; Cambet, Yves; Nichols, Anthony; Martinou, Isabelle; Burgat-Charvillon, Fabienne; Rivron, Delphine; Donini, Cristina; Schott, Olivier; Eligert, Valerie; Novo-Perez, Laurence; Vitte, Pierre-Alain; Arrighi, Jean-François


    The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.

  4. Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists


    Maslov, Leonid N; Khaliulin, Igor; Oeltgen, Peter R; Naryzhnaya, Natalia V.; Pei, Jian‐Ming; Brown, Stephen A; Lishmanov, Yury B.; Downey, James M


    Abstract It has now been demonstrated that the μ, δ1, δ2, and κ1 opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct‐reducing effect with prophylactic administration and prevent reperfusi...

  5. Structural determinants of agonist-specific kinetics at the ionotropic glutamate receptor 2. (United States)

    Holm, Mai Marie; Lunn, Marie-Louise; Traynelis, Stephen F; Kastrup, Jette S; Egebjerg, Jan


    Glutamate receptors (GluRs) are the most abundant mediators of the fast excitatory neurotransmission in the human brain. Agonists will, after activation of the receptors, induce different degrees of desensitization. The efficacy of agonists strongly correlates with the agonist-induced closure of the ligand-binding domain. However, the differences in desensitization properties are less well understood. By using high-resolution x-ray structure of the GluR2 flop (GluR2o) ligand-binding core protein in complex with the partial glutamate receptor agonist (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isothiazolyl)propionic acid [(S)-thio-ATPA], we show that (S)-thio-ATPA induces an 18 degrees closure of the binding core similar to another partial agonist, (S)-2-amino-3-(4-bromo-3-hydroxy-5-isoxazolyl)propionic acid [(S)-Br-HIBO]. Despite the similar closure of the ligand-binding domain, we find in electrophysiological studies that (S)-thio-ATPA induced a 6.4-fold larger steady-state current than (RS)-Br-HIBO, and rapid agonist applications show that (S)-thio-ATPA induces a 3.6-fold higher steady-state/peak ratio and a 2.2-fold slower desensitization time constant than (RS)-Br-HIBO. Structural comparisons reveal that (S)-Br-HIBO, but not (S)-thio-ATPA, induces a twist of the ligand-binding core compared with the apostructure, and the agonist-specific conformation of Leu-650 correlates with the different kinetic profiles pointing at a key role in defining the desensitization kinetics. We conclude that, especially for intermediate efficacious agonists, the desensitization properties are influenced by additional ligand-induced factors beyond domain closure.

  6. Identification of benzoxazole analogs as novel, S1P(3) sparing S1P(1) agonists. (United States)

    Deng, Guanghui; Meng, Qinghua; Liu, Qian; Xu, Xuesong; Xu, Qiongfeng; Ren, Feng; Guo, Taylor B; Lu, Hongtao; Xiang, Jia-Ning; Elliott, John D; Lin, Xichen


    A novel series of benzoxazole-derived S1P(1) agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P(1) agonist (over S1P(3)) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.

  7. SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist. (United States)

    Sard, Howard; Kumaran, Govindaraj; Morency, Cynthia; Roth, Bryan L; Toth, Beth Ann; He, Ping; Shuster, Louis


    An SAR study of psilocybin and psilocin derivatives reveals that 1-methylpsilocin is a selective agonist at the h5-HT(2C) receptor. The corresponding phosphate derivative, 1-methylpsilocybin, shows efficacy in an animal model for obsessive-compulsive disorder, as does 4-fluoro-N,N-dimethyltryptamine. These results suggest a new area for development of novel 5-HT(2C) agonists with applications for drug discovery.

  8. Early administration of RS 67333, a specific 5-HT4 receptor agonist, prevents amyloidogenesis and behavioral deficits in the 5XFAD mouse model of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Patrizia eGiannoni


    Full Text Available Amyloid β (Aβ accumulation is considered the main culprit in the pathogenesis of Alzheimer's disease (AD. Recent studies suggest that decreasing Aβ production at very early stages of AD could be a promising strategy to slow down disease progression. Serotonin 5-HT4 receptor activation stimulates α-cleavage of the amyloid precursor protein (APP, leading to the release of the soluble and neurotrophic sAPPα fragment and thus precluding Aβ formation. Using the 5XFAD mouse model of AD that shows accelerated Aβ deposition, we investigated the effect of chronic treatments (treatment onset at different ages and different duration with the 5-HT4 receptor agonist RS 67333 during the asymptomatic phase of the disease. Chronic administration of RS 67333 decreased concomitantly the number of amyloid plaques and the level of Aβ species. Reduction of Aβ levels was accompanied by a striking decrease in hippocampal astrogliosis and microgliosis. RS 67333 also transiently increased sAPPα concentration in the cerebrospinal fluid and brain. Moreover, a specific 5-HT4 receptor antagonist (RS 39604 prevented the RS 67333-mediated reduction of the amyloid pathology. Finally, the novel object recognition test deficits of 5XFAD mice were reversed by chronic treatment with RS 67333. Collectively, these results strongly highlight this 5-HT4 receptor agonist as a promising disease modifying-agent for AD.

  9. Toll-like receptor 4 agonistic antibody promotes innate immunity against severe pneumonia induced by coinfection with influenza virus and Streptococcus pneumoniae. (United States)

    Tanaka, Akitaka; Nakamura, Shigeki; Seki, Masafumi; Fukudome, Kenji; Iwanaga, Naoki; Imamura, Yoshifumi; Miyazaki, Taiga; Izumikawa, Koichi; Kakeya, Hiroshi; Yanagihara, Katsunori; Kohno, Shigeru


    Coinfection with bacteria is a major cause of mortality during influenza epidemics. Recently, Toll-like receptor (TLR) agonists were shown to have immunomodulatory functions. In the present study, we investigated the effectiveness and mechanisms of the new TLR4 agonistic monoclonal antibody UT12 against secondary pneumococcal pneumonia induced by coinfection with influenza virus in a mouse model. Mice were intranasally inoculated with Streptococcus pneumoniae 2 days after influenza virus inoculation. UT12 was intraperitoneally administered 2 h before each inoculation. Survival rates were significantly increased and body weight loss was significantly decreased by UT12 administration. Additionally, the production of inflammatory mediators was significantly suppressed by the administration of UT12. In a histopathological study, pneumonia in UT12-treated mice was very mild compared to that in control mice. UT12 increased antimicrobial defense through the acceleration of macrophage recruitment into the lower respiratory tract induced by c-Jun N-terminal kinase (JNK) and nuclear factor kappaB (NF-κB) pathway-dependent monocyte chemoattractant protein 1 (MCP-1) production. Collectively, these findings indicate that UT12 promoted pulmonary innate immunity and may reduce the severity of severe pneumonia induced by coinfection with influenza virus and S. pneumoniae. This immunomodulatory effect of UT12 improves the prognosis of secondary pneumococcal pneumonia and makes UT12 an attractive candidate for treating severe infectious diseases.

  10. Accelerate! (United States)

    Kotter, John P


    The old ways of setting and implementing strategy are failing us, writes the author of Leading Change, in part because we can no longer keep up with the pace of change. Organizational leaders are torn between trying to stay ahead of increasingly fierce competition and needing to deliver this year's results. Although traditional hierarchies and managerial processes--the components of a company's "operating system"--can meet the daily demands of running an enterprise, they are rarely equipped to identify important hazards quickly, formulate creative strategic initiatives nimbly, and implement them speedily. The solution Kotter offers is a second system--an agile, networklike structure--that operates in concert with the first to create a dual operating system. In such a system the hierarchy can hand off the pursuit of big strategic initiatives to the strategy network, freeing itself to focus on incremental changes to improve efficiency. The network is populated by employees from all levels of the organization, giving it organizational knowledge, relationships, credibility, and influence. It can Liberate information from silos with ease. It has a dynamic structure free of bureaucratic layers, permitting a level of individualism, creativity, and innovation beyond the reach of any hierarchy. The network's core is a guiding coalition that represents each level and department in the hierarchy, with a broad range of skills. Its drivers are members of a "volunteer army" who are energized by and committed to the coalition's vividly formulated, high-stakes vision and strategy. Kotter has helped eight organizations, public and private, build dual operating systems over the past three years. He predicts that such systems will lead to long-term success in the 21st century--for shareholders, customers, employees, and companies themselves.

  11. The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates.

    Directory of Open Access Journals (Sweden)

    Vadim I Krivokrysenko

    Full Text Available There are currently no approved medical radiation countermeasures (MRC to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care administered in a mitigative regimen, 1-48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01 absolute survival advantage of 40-60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05 effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters.

  12. GLP-1 receptor agonists or DPP-4 inhibitors: how to guide the clinician? (United States)

    Scheen, André J


    Pharmacological treatment of type 2 diabetes has been enriched during recent years, with the launch of incretin therapies targeting glucagon-like peptide-1 (GLP-1). Such medications comprise either GLP-1 receptor agonists, with short (one or two daily injections: exenatide, liraglutide, lixisenatide) or long duration (one injection once weekly: extended-released exenatide, albiglutide, dulaglutide, taspoglutide); or oral compounds inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme that inactives GLP-1, also called gliptins (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin). Although both pharmacological approaches target GLP-1, important differences exist concerning the mode of administration (subcutaneous injection versus oral ingestion), the efficacy (better with GLP-1 agonists), the effects on body weight and systolic blood pressure (diminution with agonists versus neutrality with gliptins), the tolerance profile (nausea and possibly vomiting with agonists) and the cost (higher with GLP-1 receptor agonists). Both agents may exert favourable cardiovascular effects. Gliptins may represent a valuable alternative to a sulfonylurea or a glitazone after failure of monotherapy with metformin while GLP-1 receptor agonists may be considered as a good alternative to insulin (especially in obese patients) after failure of a dual oral therapy. However, this scheme is probably too restrictive and modalities of using incretins are numerous, in almost all stages of type 2 diabetes. Physicians may guide the pharmacological choice based on clinical characteristics, therapeutic goals and patient's preference.

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

    Energy Technology Data Exchange (ETDEWEB)

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


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

  14. Substrate specificity of the agonist-stimulated release of polyunsaturated fatty acids from vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Rosenthal, M.D.; Garcia, M.C.; Sprecher, H. (Eastern Virginia Medical School, Norfolk (USA))


    Stimulation of vascular endothelial cells with agonists such as histamine and thrombin results in release of arachidonic acid from membrane lipids and subsequent eicosanoid synthesis. As shown previously, the agonist-stimulated deacylation is specific for arachidonate, eicosapentaenoate, and 5,8,11-eicosatrienoate. This study has utilized radiolabeled fatty acids differing in chain length and position of double bonds to further elucidate the fatty acyl specificity of agonist-stimulated deacylation. Replicate wells of confluent human umbilical vein endothelial cells were incubated with 14C-labeled fatty acids and then challenged with histamine, thrombin, or the calcium ionophore A23187. Comparison of the results obtained with isomeric eicosatetraenoic fatty acids with initial double bonds at carbons 4, 5, or 6 indicated that the deacylation induced by all three agonists exhibited marked specificity for the cis-5 double bond. Lack of stringent chain length specificity was indicated by agonist-stimulated release of 5,8,11,14- tetraenoic fatty acids with 18, 19, 20, and 21 carbons. Release of 5,8,14-(14C)eicosatrienoate was two-to threefold that of 5,11,14-(14C)eicosatrienoate, thus indicating that the cis-8 double bond may also contribute to the stringent recognition by the agonist-sensitive phospholipase. The present study has also demonstrated that histamine, thrombin, and A23187 do not stimulate release of docosahexaenoate from endothelial cells.

  15. Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor

    Directory of Open Access Journals (Sweden)

    Ling Yang


    Full Text Available The nociceptin/orphanin FQ (NOP receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structure–activity relationship (3D-QSAR studies were carried out using comparative molecular field analysis (CoMFA and comparative molecular similarity indices analysis (CoMSIA techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand-based CoMSIA model exhibited Q2 of 0.501, R2ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R2pred value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity.

  16. Fluorescence characteristics of hydrophobic partial agonist probes of the cholecystokinin receptor. (United States)

    Harikumar, Kaleeckal G; Pinon, Delia I; Miller, Laurence J


    Fluorescence spectroscopic studies are powerful tools for the evaluation of receptor structure and the dynamic changes associated with receptor activation. Here, we have developed two chemically distinct fluorescent probes of the cholecystokinin (CCK) receptor by attaching acrylodan or a nitrobenzoxadiazole moiety to the amino terminus of a partial agonist CCK analogue. These two probes were able to bind to the CCK receptor specifically and with high affinity, and were able to elicit only submaximal intracellular calcium responses typical of partial agonists. The fluorescence characteristics of these probes were compared with those previously reported for structurally-related full agonist and antagonist probes. Like the previous probes, the partial agonist probes exhibited longer fluorescence lifetimes and increased anisotropy when bound to the receptor than when free in solution. The receptor-bound probes were not easily quenched by potassium iodide, suggesting that the fluorophores were protected from the extracellular aqueous milieu. The fluorescence characteristics of the partial agonist probes were quite similar to those of the analogous full agonist probes and quite distinct from the analogous antagonist probes. These data suggest that the partially activated conformational state of this receptor is more closely related to its fully active state than to its inactive state.

  17. PPARα-Independent Arterial Smooth Muscle Relaxant Effects of PPARα Agonists. (United States)

    Silswal, Neerupma; Parelkar, Nikhil K; Wacker, Michael J; Badr, Mostafa; Andresen, Jon


    We sought to determine direct vascular effects of peroxisome proliferator-activated receptor alpha (PPARα) agonists using isolated mouse aortas and middle cerebral arteries (MCAs). The PPARα agonists GW7647, WY14643, and gemfibrozil acutely relaxed aortas held under isometric tension and dilated pressurized MCAs with the following order of potency: GW7647≫WY14643>gemfibrozil. Responses were endothelium-independent, and the use of PPARα deficient mice demonstrated that responses were also PPARα-independent. Pretreating arteries with high extracellular K(+) attenuated PPARα agonist-mediated relaxations in the aorta, but not in the MCA. In the aorta, the ATP sensitive potassium (K(ATP)) channel blocker glibenclamide also impaired relaxations whereas the other K(+) channel inhibitors, 4-aminopyridine and Iberiotoxin, had no effect. In aortas, GW7647 and WY14643 elevated cGMP levels by stimulating soluble guanylyl cyclase (sGC), and inhibition of sGC with ODQ blunted relaxations to PPARα agonists. In the MCA, dilations were inhibited by the protein kinase C (PKC) activator, phorbol 12,13-dibutyrate, and also by ODQ. Our results demonstrated acute, nonreceptor-mediated relaxant effects of PPARα agonists on smooth muscle of mouse arteries. Responses to PPARα agonists in the aorta involved K(ATP) channels and sGC, whereas in the MCA the PKC and sGC pathways also appeared to contribute to the response.

  18. The Radiological Research Accelerator Facility

    Energy Technology Data Exchange (ETDEWEB)

    Hall, E.J.


    The Radiological Research Accelerator Facility (RARAF) is based on a 4-MV Van de Graaff accelerator, which is used to generate a variety of well-characterized radiation beams for research in radiobiology, radiological physics, and radiation chemistry. It is part of the Center for Radiological Research (CRR) -- formerly the Radiological Research Laboratory (RRL) -- of Columbia University, and its operation is supported as a National Facility by the US Department of Energy (DOE). As such, RARAF is available to all potential users on an equal basis, and scientists outside the CRR are encouraged to submit proposals for experiments at RARAF. The operation of the Van de Graaff is supported by the DOE, but the research projects themselves must be supported separately. Experiments performed from May 1991--April 1992 are described.

  19. The Radiological Research Accelerator Facility

    Energy Technology Data Exchange (ETDEWEB)

    Hall, E.J.; Marino, S.A.


    The Radiological Research Accelerator Facility (RARAF) is based on a 4-MV Van de Graaff accelerator, which is used to generate a variety of well-characterized radiation beams for research in radiobiology, radiological physics, and radiation chemistry. It is part of the Center for Radiological Research (CRR) - formerly the Radiological Research Laboratory of Columbia University, and its operation is supported as a National Facility by the US Department of Energy (DOE). As such, RARAF is available to all potential users on an equal basis and scientists outside the CRR are encouraged to submit proposals for experiments at RARAF. The operation of the Van de Graaff is supported by the DOE, but the research projects themselves must be supported separately. This report provides a listing and brief description of experiments performed at RARAF during the May 1, 1992 through April 30, 1993.

  20. Accelerating Expansion of the Universe

    CERN Document Server

    Chakraborty, Writambhara


    This thesis concentrates on the accelerated expansion of the Universe recently explored by measurements of redshift and luminosity-distance relations of type Ia Supernovae. We have considered a model of the universe filled with modified Chaplygin gas and barotropic fluid. The role of dynamical cosmological constant has been explored with Modified Chaplygin Gas as the background fluid. Various phenomenological models for \\Lambda have been studied in presence of the gravitational constant G to be constant or time dependent. A new form of the well known Chaplygin gas model has been presented by introducing inhomogeneity in the EOS. This model explains w=-1 crossing. An interaction of this model with the scalar field has also been investigated through a phenomenological coupling function. Tachyonic field has been depicted as dark energy model to represent the present acceleration of the Universe. A mixture of the tachyonic fluid has been considered with Generalized Chaplygin Gas to show the role of the later as a...

  1. History of hadron therapy accelerators. (United States)

    Degiovanni, Alberto; Amaldi, Ugo


    In the last 60 years, hadron therapy has made great advances passing from a stage of pure research to a well-established treatment modality for solid tumours. In this paper the history of hadron therapy accelerators is reviewed, starting from the first cyclotrons used in the thirties for neutron therapy and passing to more modern and flexible machines used nowadays. The technical developments have been accompanied by clinical studies that allowed the selection of the tumours which are more sensitive to this type of radiotherapy. This paper aims at giving a review of the origin and the present status of hadron therapy accelerators, describing the technological basis and the continuous development of this application to medicine of instruments developed for fundamental science. At the end the present challenges are reviewed.

  2. Hardware-Accelerated Simulated Radiography

    Energy Technology Data Exchange (ETDEWEB)

    Laney, D; Callahan, S; Max, N; Silva, C; Langer, S; Frank, R


    We present the application of hardware accelerated volume rendering algorithms to the simulation of radiographs as an aid to scientists designing experiments, validating simulation codes, and understanding experimental data. The techniques presented take advantage of 32-bit floating point texture capabilities to obtain solutions to the radiative transport equation for X-rays. The hardware accelerated solutions are accurate enough to enable scientists to explore the experimental design space with greater efficiency than the methods currently in use. An unsorted hexahedron projection algorithm is presented for curvilinear hexahedral meshes that produces simulated radiographs in the absorption-only regime. A sorted tetrahedral projection algorithm is presented that simulates radiographs of emissive materials. We apply the tetrahedral projection algorithm to the simulation of experimental diagnostics for inertial confinement fusion experiments on a laser at the University of Rochester.

  3. Self accelerating electron Airy beams

    CERN Document Server

    Voloch-Bloch, Noa; Lilach, Yigal; Gover, Avraham; Arie, Ady


    We report the first experimental generation and observation of Airy beams of free electrons. The electron Airy beams are generated by diffraction of electrons through a nanoscale hologram, that imprints a cubic phase modulation on the beams' transverse plane. We observed the spatial evolution dynamics of an arc-shaped, self accelerating and shape preserving electron Airy beams. We directly observed the ability of electrons to self-heal, restoring their original shape after passing an obstacle. This electromagnetic method opens up new avenues for steering electrons, like their photonic counterparts, since their wave packets can be imprinted with arbitrary shapes or trajectories. Furthermore, these beams can be easily manipulated using magnetic or electric potentials. It is also possible to efficiently self mix narrow beams having opposite signs of acceleration, hence obtaining a new type of electron interferometer.

  4. Accelerating optimization by tracing valley (United States)

    Li, Qing-Xiao; He, Rong-Qiang; Lu, Zhong-Yi


    We propose an algorithm to accelerate optimization when an objective function locally resembles a long narrow valley. In such a case, a conventional optimization algorithm usually wanders with too many tiny steps in the valley. The new algorithm approximates the valley bottom locally by a parabola that is obtained by fitting a set of successive points generated recently by a conventional optimization method. Then large steps are taken along the parabola, accompanied by fine adjustment to trace the valley bottom. The effectiveness of the new algorithm has been demonstrated by accelerating the Newton trust-region minimization method and the Levenberg-Marquardt method on the nonlinear fitting problem in exact diagonalization dynamical mean-field theory and on the classic minimization problem of the Rosenbrock's function. Many times speedup has been achieved for both problems, showing the high efficiency of the new algorithm.

  5. The US Muon Accelerator Program

    Energy Technology Data Exchange (ETDEWEB)

    Torun, Y.; /IIT, Chicago; Kirk, H.; /Brookhaven; Bross, A.; Geer, Steve; Shiltsev, Vladimir; /Fermilab; Zisman, M.; /LBL, Berkeley


    An accelerator complex that can produce ultra-intense beams of muons presents many opportunities to explore new physics. A facility of this type is unique in that, in a relatively straightforward way, it can present a physics program that can be staged and thus move forward incrementally, addressing exciting new physics at each step. At the request of the US Department of Energy's Office of High Energy Physics, the Neutrino Factory and Muon Collider Collaboration (NFMCC) and the Fermilab Muon Collider Task Force (MCTF) have recently submitted a proposal to create a Muon Accelerator Program that will have, as a primary goal, to deliver a Design Feasibility Study for an energy-frontier Muon Collider by the end of a 7 year R&D program. This paper presents a description of a Muon Collider facility and gives an overview of the proposal.

  6. Industrial Applications of Accelerator Technologies

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jaesang; Park, Jaewon; Lee, Chanyoung; and others


    PEFP(Proton Engineering Frontier Project) put its aim on development of high power linear proton accelerator and its beam applications. So, it has, since late 1990's, accumulated accelerator and ion source technologies, supplied beam utilization service to related industry. As of now, right after 10 year long project(PEFP), many of its low energy beam technologies seem to be successfully utilized for industrial purpose to meet the market needs, especially in improvement of production process and manufacturing performance, new substance development, etc. In this context, it is high time to carry out in-depth industrialization development on PEFP's retained ion beam technology prowess: To help them diffused profitable markets as soon as possible. So, in this work, through verification on the industrialization feasibility by experiments, it is going to get it started, with cooperation of participatory company, to enter into markets with developed technology and products.

  7. Particle Accelerators for PET radionuclides

    DEFF Research Database (Denmark)

    Jensen, Mikael


    The requirements set for particle accelerators for production of radioactive isotopes for PET can easily be derived from first principles. The simple general need is for proton beams with energy in the region 10–20 MeV and current 20–100 microAmps. This is most reliably and cost-effectively achie......The requirements set for particle accelerators for production of radioactive isotopes for PET can easily be derived from first principles. The simple general need is for proton beams with energy in the region 10–20 MeV and current 20–100 microAmps. This is most reliably and cost...... different manufacturers will be discussed the light of what is actually needed for a given PET site operation. Alternatives to the conventional cyclotron have been proposed and tested but have at present very limited use. These alternatives will be discussed, as well as the future possibilities of supplying...

  8. Observational Probes of Cosmic Acceleration

    CERN Document Server

    Weinberg, David H; Eisenstein, Daniel J; Hirata, Christopher; Riess, Adam G; Rozo, Eduardo


    The accelerating expansion of the universe is the most surprising cosmological discovery in many decades, implying that the universe is dominated by some form of "dark energy" with exotic physical properties, or that Einstein's theory of gravity breaks down on cosmological scales. The profound implications of cosmic acceleration have inspired ambitious experimental efforts to measure the history of expansion and growth of structure with percent-level precision or higher. We review in detail the four most well established methods for making such measurements: Type Ia supernovae, baryon acoustic oscillations (BAO), weak gravitational lensing, and galaxy clusters. We pay particular attention to the systematic uncertainties in these techniques and to strategies for controlling them at the level needed to exploit "Stage IV" dark energy facilities such as BigBOSS, LSST, Euclid, and WFIRST. We briefly review a number of other approaches including redshift-space distortions, the Alcock-Paczynski test, and direct meas...

  9. Greece welcomes CERN Accelerator School

    CERN Multimedia

    CAS School


    The CERN Accelerator School (CAS) and the University of the Aegean jointly organised a course on intermediate-level Accelerator Physics in Chios, Greece, from 19 to 30 September, 2011.   CAS Students pose for a group photo in Chios, Greece. This course followed the established format of the intermediate school, with lectures in the mornings and specialised courses in the afternoons. The latter provided “hands-on” education and experience in three topics: “RF Measurement Techniques”, “Beam Instrumentation and Diagnostics” and “Optics Design and Correction”.  Participants selected one of the three courses and followed the chosen topic throughout the school. Guided studies and tutorials on core subjects, seminars and a poster session completed the programme. An excursion included a visit to the Nea Moni monastery, a guided tour of two medieval villages, Pyrgi and Mesta, and finished with a typical Greek me...

  10. Industrial applications of electron accelerators

    CERN Document Server

    Cleland, M R


    This paper addresses the industrial applications of electron accelerators for modifying the physical, chemical or biological properties of materials and commercial products by treatment with ionizing radiation. Many beneficial effects can be obtained with these methods, which are known as radiation processing. The earliest practical applications occurred during the 1950s, and the business of radiation processing has been expanding since that time. The most prevalent applications are the modification of many different plastic and rubber products and the sterilization of single-use medical devices. Emerging applications are the pasteurization and preservation of foods and the treatment of toxic industrial wastes. Industrial accelerators can now provide electron energies greater than 10 MeV and average beam powers as high as 700 kW. The availability of high-energy, high-power electron beams is stimulating interest in the use of X-rays (bremsstrahlung) as an alternative to gamma rays from radioactive nuclides.

  11. Accelerating structure with linear excitation

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, J.; Srinivasan-Rao, T.


    The switched power linac (SPL) structures require a ring-shaped laser beam pulse of uniform intensity to avoid transverse field components of the accelerating field at the center. In order to also utilize the reflection of the outgoing EM wave, the switching element has to be very close to the outer edge of the structure to ensure nearly synchronous superposition at the beam hole with the original inward going wave. It is sometimes easier to produce linear (flat) laser beams, e.g., from powerful excimer lasers which have beams of rectangular cross section. Such flat beams could be used to excite linear photocathode switches or be used to produce flat electron beam pulses in electron sources. In this paper, an accelerator structure is proposed which may be considered a variant of the SPL disk structure, but could be used with linear beams. The structure utilizes a double parabolic horn. 8 refs., 9 figs.

  12. String worldsheet for accelerating quark (United States)

    Hubeny, Veronika E.; Semenoff, Gordon W.


    We consider the AdS bulk dual to an external massive quark in SYM following an arbitrary trajectory on Minkowski background. While a purely outgoing boundary condition on the gluonic field allows one to express the corresponding string worldsheet in a closed form, the setup has curious consequences. In particular, we argue that any quark whose trajectory on flat spacetime approaches that of a light ray in the remote past (as happens e.g. in the case of uniform acceleration) must necessarily be accompanied by an anti-quark. This is puzzling from the field theory standpoint, since one would expect that a sole quark following any timelike trajectory should be allowed. We explain the resolution in terms of boundary and initial conditions. We analyze the configuration in global AdS, which naturally suggests a modification to the boundary conditions allowing for a single accelerated quark without accompanying anti-quark. We contrast this resolution with earlier proposals.

  13. Radiolabelled D2 agonists as prolactinoma imaging agents

    Energy Technology Data Exchange (ETDEWEB)

    Otto, C.A.


    During the past year, further studies on mAChR were conducted. These studies included verification of the difference in pituitary distribution based on ligand charge. The pituitary localization of TRB. A neutral mAChR ligand, was verified. The lack of QNB blockade of TRB uptake was tested by blockage with scopolamine, another mAChR antagonist and by testing the effect in a different strain of rat. Neither scopolamine or change of rat strain had any effect. We concluded that TRB uptake in pituitary is not a receptor-mediated process. Further studies were conducted with an additional quaternized mAChR ligand: MQNB. Pituitary localization of MQNB, like MTRB, could be blocked by pretreatment with QNB. We have tentatively concluded that permanent charge on a mAChR antagonist changes the mechanism of uptake in the pituitary. Time course studies and the effects of DES on myocardial uptake are reported. A brief report on preliminary results of evaluation of quaternized mAChR ligands in the heart is included. In a limited series of such ligands, we have observed a single binding site and a difference in B{sub max} values: QNB competition studies yield larger B{sub max} values than studies with {sup 3}H-NMS. Progress in the synthesis of D{sub 2} agonists includes solving a synthetic problem and preparation of the cold'' analogue of N-0437 using procedures applicable to eventual synthesis with {sup 11}C-CH{sub 3}I. 2 refs., 5 figs., 1 tab.

  14. Accelerating Around an Unbanked Curve (United States)

    Mungan, Carl E.


    The December 2004 issue of TPT presented a problem concerning how a car should accelerate around an unbanked curve of constant radius r starting from rest if it is to avoid skidding. Interestingly enough, two solutions were proffered by readers.2 The purpose of this note is to compare and contrast the two approaches. Further experimental investigation of various turning strategies using a remote-controlled car and overhead video analysis could make for an interesting student project.

  15. Geometry for the accelerating universe

    CERN Document Server

    Punzi, R; Wohlfarth, M N R; Punzi, Raffaele; Schuller, Frederic P.; Wohlfarth, Mattias N.R.


    The Lorentzian spacetime metric is replaced by an area metric which naturally emerges as a generalized geometry in quantum string and gauge theory. Employing the area metric curvature scalar, the gravitational Einstein-Hilbert action is re-interpreted as dynamics for an area metric. Without the need for dark energy or fine-tuning, area metric cosmology explains the observed small acceleration of the late Universe.

  16. Accelerator x-ray sources

    CERN Document Server

    Talman, Richard


    This first book to cover in-depth the generation of x-rays in particle accelerators focuses on electron beams produced by means of the novel Energy Recovery Linac (ERL) technology. The resulting highly brilliant x-rays are at the centre of this monograph, which continues where other books on the market stop. Written primarily for general, high energy and radiation physicists, the systematic treatment adopted by the work makes it equally suitable as an advanced textbook for young researchers.

  17. Status of JAERI tandem accelerator

    Energy Technology Data Exchange (ETDEWEB)

    Yoshida, Tadashi; Kanda, Susumu; Takeuchi, Suehiro [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment] (and others)


    JAERI Tandem Accelerator had been operated approximately 230 days in fiscal year of 1999. Meanwhile, we had three times of maintenance period with vent. Total operation-times were 5273 hours. We could not carry out the experiment using rare gas, due to malfunction of the RF power supply for the ECR ion source. The type of the RF power supply is peculiar and it is impossible to get spare parts for repair. We are now investigating the backup RF power supply. The power supply for the magnet became unstable due to degradation of insulation in the shunt resistance, which is used for feedback stabilization. Stability was recovered after cleaning. The acrylic resin shaft was cracked. This cracks have a potential for severe accidents. So far bearing of the shaft has no problem. The reason of cracks may be self-destruction by charge accumulation in the shaft. JAERI Tandem Accelerator is approximately 20 years old. There appear requirements on the higher ion currents for additional ion species. Therefore, authors are investigating cost effective improvement plans of RFQ (Radio Frequency Quadra-pole) and IH type accelerator based on KEK (High Energy Accelerator Research Organization) R and D. As a whole, maintenance services for the control system are increasing due to some changes of computer programs. There are some difficulties to keep skilled personnel for facilities operation. Authors are gradually increasing hired personnel with contract from 1993. However, loads for JAERI permanent staffs are still heavy. It takes much longer time to educate skilled persons especially for safety. (Y. Tanaka)

  18. An accelerator worth fighting for

    CERN Multimedia


    Financial pressures from member states have upset the calculations of the European Laboratory for Particle Physics's (CERN) major accelerator, the Large Hadron Collider (LHC). Despite preference for domestic high energy programs, CERN members accord high priority to LHC physics. Converting to a global facility can help spread the high annual cost of subscription. But given the political realities, a revision of the LHC project appears more feasible. CERN's management needs to deploy its skills to overcome the financial obstacles to the facility.

  19. Symplectic maps for accelerator lattices

    Energy Technology Data Exchange (ETDEWEB)

    Warnock, R.L.; Ruth, R.; Gabella, W.


    We describe a method for numerical construction of a symplectic map for particle propagation in a general accelerator lattice. The generating function of the map is obtained by integrating the Hamilton-Jacobi equation as an initial-value problem on a finite time interval. Given the generating function, the map is put in explicit form by means of a Fourier inversion technique. We give an example which suggests that the method has promise. 9 refs., 9 figs.

  20. Self-accelerating Warped Braneworlds

    Energy Technology Data Exchange (ETDEWEB)

    Carena, Marcela; Lykken, Joseph; /Fermilab; Park, Minjoon; /UC, Davis; Santiago, Jose; /Fermilab


    Braneworld models with induced gravity have the potential to replace dark energy as the explanation for the current accelerating expansion of the Universe. The original model of Dvali, Gabadadze and Porrati (DGP) demonstrated the existence of a ''self-accelerating'' branch of background solutions, but suffered from the presence of ghosts. We present a new large class of braneworld models which generalize the DGP model. Our models have negative curvature in the bulk, allow a second brane, and have general brane tensions and localized curvature terms. We exhibit three different kinds of ghosts, associated to the graviton zero mode, the radion, and the longitudinal components of massive graviton modes. The latter two species occur in the DGP model, for negative and positive brane tension respectively. In our models, we find that the two kinds of DGP ghosts are tightly correlated with each other, but are not always linked to the feature of self-acceleration. Our models are a promising laboratory for understanding the origins and physical meaning of braneworld ghosts, and perhaps for eliminating them altogether.

  1. Time derivative of earthquake acceleration

    Institute of Scientific and Technical Information of China (English)

    Mai Tong; Guo-Quan Wang; George C.Lee


    Unlike acceleration, velocity, and displacement, the time derivative of acceleration (TDoA) of ground motion has not been extensively studied. In this paper, the basic characteristics of TDoA are evaluated based on records from the 1999Chi-Chi, earthquake (Mw 7.6) and one of its aftershocks (Mw 6.2). It is found that the maximum TDoA at a free-field station was over 31,200 crm/s3 (31.8 g/s); and the duration of "strong" TDoA, between the first and the last time points exceeding 2,000 cm/s3 (2 g/s), was almost one minute near the epicenter area. Since ground TDoA sensors are not commonly available,the time series are calculated by direct numerical differentiation of acceleration time series. Relative error analysis shows that the error is non-transitive and total error is within 4%. The density function of TDoA amplitude, frequency content and spatial distribution of peak ground jerk (PGJ) are evaluated. The study also includes examination of some TDoA responses from a seven-story building and comparison of ground TDoA with the limit TDoA used in the transportation industry for ride comfort. Some potential impacts of TDoA on humans have also been reviewed.

  2. Accelerated Hypertension after Venlafaxine Usage

    Directory of Open Access Journals (Sweden)

    Yüksel Kıvrak


    Full Text Available Venlafaxine is the first antidepressant that acts via inhibiting serotonin and noradrenaline reuptake. Hypertension is observed in doses exceeding 300 mg/day and is the most feared complication. We report a patient with accelerated hypertension after venlafaxine use observed at a dose of 150 mg/day. A 23-year-old patient with symptoms of insomnia, depression, anhedonia, fatigue admitted our clinic. Venlafaxine at a dose of 75 mg/day was initiated after he was diagnosed with major depressive disorder. After 5 months, venlafaxine dose was uptitrated to 150 mg/day due to inadequate response to drug. After using venlafaxine for ten months at the dose of 150 mg/day, he admitted our clinic with headache and epistaxis. He was hospitalized after his blood pressure was measured as 210/170 mmHg. No secondary causes for hypertension were found, and venlafaxine treatment was considered possible etiologic factor. After stopping venlafaxine treatment, his blood pressure was reverted back to normal limits. While mild elevation of blood pressure could be observed after venlafaxine treatment, this case shows that accelerated hypertension with a diastolic blood pressure rise above 120 mmHg could be observed at relatively low doses of venlafaxine. Close monitoring of blood pressure is necessary after initiation of treatment, as accelerated hypertension could cause endorgan damage with potentially catastrophic results.

  3. Compensation Techniques in Accelerator Physics

    Energy Technology Data Exchange (ETDEWEB)

    Sayed, Hisham Kamal [Old Dominion Univ., Norfolk, VA (United States)


    Accelerator physics is one of the most diverse multidisciplinary fields of physics, wherein the dynamics of particle beams is studied. It takes more than the understanding of basic electromagnetic interactions to be able to predict the beam dynamics, and to be able to develop new techniques to produce, maintain, and deliver high quality beams for different applications. In this work, some basic theory regarding particle beam dynamics in accelerators will be presented. This basic theory, along with applying state of the art techniques in beam dynamics will be used in this dissertation to study and solve accelerator physics problems. Two problems involving compensation are studied in the context of the MEIC (Medium Energy Electron Ion Collider) project at Jefferson Laboratory. Several chromaticity (the energy dependence of the particle tune) compensation methods are evaluated numerically and deployed in a figure eight ring designed for the electrons in the collider. Furthermore, transverse coupling optics have been developed to compensate the coupling introduced by the spin rotators in the MEIC electron ring design.

  4. Analytical tools in accelerator physics

    Energy Technology Data Exchange (ETDEWEB)

    Litvinenko, V.N.


    This paper is a sub-set of my lectures presented in the Accelerator Physics course (USPAS, Santa Rosa, California, January 14-25, 2008). It is based on my notes I wrote during period from 1976 to 1979 in Novosibirsk. Only few copies (in Russian) were distributed to my colleagues in Novosibirsk Institute of Nuclear Physics. The goal of these notes is a complete description starting from the arbitrary reference orbit, explicit expressions for 4-potential and accelerator Hamiltonian and finishing with parameterization with action and angle variables. To a large degree follow logic developed in Theory of Cyclic Particle Accelerators by A.A.Kolmensky and A.N.Lebedev [Kolomensky], but going beyond the book in a number of directions. One of unusual feature is these notes use of matrix function and Sylvester formula for calculating matrices of arbitrary elements. Teaching the USPAS course motivated me to translate significant part of my notes into the English. I also included some introductory materials following Classical Theory of Fields by L.D. Landau and E.M. Liftsitz [Landau]. A large number of short notes covering various techniques are placed in the Appendices.

  5. Injector Design for Advanced Accelerators (United States)

    Henestroza, Enrique; Faltens, A.


    Accelerator designs intended to provide acceleration at a much lower cost per Joule than the ILSE or ELISE designs are under study. For these designs, which typically have many beams, an injector of significantly lower cost is needed. A goal, which from our design appears to be achievable, is to reduce the transverse dimension to half that of the 2 MeV, 800 mA ILSE injector(E. Henestroza, ``Injectors for Heavy Ion Fusion", Proc. of the 11th International Wkshp. on Laser Interaction and Related Plasma Phenomena, 1993.) while generating about the same current. A single channel of a lower cost injector includes an 800 kV column, accelerating a 700 mA beam extracted from a potassium source of 4 cm radius by a 120 kV electrode. The beam passes into a superconducting 7 T solenoid of 15 cm aperture and 15 cm length. This high-field solenoid provides the focusing needed for a small beam without increasing the electric field gradient. The injector and its matching section, also designed, fit within a 12 cm radius, which is small enough to allow construction of attractive multi-beam injectors. We will present solutions for the generation and transport of 700 mA potassium beams of up to 1.6 MeV within the same transverse constraint.

  6. Low voltage electron beam accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Ochi, Masafumi [Iwasaki Electric Co., Ltd., Tokyo (Japan)


    Widely used electron accelerators in industries are the electron beams with acceleration voltage at 300 kV or less. The typical examples are shown on manufactures in Japan, equipment configuration, operation, determination of process parameters, and basic maintenance requirement of the electron beam processors. New electron beam processors with acceleration voltage around 100 kV were introduced maintaining the relatively high dose speed capability of around 10,000 kGy x mpm at production by ESI (Energy Science Inc. USA, Iwasaki Electric Group). The application field like printing and coating for packaging requires treating thickness of 30 micron or less. It does not require high voltage over 110 kV. Also recently developed is a miniature bulb type electron beam tube with energy less than 60 kV. The new application area for this new electron beam tube is being searched. The drive force of this technology to spread in the industries would be further development of new application, process and market as well as the price reduction of the equipment, upon which further acknowledgement and acceptance of the technology to societies and industries would entirely depend. (Y. Tanaka)

  7. On the solutions to accelerating cosmologies

    CERN Document Server

    Ito, M


    Motivated by recent accelerating cosmological model, we derive the solutions to vacuum Einstein equation in $(d+1)$-dimensional Minkowski space with $n$-dimensional hyperbolic manifold. The conditions of accelerating expansion are given in such a set up.

  8. Symposium report on frontier applications of accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Parsa, Z. [ed.


    This report contains viewgraph material on the following topics: Electron-Positron Linear Colliders; Unconventional Colliders; Prospects for UVFEL; Accelerator Based Intense Spallation; Neutron Sources; and B Physics at Hadron Accelerators with RHIC as an Example.

  9. Snowmass 2013 Computing Frontier: Accelerator Science

    CERN Document Server

    Spentzouris, P; Joshi, C; Amundson, J; An, W; Bruhwiler, D L; Cary, J R; Cowan, B; Decyk, V K; Esarey, E; Fonseca, R A; Friedman, A; Geddes, C G R; Grote, D P; Kourbanis, I; Leemans, W P; Lu, W; Mori, W B; Ng, C; Qiang, Ji; Roberts, T; Ryne, R D; Schroeder, C B; Silva, L O; Tsung, F S; Vay, J -L; Vieira, J


    This is the working summary of the Accelerator Science working group of the Computing Frontier of the Snowmass meeting 2013. It summarizes the computing requirements to support accelerator technology in both Energy and Intensity Frontiers.

  10. Accelerated Cure Project for Multiple Sclerosis (United States)

    ... main content Accelerating research toward a cure for multiple sclerosis Home Contact Us Search form Search Connect Volunteer ... is to accelerate efforts toward a cure for multiple sclerosis by rapidly advancing research that determines its causes ...

  11. Berkeley Lab Laser Accelerator (BELLA) facility (United States)

    Federal Laboratory Consortium — The Berkeley Lab Laser Accelerator (BELLA) facility (formerly LOASIS) develops advanced accelerators and radiation sources. High gradient (1-100 GV/m) laser-plasma...

  12. A Critical Theory Perspective on Accelerated Learning. (United States)

    Brookfield, Stephen D.


    Critically analyzes accelerated learning using concepts from Herbert Marcuse (rebellious subjectivity) and Erich Fromm (automaton conformity). Concludes that, by providing distance and separation, accelerated learning has more potential to stimulate critical autonomous thought. (SK)

  13. Tuning and Matching of Constant Impedance Travelling Wave Accelerating Structure

    Institute of Scientific and Technical Information of China (English)

    YANG; Jing-he; ZHU; Zhi-bin; WU; Qing-feng; ZENG; Zi-qiang; WANG; Xiu-long; ZHOU; Wen-zhen


    As the penetration depth of electron accelerated by 10MeV electron irradiating accelerator is deep,and the accelerator has broad application prospects.The performance of the accelerator is influenced,to a great extent,by the traveling wave accelerating tube,which is the core component of the accelerator.To develop the accelerator

  14. Resolving beam transport problems in electrostatic accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Larson, J.D.


    A review is given of problem areas in beam transmission which are frequently encountered during the design, operation and upgrading of electrostatic accelerators. Examples are provided of analytic procedures that clarify accelerator ion optics and lead to more effective beam transport. Suggestions are made for evaluating accelerator design with the goal of improved performance.

  15. Gonadotropin-releasing hormone agonist use in men without a cancer registry diagnosis of prostate cancer

    Directory of Open Access Journals (Sweden)

    Kuo Yong-fang


    Full Text Available Abstract Background Use of gonadotropin-releasing hormone (GnRH agonists has become popular for virtually all stages of prostate cancer. We hypothesized that some men receive these agents after only a limited work-up for their cancer. Such cases may be missed by tumor registries, leading to underestimates of the total extent of GnRH agonist use. Methods We used linked Surveillance, Epidemiology and End-Results (SEER-Medicare data from 1993 through 2001 to identify GnRH agonist use in men with either a diagnosis of prostate cancer registered in SEER, or with a diagnosis of prostate cancer based only on Medicare claims (from the 5% control sample of Medicare beneficiaries residing in SEER areas without a registered diagnosis of cancer. The proportion of incident GnRH agonist users without a registry diagnosis of prostate cancer was calculated. Factors associated with lack of a registry diagnosis were examined in multivariable analyses. Results Of incident GnRH agonist users, 8.9% had no diagnosis of prostate cancer registered in SEER. In a multivariable logistic regression model, lack of a registry diagnosis of prostate cancer in GnRH agonist users was significantly more likely with increasing comorbidity, whereas it was less likely in men who had undergone either inpatient admission or procedures such as radical prostatectomy, prostate biopsy, or transurethral resection of the prostate. Conclusion Reliance solely on tumor registry data may underestimate the rate of GnRH agonist use in men with prostate cancer.

  16. Desensitization of functional µ-opioid receptors increases agonist off-rate. (United States)

    Williams, John T


    Desensitization of µ-opioid receptors (MORs) develops over 5-15 minutes after the application of some, but not all, opioid agonists and lasts for tens of minutes after agonist removal. The decrease in function is receptor selective (homologous) and could result from 1) a reduction in receptor number or 2) a decrease in receptor coupling. The present investigation used photolysis of two caged opioid ligands to examine the kinetics of MOR-induced potassium conductance before and after MOR desensitization. Photolysis of a caged antagonist, carboxynitroveratryl-naloxone (caged naloxone), blocked the current induced by a series of agonists, and the time constant of decline was significantly decreased after desensitization. The increase in the rate of current decay was not observed after partial blockade of receptors with the irreversible antagonist, β-chlornaltrexamine (β-CNA). The time constant of current decay after desensitization was never more rapid than 1 second, suggesting an increased agonist off-rate rather than an increase in the rate of channel closure downstream of the receptor. The rate of G protein-coupled K(+) channel (GIRK) current activation was examined using photolysis of a caged agonist, carboxynitrobenzyl-tyrosine-[Leu(5)]-enkephalin. After acute desensitization or partial irreversible block of MORs with β-CNA, there was an increase in the time it took to reach a peak current. The decrease in the rate of agonist-induced GIRK conductance was receptor selective and dependent on receptor number. The results indicate that opioid receptor desensitization reduced the number of functional receptor and that the remaining active receptors have a reduced agonist affinity.

  17. The Effect of Coasting on Intracytoplasmic Sperm Injection Outcome in Antagonist and Agonist Cycle

    Directory of Open Access Journals (Sweden)

    İltemir Duvan Z.Candan,


    Full Text Available Background Coasting can reduce the ovarian hyperstimulation syndrome (OHSS risk in ovulation induction cycles before intracytoplasmic sperm injection (ICSI. This study aimed to investigate the effect of gonadotropin-releasing hormone (GnRH agonist and GnRH antagonist protocols to controlled ovarian hyperstimulation (COH cycles with coasting on the parameters of ICSI cycles and the outcome. Materials and Methods In a retrospective cohort study, 117 ICSI cycles were per- formed and coasting was applied due to hyperresponse, between 2006 and 2011. The ICSI outcomes after coasting were then compared between the GnRH agonist group (n=91 and the GnRH antagonist group (n=26. Results The duration of induction and the total consumption of gonadotropins were found to be similar. Estradiol (E2 levels on human chorionic gonadotropin (hCG day were found higher in the agonist group. Coasting days were similar when the two groups were compared. The number of mature oocytes and the fertilization rates were similar in both groups; however, the number of grade 1 (G1 embryos and the number of transferred embryos were higher in the agonist group. Implantation rates were significantly higher in the antagonist group compared to the agonist group. Pregnancy rates/embryo transfer rates were higher in the antagonist group; however, this difference was not statistically significant (32.8% for agonist group vs. 39.1% for antagonist group, P>0.05. Conclusion The present study showed that applying GnRH-agonist and GnRH-antago- nist protocols to coasted cycles did not result in any differences in cycle parameters and clinical pregnancy rates.

  18. Ascorbic acid enables reversible dopamine receptor /sup 3/H-agonist binding

    Energy Technology Data Exchange (ETDEWEB)

    Leff, S.; Sibley, D.R.; Hamblin, M.; Creese, I.


    The effects of ascorbic acid on dopaminergic /sup 3/H-agonist receptor binding were studied in membrane homogenates of bovine anterior pituitary and caudate, and rat striatum. In all tissues virtually no stereospecific binding (defined using 1uM (+)butaclamol) of the /sup 3/H-agonists N-propylnorapomorphine (NPA), apomorphine, or dopamine could be demonstrated in the absence of ascorbic acid. Although levels of total /sup 3/H-agonist binding were three to five times greater in the absence than in the presence of 0.1% ascorbic acid, the increased binding was entirely non-stereospecific. Greater amounts of dopamine-inhibitable /sup 3/H-NPA binding could be demonstrated in the absence of 0.1% ascorbic acid, but this measure of ''specific binding'' was demonstrated not to represent dopamine receptor binding since several other catecholamines and catechol were equipotent with dopamine and more potent than the dopamine agonist (+/-)amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene (ADTN) in inhibiting this binding. High levels of dopamine-displaceable /sup 3/H-agonist binding were detected in fresh and boiled homogenates of cerebellum, an area of brain which receives no dopaminergic innervation, further demonstrating the non-specific nature of /sup 3/H-agonist binding in the absence of ascorbic acid. These studies emphasize that under typical assay conditions ascorbic acid is required in order to demonstrate reversible and specific /sup 3/H-agonist binding to dopamine receptors.

  19. A molecular characterization of the agonist binding site of a nematode cys-loop GABA receptor (United States)

    Kaji, Mark D; Kwaka, Ariel; Callanan, Micah K; Nusrat, Humza; Desaulniers, Jean-Paul; Forrester, Sean G


    Background and Purpose Cys-loop GABA receptors represent important targets for human chemotherapeutics and insecticides and are potential targets for novel anthelmintics (nematicides). However, compared with insect and mammalian receptors, little is known regarding the pharmacological characteristics of nematode Cys-loop GABA receptors. Here we have investigated the agonist binding site of the Cys-loop GABA receptor UNC-49 (Hco-UNC-49) from the parasitic nematode Haemonchus contortus. Experimental Approach We used two-electrode voltage-clamp electrophysiology to measure channel activation by classical GABA receptor agonists on Hco-UNC-49 expressed in Xenopus laevis oocytes, along with site-directed mutagenesis and in silico homology modelling. Key Results The sulphonated molecules P4S and taurine had no effect on Hco-UNC-49. Other classical Cys-loop GABAA receptor agonists tested on the Hco-UNC-49B/C heteromeric channel had a rank order efficacy of GABA > trans-4-aminocrotonic acid > isoguvacine > imidazole-4-acetic acid (IMA) > (R)-(−)-4-amino-3-hydroxybutyric acid [R(−)-GABOB] > (S)-(+)-4-amino-3-hydroxybutyric acid [S(+)-GABOB] > guanidinoacetic acid > isonipecotic acid > 5-aminovaleric acid (DAVA) (partial agonist) > β-alanine (partial agonist). In silico ligand docking revealed some variation in binding between agonists. Mutagenesis of a key serine residue in binding loop C to threonine had minimal effects on GABA and IMA but significantly increased the maximal response to DAVA and decreased twofold the EC50 for R(−)- and S(+)-GABOB. Conclusions and Implications The pharmacological profile of Hco-UNC-49 differed from that of vertebrate Cys-loop GABA receptors and insect resistance to dieldrin receptors, suggesting differences in the agonist binding pocket. These findings could be exploited to develop new drugs that specifically target GABA receptors of parasitic nematodes. PMID:25850584

  20. Effects of PPARg agonist pioglitazone on rat hepatic fibrosis

    Institute of Scientific and Technical Information of China (English)

    Guang-Jin Yuan; Ming-Liang Zhang; Zuo-Jiong Gong


    dramatically compared with model group.CONCLUSION: PPARγ agonist pioglitazone greatly retards the progression of rat hepatic fibrosis induced by CCl4through inhibition of HSC activation and amelioration of hepatocyte necroinflammation in rats.

  1. Selective imidazoline agonist moxonidine in obese hypertensive patients. (United States)

    Sanjuliani, A F; de Abreu, V G; Francischetti, E A


    Obesity is the major risk factor for the development of hypertension. This association accentuates the risk of cardiovascular disease, as it is frequently accompanied by the components of the metabolic syndrome. This randomised open parallel study evaluated the chronic effects of moxonidine--a selective imidazoline receptor agonist--on blood pressure, plasma catecholamines, leptin, insulin and components of the metabolic syndrome in obese hypertensives. Amlodipine was used as the control drug. Our results showed that moxonidine and amlodipine significantly reduced blood pressure when measured using the oscillometric method and 24-hour blood pressure monitoring. Moxonidine therapy decreased systolic blood pressure from 160.4 +/- 2.4 to 142.1 +/- 3.3 mmHg (p < 0.005) and diastolic blood pressure from 102.4 +/- 1.3 to 89.7 +/- 1.6 mmHg (p < 0.005) after 24 weeks of treatment. Moxonidine administration reduced the supine arterial plasma levels of adrenaline from 63.2 +/- 6.6 to 49.0 +/- 6.7 pg/ml (p < 0.005), the supine arterial plasma levels of noradrenaline from 187.9 +/- 10.7 to 149.7 +/- 13.2 pg/ml (p < 0.01) and the orthostatic venous plasma levels of noradrenaline from 258.6 +/- 25.0 to 190.3 +/- 16.4 pg/ml (p = 0.03). Those variables were not changed by amlodipine. The plasma levels of leptin and insulin 120 min after a glucose load decreased after moxonidine administration from 27.2 +/- 3.5 to 22.6 +/- 2.9 pg/ml (p < 0.05) and from 139.7 +/- 31.2 to 76.0 +/- 15.2 U/ml (p < 0.05), respectively. Amlodipine, however, did not modify those variables. This study showed a comparable reduction in blood pressure with both antihypertensive drugs. Moxonidine decreased sympathetic nervous activity, improved insulin resistance and reduced the plasma levels of leptin.

  2. High-energy cosmic-ray acceleration

    CERN Document Server

    Bustamante, M; de Paula, W; Duarte Chavez, J A; Gago, A M; Hakobyan, H; Jez, P; Monroy Montañez, J A; Ortiz Velasquez, A; Padilla Cabal, F; Pino Rozas, M; Rodriguez Patarroyo, D J; Romeo, G L; Saldaña-Salazar , U J; Velasquez, M; von Steinkirch, M


    We briefly review the basics of ultrahigh-energy cosmic-ray acceleration. The Hillas criterion is introduced as a geometrical criterion that must be fulfilled by potential acceleration sites, and energy losses are taken into account in order to obtain a more realistic scenario. The different available acceleration mechanisms are presented, with special emphasis on Fermi shock acceleration and its prediction of a power-law cosmic-ray energy spectrum. We conclude that first-order Fermi acceleration, though not entirely satisfactory, is the most promising mechanism for explaining the ultra-high-energy cosmic-ray flux.

  3. Health physics practices at research accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, R.H.


    A review is given of the uses of particle accelerators in health physics, the text being a short course given at the Health Physics Society Ninth Midyear Topical Symposium in February, 1976. Topics discussed include: (1) the radiation environment of high energy accelerators; (2) dosimetry at research accelerators; (3) shielding; (4) induced activity; (5) environmental impact of high energy accelerators; (6) population dose equivalent calculation; and (7) the application of the ''as low as practicable concept'' at accelerators. (PMA)

  4. Accelerator Technology Division progress report, FY 1992

    Energy Technology Data Exchange (ETDEWEB)

    Schriber, S.O.; Hardekopf, R.A.; Heighway, E.A.


    This report briefly discusses the following topics: The Ground Test Accelerator Program; Defense Free-Electron Lasers; AXY Programs; A Next Generation High-Power Neutron-Scattering Facility; JAERI OMEGA Project and Intense Neutron Sources for Materials Testing; Advanced Free-Electron Laser Initiative; Superconducting Supercollider; The High-Power Microwave (HPM) Program; Neutral Particle Beam (NPB) Power Systems Highlights; Industrial Partnering; Accelerator Physics and Special Projects; Magnetic Optics and Beam Diagnostics; Accelerator Design and Engineering; Radio-Frequency Technology; Accelerator Theory and Free-Electron Laser Technology; Accelerator Controls and Automation; Very High-Power Microwave Sources and Effects; and GTA Installation, Commissioning, and Operations.

  5. Deuterium accelerator experiments for APT.

    Energy Technology Data Exchange (ETDEWEB)

    Causey, Rion A. (Sandia National Laboratories, Livermore, CA); Hertz, Kristin L. (Sandia National Laboratories, Livermore, CA); Cowgill, Donald F. (Sandia National Laboratories, Livermore, CA)


    Sandia National Laboratories in California initiated an experimental program to determine whether tritium retention in the tube walls and permeation through the tubes into the surrounding coolant water would be a problem for the Accelerator Production of Tritium (APT), and to find ways to mitigate the problem, if it existed. Significant holdup in the tube walls would limit the ability of APT to meet its production goals, and high levels of permeation would require a costly cleanup system for the cooling water. To simulate tritium implantation, a 200 keV accelerator was used to implant deuterium into Al 6061-T and SS3 16L samples at temperatures and particle fluxes appropriate for APT, for times varying between one week and five months. The implanted samples were characterized to determine the deuterium retention and Permeation. During the implantation, the D(d,p)T nuclear reaction was used to monitor the build-up of deuterium in the implant region of the samples. These experiments increased in sophistication, from mono-energetic deuteron implants to multi-energetic deuteron and proton implants, to more accurately reproduce the conditions expected in APT. Micron-thick copper, nickel, and anodized aluminum coatings were applied to the front surface of the samples (inside of the APT walls) in an attempt to lower retention and permeation. The reduction in both retention and permeation produced by the nickel coatings, and the ability to apply them to the inside of the APT tubes, indicate that both nickel-coated Al 6061-T6 and nickel-coated SS3 16L tubes would be effective for use in APT. The results of this work were submitted to the Accelerator Production of Tritium project in document number TPO-E29-Z-TNS-X-00050, APT-MP-01-17.

  6. Accelerated Adaptive MGS Phase Retrieval (United States)

    Lam, Raymond K.; Ohara, Catherine M.; Green, Joseph J.; Bikkannavar, Siddarayappa A.; Basinger, Scott A.; Redding, David C.; Shi, Fang


    The Modified Gerchberg-Saxton (MGS) algorithm is an image-based wavefront-sensing method that can turn any science instrument focal plane into a wavefront sensor. MGS characterizes optical systems by estimating the wavefront errors in the exit pupil using only intensity images of a star or other point source of light. This innovative implementation of MGS significantly accelerates the MGS phase retrieval algorithm by using stream-processing hardware on conventional graphics cards. Stream processing is a relatively new, yet powerful, paradigm to allow parallel processing of certain applications that apply single instructions to multiple data (SIMD). These stream processors are designed specifically to support large-scale parallel computing on a single graphics chip. Computationally intensive algorithms, such as the Fast Fourier Transform (FFT), are particularly well suited for this computing environment. This high-speed version of MGS exploits commercially available hardware to accomplish the same objective in a fraction of the original time. The exploit involves performing matrix calculations in nVidia graphic cards. The graphical processor unit (GPU) is hardware that is specialized for computationally intensive, highly parallel computation. From the software perspective, a parallel programming model is used, called CUDA, to transparently scale multicore parallelism in hardware. This technology gives computationally intensive applications access to the processing power of the nVidia GPUs through a C/C++ programming interface. The AAMGS (Accelerated Adaptive MGS) software takes advantage of these advanced technologies, to accelerate the optical phase error characterization. With a single PC that contains four nVidia GTX-280 graphic cards, the new implementation can process four images simultaneously to produce a JWST (James Webb Space Telescope) wavefront measurement 60 times faster than the previous code.

  7. Microwave View on Particle Acceleration in Flares

    CERN Document Server

    Fleishman, Gregory D


    The thermal-to-nonthermal partition was found to vary greatly from one flare to another resulting in a broad variety of cases from 'heating without acceleration' to 'acceleration without heating'. Recent analysis of microwave data of these differing cases suggests that a similar acceleration mechanism, forming a power-law nonthermal tail up to a few MeV or even higher, operates in all the cases. However, the level of this nonthermal spectrum compared to the original thermal distribution differs significantly from one case to another, implying a highly different thermal-to-nonthermal energy partition in various cases. This further requires a specific mechanism capable of extracting the charged particles from the thermal pool and supplying them to a bulk acceleration process to operate in flares \\textit{in addition} to the bulk acceleration process itself, which, in contrast, efficiently accelerates the seed particles, while cannot accelerate the thermal particles. Within this 'microwave' view on the flare ener...

  8. Multi-beam linear accelerator EVT

    Energy Technology Data Exchange (ETDEWEB)

    Teryaev, Vladimir E., E-mail: [Omega-P, Inc., New Haven, CT 06510 (United States); Kazakov, Sergey Yu. [Fermilab, Batavia, IL 60510 (United States); Hirshfield, Jay L. [Omega-P, Inc., New Haven, CT 06510 (United States); Yale University, New Haven, CT 06511 (United States)


    A novel electron multi-beam accelerator is presented. The accelerator, short-named EVT (Electron Voltage Transformer) belongs to the class of two-beam accelerators. It combines an RF generator and essentially an accelerator within the same vacuum envelope. Drive beam-lets and an accelerated beam are modulated in RF modulators and then bunches pass into an accelerating structure, comprising uncoupled with each other and inductive tuned cavities, where the energy transfer from the drive beams to the accelerated beam occurs. A phasing of bunches is solved by choice correspond distances between gaps of the adjacent cavities. Preliminary results of numerical simulations and the initial specification of EVT operating in S-band, with a 60 kV gun and generating a 2.7 A, 1.1 MV beam at its output is presented. A relatively high efficiency of 67% and high design average power suggest that EVT can find its use in industrial applications.

  9. Cosmic-ray acceleration in young protostars

    CERN Document Server

    Padovani, Marco; Marcowith, Alexandre; Ferrière, Katia


    The main signature of the interaction between cosmic rays and molecular clouds is the high ionisation degree. This decreases towards the densest parts of a cloud, where star formation is expected, because of energy losses and magnetic effects. However recent observations hint to high levels of ionisation in protostellar systems, therefore leading to an apparent contradiction that could be explained by the presence of energetic particles accelerated within young protostars. Our modelling consists of a set of conditions that has to be satisfied in order to have an efficient particle acceleration through the diffusive shock acceleration mechanism. We find that jet shocks can be strong accelerators of protons which can be boosted up to relativistic energies. Another possibly efficient acceleration site is located at protostellar surfaces, where shocks caused by impacting material during the collapse phase are strong enough to accelerate protons. Our results demonstrate the possibility of accelerating particles du...

  10. Introduction to Particle Acceleration in the Cosmos (United States)

    Gallagher, D. L.; Horwitz, J. L.; Perez, J.; Quenby, J.


    Accelerated charged particles have been used on Earth since 1930 to explore the very essence of matter, for industrial applications, and for medical treatments. Throughout the universe nature employs a dizzying array of acceleration processes to produce particles spanning twenty orders of magnitude in energy range, while shaping our cosmic environment. Here, we introduce and review the basic physical processes causing particle acceleration, in astrophysical plasmas from geospace to the outer reaches of the cosmos. These processes are chiefly divided into four categories: adiabatic and other forms of non-stochastic acceleration, magnetic energy storage and stochastic acceleration, shock acceleration, and plasma wave and turbulent acceleration. The purpose of this introduction is to set the stage and context for the individual papers comprising this monograph.

  11. Future HEP Accelerators: The US Perspective

    CERN Document Server

    Bhat, Pushpalatha


    Accelerator technology has advanced tremendously since the introduction of accelerators in the 1930s, and particle accelerators have become indispensable instruments in high energy physics (HEP) research to probe Nature at smaller and smaller distances. At present, accelerator facilities can be classified into Energy Frontier colliders that enable direct discoveries and studies of high mass scale particles and Intensity Frontier accelerators for exploration of extremely rare processes, usually at relatively low energies. The near term strategies of the global energy frontier particle physics community are centered on fully exploiting the physics potential of the Large Hadron Collider (LHC) at CERN through its high-luminosity upgrade (HL-LHC), while the intensity frontier HEP research is focused on studies of neutrinos at the MW-scale beam power accelerator facilities, such as Fermilab Main Injector with the planned PIP-II SRF linac project. A number of next generation accelerator facilities have been proposed...

  12. Electron Acceleration by Transient Ion Foreshock Phenomena (United States)

    Wilson, L. B., III; Turner, D. L.


    Particle acceleration is a topic of considerable interest in space, laboratory, and astrophysical plasmas as it is a fundamental physical process to all areas of physics. Recent THEMIS [e.g., Turner et al., 2014] and Wind [e.g., Wilson et al., 2013] observations have found evidence for strong particle acceleration at macro- and meso-scale structures and/or pulsations called transient ion foreshock phenomena (TIFP). Ion acceleration has been extensively studied, but electron acceleration has received less attention. Electron acceleration can arise from fundamentally different processes than those affecting ions due to differences in their gyroradii. Electron acceleration is ubiquitous, occurring in the solar corona (e.g., solar flares), magnetic reconnection, at shocks, astrophysical plasmas, etc. We present new results analyzing the dependencies of electron acceleration on the properties of TIFP observed by the THEMIS spacecraft.

  13. ACFA and IPAC announce accelerator prizes

    CERN Multimedia

    CERN Bulletin


    Steve Myers, CERN's Director for Accelerators and Technology. The Asian Committee for Future Accelerators (ACFA) has joined forces with the first International Particle Accelerator Conference, IPAC’10, to award prizes for outstanding work in the field of accelerators. The conference replaces the regional conferences of the Americas, Europe and Asia and will be hosted by the three regions on a rotational basis (see CERN Courier). The ACFA/IPAC’10 Prizes Selection Committee, chaired by Won Namkung of Pohang Accelerator Laboratory, decided on the prizes and the names of the winners at a meeting on 20 January. The awards will be made during IPAC’10, which will be held in Kyoto on 23-28 May. Jie Wei. (Courtesy Tsinghua University.) Steve Myers, Director for Accelerators and Technology at CERN, receives an Achievement Prize for Outstanding Work in the Accelerator Field with no Age Limit “for his numerous outstanding contributions to the design, construction, commissio...

  14. Plasma Channel Guided Laser Wakefield Accelerator

    CERN Document Server

    Geddes, C G


    High quality electron beams (several 109 electrons above 80 MeV energy with percent energy spread and low divergence) have been produced for the first time in a compact, high gradient, all-optical laser accelerator by extending the interaction distance using a pre-formed plasma density channel to guide the drive laser pulse. Laser-driven accelerators, in which particles are accelerated by the electric field of a plasma wave (wake) driven by the radiation pressure of an intense laser, have over the past decade demonstrated accelerating fields thousands of times greater than those achievable in conventional radio-frequency accelerators. This has spurred interest in them as compact next- generation sources of energetic electrons and radiation. To date, however, acceleration distances have been severely limited by the lack of a controllable method for extending the propagation distance of the focused laser pulse. The ensuing short acceleration distance resulted in low-energy beams with 100 percent electron energy...

  15. Technical report on the accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Bex, L. [ed.


    GANIL operation and the technical studies performed in 1994 are described. The milestones for 1994 are: SISSI (Source d`Ions Secondaires a Supraconducteurs Intense) has been in operation and used for secondary beam production with four different primary beams. The 100 kV platform for beam injection in the CO1 has been in operation for production of metallic beams which demand is increasing. Finally the SPIRAL project (Systeme de Production d`Ions Radioactifs Acceleres en Ligne) is in progress. In late 1994 the civil work has started in view of the installation of the machine in the north part of the GANIL machine building. (K.A.). 48 refs.


    Directory of Open Access Journals (Sweden)

    Drakulić Danica


    Full Text Available The wurk points to the importance of ICT (Information Communication Technologies, as one of the main trajectories by which advanced economies have come to the high dynamism and richness. How do the performsnces of these technological changes, determined mainly by ICT, exert influences on the economicgrowth or, in general, on production results at the aggregate, macroeconomic level. The U.S.A. supremacy in this field has faced challenges. It loses tempo, and the EU countries, after the multi-decade syndrome of technological catching up to U.S.A., go through faster into the future, giving an accelerating tone to the technological race.

  17. Flow accelerated organic coating degradation (United States)

    Zhou, Qixin

    Applying organic coatings is a common and the most cost effective way to protect metallic objects and structures from corrosion. Water entry into coating-metal interface is usually the main cause for the deterioration of organic coatings, which leads to coating delamination and underfilm corrosion. Recently, flowing fluids over sample surface have received attention due to their capability to accelerate material degradation. A plethora of works has focused on the flow induced metal corrosion, while few studies have investigated the flow accelerated organic coating degradation. Flowing fluids above coating surface affect corrosion by enhancing the water transport and abrading the surface due to fluid shear. Hence, it is of great importance to understand the influence of flowing fluids on the degradation of corrosion protective organic coatings. In this study, a pigmented marine coating and several clear coatings were exposed to the laminar flow and stationary immersion. The laminar flow was pressure driven and confined in a flow channel. A 3.5 wt% sodium chloride solution and pure water was employed as the working fluid with a variety of flow rates. The corrosion protective properties of organic coatings were monitored inline by Electrochemical Impedance Spectroscopy (EIS) measurement. Equivalent circuit models were employed to interpret the EIS spectra. The time evolution of coating resistance and capacitance obtained from the model was studied to demonstrate the coating degradation. Thickness, gloss, and other topography characterizations were conducted to facilitate the assessment of the corrosion. The working fluids were characterized by Fourier Transform Infrared Spectrometer (FTIR) and conductivity measurement. The influence of flow rate, fluid shear, fluid composition, and other effects in the coating degradation were investigated. We conclude that flowing fluid on the coating surface accelerates the transport of water, oxygen, and ions into the coating, as

  18. AESS: Accelerated Exact Stochastic Simulation (United States)

    Jenkins, David D.; Peterson, Gregory D.


    The Stochastic Simulation Algorithm (SSA) developed by Gillespie provides a powerful mechanism for exploring the behavior of chemical systems with small species populations or with important noise contributions. Gene circuit simulations for systems biology commonly employ the SSA method, as do ecological applications. This algorithm tends to be computationally expensive, so researchers seek an efficient implementation of SSA. In this program package, the Accelerated Exact Stochastic Simulation Algorithm (AESS) contains optimized implementations of Gillespie's SSA that improve the performance of individual simulation runs or ensembles of simulations used for sweeping parameters or to provide statistically significant results. Program summaryProgram title: AESS Catalogue identifier: AEJW_v1_0 Program summary URL: Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: University of Tennessee copyright agreement No. of lines in distributed program, including test data, etc.: 10 861 No. of bytes in distributed program, including test data, etc.: 394 631 Distribution format: tar.gz Programming language: C for processors, CUDA for NVIDIA GPUs Computer: Developed and tested on various x86 computers and NVIDIA C1060 Tesla and GTX 480 Fermi GPUs. The system targets x86 workstations, optionally with multicore processors or NVIDIA GPUs as accelerators. Operating system: Tested under Ubuntu Linux OS and CentOS 5.5 Linux OS Classification: 3, 16.12 Nature of problem: Simulation of chemical systems, particularly with low species populations, can be accurately performed using Gillespie's method of stochastic simulation. Numerous variations on the original stochastic simulation algorithm have been developed, including approaches that produce results with statistics that exactly match the chemical master equation (CME) as well as other approaches that approximate the CME. Solution

  19. Decay of Quantum Accelerator Modes

    CERN Document Server

    Sheinman, M; Guarneri, I; Rebuzzini, L; Fishman, Shmuel; Guarneri, Italo; Rebuzzini, Laura; Sheinman, Michael


    Experimentally observable Quantum Accelerator Modes are used as a test case for the study of some general aspects of quantum decay from classical stable islands immersed in a chaotic sea. The modes are shown to correspond to metastable states, analogous to the Wannier-Stark resonances. Different regimes of tunneling, marked by different quantitative dependence of the lifetimes on 1/hbar, are identified, depending on the resolution of KAM substructures that is achieved on the scale of hbar. The theory of Resonance Assisted Tunneling introduced by Brodier, Schlagheck, and Ullmo [9], is revisited, and found to well describe decay whenever applicable.

  20. Gauge fields in accelerated frames

    CERN Document Server

    Lenz, F


    Quantized fields in accelerated frames (Rindler spaces) with emphasis on gauge fields are investigated. Important properties of the dynamics in Rindler spaces are shown to follow from the scale invariance of the corresponding Hamiltonians. Origin and consequences of this extraordinary property of Hamiltonians in Rindler spaces are elucidated. Characteristics of the Unruh radiation, the appearance of a photon condensate and the interaction energy of vector and scalar static charges are discussed and implications for Yang-Mills theories and QCD in Rindler spaces are indicated.

  1. Community Petascale Project for Accelerator Science and Simulation: Advancing Computational Science for Future Accelerators and Accelerator Technologies

    Energy Technology Data Exchange (ETDEWEB)

    Spentzouris, P.; /Fermilab; Cary, J.; /Tech-X, Boulder; McInnes, L.C.; /Argonne; Mori, W.; /UCLA; Ng, C.; /SLAC; Ng, E.; Ryne, R.; /LBL, Berkeley


    The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessary accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R&D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors. ComPASS is in the first year of executing its plan to develop the next-generation HPC accelerator modeling tools. ComPASS aims to develop an integrated simulation environment that will utilize existing and new accelerator physics modules with petascale capabilities, by employing modern computing and solver technologies. The ComPASS vision is to deliver to accelerator scientists a virtual accelerator and virtual prototyping modeling environment, with the necessary multiphysics, multiscale capabilities. The plan for this development includes delivering accelerator modeling applications appropriate for each stage of the ComPASS software evolution. Such applications are already being used to address challenging problems in accelerator design and optimization. The ComPASS organization


    Energy Technology Data Exchange (ETDEWEB)

    Shiltsev, Vladimir [Fermilab


    The 2014 P5 report indicated the accelerator-based neutrino and rare decay physics research as a centrepiece of the US domestic HEP program at Fermilab. Operation, upgrade and development of the accelerators for the near- term and longer-term particle physics program at the Intensity Frontier face formidable challenges. Here we discuss key elements of the accelerator physics and technology R&D program toward future multi-MW proton accelerators and present its status and progress. INTENSITY FRONTIER ACCELERATORS

  3. Quantitative encoding of a partial agonist effect on individual opioid receptors by multi-site phosphorylation and threshold detection


    Lau, Elaine K.; Trester-Zedlitz, Michelle; Trinidad, Jonathan C.; Kotowski, Sarah J.; Krutchinsky, Andrew N.; Burlingame, Alma L; von Zastrow, Mark


    Many drugs act as partial agonists of seven-transmembrane signaling receptors when compared to endogenous ligands. Partial agonism is well described as a 'macroscopic' property manifest at the level of physiological systems or cell populations, but it is not known whether partial agonists encode discrete regulatory information at the 'microscopic' level of individual receptors. We addressed this question by focusing on morphine, a partial agonist drug for µ-type opioid peptide receptors, and ...

  4. Imidazopyridine CB2 agonists: optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy. (United States)

    Trotter, B Wesley; Nanda, Kausik K; Burgey, Christopher S; Potteiger, Craig M; Deng, James Z; Green, Ahren I; Hartnett, John C; Kett, Nathan R; Wu, Zhicai; Henze, Darrell A; Della Penna, Kimberly; Desai, Reshma; Leitl, Michael D; Lemaire, Wei; White, Rebecca B; Yeh, Suzie; Urban, Mark O; Kane, Stefanie A; Hartman, George D; Bilodeau, Mark T


    A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.

  5. Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay.

    Directory of Open Access Journals (Sweden)

    Yiyi Sun

    Full Text Available Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (--arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases.

  6. Structure-Activity Relationship and Signaling of New Chimeric CXCR4 Agonists. (United States)

    Mona, Christine E; Besserer-Offroy, Élie; Cabana, Jérôme; Lefrançois, Marilou; Boulais, Philip E; Lefebvre, Marie-Reine; Leduc, Richard; Lavigne, Pierre; Heveker, Nikolaus; Marsault, Éric; Escher, Emanuel


    The CXCR4 receptor binds with meaningful affinities only CXCL12 and synthetic antagonists/inverse agonists. We recently described high affinity synthetic agonists for this chemokine receptor, obtained by grafting the CXCL12 N-terminus onto the inverse agonist T140. While those chimeric molecules behave as agonists for CXCR4, their binding and activation mode are unknown. The present SAR of those CXCL12-oligopeptide grafts reveals the key determinants involved in CXCR4 activation. Position 3 (Val) controls affinity, whereas position 7 (Tyr) acts as an efficacy switch. Chimeric molecules bearing aromatic residues in position 3 possess high binding affinities for CXCR4 and are Gαi full agonists with robust chemotactic properties. Fine-tuning of electron-poor aromatic rings in position 7 enhances receptor activation. To rationalize these results, a homology model of a receptor-ligand complex was built using the published crystal structures of CXCR4. Molecular dynamics simulations reveal further details accounting for the observed SAR for this series.

  7. Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor. (United States)

    Scott, Caitlin E; Ahn, Kwang H; Graf, Steven T; Goddard, William A; Kendall, Debra A; Abrol, Ravinder


    Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci. 2013 , 22 , 101 - 113 ; Ahn, K. H. et al. Proteins 2013 , 81 , 1304 - 1317] are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives. This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions. We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization. This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.

  8. Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis. (United States)

    Fairbanks, Carolyn A; Stone, Laura S; Wilcox, George L


    Endogenous, descending noradrenergic fibers impose analgesic control over spinal afferent circuitry mediating the rostrad transmission of pain signals. These fibers target alpha 2 adrenergic receptors (alpha(2)ARs) on both primary afferent terminals and secondary neurons, and their activation mediates substantial inhibitory control over this transmission, rivaling that of opioid receptors which share a similar pattern of distribution. The terminals of primary afferent nociceptive neurons and secondary spinal dorsal horn neurons express alpha(2A)AR and alpha(2C)AR subtypes, respectively. Spinal delivery of these agents serves to reduce their side effects, which are mediated largely at supraspinal sites, by concentrating the drugs at the spinal level. Targeting these spinal alpha(2)ARs with one of five selective therapeutic agonists, clonidine, dexmedetomidine, brimonidine, ST91 and moxonidine, produces significant antinociception that can work in concert with opioid agonists to yield synergistic antinociception. Application of several genetically altered mouse lines had facilitated identification of the primary receptor subtypes that likely mediate the antinociceptive effects of these agents. This review provides first an anatomical description of the localization of the three subtypes in the central nervous system, second a detailed account of the pharmacological history of each of the six primary agonists, and finally a comprehensive report of the specific interactions of other GPCR agonists with each of the six principal alpha(2)AR agonists featured.

  9. Effects of glucagon-like peptide-1 receptor agonists on renal function

    Institute of Scientific and Technical Information of China (English)

    Theodosios; D; Filippatos; Moses; S; Elisaf


    Glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of case reports show an association of GLP-1receptor agonists,mainly exenatide,with the development of acute kidney injury.The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function,their use in subjects with chronic renal failure and their possible association with acute kidney injury.Based on the current evidence,exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease.Liraglutide is not eliminated by renal or hepatic mechanisms,but it should be used with caution since there are only limited data in patients with renal or hepatic impairment.There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect.Additionally,there is evidence that GLP-1 receptor agonists influence water and electrolyte balance.These effects may represent new ways to improve or even prevent diabetic nephropathy.

  10. Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors. (United States)

    Koshimizu, Taka-Aki; Kashiwazaki, Aki; Taniguchi, Junichi


    Reducing Na(+) in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na(+)-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na(+) sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na(+) increased cell surface [(3)H]AVP binding and decreased receptor internalization. Substitution of Na(+) by Cs(+) or NH4(+) inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na(+) over Cs(+). Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations.

  11. Cocaine synergism with alpha agonists in rat aorta: computational analysis reveals an action beyond reuptake inhibition* (United States)

    Lamarre, Neil S.; Raffa, Robert B.; Tallarida, Ronald J.


    BACKGROUND Cocaine has long been known to increase blood pressure, but the degree and mechanism of vasoconstricting action remain poorly understood. Here we examine the interaction between cocaine and alpha-adrenoceptor agonists, with the action of reuptake inhibition minimized. METHODS Cocaine was administered to isolated rings of rat thoracic aorta, alone and in combination with three different adrenoceptor agonists: phenylephrine, methoxamine, and norepinephrine. Synergy analysis begins with the predicted additive effect of the combination of two agonists, based upon dose equivalence theory. This case where one agonist (cocaine) has no effect when administered alone requires only a t-test to demonstrate that a departure from additivity has occurred. RESULTS At doses where cocaine alone produced no vasoconstriction, it potentiated the vasoconstriction produced by all three alpha agonists, a clear indication of synergism between cocaine and these agents. Higher doses of cocaine in combination with alpha adrenoceptor agents gave an inverted-U shaped (hormetic) dose-effect curve, i.e., dose-related relaxation at higher doses. The hormetic dose-effect relation was analyzed using computational methodology based on dose equivalence to derive the unknown second component of action that causes relaxation. CONCLUSIONS Cocaine exhibits both vasoconstricting and vasorelaxant effects. This relaxing component, possibly related to activation of myosin light chain phosphatase, was quantified as a dose-effect curve. Most important is the synergism between cocaine and alpha-adrenoceptor stimulation which cannot be explained as an action due to reuptake inhibition, and has not been previously described. PMID:23270987

  12. Reconstitution of high-affinity opioid agonist binding in brain membranes

    Energy Technology Data Exchange (ETDEWEB)

    Remmers, A.E.; Medzihradsky, F. (Univ. of Michigan Medical School, Ann Arbor (United States))


    In synaptosomal membranes from rat brain cortex, the {mu} selective agonist ({sup 3}H)dihydromorphine in the absence of sodium, and the nonselective antagonist ({sup 3}H)naltrexone in the presence of sodium, bound to two populations of opioid receptor sites with K{sub d} values of 0.69 and 8.7 nM for dihydromorphine, and 0.34 and 5.5 nM for naltrexone. The addition of 5 {mu}M guanosine 5{prime}-({gamma}-thio)triphosphate (GTP({gamma}S)) strongly reduced high-affinity agonist but not antagonist binding. Exposure of the membranes to high pH reduced the number of GTP({gamma}-{sup 35}S) binding sites by 90% and low K{sub m}, opioid-sensitive GTPase activity by 95%. In these membranes, high-affinity agonist binding was abolished and modulation of residual binding by GTP({gamma}S) was diminished. Alkali treatment of the glioma cell membranes prior to fusion inhibited most of the low K{sub m} GTPase activity and prevented the reconstitution of agonist binding. The results show that high-affinity opioid agonist binding reflects the ligand-occupied receptor - guanine nucleotide binding protein complex.

  13. Evolution of the Bifunctional Lead μ Agonist / δ Antagonist Containing the Dmt-Tic Opioid Pharmacophore. (United States)

    Balboni, Gianfranco; Salvadori, Severo; Trapella, Claudio; Knapp, Brian I; Bidlack, Jean M; Lazarus, Lawrence H; Peng, Xuemei; Neumeyer, John L


    Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH(3), partially -NO(2), inactive -NH(2)) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA(2) = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.

  14. Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γ Agonists

    Directory of Open Access Journals (Sweden)

    Martin B. Oleksiewicz


    Full Text Available Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology. Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

  15. Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver. (United States)

    Zhu, Yun-Xia; Zhang, Ming-Liang; Zhong, Yuan; Wang, Chen; Jia, Wei-Ping


    Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARγ and PPARα, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARγ or PPARα agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis.

  16. Normalization of Gravitational Acceleration Models (United States)

    Eckman, Randy A.; Brown, Aaron J.; Adamo, Daniel R.


    Unlike the uniform density spherical shell approximations of Newton, the con- sequence of spaceflight in the real universe is that gravitational fields are sensitive to the nonsphericity of their generating central bodies. The gravitational potential of a nonspherical central body is typically resolved using spherical harmonic approximations. However, attempting to directly calculate the spherical harmonic approximations results in at least two singularities which must be removed in order to generalize the method and solve for any possible orbit, including polar orbits. Three unique algorithms have been developed to eliminate these singularities by Samuel Pines [1], Bill Lear [2], and Robert Gottlieb [3]. This paper documents the methodical normalization of two1 of the three known formulations for singularity-free gravitational acceleration (namely, the Lear [2] and Gottlieb [3] algorithms) and formulates a general method for defining normalization parameters used to generate normalized Legendre Polynomials and ALFs for any algorithm. A treatment of the conventional formulation of the gravitational potential and acceleration is also provided, in addition to a brief overview of the philosophical differences between the three known singularity-free algorithms.

  17. GPU Accelerated Vector Median Filter (United States)

    Aras, Rifat; Shen, Yuzhong


    Noise reduction is an important step for most image processing tasks. For three channel color images, a widely used technique is vector median filter in which color values of pixels are treated as 3-component vectors. Vector median filters are computationally expensive; for a window size of n x n, each of the n(sup 2) vectors has to be compared with other n(sup 2) - 1 vectors in distances. General purpose computation on graphics processing units (GPUs) is the paradigm of utilizing high-performance many-core GPU architectures for computation tasks that are normally handled by CPUs. In this work. NVIDIA's Compute Unified Device Architecture (CUDA) paradigm is used to accelerate vector median filtering. which has to the best of our knowledge never been done before. The performance of GPU accelerated vector median filter is compared to that of the CPU and MPI-based versions for different image and window sizes, Initial findings of the study showed 100x improvement of performance of vector median filter implementation on GPUs over CPU implementations and further speed-up is expected after more extensive optimizations of the GPU algorithm .

  18. Ponderomotive Acceleration in Coronal Loops

    CERN Document Server

    Dahlburg, R B; Taylor, B D; Obenschain, K


    Ponderomotive acceleration has been asserted to be a cause of the First Ionization Potential (FIP) effect, the by now well known enhancement in abundance by a factor of 3-4 over photospheric values of elements in the solar corona with FIP less than about 10 eV. It is shown here by means of numerical simulations that ponderomotive acceleration occurs in solar coronal loops, with the appropriate magnitude and direction, as a "byproduct" of coronal heating. The numerical simulations are performed with the HYPERION code, which solves the fully compressible three-dimensional magnetohydrodynamic equations including nonlinear thermal conduction and optically thin radiation. Numerical simulations of a coronal loops with an axial magnetic field from 0.005 Teslas to 0.02 Teslas and lengths from 25000 km to 75000 km are presented. In the simulations the footpoints of the axial loop magnetic field are convected by random, large-scale motions. There is a continuous formation and dissipation of field-aligned current sheets...

  19. High Temperature Superconductor Accelerator Magnets

    CERN Document Server

    AUTHOR|(CDS)2079328; de Rijk, Gijs; Dhalle, Marc


    For future particle accelerators bending dipoles are considered with magnetic fields exceeding $20T$. This can only be achieved using high temperature superconductors (HTS). These exhibit different properties from classical low temperature superconductors and still require significant research and development before they can be applied in a practical accelerator magnet. In order to study HTS in detail, a five tesla demonstrator magnet named Feather-M2 is designed and constructed. The magnet is based on ReBCO coated conductor, which is assembled into a $10kA$ class Roebel cable. A new and optimized Aligned Block layout is used, which takes advantage of the anisotropy of the conductor. This is achieved by providing local alignment of the Roebel cable in the coil windings with the magnetic field lines. A new Network Model capable of analyzing transient electro-magnetic and thermal phenomena in coated conductor cables and coils is developed. This model is necessary to solve critical issues in coated conductor ac...

  20. Winter therapy for the accelerators

    CERN Multimedia

    Corinne Pralavorio


    Hundreds of people are hard at work during the year-end technical stop as all the accelerators are undergoing maintenance, renovation and upgrade operations in parallel.   The new beam absorber on its way to Point 2 before being lowered into the LHC tunnel for installation. The accelerator teams didn’t waste any time before starting their annual winter rejuvenation programme over the winter. At the end of November, as the LHC ion run was beginning, work got under way on the PS Booster, where operation had already stopped. On 14 December, once the whole complex had been shut down, the technical teams turned their attention to the other injectors and the LHC. The year-end technical stop (YETS) provides an opportunity to carry out maintenance work on equipment and repair any damage as well as to upgrade the machines for the upcoming runs. Numerous work projects are carried out simultaneously, so good coordination is crucial. Marzia Bernardini's team in the Enginee...

  1. Identification of PPARgamma partial agonists of natural origin (I: development of a virtual screening procedure and in vitro validation.

    Directory of Open Access Journals (Sweden)

    Laura Guasch

    Full Text Available BACKGROUND: Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARγ partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARγ partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARγ partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARγ partial agonists: they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPARγ partial agonists.

  2. Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner. (United States)

    Blume, Lawrence C; Leone-Kabler, Sandra; Luessen, Deborah J; Marrs, Glen S; Lyons, Erica; Bass, Caroline E; Chen, Rong; Selley, Dana E; Howlett, Allyn C


    Cannabinoid receptor interacting protein 1a (CRIP1a) is a CB1 receptor (CB1 R) distal C-terminus-associated protein that modulates CB1 R signaling via G proteins, and CB1 R down-regulation but not desensitization (Blume et al. [2015] Cell Signal., 27, 716-726; Smith et al. [2015] Mol. Pharmacol., 87, 747-765). In this study, we determined the involvement of CRIP1a in CB1 R plasma membrane trafficking. To follow the effects of agonists and antagonists on cell surface CB1 Rs, we utilized the genetically homogeneous cloned neuronal cell line N18TG2, which endogenously expresses both CB1 R and CRIP1a, and exhibits a well-characterized endocannabinoid signaling system. We developed stable CRIP1a-over-expressing and CRIP1a-siRNA-silenced knockdown clones to investigate gene dose effects of CRIP1a on CB1 R plasma membrane expression. Results indicate that CP55940 or WIN55212-2 (10 nM, 5 min) reduced cell surface CB1 R by a dynamin- and clathrin-dependent process, and this was attenuated by CRIP1a over-expression. CP55940-mediated cell surface CB1 R loss was followed by a cycloheximide-sensitive recovery of surface receptors (30-120 min), suggesting the requirement for new protein synthesis. In contrast, WIN55212-2-mediated cell surface CB1 Rs recovered only in CRIP1a knockdown cells. Changes in CRIP1a expression levels did not affect a transient rimonabant (10 nM)-mediated increase in cell surface CB1 Rs, which is postulated to be as a result of rimonabant effects on 'non-agonist-driven' internalization. These studies demonstrate a novel role for CRIP1a in agonist-driven CB1 R cell surface regulation postulated to occur by two mechanisms: 1) attenuating internalization that is agonist-mediated, but not that in the absence of exogenous agonists, and 2) biased agonist-dependent trafficking of de novo synthesized receptor to the cell surface.

  3. Radiative damping in plasma-based accelerators (United States)

    Kostyukov, I. Yu.; Nerush, E. N.; Litvak, A. G.


    The electrons accelerated in a plasma-based accelerator undergo betatron oscillations and emit synchrotron radiation. The energy loss to synchrotron radiation may seriously affect electron acceleration. The electron dynamics under combined influence of the constant accelerating force and the classical radiation reaction force is studied. It is shown that electron acceleration cannot be limited by radiation reaction. If initially the accelerating force was stronger than the radiation reaction force, then the electron acceleration is unlimited. Otherwise the electron is decelerated by radiative damping up to a certain instant of time and then accelerated without limits. It is shown that regardless of the initial conditions the infinite-time asymptotic behavior of an electron is governed by a self-similar solution providing that the radiative damping becomes exactly equal to 2/3 of the accelerating force. The relative energy spread induced by the radiative damping decreases with time in the infinite-time limit. The multistage schemes operating in the asymptotic acceleration regime when electron dynamics is determined by the radiation reaction are discussed.

  4. Conception design of helium ion FFAG accelerator with induction accelerating cavity

    Institute of Scientific and Technical Information of China (English)

    LUO Huan-Li; XU Yu-Cun; WANG Xiang-Qi; XU Hong-Liang


    In the recent decades of particle accelerator R&D area,the fixed field alternating gradient (FFAG) accelerator has become a highlight for some advantages of its higher beam intensity and lower cost,although there are still some technical challenges.In this paper,the FFAG accelerator is adopted to accelerate a helium ion beam on the one hand for the study of helium embrittlement on fusion reactor envelope material and on the other hand for promoting the conception research and design of the FFAG accelerator and exploring the possibility of developing high power FFAG accelerators.The conventional period focusing unit of the helium ion FFAG accelerator and threedimensional model of the large aperture combinatorial magnet by OPERA-TOSCA are given.For low energy and low revolution frequency,induction acceleration is proposed to replace conventional radio frequency (RF) acceleration for the helium ion FFAG accelerator,which avoids the potential breakdown of the acceleration field caused by the wake field and improves the acceleration repetition frequency to gain higher beam intensity.The main parameters and three-dimensional model of induction cavity are given.Two special constraint waveforms are proposed to refrain from particle accelerating time slip (AT) caused by accelerating voltage drop of flat top and energy deviation.The particle longitudinal motion in two waveforms is simulated.

  5. The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives

    DEFF Research Database (Denmark)

    Humaidan, Peter; Papanikolaou, E G; Kyrou, D;


    is the use of GnRH agonist (GnRHa) which reduces or even prevents ovarian hyperstimulation syndrome (OHSS). Interestingly, the current regimens of luteal support after HCG triggering are not sufficient to secure the early implanting embryo after GnRHa triggering. This review discusses the luteal...... phase - the phase after egg transfer - necessitating hormonal support with vaginally applied progesterone to obtain ongoing pregnancies. With the introduction of the gonadotrophin-releasing hormone (GnRH) antagonist protocol (short protocol) it became possible to perform final oocyte maturation...... with a GnRH agonist instead of human chorionic gonadotrophin (HCG). The first studies applying this concept, however, showed a very poor pregnancy rate, despite standard luteal-phase support with progesterone. This review discusses the reason for the poor results and the newest studies, using GnRH agonist...

  6. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists. (United States)

    Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Beneton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodeme, Edwige; Grillot, Didier; Martres, Paul


    Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat).

  7. 2-Thiazolylethylamine, a selective histamine H1 agonist, decreases seizure susceptibility in mice. (United States)

    Yokoyama, H; Onodera, K; Iinuma, K; Watanabe, T


    The effects of intracerebroventricular (ICV) administration of histamine and its selective agonists on electrically and pentylenetetrazole-induced convulsions in mice were studied. The ICV administration of histamine decreased seizure susceptibility on electrically and pentylenetetrazole-induced convulsions significantly and dose-dependently. The inhibitory effects of histamine were well antagonized by centrally acting histamine H1 antagonists such as pyrilamine (or mepyramine) and ketotifen, but not by a peripherally acting histamine H1 antagonist, astemizole, or a centrally acting H2 antagonist, zolantidine. The ICV administration of 2-thiazolylethylamine, a selective histamine H1 agonist, also decreased seizure susceptibility, which could be antagonized by centrally acting histamine H1 antagonists, whereas dimaprit, a selective histamine H2 agonist, did not affect seizure susceptibility. These findings strengthened the idea that the central histaminergic neuron system plays an inhibitory role in convulsions.

  8. Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands. (United States)

    Vardanyan, Ruben; Kumirov, Vlad K; Nichol, Gary S; Davis, Peg; Liktor-Busa, Erika; Rankin, David; Varga, Eva; Vanderah, Todd; Porreca, Frank; Lai, Josephine; Hruby, Victor J


    Newly designed bivalent ligands-opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials-carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds-amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited μ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.

  9. beta2 adrenergic agonists in acute lung injury? The heart of the matter. (United States)

    Lee, Jae W


    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of beta2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to increase the resolution of pulmonary edema. However, the results of clinical trials of beta agonist therapy for ALI/ARDS have been conflicting in terms of benefit. In the previous issue of Critical Care, Briot and colleagues present evidence that may help clarify the inconsistent results. The authors demonstrate that, in oleic acid lung injury in dogs, the inotropic effect of beta agonists may recruit damaged pulmonary capillaries, leading to increased lung endothelial permeability.

  10. Small-molecule agonists for the glucagon-like peptide 1 receptor

    DEFF Research Database (Denmark)

    Knudsen, Lotte Bjerre; Kiel, Dan; Teng, Min;


    described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor...... and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also......The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been...

  11. Oxidation of nutrients in bull calves treated with beta-adrenergic agonists

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G


    Oxidation of protein (OXP), carbohydrate (OXCHO) and fat (OXF) was investigated with 12 growing bulls treated with beta-agonist (L-644, 969) during two 6 weeks trials (Section A and B) at a mean live weight of 195 and 335 kg. Heat production and nutrient oxidation was calculated from gas exchange......, with CO2 reduced for CO2 from fermentation processes, and nitrogen excretion in urine. The beta-agonist had no effect on the level of rumen fermentation as indicated by the same methane production for control and treated animals. Heat Production (HE, RQx) increased by the treatment of beta......-agonist corresponding to the increment in the protein retention. OXP/HE,RQx was reduced to about 10% in treated animals, indicating that in order to supply amino acids for an increased protein deposition oxidation of protein is decreased. OXF/HE,RQx were markedly higher in treated animals, but as indicated by the same...

  12. Xamoterol, a new selective beta-1-adrenoceptor partial agonist, in the treatment of postural hypotension

    DEFF Research Database (Denmark)

    Mehlsen, J; Trap-Jensen, J


    Three patients severely disabled from postural hypotension were treated with xamoterol, a selective beta-1-adrenoceptor antagonist with a high degree of partial agonist activity. Oral treatment (200 mg b.i.d.) was chosen on the basis of the effects of acute intravenous administration of xamoterol...... and pindolol, a non-selective beta-adrenoceptor antagonist with partial agonist activity. In these patients pindolol had a predominantly antagonist effect, whereas xamoterol had a predominantly agonist effect after intravenous administration. Oral treatment was carried out with placebo control in a single......, supine). During the placebo period (2 weeks) heart rate decreased to pretreatment levels and mean blood pressure was reduced by only 14 mmHg. The patients reported substantial improvement in their condition during active medication. Xamoterol seems to be a useful alternative in the treatment of postural...

  13. An aryloxypropanolamine hβ3-adrenoceptor agonist as bladder smooth muscle relaxant. (United States)

    Tasler, Stefan; Baumgartner, Roland; Behr-Roussel, Delphine; Oger-Roussel, Stephanie; Gorny, Diane; Giuliano, Francois; Ney, Peter


    The relaxant effect of an aryloxypropanolamine β3-adrenoceptor agonist on carbachol pre-contracted human detrusor muscle strips was evaluated and compared with literature results from reference compounds of similar mode of action, including mirabegron. A significant relaxation was observed for rac-4-{2-hydroxy-3-[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino]propoxy}-2-(hydroxymethyl)phenol which was similar to that exerted by mirabegron. In order to allow for a thorough discussion of results in comparison to reference compounds, their affinity, selectivity and efficacy as hβ3-AR agonists have been evaluated and discussed thoroughly. A ranking of hβ3-AR agonists by relative efficacy resulted in the closest analogy to the order of relaxation potential, with only the relaxant effect of mirabegron not reflecting its excellent relative efficacy as such.

  14. Metabotropic glutamate receptor agonists potentiate a slow afterdepolarization in CNS neurons (United States)

    Zheng, F.; Gallagher, J. P.


    We have previously reported that, in the rat dorsolateral septal nucleus (DLSN), metabotropic glutamate receptor (met-GluR) agonists evoked a slow depolarization accompanied by an increase in membrane conductance and burst firing. We have speculated that the burst firing elicited by met-GluR agonists may be due to activation or enhancement of a non-specific cation current, which exists in some DLSN neurons. Now we report that a slow afterdepolarization (sADP) mediated by a non-specific cation current was potentiated by both 1S,3R-ACPD and quisqualate. In addition, met-GluR agonists unmask a sADP in DLSN neurons which did not show a sADP under control conditions. Our data suggest that a non-specific cation current can be potentiated by activation of the met-GluR.

  15. New 1,4-dihydropyridines endowed with NO-donor and calcium channel agonist properties. (United States)

    Visentin, Sonja; Rolando, Barbara; Di Stilo, Antonella; Fruttero, Roberta; Novara, Monica; Carbone, Emilio; Roussel, Christian; Vanthuyne, Nicolas; Gasco, Alberto


    A new series of calcium channel agonists structurally related to Bay K8644, containing NO donor furoxans and the related furazans unable to release NO, is described. The racemic mixtures were studied for their action on L-type Ca(2+) channels expressed in cultured rat insulinoma RINm5F cells. All the products proved to be potent calcium channel agonists. All the racemic mixtures, with the only exception of the carbamoyl derivatives 9, 12 endowed with scanty solubility, were separated by chiral chromatography into the corresponding enantiomers; the (+) enantiomers were found to be potent agonists while the (-) ones were feeble antagonists. The racemic mixtures were also assessed for their positive inotropic activity on electrically stimulated rat papillary muscle and for their ability to increase Ca(2+) entry into the vascular smooth muscle of rat aorta strips. The cyanofuroxan 8 proved to be an interesting product with dual Ca(2+)-dependent positive inotropic and NO-dependent vasodilating activity.

  16. Nitric oxide donor beta2-agonists: furoxan derivatives containing the fenoterol moiety and related furazans. (United States)

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


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

  17. Commnity Petascale Project for Accelerator Science And Simulation: Advancing Computational Science for Future Accelerators And Accelerator Technologies

    Energy Technology Data Exchange (ETDEWEB)

    Spentzouris, Panagiotis; /Fermilab; Cary, John; /Tech-X, Boulder; Mcinnes, Lois Curfman; /Argonne; Mori, Warren; /UCLA; Ng, Cho; /SLAC; Ng, Esmond; Ryne, Robert; /LBL, Berkeley


    The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessary accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R&D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors.

  18. Inhibitory effects of peroxisome proliferator-activated receptor γ agonists on collagen IV production in podocytes. (United States)

    Li, Yanjiao; Shen, Yachen; Li, Min; Su, Dongming; Xu, Weifeng; Liang, Xiubin; Li, Rongshan


    Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have beneficial effects on the kidney diseases through preventing microalbuminuria and glomerulosclerosis. However, the mechanisms underlying these effects remain to be fully understood. In this study, we investigate the effects of PPAR-γ agonist, rosiglitazone (Rosi) and pioglitazone (Pio), on collagen IV production in mouse podocytes. The endogenous expression of PPAR-γ was found in the primary podocytes and can be upregulated by Rosi and Pio, respectively, detected by RT-PCR and Western blot. PPAR-γ agonist markedly blunted the increasing of collagen IV expression and extraction in podocytes induced by TGF-β. In contrast, adding PPAR-γ antagonist, GW9662, to podocytes largely prevented the inhibition of collagen IV expression from Pio treatment. Our data also showed that phosphorylation of Smad2/3 enhanced by TGF-β in a time-dependent manner was significantly attenuated by adding Pio. The promoter region of collagen IV gene contains one putative consensus sequence of Smad-binding element (SBE) by promoter analysis, Rosi and Pio significantly ameliorated TGF-β-induced SBE4-luciferase activity. In conclusion, PPAR-γ activation by its agonist, Rosi or Pio, in vitro directly inhibits collagen IV expression and synthesis in primary mouse podocytes. The suppression of collagen IV production was related to the inhibition of TGF-β-driven phosphorylation of Smad2/3 and decreased response activity of SBEs of collagen IV in PPAR-γ agonist-treated mouse podocytes. This represents a novel mechanistic support regarding PPAR-γ agonists as podocyte protective agents.

  19. Pungency of TRPV1 agonists is directly correlated with kinetics of receptor activation and lipophilicity. (United States)

    Ursu, Daniel; Knopp, Kelly; Beattie, Ruth E; Liu, Bin; Sher, Emanuele


    TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In vivo activation of TRPV1 receptors by natural agonists like capsaicin is associated with a sharp and burning pain, frequently described as pungency. To elucidate the mechanisms underlying pungency we investigated a series of TRPV1 agonists that included both pungent and non-pungent compounds covering a large range of potencies. Pungency of capsaicin, piperine, arvanil, olvanil, RTX (resiniferatoxin) and SDZ-249665 was evaluated in vivo, by determining the increase in the number of eye wipes caused by direct instillation of agonist solutions into the eye. Agonist-induced calcium fluxes were recorded using the FLIPR technique in a recombinant, TRPV1-expressing cell line. Current-clamp recordings were performed in rat DRG (dorsal root ganglia) neurons in order to assess the consequences of TRPV1 activation on neuronal excitability. Using the eye wipe assay the following rank of pungency was obtained: capsaicin>piperine>RTX>arvanil>olvanil>SDZ-249665. We found a strong correlation between kinetics of calcium flux, pungency and lipophilicity of TRPV1 agonists. Current-clamp recordings confirmed that the rate of receptor activation translates in the ability of agonists to generate action potentials in sensory neurons. We have demonstrated that the lipophilicity of the compounds is directly related to the kinetics of TRPV1 activation and that the latter influences their ability to trigger action potentials in sensory neurons and, ultimately, pungency.

  20. Ligand-based receptor tyrosine kinase partial agonists: New paradigm for cancer drug discovery? (United States)

    Riese, David J.


    Introduction Receptor tyrosine kinases (RTKs) are validated targets for oncology drug discovery and several RTK antagonists have been approved for the treatment of human malignancies. Nonetheless, the discovery and development of RTK antagonists has lagged behind the discovery and development of agents that target G-protein coupled receptors. In part, this is because it has been difficult to discover analogs of naturally-occurring RTK agonists that function as antagonists. Areas covered Here we describe ligands of ErbB receptors that function as partial agonists for these receptors, thereby enabling these ligands to antagonize the activity of full agonists for these receptors. We provide insights into the mechanisms by which these ligands function as antagonists. We discuss how information concerning these mechanisms can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors and how such antagonists hold great potential as targeted cancer chemotherapeutics. Expert opinion While there have been a number of important key findings into this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not proven to be good platforms for oncology drug discovery; addressing the fundamental issues of antagonistic partial agonists for receptor tyrosine kinases has the potential to steer oncology drug discovery in new directions. Mechanism based approaches are now emerging to enable the discovery of RTK partial agonists that may antagonize both agonist-dependent and –independent RTK signaling and may hold tremendous promise as targeted cancer chemotherapeutics. PMID:21532939